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2012N142276_00 CONFIDENTIALGlaxoSmithKline group of companies MEA115921

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TITLE PAGE

Division: Worldwide DevelopmentInformation Type: Clinical Protocol

Title: A Double-blind, Randomised, Placebo-controlled Study to Investigate the Efficacy and Safety of Mepolizumab in the Treatment of Eosinophilic Granulomatosis with Polyangiitis in Subjects Receiving Standard of Care Therapy.

Compound Number: SB-240563

Development Phase III

Effective Date: 29-AUG-2013

Subject: Eosinophilic granulomatosis with polyangiitis, mepolizumab, eosinophils, SB-240563, efficacy, safety, corticosteroids, quality of life, biomarkers.

Author(s):;

Copyright 2013 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised copying or use of this information is prohibited.

2012N142276_00 CONFIDENTIALMEA115921

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SPONSOR INFORMATION PAGE

Clinical Study Identifier: MEA115921

Sponsor Legal Registered Address:

GlaxoSmithKline Research & Development Limited980 Great West RoadBrentfordMiddlesex, TW8 9GSUK

Sponsor Contact Address

GlaxoSmithKline Research & Development LimitedIron Bridge Road Stockley Park West, Uxbridge, Middlesex, UB11 1BU, UKTelephone:

GlaxoSmithKline Research & Development LimitedFive Moore Drive P.O. 13398Research Triangle Park, NC 27709-3398, USATelephone:

In some countries, the clinical trial sponsor may be the local GlaxoSmithKline affiliate company (or designee). Where applicable, the details of the Sponsor and contact person will be provided to the relevant regulatory authority as part of the clinical trial submission.

Sponsor Global Medical Monitor Contact Information:

BSc MBBS MRCP FFPM (Rare Diseases Area Head, Rare Diseases Unit)

Tel:

Mobile:

Sponsor Global Back-up Medical Monitor Contact Information:

BSc MBChB FRCA PhD (Director, Immuno-Inflammation Therapeutic Area Unit)

Tel:

Mobile:


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Sponsor Serious Adverse Events (SAE) Contact Information:

Tel:

Mobile:

FAX:

Regulatory Agency Identifying Number(s):

EudraCT number: 2012-004385-17

IND No. 006971


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INVESTIGATOR PROTOCOL AGREEMENT PAGE

I confirm agreement to conduct the study in compliance with the protocol.

I acknowledge that I am responsible for overall study conduct. I agree to personally conduct or supervise the described clinical study.

I agree to ensure that all associates, colleagues and employees assisting in the conduct of the study are informed about their obligations. Mechanisms are in place to ensure that site staff receives the appropriate information throughout the study.

Investigator Name: _____________________________

Investigator Signature Date


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TABLE OF CONTENTS

PAGE

LIST OF ABBREVIATIONS.............................................................................................9

PROTOCOL SUMMARY...............................................................................................12

1. INTRODUCTION....................................................................................................171.1. Background ................................................................................................171.2. Rationale ....................................................................................................191.3. Dose Rationale ...........................................................................................191.4. Benefit:Risk Assessment ............................................................................20

1.4.1. Risk Assessment .........................................................................201.4.2. Benefit Assessment .....................................................................271.4.3. Overall Benefit:Risk Assessment .................................................27

2. OBJECTIVES.........................................................................................................27

3. INVESTIGATIONAL PLAN.....................................................................................283.1. Study Design ..............................................................................................283.2. Discussion of Design ..................................................................................33

4. SUBJECT SELECTION AND WITHDRAWAL CRITERIA.......................................344.1. Number of Subjects ....................................................................................344.2. Inclusion Criteria .........................................................................................344.3. Exclusion Criteria........................................................................................364.4. Randomisation Criteria ...............................................................................394.5. Withdrawal Criteria .....................................................................................39

4.5.1. Withdrawal from Study Treatment................................................394.5.2. Withdrawal from Study.................................................................40

4.6. Screening and Run-in Failures....................................................................41

5. STUDY TREATMENTS..........................................................................................415.1. Investigational Product and Other Study Treatment....................................415.2. Treatment Assignment................................................................................425.3. Dosage and Administration.........................................................................425.4. Blinding.......................................................................................................435.5. Product Accountability ................................................................................445.6. Treatment Compliance................................................................................445.7. Concomitant Medications and Non-Drug Therapies....................................44

5.7.1. Permitted Medications and Non-Drug Therapies..........................445.7.2. Prohibited Medications and Non-Drug Therapies.........................44

5.8. Treatment after the End of the Study ..........................................................455.9. Treatment of Study Treatment Overdose....................................................45

6. STUDY ASSESSMENTS AND PROCEDURES .....................................................456.1. Critical Baseline Assessments ....................................................................50

6.1.1. Critical Procedures Performed at Screening (Visit 1) ...................506.1.2. Critical Procedures Performed at Baseline (Visit 2)......................516.1.3. Cardiovascular Assessment.........................................................52

6.2. Efficacy.......................................................................................................52


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6.2.1. Efficacy Endpoints .......................................................................526.2.1.1. Birmingham Vasculitis Activity Score..........................546.2.1.2. Relapse ......................................................................546.2.1.3. Vasculitis Damage Index ............................................556.2.1.4. Sino-nasal Symptoms.................................................556.2.1.5. Asthma Control Questionnaire....................................566.2.1.6. Spirometry..................................................................566.2.1.7. Fractional Concentration of Exhaled Nitric

Oxide (FeNO) .............................................................576.3. Safety .........................................................................................................57

6.3.1. Safety Endpoints..........................................................................576.3.2. Liver Chemistry Stopping and Follow-up Criteria .........................586.3.3. Adverse Events............................................................................61

6.3.3.1. Definition of an AE......................................................616.3.3.2. Definition of an SAE ...................................................62

6.3.4. Laboratory and Other Safety Assessment Abnormalities Reported as AEs and SAEs.........................................................63

6.3.5. Cardiovascular Events .................................................................636.3.6. Death Events ...............................................................................636.3.7. Pregnancy ...................................................................................646.3.8. Time Period and Frequency of Detecting AEs and SAEs.............646.3.9. Method of Detecting AEs and SAEs.............................................646.3.10. Prompt Reporting of Serious Adverse Events and Other

Events to GSK .............................................................................656.3.10.1. Regulatory Reporting Requirements for SAEs............66

6.3.11. Other Safety Outcomes ...............................................................676.3.11.1. Vital Signs, Height and Weight ...................................676.3.11.2. Twelve-lead Electrocardiogram (ECG) .......................676.3.11.3. Clinical Laboratory Parameters...................................676.3.11.4. Physical Examination .................................................70

6.4. Health Outcomes........................................................................................706.4.1. Health Outcomes Endpoints ........................................................70

6.4.1.1. Short Form-36 (SF-36) ...............................................706.4.1.2. Work Productivity and Activity Impairment

(WPAI) Questionnaire.................................................706.4.1.3. Use of Health Care Resources ...................................71

6.5. Pharmacokinetics/Pharmacodynamics/Biomarker(s) ..................................716.5.1. Pharmacokinetics ........................................................................716.5.2. Pharmacodynamics .....................................................................71

6.6. Immunogenicity...........................................................................................716.7. Biomarkers .................................................................................................71

6.7.1. Mechanistic/Biomarker Sub-studies.............................................726.8. Pharmacogenetics Research......................................................................72

7. DATA MANAGEMENT ...........................................................................................72

8. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS...................................738.1. Hypotheses.................................................................................................738.2. Study Design Considerations......................................................................74

8.2.1. Sample Size Assumptions ...........................................................748.2.2. Sample Size Sensitivity................................................................748.2.3. Sample Size Re-estimation..........................................................75


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8.3. Data Analysis Considerations .....................................................................758.3.1. Analysis Populations....................................................................758.3.2. Analysis Data Sets.......................................................................768.3.3. Treatment Comparisons ..............................................................76

8.3.3.1. Primary Comparisons of Interest ................................768.3.3.2. Other Comparisons of Interest....................................77

8.3.4. Interim Analysis ...........................................................................778.3.5. Key Elements of Analysis Plan ....................................................77

8.3.5.1. Efficacy Analyses .......................................................778.3.5.2. Safety Analyses..........................................................818.3.5.3. Health Outcomes Analyses ........................................828.3.5.4. Pharmacokinetic Analyses..........................................828.3.5.5. Pharmacodynamic Analyses ......................................828.3.5.6. Mechanistic/Biomarker Sub-studies............................828.3.5.7. Genetics/Pharmacogenetics Analyses........................82

9. STUDY CONDUCT CONSIDERATIONS ...............................................................839.1. Posting of Information on Publicly Available Clinical Trial Registers............839.2. Regulatory and Ethical Considerations, Including the Informed

Consent Process ........................................................................................839.3. Quality Control (Study Monitoring) ..............................................................839.4. Quality Assurance.......................................................................................849.5. Study and Site Closure ...............................................................................849.6. Records Retention ......................................................................................859.7. Provision of Study Results to Investigators, Posting of Information

on Publicly Available Clinical Trials Registers and Publication ....................859.8. Independent Data Monitoring Committee (IDMC) .......................................86

10. REFERENCES.......................................................................................................87

11. APPENDICES ........................................................................................................9111.1. Appendix 1: Genetics/Pharmacogenetics Research ...................................9111.2. Appendix 2: Country Specific Requirements ...............................................9711.3. Appendix 3: Recommended Prednisolone/Prednisone Tapering

Schedule from Week 4................................................................................9811.4. Appendix 4: Acceptable Birth Control..........................................................9911.5. Appendix 5: New York Heart Association Functional Classification

of Congestive Heart Failure ......................................................................10111.6. Appendix 6: Cardiovascular Screening Questions ....................................10211.7. Appendix 7: Birmingham Vasculitis Activity Score version 3 .....................10311.8. Appendix 8: Vasculitis Damage Index.......................................................10411.9. Appendix 9: Asthma Control Questionnaire ..............................................10511.10. Appendix 10: SNOT-22.............................................................................10611.11. Appendix 11: Anaphylaxis Criteria ............................................................10711.12. Appendix 12: Liver Chemistry Stopping and Follow-up Criteria.................108


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LIST OF ABBREVIATIONS

ACQ-6 Asthma Control Questionnaire-6ADA Anti-drug antibodyACR American College of RheumatologyAE Adverse EventALT Alanine transaminaseANCA anti-neutrophil cytoplasmic antibodiesANCA-MPO ANCA-Myeloperoxidase ANCA-PR3 ANCA-Proteinase 3AST Aspartate transaminaseBP Blood pressureBVAS Birmingham Vasculitis Activity ScoreCCR3 CC chemokine receptor 3CNS Central nervous systemCRP C-reactive proteinCSS Churg-Strauss SyndromeCYC CyclophosphamideCV CardiovascularDCSI Developmental Core Safety InformationDNA Deoxyribonucleic acidECG ElectrocardiogrameCRF Electronic case report formeDiary Electronic DiaryEGPA Eosinophilic Granulomatosis with PolyangiitisESR Erythrocyte sedimentation rateEULAR European League Against RheumatismFCBP Female of childbearing potentialFeNO Fractional Concentration of Exhaled Nitric OxideFEV1 Forced Expiratory Volume in one secondFVC Forced Vital CapacityGCP Good Clinical PracticeGCSP Global Clinical Safety and PharmacovigilenceGI GastrointestinalGPA Granulomatosis with polyangiitisGSK GlaxoSmithKlineHBsAg Hepatitis B Surface AntigenHES Hypereosinophilic SyndromeHIV Human Immunodeficiency VirusHPLC High Performance Liquid ChromatographyHRT Hormone replacement therapyIB Investigator’s BrochureICH International Conference on HarmonisationIDMC Independent data monitoring committeeIEC Independent Ethics CommitteeIg ImmunoglobulinIL InterleukinINR International normalised ratio


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IRB Institutional review BoardITT Intent-to-TreatIUD Intrauterine deviceIV Intravenous(ly)IVRS Interactive Voice Response Systemkg kilogramLABA Long acting beta2 agonistmAb Monoclonal antibodyMedDRA Medical Dictionary for Regulatory Activitiesmg milligramsMPA Microscopic polyangiitis MRI Magnetic resonance imagingMSDS Material Safety Data Sheetmsec millisecondNAB Neutralizing antibodiesOCS Oral CorticosteroidPBMC Peripheral blood mononuclear cellsPCR Polymerase chain reactionPD PharmacodynamicsPEF Peak expiratory flowPK PharmacokineticsPGx PharmacogeneticsPP Per protocolQTcB QT interval corrected for heart rate according to Bazett’s

formulaQTcF QT interval corrected for heart rate according to Fridericia’s

formulaRAP Reporting and Analysis PlanRBC Red blood cellRNA Ribonucleic acidRPGN Rapidly progressive glomerulonephritis SABA Short acting beta-agonistSAE Serious Adverse EventSC Subcutaneous(ly)SF-36 Short-form 36SNOT-22 Sino-nasal Outcome Test-22SOC System organ classSPM Study procedures manualSRT Safety review teamTNF Tumour necrosis factorULN Upper limit of normalUS United StatesWBC White blood cellWPAI Work Productivity Activity ImpairmentVDI Vasculitis Damage Index


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Trademark Information

Trademarks of the GlaxoSmithKline group of companies

Trademarks not owned by the GlaxoSmithKline group of companies

VENTOLIN NONMEM 7


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PROTOCOL SUMMARY

Rationale

Eosinophilia is central to the pathophysiology of Eosinophilic Granulomatosis with Polyangiitis (EGPA) and interleukin-5 (IL-5) is a key cytokine regulating the life-cycle of the eosinophil. Neutralisation of IL-5 with mepolizumab, an anti-IL5 monoclonal antibody, therefore offers a potential therapeutic option for EGPA. This is supported by data from two investigator-sponsored studies which attest to the clinical utility/proof-of-concept of mepolizumab in the treatment of EGPA by demonstrating the potential for mepolizumab to allow safe reduction in corticosteroid dose while maintaining clinical stability (study CRT109797) and for induction of remission (study MHE109435) in subjects with EGPA.

The purpose of this randomised, double-blind study is to investigate the efficacy and safety of mepolizumab (300 mg subcutaneously [SC] every 4 weeks) compared withplacebo over a 52-week study treatment period in subjects with relapsing or refractory EGPA receiving standard of care therapy including background corticosteroid therapy with or without immunosuppressive therapy. During the treatment period, in accordance with standard of care, corticosteroid dose will be tapered. The key outcomes in the study focus on evaluation of clinical remission, defined as Birmingham Vasculitis Activity Score (BVAS) =0 with a corticosteroid dose of 4 mg/day prednisolone/prednisone,reduction in disease relapse and reduction in corticosteroid requirement.

Data from this study will be used to support regulatory approval for mepolizumab for the treatment of EGPA.

Objectives

Primary

To investigate the efficacy of mepolizumab plus standard of care compared withplacebo plus standard of care on duration of clinical remission, defined as accrued duration in weeks where a subject achieves a BVAS=0 and corticosteroid dose ≤4 mg/day prednisolone/prednisone in subjects with relapsing or refractory eosinophilic granulomatosis with polyangiitis (EGPA) receiving standard of care therapy including corticosteroid therapy reduction/withdrawal.

To investigate the durability of response to treatment with mepolizumab plus standard of care compared with placebo plus standard of care, assessed by the proportion of subjects in remission at both Weeks 36 and 48.

Secondary

To investigate the efficacy of mepolizumab compared with placebo on time to relapse in subjects with EGPA on background standard of care treatment including corticosteroid therapy reduction/withdrawal.

To compare the average daily dose of corticosteroid required during the last 4 weeks of the study treatment period.


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To evaluate the proportion of subjects who achieve remission within the first 24 weeks of the study and remain in remission for the remainder of the study treatment period.

To investigate the safety of mepolizumab compared with placebo in subjects with EGPA on background standard of care treatment.

Other

To investigate additional measures of the efficacy and quality of life including duration of remission; relapse; corticosteroid reduction; BVAS; vasculitis damage index (VDI); health-related quality of life (SF-36); asthma symptoms (asthma control questionnaire and lung function tests); sino-nasal symptoms(including the sino-nasal outcome test (SNOT-22) questionnaire); blood eosinophil counts and biomarkers of inflammation.

To investigate the pharmacokinetics (PK) of mepolizumab in subjects with EGPA.

To investigate the effect of mepolizumab on serum free and total IL-5 levels in subjects with EGPA.

To investigate the effect of mepolizumab on Fractional Concentration of Exhaled Nitric Oxide (FeNO).

To investigate the immunogenicity (occurrence of anti-drug antibodies) of mepolizumab in subjects with EGPA.

To investigate the impact of mepolizumab on work and activity (Work Productivity and Activity Impairment [WPAI] questionnaire) in patients with EGPA.

To monitor healthcare resource utilisation during the study.

Study Design

This is a randomised, double-blind, placebo-controlled, parallel group, multicentre study of mepolizumab in subjects with a history of relapsing or refractory EGPA on stable corticosteroid therapy with or without concomitant stable immunosuppressant therapy. The study will comprise a screening period of up to 4 weeks (and minimum of 1 week)followed by a 52-week study treatment period and 8-week follow-up period.

As specified in the inclusion criteria, subjects will be required to be on a stable dose of oral corticosteroid (OCS), i.e., ≥7.5 mg/day prednisolone/prednisone (but not >50 mg/day), for at least 4 weeks prior to Baseline (Visit 2). Use of daily or alternate-day dosing with prednisolone/prednisone is acceptable. For alternate-day dosing the daily dose will be considered to be equivalent to half the alternate-day dose (e.g., 5 mg taken on alternate days is equivalent to a 2.5 mg/day daily dose). If being taken, the subject must be on a stable dose of immunosuppressive therapy for at least 4 weeks prior to Baseline (Visit 2) and for the duration of the study.

At Baseline (Visit 2) 130 subjects will be randomised in a 1:1 ratio to receive either:


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300 mg mepolizumab SC every 4 weeks (n=65) or

Placebo SC every 4 weeks (n=65).

The final dose of study treatment will be given at Week 48 with completion of the study treatment period at Week 52. At this point, subjects will enter the follow-up period and be monitored for an additional 8 weeks and complete the study at Week 60 giving a total duration for study participation of up to 64 weeks from screening. Subjects who withdraw from study treatment prematurely (for any reason) should, where possible, continue to be followed up as per protocol until the end of follow-up at Week 60.

Between baseline (randomisation) and Week 4, subjects will be required to continue on their stable OCS (prednisolone/prednisone) dose (if necessary, upward adjustments are permitted for clinical management of the patient). From Week 4 post-baseline onwards, if the subject’s BVAS=0 their oral OCS dose should be tapered downwards according to standard of care practice. A recommended tapering schedule provided in the protocol enables a reduction in OCS dose every 2 weeks, with the intention of achieving a prednisolone/prednisone dose of 4 mg/day or less. Once a subject has achieved a dose of 4 mg/day prednisolone/prednisone, the investigator is encouraged to continue tapering downwards, if clinically warranted, at dose increments of 0.5-1.0 mg every 2 weeks.

In this study EGPA remission is defined as BVAS=0 plus OCS dose of prednisolone/prednisone 4 mg/day. In defining EGPA remission, asthma and sino-nasalsymptoms /signs related to EGPA activity, if not specifically covered by the BVAS assessment, will be considered to be controlled by virtue of the low OCS dose (i.e., 4 mg/day prednisolone/prednisone) and are therefore not included in the remission definition.

EGPA relapse will be defined as worsening or persistence of active disease since the last visit characterised by: a) active vasculitis (BVAS >0); OR b) active asthma symptoms and/or signs with a corresponding worsening in ACQ-6 score (compared to the most recent previous score); OR c) active nasal and/or sinus disease with a corresponding worsening in at least one of the sino-nasal symptom questions (compared to the most recent previous assessment) warranting: i) an increased dose of OCS therapy OR ii) an increased dose or addition of immunosuppressive therapy; OR iii) hospitalisation related to EGPA worsening. A full assessment, including evaluation of BVAS, asthma and sino-nasal signs and/or symptoms will be conducted at the time of a relapse. The time of onset of a relapse will be defined as time to change BVAS, asthma or sino-nasal signs and/or symptoms that warranted increase in corticosteroid therapy, increase in dose or addition of immunosuppressive therapy or hospitalisation. In the event a subject has achieved remission (i.e., BVAS=0 and prednisolone/prednisone dose ≤4 mg/day) and at anysubsequent visit has a BVAS = 1 which does not require an increase in corticosteroid dose above 4 mg/day, or any other significant clinical intervention or investigation, the subject will be considered to be in continued remission.

A major relapse (a sub-set of the total relapse events) will be defined as: any organ or life-threatening EGPA event; OR BVAS ≥6 (involving at least two organ systems in addition to any general symptoms where present [myalgia, arthralgia/arthritis, fever


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>38ºC or weight loss >2 kg]); OR an asthma relapse requiring urgent care visit or hospitalisation; OR sino-nasal relapse requiring hospitalisation.

The minimally effective dose of OCS (prednisolone/prednisone) for each subject will be defined as the dose of OCS one step above the OCS dose at which the first relapse occurred. Where the subject has achieved a dose of OCS of 0-3.5 mgprednisolone/prednisone, the minimally effective dose will be defined as 4.0 mg/day. Upwards dose adjustments within the 0-4.0 mg range are permitted without necessarily being considered a relapse.

The management of subjects who relapse will be according to standard of care and may involve increasing the dose or oral corticosteroids or adjustment in immunosuppressive therapy.

If the subject’s first relapse is managed with the use of an increase in corticosteroid dose, tapering should be recommenced as soon as the relapse has been appropriately controlled, as per standard of care practice. Once the minimally effective dose of OCS is achieved, any down-tapering below this dose level will be at the discretion of the investigator, based on the clinical condition of the subject. In the event of a second or subsequent relapse, any further OCS tapering, post-relapse, will be conducted at the discretion of the investigator.

If a relapse is managed by increasing the dose of or initiating immunosuppressive therapy, the subject must be withdrawn from receiving further study treatment and, where possible, continue to be followed up as per protocol.

If a subject experiences one organ-threatening or one life-threatening relapse he/she will be withdrawn from receiving further study treatment and, where possible, continue to be followed up as per protocol.

Investigators, participating subjects, and GlaxoSmithKline (GSK) personnel will be blinded to absolute eosinophil counts, total white blood counts and differentials (%) for the duration of each subject’s participation in the study post-randomisation (baseline). Absolute neutrophil, lymphocyte, monocyte, and basophil counts will be provided. Investigators will ensure participating subjects and any physicians managing study patients during the course of the study are informed of this requirement.

Approximately 150 subjects will be screened to provide 130 randomised subjects (65 per group). Randomisation will be stratified by region (Japan and rest of world) but not by centre due to the potentially small number of subjects per site.

Investigator-sponsored ‘mechanistic/biomarker’ sub-studies will be conducted at selected sites in the United States (US) and Europe using samples collected from consenting subjects participating in the study. The objective of these studies will be to examine molecular profiles and biomarkers associated with EGPA and response to anti-IL-5 therapy. Specific details of the planned analyses will be outlined in the individual protocols and/or analysis plans for these sub-studies.


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Study Endpoints/Assessments

The co-primary endpoints are:

1. the total accrued duration of remission, i.e., the accrued number of weeks where BVAS=0 plus prednisolone/prednisone dose 4 mg/day over the 52 week study treatment period reported as proportion of subjects achieving remission in the following categories: Zero; >0 to <12 weeks; 12 to <24 weeks; 24 to <36 weeks and ≥36 weeks, and

2. the proportion of subjects who are in remission at both Weeks 36 and 48 of the study treatment period.

The secondary endpoints are:

i. time to first confirmed EGPA relapse,

ii. the proportion of subjects with an average daily prednisolone/prednisone dose during the last 4 weeks of the study treatment period (48 through 52) in each of the following categories: Zero; >0 to ≤4.0 mg; >4.0 to ≤7.5 mg and >7.5 mg, and,

iii. the proportion of subjects who achieve remission (BVAS=0 and prednisolone/prednisone 4 mg/day) within the first 24 weeks of the study and remain in remission for the remainder of the study treatment period.

Other planned assessments include:

Efficacy: VDI; evaluation of sino-nasal symptoms (symptom questionnaire and the SNOT-22); spirometry (FEV1 and FVC); asthma control questionnaire, C-reactive protein, and erythrocyte sedimentation rate.

Safety: adverse events; vital signs (blood pressure, pulse rate, and temperature); ECGs; clinical laboratory tests and immunogenicity (mepolizumab anti-drug antibody).

PK/PD: Plasma mepolizumab concentrations; blood eosinophil count, IL-5 levels (total and free), and FeNO.

Health outcomes: SF-36; WPAI questionnaire, and use of healthcare resources.


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1. INTRODUCTION

1.1. Background

Eosinophilic Granulomatosis with Polyangiitis (EGPA), also referred to as Churg-Strauss syndrome (CSS), is a rare hypereosinophilic syndrome characterised by small vessel vasculitis in association with asthma, sinusitis, and pulmonary infiltrates. Multiple organs can be affected including the heart, lungs, skin, gastrointestinal tract, kidneys, and nervous system [Keogh, 2006; Vaglio, 2012; Holle, 2009] The mean age of diagnosis of EGPA is 48 years, with a gender ratio of approximately 1:1 [Pagnoux, 2007]; the incidence has been estimated as 1-4 per million per year [Lane, 2005]. EGPA is associated with a positive status for anti-neutrophil cytoplasmic antibodies (ANCAs), typically ANCA-Myeloperoxidase (MPO) and ANCA-Proteinase 3 (PR3), in approximately 40% of patients [Holle, 2009; Sinico, 2005]. In addition, the role of allergy in EGPA is widely acknowledged, especially in the prodromal disease phase that is characterized by typical allergic manifestations such as asthma, sinusitis, and nasal polyposis with raised serum IgE levels observed in approximately 90% of EGPA patients[Vaglio, 2012]. In recent proposed classification systems for eosinophil disorders, EGPA has been described as being associated with Hypereosinophilic Syndrome (HES) [Simon, 2010], although it should nevertheless be distinguished from true HES [Valent, 2012].

Prior to the advent of treatment for EGPA, in excess of 50% of patients died within 3 months of diagnosis. Recently, with the advance in treatment strategies, patient survival has been reported as 93% to 94% at 1 year and 60% to 97% at 5 years [Baldini, 2010]. The current approach to the management of EGPA is based on reduction of active inflammation, suppression of the immune response, and treatment of disease-specific and/or treatment-related complications. Corticosteroid therapy is the cornerstone therapy for the treatment of both poor- and good-prognosis EGPA patients. However, use of corticosteroids, particularly longer-term, is associated with significant side effects, including weight gain, osteoporosis, hyperglycaemia, depression, and increased risk of infection, which can limit the benefits [Poetker, 2010]. Furthermore, although remission can be achieved in a proportion of patients with corticosteroid therapy alone, addition of more potent immunosuppressive therapies (e.g., azathioprine, methotrexate, or mycophenolate mofetil) to maintain remission is commonly required [Baldini, 2010; Vaglio, 2012; Dunogué, 2011; Holle, 2009; Mukhtyar, 2009a]. For poor-prognosis patients cytotoxic therapy such as cyclophosphamide is required for induction of remission with a switch to less toxic immunosuppressant therapy, e.g., azathioprine or methotrexate, for maintenance of remission. In general, although the use of these treatments is effective for establishing remission, patients remain vulnerable to either the complications of the long-term use of these therapies, or to the risk of relapse, particularly if the dose of corticosteroid is reduced. A relapse rate of 30-40% is reported, which increases with time [Baldini, 2010]. Furthermore, recurrent relapse is considered to place the patient at risk of permanent tissue and/or organ damage secondary to the vasculitic process. Therefore, the key goal in the treatment of EGPA is to induce and maintain remission whilst reducing the burden of corticosteroid usage and other immunosuppressive therapies.


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Interleukin-5 (IL-5) is the major hematopoietin regulating the life-cycle of eosinophils [Clutterbuck, 1989; Lopez, 1988; Rothenberg, 2006]. In EGPA the mechanism of tissue injury is poorly understood, but the degree of blood and tissue eosinophilia appears to be associated with disease pathogenesis [Schnabel, 1999]. In a series of in vitro studies it has been shown that circulating levels of IL-5 are increased in patients with active EGPA,that peripheral blood mononuclear cells (PBMCs) are the likely source of elevated plasma IL-5 in the disease, and that T cell activation is required for increased IL-5 release by the PBMCs [Shonermarck, 2000; Kiene, 2001; Hellmich, 2005; Hellmich, 2003]. Of particular interest with regard to the pathogenesis of EGPA and associated vasculitis isthe ability of IL-5 to promote the adhesion of eosinophils to vascular endothelium and CC chemokine receptor 3 (CCR3)-dependent migration of eosinophils from the vasculature [Shahabuddin, 2000]. Thus, the elevated production of IL-5 by PMBCs in EGPA may be relevant pathogenetically not only for eosinophilia, but also for the development of vasculitis by promoting transvascular migration and functional activation of eosinophils.

Mepolizumab is a fully humanized monoclonal antibody (IgG1, kappa, mAb) which is specific for human IL-5 and which blocks binding of human IL-5 (hIL-5) to the alpha chain of the IL-5 receptor complex expressed on the eosinophil cell surface. In patients with conditions where eosinophilia is considered to play an important part in the pathology, a consistent reduction in eosinophil number is observed in association with mepolizumab administration, with concomitant clinical improvement [Haldar, 2009;Pavord, 2012; Stein 2006, Rothenberg 2008; Nair, 2009].

The hypothesis that IL-5 is central to the pathology and clinical manifestations of EGPA is supported by clinical data providing ‘proof-of-concept’ evidence of efficacy of IL-5 blockade in the treatment of subjects with this condition. Firstly, a case report of a female with refractory EGPA treated with mepolizumab (750 mg intravenously [IV]monthly) showed sustained reduction in eosinophils and clinical improvement[Kahn, 2010]. Subsequently, two exploratory, investigator-sponsored studies of mepolizumab in EGPA have been reported. In the first study 10 EGPA patients on stable prednisolone (10 mg/day) and stable immunosuppressive therapy received 750 mg IV mepolizumab every 4 weeks (4 infusions) for 12 weeks. Mepolizumab reduced eosinophil counts and allowed for safe corticosteroid reduction (study CRT109797 [IB; GlaxoSmithKline Document Number: CM2003/00010/08]; [Kim, 2010]). On cessation of mepolizumab, EGPA manifestations recurred necessitating an increase in corticosteroid dose (‘steroid burst’). In the second study 10 EGPA patients with active refractory or relapsing disease were withdrawn from immunosuppressant therapy and treated with 750 mg mepolizumab IV every 4 weeks (9 infusions). Eight patients achieved remission (defined as Birmingham Vasculitis Activity Score [BVAS] =0 and corticosteroid dose <7.5 mg/day); one achieved BVAS=0 but not corticosteroid dose <7.5 mg/day) and the final patient achieved remission but was excluded due to non-adherence. Eosinophil counts rapidly decreased after the first mepolizumab infusion and remained near zero during the active treatment phase (study MHE109435 [IB; GlaxoSmithKline Document Number: CM2003/00010/08]; [Moosig, 2011]). Mepolizumab was reported as being well-tolerated in both studies.


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1.2. Rationale

Eosinophilia is central to the pathophysiology of EGPA and IL-5 is a key cytokine regulating the life-cycle of the eosinophil. Neutralisation of IL-5 with mepolizumab, an anti-IL5 monoclonal antibody, therefore offers a potential therapeutic option for EGPA.

The purpose of this randomised, double-blind study is to investigate the efficacy and safety of mepolizumab (300 mg subcutaneously [SC] every 4 weeks) compared with placebo over a 52-week study treatment period in subjects with relapsing or refractory EGPA receiving standard of care therapy including background corticosteroid therapy with or without immunosuppressive therapy. In accordance with standard of care, corticosteroid dose tapering will be permitted during the study. The key outcomes of this study focus on evaluation of clinical remission, defined as BVAS=0 with a corticosteroid dose of ≤4 mg/day prednisolone/prednisone, reduction in disease relapse and reduction in corticosteroid requirement.

1.3. Dose Rationale

A dose of 300 mg administered SC every 4 weeks has been selected for investigation in this study supported by the following:

The two investigator-sponsored studies (CRT109797 and MHE109435), investigating mepolizumab at a dose of 750 mg IV administered every 4 weeks have provided preliminary ‘proof-of-concept’ evidence of the potential benefit of mepolizumab in treating EGPA.

Mepolizumab (750 mg IV every 4 weeks) was shown to be well-tolerated in studies CRT109797 and MHE109435 consistent with the overall safety profile previously demonstrated in over 1300 subjects treated with mepolizumab across different eosinophilic conditions (i.e., severe asthma, HES, eosinophilicesophagitis, atopic dermatitis and nasal polyposis). For details see the Investigator’s Brochure [IB; GlaxoSmithKline Document Number:CM2003/00010/08].

A completed study (MEA112997) evaluating 3 doses of mepolizumab (75 mg, 250 mg and 750 mg administered IV every 4 weeks) over a 52 week treatment period, in adult and adolescent subjects with severe uncontrolled refractory asthma, demonstrated similar and statistically significant (p<0.001) reductions in the frequency of clinically significant exacerbations of asthma (primary endpoint) in all mepolizumab groups compared with the placebo group [Pavord, 2012] . In addition, mepolizumab significantly lowered the absolute blood eosinophil counts but in a dose dependent manner with greatest reductions observed in the 250 mg and 750 mg IV groups (but overall similar at these 2 doses) compared with the 75 mg IV group. All doses were statistically superior to placebo for this endpoint.

A non-linear inhibition dose-response model based on blood eosinophil counts, developed from a pharmacokinetic/pharmacodynamic (PK/PD) study of mepolizumab in adult subjects with asthma and elevated blood eosinophil levels (study MEA114092), has identified 75 mg IV every 4 weeks as the ID90 (i.e., dose providing 90% of the maximum blood eosinophil reduction achievable by the drug) for blood eosinophil reduction. The estimated absolute bioavailability


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for SC route of administration in the upper arm in this study was approximately 75% [IB; GlaxoSmithKline Document Number: CM2003/00010/08]. Therefore a dose of 100 mg SC is anticipated to provide similar exposure to a 75mg IV dose. A 100 mg SC dose every 4 weeks is therefore being investigated in confirmatory studies in severe asthma as the SC route is more convenient compared with IV and is generally preferred by patients.

EGPA involves greater implication of eosinophils at multiple target organs and there is potential for significant increase in blood eosinophils preceding relapse or during oral corticosteroid (OCS) taper. It is therefore considered that a higher dose of mepolizumab will be required in EGPA to confer therapeutic benefit, compared with severe asthma. Thus, an every 4 weeks subcutaneous dose of 300 mg (delivered as 3X 100 mg SC injections and approximately equivalent to 225 mg IV) has been selected for investigation in this study since data from the severe asthma study showed the 250 mg and 750 mg IV every 4 weeks doses to provide greater reduction in blood eosinophils compared with 75 mg IV every 4 weeks).

1.4. Benefit:Risk Assessment

1.4.1. Risk Assessment

Across the mepolizumab development program, chronic dosing of mepolizumab up to 750 mg IV every 4 weeks has been associated with an adverse event (AE) profile similar to placebo in the patient populations studied, including mild to moderate asthma, severe refractory asthma and HES.

Reports of systemic non-allergic and allergic (i.e., hypersensitivity) reactions have been non-serious and resolved without sequelae following minimal supportive care. To date, there have been no reports of severe life-threatening anaphylaxis.

Measurable levels of anti-drug antibodies (ADA) have been observed infrequently and have not been associated with negative clinical outcomes; there has been no evidence of untoward or persistent neutralizing antibodies (NAB) at any dose.

Infection rates have been generally similar across treatment groups. The data to date do not support an association between treatment with mepolizumab and an increased risk of clinically serious opportunistic or parasitic infections.

Reports of malignancies have been generally similar between treatment groups in placebo-controlled trials. The known biology of IL-5 and eosinophils suggest that blocking the binding of IL-5 to its receptor with mepolizumab would not likely induce an immuno-suppressive effect that would impair host surveillance against malignancy.

Reports of serious cardiac AEs have been similar between treatment groups in placebo-controlled multiple-dose asthma trials completed to date.

Summaries of findings from both clinical and non-clinical studies conducted with mepolizumab can be found in the Investigator Brochure (GlaxoSmithKline Document Number: CM2003/00010/08). Table 1 summarises the risk assessment and mitigation strategy for this protocol.


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Table 1 Risk Assessment for Mepolizumab

Potential Risk of Clinical Significance

Data/Rationale for Risk Mitigation Strategy

Investigative Medicinal Product (IMP): MepolizumabPre-Clinical and Clinical Findings

Risk of Systemic Allergic and Non-allergic Reactions, including Anaphylaxis

Biopharmaceutical products may elicit ADA and NAB, which have the potential to modulate PK, PD or produce adverse reactions. However, humanized and fully human antibodies are less immunogenic than mouse or chimeric monoclonal antibodies.

Reactions reported to date across the mepolizumab program are summarized in the IB; see ‘Special Warnings and Special Precautions for Use’ section located in Section 6 titled ‘Summary of Data and Guidance for the Investigator’.

Daily monitoring of SAEs by medical monitor; regular systematic review of AE/SAE data from ongoing studies by a GSK safety review team.

Independent Data Monitoring Committee (IDMC) will be utilized during study.

Specific CRF pages utilized for targeted collection of reactions data.

Utilization of Joint NIAID/FAAN 2nd Symposium on Anaphylaxis to collect data on reports of anaphylaxis (see Appendix 11).

Subjects are monitored in clinic for 1 hour following dosing.

Risk of Immunogenicity See previous risk for background information in literature.

Immunogenicity data reported to date across the mepolizumab development program are summarized in the IB; see Section 5.4 ‘Clinical Immunogenicity’ and a summary of immunogenicity findings in the ‘Other Potentially Clinically Relevant Information for the Investigator’ section located in Section 6 titled ‘Summary of Data and Guidance for the Investigator’.

Blood samples are collected in clinical studies for detection of both ADA and NAB.

See previous risk for mitigation strategy related to clinical safety risks.


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Potential risk for adverse cardiovascular (CV) effects

Mepolizumab binding restricted to human lymphoid tissues in an immunohistochemistry tissue binding study suggesting a low likelihood of non-pharmacologic effects on CV function.

No adverse effects on cardiac conduction or repolarization evident in cynomolgus monkeys at doses at least 10-fold in excess of humans dosed at 10 mg/kg or 750 mg.

No clinically relevant trends observed in ECG data in humans.

In one study in subjects with severe refractory asthma, cardiac events were reported in similar frequencies across treatment groups with a small numerical increase observed in serious ischemic cardiac events in the mepolizumab-treated groups. However, an integrated safety analysis of all placebo-controlled multiple-dose asthma trials showed a similar frequency of SAEs reported overall from the cardiac and vascular system organ class (SOC). Additionally, similar findings were observed in other SOCs with thrombotic events (e.g., stroke in the Nervous System SOC).

Daily monitoring of SAE by medical monitor; regular systematic review of AE/SAE data from ongoing studies by a GSK safety review team.

CV monitoring for study includes:

Enhanced baseline collection of CV risk factors & functional status;

Baseline evaluation of clinical symptoms of ischemic heart disease, if clinically indicated;

ECG monitoring during the trial;

Measurement of troponin during the study;

Use of standardized CRFs to collect relevant data on CV events of interest (i.e.,myocardial infarction, hospitalization for unstable angina and congestive heart failure, arterial thrombosis, pulmonary embolism and deep vein thrombosis);

Use of an IDMC and external adjudication panel for CV events.


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Potential risk for increase in infections - theoretical concern with biologics; however, the pharmacological properties of mepolizumab suggest the risk is low.

No evidence of increased incidence of infections in any preclinical studies.

Murine data demonstrate that IL-5 antagonism is unlikely to influence cellular or humoral immunity, particularly in response to parasitic infections.

No mepolizumab-related effects on lymphocyte Immunophenotyping in monkeys or humans, including T-cell activation, distribution of CD4/CD8 subtypes or Th1/Th2 cytokine patterns, B-cells, NK cells or γδ-T-cells.

An integrated safety analysis of all placebo-controlled multiple dose asthma trials showed SAEs reported in the infection and infestation SOC were 5/345 (1%) in placebo subjects and 18/754 (2%) in mepolizumab subjects.

Infections reported to date across the mepolizumab development program are summarized in the IB; see ‘Special Precautions and Warnings’ (for exclusion of subjects with underlying parasitic infections) and ‘Undesirable Effects’ (for very common infections of nasopharyngitis, URTI, rhinitis and bronchitis reported in other patient populations) sections located in Section 6 titled ‘Summary of Data and Guidance for the Investigator’.

Daily monitoring of SAE by medical monitor; regular systematic review of AE/SAE data from ongoing studies by a GSK safety review team

IDMC will be utilized during study.

Standard safety assessments to be conducted as outlined in protocols.


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Potential risk for increase in malignancies - theoretical concern with biologics; however, blockade of IL-5 is not associated with generalized immuno-suppression or impaired host resistance.

Role of IL-5 and eosinophils in tumour surveillance is not fully characterised in the literature.

No evidence of defective tumour surveillance in IL-5 or eosinophil deficient mice.

Direct assessment of the carcinogenic potential of long-term IL-5 blockade in rodent models not technically feasible.

Malignancies reported to date across the mepolizumab development program are summarized in the IB.



Standard safety assessments to be conducted as outlined in protocols

Potential risk for rebound eosinophilia with associated clinical consequences, including potential risk of EGPA relapse.

Early published data with Schering-Plough anti- IL5 mAb suggested potential for rebound eosinophilia and disease exacerbation when treatment was stopped [Kim, 2004; Gevaert, 2006]; however, no standard definition of rebound was used and criteria for reporting was variable.

There have been no verbatim reports of ‘rebound’ from completed clinical trials of subjects with asthma, atopic dermatitis and eosinophilic esophagitis. Furthermore, the data do not support an exaggerated return of symptoms after cessation of treatment.





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Study Procedures

Inclusion of a placebo arm The objective of the study is to compare the efficacy and safety of mepolizumab versus placebo in subjects receiving standard of care therapy

Because all subjects are receiving background standard of care therapy in this study the Sponsor considers inclusion of a placebo arm to be justified.

Risk of relapse in a study including corticosteroid tapering.

Subjects with EGPA, despite being managed with standard of care therapy, are at risk of relapse. Corticosteroid tapering is usually only initiated when a patient’s disease is controlled.

In this study, it is recommended that corticosteroid dose is tapered only in the event a subject’s BVAS=0.

The minimally effective dose of OCS(prednisolone/prednisone) for each subject will be defined as the dose of OCS one step above the OCS dose at which the first relapse occurred. Once the minimally effective dose of OCS is achieved, any down-tapering below this dose level will be at the discretion of the investigator, based on the clinical condition of the subject.

In the event of a second or subsequent relapse, any further OCS tapering, post-relapse, will be conducted at the discretion of the investigator.

Any subject who experiences an organ- or life-threatening relapse will be withdrawn from study treatment.


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Risk of Addisonian symptoms with OCS tapering

Some patients on long-term OCS therapy may be at risk of Addisonian symptoms on withdrawal of OCS

Upward adjustment of OCS dose within the 0-4 mg/day range will be permitted without being considered a relapse.

Blinding eosinophil counts This study is a double-blind study which will be used to support approval for the use of mepolizumab in the treatment of EGPA. Unblinding eosinophil counts would compromise the integrity of the study.

Neither the site nor GSK personnel will be sent results from the central laboratory for: i) total white blood count, ii) absolute eosinophil count or iii) white blood count differentials (%), for each subject’s duration in the study for any visits post-randomisation. However, sites will be sent absolute neutrophil, lymphocyte, monocyte, and basophil counts throughout the study.


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1.4.2. Benefit Assessment

Study MEA115921 is a double-blind, randomised, placebo-controlled study to investigate the efficacy and safety of mepolizumab in the treatment of EGPA in subjects receiving standard of care therapy.

Data from two investigator-sponsored studies attest to the clinical utility/proof-of-concept of mepolizumab in the treatment of EGPA having demonstrated the potential for mepolizumab to allow safe reduction in corticosteroid dose while maintaining clinical stability (study CRT109797; [Kim, 2010; IB; GlaxoSmithKline Document Number: CM2003/00010/08]) and for induction of remission (study MHE109435; [Moosig, 2011; IB; GlaxoSmithKline Document Number: CM2003/00010/08]) in subjects with EGPA. Furthermore, mepolizumab has also demonstrated clinical benefit in other conditions where eosinophilia is considered to play an important part in the pathology, e.g., severe asthma [Haldar, 2009; Nair, 2009; Pavord, 2012], HES [Rothenberg, 2008] and eosinophilic esophagitis [Stein, 2006].

Data obtained from study MEA115921 will provide a robust evaluation of the efficacy and safety of mepolizumab in the treatment of EGPA with a view to supporting a regulatory approval for mepolizumab for the treatment of EGPA.

Subjects participating in this study will be required to attend monthly visits and therefore may benefit from the additional monitoring to their regular standard of care.

1.4.3. Overall Benefit:Risk Assessment

Current data from mepolizumab preclinical and clinical development indicate the ability of mepolizumab to inhibit IL-5, with demonstration of the potential for clinical utility in the treatment of conditions associated with hypereosinophilia such as EGPA. To date, the safety profile of mepolizumab has been favourable and AEs reported commonly are non-serious and manageable with minimal supportive care. Furthermore, there have been no safety concerns identified or signals observed with mepolizumab that would preclude investigation in EGPA. The Sponsor therefore considers that investigation of the efficacy, safety and tolerability of mepolizumab is justified in study MEA115921 with a positive benefit/risk ratio.

2. OBJECTIVES

Primary

To investigate the efficacy of mepolizumab plus standard of care compared withplacebo plus standard of care on duration of clinical remission, defined as accrued duration in weeks where a subject achieves a BVAS=0 and corticosteroid dose ≤4 mg/day prednisolone/prednisone, in subjects with relapsing or refractory eosinophilic granulomatosis with polyangiitis (EGPA) receiving standard of care therapy including corticosteroid therapy reduction/withdrawal.


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Secondary





Other

To investigate additional measures of the efficacy and quality of life including duration of remission; relapse; corticosteroid reduction; BVAS; vasculitis damage index (VDI); health-related quality of life (SF-36); asthma symptoms (asthma control questionnaire and lung function tests); sino-nasal symptoms(including the SNOT-22 questionnaire); blood eosinophil counts and biomarkers of inflammation.

To investigate the PK of mepolizumab in subjects with EGPA.






3. INVESTIGATIONAL PLAN

3.1. Study Design

Protocol waivers or exemptions are not allowed with the exception of immediate safety concerns. Therefore, adherence to the study design requirements, including those


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specified in the Time and Events Table (Table 2), are essential and required for study conduct.

Supplementary study conduct information not mandated to be present in this protocol is provided in the accompanying Study Procedures Manual (SPM). The SPM will provide the site personnel with administrative and detailed technical information that does not impact subject safety.

This is a randomised, double-blind, placebo-controlled, parallel group, multicentre study of mepolizumab in subjects with a history of relapsing or refractory EGPA on stable corticosteroid therapy with or without concomitant stable immunosuppressant therapy. The study will comprise a screening period of up to 4 weeks (and minimum of 1 week) followed by a 52-week study treatment period and 8-week follow-up period

As specified in the inclusion criteria, subjects will be required to be on a stable dose of OCS, i.e., ≥7.5 mg/day prednisolone/prednisone (but not >50 mg/day), for at least 4 weeks prior to Baseline (Visit 2). Use of daily or alternate-day dosing with prednisolone/prednisone is acceptable. For alternate-day dosing the daily dose will be considered to be equivalent to half the alternate-day dose (e.g., 5 mg taken on alternate days is equivalent to a 2.5 mg/day daily dose). If being taken, the subject must be on a stable dose of immunosuppressive therapy for at least 4 weeks prior to Baseline (Visit 2) and for the duration of the study.

At Baseline (Visit 2) 130 subjects will be randomised in a 1:1 ratio to receive either 300 mg mepolizumab (n=65) or placebo (n=65) SC every 4 weeks. The final dose of study treatment will be given at Week 48 with completion of the treatment period at Week 52. At this point, subjects will enter the follow-up period and be monitored for an additional 8 weeks and complete the study at Week 60 giving a total duration for study participation of up to 64 weeks from screening. Subjects who withdraw from study treatment prematurely (for any reason) should, where possible, continue to be followed up as per protocol until the end of follow-up at Week 60.


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Figure 1 Study Schematic

Between baseline (randomisation) and Week 4, subjects will be required to continue on their stable OCS (prednisolone/prednisone) dose (if necessary, upward adjustments are permitted for clinical management of the patient). From Week 4 post-baseline (Visit 4) onwards, if the subject’s BVAS = 0 their oral OCS dose should be tapered downwards according to standard of care practice. A recommended tapering schedule for this purpose is provided in Appendix 3 (see Section 11.3). The recommended tapering schedule enables a reduction in OCS dose every 2 weeks, with the intention of achieving a prednisolone/prednisone dose of 4 mg/day or less. Once a subject has achieved a dose of 4 mg/day prednisolone/prednisone, the investigator is encouraged to continue tapering downwards, if clinically warranted, at dose increments of 0.5-1.0 mg every 2 weeks.

In this study EGPA remission is defined as BVAS = 0 plus OCS dose of prednisolone/prednisone 4 mg/day. In defining EGPA remission, asthma and sino-nasalsymptoms /signs related to EGPA activity, if not specifically covered by the BVAS assessment, will be considered to be controlled by virtue of the low OCS dose (i.e., 4 mg/day prednisolone/prednisone) and are therefore not included in the remission definition. EGPA relapse will be defined as worsening or persistence of active disease since the last visit characterised by:

active vasculitis (BVAS >0); OR

active asthma symptoms and/or signs with a corresponding worsening in ACQ-6 score (compared to the most recent previous score); OR

active nasal and/or sinus disease with a corresponding worsening in at least one of the sino-nasal symptom questions (compared to the most recent previous assessment);


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warranting:

an increased dose of OCS therapy; OR

an increased dose or addition of immunosuppressive therapy; OR

hospitalisation related to EGPA worsening.

A full assessment, including evaluation of BVAS, asthma and sino-nasal signs and/or symptoms will be conducted at the time of a relapse. The time of onset of a relapse will be defined as time to change BVAS, asthma or sino-nasal signs and/or symptoms that warranted increase in corticosteroid therapy, increase in dose or addition of immunosuppressive therapy or hospitalisation. In the event a subject has achieved remission (i.e., BVAS=0 and prednisolone/prednisone dose ≤4 mg/day) and at anysubsequent visit has a BVAS=1 which does not require an increase in prednisolone/prednisone dose above 4 mg/day, or any other significant clinical intervention or investigation, the subject will be considered to be in continued remission.

A major relapse (a sub-set of the total relapse events) will be defined as: any organ or life-threatening EGPA event; OR BVAS ≥6 (involving at least two organ systems in addition to any general symptoms where present [myalgia, arthralgia/arthritis, fever >38ºC or weight loss >2 kg]); OR an asthma relapse requiring urgent care visit or hospitalisation; OR sino-nasal relapse requiring hospitalisation.

The minimally effective dose of OCS (prednisolone/prednisone) for each subject will be defined as the dose of OCS one step above the OCS dose at which the first relapse occurred. Where the subject has achieved a dose of OCS of 0-3.5 mgprednisolone/prednisone, the minimally effective dose will be defined as 4.0 mg/day. Upwards dose adjustments within the 0-4.0 mg range are permitted without necessarily being considered a relapse.

The management of subjects who relapse will be according to standard of care and may involve increasing the dose or oral corticosteroids or adjustment in immunosuppressivetherapy.

If the subject’s first relapse is managed with the use of an increase in corticosteroid dose, tapering should be recommenced as soon as the relapse has been appropriately controlled, as per standard of care practice. As stated above, the recommended tapering schedule is provided in Appendix 3 (see Section 11.3), although after the first relapse the investigator may opt to use larger dose increments and shorter dose intervals than outlined in the schedule, if clinically indicated. Once the minimally effective dose of OCS is achieved, any down-tapering below this dose level will be at the discretion of the investigator, based on the clinical condition of the subject. In the event of a second or subsequent relapse, any further OCS tapering, post-relapse, will be conducted at the discretion of the investigator.


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If a relapse is managed by increasing the dose of or initiating immunosuppressive therapy, the subject must be withdrawn from receiving further study treatment and where possible, continue to be followed up as per protocol.


Investigators, participating subjects, and GlaxoSmithKline (GSK) personnel will be blinded to absolute eosinophil counts, total white blood counts and differentials (%) for the duration of each subject’s participation in the study post-randomisation (baseline). Absolute neutrophil, lymphocyte, monocyte, and basophil counts will be provided.Investigators will ensure participating subjects and any physicians managing study patients during the course of the study are informed of this requirement.

Serious adverse events (SAEs) reported from ongoing clinical studies with mepolizumab are reviewed daily by the project Medical Monitor. Additionally, regular, systematic reviews of emerging safety data from all clinical studies are conducted by an in-house multi-disciplinary Safety Review Team (SRT) which provides a central and dedicated forum for review of emerging data which could impact subject safety. The SRT, which includes the project Medical Monitor, other physicians assigned to the project, clinical scientists and a statistician, review blinded and unblinded (i.e., from open-label trials) safety data from ongoing clinical studies with mepolizumab on a regular basis and conduct a comprehensive evaluation of the safety data upon completion of each study. Moreover, an integrated analysis of safety across the program is completed annuallywhen additional safety data are available from completed studies. A re-assessment of benefit risk and the current Developmental Core Safety Information (DCSI) is completed at each SRT meeting subsequent to review of new data. Additionally, an Independent Data Monitoring Committee (IDMC) will be utilized during the study; their primary focus will be the monitoring of cardiovascular safety and all cause mortality.

Furthermore, GSK has a standard and comprehensive process for the reporting and management of Sentinel Events. A sentinel event is an SAE that is not necessarily drug-related, but that has been associated historically with adverse reactions for other drugs, and is therefore worthy of heightened pharmacovigilance. Sentinel Events include acquired long QT syndrome, agranulocytosis, anaphylactic and anaphylactoid reactions, hepatotoxicity, renal failure, seizures, and Stevens Johnson syndrome/toxic epidermal necrolysis. Subsequent to the reporting of a sentinel event, the Medical Monitor promptly notifies the SRT and the GSK Global Safety Board and leads a thorough and comprehensive follow-up of the sentinel event with collection of all relevant data.

Investigator-sponsored ‘mechanistic/biomarker’ sub-studies will be conducted at selected sites in the United States (US) and Europe using samples collected from consenting subjects participating in the study. The objective of these studies will be to examine molecular profiles and biomarkers associated with EGPA and response to anti-IL-5 therapy. Specific details of the planned analyses will be outlined in the individual protocols and/or analysis plans for these studies.


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3.2. Discussion of Design

This study is designed to evaluate the efficacy and safety of mepolizumab in subjects with relapsing or refractory EGPA receiving standard of care therapy. Allowing use of background standard of care therapy supports inclusion of a placebo group contributing to a favourable benefit:risk profile for participating subjects. Subjects will therefore be receiving background corticosteroid therapy, with or without stable immunosuppressive treatment and only undergo corticosteroid reduction with onset of a reduced disease activity status. Use of cyclophosphamide, from baseline onwards, is excluded since the toxicity associated with this agent precludes its use at a stable dose for the 52-week study treatment duration.

Although there are criteria from the American College of Rheumatology (ACR) availablefor the classification of EGPA for which a patient is required to have 4 of the 6 following criteria to be considered to have EGPA: asthma, eosinophilia >10%, neuropathy (mono or poly), pulmonary infiltrates, non-fixed, paranasal sinus abnormality and extravascular eosinophils, these criteria were not designed to be used for diagnostic purposes [Masi, 1990; Basu, 2010]. These classification criteria have therefore been modified for the purpose of this study to ensure recruited subjects have a diagnosis of EGPA including key manifestations of this condition. Specifically, all subjects will be required to have had asthma plus eosinophilia in addition to two further major features of EGPA as outlined in inclusion criterion #3.

Subjects entering this study are required to have a history of relapsing or refractory disease as these subjects are considered to be most likely to benefit from addition of mepolizumab to existing therapy. Specifically excluded from the study will be subjects with organ-threatening or life-threatening disease, since it is likely these subjects will require treatment with cyclophosphamide (excluded from use during the study) and there are limited data to support the use of mepolizumab in these subjects. Nevertheless, subjects with refractory disease will be included in the study, which will allow mepolizumab to be evaluated in patients with relatively severe disease.

European League Against Rheumatism (EULAR) recommendations for clinical studies in systemic vasculitis encourage demonstration of corticosteroid-sparing as a trial outcome with a proposed definition of remission including disease control (i.e., BVAS=0) with prednisolone dose of ≤7.5 mg/day for a prolonged period [Hellmich, 2007]. In this study, the definition of remission requires a BVAS=0 with prednisolone/prednisone dose of ≤4.0 mg/day. This more stringent requirement reflects the evidence that doses in excess of 7.5 mg/day prednisolone (or equivalent) are associated with an increased risk of long-term complications [Sarnes, 2011].

The total study treatment duration is 52 weeks. This duration permits downwards tapering of OCS dose to a target of 4 mg/day prednisolone/prednisone and evaluation of disease control over an extended period, and balances the need to assess the experimental therapy for at least 12 months and the feasibility of retaining subjects in a clinical trial over a prolonged period of time. The protocol provides a recommended schedule from Week 4 for gradual tapering of corticosteroids down to 4 mg/dayprednisolone/prednisone where the subject’s BVAS=0 (Appendix 3; see Section 11.3).


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Once subjects have reached a dose of 4 mg/day prednisolone/prednisone, further tapering downwards may be continued. However, upward adjustment in the dose of OCS is permitted within the 0-4.0 mg range without necessarily being defined as a relapse. This approach recognises that some subjects on long-term OCSs are relatively resistant to complete discontinuation of therapy, and are vulnerable to precipitation of Addisonian symptoms.

The minimally effective dose of OCS in each subject will be defined as the dose of prednisolone/prednisone one step above the dose at which the first relapse occurs. Where the subject has achieved a dose of OCS of 0-3.5 mg, the minimally effective dose will be defined as 4.0 mg/day prednisolone/prednisone. The intention of defining the minimally effective OCS dose is to provide information to the investigator for use during any subsequent tapering. This will reduce the likelihood that a subject will experience a second relapse during the study, and therefore balances the efficacy objectives of the study with subject safety.

4. SUBJECT SELECTION AND WITHDRAWAL CRITERIA

4.1. Number of Subjects

Approximately 150 subjects with EGPA receiving standard of care therapy including a stable dose of oral corticosteroids of ≥7.5 mg/day (but not >50 mg/day) prednisolone/prednisone will be screened to provide 130 subjects (65 per group).

4.2. Inclusion Criteria

Specific information regarding warnings, precautions, contraindications, AEs, and other pertinent information on the GSK investigational product or other study treatment that may impact subject eligibility is provided in the mepolizumab IB, GlaxoSmithKlineDocument Number: CM2003/00010/08.

Deviations from inclusion criteria are not allowed because they can potentially jeopardise the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.

Subjects eligible for enrolment in the study must meet all of the following criteria:

1. Informed Consent: Able to give written informed consent prior to participation in the study, which will include the ability to comply with the requirements and restrictions listed in the consent form. Subjects must be able to read, comprehend, and write at a level sufficient to complete study related materials.

2. Age and gender: Male or female subjects age 18 years or older.

3. EGPA diagnosis: subjects who have been diagnosed with EGPA for at least 6 months based on the history or presence of: asthma plus eosinophilia (>1.0x109/L and/or >10% of leucocytes) plus at least two of the following additional features of EGPA


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a biopsy showing histopathological evidence of eosinophilic vasculitis, or perivascular eosinophilic infiltration, or eosinophil-rich granulomatous inflammation;

neuropathy, mono or poly (motor deficit or nerve conduction abnormality);

pulmonary infiltrates, non-fixed;

sino-nasal abnormality;

cardiomyopathy (established by echocardiography or MRI);

glomerulonephritis (haematuria, red cell casts, proteinuria);

alveolar haemorrhage (by bronchoalveolar lavage);

palpable purpura;

ANCA positive (MPO or PR3).

4. History of relapsing OR refractory disease defined as:

Relapsing disease: Subject must have a past history of at least one confirmed EGPA relapse (i.e., requiring increase in OCS dose, initiation/increased dose of immunosuppressive therapy or hospitalisation) within the past 2 years which occurred at least 12 weeks prior to Screening (Visit 1) whilst receiving a dose of prednisolone (or equivalent) of ≥7.5 mg/day.

Refractory disease:

Either: Failure to attain remission (BVAS=0 and OCS dose ≤7.5 mg/day prednisolone or equivalent) within the last 6 months following induction treatment with a standard regimen, administered for at least 3 months. Note:

a. Subjects who have received a cyclophosphamide (CYC) induction regimen may be included a minimum of 2 weeks after the last dose of daily oral CYC, or 3 weeks after the last dose of pulsed IV CYC prior to Baseline (Visit 2), if their total WBC is ≥4x109/L (tested at the local laboratory, if necessary) prior to randomisation.

b. Subjects who have received a methotrexate, azathioprine, or mycophenolate mofetil induction regimen may be included if on a stable dose for at least 4 weeks prior to Baseline (Visit 2).

c. Subjects who have received an induction regimen comprising corticosteroids alone may be included only if they have failed to attain remission after 3 months of treatment AND the corticosteroid dose is ≥15 mg/day prednisolone or equivalent for the 4 weeks prior to Baseline (Visit 2).

Or: Within 6 months prior to Screening (Visit 1), recurrence of symptoms of EGPA (not necessarily meeting the protocol definition of relapse)


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whilst tapering OCS, occurring at any dose level ≥7.5 mg/day prednisolone or equivalent.

5. Corticosteroid therapy: Subject must be on a stable dose of oral prednisolone or prednisone of ≥7.5 mg/day (but not >50 mg/day) for at least 4 weeks prior to Baseline (Visit 2).

6. Immunosuppressive therapy: If receiving immunosuppressive therapy (excluding cyclophosphamide) the dosage must be stable for the 4 weeks prior to Baseline (Visit 2) and during the study (dose reductions for safety reasons will be permitted).

7. ECG measurements: QTc(F)<450 msec or QTc(F)<480 msec for patients with bundle branch block.

The QTc is the QT interval corrected for heart rate according to either Bazett’s formula (QTcB), Fridericia’s formula (QTcF), or another method, machine or manual overread.

For subject eligibility and withdrawal decisions, QTcF will be used.

For purposes of data analysis, QTcF will be used as primary though data using both correction formulas will be collected and analysed.

The QTc should be based on single or averaged QTc values of triplicate electrocardiograms (ECGs) obtained over a brief recording period.

8. Female subjects: To be eligible for entry into the study, females of childbearing potential (FCBP) must commit to consistent and correct use of an acceptable method of birth control (Appendix 4; see Section 11.4) beginning with consent, for the duration of the trial and for 4 months after the last study drug administration.

French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.

4.3. Exclusion Criteria

Deviations from exclusion criteria are not allowed because they can potentially jeopardise the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.

Subjects meeting any of the following criteria must not be enrolled in the study:

1. GPA or MPA: Diagnosed with granulomatosis with polyangiitis (GPA; previously known as Wegener’s granulomatosis) or microscopic polyangiitis (MPA).

2. Organ-threatening EGPA: Organ-threatening EGPA as per EULAR criteria, i.e., organ failure due to active vasculitis, creatinine >5.8 g/dL (>513 µmol/L) within 3 months prior to Screening (Visit 1).

3. Life-threatening EGPA: Imminently life-threatening EGPA disease defined as any of the following within 3 months prior to Screening (Visit 1).

Intensive care required


37

Severe alveolar haemorrhage or haemoptysis requiring transfusion or ventilation or haemoglobin < 8 g/dL (<80 g/L) or drop in haemoglobin > 2 g/dL (>20 g/L) over a 48 hour period due to alveolar haemorrhage

Rapidly progressive glomerulonephritis (RPGN) with creatinine > 2.5 mg/dL (>221 µmol/L) or rise in creatinine > 2 mg/dL (>177 µmol/L) over a 48 hour period

Severe gastrointestinal (GI) involvement, e.g., gangrene, bleeding requiring surgery

Severe central nervous system (CNS) involvement

Severe cardiac involvement, e.g., life-threatening arrhythmia, cardiac failure: ejection fraction < 20%, New York Heart Association Class III/IV(Appendix 5; see Section 11.5), acute myocardial infarction.

4. Malignancy: A current malignancy or previous history of cancer in remission for less than 12 months prior screening (Subjects that had localized carcinoma (i.e., basal or squamous cell) of the skin which was resected for cure will not be excluded).

5. Liver disease: Unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, esophageal or gastric varices or persistent jaundice), cirrhosis, and known biliary abnormalities (with the exception of Gilbert’s syndrome or asymptomatic gallstones).

6. Cardiovascular: Subjects who have severe or clinically significant cardiovascular disease uncontrolled with standard treatment including but not limited to:

Known ejection fraction of <30%, OR

Severe heart failure that meets New York Heart Association Class IV(Appendix 5; see Section 11.5), OR

Hospitalised in the 12 months prior to Visit 1 for severe heart failure meeting New York Heart Association Class III (Appendix 5; see Section 11.5), OR

Angina diagnosed less than 3 months prior to or at Visit 1 (Screening).

7. Other concurrent medical conditions: Subjects who have known, pre-existing, clinically significant endocrine, autoimmune, metabolic, neurological, renal, gastrointestinal, hepatic, haematological, respiratory or any other system abnormalities that are not associated with EGPA and are uncontrolled with standard treatment.

8. Infectious disease: Chronic or ongoing active infectious disease requiring systemic treatment.

9. Parasitic infection: Subjects with a parasitic infestation within 6 months prior to Screening (Visit 1).

10. Hepatitis status: Diagnosis of chronic hepatitis B, as evidenced by positive Hepatitis B surface antigen (HBsAg) at Screening (Visit 1).

11. HIV: Subjects with a known human immunodeficiency virus infection.


38

12. Hypersensitivity: Subjects with a known allergy or intolerance to a monoclonal antibody or biologic therapy.

13. Previous mepolizumab: Subjects who have previously received mepolizumab within a 1 year period prior to Screening (Visit 1).

14. Prohibited medications: Subjects receiving any of the following:

OCS: Subject requires an oral corticosteroid dose of >50 mg/day prednisolone/prednisone in the 4-week period prior to Baseline (Visit 2).

Intravenous or SC corticosteroids in the 4-week period prior to Baseline (Visit 2).

Omalizumab within 130 days prior to Screening (Visit 1).

Cyclophosphamide: oral CYC within 2 weeks prior to Baseline (Visit 2) and IV CYC within 3 weeks prior to Baseline (Visit 2), if their total WBC is 4x109/L (measured using the local laboratory if necessary).

Rituximab within 12 months prior to Screening (Visit 1); in addition, the subject must have shown recovery of peripheral B-cell count to within the normal range.

IV or SC immunoglobulin within 6 months prior to Screening (Visit 1).

Interferon- within 6 months prior to Screening (Visit 1).

Anti-TNF therapy within 12 weeks prior to Screening (Visit 1).

Anti-CD52 (alemtuzumab) within 6 months prior to Screening (Visit 1).

15. Other laboratory parameter exclusions:

Creatinine > 2.5 mg/dL (221 µmol/L)

WBC < 4 x109/L

Platelet count <120,000/mm3

Haemoglobin <8 g/dL (<80 g/L)

16. Pregnancy: Subjects who are pregnant or breastfeeding. Subjects should not be enrolled if they plan to become pregnant during the time of study participation.

17. Alcohol/substance abuse: A history (or suspected history) of alcohol misuse or substance abuse within 2 years prior to Screening (Visit 1).

18. Other investigational product: Subjects who have received treatment with an investigational drug within the past 30 days or 5 terminal phase half-lives of the drug whichever is longer, prior to Screening (Visit 1) (this also includes investigational formulations of marketed products).

19. Other clinical study: Subject is currently participating in any other interventional clinical study.

20. Adherence: Subjects who have known evidence of lack of adherence to controller medications and/or ability to follow physician’s recommendations.


39

French subjects: the French subject has participated in any study using an investigational drug during the previous 30 days or 5 half-lives (whichever is longer).

4.4. Randomisation Criteria

Those subjects who meet the randomisation criteria will be randomised into the study until the target of 130 randomised subjects is reached. Randomisation will be stratified by region (Japan and rest of world) but not by centre due to the potentially small number of subjects per site.

At the end of the screening period, study subjects must fulfil the following additional criteria in order to be randomised to study treatment at Baseline (Visit 2):

1. Corticosteroid and immunosuppressive therapy standard of care treatment:Prednisolone/prednisone (≥7.5 mg/day) and immunosuppressive therapy (if being taken) have been stable for a period of at least 4 weeks prior to randomisation at Baseline (Visit 2).

2. Laboratory abnormality: No evidence of clinically significant abnormality in the haematological, biochemical or urinalysis screen at Screening (Visit 1), as judged by the investigator. Exception: Subjects who have received a CYC induction regimen may be randomised a minimum of 2 weeks after the last dose of daily oral CYC, or 3 weeks after the last dose of pulsed IV CYC, if their total WBC is ≥4x109/L (tested at the local laboratory if necessary).

3. Hepatitis status: No diagnosis of chronic hepatitis B, as evidenced by positive HBsAg at Screening (Visit 1).

4. Liver Function Tests: obtained at Screening (Visit 1):

ALT<2x ULN (upper limit of normal) or if subject is on background methotrexate or azathioprine <3x ULN

AST<2x ULN or if subject is on background methotrexate or azathioprine <3x ULN

Alkaline Phosphatase ≤2.0x ULN

Bilirubin ≤ 1.5x ULN (isolated bilirubin>1.5x ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%)

5. ECG over-read: No evidence of significant abnormality in the 12-lead ECG over-read from the Screening visit (Visit 1).

4.5. Withdrawal Criteria

4.5.1. Withdrawal from Study Treatment

Subjects may be withdrawn (discontinued) from study treatment at anytime. Subjects who withdraw from study treatment prematurely (for any reason) should, where possible, continue to be followed up as per protocol until the end of follow-up at Week 60. In addition, at the study visit approximately 12 weeks after the last dose of


40

study treatment was administered, a blood sample for measurement of anti-drug antibodies should be collected.

Reasons for premature discontinuation of study treatment must be captured in the electronic case report form (eCRF), e.g., AE, lack of efficacy, protocol deviation, investigator discretion, consent withdrawn etc. In addition, subjects will be withdrawn from study treatment for any of the following reasons:

Immunosuppressive therapy: Increasing the dose of or initiating immunosuppressive therapy (e.g., in the event of relapse).

Concurrent medication: Use of prohibited concurrent medication (i.e. as noted in Exclusion Criterion #14 (Prohibited medications) includingcyclophosphamide.

EGPA relapse: Subject experiences one organ-threatening or life-threatening relapse.

ECG abnormalities:

QTc >500 msec

Uncorrected QT >600 msec

Change from baseline: QTc > 60 msec

These criteria should be based on the average QTc value of triplicate ECGs. For example, if an ECG demonstrates a prolonged QT interval, obtain two more ECGs over a brief period, and then use the averaged QTc values of the three ECGs to determine whether the patient should be discontinued from the study.

For subjects with underlying Bundle Branch Block discontinuation due to QTc is based on the QTc value at baseline; see table below:

Baseline QTc with Bundle Branch Block

Discontinuation QTc with Bundle Branch Block

<450 msec >500 msec

450-480 msec ≥530 msec

Treatment code unblinded: Subjects must be discontinued from study treatment if the treatment code is unblinded by the Investigator or treating physician. The primary reason for withdrawal, (the event or condition which led to the unblinding) will be recorded in the eCRF.

4.5.2. Withdrawal from Study

Subjects are free to withdraw consent to participate in the study at anytime.

Reasons for withdrawal must be captured in the eCRF, e.g., AE, lack of efficacy, protocol deviation, consent withdrawn, lost to follow-up, study terminated etc.


41

A subject should be designated as lost to follow-up only if the site is unable to establish contact with the subject. The site must attempt to contact the subject on multiple occasions and only determine the subject to be ‘lost to follow-up’ after there have been at least 3 documented attempts, via at least 2 different methods (phone, text, e-mail, certified letter, etc), to contact the subject.

In the event of early withdrawal from the study, every effort should be made to have the subject to return to the clinic for an Early Withdrawal visit and to return all study related materials. Separate Early Withdrawal visits are described in the Time and Events Table (Table 2) i.e., ‘Early Withdrawal Visit 1’ for subjects withdrawing from the study during the study treatment period versus ‘Early Withdrawal Visit 2’ for subjects withdrawing from the study during the study follow-up period.

Following withdrawal from the study, investigators and participating subjects should, where possible, continue to be blinded to absolute eosinophil counts, total white blood counts and differentials (%) for a period of 12 weeks after the last dose of study medication was administered.

4.6. Screening and Run-in Failures

Those subjects who complete at least one procedure at the Screening Visit (Visit 1) but do not complete the Baseline Visit (Visit 2) will be designated as screen failures. Subjects who fail to meet the randomisation criteria at the Baseline Visit (Visit 2) will be designated as run-in failures.

Information to be collected for screen and run-in failure subjects will be detailed in the eCRF completion guidelines.

Re-screening of subjects will be allowed only upon approval by the medical monitor.

5. STUDY TREATMENTS

5.1. Investigational Product and Other Study Treatment

Mepolizumab (SB-240563) is a fully humanised monoclonal antibody (IgG1, kappa, mAb) with human heavy and light chain frameworks. Mepolizumab will be provided as a lyopholised cake in sterile vials for individual use. The vial will be reconstituted with Sterile Water for Injection, just prior to use. Further details of dose preparation and administration can be found in the IB (GlaxoSmithKline Document Number:CM2003/00010/08), and the SPM.

The contents of the label will be in accordance with all applicable regulatory requirements.

Under normal conditions of handling and administration, investigational product is not expected to pose significant safety risks to site staff. Take adequate precautions to avoid direct eye or skin contact and the generation of aerosols or mists. Notify the monitor of any unintentional occupational exposure. A Material Safety Data Sheet (MSDS) describing the occupational hazards and recommended handling precautions will be


42

provided to site staff if required by local laws or will otherwise be available from GSK upon request.

Investigational product must be stored in a secure area under the appropriate physical conditions for the product. Access to investigational product will be limited to the investigator’s authorized unblinded site staff. Mepolizumab must be stored under the appropriate physical conditions which includes storage in a refrigerator or at a temperature of 2-8C and protected from light. Maintenance of a temperature log (manual or automated) is required. Investigational product must be dispensed or administered only to subjects enrolled in the study and in accordance with the protocol.

Adequate precautions must be taken to avoid direct contact with the investigational product. The occupational hazards and recommended handling procedures are provided in the MSDS.

5.2. Treatment Assignment

A unique Subject Number will be assigned to any subject who is consented. This unique subject number will be used to identify the individual subject throughout the study and will not be re-assigned to any other subject. Randomisation will be stratified by region (Japan and rest of world).

Subjects will be assigned to study treatment in accordance with the Randomisation Schedule. Once a randomisation number has been assigned to a subject, it cannot be reassigned to any other subject in the study.

The Randomisation Schedule will be generated using the GSK validated randomisation software RandAll. Equal numbers of subjects will be allocated to each treatment. The Randomisation Schedule will be used to identify the treatment arm a subject is randomised to.

The double-blind treatment will be prepared in accordance with the Randomisation Schedule. The Randomisation Schedule will be sent by GSK as a signed, hard copy, controlled document, marked as private, for the attention of the unblinded qualified designee at each centre or sent as a GSK Secure email to the attention of the unblinded qualified designee. The Randomisation Schedule needs to be stored in a secure location.

5.3. Dosage and Administration

Subjects will be assigned to study treatment in accordance with the randomization schedule to receive either:

Mepolizumab: OR Placebo (0.9% sodium chloride):

300 mg SC injection administered every 4 weeks (13 administrations)

SC injection administered every 4 weeks (13 administrations)

An unblinded site staff member will be assigned to the study to prepare the appropriate medication according to the study subject’s treatment assignment. Subjects eligible to


43

enter the study will be assigned to treatment randomly through a telephone interactive voice response system (IVRS).

Prior to administration, each vial of mepolizumab will need to be reconstituted and swirled gently to enable complete dissolution of the product. Detailed instructions can be found within the pharmacy manual.

Mepolizumab or placebo (0.9% sodium chloride) will be administered as 3 separate injections. To administer each mepolizumab 100 mg SC injection (total dose 300 mg SC), reconstituted mepolizumab for injection will be drawn into a suitable syringe. To administer each placebo SC injection, an equivalent volume of 0.9% sodium chloride will be drawn into an identical syringe such that once prepared the active treatment will be indistinguishable from the placebo. Further details on administration are provided in the pharmacy manual.

Procedures must be in place to ensure the blind is maintained by any site staff involved in administration of the drug or clinical care or assessment of the subject, and by the subject themselves.

A blinded staff member will administer each of the 3 SC injections into any of the upper arm, thigh or anterior abdominal wall. It is recommended that individual injection sites are separated by at least 5 cm. Investigators will be required to record the site of all 3 injections in the eCRF for each study treatment administration.

Safety monitoring of subjects will occur during SC administration and for 1 hour after the end of injection. Such monitoring will include general safety monitoring including monitoring for both systemic hypersensitivity (i.e., allergic/IgE-mediated and non-allergic) and local site reactions. Trained rescue personnel and rescue medications/equipment must be available for use at all times. See Appendix 11(Section 11.11) for additional information.

5.4. Blinding

The investigator or treating physician may unblind a subject’s treatment assignment only in the case of an emergency or in the event of a serious medical condition, when knowledge of the study treatment is essential for the appropriate clinical management or welfare of the subject, as judged by the investigator. Investigators have direct access to the subject’s individual study treatment. It is preferred (but not required) that the investigator first contacts the GSK Medical Monitor or appropriate GSK study personnel to discuss options before unblinding the subject’s treatment assignment. If GSK study personnel are not contacted before the unblinding, the investigator must notify GSK as soon as possible after unblinding, but without revealing the treatment assignment of the unblinded subject, unless that information is important for the safety of subjects currently in the study. The date and reason for the unblinding must be fully documented in the appropriate data collection tool.

GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the treatment assignment for any subject with an SAE. If the SAE requires that an expedited regulatory report be sent to one or more regulatory agencies, a copy of the report, identifying the subject’s treatment assignment, may be sent to clinical investigators in accordance with local regulations and/or GSK policy.


44

5.5. Product Accountability

In accordance with local regulatory requirements, the investigator, designated site staff, or head of the medical institution (where applicable) must document the amount of investigational product dispensed and/or administered to study subjects, the amount returned by study subjects, and the amount received from and returned to GSK, when applicable. Product accountability records must be maintained throughout the course of the study.

5.6. Treatment Compliance

All doses will be administered at the study site by designated blinded site staff. Drug dispensing/accountability logs will be maintained by a designated unblinded member of the site staff.

5.7. Concomitant Medications and Non-Drug Therapies

All concomitant medications taken during the study will be recorded in the eCRF. With the exception of corticosteroids and immunosuppressive therapy, the minimum requirement is that drug name and the dates of administration are to be recorded.

For corticosteroids (prednisolone/prednisone) and immunosuppressive therapy, the dose must be recorded as well as all dose changes. Subjects will be required to record their dose of prednisolone/prednisone taken each day on an electronic diary (eDiary).

5.7.1. Permitted Medications and Non-Drug Therapies

Use of immunosuppressive therapy (e.g., methotrexate, azathioprine, mycophenolate mofetil) will be permitted during the study as long as the dosage remains stable from screening to study completion. Reduction in dose for safety reasons, with return to the original dose, where possible, is permitted.

Use of inhaled and topical steroids will be permitted throughout the study.

5.7.2. Prohibited Medications and Non-Drug Therapies

The following medications are not permitted prior to screening or during the study in accordance with the following specified washout periods:

Medication Washout prior to Screening (Visit 1)

Omalizumab 130 days

Rituximab 12 months (in addition subject must have shown recovery of peripheral blood B-lymphocytes)

IV or SC immunoglobulin 6 months

Interferon- 6 months

Anti-TNF 12 weeks

Anti-CD52 (alemtuzumab) 6 months


45

In addition, the following medication will be prohibited:

Intravenous or SC corticosteroid therapy: prohibited during the 4 weeks prior to Baseline (Visit 2).

Cyclophosphamide: prohibited from baseline onwards. Subjects who have received a CYC induction regimen may be randomised a minimum of 2 weeks after the last dose of daily oral CYC, or 3 weeks after the last dose of pulsed IV CYC, if their total WBC is ≥4x109/L (measured using the local laboratory if necessary).

Other investigational agents (biologic or non-biologic). Investigational applies to any drug not approved for sale in the country in which it is being used.

Acetaminophen is not used in patients with acute viral hepatitis.

5.8. Treatment after the End of the Study

The investigator is responsible for ensuring that consideration has been given to the post-study care of the subject’s medical condition whether or not GSK is providing specific post-study treatment.

5.9. Treatment of Study Treatment Overdose

The dose of mepolizumab considered to be an overdose has not been defined. There are no known antidotes and GSK does not recommend a specific treatment in the event of a suspected overdose. The investigator will use clinical judgement in treating the symptoms of a suspected overdose.

6. STUDY ASSESSMENTS AND PROCEDURES

A Time and Events table is provided in Table 2.

Subjects will be issued with an eDiary and instructed on how to use it at the start of the study. The asthma control questionnaire (ACQ-6), questions regarding sino-nasalsymptoms and the subject’s daily corticosteroid dose will be recorded on the eDiary.

Throughout the study subjects will be required to complete the following paper questionnaires at the study site: Sino-nasal Outcome Test-22 (SNOT-22), the Short Form-36 (SF-36), and the Work Productivity and Activity Impairment (WPAI) Index.


46

Table 2 Time and Events

Procedures Treatment PeriodFollow-up

period

Study visits 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17Early

W/D(1)

18 19Early

W/D(2)

Study week(specified no. of days)

Pre-screen

SCREEN-1 to -4weeks

BASE LINE

13

47

87

127

167

207

247

287

293

327

367

407

447

487

527

567

607

Informed consent1 XDemography XMedical history XHistory of EGPA and treatment

X

CV history/risk factors2 XInclusion/exclusion X XHeight and weight3 X X X X X X X X X X X X X X X X X X XRandomisation criteria XEfficacy assessmentsBVAS X X X X X X X X X X X X X X X X X X XRelapse detail4 X X X X X X X X X X X X X X X X X XVasculitis score (VDI) X X X XOCS dose5 X X X X X X X X X X X X X X X X X X XSino-nasal symptoms6 X X X X X X X X X X X X X X X X X X XACQ-66 X X X X X X X X X X X X X X X X X X XSpirometry (FEV1 and FVC)7

X X X X X X X X X X X X X X X X

Spirometry (reversibility testing)7

X

FeNO8 X X X XSNOT-229 X X X X X XSF-369 X X X X X XWPAI questionnaire9 X X X X X XHealth resource use10 X X X X X X X X X X X X X X X


47


period


W/D(1)

18 19Early

W/D(2)


Pre-screen

SCREEN-1 to -4weeks

BASE LINE

13

47

87

127

167

207

247

287

293

327

367

407

447

487

527

567

607

Safety assessmentsConcomitant meds X X X X X X X X X X X X X X X X X X XPhysical exam (full) X X X XPhysical exam (brief) X X X X X X X X X X X X X X XVital signs11 X X X X X X X X X X X X X X X X X X XECG12 X X X X X X X X X X XAdverse events X X X X X X X X X X X X X X X X X X X XSAEs X X X X X X X X X X X X X X X X X X X X XLaboratory assessments13

Haematology(with WBC differential)

X X X X X X X X X X X X X X X X X X X

Chemistry X X X X X X X X X X X X X X X X X X XTroponin X X X X X X X X X X X X X X X X X X XLipoproteins (fasting)14 X X XUrinalysis15 X X X X X X X X X X X X X X X XHep B & C serology16 XPregnancy test17 S U U U U U U U U U U U U U S S U U UIL-5 X X X X X X X X XCRP X X X X X X X X X X X X X X X XESR (local testing) X X X X X X X X X X X X X X X XANCA X X X XIgE XPK18 X X X X X X X X XAnti-drug antibody19 X X X X X X XGenetics/PGx20 XBiomarker Sub-studies21

Blood sample X X X X X X X X X XSputum sample X X X X


48


period


W/D(1)

18 19Early

W/D(2)


Pre-screen

SCREEN-1 to -4weeks

BASE LINE

13

47

87

127

167

207

247

287

293

327

367

407

447

487

527

567

607

Tissue sample22

Investigational productMepolizumab or Placebo Administration23 X X X X X X X X X X X X X

RAMOS/eCRFCall RAMOS to register visits

X X X X X X X X X X X X X X X X X X X X X

Complete eCRF X X X X X X X X X X X X X X X X X X X X X1. Pre-screen visit to obtain informed consent can occur on the same day as Visit 1, but informed consent must be obtained prior to starting Visit 1 procedures.2. Cardiovascular History/Risk Factors and CV screening questions3. Height to be measured at screening only.4. In the event of a relapse, detail of the event to be recorded in the eCRF. A blood, sputum and, where possible, biopsy sample to be collected in the event of relapse from

subjects participating at US sites in the ‘mechanistic’ sub-study.5. Subject to record daily prednisolone/prednisone dose on provided eDiary device. Investigator to record prescribed dose in the eCRF.6. Sino-nasal questionnaire and ACQ to be completed weekly by the subject using provided eDiary device.7. Spirometry: Airway reversibility to be measured at baseline only; FEV1 and FVC to be measured at all other visits.8. FeNO: To be measured at sites only if local equipment available.9. SNOT-22, SF-36 and WPAI questionnaires to be completed on paper forms. 10. At visits when health resource use is being collected, the investigator should ask the subject if they have had any need to seek medical treatment for EGPA or an EGPA-

related episode since the previous scheduled visit. 11. Vital sign measurements will include temperature, systolic and diastolic blood pressure and pulse rate.12. 12-lead ECG monitoring.13. During the treatment period, all lab samples should be obtained pre-dose.14. Lipoprotein (fasting) included in Clinical Chemistry. Subject must be in fasting state. If the subject has not fasted, he/she may return to the clinic to collect this sample as soon

as possible.15. Urinalysis Screen sample (Visit 1) to be analysed by the central laboratory; all other tests to be conducted using by dipstick.16. Hepatitis B Surface Antigen and Hepatitis C antibody (if hepatitis C antibody positive, a HCV RNA test (either quantitative or qualitative) should be performed).17. Serum pregnancy test (S) to be conducted in women of childbearing potential at Screening (Visit 1) and Week 52 (or early withdrawal); urine pregnancy tests (U) to be

conducted at all other indicated visits.


49


period


W/D(1)

18 19Early

W/D(2)


Pre-screen

SCREEN-1 to -4weeks

BASE LINE

13

47

87

127

167

207

247

287

293

327

367

407

447

487

527

567

607

18. PK sampling: At Baseline and Weeks 4, 28 and 48 the PK sample should be taken pre-dose. At Weeks 1 and 29, where practical, a PK sample is to be collected.19. In the event of premature discontinuation of study medication, a sample for measurement of anti-drug antibodies should be collected at the nearest scheduled study visit

approximately 12 weeks after the last dose of study medication was administered.20. Genetics/PGx: Sample collection is recommended at baseline but may be drawn at any time after the subject is randomised.21. Biomarker samples: Blood and sputum samples to be collected from consenting subjects participating at US sites in the ‘mechanistic/biomarker’ sub-study only. Where

possible, blood and sputum samples also to be collected in the event of relapse. Blood samples to be collected from consenting subjects at sites participating in the European ‘mechanistic/biomarker’ sub-study.

22. Tissue sample: To be collected, where possible, i.e., as part of standard of care evaluation, in the event of relapse from consenting subjects participating at US sites in the ‘mechanistic/biomarker’ sub-study only.

23. Safety monitoring: Subjects should be monitored for a minimum of 1-hour following study medication administration.


50

6.1. Critical Baseline Assessments

Informed Consent will be obtained at the pre-screen visit.

6.1.1. Critical Procedures Performed at Screening (Visit 1)

Demographic information including gender, ethnic origin, race and date of birth, height and weight.

Medical history including the following relating to the subject’s EGPA:

Date of diagnosis and/or approximate duration since diagnosis

Number of EGPA relapses experienced during the 2 years prior to Screening (Visit 1).

Requirement for immunosuppressive therapy in addition to OCS for management of their EGPA.

Requirement for cyclophosphamide for management of their EGPA.

Admissions to an Intensive Therapy Unit for management of their EGPA.

Documentation of any of the following complications of EGPA: gangrene; massive pulmonary haemorrhage or respiratory failure requiring ventilator support; congestive cardiac failure; renal failure requiring dialysis; cerebrovascular accident.

Cardiovascular medical history/risk factors will be assessed at screening. This assessment must include a review of the subject responses to the cardiovascular assessment questions (Appendix 6; see Section 11.6) and height, weight, blood pressure, smoking history, medical conditions, and family history of premature cardiovascular disease.

BVAS (see Section 6.2.1.1).

OCS (prednisolone/prednisone) dose.

Sino-nasal symptom questionnaire (see Section 6.2.1.4).

ACQ-6 (see Section 6.2.1.5).

Spirometry: FEV1 and FVC (see Section 6.2.1.6).

Concomitant medications.

Physical examination (full; see Section 6.3.11.4).

Vital signs (see Section 6.3.11.1).

12-lead ECG (see Section 6.3.11.2).

Laboratory tests including (see Section 6.3.11.3):

Haematology (including WBC differential with eosinophil count).

Clinical chemistry plus lipoprotein panel.


51

Urinalysis.

HBsAg and hepatitis C antibody.

Serum pregnancy test (all females of childbearing potential).

C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR).

ANCA (MPO and PR3).

Mechanistic Sub-study only: Biomarker sample collection.

6.1.2. Critical Procedures Performed at Baseline (Visit 2)

Review of randomization criteria including data collected at the Screening visit (Visit 1).

Weight.


Relapse detail, if applicable (see Section 6.2.1.2).

Vasculitis Damage Index (VDI) (see Section 6.2.1.3).




Spirometry: FEV1 and FVC including reversibility assessment (see Section 6.2.1.6).

Fractional Concentration of Exhaled Nitric Oxide (FeNO) (see Section 6.2.1.7).

SNOT-22 questionnaire (see Section 6.2.1.4).

SF-36 (see Section 6.4.1.1).

WPAI questionnaire (see Section 6.4.1.2).

Health resource use (see Section 6.4.1.3).


Physical examination (brief; see Section 6.3.11.4).





Clinical chemistry.

Urinalysis.

Urine pregnancy test (all females of childbearing potential).


52

IL-5.

CRP and ESR.

IgE.

Blood for baseline immunogenicity and PK.


6.1.3. Cardiovascular Assessment

The cardiovascular assessment (Appendix 6; see Section 11.6) will be administered by site personnel at the Screening visit (Visit 1). If the subject responds ‘Yes’ to any of the questions a physician must conduct a further evaluation to assess for previously unrecognized and undiagnosed angina. The results of the evaluation should be considered when determining subject eligibility (see Exclusion Criterion #6). Subject responses will be entered into the eCRF.

6.2. Efficacy

6.2.1. Efficacy Endpoints

Primary

Total accrued duration of remission, i.e., the accrued number of weeks where BVAS=0 plus prednisolone/prednisone dose 4 mg/day over the 52 week study treatment period reported as proportion of subjects achieving remission in the following categories:

Zero

>0 to <12 weeks

12 to <24 weeks

24 to <36 weeks

≥36 weeks

The proportion of subjects who are in remission at both Weeks 36 and 48 of the study treatment period.

Secondary

Time to first confirmed EGPA relapse.

The proportion of subjects with an average daily prednisolone/prednisone dose during the last 4 weeks of the study treatment period (48 through 52) in each of the following categories:

Zero

>0 to ≤4.0 mg

>4.0 to ≤7.5 mg


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>7.5 mg

The proportion of subjects in each treatment group who achieve remission (BVAS=0 and prednisolone/prednisone dose ≤4 mg/day) within the first 24 weeks of the study and then remain in remission for the remainder of the study treatment period.

Other

Total duration of sustained remission, i.e., longest uninterrupted period of weeks where BVAS=0 plus prednisolone/prednisone ≤4 mg/day over the 52 week study treatment period, reported as proportion of subjects achieving sustained remission in the following categories:

Zero

>0 to <12 weeks

12 to <24 weeks

24 to <36 weeks

≥36 weeks

Frequency of EGPA all relapses.

Frequency of major relapses.

Time to first major relapse.

Change from baseline in daily prednisolone/prednisone dose over the 52 week study treatment period (Weeks 0 through 52).

The proportion of subjects with a percentage reduction in the average prednisolone/prednisone dose during the last 4 weeks of the study treatment period (48 through 52) compared with baseline in each of the following categories:

No reduction or withdrawal from treatment

<25%

25 to <50%

50 to <75%

75 to <100%

100%

Change from baseline in BVAS.

Change from baseline in VDI.

Change from baseline in ACQ-6.

Change from baseline in lung function tests (FEV1 and FVC).

Change from baseline in FeNO.

Change from baseline in SF-36 score.


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Change from baseline in SNOT-22 score.

Absolute blood eosinophil count (expressed as a ratio to baseline).

Change from baseline in biomarkers of inflammation: CRP and ESR.

Change from baseline in the WPAI index.

Use of healthcare resources.

6.2.1.1. Birmingham Vasculitis Activity Score

The Birmingham Vasculitis Assessment Score (BVAS) is a validated, clinician-completed tool used for the comprehensive multisystem clinical assessment of disease activity in systemic vasculitis [Luqmani, 1994; Luqmani, 1997; Mukhtyar, 2009b]. A copy of the BVAS questionnaire is provided in Appendix 7 (see Section 11.7).

The investigator will be required to complete the BVAS form in the eCRF at Screening (Visit 1), Baseline (Visit 2) and every 4 weeks until study completion at Week 60 or Early Withdrawal, as specified in the Time and Events Table (Table 2).

The BVAS form is divided into 9 organ-based systems, with each section including symptoms/signs that are typical of that particular organ involvement in systemic vasculitis. The form is designed to record features that are attributable to current vasculitis, after exclusion of other causes such as infection, hypertension etc. The scoring sheet records the presence or absence of each item. Each item is weighted and a maximum total score applied to each system. The total score on all 9 organ systems gives an indication of the disease activity of each patient at the time of scoring and reflects the need for therapy.

Guidance on completing the BVAS form will be provided in the SPM.

6.2.1.2. Relapse

EGPA relapse will be defined as worsening or persistence of active disease since the last visit characterised by:

Active vasculitis (BVAS >0); OR

Active asthma symptoms and/or signs with a corresponding worsening in ACQ-6 score (compared to the most recent previous score); OR

Active nasal and/or sinus disease, with a corresponding worsening in at least one of the sino-nasal symptom questions (compared to the most recent previous assessment);

warranting:

An increased dose of OCS therapy; OR

An increased dose or addition of immunosuppressive therapy; OR

Hospitalisation related to EGPA worsening.


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The time of onset of a relapse will be defined as time to change BVAS, asthma or sino-nasal signs and/or symptoms that warranted increase in corticosteroid therapy, increase in dose or addition of immunosuppressive therapy or hospitalisation.

Investigators will be required to record details pertaining to the relapse event in the eCRF from Baseline (Visit 2) until study completion at Week 60 or Early Withdrawal, e.g., details regarding the BVAS item, asthma or nasal/sinus disease resulting in the relapse with detail of the required intervention(s), e.g., OCS dose increase, use or change in immunosuppressive therapy or requirement for hospitalisation. For consenting subjects participating in the US ‘mechanistic’ sub-study, where possible, a blood, sputum and, tissue (biopsy) sample should be collected in the event of relapse.

Note, in the event a subject has achieved remission (i.e., BVAS=0 and prednisolone/prednisone dose ≤4 mg/day) and at a subsequent visit has a BVAS=1 which does not require an increase in corticosteroid dose above 4 mg/day, or any other significant clinical intervention or investigation, this will not be considered a relapse.

6.2.1.3. Vasculitis Damage Index

The Vasculitis Damage Index (VDI; [Exley, 1998]) will be used to document those features of vasculitis which are due to persistent damage, where there is no current disease activity [Exley, 1998]. Damage is defined as the presence of non-healing scars and does not give any indication of current disease activity. The VDI is divided into 11 organ systems and records items of damage, due to vasculitis, treatment or unrelated, that have occurred since the onset of vasculitis. Completion of the form provides a numerical score. A copy of the VDI questionnaire is provided in Appendix 8 (see Section 11.8).

The investigator will be required to complete the VDI form in the eCRF at Baseline (Visit 2), Week 24, and Week 52 or Early Withdrawal, as specified in the Time and Events Table (Table 2).

Guidance on completing the VDI form will be provided in the SPM.

6.2.1.4. Sino-nasal Symptoms

Subjects will be asked to rate the following sino-nasal symptoms on a weekly basis at home from Screening (Visit 1) until study completion at Week 60 or Early Withdrawalusing an eDiary in response to the question:

“Considering your sinus and nasal symptoms over the last week, rate each symptom against the following categories: Very severe; severe; moderate; mild; none.”

Runny nose

Post-nasal discharge (sensation of liquid in your throat)

Facial pain/pressure

Loss or reduction in sense of taste/smell


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Blockage/congestion of nose

In addition, the SNOT-22 patient-reported outcome tool will be used to evaluate symptoms relating to rhinosinusitis. The SNOT-22 is a validated, patient-reported outcome measure developed for use in chronic rhinosinusitis with or without nasal polyposis [Hopkins, 2009]. The SNOT contains 22 questions regarding the symptoms and social/emotional consequences of the patient’s nasal disorder. A copy of the SNOT-22 questionnaire is provided in Appendix 10 (see Section 11.10).

Subjects will be required to complete a paper form of the questionnaire at the study site at the visits specified in the Time and Events Table (Table 2). Site staff will transcribe the responses into the eCRF.

6.2.1.5. Asthma Control Questionnaire

The ACQ-6 is a 6-item questionnaire, which has been developed as a measure of a subject’s asthma control that can be quickly and easily completed [Juniper, 1999; Juniper, 2000]. A copy of the ACQ-6 is provided in Appendix 9 (see Section 11.9). The questions are designed to be self-completed by the subject. The first 5 questions enquire about the frequency and/or severity of symptoms (nocturnal awakening on waking in the morning, activity limitation, and shortness of breath, wheeze) during the past week. The sixth question enquires how many puffs/inhalations of short-acting bronchodilator (e.g., VENTOLIN/Bricanyl) the subject required each day in the previous week.

The subject will be provided with an eDiary including the ACQ-6 for completion at home on a weekly basis until study completion at Week 60 or Early Withdrawal.

6.2.1.6. Spirometry

Spirometry will be conducted, using the site’s own equipment at the visits specified in the Time and Events schedule (Table 2).

The spirometer should meet American Thoracic Society standards and produce a printout of all data generated, which should be stored in the subject’s notes. The spirometer should be calibrated in accordance with the manufacturer’s instructions and a calibration log maintained.

Prior to the Baseline visit (Visit 2) subjects should withhold short-acting beta-2-agonists (SABAs) for at least 6 hours and long-acting beta-2-agonists (LABAs) for at least 12 hours to enable reversibility testing to be performed. Specifically, FEV1 will be measured pre-salbutamol/albuterol and within 30 minutes [±15 minutes] following up to 4 inhalations of salbutamol/albuterol (a spacer device may be used if required) or equivalent nebulised treatment with salbutamol/albuterol solution. The reversibility test must be performed in the morning only at Baseline (Visit 2).


57

Percent reversibility will be calculated as follows:

Percent reversibility = (Post-bronchodilator FEV1 – Pre-bronchodilator FEV1 ) X 100%Pre-bronchodilator FEV1

At all other clinic visits FEV1 and FVC will be measured with no requirement to withhold asthma medications prior to the visit. However, due to diurnal variation associated with lung function, when possible, spirometry should be performed at the same time of day (+ 1 hour) as for the Baseline (Visit 2) assessment.

6.2.1.7. Fractional Concentration of Exhaled Nitric Oxide (FeNO)

If there is local equipment available (e.g., NIOX MINO, Aerocrine), FeNO should be measured at the visits specified in the Time and Events schedule (Table 2). Measurements should be made before spirometry is performed.

6.3. Safety

6.3.1. Safety Endpoints

Adverse Events including systemic (i.e., allergic/IgE-mediated and non-allergic) and local site injection-related reactions reported throughout the 52-week study treatment period.

NOTE: Systemic reactions can be allergic or non-allergic in nature and are typically mild to moderate in intensity, generally develop within several hours of the injection, and are most commonly associated with a complex of symptoms including chills, fever, nausea, vomiting, asthenia, headache, skin rash, pruritus, urticaria, arthralgia/myalgia, hypotension/hypertension, dizziness, bronchospasm, dyspnea or cough. Anaphylaxis, the most severe form of hypersensitivity reactions will be assessed using the diagnostic criteria as outlined by the 2006 Joint NIAID/FAAN Second Symposium on Anaphylaxis ([Sampson, 2006] Appendix 11; see Section 11.11). Information will be also collected from subjects to help with the assessment of potential localised injection site reactions.

Haematological and clinical chemistry parameters throughout the 52-week study treatment period and 8-week follow-up period.

Vital signs (pulse rate, temperature and systolic and diastolic blood pressure) throughout the 52-week study treatment period and 8-week follow-up period.

Presence of anti-drug antibodies to mepolizumab.

The following endpoints will be derived:

Change from baseline in systolic blood pressure

Change from baseline diastolic blood pressure

Change from baseline in pulse rate

12-lead ECG to derive the following endpoints:


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Mean change from baseline in the QTc(F) (QT interval corrected by Fridericia's method)

Mean change from baseline in QTc(B) (QT interval corrected by Bazett's method)

Maximum change from baseline for QTc(F) and QTc(B).

6.3.2. Liver Chemistry Stopping and Follow-up Criteria

Phase III-IV liver chemistry stopping and follow up criteria have been designed to assure subject safety and evaluate liver event etiology (in alignment with the FDA premarketing clinical liver safety guidance).

Phase III-IV liver chemistry stopping criteria 1-5 are defined below and are presented in a figure in Appendix 12 (see Section 11.12).

1. ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) (or ALT 3xULN and INR>1.5, if INR measured)

NOTE: if serum bilirubin fractionation is not immediately available, withdraw study drugfor that subject if ALT 3xULN and bilirubin 2xULN. Serum bilirubin fractionation should be performed if testing is available. If testing is unavailable, record presence of detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury.

2. ALT 8xULN.

3. ALT 5xULN but <8 xULN persists for 2 weeks

4. ALT 3xULN if associated with symptoms (new or worsening) believed to be related to hepatitis (such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, or jaundice) or hypersensitivity (such as fever, rash or eosinophilia).

5. ALT 5xULN but <8 xULN and cannot be monitored weekly for 2 weeks

When any of the liver chemistry stopping criteria 1-5 is met, do the following:

Immediately withdraw investigational product for that subject

Report the event to GSK within 24 hours of learning its occurrence

Complete the liver event CRF and SAE data collection tool if the event also meets the criteria for an SAE. All events of ALT 3xULN and bilirubin 2xULN (>35% direct) (or ALT 3xULN and INR>1.5, if INR measured); INR measurement is not required and the threshold value stated will not apply to patients receiving anticoagulants), termed ‘Hy’s Law’, must be reported as an SAE (excluding studies of hepatic impairment or cirrhosis).

NOTE: if serum bilirubin fractionation is not immediately available, withdraw study drugfor that subject if ALT 3xULN and bilirubin 2xULN. Serum bilirubin fractionation should be performed if testing is available. If testing is unavailable, record presence of


59

detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury.

Complete the liver imaging and/or liver biopsy CRFs if these tests are performed

Perform liver event follow up assessments, and monitor the subject until liver chemistries resolve, stabilise, or return to baseline values as described below.

Withdraw the subject from the study (unless further safety follow-up is required) after completion of the liver chemistry monitoring as described below.

Do not restart investigational product.

In addition, for criterion 1:

Make every reasonable attempt to have subjects return to clinic within 24 hours for repeat liver chemistries, liver event follow up assessments (see below), and close monitoring

A specialist or hepatology consultation is recommended

Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline phosphatase, bilirubin) resolve, stabilise or return to within baseline values

For criteria 2, 3, 4 and 5:

Make every reasonable attempt to have subjects return to clinic within 24-72 hrs for repeat liver chemistries and liver event follow up assessments (see below)

Monitor subjects weekly until liver chemistries (ALT, AST, alkaline phosphatase, bilirubin) resolve, stabilise or return to within baseline values; criterion 5 subjects should be monitored as frequently as possible.

Subjects with ALT 5xULN and <8xULN which exhibit a decrease to ALT x3xULN, but <5xULN and bilirubin <2xULN without hepatitis symptoms or rash, and who can be monitored weekly for 4 weeks:

Notify the GSK medical monitor within 24 hours of learning of the abnormality to discuss subject safety

Can continue investigational product

Must return weekly for repeat liver chemistries (ALT, AST, alkaline phosphatase, bilirubin) until they resolve, stabilise or return to within baseline

If at any time these subjects meet the liver chemistry stopping criteria, proceed as described above

If, after 4 weeks of monitoring, ALT <3xULN and bilirubin <2xULN, monitor subjects twice monthly until liver chemistries normalise or return to within baseline values.

For criteria 1-5, make every attempt to carry out the liver event follow up assessmentsdescribed below:


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Viral hepatitis serology including:

Hepatitis A IgM antibody;

Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM);

Hepatitis C RNA;

Cytomegalovirus IgM antibody;

Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile antibody or monospot testing);

Hepatitis E IgM antibody

Blood sample for PK analysis obtained within 1 week of the liver event. Record the date/time of the PK blood sample draw and the date/time of the last dose of investigational product prior to blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected within a week of the liver event, do not obtain a PK sample. Instructions for sample handling and shipping are in the SPM.

Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total bilirubin 2xULN.

Obtain complete blood count with differential to assess eosinophilia.

Record the appearance or worsening of clinical symptoms of hepatitis or hypersensitivity, such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever rash or eosinophilia as relevant on the AE report form.

Record use of concomitant medications, acetaminophen, herbal remedies, other over the counter medications, or putative hepatotoxins, on the concomitant medications report form.

Record alcohol use on the liver event alcohol intake case report form.

The following are required for subjects with ALT 3xULN and bilirubin 2xULN (>35% direct) but are optional for other abnormal liver chemistries:

Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney microsomal antibodies and quantitative total immunoglobulin G (IgG or gamma globulins).

Serum acetaminophen adduct HPLC assay (quantifies potential acetaminophen contribution to liver injury in subjects with definite or likely acetaminophen use in the preceding week [James, 2009]). NOTE: not required in China.

Only in those with underlying chronic hepatitis B at study entry (identified by positive hepatitis B surface antigen): quantitative hepatitis B DNA and hepatitis delta antibody. NOTE: if hepatitis delta antibody assay cannot be performed, it can be replaced with a PCR of hepatitis D RNA virus (where needed) [Le Gal, 2005].


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Liver imaging (ultrasound, magnetic resonance, or computerised tomography) to evaluate liver disease.

6.3.3. Adverse Events

The investigator or site staff will be responsible for detecting, documenting and reporting events that meet the definition of an AE or SAE.

6.3.3.1. Definition of an AE

Any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

Note: An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse.

Events meeting the definition of an AE include:

Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency and/or intensity of the condition

New conditions detected or diagnosed after study treatment administration even though it may have been present prior to the start of the study

Signs, symptoms, or the clinical sequelae of a suspected interaction

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study treatment or a concomitant medication (overdose per se will not be reported as an AE/SAE) unless this is an intentional overdose taken with possible suicidal/self-harming intent. This should be reported regardless of sequelae.

“Lack of efficacy” or “failure of expected pharmacological action” per se will not be reported as an AE or SAE. However, the signs and symptoms and/or clinical sequelae resulting from lack of efficacy will be reported if they fulfil the definition of an AE or SAE.

Events that do not meet the definition of an AE include:

Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that leads to the procedure is an AE

Situations where an untoward medical occurrence did not occur (social and/or convenience admission to a hospital)

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the start of the study that do not worsen


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The disease/disorder being studied, or expected progression, signs, or symptoms of the disease/disorder being studied, unless more severe than expected for the subject’s condition.

6.3.3.2. Definition of an SAE

A serious adverse event is any untoward medical occurrence that, at any dose:

a) Results in death

b) Is life-threatening

NOTE: The term 'life-threatening' in the definition of 'serious' refers to an event in which the subject was at risk of death at the time of the event. It does not refer to an event, which hypothetically might have caused death, if it were more severe.

c) Requires hospitalisation or prolongation of existing hospitalisation

NOTE: In general, hospitalisation signifies that the subject has been detained (usually involving at least an overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have been appropriate in the physician’s office or out-patient setting. Complications that occur during hospitalisation are AEs. If a complication prolongs hospitalisation or fulfills any other serious criteria, the event is serious. When in doubt as to whether “hospitalisation” occurred or was necessary, the AE should be considered serious.

Hospitalisation for elective treatment of a pre-existing condition that did not worsen from baseline is not considered an AE.

d) Results in disability/incapacity, or

NOTE: The term disability means a substantial disruption of a person’s ability to conduct normal life functions. This definition is not intended to include experiences of relatively minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday life functions but do not constitute a substantial disruption.

e) Is a congenital anomaly/birth defect

f) Medical or scientific judgment should be exercised in deciding whether reporting is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalisation but may jeopardisethe subject or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition. These should also be considered serious. Examples of such events are invasive or malignant cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation, or development of drug dependency or drug abuse.

g) All events of possible drug-induced liver injury with hyperbilirubinaemia defined as ALT 3xULN and bilirubin 2xULN (>35% direct) (or ALT 3xULN and INR>1.5, if INR measured) termed ‘Hy’s Law’ events (INR measurement is not


63

required and the threshold value stated will not apply to patients receiving anticoagulants).

NOTE: bilirubin fractionation is performed if testing is available. If testing is unavailable, record presence of detectable urinary bilirubin on dipstick indicating direct bilirubin elevations and suggesting liver injury. If testing is unavailable and a subject meets the criterion of total bilirubin 2xULN, then the event is still reported as an SAE. If INR is obtained, include values on the SAE form. INR elevations >1.5 suggest severe liver injury.

6.3.4. Laboratory and Other Safety Assessment Abnormalities Reported as AEs and SAEs

Any abnormal laboratory test results (haematology, clinical chemistry, or urinalysis) or other safety assessments (e.g., ECGs, radiological scans, vital signs measurements), including those that worsen from baseline, and felt to be clinically significant in the medical and scientific judgement of the investigator are to be recorded as AEs or SAEs.However, any clinically significant safety assessments that are associated with the underlying disease, unless judged by the investigator to be more severe than expected for the subject’s condition, are not to be reported as AEs or SAEs.

6.3.5. Cardiovascular Events

Investigators will be required to fill out event specific data collection tools for the following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thrombosis

Deep venous thrombosis

Revascularisation

This information should be recorded within one week of when the AE/SAE(s) are first reported.

6.3.6. Death Events

In addition, all deaths will require a specific death data collection tool to be completed. The death data collection tool includes questions regarding cardiovascular (including sudden cardiac death) and non-cardiovascular death.

This information should be recorded within one week of when the death is first reported.


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6.3.7. Pregnancy

Any pregnancy that occurs during study participation must be reported using a clinical trial pregnancy form. To ensure subject safety, each pregnancy must be reported to GSK within 2 weeks of learning of its occurrence. The pregnancy must be followed up to determine outcome (including premature termination) and status of mother and child. Pregnancy complications and elective terminations for medical reasons must be reported as an AE or SAE. Spontaneous abortions must be reported as an SAE.

Any SAE occurring in association with a pregnancy, brought to the investigator’s attention after the subject has completed the study and considered by the investigator as possibly related to the study treatment, must be promptly reported to GSK.

6.3.8. Time Period and Frequency of Detecting AEs and SAEs

The investigator or site staff is responsible for detecting, documenting and reporting events that meet the definition of an AE or SAE.

AEs will be collected from the start of study treatment and until the end of follow up contact.

SAEs will be collected over the same time period as stated above for AEs. However, any SAEs assessed as related to study participation (e.g., study treatment, protocol-mandated procedures, invasive tests, or change in existing therapy) or related to a GSK concomitant medication, will be recorded from the time a subject consents to participate in the study up to and including any follow up contact. All SAEs will be reported to GSK within 24 hours, as indicated in Section 6.3.10.

6.3.9. Method of Detecting AEs and SAEs

Care must be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-leading verbal questioning of the subject is the preferred method to inquire about AE occurrence. Appropriate questions include:

“How are you feeling?” or for paediatric studies, “How does your child seem to feel?”

“Have you had any (other) medical problems since your last visit/contact?” or for paediatric studies, “Has your child had any (other) medical problems or seem to act differently in any way since his/her last visit/contact?”

“Have you taken any new medicines, other than those provided in this study, since your last visit/contact?” or for paediatric studies, ”Has your child needed to take any medicines, other than those provided in this study, since his/her last visit/contact?”


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6.3.10. Prompt Reporting of Serious Adverse Events and Other Events to GSK

SAEs, pregnancies, and liver function abnormalities meeting pre-defined criteria will be reported promptly by the investigator to GSK as described in the following table once the investigator determines that the event meets the protocol definition for that event.

Initial Reports Follow-up Information on a Previous Report

Type of Event Time Frame Documents Time Frame DocumentsAll SAEs 24 hours “SAE” data

collection tool“CV events”

and/or “death” data collection

tool(s) if applicable

24 hours Updated “SAE” data collection tool“CV events” and/or

“death” data collection tool(s) if

applicable

Pregnancy 2 weeks “Pregnancy Notification Form”

2 weeks “Pregnancy Follow-up Form”

Liver chemistry abnormalities for Phase I to IV:

ALT3xULN andBilirubin2xULN (>35% direct) (or ALT3xULN andINR>1.5, if INR

measured)1

24 hours2 “SAE” data collection tool.

“Liver Event CRF” and “Liver

Imaging” and/or“Liver Biopsy”

CRFs, if applicable3

24 hours Updated “SAE” data collection

tool/“Liver Event” Documents3

Remaining liver chemistry abnormalities Phase III to IV:

ALT8xULN; ALT3xULN with

hepatitis or rash or 3xULN and <5xULN

that persists4 weeks

24 hours2 “Liver Event” Documents

(defined above)3

24 hours Updated “Liver Event” Documents3

ALT5xULN plus bilirubin <2xULN


(defined above) do not need

completing unless elevations persist

for 2 weeks or subject cannot be monitored weekly

for 2 weeks3

24 hours Updated “Liver Event” Documents,

if applicable3


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Type of Event Time Frame Documents Time Frame Documents

ALT5xULN and bilirubin <2xULN that

persists 2 weeks


(defined above)3


ALT3xULN and <5x ULN and bilirubin

<2xULN





for 4 weeks3


if applicable3

1. INR measurement is not required; if measured, the threshold value stated will not apply to patients receiving anticoagulants.

2. GSK must be contacted at onset of liver chemistry elevations to discuss subject safety3. Liver Event Documents (i.e., “Liver Event CRF” and “Liver Imaging CRF” and/or “Liver Biopsy CRF”, as

applicable) should be completed as soon as possible.

The method of recording, evaluating and follow-up of AEs and SAEs plus procedures for completing and transmitting SAE reports to GSK are provided in the SPM. Procedures for post-study AEs/SAEs are provided in the SPM.

6.3.10.1. Regulatory Reporting Requirements for SAEs

Prompt notification of SAEs by the investigator to GSK is essential so that legal obligations and ethical responsibilities towards the safety of subjects are met.

GSK has a legal responsibility to notify both the local regulatory authority and other regulatory agencies about the safety of a product under clinical investigation. GSK will comply with country specific regulatory requirements relating to safety reporting to the regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee (IEC) and investigators.

Investigator safety reports are prepared for suspected unexpected serious adverse reactions according to local regulatory requirements and GSK policy and are forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE(s) or other specific safety information (e.g., summary or listing of SAEs) from GSK will file it with the IB and will notify the IRB/IEC, if appropriate according to local requirements.


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6.3.11. Other Safety Outcomes

6.3.11.1. Vital Signs, Height and Weight

Vital signs include temperature, blood pressure (systolic and diastolic), and pulse rate.Measurements will be performed by the investigator or qualified designee, as outlined in Time and Events schedule (Table 2).

Sitting pulse rate and blood pressure measurements will be performed pre-injection with the subject sitting, having rested in this position for at least 5 minutes before each reading. They will be taken before measurement of any clinic lung function tests or ECGs at the specified time point.

Height will be measured without shoes and body weight will be measured without shoes and overcoat.

6.3.11.2. Twelve-lead Electrocardiogram (ECG)

Twelve-lead ECGs will be performed at the visits specified in the Time and Events schedule (Table 2).

Electrocardiogram measurements will be made after the subject has rested in the supine position for 5 minutes. The ECG should be obtained before lung function testing followed by other study procedures. Collection shortly after a meal or during sleep should be avoided since QT prolongation can occur at these times.

Investigators will be provided with ECG machines by GSK through a designated central laboratory. Paper ECG traces will be recorded at a standard paper speed of 25 mm/sec and gain of 10 mm/mV, with a lead II rhythm strip. There will be electronic capture and storage of the data by a validated method, with subsequent transferral to the central laboratory for manual reading and calculation of the electrocardiographic parameters.

Subjects with evidence of significant abnormality in the 12-lead ECG or a QTc(F) 450 msec or QTc(F) 480 msec for patients with Bundle Branch Block at screening will be excluded from randomisation.

Paper traces are required to be maintained at the site with other source documents.

6.3.11.3. Clinical Laboratory Parameters

All protocol required laboratory assessments, as defined in Table 3, must be performed by the central laboratory, Quest Diagnostics. Laboratory assessments must be conducted in accordance with the Central Laboratory Manual and Protocol Time and Events Schedule (Table 2). Laboratory requisition forms must be completed and samples must be clearly labelled with the subject number, protocol number, site/centre number, and visit date. Details for the preparation and shipment of samples will be provided by Quest Diagnostics. Reference ranges for all safety parameters will be provided to the site by Quest Diagnostics.


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All study-required laboratory assessments will be performed by the central laboratory, apart from:

Mepolizumab (PK samples; see Section 6.5.1).

Anti-mepolizumab antibodies (Immunogenicity; see Section 6.6).

IL-5 (see Section 6.5.2).

Sub-study biomarkers (see Section 6.7.1).

ESR (local testing) (see Section 6.7).

Haematology WBC* at baseline (prior to randomisation): for subjects who have discontinued oral cyclophosphamide within 2 weeks of Baseline (Visit 2) or IV cyclophosphamide within 3 weeks of Baseline (Visit 2).

* Local haematology results at baseline (prior to randomisation) are only required in the event that the central haematology results are not available in time. If a local haematology sample is required it is important that the sample for central haematology analysis is obtained at the same time.

If additional non-protocol specified laboratory assessments are performed at the institution’s local laboratory and result in a change in patient management or are considered clinically significant by the investigator (e.g., SAE or AE or dose modification) the results must be recorded in the subject’s eCRF. Refer to the SPM for appropriate processing and handling of samples to avoid duplicate and/or additional blood draws.

All blood samples should be taken prior to injection of investigational product (for dosing visits).


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Table 3 Clinical Laboratory Parameters

Routine Clinical Chemistry Routine HaematologySodium HaemoglobinPotassium Red Cell CountChloride Platelet CountCalcium ReticulocytesPhosphorous inorganic White Cell CountGlucose Neutrophil (absolute and differential [%])Protein, total Lymphocytes (absolute and differential [%])Albumin Monocytes (absolute and differential [%])CPK, total Eosinophils (absolute and differential [%])Creatinine Basophils (absolute and differential [%])Urea nitrogen Mean Corpuscular Volume (MCV)Lactic dehydrogenase Mean Corpuscular Haemoglobin (MCH)Cholesterol, total Mean Corpuscular Haemoglobin

Concentration (MCHC)High Density Lipoprotein, Cholesterol, direct Urinalysis (Screening; Visit 1)Low Density Lipoprotein, calculation Protein Qualitative

Very Low Density Lipoprotein, calculation Glucose

Bilirubin, direct Ketones

Bilirubin, indirect Occult Blood

Bilirubin, total Microscopic: WBC and RBC

Aspartate Amino Transferase Other laboratory parametersAlanine Amino Transferase Hepatitis B Surface Antigen Gamma Glutamyl Transaminase Hepatitis C antibodyAlkaline Phosphatase ANCA (MPO and PR3)Serum pregnancy test IgETroponin C-reactive protein

After Screening (Visit 1), urinalysis will be analysed using dipstick testing.

Full details of the collection and shipping requirements for the central laboratory are provided in the Central Laboratory Investigator Manual. The central laboratory will fax laboratory results to the Investigator and will transmit the results electronically to GSK.

To maintain the treatment blind, neither the site nor GSK personnel will be sent results from the central laboratory for: i) total white blood count, ii) absolute eosinophil count or iii) white blood count differentials (%), for each subject’s duration in the study for any visits post-randomisation (baseline). Sites will be sent absolute neutrophil, lymphocyte, monocyte, and basophil counts throughout the study.

ANCA (MPO and PR3) status, included as a diagnostic criterion for EGPA diagnosis (see Section 4.2) will be measured at Screening (Visit 1) and throughout the study period as indicated in the Time and Events table (Table 2). IgE, which can be elevated in patients with EGPA, will be measured at Baseline (Visit 2).


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C-reactive protein and ESR as markers of inflammation will be evaluated throughout the study period as indicated in the Time and Events table (Table 2).

6.3.11.4. Physical Examination

Physical examinations will be performed by the investigator or qualified designee at the visits specified in the Time and Events schedule (Table 2).

As a minimum, full physical examination will include assessment of the head, eyes, ears, nose, throat, skin, thyroid, neurological, lungs, cardiovascular, abdomen (liver andspleen), lymph nodes and extremities.

As a minimum, brief physical examination will include assessment of the skin, lungs, cardiovascular system, and abdomen (liver and spleen).

6.4. Health Outcomes

6.4.1. Health Outcomes Endpoints

SF-36

WPAI index.


6.4.1.1. Short Form-36 (SF-36)

The SF-36 (version 2) is a short form health survey that contains 36 questions. The SF-36 yields an eight-scale profile of functional health and well-being scores as well as psychometrically-based physical and mental health summary measures. The standard 4-week recall questionnaire will be used.


6.4.1.2. Work Productivity and Activity Impairment (WPAI) Questionnaire

The WPAI (General Health version 2.0) is a self or interviewer administered tool comprised of 6 questions which address absenteeism, presenteeism (reduced effectiveness while working), overall work productivity loss (absenteeism plus presenteeism), and activity impairment. This validated tool captures data from the past 7 days. WPAI outcomes are scored as impairment percentages, with a higher percentage indicating greater impairment and less productivity [Reily Associates, 2012].



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6.4.1.3. Use of Health Care Resources

At visits when health care resource use is being collected, as specified in the Time and Events Table (Table 2), the investigator should ask the subject if they have had any need to seek medical treatment for EGPA or an EGPA-related episode since the previous scheduled visit.

Details of all healthcare resource utilisation related to treatment for EGPA or an EGPA-related episode will be recorded by the investigator or designee in the eCRF.

6.5. Pharmacokinetics/Pharmacodynamics/Biomarker(s)

6.5.1. Pharmacokinetics

Blood samples for analysis of mepolizumab plasma concentration will be obtained as per the Time and Events table (Table 2). The date and exact time of collection for each sample will be documented in the eCRF.

Plasma analysis will be performed under the control of GSK PTS-DMPK/Scinovo, the details of which will be included in the SPM. Concentrations of mepolizumab will be determined in plasma samples using the currently approved bioanalytical methodology. Raw data will be archived at the bioanalytical site (detailed in the SPM).

Details for collection and processing of samples are provided in the SPM.

6.5.2. Pharmacodynamics

Blood eosinophil counts are included as part of the standard haematology assessments (see Table 3) performed at the visits specified in the Time and Events table (Table 2).

Blood samples will be collected for measurement of serum free and total IL-5 levels at the visits specified in the Time and Events table (Table 2). Details for sample collection and processing are provided in the SPM. Investigators and GSK study team members will blinded to IL-5 results until completion of the study.

Fractional Concentration of Exhaled Nitric Oxide (FeNO) will be measured at sites where there is local equipment available at the visits specified in the Time and Events table (Table 2).

6.6. Immunogenicity

Blood samples will be collected for the determination of anti-mepolizumab antibodies, prior to dosing and at the visits specified in the Time and Events table (Table 2).

Details for sample collection and processing are provided in the SPM.

6.7. Biomarkers

Blood samples will be collected for measurement of CRP and ESR at the visits specified in the Time and Events table (Table 2). Samples for CRP measurement will be sent to a


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central laboratory for analysis and local testing will be used for ESR samples (see Table 2; details are provided in the SPM).

6.7.1. Mechanistic/Biomarker Sub-studies

US: Samples (blood and/or sputum, and in case of relapse, where possible, tissue) for the investigator-sponsored, ‘mechanistic’ sub-study, will be collected from specified US sites only at the visits specified in the Time and Events table (Table 2). Procedures for sample management and shipment for this sub-study will be provided to the relevant sites.

Europe: Blood samples for the investigator-sponsored ‘biomarker’ sub-study will be collected from participating EU sites only at the visits specified in the Time and Events table (Table 2). Procedures for sample management and shipment for this sub-study will be provided to the relevant sites.

6.8. Pharmacogenetics Research

Information regarding genetics and pharmacogenetics (PGx) research is included in Appendix 1 (see Section 11.1).

7. DATA MANAGEMENT

For this study subject data will be entered into GSK defined eCRFs, transmitted electronically to GSK or designee and combined with data provided from other sources in a validated data system.

Management of clinical data will be performed in accordance with applicable GSK standards and data cleaning procedures to ensure the integrity of the data, e.g., removing errors and inconsistencies in the data. Adverse events and concomitant medications terms will be coded using Medical Dictionary for Regulatory Activities (MedDRA) and an internal validated medication dictionary, GSKDrug. eCRFs (including queries and audit trails) will be retained by GSK, and copies will be sent to the investigator to maintain as the investigator copy.

GSK shall ensure that Research Subject Personal Identifiable Information (PII) is key-coded to protect the privacy of Research Subjects. In particular, GSK shall ensure that the collection and/or use of patient initials and/or full dates of birth are avoided unless there is a genuine research need (e.g. in general paediatric populations) to do so or it is expressly permitted under Applicable Laws.


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8. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS

8.1. Hypotheses

The co-primary efficacy endpoints are: 1) the total accrued duration of remission, i.e., the accrued number of weeks where BVAS=0 plus prednisolone/prednisone dose 4 mg/day over the 52 week study treatment period reported as proportion of subjects achieving remission in the following categories: zero; >0 to <12 weeks; 12 to <24 weeks; 24 to <36 weeks and ≥36 weeks, and 2) the proportion of subjects who are in remission at both Weeks 36 and 48 of the study treatment period. This study is designed to test the superiority of mepolizumab plus standard of care versus placebo plus standard of care.

The analysis of the total accrued duration of remission will test the following hypotheses:

Null hypothesis: there is no difference between mepolizumab plus standard of care relative to placebo plus standard of care for the total accrued duration of remission. This means that the odds of having a longer duration of accrued remission versus a shorter duration for mepolizumab plus standard of care are the same as those for placebo plus standard of care, i.e., odds ratio is equal to one.

Alternative hypothesis: there is a difference between mepolizumab plus standard of care relative to placebo plus standard of care for the total accrued duration of remission. This means that the odds of having a longer duration of accrued remission versus a shorter duration for mepolizumab plus standard of care are not the same as those for placebo plus standard of care, i.e., odds ratio not equal to one.

The analysis of the proportion of subjects who are in remission at both Weeks 36 and 48 of the study treatment period will test the following hypotheses:

Null hypothesis: there is no difference between mepolizumab plus standard of care relative to placebo plus standard of care for the proportion of subjects who are in remission at both Weeks 36 and 48 of the study treatment period. This means that the odds of a subject being in remission at both Weeks 36 and 48 of the study treatment period versus not being in remission at both Weeks 36 and 48 of the study treatment period for mepolizumab plus standard of care are the same as those for placebo plus standard of care, i.e., odds ratio is equal to one.

Alternative hypothesis: there is a difference between mepolizumab plus standard of care relative to placebo plus standard of care for the proportion of subjects who are in remission at both Weeks 36 and 48 of the study treatment period. This means that the odds of a subject being in remission at both Weeks 36 and 48 of the study treatment period versus not being in remission at both Weeks 36 and 48 of the study treatment period for mepolizumab plus standard of care are not the same as those for placebo plus standard of care, i.e., odds ratio not equal to one.

Significance tests will be performed at the two-sided 5% level (one sided 2.5%). As both co-primary endpoints must be positive to declare success, type one error is preserved. For secondary endpoints, to control for multiple comparisons, a Sequential (Gatekeeping) testing procedure will be used as described in Section 8.3.3.1.


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8.2. Study Design Considerations

8.2.1. Sample Size Assumptions

The sample size is based on the primary efficacy endpoint, ‘1’, the total accrued duration of remission, i.e., the accrued number of weeks where BVAS=0 plus prednisolone/prednisone dose 4 mg/day over the 52 week treatment period reported as proportion of subjects achieving remission in the following categories: Zero; >0 to <12 weeks; 12 to <24 weeks; 24 to <36 weeks and ≥36 weeks.

A study with 65 subjects randomised to each treatment arm is estimated to have at least 90% power to detect a 29% difference in the proportion of subjects who achieve remission for at least 24 weeks on mepolizumab plus standard of care compared with placebo plus standard of care at the two sided 5% significance level. The power calculation has used a test for proportions and assumes that 25% of subjects on placebo will achieve accrued remission of at least 24 weeks compared with 54% on mepolizumab. This is equivalent to an odds ratio of 3.5.

While this endpoint is novel, and has not explicitly been used in clinical trials of EGPA before, it has been discussed with a number of experts in the field and an improvement of this magnitude is felt to be clinically meaningful.

There is little previous data on the duration of accrued remission; however the estimate of 25% of placebo subjects achieving ≥24 weeks is felt by clinical experts to be reasonable for this population. The following section (Section 8.2.2) illustrates the power achievable with the proposed sample size under various different assumptions of placebo response and effect sizes.

For the co-primary endpoint ‘2’, the proportion of subjects who are in remission at both Weeks 36 and 48 of the study treatment period, it is similarly assumed that 25% of subjects receiving placebo achieve remission at both time points, while 54% of mepolizumab subjects achieve remission at both time points. Under these assumptions, the previously described calculations for accrued remission are applicable to the second co-primary endpoint.

8.2.2. Sample Size Sensitivity

If either the actual percentage of patients on placebo with accrued duration of remission ≥24 weeks or the impact of mepolizumab is different from the values assumed in Section 8.2.1, the power to detect a change in accrued duration of remission will be affected. Similarly, if either the actual percentage of patients on placebo that are in remission at Weeks 36 and 48 or the impact of mepolizumab is different from the values assumed in Section 8.2.1, the power to detect a change in the proportion of subjects that are in remission at both time points will be affected..

Table 4 illustrates the estimated power which would be obtained with different combinations of the percentage of subjects on placebo plus standard of care and mepolizumab plus standard of care with reaching success, as defined in one case as the percentage of subjects obtaining accrued duration of remission ≥24 weeks, and in the


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other case as the percentage of subjects in remission at Weeks 36 and 48, and assuming a sample size of 65 randomised subjects. This uses a test for proportions - the actual power obtained using a logistic proportional odds model analysis, or the logistic regression, should be higher, but requires stronger assumptions, and the test for proportions should give a conservative estimate.

Table 4 Power for Various Placebo and Mepolizumab Success Rates

Percent Success

(For either Subjects with Accrued Remission ≥24 weeks or Subjects in Remission at Weeks 36

and 48)

Placebo Mepolizumab Difference Odds Ratio Power

15% 44% 29% 4.5 93%

20% 49% 29% 3.8 91%

25% 54% 29% 3.5 90%

30% 59% 29% 3.4 89%

16% 40% 24% 3.5 82%

40% 70% 30% 3.5 91%

72% 90% 18% 3.5 66%

8.2.3. Sample Size Re-estimation

No sample size re-estimation is planned.

8.3. Data Analysis Considerations

All pre-specified analyses will be described in a full Reporting and Analysis Plan (RAP) which will be finalised prior to un-blinding.

The study will be unblinded once the final subject has completed the Week 52 visit plus the follow-up visit, all queries for data collected up to this time are resolved and the clinical study database is frozen.

8.3.1. Analysis Populations

Intent-to-Treat Population:

The intent-to-treat (ITT) population will consist of all subjects who are randomised and who receive at least one dose of trial medication. Randomised subjects will be assumed


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to have received study treatment unless definitive evidence to the contrary exists. This will constitute the primary population for all analyses of efficacy measures.

Per Protocol Population:

The Per Protocol (PP) population will consist of all subjects in the Intent-to-Treat population not identified as full protocol deviators with respect to criteria that are considered to impact the primary efficacy analysis. The decision to exclude a subject from the PP population or exclude part of their data from the PP population analyses will be made prior to breaking the blind. The PP population will be used for a supplementary analysis of the primary endpoint.

Safety Population:

It is expected that the ITT population will be used for the analyses of safety measures. However if a significant number of patients receive the wrong study treatment for the majority of their time on treatment a Safety population may be defined, where the treatment group a subject is assigned to may differ from that in the ITT population.

PK Population:

The PK population is defined as all subjects in the ITT population who received at least one dose of study medication for whom at least a PK sample was obtained, analysed and was measurable. This will be the primary population for assessing PK.

PD Population:

The PD population is defined as all subjects in the ITT population who received at least one dose of study treatment and who also have a baseline PD measurement and at least one post-treatment PD measurement. This will be the primary population for assessing PD.

8.3.2. Analysis Data Sets

Details of the derived data in analysis datasets to be created will be given in the RAP.

8.3.3. Treatment Comparisons

All treatment comparisons are between mepolizumab plus standard of care and placebo plus standard of care.

8.3.3.1. Primary Comparisons of Interest

The primary treatment comparison will be mepolizumab plus standard of care versus placebo plus standard of care for the primary efficacy endpoints of accrued remission and proportion of subjects who are in remission at both Week 36 and 48. These will be performed for the primary analysis population: the ITT population.


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8.3.3.2. Other Comparisons of Interest

Other comparisons of interest are mepolizumab versus placebo for each of the 3 secondary endpoints. In order to make inferences for the pre-defined secondary endpoints while controlling the overall type I error, multiplicity across these comparisons will be controlled using a closed testing procedure where the secondary endpoints will be nested under the primary efficacy endpoint, followed by a further hierarchical procedure within the secondary endpoints, in the order of: i) time to relapse, ii) prednisolone/prednisone dose followed by, iii) proportion of subjects who achieve remission within the first 24 weeks of the study and then remain in remission. That is:

statistical testing of the primary endpoints will initially be performed, and if these are significant at the two-sided 5% level,

then the endpoint of time to relapse will be tested and if this is significant at the two-sided 5% level,

then the endpoint of prednisolone/prednisone dose will be tested and if this is significant at the two-sided 5% level,

then the endpoint of the proportion of subjects who achieve remission within the first 24 weeks of the study and then remain in remission will be tested.

8.3.4. Interim Analysis

An Independent Data Monitoring Committee (IDMC) will be utilized in this study to ensure external objective review of safety issues in order to protect the ethical and safety interests of subjects and to protect the scientific validity of the study (see Section 9.8). The schedule of any planned interim analysis and the analysis plan for IDMC review is described in the charter, which is available upon request.

Only members of the IDMC and the independent statistical centre responsible for preparing results for the IDMC will have access to unblinded randomisation codes and the interim results. The study statistician, investigators, and GSK personnel involved in monitoring of the study will not be unblinded until the study completes as planned or is terminated.

It is not planned to stop the study early for efficacy reasons, so this will have no impact on the final type I error.

8.3.5. Key Elements of Analysis Plan

8.3.5.1. Efficacy Analyses

Primary Efficacy Endpoints

The co-primary efficacy endpoints are:

1. The total accrued duration of remission (co-primary endpoint ‘1’), i.e., the accrued number of weeks where BVAS=0 plus prednisolone/prednisone dose 4 mg/day over the 52 week study treatment period reported as proportion of subjects achieving


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remission in the following categories: Zero; >0 to <12 weeks; 12 to <24 weeks; 24 to <36 weeks and ≥36 weeks, and

2. The proportion of subjects who are in remission at both Weeks 36 and 48 of the study treatment period (co-primary endpoint ‘2’).

The primary analysis of co-primary endpoint ’1’ will use a logistic proportional odds regression model for ordered categorical data for the proportion of subjects who achieve remission categorised, as above, for the ITT population. Baseline covariates to be included in the model are: i) baseline steroid dose, ii) ANCA status (due to potential for association with risk of relapse [Sablé-Fourtassou, 2005; Sinico, 2005]) and iii) region (Japan versus rest-of-world for administrative reasons).

The comparison of mepolizumab with placebo will be expressed as an odds ratio. The model will be used to estimate the odds ratio for the treatment difference and associated p-value and 95% confidence limit.

The primary analysis of co-primary endpoint ’2’ will use a logistic regression model, using the same covariates as those used for the primary endpoint ‘1’.


Evaluating Model Assumptions

The logistic proportional odds regression model for ordered categorical data assumes that the odds are proportional. This assumption will be assessed with a Score Test for the Proportional Odds Assumption. If this test is significant, analysis using a Wilcoxon-Mann-Whitney test will be conducted, adjusting for strata (van Elteren statistic). For this analysis, baseline steroid dose will be categorized as ’low’ versus ‘high’.

Analyses will be replicated without baseline covariates in order to assess their impact on the conclusions.

A sensitivity analysis will be performed, using the actual accrued duration of remission in weeks, rather than in categories, using a Wilcoxon-Mann-Whitney test.

Missing Data in Primary Endpoints

For both of the co-primary endpoints, in the event of a missing value, the last available observation will be carried forward until a value is observed supporting a change in state. For example, if a subject is in remission he/she will be assumed to still be in remission until there are data to indicate he/she is not in remission. Similarly, if a subject is not in remission, it will be assumed the subject is not in remission until there are data to indicate that he/she is in remission.

In general, as BVAS scores are scheduled on a monthly basis, it assumed for purpose of determining remission that the score has not changed until a new BVAS score has been calculated.


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For subjects withdrawing prematurely from treatment it will be assumed that they are no longer in remission over the remainder of the planned observation period of the study.

Sensitivity analyses to evaluate the assumption that subjects withdrawing prematurely from study treatment are no longer in remission will be performed for the accrued duration of remission as follows:

a. Analyses will be replicated using observed data for subjects who withdraw prematurely from study treatment and continue to be followed in the observation period to determine duration of remission. For subjects who withdraw prematurely from the study and are no longer under observation, analyses will be replicated assuming post-withdrawal values are ‘not in remission’.

b. Analyses will be replicated assuming placebo subjects who withdraw prematurely from study treatment are in remission for various percentages of time post-treatment to determine what, if any, assumption around missing data would result in a non-significant p-value.

Sensitivity analyses evaluating the assumption that subjects withdrawing prematurely from study treatment are no longer in remission will be performed for the proportion of subjects who are in remission at both Weeks 36 and 48 of the study treatment period as follows:

a. Analyses will be replicated using observed data for subjects who withdraw prematurely from study treatment and continued to be followed in the observation period to determine remission at Weeks 36 and 48. For subjects who withdraw prematurely from the study and are no longer under observation, analyses will be replicated assuming post-withdrawal values at Weeks 36 and 48 are ‘not in remission’.

b. Analyses will be replicated assuming various percentages of placebo subjects withdrawing prematurely from study treatment are in remission at Weeks 36 and 48, to determine what, if any, assumption around missing data would result in a non-significant p-value.

For both co-primary endpoints, sensitivity analyses will be conducted evaluating alternatives to the assumption that the last available observation will be carried forward until a value is observed supporting a change in state; alternative assumptions that will be evaluated are:

a. Various percentages of on treatment missing values for placebo subjects are always in remission

b. Various percentages of on treatment missing values for mepolizumab subjects are always not in remission.

A supporting analysis of the PP population will also be performed.

Subgroups and covariates in Primary Endpoints


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Interactions of treatment with subgroups and covariates of specific clinical interest will also be explored; these will be defined in the RAP. Note, this will include investigation of the subgroup of subjects with biopsy-proven EGPA.

A sensitivity analysis may be performed, using the actual accrued duration of remission in weeks, rather than in categories, using a Wilcoxon-Mann-Whitney test.

Secondary Endpoints

i. Time to first confirmed EGPA relapse.

ii. The proportion of subjects with an average daily prednisolone/prednisone dose during the last 4 weeks of the study treatment period (48 through 52) in each of the following categories: Zero; >0 to ≤4.0 mg; >4.0 to ≤7.5 mg and >7.5 mg.

iii. The proportion of subjects who achieve remission (BVAS=0 and prednisolone/prednisone dose ≤4 mg/day) within the first 24 weeks of the study and then remain in remission for the remainder of the treatment period.

Time to first confirmed EGPA relapse will be analysed using a Cox proportional hazards regression model allowing for similar covariates as those specified for analysis of the primary endpoints. The hazard ratio will be derived along with 95% confidence limits. Cumulative event rates will be calculated using the Kaplan-Meier method. The proportional hazards assumption will be assessed, with details to be provided in the RAP. If the validity of the proportional hazards assumption is not acceptable, the treatment effect will be assessed using the Log-Rank Test.

The analysis will be based on the time to observed relapse. In the event that a subject withdraws prematurely from study treatment or from the study, then the event time for that subject will be censored at the time of withdrawal from treatment.

Sensitivity analyses will be conducted assuming:

a. Subjects who withdraw prematurely from study treatment had an event at the time of withdrawal.

b. Subjects who withdraw prematurely from study treatment due to a treatment related reason had an event at the time of treatment withdrawal.

c. Subjects who withdraw prematurely from study treatment and continue to be followed in the study will be deemed to have an event at the time an event is observed. As in the planned analysis for time to observed relapse, subjects that withdraw from the study are censored at the time of withdrawal.

The proportion of subjects with an average daily prednisolone/prednisone dose during the last 4 weeks of the treatment period (Weeks 48 through 52) will be analysed in the same way as the primary endpoint, i.e. using a logistic proportional odds regression model using similar covariates. For subjects who withdraw prematurely from study treatment it will be assumed that their final average daily OCS dose was the average during the 4 weeks immediately following the last dose of study medication. If this is not available,


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then it will be assumed that their final average daily OCS dose was the average of the last 4 weeks available. Sensitivity analysis will be conducted as follows:

a. The analysis will be replicated using observed data for subjects who prematurely withdraw from treatment, assuming that their final average daily OCS dose was the average during the last 4 weeks of observation while still in the study

b. The analysis will be replicated with missing week 48 to 52 OCS dose decreasedfrom the value used in the primary analysis for placebo and increased from the value used in the primary analysis in mepolizumab in order to determine a level where the p-value changes from significant to non-significant.

The proportion of subjects who achieve remission within the first 24 weeks of the study and then remain in remission for the remainder of the treatment period will be analysed using a logistic regression model, using the same covariates as those used for the co-primary endpoints. For subjects who withdraw prematurely from study treatment it will be assumed that they are no longer in remission after treatment withdrawal. Sensitivity analyses will be conducted as follows:

a. The analysis will be replicated using observed data for subjects who prematurely withdraw from study treatment to determine remission and assuming that all unobserved data have the value of ‘not in remission’.

b. The analysis will be replicated assuming various percentages of placebo subjects who withdraw prematurely from study treatment are in remission for the remainder of the study, to determine what, if any, assumption around missing data would result in a non-significant p-value.

Other Efficacy Endpoints

Full details of the analyses to be performed on all efficacy endpoints will be given in the RAP.

8.3.5.2. Safety Analyses

AEs will be coded using the MedDRA coding dictionary and summarised by preferred term and treatment group. Adverse events and SAEs occurring pre-treatment, during active treatment and post-treatment will be summarised separately. Separate summaries will be provided for all AEs, investigational product-related AEs, SAEs, events of special interest (including systemic [non-IgE-mediated] and hypersensitivity [IgE-mediated] reactions and local site reactions) and for AEs leading to permanent discontinuation of investigational product or withdrawal from the study. All laboratory parameters for clinical chemistry and haematology will be summarised and tabulated.

Each ECG parameter at every assessed time point will be summarised using summary statistics. Summary statistics of QT interval corrected for heart rate according to Fridericia’s formula (QTcF) and QT interval corrected for heart rate according to Bazett’s formula (QTcB) as well as change from baseline value will be presented by visit.


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Summary statistics of pulse rate and systolic and diastolic blood pressure will be presented by visit.

Immunogenicity will be summarised using appropriate descriptive statistics.

8.3.5.3. Health Outcomes Analyses

Full details of the analyses to be performed on all health outcomes endpoints will be given in the RAP.

8.3.5.4. Pharmacokinetic Analyses

Blood samples will be collected to determine mepolizumab plasma concentrations (refer to Time & Events table; Table 2). Sparse blood sampling is being implemented in this study. The mepolizumab plasma concentrations from this study will be evaluated using the population PK model developed based on previous mepolizumab studies conducted in different populations including healthy and asthmatic subjects. The analysis will be conducted using for example NONMEM 7 and will allow the determination for example of the population and/or individual systemic exposure, volume of distribution, clearance and the maximum concentration (Cmax) as well as characterise the between- and within-subject variability. The effect of subjects’ characteristics such as, for example, bodyweight, age, sex, serum creatinine on mepolizumab systemic exposure will also be explored in order to explain the inter-subject variability in drug exposure. Pharmacokinetic data will be presented in graphical and/or tabular form and will be summarized descriptively.

No statistical analysis of PK data will be carried out.

Further details of the analysis will be described in the RAP.

8.3.5.5. Pharmacodynamic Analyses

The PD data will be presented in graphical and/or tabular form and will be summarized descriptively.

8.3.5.6. Mechanistic/Biomarker Sub-studies

Specific details of the planned analyses will be outlined in the individual protocols and/or analysis plans for the mechanistic/biomarker sub-studies. Results of these analyses will be included in a dedicated report separate from the clinical study report.

8.3.5.7. Genetics/Pharmacogenetics Analyses

If genetics/pharmacogenetics analysis is warranted, then a separate research analysis plan will be drafted. See Appendix 1 (Section 11.1 for details about the Genetics/Pharmacogenetics Analysis Plan).


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9. STUDY CONDUCT CONSIDERATIONS

9.1. Posting of Information on Publicly Available Clinical Trial Registers

Study information from this protocol will be posted on publicly available clinical trial registers before enrolment of subjects begins.

9.2. Regulatory and Ethical Considerations, Including the Informed Consent Process

Prior to initiation of a study site, GSK will obtain favourable opinion/approval from the appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical Practice (GCP) and applicable country-specific regulatory requirements.

The study will be conducted in accordance with all applicable regulatory requirements.

The study will be conducted in accordance with ICH GCP, all applicable subject privacy requirements, and the ethical principles that are outlined in the Declaration of Helsinki2008, including, but not limited to:

Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and favourable opinion/approval of study protocol and any subsequent amendments.

Subject informed consent.

Investigator reporting requirements.

GSK will provide full details of the above procedures, either verbally, in writing, or both.

Written informed consent must be obtained from each subject prior to participation in the study.

In approving the clinical protocol the IEC/IRB and, where required, the applicable regulatory agency are also approving the optional assessments (e.g., genetic/PGx assessments described in Appendix 1; see Section 11.1), unless otherwise indicated. Where permitted by regulatory authorities, approval of the optional assessments can occur after approval is obtained for the rest of the study. If so, then the written approval will clearly indicate approval of the optional assessments is being deferred and the study, except for the optional assessments, can be initiated. When the optional assessments are not approved, then approval for the rest of the study will clearly indicate this and therefore, the optional assessments will not be conducted.

9.3. Quality Control (Study Monitoring)

In accordance with applicable regulations, GCP, and GSK procedures, GSK monitors will contact the site prior to the start of the study to review with the site staff the protocol, study requirements, and their responsibilities to satisfy regulatory, ethical, and GSK


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requirements. When reviewing data collection procedures, the discussion will include identification, agreement and documentation of data items for which the CRF will serve as the source document.

GSK will monitor the study to ensure that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and anyother study agreements, GCP, and all applicable regulatory requirements.

The investigator and the head of the medical institution (where applicable) agrees to allow the monitor direct access to all relevant documents.

9.4. Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK may conduct a quality assurance assessment and/or audit of the site records, and the regulatory agencies may conduct a regulatory inspection at any time during or after completion of the study. In the event of an assessment, audit or inspection, the investigator (and institution) must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all relevant documents and to allocate their time and the time of their staff to discuss the conduct of the study, any findings/relevant issues and to implement any corrective and/or preventative actions to address any findings/issues identified.

9.5. Study and Site Closure

Upon completion or termination of the study, the GSK monitor will conduct site closure activities with the investigator or site staff (as appropriate), in accordance with applicable regulations, GCP, and GSK Standard Operating Procedures.

GSK reserves the right to temporarily suspend or terminate the study at any time for reasons including (but not limited to) safety issues, ethical issues, or severe non-compliance. If GSK determines that such action is required, GSK will discuss the reasons for taking such action with the investigator or head of the medical institution (where applicable). When feasible, GSK will provide advance notice to the investigator or head of the medical institution of the impending action.

If a study is suspended or terminated for safety reasons, GSK will promptly inform all investigators, heads of the medical institutions (where applicable),and/or institutions conducting the study. GSK will also promptly inform the relevant regulatory authorities of the suspension/termination along with the reasons for such action. Where required by applicable regulations, the investigator or head of the medical institution must inform the IRB/IEC promptly and provide the reason(s) for the suspension/termination.


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9.6. Records Retention

Following closure of the study, the investigator or head of the medical institution (where applicable) must maintain all site study records (except for those required by local regulations to be maintained elsewhere) in a safe and secure location. The records must be easily accessible when needed (e.g., for a GSK audit or regulatory inspection) and must be available for review in conjunction with assessment of the facility, supporting systems, and relevant site staff.

Where permitted by local laws/regulations or institutional policy, some or all of the records may be maintained in a format other than hard copy (e.g., microfiche, scanned, electronic); however, caution must be exercised before such action is taken. The investigator must ensure that all reproductions are legible and are a true and accurate copy of the original. In addition, they must meet accessibility and retrieval standards, including regeneration of a hard copy, if required. The investigator must also ensure that an acceptable back-up of the reproductions exists and that there is an acceptable quality control procedure in place for creating the reproductions.

GSK will inform the investigator of the time period for retaining the site records in order to comply with all applicable regulatory requirements. The minimum retention time will meet the strictest standard applicable to a particular site, as dictated by local laws/regulations, GSK standard operating procedures, and/or institutional requirements.

The investigator must notify GSK of any changes in the archival arrangements, including, but not limited to archival of records at an off-site facility or transfer of ownership of the records in the event that the investigator is no longer associated with the site.

9.7. Provision of Study Results to Investigators, Posting of Information on Publicly Available Clinical Trials Registers and Publication

Where required by applicable regulatory requirements, an investigator signatory will be identified for the approval of the clinical study report. The investigator will be provided reasonable access to statistical tables, figures, and relevant reports and will have the opportunity to review the complete study results at a GSK site or other mutually-agreeable location.

GSK will also provide the investigator with the full summary of the study results. The investigator is encouraged to share the summary results with the study subjects, as appropriate.

GSK will provide the investigator with the randomisation codes for their site only after completion of the full statistical analysis.

The results summary will be posted to the Clinical Study Register no later than eight months after the final primary completion date, the date that the final subject was examined or received an intervention for the purposes of final collection of data for the primary outcome. In addition, a manuscript will be submitted to a peer reviewed journal for publication no later than 18 months after the last subject’s last visit (LSLV). When


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manuscript publication in a peer reviewed journal is not feasible, a statement will be added to the register to explain the reason for not publishing.

A manuscript will be progressed for publication in the scientific literature if the results provide important scientific or medical knowledge.

9.8. Independent Data Monitoring Committee (IDMC)

An IDMC will be utilised in this study to ensure external objective medical and/or statistical review of safety and/or efficacy issues in order to protect the ethical and safety interests of subjects and to protect the scientific validity of the study. The schedule of any planned interim analysis and the analysis plan for IDMC review is described in the charter, which is available upon request.


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Baldini C, Talarico R, Della Rossa A, Bombardieri S. Clinical manifestations and treatment of Churg-Strauss Syndrome. Rheum Dis Clin N Am 2010;36:527-543.

Basu N, Watts R, Bajema I, et al. EULAR points to consider in the development of classification and diagnostic criteria in systemic vasculitis. Ann Rheum Dis 2010;69:1744-1750.

Clutterbuck E, Hirst E, Sanderson C. Human interleukin-5 (IL-5) regulates the production of eosinnophils in human bone marrow cultures: comparison and interaction with IL-1, IL-3, IL-6 and GMCSF. Blood 1989;73:1504-1512.

Dunogué B, Pagnoux C, Guillevin L. Churg-Strauss Syndrome: Clinical symptoms, complementary investigations, prognosis and outcome, and treatment. Semin Respir Crit Care Med 2011;32:298–309.

Exley AR, Bacon PA, Luqmani RA, et al. Examination of disease severity in systemic vasculitis from the novel perspective of damage using the vasculitis damage index (VDI). Br J Rheumatol 1998;37:57–63.

Gevaert P, Lang-Loidolt D, Lackner A, et al. Nasal IL-5 levels determine the response to anti-IL-5 treatment in patients with nasal polyps. J Allergy Clin Immunol2006;118:1133-41.

GlaxoSmithKline Document Number CM2003/00010/08 Mepolizumab (SB-240563) Investigator’s brochure. Version 12, Report Date 08 Apr 2013.

Haldar P, Brightling C, Hargadon B, et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med 2009;360:973-984.

Hellmich B, Csernok E, Gross WL. Proinflammatory cytokines and autoimmunity in Churg-Strauss Syndrome. Ann NY Acad Sci 2005;1051:121-131.

Hellmich B, Ehlers S, Csernok E, Gross W. Update on the pathogenesis of Churg-Strauss syndrome. Clin Exp Rheumatol 2003;21:S69-77.

Hellmich B, Flossmann O, Gross WL, et al. EULAR recommendations for conducting clinical studies and/or clinical trials in systemic vasculitis: focus on anti-neutrophil cytoplasm antibody-associated vasculitis. Ann Rheum Dis 2007;66:605–617.

Holle J, Moosig F, Gross WL. Diagnostic and therapeutic management of Churg-Strauss. Expert Rev Clin Immunol 2009;5:813-823.


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Hopkins C, Gillett S, Slack R, Lund V, Browne JP. Psychometric validity of the 22-item Sinonasal Outcome Test. Clin Otolaryngol 2009;34:447-454.

James LP, Letzig L, Simpson PM, et al. Pharmacokinetics of acetaminophen-protein adducts in adults with acetaminophen overdose and acute liver failure. Drug Metab Dispos 2009;37:1779-1784.

Juniper EF, O'Byrne PM, Ferrie PJ, et al. Measuring asthma control: clinic questionnaire or daily diary? Am J Respir Crit Care Med 2000;163:1330-1334

Juniper EF, O'Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of a questionnaire to measure asthma control. Eur Respir J 1999;14:902-907.

Kahn J, Grandpeix-Guyodo C, Marroun I, et al. Sustained response to mepolizumab in refractory Churg-Strauss syndrome. J Allergy Clin Immunol 2010;125:267-270.

Keogh KA, Specks U. Churg-Strauss Syndrome. Semin Respir Crit Care Med 2006;27:148-157.

Kiene M, Csernok E, Muller A, et al. Elevated interleukin-4 and interleukin-13 production by T cell lines from patients with Churg-Strauss Syndrome. Arthritis Rheum 2001;44:469-473.

Kim S, Marigowda G, Oren E, Israel E, Wechsler M. Mepolizumab as a steroid-sparing treatment option in patients with Churg-Strauss Syndrome. J Allergy Clin Immunol 2010;125:1336-43.

Kim YJ, Prussin C, Martin B, et al. Rebound eosinophilia after treatment of hypereosinophilic syndrome and eosinophilic gastroenteritis with monoclonal anti–IL-5 antibody SCH55700. J Allergy Clin Immunol 2004;114:1449-55.

Lane SE, Watts RA, Scott DG. Epidemiology of systemic vasculitis. Curr Rheumatol Reports 2005;7:270-275.

Le Gal F, Gordien E, Affolabi D, et al. Quantification of hepatitis delta virus RNA in serum by consensus real-time PCR indicates different patterns of virological response to interferon therapy in chronically infected patients. Clin Microbiol 2005;43(5):2363–2369.

Lopez A, Sanderson C, Gamble J, et al. Recombinant human interleukin 5 is a selective activator of human eosinophil function. J Exp Med 1988;167:219-224.

Luqmani RA, Bacon PA, Moots RJ, et al. Birmingham Vasculitis Activity Score (BVAS) in systemic necrotising vasculitis. Q J Med 1994;87:671-678.

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Masi AT, Hunder GG, Lie JT, et al. The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis). Arthritis Rheum 1990;33:1094-1100.

Moosig F, Gross WL, Herrmann K, Bremer JP. Targeting interleukin-5 in refractory and relapsing Churg–Strauss Syndrome. Ann Int Med 2011;155:341-343.

Mukhtyar C, Guillevin L, Cid MC, et al. EULAR recommendations for the management of primary small and medium vessel vasculitis. Ann Rheum Dis 2009a;68:310-317.

Mukhtyar C, Lee L, Brown D, Carruthers D, Dasgupta B, Dubey S. Modification and validation of the Birmingham Vasculitis Activity Score (version 3). Ann Rheum Dis 2009b;68:1827-1832.

Nair P, Pizzichini M, Kjarsgaard M, et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med 2009;360:985-993.

Pagnoux C, Guilpain P, Guillevin L. Churg-Strauss syndrome. Curr Opin Rheumatol 2007;19:25-32.

Pavord ID, Korn S, Howarth P, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet 2012;380:651–59.

Poetker DM, Reh, DD. A comprehensive review of the adverse effects of systemic corticosteroids. Otolaryngol Clin N Am 2010;43:753–768

Reily Associates. Scoring of WPAI. Available at: http://www.reillyassociates.net/WPAI_Scoring.html. Accessed on May 16, 2012.

Rothenberg ME, Hogan SA. The eosinophil. Annu Rev Immunol 2006;24:147–74.

Rothenberg ME, Klion AD, Roufosse FE, et al. Treatment of patients with hypereosinophilic syndrome with mepolizumab. N Engl J Med 2008;358:1215-1228.

Sablé-Fourtassou R, Cohen P, Mahr A, et al. Antineutrophil cytoplasmic antibodies and the Churg-Strauss syndrome. Ann Intern Med 2005;143:632-8.

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Shonermarck U, Csernok E, Trabandt A, Hansen H, Gross WL. Circulating cytokines and soluble CD23, CD26 and CD30 in ANCA-associated vasculitides. Clin Exp Rheumatol 2000;18:457-463.

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11. APPENDICES

11.1. Appendix 1: Genetics/Pharmacogenetics Research

Genetics/Pharmacogenetics – Background

Genetics is the study of variability in traits due to hereditary factors in populations. Pharmacogenetics (PGx) is the study of variability in drug response due to hereditary factors in populations. There is increasing evidence that an individual's genetic background (i.e., genotype) may impact not only disease susceptibility and prognosis but also the pharmacokinetics (absorption, distribution, metabolism, elimination), pharmacodynamics (relationship between concentrations and pharmacologic effects or the time course of pharmacologic effects) and/or clinical outcome (in terms of efficacy and/or safety and tolerability). Some reported examples of PGx associations with safety/adverse events include:

Drug Disease Gene Variant OutcomeAbacavir HIV

[Hetherington,2002; Mallal, 2002; Mallal, 2008]

HLA-B* 57:01 (Human Leukocyte Antigen B)

Carriage of the HLA-B*57:01 variant has been shown to increase a patient's risk for experiencing hypersensitivity to abacavir. Prospective HLA-B*57:01 screening and exclusion of HLA-B*57:01 positive patients from abacavir treatment significantly decreased the incidence of abacavir hypersensitivity. Treatment guidelines and abacavir product labeling in the United States and Europe now recommend (US) or require (EU) prospective HLA-B*57:01 screening prior to initiation of abacavir to reduce the incidence of abacavir hypersensitivity. HLA-B*57:01screening should supplement but must never replace clinical risk management strategies for abacavir hypersensitivity.

Carbamazepine

Seizure, Bipolar disorders & Analgesia Chung, 2010; Ferrell, 2008

HLA-B*15:02 Independent studies indicated that patients of East Asian ancestry who carry HLA-B*15:02are at higher risk of Stevens-Johnson Syndrome and toxic epidermal necrolysis. Regulators, including the US FDA and the Taiwanese TFDA, have updated the carbamazepine drug label to indicate that patients with ancestry in genetically at risk populations should be screened for the presence of HLA-B*15:02 prior to initiating treatment with carbamazepine.


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Irinotecan Cancer [Innocenti,2004;Liu, 2008; Schulz, 2009]

UGT1A1*28 Variations in the UGT1A1 gene can influence a patient’s ability to break down irinotecan, which can lead to increased blood levels of the drug and a higher risk of side effects. A dose of irinotecan that is safe for one patient with a particular UGT1A1 gene variation might be too high for another patient without this variation, raising the risk of certain side-effects that include neutropenia following initiation of Irinotecan treatment. The irinotecan drug label indicates that individuals who have two copies of the UGT1A1*28 variant are at increased risk of neutropenia. A genetic blood test is available that can detect variations in the gene.

A key component to successful genetic and PGx research is the collection of samples during the conduct of clinical studies.

Eosinophilic Granulomatosis with Polyangiitis (EGPA) is a rare disease with a complex genetic component. Many of the genetic studies in EGPA patients have been limited by the relatively small subject numbers available. Some genetic associations with susceptibility to disease have been replicated in multiple studies (e.g., HLA effects), while other genetic associations with susceptibility have not. Some genetic associations with varied pathology have been identified in patients with EGPA or related pathology. The pathogenesis of ANCA-associated vasculitis may have a genetic component. In one study, strong genetic associations were found between anti-proteinase 3 ANCA and HLA-DP, SERPINA1 and PRTN3. HLA-DQ gave evidence of association with microscopic polyangiitis risk (myeloperoxidase-ANCA positivity) [Lyons, 2012]. Additional genetic variants in IL10 have been identified associated with more severe vasculitis in ANCA-negative EGPA patients [Wieczorek, 2008]. Recent work suggests that overproduction of IL-5 (as a consequence of the T cell receptor gene rearrangement) could be involved in CSS pathogenesis [Horai, 2011].

Collection of whole blood samples, even when no a priori hypothesis has been identified, may enable PGx analysis to be conducted if at any time it appears that there is a potential unexpected or unexplained variation in response to mepolizumab or other study treatment. Although no genetic variants have been reported that are associated with mepolizumab response, the association of genetic variants in TPMT with response to azathioprine is well-recognized with a recommendation for determination of functional alleles by genotyping or phenotyping prior to start of azathioprine treatment in the FDA approved package insert. Genetic variants in ITPA and ATIC have been identified that are associated with methotrexate response [Hinks, 2011]. PGx research recently identified an association between genetic variants in the gene GLCCI1 and response to glucocorticoid therapy in asthma patients [Tantisira, 2011].


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Genetic/Pharmacogenetic Research Objectives

The objective of the potential Genetic research (if suggested by variation in pathologic status in EGPA patients enrolled in this clinical study) is to investigate a possible genetic relationship with EGPA severity, progression, or symptoms.

The objective of the PGx research (if there is a potential unexpected or unexplained variation) is to investigate a relationship between genetic factors and response to mepolizumab or other treatment during the study. If at any time it appears there is potential variability in response in this clinical study or in a series of clinical studies with mepolizumab and other treatment during the study,the following objectives may be investigated – the relationship between genetic variants and study treatment with respect to:

Pharmacokinetics and/or pharmacodynamics of study treatment

Safety and/or tolerability

Efficacy

Study Population

Any subject who is enrolled in the clinical study, can participate in Genetic or PGx research. Any subject who has received an allogeneic bone marrow transplant must be excluded from the Genetic or PGx research.

Subject participation in the Genetic or PGx research is voluntary and refusal to participate will not indicate withdrawal from the clinical study or result in any penalty or loss of benefits to which the subject would otherwise be entitled.

Study Assessments and Procedures

Blood samples can be taken for Deoxyribonucleic acid (DNA) extraction and used in Genetics or PGx assessments.

If taking blood samples: in addition to any blood samples taken for the clinical study, a whole blood sample (~6 mL) will be collected for the Genetics/PGx research using a tube containing EDTA. It is recommended that the blood sample be taken at the first opportunity after a subject has been randomised and provided informed consent for PGx research, but may be taken at any time while the subject is participating in the clinical study.

The Genetics/PGx sample is labelled (or “coded”) with a study specific number that can be traced or linked back to the subject by the investigator or site staff. Coded samples do not carry personal identifiers (such as name or social security number). The blood sample is taken on a single occasion unless a duplicate sample is required due to inability to utilise the original sample.

The DNA extracted from the blood sample may be subjected to sample quality control analysis. This analysis will involve the genotyping of several genetic markers to confirm


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the integrity of individual samples. If inconsistencies are noted in the analysis, then those samples may be destroyed.

The need to conduct Genetic or PGx analysis may be identified after a study (or a set of studies) of mepolizumab has been completed and the clinical study data reviewed. In some cases, the samples may not be studied (e.g., no questions are raised about how people respond to mepolizumab or other study treatment).

Samples will be stored securely and may be kept for up to 15 years after the last subject completes the study or GSK may destroy the samples sooner. GSK or those working with GSK (for example, other researchers) will use samples collected from the study for the purpose stated in this protocol and in the informed consent form.

Subjects can request their sample to be destroyed at any time.

Subject Withdrawal from Study

If a subject who has consented to participate in Genetics or PGx research withdraws from the clinical study for any reason other than being lost to follow-up, the subject will be given a choice of one of the following options concerning the Genetics/PGx sample, if already collected:

Continue to participate in the Genetics or PGx research with the Genetics/PGx sample retained for analysis

Withdraw from the Genetics or PGx research and destroy the Genetics/PGx sample

If a subject withdraws consent for Genetics or PGx research or requests sample destruction for any reason, the investigator must complete the appropriate documentation to request sample destruction within the timeframe specified by GSK and maintain the documentation in the site study records. The investigator should forward the Genetics/Pharmacogenetic Sample Destruction Request Form to GSK as directed on the form. This can be done at any time when a subject wishes to withdraw from the Genetic or PGx research or have their sample destroyed whether during the study or during the retention period following close of the main study.

Screen and Baseline Failures

If a blood sample for Genetics or PGx research has been collected and it is determined that the subject does not meet the entry criteria for participation in the clinical study, then the investigator should instruct the participant that their Genetics/PGx sample will be destroyed. No forms are required to complete this process as it will be completed as part of the consent and sample reconciliation process. In this instance a sample destruction form will not be available to include in the site files.

Genetics or Pharmacogenetics Analyses

1. Specific genes may be studied that encode the drug targets, or mechanism of action pathways, drug metabolizing enzymes, drug transporters or which may underpin


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adverse events, disease risk or drug response. These candidate genes may include a common set of ADME (Absorption, Distribution, Metabolism and Excretion) genes that are studied to determine the relationship between gene variants or treatment response and/or tolerance.

In addition, continuing research may identify other enzymes, transporters, proteins or receptors that may be involved in response to mepolizumab or other study treatment. The genes that may code for these proteins may also be studied.

2. Genome-wide scans involving a large number of polymorphic markers (e.g., single nucleotide polymorphisms) at defined locations in the genome, often correlated with a candidate gene locus, or gene expression or function, may be studied to determine the relationship between genetic variants and treatment response or tolerance. This approach is often employed when a definitive candidate gene(s) does not exist and/or the potential genetic effects are not well understood.

Technological approaches to investigate the role of genetic variation in understanding genetics and pharmacogenetics could vary. These could include, but not be limited to, single nucleotide polymorphism evaluations, DNA sequence specific analysis (commonly used to identify rare variants or insertions/deletions in the genome), or epigenetic approaches (to investigate methylation or acetylation of the DNA). The specific methodology to be used will depend upon study need.

If applicable and Genetics or PGx research is conducted, appropriate statistical analysis methods will be used to evaluate genetic or pharmacogenetic data in the context of the other clinical data. Results of Genetics or PGx investigations will be reported either as part of the main clinical study report or as a separate report. Endpoints of interest from all comparisons will be descriptively and/or graphically summarised as appropriate to the data. A detailed description of the analysis to be performed will be documented in the study reporting and analysis plan (RAP) or in a separate pharmacogenetics RAP, as appropriate.

Informed Consent

Subjects who do not wish to participate in the Genetics or PGx research may still participate in the clinical study. Genetics or PGx informed consent must be obtained prior to any blood being taken for Genetics or PGx research.

Provision of Study Results and Confidentiality of Subject’s Genetics or PGx Data

GSK may summarise the Genetics or PGx research results in the clinical study report, or separately, or may publish the results in scientific journals.

GSK does not inform the investigator, subject, or anyone else (e.g., family members, study investigators, primary care physicians, insurers, or employers) of individual genotyping results that are not known to be relevant to the subject’s medical care at the time of the study, unless required by law. This is due to the fact that the information generated from Genetics or PGx studies is generally preliminary in nature, and therefore the significance and scientific validity of the results are undetermined.


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References

Chung WH, Hung SL, Chen YT. Genetic predisposition of life-threatening antiepileptic-induced skin reactions. Expert Opin Drug Saf 2010;9:15-21.

Ferrell PB, McLeod HL. Carbamazepine, HLA-B*1502 and risk of Stevens-Johnson syndrome and toxic epidermal necrolysis: US FDA recommendations. Pharmacogenomics 2008;9:1543-1546.

Hetherington S, Hughes AR, Mosteller M, et al. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. Lancet 2002;359:1121-1122.

Hinks A, Moncrieffe H, Martin P, et al. Association of the 5-aminoimidazole-4-carboxamide ribonucleotide transformylase gene with response to methotrexate in juvenile idiopathic arthritis. Ann Rheum Dis 2011;70:1395-1400.

Horai Y, Miyamura T, Takahama S, et al. Churg-Strauss syndrome associated with elevated levels of serum interleukin-5 and T cell receptor-C gene rearrangement. Mod Rheumatol 2011;21:76-78.

Innocenti F, Undevia SD, Iyer L, et al. Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol 2004;22:1382-1388.

Liu CY, Chen PM, Chiou TJ, et al. UGT1A1*28 polymorphism predicts irinotecan-induced severe toxicities without affecting treatment outcome and survival in patients with metastatic colorectal carcinoma. Cancer 2008;112:1932-1940.

Lyons P, Rayner T, Trivedi S ,et al. Genetically distinct subsets within ANCA-associated vasculitis. N Engl J Med 2012;367:214-23.

Mallal S, Nolan D, Witt C, et al. Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet 2002;359:727-732.

Mallal S, Phillips E, Carosi G, et al. PREDICT-1 Study Team. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med 2008;358;568-579

Schulz C, Heinemann V, Schalhorn A et al. UGT1A1 gene polymorphism: Impact on toxicity and efficacy of irinotecan-based regimens in metastatic colorectal cancer. World J Gastroenterol 2009;15:5058-5066.

Tantisira G, Lasky-Su J, Harada M et al. Genomewide association between GLCCI1 and response to glucocorticoid therapy in asthma. N Engl J Med 2011;365:1173-83.

Wieczorek S, Hellmich B, Arning L, et al. Functionally relevant variations of the interleukin-10 gene associated with antineutrophil cytoplasmic antibody-negative Churg-Strauss syndrome, but not with Wegener’s granulomatosis. Arthritis Rheum 2008;58:1839-48.


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11.2. Appendix 2: Country Specific Requirements

Genetics research as outlined in Appendix 1 will not be conducted in Japan. In Japanpharmacogenetic research will be conducted and restricted to investigations related to mepolizumab treatment only.


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11.3. Appendix 3: Recommended Prednisolone/Prednisone Tapering Schedule from Week 4

Recommended corticosteroid tapering schedule to be initiated from Week 4 (Visit 4) when the subject’s BVAS=0, according to standard of care practice. Note: Use of alternate-day dosing is acceptable.

Baseline prednisolone/prednisone dose


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11.4. Appendix 4: Acceptable Birth Control

To be eligible for entry into the study, females of childbearing potential (FCBP) must commit to consistent and correct use of an acceptable method of birth control from the time of consent, for the duration of the trial, and for 4 months after the last study drug administration.

Male partner who is sterile prior to the female subject’s entry into the study and is the sole sexual partner for that female subject

Abstinence from penile-vaginal intercourse

Implants of levonorgestrel or etonogestrel

Injectable progestogen

Oral contraceptive (either combined or progestogen alone)

Estrogenic vaginal ring

Percutaneous contraceptive patches

Any intrauterine device (IUD) with a documented failure rate of less than 1% per year.

Male condom combined with a vaginal spermicide (foam, gel, film, cream, or suppository)

Male condom combined with a female diaphragm, either with or without a vaginal spermicide (foam, gel, film, cream, or suppository)

Females of childbearing potential are defined as females with functioning ovaries (i.e., post-menarche, premenopausal women with no documented impairment of oviductal or uterine function that would cause sterility). This category includes females with oligomenorrhea, females who are peri-menopausal, and young females who have begun to menstruate (adolescents). The information on the lack of impairment of oviductal or uterine function that would cause sterility can come from the site personnel’s:

Review of subject’s medical records

Medical examination of the subject

Interview with the subject on her medical history.

Females of non-childbearing potential are defined as females with functioning ovaries and with a documented tubal ligation or hysterectomy; or females who are postmenopausal defined as 12 months of spontaneous amenorrhea with an appropriate clinical profile, e.g. age appropriate, >45 years, in the absence of hormone replacement therapy (HRT).

In questionable cases a blood sample for follicle stimulating hormone (FSH) and estradiol will be obtained and analyzed to confirm childbearing potential.


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Females on HRT and whose menopausal status is in doubt will be required to use one of the contraception methods listed above for females of childbearing potential if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2-4 weeks should elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method.

Based on the absence of an identified reproductive hazard from preclinical studies, absence of a genotoxic potential, and very low levels of mepolizumab that might be present in semen, there is no recognized risk for mepolizumab to affect human sperm or the fetus if transferred to a female partner via semen. Therefore, the use of condoms or other methods of contraception in the male study subject is not required.


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11.5. Appendix 5: New York Heart Association Functional Classification of Congestive Heart Failure

Class Patient SymptomsClass I (Mild) No limitation of physical activity. Ordinary physical activity does not cause undue fatigue,

palpitation, or dyspnea (shortness of breath).

Class II (Mild) Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in fatigue, palpitation, or dyspnea.

Class III (Moderate)

Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes fatigue, palpitation, or dyspnea.

Class IV (Severe) Unable to carry out any physical activity without discomfort. Symptoms of cardiac insufficiency at rest. If any physical activity is undertaken, discomfort is increased.

1. Adapted from American Heart Association, 2012


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11.6. Appendix 6: Cardiovascular Screening Questions

At screening each subject should be asked the following:

Unrelated to the symptoms you experience with your asthma:

1) Do you have any pain or discomfort (such as pressure) in your chest?

If yes, does this pain/discomfort/pressure go to other areas of your body such as neck, jaw, throat, or down your arms (including a numbness feeling in your arm) when it occurs?

2) When you walk at an ordinary pace on a level surface does this produce chest pain? If yes, respond to a and b:

a) Does this chest pain or discomfort occur when you are not doing any activities such as resting in bed or sitting in a chair?

b) Has this chest pain/discomfort been more frequent or more intense or last longer or come on with less exertion lately?

3) When you walk uphill or hurry does this produce chest pain/discomfort?

4) Do you use or have you been previously prescribed nitroglycerine to relieve the discomfort?

If yes, have you needed to increase the number of pills or frequency of using the pills recently?

If the subject responds “yes” to any of the above questions a study physician should further assess for the presence of undiagnosed or unrecognized angina when evaluating Exclusion Criterion 6.


103

11.7. Appendix 7: Birmingham Vasculitis Activity Score version 3

This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by copyright laws and therefore have been excluded.


104

11.8. Appendix 8: Vasculitis Damage Index



105

11.9. Appendix 9: Asthma Control Questionnaire



106

11.10. Appendix 10: SNOT-22

Copyright Washington University



107

11.11. Appendix 11: Anaphylaxis Criteria

Hypersensitivity reactions will be monitored using the diagnostic criteria for anaphylaxis as outlined by the Joint NIAID/FAAN Second Symposium on Anaphylaxis [Sampson 2006]. The criteria do not make a distinction based on underlying mechanism. These criteria are summarized as follows:

1) Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, swollen lips-tongue-uvula), and at least one of the following:

a) Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced PEF, hypoxemia)

b) Reduced BP or associated symptoms of end-organ dysfunction (e.g., hypotonia [collapse], syncope, incontinence)

2) Two or more of the following that occur rapidly after exposure to a likely allergen for that patient (minutes to several hours):

a) Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, swollen lips-tongue-uvula)

b) Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced PEF, hypoxemia)

c) Reduced BP or associated symptoms (e.g., hypotonia [collapse], syncope, incontinence)

d) Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting)

3) Reduced BP after exposure to known allergen for that patient (minutes to several hours):

a) Infants and children: low systolic BP (age specific) or greater than 30% decrease in systolic BP

b) Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that person’s baseline


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11.12. Appendix 12: Liver Chemistry Stopping and Follow-up Criteria

Phase III-IV Liver Safety Algorithms

ALT>3xULN

plus bilirubin >2x ULN (>35%

direct) (or plusINR >1.5, if measured)*

No

Yes

Yes•Instruct subject to stop investigational product (IP)•Notify GSK within 24h and arrange clinical followup within 24-72h•Perform liver chemistries and liver event follow up assessments (serology, PK sample etc as in protocol) •Complete liver event CRF, SAE data collection tool if

appropriate, and liver imaging and/or biopsy CRFs if

tests performed.•Obtain weekly liver chemistries [**as far as possible in these subjects] until resolved, stabilised or returned to baseline •Withdraw subject from study after monitoring complete unless protocol has option to restart drug

•Instruct subject to stop investigational product (IP)•Notify GSK and arrange clinical followup within 24h•Perform liver chemistries and liver event follow up assessments (serology, PK sample etc as in protocol) •Report as SAE (excl. hepatic impairment or cirrhosis studies) and complete liver event CRF, SAE data collection tool, and liver imaging and/or biopsy CRFs if tests performed.•Obtain twice weekly liver chemistries until resolved, stabilised or returned to baseline values•Consultation with hepatologist/specialist recommended•Withdraw subject from study after monitoring complete unless protocol has option to restart drug

Hepatitis symptomsor rash?

No

Able to monitor

weekly for 4 weeks?

Yes

No**

Yes

Continue IPObtain twice monthly liver

chemistries until normalised or

back to baseline values

Yes

Yes

ALT<3xULN + bilirubin <2xULN after ≤ 4

wks?

Yes

ALT >5xULN

but <8xULN

NoALT >8xULN

Yes

ALT >5 and

<8xULN for > 2

wksYes No

ALT>3xULN but <5xULN +

bilirubin <2xULN+no symptoms

No

Able to monitor

weekly for

> 2 wks?

No

No

Notify GSK within 24h to discuss subject safety; continue IP;check liver chemistry weekly for 4 weeks

Yes No

*INR value not applicable to subjects on anticoagulants

2012N142276_01 CONFIDENTIALThe GlaxoSmithKline group of companies MEA115921

1

TITLE PAGE

Division: Worldwide DevelopmentInformation Type: Protocol Amendment

Title: A Double-blind, Randomised, Placebo-controlled Study toInvestigate the Efficacy and Safety of Mepolizumab in theTreatment of Eosinophilic Granulomatosis with Polyangiitis inSubjects Receiving Standard of Care Therapy


Effective Date: 15-OCT-2013

Protocol Amendment Number: 01

Subject: Eosinophilic granulomatosis with polyangiitis, mepolizumab, eosinophils, SB-240563, efficacy, safety, corticosteroids, quality of life, biomarkers

Author:

Revision Chronology:

2012N142276_00 2013-AUG-29 Original

2012N142276_01 2013-OCT-15 Amendment No.:01 Generated to remove evaluation of ACQ-6 and sino-nasal symptoms at the time of relapse and to clarify the definition of time of onset of relapse; country-specific requirements for Japan regarding hepatitis B screening added as well as clarification to text as needed and administrative changes. A detailed list of changes is provided in Appendix 13.



3











Tel:

Mobile:



Tel:

Mobile:


4


Tel:

Mobile:

FAX: +



IND No. 006971


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INVESTIGATOR AGREEMENT PAGE

For protocol number MEA115921, Amendment 01

I confirm agreement to conduct the study in compliance with the protocol, as amended by this protocol amendment.

I acknowledge that I am responsible for overall study conduct. I agree to personally conduct or supervise the described clinical study.


Investigator Name: _____________________________



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TABLE OF CONTENTS

PAGE

LIST OF ABBREVIATIONS.............................................................................................9




2. OBJECTIVES.........................................................................................................28










6.2. Efficacy.......................................................................................................546.2.1. Efficacy Endpoints .......................................................................54


7

6.2.1.1. Birmingham Vasculitis Activity Score..........................566.2.1.2. Relapse ......................................................................566.2.1.3. Vasculitis Damage Index ............................................576.2.1.4. Sino-nasal Symptoms.................................................576.2.1.5. Asthma Control Questionnaire....................................586.2.1.6. Spirometry..................................................................586.2.1.7. Fractional Concentration of Exhaled Nitric














7. DATA MANAGEMENT ...........................................................................................74



8.3. Data Analysis Considerations .....................................................................77


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8.3.1. Analysis Populations....................................................................778.3.2. Analysis Data Sets.......................................................................788.3.3. Treatment Comparisons ..............................................................78







10. REFERENCES.......................................................................................................89

11. APPENDICES ........................................................................................................9311.1. Appendix 1: Genetics/Pharmacogenetics Research ...................................9311.2. Appendix 2: Country Specific Requirements ...............................................9911.3. Appendix 3: Recommended Prednisolone/Prednisone Tapering

Schedule from Week 4..............................................................................10011.4. Appendix 4: Acceptable Birth Control........................................................10111.5. Appendix 5: New York Heart Association Functional Classification

of Congestive Heart Failure ......................................................................10311.6. Appendix 6: Cardiovascular Screening Questions ....................................10411.7. Appendix 7: Birmingham Vasculitis Activity Score version 3 .....................10511.8. Appendix 8: Vasculitis Damage Index.......................................................10611.9. Appendix 9: Asthma Control Questionnaire ..............................................10711.10. Appendix 10: SNOT-22.............................................................................10811.11. Appendix 11: Anaphylaxis Criteria ............................................................10911.12. Appendix 12: Liver Chemistry Stopping and Follow-up Criteria.................11011.13. Appendix 13: Protocol Changes................................................................111


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ACQ-6 Asthma Control Questionnaire-6ACR American College of RheumatologyADA Anti-drug antibodyAE Adverse EventALT Alanine transaminaseANCA anti-neutrophil cytoplasmic antibodiesANCA-MPO ANCA-Myeloperoxidase ANCA-PR3 ANCA-Proteinase 3AST Aspartate transaminaseBP Blood pressureBVAS Birmingham Vasculitis Activity ScoreCCR3 CC chemokine receptor 3CNS Central nervous systemCRP C-reactive proteinCSS Churg-Strauss SyndromeCV CardiovascularCYC CyclophosphamideDCSI Developmental Core Safety InformationDNA Deoxyribonucleic acidECG ElectrocardiogrameCRF Electronic case report formeDiary Electronic DiaryEGPA Eosinophilic Granulomatosis with PolyangiitisESR Erythrocyte sedimentation rateEULAR European League Against RheumatismFCBP Female of childbearing potentialFeNO Fractional Concentration of Exhaled Nitric OxideFEV1 Forced Expiratory Volume in one secondFVC Forced Vital CapacityGCP Good Clinical PracticeGCSP Global Clinical Safety and PharmacovigilenceGI GastrointestinalGPA Granulomatosis with polyangiitisGSK GlaxoSmithKlineHBcAb Hepatitis B Core AntibodyHBsAb Hepatitis B Surface AntibodyHBsAg Hepatitis B Surface AntigenHES Hypereosinophilic SyndromeHIV Human Immunodeficiency VirusHPLC High Performance Liquid ChromatographyHRT Hormone replacement therapyIB Investigator’s BrochureICH International Conference on HarmonisationIDMC Independent data monitoring committeeIEC Independent Ethics CommitteeIg Immunoglobulin


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IL InterleukinINR International normalised ratioIRB Institutional review BoardITT Intent-to-TreatIUD Intrauterine deviceIV Intravenous(ly)IVRS Interactive Voice Response Systemkg kilogramLABA Long acting beta2 agonistmAb Monoclonal antibodyMedDRA Medical Dictionary for Regulatory Activitiesmg milligramsMPA Microscopic polyangiitis MRI Magnetic resonance imagingMSDS Material Safety Data Sheetmsec millisecondNAB Neutralizing antibodiesOCS Oral CorticosteroidPBMC Peripheral blood mononuclear cellsPCR Polymerase chain reactionPD PharmacodynamicsPEF Peak expiratory flowPGx PharmacogeneticsPK PharmacokineticsPMDA Pharmaceuticals and Medical Devices Agency (Japan)PP Per protocolQTcB QT interval corrected for heart rate according to Bazett’s


formulaRAP Reporting and Analysis PlanRBC Red blood cellRNA Ribonucleic acidRPGN Rapidly progressive glomerulonephritis SABA Short acting beta-agonistSAE Serious Adverse EventSC Subcutaneous(ly)SF-36 Short-form 36SNOT-22 Sino-nasal Outcome Test-22SOC System organ classSPM Study procedures manualSRT Safety review teamTNF Tumour necrosis factorULN Upper limit of normalUS United StatesVDI Vasculitis Damage IndexWBC White blood cellWPAI Work Productivity Activity Impairment


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VENTOLIN NONMEM 7


12

PROTOCOL SUMMARY

Rationale


The purpose of this randomised, double-blind study is to investigate the efficacy and safety of mepolizumab (300 mg subcutaneously [SC] every 4 weeks) compared with placebo over a 52-week study treatment period in subjects with relapsing or refractory EGPA receiving standard of care therapy including background corticosteroid therapy with or without immunosuppressive therapy. During the treatment period, in accordance with standard of care, corticosteroid dose will be tapered. The key outcomes in the study focus on evaluation of clinical remission, defined as Birmingham Vasculitis Activity Score (BVAS) =0 with a corticosteroid dose of 4 mg/day prednisolone/prednisone, reduction in disease relapse and reduction in corticosteroid requirement.


Objectives

Primary

To investigate the efficacy of mepolizumab plus standard of care compared with placebo plus standard of care on duration of clinical remission, defined as accrued duration in weeks where a subject achieves a BVAS=0 and corticosteroid dose ≤4 mg/day prednisolone/prednisone in subjects with relapsing or refractory eosinophilic granulomatosis with polyangiitis (EGPA) receiving standard of care therapy including corticosteroid therapy reduction/withdrawal.


Secondary




13



Other

To investigate additional measures of the efficacy and quality of life including duration of remission; relapse; corticosteroid reduction; BVAS; vasculitis damage index (VDI); health-related quality of life (SF-36); asthma symptoms (asthma control questionnaire and lung function tests); sino-nasal symptoms (including the sino-nasal outcome test (SNOT-22) questionnaire); blood eosinophil counts and biomarkers of inflammation.







Study Design

This is a randomised, double-blind, placebo-controlled, parallel group, multicentre study of mepolizumab in subjects with a history of relapsing or refractory EGPA on stable corticosteroid therapy with or without concomitant stable immunosuppressant therapy. The study will comprise a screening period of up to 4 weeks (and minimum of 1 week) followed by a 52-week study treatment period and 8-week follow-up period.




14




Between baseline (randomisation) and Week 4, subjects will be required to continue on their stable OCS (prednisolone/prednisone) dose (if necessary, upward adjustments are permitted for clinical management of the patient). From Week 4 post-baseline onwards, if the subject’s BVAS=0 their oral OCS dose should be tapered downwards according to standard of care practice. A recommended tapering schedule provided in the protocol enables a reduction in OCS dose every 2 weeks, with the intention of achieving a prednisolone/prednisone dose of 4 mg/day or less. Once a subject has achieved a dose of 4 mg/day prednisolone/prednisone, the investigator is encouraged to continue tapering downwards, if clinically warranted, at dose increments of 0.5-1.0 mg every 2 weeks.

In this study EGPA remission is defined as BVAS=0 plus OCS dose of prednisolone/prednisone 4 mg/day. In defining EGPA remission, asthma and sino-nasal symptoms /signs related to EGPA activity, if not specifically covered by the BVAS assessment, will be considered to be controlled by virtue of the low OCS dose (i.e., 4 mg/day prednisolone/prednisone) and are therefore not included in the remission definition.

EGPA relapse will be defined as worsening or persistence of active disease since the last visit characterised by: a) active vasculitis (BVAS >0); OR b) active asthma symptoms and/or signs with a corresponding worsening in ACQ-6 score (compared to the most recent previous score); OR c) active nasal and/or sinus disease with a corresponding worsening in at least one of the sino-nasal symptom questions (compared to the most recent previous assessment) warranting: i) an increased dose of OCS therapy OR ii) an increased dose or addition of immunosuppressive therapy; OR iii) hospitalisation related to EGPA worsening. A BVAS evaluation will be conducted at the time of a relapse, or as soon as possible afterwards. The time of onset of a relapse will be defined as i) the time of increase in dose of OCS therapy, and/or ii) increase in dose or addition of immunosuppressive therapy, and/or iii) hospitalisation, in association with the worsening in BVAS, asthma or sino-nasal symptoms. In the event a subject has achieved remission (i.e., BVAS=0 and prednisolone/prednisone dose ≤4 mg/day) and at any subsequent visit has a BVAS = 1 which does not require an increase in corticosteroid dose above 4 mg/day, or any other significant clinical intervention or investigation, the subject will be considered to be in continued remission.

A major relapse (a sub-set of the total relapse events) will be defined as: any organ or life-threatening EGPA event; OR BVAS ≥6 (involving at least two organ systems in addition to any general symptoms where present [myalgia, arthralgia/arthritis, fever


15

>38ºC or weight loss >2 kg]); OR an asthma relapse requiring urgent care visit or hospitalisation; OR sino-nasal relapse requiring hospitalisation.

The minimally effective dose of OCS (prednisolone/prednisone) for each subject will be defined as the dose of OCS one step above the OCS dose at which the first relapse occurred. Where the subject has achieved a dose of OCS of 0-3.5 mg prednisolone/prednisone, the minimally effective dose will be defined as 4.0 mg/day. Upwards dose adjustments within the 0-4.0 mg range are permitted without necessarily being considered a relapse.

The management of subjects who relapse will be according to standard of care and may involve increasing the dose of oral corticosteroids or adjustment in immunosuppressive therapy.





Approximately 150 subjects will be screened to provide 130 randomised subjects (65 per group). Randomisation will be stratified by; i) subjects in the US participating in the US ‘mechanistic/biomarker’ sub-study (approximately 50 subjects), ii) subjects recruited in Japan and iii) the remainder of the recruited subjects.

Investigator-sponsored ‘mechanistic/biomarker’ sub-studies will be conducted at selected sites in the United States (US) and Europe using samples collected from consenting subjects participating in the study. The objective of these studies will includeexamination of molecular profiles and biomarkers associated with EGPA and response to anti-IL-5 therapy. Specific details of the planned analyses will be outlined in the individual protocols and/or analysis plans for these sub-studies.


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17

1. INTRODUCTION

1.1. Background

Eosinophilic Granulomatosis with Polyangiitis (EGPA), also referred to as Churg-Strauss syndrome (CSS), is a rare hypereosinophilic syndrome characterised by small vessel vasculitis in association with asthma, sinusitis, and pulmonary infiltrates. Multiple organs can be affected including the heart, lungs, skin, gastrointestinal tract, kidneys, and nervous system [Keogh, 2006; Vaglio, 2012; Holle, 2009] The mean age of diagnosis of EGPA is 48 years, with a gender ratio of approximately 1:1 [Pagnoux, 2007]; the incidence has been estimated as 1-4 per million per year [Lane, 2005]. EGPA is associated with a positive status for anti-neutrophil cytoplasmic antibodies (ANCAs), typically ANCA-Myeloperoxidase (MPO) and ANCA-Proteinase 3 (PR3), in approximately 40% of patients [Holle, 2009; Sinico, 2005]. In addition, the role of allergy in EGPA is widely acknowledged, especially in the prodromal disease phase that is characterized by typical allergic manifestations such as asthma, sinusitis, and nasal polyposis with raised serum IgE levels observed in approximately 90% of EGPA patients [Vaglio, 2012]. In recent proposed classification systems for eosinophil disorders, EGPA has been described as being associated with Hypereosinophilic Syndrome (HES) [Simon, 2010], although it should nevertheless be distinguished from true HES [Valent, 2012].



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Interleukin-5 (IL-5) is the major hematopoietin regulating the life-cycle of eosinophils [Clutterbuck, 1989; Lopez, 1988; Rothenberg, 2006]. In EGPA the mechanism of tissue injury is poorly understood, but the degree of blood and tissue eosinophilia appears to be associated with disease pathogenesis [Schnabel, 1999]. In a series of in vitro studies it has been shown that circulating levels of IL-5 are increased in patients with active EGPA, that peripheral blood mononuclear cells (PBMCs) are the likely source of elevated plasma IL-5 in the disease, and that T cell activation is required for increased IL-5 release by the PBMCs [Shonermarck, 2000; Kiene, 2001; Hellmich, 2005; Hellmich, 2003]. Of particular interest with regard to the pathogenesis of EGPA and associated vasculitis is the ability of IL-5 to promote the adhesion of eosinophils to vascular endothelium and CC chemokine receptor 3 (CCR3)-dependent migration of eosinophils from the vasculature [Shahabuddin, 2000]. Thus, the elevated production of IL-5 by PMBCs in EGPA may be relevant pathogenetically not only for eosinophilia, but also for the development of vasculitis by promoting transvascular migration and functional activation of eosinophils.

Mepolizumab is a fully humanized monoclonal antibody (IgG1, kappa, mAb) which is specific for human IL-5 and which blocks binding of human IL-5 (hIL-5) to the alpha chain of the IL-5 receptor complex expressed on the eosinophil cell surface. In patients with conditions where eosinophilia is considered to play an important part in the pathology, a consistent reduction in eosinophil number is observed in association with mepolizumab administration, with concomitant clinical improvement [Haldar, 2009;Pavord, 2012; Stein 2006, Rothenberg 2008; Nair, 2009].

The hypothesis that IL-5 is central to the pathology and clinical manifestations of EGPA is supported by clinical data providing ‘proof-of-concept’ evidence of efficacy of IL-5 blockade in the treatment of subjects with this condition. Firstly, a case report of a female with refractory EGPA treated with mepolizumab (750 mg intravenously [IV] monthly) showed sustained reduction in eosinophils and clinical improvement [Kahn, 2010]. Subsequently, two exploratory, investigator-sponsored studies of mepolizumab in EGPA have been reported. In the first study 10 EGPA patients on stable prednisolone (10 mg/day) and stable immunosuppressive therapy received 750 mg IV mepolizumab every 4 weeks (4 infusions) for 12 weeks. Mepolizumab reduced eosinophil counts and allowed for safe corticosteroid reduction (study CRT109797 [IB; GlaxoSmithKline Document Number: CM2003/00010/08]; [Kim, 2010]). On cessation of mepolizumab, EGPA manifestations recurred necessitating an increase in corticosteroid dose (‘steroid burst’). In the second study 10 EGPA patients with active refractory or relapsing disease were withdrawn from immunosuppressant therapy and treated with 750 mg mepolizumab IV every 4 weeks (9 infusions). Eight patients achieved remission (defined as Birmingham Vasculitis Activity Score [BVAS] =0 and corticosteroid dose <7.5 mg/day); one achieved BVAS=0 but not corticosteroid dose <7.5 mg/day) and the final patient achieved remission but was excluded due to non-adherence. Eosinophil counts rapidly decreased after the first mepolizumab infusion and remained near zero during the active treatment phase (study MHE109435 [IB; GlaxoSmithKline Document Number: CM2003/00010/08]; [Moosig, 2011]). Mepolizumab was reported as being well-tolerated in both studies.


19

1.2. Rationale



1.3. Dose Rationale



Mepolizumab (750 mg IV every 4 weeks) was shown to be well-tolerated in studies CRT109797 and MHE109435 consistent with the overall safety profile previously demonstrated in over 1300 subjects treated with mepolizumab across different eosinophilic conditions (i.e., severe asthma, HES, eosinophilic esophagitis, atopic dermatitis and nasal polyposis). For details see the Investigator’s Brochure [IB; GlaxoSmithKline Document Number: CM2003/00010/08].


A non-linear inhibition dose-response model based on blood eosinophil counts, developed from a pharmacokinetic/pharmacodynamic (PK/PD) study of mepolizumab in adult subjects with asthma and elevated blood eosinophil levels (study MEA114092), has identified 75 mg IV every 4 weeks as the ID90 (i.e., dose providing 90% of the maximum blood eosinophil reduction achievable by


20

the drug) for blood eosinophil reduction. The estimated absolute bioavailability for SC route of administration in the upper arm in this study was approximately 75% [IB; GlaxoSmithKline Document Number: CM2003/00010/08]. Therefore a dose of 100 mg SC is anticipated to provide similar exposure to a 75mg IV dose. A 100 mg SC dose every 4 weeks is therefore being investigated in confirmatory studies in severe asthma as the SC route is more convenient compared with IV and is generally preferred by patients.










Summaries of findings from both clinical and non-clinical studies conducted with mepolizumab can be found in the Investigator Brochure (GlaxoSmithKline Document


21

Number: CM2003/00010/08). Table 1 summarises the risk assessment and mitigation strategy for this protocol.


22







Reactions reported to date across the mepolizumab program are summarized in the IB; see ‘Special Warnings and Special Precautions for Use’ section located in Section 6 titled ‘Summary of Data and Guidance for the Investigator’.




Utilization of Joint NIAID/FAAN 2nd Symposiumon Anaphylaxis to collect data on reports of anaphylaxis (see Appendix 11).







23







In one study in subjects with severe refractory asthma, cardiac events were reported in similar frequencies across treatment groups with a small numerical increase observed in serious ischemic cardiac events in the mepolizumab-treated groups. However, an integrated safety analysis of all placebo-controlled multiple-dose asthma trials showed a similar frequency of SAEs reported overall from the cardiac and vascular system organ class (SOC). Additionally, similar findings were observed in other SOCs with thrombotic events (e.g., stroke in the Nervous System SOC).







Use of standardized CRFs to collect relevant data on CV events of interest (i.e., myocardial infarction, hospitalization for unstable angina and congestive heart failure, arterial thrombosis, pulmonary embolism and deep vein thrombosis);



24








Infections reported to date across the mepolizumab development program are summarized in the IB; see ‘Special Precautions and Warnings’ (for exclusion of subjects with underlying parasitic infections) and ‘Undesirable Effects’ (for very common infections of nasopharyngitis, URTI, rhinitis and bronchitis reported in other patient populations) sections located in Section 6 titled ‘Summary of Data and Guidance for the Investigator’.





25


















26



Study Procedures






The minimally effective dose of OCS (prednisolone/prednisone) for each subject will be defined as the dose of OCS one step above the OCS dose at which the first relapse occurred. Once the minimally effective dose of OCS is achieved, any down-tapering below this dose level will be at the discretion of the investigator, based on the clinical condition of the subject.




27









28








2. OBJECTIVES

Primary

To investigate the efficacy of mepolizumab plus standard of care compared with placebo plus standard of care on duration of clinical remission, defined as accrued duration in weeks where a subject achieves a BVAS=0 and corticosteroid dose ≤4 mg/day prednisolone/prednisone, in subjects with relapsing or refractory eosinophilic granulomatosis with polyangiitis (EGPA) receiving standard of care therapy including corticosteroid therapy reduction/withdrawal.


29


Secondary





Other

To investigate additional measures of the efficacy and quality of life including duration of remission; relapse; corticosteroid reduction; BVAS; vasculitis damage index (VDI); health-related quality of life (SF-36); asthma symptoms (asthma control questionnaire and lung function tests); sino-nasal symptoms (including the SNOT-22 questionnaire); blood eosinophil counts and biomarkers of inflammation.








3.1. Study Design



30







31


Between baseline (randomisation) and Week 4, subjects will be required to continue on their stable OCS (prednisolone/prednisone) dose (if necessary, upward adjustments are permitted for clinical management of the patient). From Week 4 post-baseline (Visit 4) onwards, if the subject’s BVAS = 0 their oral OCS dose should be tapered downwards according to standard of care practice. A recommended tapering schedule for this purpose is provided in Appendix 3 (see Section 11.3). The recommended tapering schedule enables a reduction in OCS dose every 2 weeks, with the intention of achieving a prednisolone/prednisone dose of 4 mg/day or less. Once a subject has achieved a dose of 4 mg/day prednisolone/prednisone, the investigator is encouraged to continue tapering downwards, if clinically warranted, at dose increments of 0.5-1.0 mg every 2 weeks.

In this study EGPA remission is defined as BVAS = 0 plus OCS dose of prednisolone/prednisone 4 mg/day. In defining EGPA remission, asthma and sino-nasal symptoms /signs related to EGPA activity, if not specifically covered by the BVAS assessment, will be considered to be controlled by virtue of the low OCS dose (i.e., 4 mg/day prednisolone/prednisone) and are therefore not included in the remission definition. EGPA relapse will be defined as worsening or persistence of active disease since the last visit characterised by:





32

warranting:




A BVAS evaluation will be conducted at the time of a relapse, or as soon as possible afterwards.

The time of onset of a relapse will be defined as i) the time of increase in dose of OCS therapy, and/or ii) increase in dose or addition of immunosuppressive therapy, and/or iii) hospitalisation, in association with the worsening in BVAS, asthma or sino-nasal symptoms.

In the event a subject has achieved remission (i.e., BVAS=0 and prednisolone/prednisone dose ≤4 mg/day) and at any subsequent visit has a BVAS=1 which does not require an increase in prednisolone/prednisone dose above 4 mg/day, or any other significant clinical intervention or investigation, the subject will be considered to be in continued remission.



The management of subjects who relapse will be according to standard of care and mayinvolve increasing the dose of oral corticosteroids or adjustment in immunosuppressive therapy.

If the subject’s first relapse is managed with the use of an increase in corticosteroid dose, tapering should be recommenced as soon as the relapse has been appropriately controlled, as per standard of care practice. As stated above, the recommended tapering schedule is provided in Appendix 3 (see Section 11.3), although after the first relapse the investigator may opt to use larger dose increments and shorter dose intervals than outlined in the schedule, if clinically indicated. Once the minimally effective dose of OCS is achieved, any down-tapering below this dose level will be at the discretion of the investigator, based on the clinical condition of the subject. In the event of a second or subsequent


33

relapse, any further OCS tapering, post-relapse, will be conducted at the discretion of the investigator.




Serious adverse events (SAEs) reported from ongoing clinical studies with mepolizumab are reviewed daily by the project Medical Monitor. Additionally, regular, systematic reviews of emerging safety data from all clinical studies are conducted by an in-house multi-disciplinary Safety Review Team (SRT) which provides a central and dedicated forum for review of emerging data which could impact subject safety. The SRT, which includes the project Medical Monitor, other physicians assigned to the project, clinical scientists and a statistician, review blinded and unblinded (i.e., from open-label trials) safety data from ongoing clinical studies with mepolizumab on a regular basis and conduct a comprehensive evaluation of the safety data upon completion of each study. Moreover, an integrated analysis of safety across the program is completed annually when additional safety data are available from completed studies. A re-assessment of benefit risk and the current Developmental Core Safety Information (DCSI) is completed at each SRT meeting subsequent to review of new data. Additionally, an Independent Data Monitoring Committee (IDMC) will be utilized during the study; their primary focus will be the monitoring of cardiovascular safety and all cause mortality.


Investigator-sponsored ‘mechanistic/biomarker’ sub-studies will be conducted at selected sites in the United States (US) and Europe using samples collected from consenting subjects participating in the study. The objective of these studies will includeexamination of molecular profiles and biomarkers associated with EGPA and response to


34

anti-IL-5 therapy. Specific details of the planned analyses will be outlined in the individual protocols and/or analysis plans for these studies.



Although there are criteria from the American College of Rheumatology (ACR) available for the classification of EGPA for which a patient is required to have 4 of the 6 following criteria to be considered to have EGPA: asthma, eosinophilia >10%, neuropathy (mono or poly), pulmonary infiltrates, non-fixed, paranasal sinus abnormality and extravascular eosinophils, these criteria were not designed to be used for diagnostic purposes [Masi, 1990; Basu, 2010]. These classification criteria have therefore been modified for the purpose of this study to ensure recruited subjects have a diagnosis of EGPA including key manifestations of this condition. Specifically, all subjects will be required to have had asthma plus eosinophilia in addition to two further major features of EGPA as outlined in inclusion criterion #3.



The total study treatment duration is 52 weeks. This duration permits downwards tapering of OCS dose to a target of 4 mg/day prednisolone/prednisone and evaluation of disease control over an extended period, and balances the need to assess the experimental therapy for at least 12 months and the feasibility of retaining subjects in a clinical trial


35

over a prolonged period of time. The protocol provides a recommended schedule from Week 4 for gradual tapering of corticosteroids down to 4 mg/day prednisolone/prednisone where the subject’s BVAS=0 (Appendix 3; see Section 11.3). Once subjects have reached a dose of 4 mg/day prednisolone/prednisone, further tapering downwards may be continued. However, upward adjustment in the dose of OCS is permitted within the 0-4.0 mg range without necessarily being defined as a relapse. This approach recognises that some subjects on long-term OCSs are relatively resistant to complete discontinuation of therapy, and are vulnerable to precipitation of Addisonian symptoms.






Specific information regarding warnings, precautions, contraindications, AEs, and other pertinent information on the GSK investigational product or other study treatment that may impact subject eligibility is provided in the mepolizumab IB, GlaxoSmithKline Document Number: CM2003/00010/08.





3. EGPA diagnosis: subjects who have been diagnosed with EGPA for at least 6 months based on the history or presence of: asthma plus eosinophilia (>1.0x109/L


36

and/or >10% of leucocytes) plus at least two of the following additional features of EGPA








palpable purpura;




Refractory disease:






37

Or: Within 6 months prior to Screening (Visit 1), recurrence of symptoms of EGPA (not necessarily meeting the protocol definition of relapse) whilst tapering OCS, occurring at any dose level ≥7.5 mg/day prednisolone or equivalent.

















38






Severe cardiac involvement, e.g., life-threatening arrhythmia, cardiac failure: ejection fraction < 20%, New York Heart Association Class III/IV (Appendix 5; see Section 11.5), acute myocardial infarction.





Severe heart failure that meets New York Heart Association Class IV (Appendix 5; see Section 11.5), OR






10. Hepatitis status: Diagnosis of chronic hepatitis B, as evidenced by positive Hepatitis B surface antigen (HBsAg) at Screening (Visit 1). Japan only: Subjects positive for HBsAg , antibodies to HBsAg, i.e., HBsAb, or Hepatitis B core antigen, i.e., HBcAb,


39

at Screening (Visit 1). Note: Subjects with antibodies to HBsAg, i.e., HBsAb positive, only (i.e., negative for HBsAg and HBcAb) with a history of hepatitis B vaccination can be included.
















WBC < 4 x109/L







40





Those subjects who meet the randomisation criteria will be randomised into the study until the target of 130 randomised subjects is reached. Randomisation will be stratified by; i) subjects in the US participating in the US ‘mechanistic/biomarker’ sub-study (approximately 50 subjects), ii) subjects recruited in Japan and iii) the remainder of the recruited subjects.




3. Hepatitis status: No diagnosis of chronic hepatitis B, as evidenced by positive HBsAg at Screening (Visit 1). Japan only: Subjects positive for HBsAg or antibodies to HBsAg, i.e., HBsAb, or Hepatitis B core antigen, i.e., HBcAb, at Screening (Visit 1) are excluded. Note: Subjects with antibodies to HBsAg, i.e., HBsAb positive, only (i.e., negative for HBsAg and HBcAb) with a history of hepatitis B vaccination can be included.







41




Subjects may be withdrawn (discontinued) from study treatment at anytime. Subjects who withdraw from study treatment prematurely (for any reason) should, where possible, continue to be followed up as per protocol until the end of follow-up at Week 60. In addition, at the study visit approximately 12 weeks after the last dose of study treatment was administered, a blood sample for measurement of anti-drug antibodies should be collected.

Reasons for premature discontinuation of study treatment must be captured in the electronic case report form (eCRF), e.g., AE, lack of efficacy, protocol deviation, investigator discretion, consent withdrawn etc. In addition, subjects will be withdrawn from study treatment for any of the following reasons:

Liver stopping criteria: Subject meeting liver stopping criteria as detailed in Section 6.3.2.


Concurrent medication: Use of prohibited concurrent medication (i.e. as noted in Exclusion Criterion #14 (Prohibited medications) including cyclophosphamide.


ECG abnormalities:

QTc >500 msec







<450 msec >500 msec

450-480 msec ≥530 msec


42






In the event of early withdrawal from the study, every effort should be made to have the subject to return to the clinic for an Early Withdrawal visit and to return all study related materials. Separate Early Withdrawal visits are described in the Time and Events Table (Table 2) i.e., ‘Early Withdrawal Visit 1’ for subjects withdrawing from the study during the study treatment period versus ‘Early Withdrawal Visit 2’ for subjects withdrawingfrom the study during the study follow-up period.







43

5. STUDY TREATMENTS


Mepolizumab (SB-240563) is a fully humanised monoclonal antibody (IgG1, kappa, mAb) with human heavy and light chain frameworks. Mepolizumab will be provided as a lyopholised cake in sterile vials for individual use. The vial will be reconstituted with Sterile Water for Injection, just prior to use. Further details of dose preparation and administration can be found in the IB (GlaxoSmithKline Document Number: CM2003/00010/08), and the SPM.


Under normal conditions of handling and administration, investigational product is not expected to pose significant safety risks to site staff. Take adequate precautions to avoid direct eye or skin contact and the generation of aerosols or mists. Notify the monitor of any unintentional occupational exposure. A Material Safety Data Sheet (MSDS) describing the occupational hazards and recommended handling precautions will be provided to site staff if required by local laws or will otherwise be available from GSK upon request.




A unique Subject Number will be assigned to any subject who is consented. This unique subject number will be used to identify the individual subject throughout the study and will not be re-assigned to any other subject. Randomisation will be stratified by; i) subjects in the US participating in the US ‘mechanistic/biomarker’ sub-study (approximately 50 subjects), ii) subjects recruited in Japan and iii) the remainder of the recruited subjects.


The Randomisation Schedule will be generated using the GSK validated randomisation software RandAll. Equal numbers of subjects will be allocated to each treatment. The


44

Randomisation Schedule will be used to identify the treatment arm a subject is randomised to.







An unblinded site staff member will be assigned to the study to prepare the appropriate medication according to the study subject’s treatment assignment. Subjects eligible to enter the study will be assigned to treatment randomly through a telephone interactive voice response system (IVRS).





Safety monitoring of subjects will occur during SC administration and for 1 hour after the end of injection. Such monitoring will include general safety monitoring including monitoring for both systemic hypersensitivity (i.e., allergic/IgE-mediated and non-allergic) and local site reactions. Trained rescue personnel and rescue


45

medications/equipment must be available for use at all times. See Appendix 11(Section 11.11) for additional information.

5.4. Blinding




In accordance with local regulatory requirements, the investigator, designated site staff, or head of the medical institution (where applicable) must document the amount of investigational product dispensed and/or administered to study subjects and the amount received from and returned to GSK, when applicable. Product accountability records must be maintained throughout the course of the study.







46







Omalizumab 130 days




Anti-TNF 12 weeks










47





Subjects will be issued with an eDiary and instructed on how to use it at the start of the study. The asthma control questionnaire (ACQ-6), questions regarding sino-nasal symptoms and the subject’s daily corticosteroid dose will be recorded on the eDiary.

Throughout the study subjects will be required to complete the following paper questionnaires at the study site: Sino-nasal Outcome Test-22 (SNOT-22), the Short Form-36 (SF-36), and the Work Productivity and Activity Impairment (WPAI) Index.


48



period


W/D (1)

18 19Early

W/D (2)

Study week (specified no. of days)

Pre-screen

SCREEN-1 to -4 weeks

BASE LINE

13

47

87

127

167

207

247

287

293

327

367

407

447

487

527

567

607


X




X



49


period


W/D (1)

18 19Early

W/D (2)


Pre-screen


BASE LINE

13

47

87

127

167

207

247

287

293

327

367

407

447

487

527

567

607





Blood sample X X X X X X X X XSputum sample X X X X


50


period


W/D (1)

18 19Early

W/D (2)


Pre-screen


BASE LINE

13

47

87

127

167

207

247

287

293

327

367

407

447

487

527

567

607

Urine sample X X X XTissue sample22




Complete eCRF X X X X X X X X X X X X X X X X X X X X X

1. Pre-screen visit to obtain informed consent can occur on the same day as Visit 1, but informed consent must be obtained prior to starting Visit 1 procedures.2. Cardiovascular History/Risk Factors and CV screening questions3. Height to be measured at screening only.4. In the event of a relapse, detail of the event to be recorded in the eCRF. A blood, urine, sputum and, where possible (i.e., if as part of standard of care management), a biopsy

sample to be collected in the event of relapse from subjects participating at US sites in the ‘mechanistic’ sub-study.5. Subject to record daily prednisolone/prednisone dose on provided eDiary device. Investigator to record prescribed dose in the eCRF.6. Sino-nasal questionnaire and ACQ to be completed weekly by the subject using provided eDiary device.7. Spirometry: Airway reversibility to be measured at baseline only; FEV1 and FVC to be measured at all other visits.8. FeNO: To be measured at sites only if local equipment available.9. SNOT-22, SF-36 and WPAI questionnaires to be completed on paper forms. 10. At visits when health resource use is being collected, the investigator should ask the subject if they have had any need to seek medical treatment for EGPA or an EGPA-related

episode since the previous scheduled visit. 11. Vital sign measurements will include temperature, systolic and diastolic blood pressure and pulse rate.12. 12-lead ECG monitoring.13. During the treatment period, all lab samples should be obtained pre-dose.14. Lipoprotein (fasting) included in Clinical Chemistry. Subject must be in fasting state. If the subject has not fasted, he/she may return to the clinic to collect this sample as soon as

possible.15. Urinalysis Screen sample (Visit 1) to be analysed by the central laboratory; all other tests to be conducted using by dipstick.


51

16. Hepatitis B Surface Antigen and Hepatitis C antibody (if hepatitis C antibody positive, a HCV RNA test (either quantitative or qualitative) should be performed). Japan only: Antibodies to Hepatitis B Surface Antigen and Hepatitis B Core Antigen, i.e., HBsAb and HBcAb, respectively.

17. Serum pregnancy test (S) to be conducted in women of childbearing potential at Screening (Visit 1) and Week 52 (or early withdrawal); urine pregnancy tests (U) to be conducted at all other indicated visits.

18. PK sampling: At Baseline and Weeks 4, 28 and 48 the PK sample should be taken pre-dose. At Weeks 1 and 29, where practical, a PK sample is to be collected.19. In the event of premature discontinuation of study medication, a sample for measurement of anti-drug antibodies should be collected at the nearest scheduled study visit

approximately 12 weeks after the last dose of study medication was administered.20. Genetics/PGx: Sample collection is recommended at baseline but may be drawn at any time after the subject is randomised.21. Biomarker samples: Blood, sputum and urine samples to be collected as indicated from Baseline (Visit 2) to Week 60 (or early withdrawal) from consenting subjects participating

at US sites in the ‘mechanistic/biomarker’ sub-study only. Where possible, blood, sputum and urine samples also to be collected in the event of relapse. Blood samples to be collected as indicated from Baseline (Visit 1) to Week 60 (or early withdrawal) from consenting subjects at sites participating in the European ‘biomarker’ sub-study.




52




Demographic information including gender, ethnic origin, race and year of birth, height and weight.






















53

Urinalysis.




ANCA (MPO and PR3).



Weight.



















Clinical chemistry.

Urinalysis.


IL-5.


54

CRP and ESR.

IgE.





6.2. Efficacy


Primary


Zero

>0 to <12 weeks

12 to <24 weeks

24 to <36 weeks

≥36 weeks


Secondary



Zero

>0 to ≤4.0 mg

>4.0 to ≤7.5 mg


55

>7.5 mg


Other


Zero

>0 to <12 weeks

12 to <24 weeks

24 to <36 weeks

≥36 weeks







<25%

25 to <50%

50 to <75%

75 to <100%

100%








56











6.2.1.2. Relapse





warranting:





57



Investigators will be required to record details pertaining to the relapse event in the eCRF from Baseline (Visit 2) until study completion at Week 60 or Early Withdrawal, e.g., details regarding the BVAS item, asthma or nasal/sinus disease resulting in the relapse with detail of the required intervention(s), e.g., OCS dose increase, use or change in immunosuppressive therapy or requirement for hospitalisation. For consenting subjects participating in the US ‘mechanistic’ sub-study, where possible, a blood, urine, and sputum sample should be collected in the event of relapse. In addition, where possible, (i.e., as part of standard of care management), a tissue (biopsy) sample should be collected.










58

Runny nose










6.2.1.6. Spirometry



Prior to the Baseline visit (Visit 2) subjects should withhold short-acting beta-2-agonists (SABAs) for at least 6 hours and long-acting beta-2-agonists (LABAs) for at least 12 hours to enable reversibility testing to be performed. Specifically, FEV1 will be measured pre-salbutamol/albuterol and within 30 minutes [±15 minutes] following up to 4 inhalations of salbutamol/albuterol (a spacer device may be used if required) or


59

equivalent nebulised treatment with salbutamol/albuterol solution. The reversibility test must be performed in the morning only at Baseline (Visit 2).






6.3. Safety










60











NOTE: if serum bilirubin fractionation is not immediately available, withdraw study drug for that subject if ALT 3xULN and bilirubin 2xULN. Serum bilirubin fractionation should be performed if testing is available. If testing is unavailable, record presence of detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury.

2. ALT 8xULN.









61




















62





Hepatitis C RNA;














Only in those with underlying chronic hepatitis B at study entry (identified by positive hepatitis B surface antigen): quantitative hepatitis B DNA and hepatitis delta antibody. NOTE: if hepatitis delta antibody assay cannot be performed, it


63

can be replaced with a PCR of hepatitis D RNA virus (where needed) [Le Gal, 2005].


















64




a) Results in death









f) Medical or scientific judgment should be exercised in deciding whether reporting is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalisation but may jeopardise the subject or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition. These should also be considered serious. Examples of such events are invasive or malignant cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation, or development of drug dependency or drug abuse.

g) All events of possible drug-induced liver injury with hyperbilirubinaemia defined as ALT 3xULN and bilirubin 2xULN (>35% direct) (or ALT 3xULN and INR>1.5, if INR measured) termed ‘Hy’s Law’ events (INR measurement is not


65

required and the threshold value stated will not apply to patients receiving anticoagulants).



Any abnormal laboratory test results (haematology, clinical chemistry, or urinalysis) or other safety assessments (e.g., ECGs, radiological scans, vital signs measurements), including those that worsen from baseline, and felt to be clinically significant in the medical and scientific judgement of the investigator are to be recorded as AEs or SAEs. However, any clinically significant safety assessments that are associated with the underlying disease, unless judged by the investigator to be more severe than expected for the subject’s condition, are not to be reported as AEs or SAEs.





Arrhythmias

Valvulopathy





Revascularisation


6.3.6. Death Events



66


6.3.7. Pregnancy













67










applicable





measured)1



Imaging” and/or “Liver Biopsy”









(defined above)3







for 2 weeks3


if applicable3


68




persists 2 weeks


(defined above)3



<2xULN





for 4 weeks3


if applicable3











69



Vital signs include temperature, blood pressure (systolic and diastolic), and pulse rate. Measurements will be performed by the investigator or qualified designee, as outlined in Time and Events schedule (Table 2).

Sitting pulse rate and blood pressure measurements will be performed pre-injection withthe subject sitting, having rested in this position for at least 5 minutes before each reading. They will be taken before measurement of any clinic lung function tests or ECGs at the specified time point.











70












71


Routine Clinical Chemistry Routine HaematologySodium HaemoglobinPotassium Red Cell CountChloride Platelet CountCalciumPhosphorous inorganic White Cell CountGlucose Neutrophil (absolute and differential [%])Protein, total Lymphocytes (absolute and differential [%])Albumin Monocytes (absolute and differential [%])CPK, total Eosinophils (absolute and differential [%])Creatinine Basophils (absolute and differential [%])Urea nitrogen Mean Corpuscular Volume (MCV)Lactic dehydrogenase Mean Corpuscular Haemoglobin (MCH)Cholesterol, total Mean Corpuscular Haemoglobin Concentration

(MCHC)High Density Lipoprotein, Cholesterol, direct Urinalysis (Screening; Visit 1)Low Density Lipoprotein, calculation Protein Qualitative





Aspartate Amino Transferase Other laboratory parametersAlanine Amino Transferase Hepatitis B Surface Antigen

Hepatitis B Surface Antibody (Japan only)Hepatitis B Core Antibody (Japan only)

Gamma Glutamyl Transaminase Hepatitis C antibodyAlkaline Phosphatase ANCA (MPO and PR3)Serum pregnancy test IgETroponin C-reactive protein




ANCA (MPO and PR3) status, included as a diagnostic criterion for EGPA diagnosis (see Section 4.2) will be measured at Screening (Visit 1) and throughout the study period as


72

indicated in the Time and Events table (Table 2). IgE, which can be elevated in patients with EGPA, will be measured at Baseline (Visit 2).




As a minimum, full physical examination will include assessment of the head, eyes, ears, nose, throat, skin, thyroid, neurological, lungs, cardiovascular, abdomen (liver and spleen), lymph nodes and extremities.




SF-36

WPAI index.


6.4.1.1. Short Form-36 (SF-36)




The WPAI (General Health version 2.0) is a self or interviewer administered tool comprised of 6 questions which address absenteeism, presenteeism (reduced effectiveness while working), overall work productivity loss (absenteeism plus presenteeism), and activity impairment. This validated tool captures data from the past 7 days. WPAI outcomes are scored as impairment percentages, with a higher percentage indicating greater impairment and less productivity [Reilly Associates, 2012].


73














6.6. Immunogenicity



74


6.7. Biomarkers

Blood samples will be collected for measurement of CRP and ESR at the visits specified in the Time and Events table (Table 2). Samples for CRP measurement will be sent to a central laboratory for analysis and local testing will be used for ESR samples (see Table 2; details are provided in the SPM).


US: Samples (blood, urine and sputum, and in case of relapse, where possible [i.e., if as part of standard of care management] a tissue sample) for the investigator-sponsored, ‘mechanistic’ sub-study, will be collected from specified US sites only at the visits specified in the Time and Events table (Table 2). Procedures for sample management and shipment for this sub-study will be provided to the relevant sites.




7. DATA MANAGEMENT





75


8.1. Hypotheses










76












77



Percent Success

(For either Subjects with Accrued Remission ≥ 24 weeks or Subjects in Remission at Weeks 36 and 48)


15% 44% 29% 4.5 93%

20% 49% 29% 3.8 91%

25% 54% 29% 3.5 90%

30% 59% 29% 3.4 89%

16% 40% 24% 3.5 82%

40% 70% 30% 3.5 91%

72% 90% 18% 3.5 66%








The intent-to-treat (ITT) population will consist of all subjects who are randomised and who receive at least one dose of trial medication. Randomised subjects will be assumed to have received study treatment unless definitive evidence to the contrary exists. This will constitute the primary population for all analyses of efficacy measures.


78



Safety Population:


PK Population:


PD Population:









Other comparisons of interest are mepolizumab versus placebo for each of the 3 secondary endpoints. In order to make inferences for the pre-defined secondary endpoints while controlling the overall type I error, multiplicity across these comparisons


79

will be controlled using a closed testing procedure where the secondary endpoints will be nested under the primary efficacy endpoint, followed by a further hierarchical procedure within the secondary endpoints, in the order of: i) time to relapse, ii) prednisolone/prednisone dose followed by, iii) proportion of subjects who achieve remission within the first 24 weeks of the study and then remain in remission. That is:













1. The total accrued duration of remission (co-primary endpoint ‘1’), i.e., the accrued number of weeks where BVAS=0 plus prednisolone/prednisone dose 4 mg/day over the 52 week study treatment period reported as proportion of subjects achieving remission in the following categories: Zero; >0 to <12 weeks; 12 to <24 weeks; 24 to <36 weeks and ≥36 weeks, and



80

The primary analysis of co-primary endpoint ’1’ will use a logistic proportional odds regression model for ordered categorical data for the proportion of subjects who achieve remission categorised, as above, for the ITT population. Baseline covariates to be included in the model are: i) baseline steroid dose, ii) ANCA status (due to potential for association with risk of relapse [Sablé-Fourtassou, 2005; Sinico, 2005]) and iii) region, i.e., i) subjects participating in the US ‘Mechanistic’ sub-study, ii) Japan (for administrative reasons) and iii) the remainder of recruited subjects.













81














82


Secondary Endpoints










The proportion of subjects with an average daily prednisolone/prednisone dose during the last 4 weeks of the treatment period (Weeks 48 through 52) will be analysed in the same way as the primary endpoint, i.e. using a logistic proportional odds regression model using similar covariates. For subjects who withdraw prematurely from study treatment it will be assumed that their final average daily OCS dose was the average during the 4 weeks immediately following the last dose of study medication. If this is not available, then it will be assumed that their final average daily OCS dose was the average of the last 4 weeks available. Sensitivity analysis will be conducted as follows:

a. The analysis will be replicated using observed data for subjects who prematurely withdraw from treatment, assuming that their final average daily


83

OCS dose was the average during the last 4 weeks of observation while still in the study

b. The analysis will be replicated with missing week 48 to 52 OCS dose decreased from the value used in the primary analysis for placebo and increased from the value used in the primary analysis in mepolizumab in order to determine a level where the p-value changes from significant to non-significant.












84




Blood samples will be collected to determine mepolizumab plasma concentrations (refer to Time & Events table; Table 2). Sparse blood sampling is being implemented in this study. The mepolizumab plasma concentrations from this study will be evaluated using the population PK model developed based on previous mepolizumab studies conducted in different populations including healthy and asthmatic subjects. The analysis will be conducted using for example NONMEM 7 and will allow the determination for example of the population and/or individual systemic exposure, volume of distribution, clearance and the maximum concentration (Cmax) as well as characterise the between- and within-subject variability. The effect of subjects’ characteristics such as, for example, body weight, age, sex, serum creatinine on mepolizumab systemic exposure will also be explored in order to explain the inter-subject variability in drug exposure. Pharmacokinetic data will be presented in graphical and/or tabular form and will be summarized descriptively.










85







The study will be conducted in accordance with ICH GCP, all applicable subject privacy requirements, and the ethical principles that are outlined in the Declaration of Helsinki 2008, including, but not limited to:








In accordance with applicable regulations, GCP, and GSK procedures, GSK monitors will contact the site prior to the start of the study to review with the site staff the protocol,


86

study requirements, and their responsibilities to satisfy regulatory, ethical, and GSK requirements. When reviewing data collection procedures, the discussion will include identification, agreement and documentation of data items for which the CRF will serve as the source document.




Study is conducted in accordance with the currently approved protocol and any other study agreements, GCP, and all applicable regulatory requirements.









87










The results summary will be posted to the Clinical Study Register no later than eight months after the final primary completion date, the date that the final subject was examined or received an intervention for the purposes of final collection of data for the primary outcome. In addition, a manuscript will be submitted to a peer reviewed journal


88

for publication no later than 18 months after the last subject’s last visit (LSLV). When manuscript publication in a peer reviewed journal is not feasible, a statement will be added to the register to explain the reason for not publishing.





89

10. REFERENCES















90
















91









Reilly Associates. Scoring of WPAI. Available at: http://www.reillyassociates.net/WPAI_Scoring.html. Accessed on May 16, 2012.








92









93

11. APPENDICES





[Hetherington, 2002; Mallal, 2002; Mallal, 2008]



Carbamazepine

Seizure, Bipolardisorders & Analgesia Chung, 2010; Ferrell, 2008



94

Irinotecan Cancer [Innocenti,2004; Liu, 2008; Schulz, 2009]

UGT1A1*28 Variations in the UGT1A1 gene can influence a patient’s ability to break down irinotecan, which can lead to increased blood levels of the drug and a higher risk of side effects. A dose of irinotecan that is safe for one patient with a particular UGT1A1 gene variation might be too high for another patient without this variation, raising the risk of certain side-effects that include neutropenia following initiation of Irinotecan treatment. The irinotecan drug label indicates that individuals who have twocopies of the UGT1A1*28 variant are at increased risk of neutropenia. A genetic blood test is available that can detect variations in the gene.


Eosinophilic Granulomatosis with Polyangiitis (EGPA) is a rare disease with a complex genetic component. Many of the genetic studies in EGPA patients have been limited by the relatively small subject numbers available. Some genetic associations with susceptibility to disease have been replicated in multiple studies (e.g., HLA effects), while other genetic associations with susceptibility have not. Some genetic associations with varied pathology have been identified in patients with EGPA or related pathology. The pathogenesis of ANCA-associated vasculitis may have a genetic component. In one study, strong genetic associations were found between anti-proteinase 3 ANCA and HLA-DP, SERPINA1 and PRTN3. HLA-DQ gave evidence of association with microscopic polyangiitis risk (myeloperoxidase-ANCA positivity) [Lyons, 2012]. Additional genetic variants in IL10 have been identified associated with more severe vasculitis in ANCA-negative EGPA patients [Wieczorek, 2008]. Recent work suggests that overproduction of IL-5 (as a consequence of the T cell receptor gene rearrangement) could be involved in EGPA pathogenesis [Horai, 2011].



95



The objective of the PGx research (if there is a potential unexpected or unexplained variation) is to investigate a relationship between genetic factors and response to mepolizumab or other treatment during the study. If at any time it appears there ispotential variability in response in this clinical study or in a series of clinical studies with mepolizumab and other treatment during the study,the following objectives may be investigated – the relationship between genetic variants and study treatment with respect to:



Efficacy

Study Population









96















97






Informed Consent






98

References



Hetherington S, Hughes AR, Mosteller M, et al. Genetic variations in HLA-B region andhypersensitivity reactions to abacavir. Lancet 2002;359:1121-1122.












99


Genetics research as outlined in Appendix 1 will not be conducted in Japan. In Japan pharmacogenetic research will be conducted and restricted to investigations related to mepolizumab treatment only.

Amendment 01 includes a country-specific local amendment generated for Japan.

The Pharmaceuticals and Medical Devices Agency (PMDA) in Japan has requested additional hepatitis B screening evaluation for potential study subjects being enrolled in Japan. Specifically, in addition to hepatitis B surface antigen (HBsAg), subjects will be screened for antibodies to hepatitis B surface antigen and hepatitis B core antigen, i.e., HBsAb and HBcAb respectively. Any subject positive for HBsAg, HBsAb or HBcAb will be excluded from participation. Note: Subjects with antibodies to HBsAg, i.e., HBsAb positive, only (i.e., negative for HBsAg and HBcAb) with a history of hepatitis B vaccination can be included.

Note, there is currently no preclinical or clinical evidence to indicate that mepolizumab administration is associated with immunosuppression. Furthermore, the risk of reactivation of HBV in the population of patients with EGPA to be enrolled in study MEA115921 is considered to be low. HBV screening for all other countries is therefore restricted to HBsAg with exclusion of any subject positive for this test.


100





101



Male partner who is sterile prior to the female subject’s entry into the study andis the sole sexual partner for that female subject

















102




103










104














105




106




107




108





109















110



ALT>3xULN



No

Yes






No

Able to monitor

weekly for 4 weeks?

Yes

No**

Yes




Yes

Yes


wks?

Yes

ALT >5xULN

but <8xULN

NoALT >8xULN

Yes

ALT >5 and

<8xULN for > 2

wksYes No



No

Able to monitor

weekly for

> 2 wks?

No

No


Yes No



111

11.13. Appendix 13: Protocol Changes

11.13.1 Protocol Amendment 01

This amendment applies to all sites.

List of protocol changes

Text which has been added to the protocol is highlighted in bold, italic typeface. Text which has been deleted from the protocol is indicated by strike-through format.

Change Section, Text affected, and Rationale

1. List of Abbreviations

Added:

HBcAb Hepatitis B Core Antibody

HBsAb Hepatitis B Surface Antibody

PMDA Pharmaceuticals and Medical Devices Agency (Japan)

Rationale: Administrative change.

2. Protocol Summary, Study Design, paragraph 7

Section 3.1, Study Design, paragraph 8

Change from:

A full assessment, including evaluation of BVAS, asthma and sino-nasal signs and/or symptoms will be conducted at the time of a relapse.The time of onset of a relapse will be defined as time to change BVAS, asthma or sino-nasal signs and/or symptoms that warranted increase in corticosteroid therapy, increase in dose or addition of immunosuppressive therapy or hospitalisation.

Change to:


The time of onset of a relapse will be defined as i) the time of increase indose of OCS therapy, and/or ii) increase in dose or addition of immunosuppressive therapy, and/or iii) hospitalisation, in association with the worsening in BVAS, asthma or sino-nasal symptoms.

Rationale: The ACQ-6 and sino-nasal symptoms will be assessed by the subject on a weekly basis using a weekly recall period. Worsening will therefore be captured by comparison with the previous week’s evaluation.


112

Inclusion of an additional evaluation of these outcomes in the event of relapse is not therefore considered relevant.

The definition of relapse requires increase in dose of corticosteroid therapy, and/or ii) increase in dose or addition of immunosuppressive therapy, and/or iii) hospitalisation, in association with an increase in BVAS or worsening in asthma and/or sino-nasal symptoms. It is the time of any such intervention that confirms/defines the relapse and is therefore considered the appropriate onset time.



Change from:


Change to:


Rationale: Correction of typographical error.


Section 4.4 Randomisation Criteria, paragraph 1

Change from:

Randomisation will be stratified by region (Japan and rest of world) but not by centre due to the potentially small number of subjects per site.

Change to:

Randomisation will be stratified by; i) subjects in the US participating in the US ‘mechanistic/biomarker’ sub-study (approximately 50 subjects), ii) subjects recruited in Japan and iii) the remainder of the recruited subjects.

Rationale: The ‘Mechanistic’ biomarker study, being conducted at selected sites in the US, will recruit approximately 50 subjects. To ensure balanced treatment allocation across this group of subjects, stratification will therefore include the group of subjects participating in the ‘Mechanistic’ sub-study.



113

Section 3.1, Study Design, last paragraph

Change from:

The objective of these studies will be to examine molecular profiles and biomarkers associated with EGPA and response to anti-IL-5 therapy.

Change to:

The objective of these studies will include examination of molecular profiles and biomarkers associated with EGPA and response to anti-IL-5 therapy.

Rationale: Clarification of sub-study objective.

6. Section 4.3, Exclusion Criteria #10

Change from:

Hepatitis status: Diagnosis of chronic hepatitis B, as evidenced by positive Hepatitis B surface antigen (HBsAg) at Screening (Visit 1).

Change to:

Hepatitis status: Diagnosis of chronic hepatitis B, as evidenced by positive Hepatitis B surface antigen (HBsAg) at Screening (Visit 1). Japan only: Subjects positive for antibodies to HBsAg, i.e., HBsAb, or Hepatitis B core antigen, i.e., HBcAb, at Screening (Visit 1). Note: Subjects with antibodies to HBsAg, i.e., HBsAb positive, only (i.e., negative for HBsAg and HBcAb) with a history of hepatitis B vaccination can be included.

Rationale: The PMDA in Japan has requested additional hepatitis B screening evaluation for potential study subjects being enrolled in Japan (see Appendix 2 for additional information).

7. Section 4.4, Randomisation Criteria #3

Change from:

Hepatitis status: No diagnosis of chronic hepatitis B, as evidenced by positive HBsAg at Screening (Visit 1).

Change to:

Hepatitis status: No diagnosis of chronic hepatitis B, as evidenced by positive HBsAg at Screening (Visit 1). Japan only: Subjects positive for HBsAg or antibodies to HBsAg, i.e., HBsAb, or Hepatitis B core antigen, i.e., HBcAb, at Screening (Visit 1) are excluded. Note: Subjects with antibodies to HBsAg, i.e., HBsAb positive, only (i.e., negative for HBsAg


114

and HBcAb) with a history of hepatitis B vaccination can be included.


8. Section 4.5.1 Withdrawal from Study Treatment, Bulleted List

Added:


Rationale: Added for consistency with information provided in Section 6.3.2.

9. Section 5.2 Treatment Assignment, paragraph 1

Change from:

Randomisation will be stratified by region (Japan and rest of world).

Change to:



10. Section 5.5 Product Accountability

Change from:


Change to:

In accordance with local regulatory requirements, the investigator, designated site staff, or head of the medical institution (where applicable) must document the amount of investigational product dispensed and/or


115

administered to study subjects and the amount received from and returned to GSK, when applicable. Product accountability records must be maintained throughout the course of the study.


11. Section 6, Table 2, Biomarker Sub-studies, Blood sample

Deleted :

“X” in column “SCREEN”

Rationale: Correction to sub-study sample collection.

12. Section 6, Table 2, Biomarker Sub-studies

Added row: Urine sample and “X” as indicated

Rationale: For consistency with changes to protocol text.

13. Section 6, Table 2, Footnote 4

Change from:

A blood, sputum and, where possible, biopsy sample to be collected in the event of relapse from subjects participating at US sites in the ‘mechanistic’ sub-study.

Change to:

A blood, urine, sputum and, where possible (i.e., if as part of standard of care management), abiopsy sample to be collected in the event of relapse from subjects participating at US sites in the ‘mechanistic’ sub-study.

Rationale: For consistency with changes to protocol text regarding urine sample collection in sub-study. Added text to provide clarification regarding sub-study biopsy sample collection.


Added:

Japan only: Antibodies to Hepatitis B Surface Antigen and Hepatitis B Core Antigen, i.e., HBsAb and HBcAb respectively.

Rationale: For consistency with changes to protocol text regarding hepatitis screening for subjects in Japan (see Appendix 2 for additional information).


Change from:

Biomarker samples: Blood and sputum samples to be collected from consenting subjects participating


116

at US sites in the ‘mechanistic/biomarker’ sub-study only. Where possible, blood and sputum samples also to be collected in the event of relapse. Blood samples to be collected from consenting subjects at sites participating in the European ‘mechanistic/biomarker’ sub-study.

Change to:

Biomarker samples: Blood, sputum and urine samples to be collected as indicated from Baseline (Visit 2) to Week 60 (or early withdrawal) from consenting subjects participating at US sites in the ‘mechanistic/biomarker’ sub-study only. Where possible, blood, sputum and urine samples also to be collected in the event of relapse. Blood samples to be collected as indicated from Baseline (Visit 1) to Week 60 (or early withdrawal) from consenting subjects at sites participating in the European ‘mechanistic/biomarker’ sub-study.

Rationale: For consistency with changes to protocol text regarding urine sample collection in sub-study. Added text to provide clarification regarding sub-study sample collection.

16. Section 6.1.1 Critical Procedures Performed at Screening (Visit 1), Bulleted list, first and last bullets

Change from:


Change to:



Change from:

Mechanistic Sub-study only: Biomarker sample collection

Rationale: Updated sampling schedule.

17. Section 6.2.2.1, Relapse, paragraph 2

Change from:

The time of onset of a relapse will be defined as time to change BVAS, asthma or sino-nasal signs and/or symptoms that warranted increase in corticosteroid therapy, increase in dose or addition of immunosuppressive therapy or hospitalisation.

Change to:

A BVAS evaluation will be conducted at the time of a relapse, or as soon


117

as possible afterwards.


Rationale: The ACQ-6 and sino-nasal symptoms will be assessed by the subject on a weekly basis using a weekly recall period. Worsening will therefore be captured by comparison with the previous week’s evaluation. Inclusion of an additional evaluation of these outcomes in the event of relapse is not therefore considered relevant.


18. Section 6.2.2.1, Relapse, paragraph 3, last sentence

Change from:

For consenting subjects participating in the US ‘mechanistic’ sub-study, where possible, a blood, sputum and, tissue (biopsy) sample should be collected in the event of relapse.

Change to:

For consenting subjects participating in the US ‘mechanistic’ sub-study, where possible, a blood, urine, sputum and tissue (biopsy) sample should be collected in the event of relapse. In addition, where possible, (i.e., as part ofstandard of care management), a tissue (biopsy) sample should be collected.

Rationale: Added urine sample to sub-study sample collection. Added text to provide clarification regarding sub-study tissue sample collection.

19. Section 6.3.11.3 Clinical Laboratory Parameters, Routine Haematology

Deleted:

Reticulocytes


20. Section 6.3.11.3 Clinical Laboratory Parameters, Other laboratory parameters


118

Added:



21. Section 6.7.1 Mechanistic/Biomarker Sub-studies

Change from:

US: Samples (blood and/or sputum, and in case of relapse, where possible, tissue) for the investigator-sponsored, ‘mechanistic’ sub-study, will be collected from specified US sites only at the visits specified in the Time and Events table (Table 2).

Change to:

US: Samples (blood, urine and sputum, and in case of relapse, where possible [i.e., if as part of standard of care management] a tissue sample) for the investigator-sponsored, ‘mechanistic’ sub-study, will be collected from specified US sites only at the visits specified in the Time and Events table (Table 2).


22. Section 8.3.5.1 Efficacy Analyses, Primary Efficacy Endpoints, Paragraph 2

Change from:

Baseline covariates to be included in the model are: i) baseline steroid dose, ii) ANCA status (due to potential for association with risk of relapse [Sablé-Fourtassou, 2005; Sinico, 2005]) and iii) region, (Japan versus rest-of-world for administrative reasons).

Change to:

Baseline covariates to be included in the model are: i) baseline steroid dose, ii) ANCA status (due to potential for association with risk of relapse [Sablé-Fourtassou, 2005; Sinico, 2005]) and iii) region, i.e., i) subjects participating in the US ‘Mechanistic’ sub-study, ii) Japan (for administrative reasons) and iii) the remainder of recruited subjects.

Rationale: For consistency with change made to stratification.

23. Section 10, References and associated cross-reference in Section 6.4.1.2

Change from:


119


[Reily Associates, 2012]

Change to:


[Reilly Associates, 2012]


24. Section 11.1, Appendix 1, Genetics/Pharmacogenetics Research, paragraph 3, last sentence

Change from:

Recent work suggests that overproduction of IL-5 (as a consequence of the T cell receptor gene rearrangement) could be involved in CSS pathogenesis [Horai, 2011].

Change to:

Recent work suggests that overproduction of IL-5 (as a consequence of the T cell receptor gene rearrangement) could be involved in EGPApathogenesis [Horai, 2011].

Rationale: Correction to text.

25. Section 11.2, Appendix 2, Country-specific Requirements

Added:



Note, there is currently no preclinical or clinical evidence to indicate that mepolizumab administration is associated with immunosuppression.


120

Furthermore, the risk of reactivation of HBV in the population of patients with EGPA to be enrolled in study MEA115921 is considered to be low. HBV screening for all other countries is therefore restricted to HBsAg with exclusion of any subject positive for this test.

Rationale: Explanation of the country-specific requirement for Japan.


1

TITLE PAGE


Title: A Double-blind, Randomised, Placebo-controlled Study to Investigate the Efficacy and Safety of Mepolizumab in the Treatment of Eosinophilic Granulomatosis with Polyangiitis in Subjects Receiving Standard of Care Therapy


Development Phase: III

Effective Date: 27-AUG-2014


Author (s):



2

Revision Chronology

GlaxoSmithKlineDocument Number

Date Version

2012N142276_00 2013-AUG-29 Original

2012N142276_01 2013-OCT-15 Amendment No. 1

Amendment No.:01 Generated to remove evaluation of ACQ-6 and sino-nasal symptoms at the time of relapse and to clarify the definition of time of onset of relapse; country-specific requirements for Japan regarding hepatitis B screening added as well as clarification to text as needed and administrative changes. A detailed list of changes is provided in Appendix 13

2012N142276_02 2014-AUG-27 Amendment No. 2

Amendment No.:02 Generated to clarify investigators can taper oral corticosteroids downward when BVAS≠0; to include additional statement in risk assessment table; to clarify that subjects who become pregnant must be withdrawn from study treatment; to clarify requirements for collection of a fasting blood sample in diabetic subjects; to clarify that collection of PK samples at Weeks 1 and 29 is optional; to delete requirement for measurement of eosinophil count as a liver event follow-up assessment; to amend the schedule for sputum sampling in the biomarker sub-study; to add country-specific change for Japan regarding definition of relapsing disease in inclusion criteria; to include SAMAs and LAMAs as bronchodilator to be withheld prior to reversibility testing; to clarify requirements for subject follow-up in the event study treatment is discontinued; to include reference to the Supplement to Version 12 of the Investigator’s Brochure and other administrative changes. A detailed list of changes is provided in Appendix 13.


4










MD, PhD (Head, Clinical Development, Alternative Development Program)

Tel:

Mobile:



Tel:

Mobile:


5


Tel:

Mobile:

FAX:

email:



IND No. 006971


6


For protocol number MEA115921.


I acknowledge that I am responsible for overall study conduct. I agree to personally conduct or supervise the described study.


Investigator Name:

Investigator Address:

Investigator Phone Number:



7

TABLE OF CONTENTS

PAGE

LIST OF ABBREVIATIONS...........................................................................................10




2. OBJECTIVES.........................................................................................................29










6.2. Efficacy.......................................................................................................55


8















7. DATA MANAGEMENT ...........................................................................................75




9








10. REFERENCES.......................................................................................................90

11. APPENDICES ........................................................................................................9411.1. Appendix 1: Genetics/Pharmacogenetics Research ...................................9411.2. Appendix 2: Country Specific Requirements .............................................10011.3. Appendix 3: Recommended Prednisolone/Prednisone Tapering



11.13.1. Protocol Amendment 01 ............................................................11211.13.2. Protocol Amendment 02 ............................................................121


10




11

IL InterleukinINR International normalised ratioIRB Institutional review BoardITT Intent-to-TreatIUD Intrauterine deviceIV Intravenous(ly)IVRS Interactive Voice Response Systemkg kilogramLABA Long acting beta2 agonistLAMA Long-acting muscarinic adrenoreceptor antagonistsmAb Monoclonal antibodyMedDRA Medical Dictionary for Regulatory Activitiesmg milligramsMPA Microscopic polyangiitis MRI Magnetic resonance imagingMSDS Material Safety Data Sheetmsec millisecondNAB Neutralizing antibodiesOCS Oral CorticosteroidPBMC Peripheral blood mononuclear cellsPCR Polymerase chain reactionPD PharmacodynamicsPEF Peak expiratory flowPGx PharmacogeneticsPK PharmacokineticsPMDA Pharmaceuticals and Medical Devices Agency (Japan)PP Per protocolQTcB QT interval corrected for heart rate according to Bazett’s


formulaRAP Reporting and Analysis PlanRBC Red blood cellRNA Ribonucleic acidRPGN Rapidly progressive glomerulonephritis SABA Short acting beta-agonistSAMA Short-acting muscarinic adrenoreceptor antagonistsSAE Serious Adverse EventSC Subcutaneous(ly)SF-36 Short-form 36SNOT-22 Sino-nasal Outcome Test-22SOC System organ classSPM Study procedures manualSRT Safety review teamTNF Tumour necrosis factorULN Upper limit of normalUS United StatesVDI Vasculitis Damage Index


12

WBC White blood cellWPAI Work Productivity Activity Impairment




VENTOLIN NONMEM 7


13

PROTOCOL SUMMARY

Rationale




Objectives

Primary

To investigate the efficacy of mepolizumab plus standard of care compared with placebo plus standard of care on duration of clinical remission, defined as accrued duration in weeks where a subject achieves a BVAS=0 and corticosteroid dose ≤4 mg/day prednisolone/prednisone in subjects with relapsing or refractory eosinophilic granulomatosis with polyangiitis (EGPA) receiving standard of care therapy including corticosteroid therapy reduction/withdrawal.


Secondary




14



Other








Study Design





15




Between baseline (randomisation) and Week 4, subjects will be required to continue on their stable OCS (prednisolone/prednisone) dose (if necessary, upward adjustments are permitted for clinical management of the patient). From Week 4 post-baseline onwards, if the subject’s BVAS=0 their oral OCS dose should be tapered downwards according to standard of care practice. A recommended tapering schedule provided in the protocol enables a reduction in OCS dose every 2 weeks, with the intention of achieving a prednisolone/prednisone dose of 4 mg/day or less. Note, where the BVAS ≠ 0, the investigator may taper the subject’s OCS downwards at his/her clinical discretion. Once a subject has achieved a dose of 4 mg/day prednisolone/prednisone, the investigator is encouraged to continue tapering downwards, if clinically warranted, at dose increments of 0.5-1.0 mg every 2 weeks.


EGPA relapse will be defined as worsening or persistence of active disease since the last visit characterised by: a) active vasculitis (BVAS >0); OR b) active asthma symptoms and/or signs with a corresponding worsening in ACQ-6 score (compared to the most recent previous score); OR c) active nasal and/or sinus disease with a corresponding worsening in at least one of the sino-nasal symptom questions (compared to the most recent previous assessment) warranting: i) an increased dose of OCS therapy OR ii) an increased dose or addition of immunosuppressive therapy; OR iii) hospitalisation related to EGPA worsening. A BVAS evaluation will be conducted at the time of a relapse, or as soon as possible afterwards. The time of onset of a relapse will be defined as i) the time of increase in dose of OCS therapy, and/or ii) increase in dose or addition of immunosuppressive therapy, and/or iii) hospitalisation, in association with the worsening in BVAS, asthma or sino-nasal symptoms. In the event a subject has achieved remission (i.e., BVAS=0 and prednisolone/prednisone dose ≤4 mg/day) and at any subsequent visit has a BVAS = 1 which does not require an increase in corticosteroid dose above 4 mg/day, or any other significant clinical intervention or investigation, the subject will be considered to be in continued remission.


16









Investigator-sponsored ‘mechanistic/biomarker’ sub-studies will be conducted at selected sites in the United States (US) and Europe using samples collected from consenting subjects participating in the study. The objective of these studies will include examination of molecular profiles and biomarkers associated with EGPA and response to


17

anti-IL-5 therapy. Specific details of the planned analyses will be outlined in the individual protocols and/or analysis plans for these sub-studies.















18

1. INTRODUCTION

1.1. Background

Eosinophilic Granulomatosis with Polyangiitis (EGPA), also referred to as Churg-Strauss syndrome (CSS), is a rare hypereosinophilic syndrome characterised by small vessel vasculitis in association with asthma, sinusitis, and pulmonary infiltrates. Multiple organs can be affected including the heart, lungs, skin, gastrointestinal tract, kidneys, and nervous system [Keogh, 2006; Vaglio, 2012; Holle, 2009]. The mean age of diagnosis of EGPA is 48 years, with a gender ratio of approximately 1:1 [Pagnoux, 2007]; the incidence has been estimated as 1-4 per million per year [Lane, 2005]. EGPA is associated with a positive status for anti-neutrophil cytoplasmic antibodies (ANCAs), typically ANCA-Myeloperoxidase (MPO) and ANCA-Proteinase 3 (PR3), in approximately 40% of patients [Holle, 2009; Sinico, 2005]. In addition, the role of allergy in EGPA is widely acknowledged, especially in the prodromal disease phase that is characterized by typical allergic manifestations such as asthma, sinusitis, and nasal polyposis with raised serum IgE levels observed in approximately 90% of EGPA patients [Vaglio, 2012]. In recent proposed classification systems for eosinophil disorders, EGPA has been described as being associated with Hypereosinophilic Syndrome (HES) [Simon, 2010], although it should nevertheless be distinguished from true HES [Valent, 2012].



19


Mepolizumab is a fully humanized monoclonal antibody (IgG1, kappa, mAb) which is specific for human IL-5 and which blocks binding of human IL-5 (hIL-5) to the alpha chain of the IL-5 receptor complex expressed on the eosinophil cell surface. In patients with conditions where eosinophilia is considered to play an important part in the pathology, a consistent reduction in eosinophil number is observed in association with mepolizumab administration, with concomitant clinical improvement [Haldar, 2009; Pavord, 2012; Stein 2006, Rothenberg 2008; Nair, 2009].



20

1.2. Rationale



1.3. Dose Rationale



Mepolizumab (750 mg IV every 4 weeks) was shown to be well-tolerated in studies CRT109797 and MHE109435 consistent with the overall safety profile previously demonstrated in over 1300 subjects treated with mepolizumab across different eosinophilic conditions (i.e., severe asthma, HES, eosinophilic esophagitis, atopic dermatitis and nasal polyposis). For details see the Investigator’s Brochure and Supplement (GlaxoSmithKline Document Number: CM2003/00010/08 and GlaxoSmithKline Document Number 2014N200212).


A non-linear inhibition dose-response model based on blood eosinophil counts, developed from a pharmacokinetic/pharmacodynamic (PK/PD) study of mepolizumab in adult subjects with asthma and elevated blood eosinophil levels (study MEA114092), has identified 75 mg IV every 4 weeks as the ID90 (i.e., dose providing 90% of the maximum blood eosinophil reduction achievable by


21

the drug) for blood eosinophil reduction. The estimated absolute bioavailability for SC route of administration in the upper arm in this study was approximately 75% [IB; GlaxoSmithKline Document Number: CM2003/00010/08]. Therefore a dose of 100 mg SC is anticipated to provide similar exposure to a 75mg IV dose. A 100 mg SC dose every 4 weeks is therefore being investigated in confirmatory studies in severe asthma as the SC route is more convenient compared with IV and is generally preferred by patients.










Summaries of findings from both clinical and non-clinical studies conducted with mepolizumab can be found in the Investigator Brochure and Supplement(GlaxoSmithKline Document Number: CM2003/00010/08 and GlaxoSmithKline


22

Document Number: 2014N200212). Table 1 summarises the risk assessment and mitigation strategy for this protocol.


23






Biopharmaceutical products may elicit ADA and NAB, which have the potential to modulate PK, PD or produce adverse reactions. However, humanized and fully human antibodies are less immunogenic than mouse or chimericmonoclonal antibodies.

Reactions reported to date across the mepolizumab program are summarized in the IB and IB supplement; see ‘Special Warnings and Special Precautions for Use’ section located in Section 6 titled ‘Summary of Data and Guidance for the Investigator’.(GlaxoSmithKline Document Number: CM2003/00010/08 and GlaxoSmithKline DocumentNumber: 2014N200212).











24







In one study in subjects with severe refractory asthma, cardiac events were reported in similar frequencies across treatment groups with a small numerical increase observed in serious ischemic cardiac events in the mepolizumab-treated groups. However, an integrated safety analysis of all placebo-controlled multiple-dose asthma trials showed a similar frequency of SAEs reported overall from the cardiac and vascular system organ class (SOC). Additionally, similar findings were observed in other SOCs with thrombotic events (e.g., stroke in the Nervous System SOC). Data from 2 subsequently completed placebo-controlled severe asthma trials did not show an increased risk of serious ischemic cardiac events; there were no new reports in any treatment groups including placebo.










25








Infections reported to date across the mepolizumab development program are summarized in the IB and IB supplement; see ‘Special Precautions and Warnings’ (for exclusion of subjects with underlying parasitic infections) and ‘Undesirable Effects’ (for very common infections of nasopharyngitis, URTI, rhinitis and bronchitis reported in other patient populations) sections located in Section 6 titled ‘Summary of Data and Guidance for the Investigator’ (GlaxoSmithKline Document Number: CM2003/00010/08 and GlaxoSmithKline Document Number: 2014N200212).





26


















27



Study Procedures










28









29








2. OBJECTIVES

Primary

To investigate the efficacy of mepolizumab plus standard of care compared with placebo plus standard of care on duration of clinical remission, defined as accrued duration in weeks where a subject achieves a BVAS=0 and corticosteroid dose ≤4 mg/day prednisolone/prednisone, in subjects with relapsing or refractory eosinophilic granulomatosis with polyangiitis (EGPA) receiving standard of care therapy including corticosteroid therapy reduction/withdrawal.


30


Secondary





Other









3.1. Study Design



31







32


Between baseline (randomisation) and Week 4, subjects will be required to continue on their stable OCS (prednisolone/prednisone) dose (if necessary, upward adjustments are permitted for clinical management of the patient). From Week 4 post-baseline (Visit 4) onwards, if the subject’s BVAS = 0 their oral OCS dose should be tapered downwards according to standard of care practice. A recommended tapering schedule for this purpose is provided in Appendix 3 (see Section 11.3). The recommended tapering schedule enables a reduction in OCS dose every 2 weeks, with the intention of achieving a prednisolone/prednisone dose of 4 mg/day or less. Note, where the BVAS ≠ 0, the investigator may taper the subject’s OCS downwards at his/her clinical discretion. Once a subject has achieved a dose of 4 mg/day prednisolone/prednisone, the investigator is encouraged to continue tapering downwards, if clinically warranted, at dose increments of 0.5-1.0 mg every 2 weeks.

In this study EGPA remission is defined as BVAS = 0 plus OCS dose of prednisolone/prednisone 4 mg/day. In defining EGPA remission, asthma and sino-nasal symptoms /signs related to EGPA activity, if not specifically covered by the BVAS assessment, will be considered to be controlled by virtue of the low OCS dose (i.e., 4 mg/day prednisolone/prednisone) and are therefore not included in the remission definition. EGPA relapse will be defined as worsening or persistence of active disease since the last visit characterised by:





33

warranting:






In the event a subject has achieved remission (i.e., BVAS=0 and prednisolone/prednisone dose ≤4 mg/day) and at any subsequent visit has a BVAS=1 which does not require an increase in prednisolone/prednisone dose above 4 mg/day, or any other significant clinical intervention or investigation, the subject will be considered to be in continued remission.




If the subject’s first relapse is managed with the use of an increase in corticosteroid dose, tapering should be recommenced as soon as the relapse has been appropriately controlled, as per standard of care practice. As stated above, the recommended tapering schedule is provided in Appendix 3 (see Section 11.3), although after the first relapse the investigator may opt to use larger dose increments and shorter dose intervals than outlined in the schedule, if clinically indicated. Once the minimally effective dose of OCS is achieved, any down-tapering below this dose level will be at the discretion of the investigator, based on the clinical condition of the subject. In the event of a second or subsequent


34

relapse, any further OCS tapering, post-relapse, will be conducted at the discretion of the investigator.






Investigator-sponsored ‘mechanistic/biomarker’ sub-studies will be conducted at selected sites in the United States (US) and Europe using samples collected from consenting subjects participating in the study. The objective of these studies will include examination of molecular profiles and biomarkers associated with EGPA and response to


35

anti-IL-5 therapy. Specific details of the planned analyses will be outlined in the individual protocols and/or analysis plans for these studies.






The total study treatment duration is 52 weeks. This duration permits downwards tapering of OCS dose to a target of 4 mg/day prednisolone/prednisone and evaluation of disease control over an extended period, and balances the need to assess the experimental therapy for at least 12 months and the feasibility of retaining subjects in a clinical trial


36

over a prolonged period of time. The protocol provides a recommended schedule from Week 4 for gradual tapering of corticosteroids down to 4 mg/day prednisolone/prednisone where the subject’s BVAS=0 (Appendix 3; see Section 11.3). Note, where the BVAS ≠ 0, the investigator may taper the subject’s OCS downwards at his/her clinical discretion. Once subjects have reached a dose of 4 mg/day prednisolone/prednisone, further tapering downwards may be continued. However, upward adjustment in the dose of OCS is permitted within the 0-4.0 mg range without necessarily being defined as a relapse. This approach recognises that some subjects on long-term OCSs are relatively resistant to complete discontinuation of therapy, and are vulnerable to precipitation of Addisonian symptoms.






Specific information regarding warnings, precautions, contraindications, AEs, and other pertinent information on the GSK investigational product or other study treatment that may impact subject eligibility is provided in the mepolizumab IB and Supplement (GlaxoSmithKline Document Number: CM2003/00010/08 and GlaxoSmithKline Document Number: 2014N200212).






37









palpable purpura;




Japan only definition of Relapsing disease:Subject must have a past history of at least one confirmed EGPA relapse (i.e., requiring increase in OCS dose, initiation of IV prednisolone (or equivalent),initiation/increased dose of immunosuppressive therapy, initiation/increased dose of intravenous immunoglobulin (IVIG) or hospitalisation) within the past 2 years which occurred at least 12 weeks prior to Screening (Visit 1) whilst receiving a dose of prednisolone (or equivalent) of ≥7.5 mg/day.

Refractory disease:




38

















39



















40



10. Hepatitis status: Diagnosis of chronic hepatitis B, as evidenced by positive Hepatitis B surface antigen (HBsAg) at Screening (Visit 1). Japan only: Subjects positive for HBsAg , antibodies to HBsAg, i.e., HBsAb, or Hepatitis B core antigen, i.e., HBcAb, at Screening (Visit 1). Note: Subjects with antibodies to HBsAg, i.e., HBsAb positive, only (i.e., negative for HBsAg and HBcAb) with a history of hepatitis B vaccination can be included.
















WBC < 4 x109/L




41












3. Hepatitis status: No diagnosis of chronic hepatitis B, as evidenced by positive HBsAg at Screening (Visit 1). Japan only: Subjects positive for HBsAg or antibodies to HBsAg, i.e., HBsAb, or Hepatitis B core antigen, i.e., HBcAb, at Screening (Visit 1) are excluded. Note: Subjects with antibodies to HBsAg, i.e., HBsAb positive, only (i.e., negative for HBsAg and HBcAb) with a history of hepatitis B vaccination can be included.



42









Reasons for premature discontinuation of study treatment must be captured in the electronic case report form (eCRF), e.g., AE, lack of efficacy, protocol deviation, pregnancy, investigator discretion, consent withdrawn etc. In addition, subjects will be withdrawn from study treatment for any of the following reasons:



Concurrent medication: Use of prohibited concurrent medication (i.e., as noted in Section 5.7.2 - Prohibited Medications and Non-Drug Therapies) including cyclophosphamide.


ECG abnormalities:

QTc >500 msec





43




<450 msec >500 msec

450-480 msec ≥530 msec












44


5. STUDY TREATMENTS








A unique Subject Number will be assigned to any subject who is consented. This unique subject number will be used to identify the individual subject throughout the study and will not be re-assigned to any other subject. Randomisation will be stratified by; i) subjects in the US participating in the US ‘mechanistic/biomarker’ sub-study (approximately 50 subjects), ii) subjects recruited in Japan and iii) the remainder of the recruited subjects.



45













Safety monitoring of subjects will occur during SC administration and for 1 hour after the end of injection. Such monitoring will include general safety monitoring includingmonitoring for both systemic hypersensitivity (i.e., allergic/IgE-mediated and non-


46

allergic) and local site reactions. Trained rescue personnel and rescue medications/equipment must be available for use at all times. See Appendix 11(Section 11.11) for additional information.

5.4. Blinding











47



In the event immunosuppressive therapy is initiated or the dose increased (e.g., in the event of relapse) study treatment should be withdrawn and, where possible, the subject continue to be followed up as per protocol until the end of follow-up at Week 60 (see Section 4.5.1 - Withdrawal from Study Treatment).





Omalizumab 130 days




Anti-TNF 12 weeks







In the event a prohibited medication is used (e.g., in the event of relapse) study treatment should be withdrawn and, where possible, the subject continue to be followed up as per protocol until the end of follow-up at Week 60 (see Section 4.5.1 - Withdrawal from


48

Study Treatment). Note, this does not include use of any other investigational agent (biologic or non-biologic) where, if used, the subject should be withdrawn from the study.








Throughout the study subjects will be required to complete the following paperquestionnaires at the study site: Sino-nasal Outcome Test-22 (SNOT-22), the Short Form-36 (SF-36), and the Work Productivity and Activity Impairment (WPAI) Index.


49



period

Study visits 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17Early W/D (1)

18 19Early W/D (2)


Pre-screen


BASE LINE

13

47

87

127

167

207

247

287

293

327

367

407

447

487

527

567

607


X




X



50


period


18 19Early W/D (2)


Pre-screen


BASE LINE

13

47

87

127

167

207

247

287

293

327

367

407

447

487

527

567

607







51


period


18 19Early W/D (2)


Pre-screen


BASE LINE

13

47

87

127

167

207

247

287

293

327

367

407

447

487

527

567

607





Complete eCRF X X X X X X X X X X X X X X X X X X X X XFootnotes on next page


52

Table 2 footnotes:




possible. The period of fasting may be adjusted at the discretion of the investigator for subjects with relevant metabolic conditions (e.g., diabetes mellitus).15. Urinalysis Screen sample (Visit 1) to be analysed by the central laboratory; all other tests to be conducted using by dipstick.16. Hepatitis B Surface Antigen and Hepatitis C antibody (if hepatitis C antibody positive, a HCV RNA test (either quantitative or qualitative) should be performed). Japan only:

Antibodies to Hepatitis B Surface Antigen and Hepatitis B Core Antigen, i.e., HBsAb and HBcAb, respectively.17. Serum pregnancy test (S) to be conducted in women of childbearing potential at Screening (Visit 1) and Week 52 (or early withdrawal); urine pregnancy tests (U) to be conducted

at all other indicated visits.18. PK sampling: At Baseline and Weeks 4, 28 and 48 the PK sample should be taken pre-dose. At Weeks 1 and 29, where practical, an optional PK sample is to be collected

(although, where possible, every effort should be made to collect these samples).19. In the event of premature discontinuation of study medication, a sample for measurement of anti-drug antibodies should be collected at the nearest scheduled study visit


at US sites in the ‘mechanistic/biomarker’ sub-study only. Where possible, blood, sputum and urine samples also to be collected in the event of relapse. Blood samples to becollected as indicated from Baseline (Visit 1) to Week 60 (or early withdrawal) from consenting subjects at sites participating in the European ‘biomarker’ sub-study.




53


























54

Urinalysis.




ANCA (MPO and PR3).



Weight.



















Clinical chemistry.

Urinalysis.


IL-5.


55

CRP and ESR.

IgE.





6.2. Efficacy


Primary


Zero

>0 to <12 weeks

12 to <24 weeks

24 to <36 weeks

≥36 weeks


Secondary



Zero

>0 to ≤4.0 mg

>4.0 to ≤7.5 mg


56

>7.5 mg


Other


Zero

>0 to <12 weeks

12 to <24 weeks

24 to <36 weeks

≥36 weeks







<25%

25 to <50%

50 to <75%

75 to <100%

100%








57











6.2.1.2. Relapse





warranting:





58













59

Runny nose










6.2.1.6. Spirometry



Prior to the Baseline visit (Visit 2) subjects should withhold short-acting beta-2-agonists (SABAs) and short-acting muscarinic adrenoreceptor antagonists (SAMAs) for at least 6 hours and long-acting beta-2-agonists (LABAs) and long-acting muscarinic adrenoreceptor antagonists (LAMAs) for at least 12 hours to enable reversibility testing to be performed. Specifically, FEV1 will be measured pre-salbutamol/albuterol and


60

within 30 minutes [±15 minutes] following up to 4 inhalations of salbutamol/albuterol (a spacer device may be used if required) or equivalent nebulised treatment with salbutamol/albuterol solution. The reversibility test must be performed in the morning only at Baseline (Visit 2).






6.3. Safety









61













2. ALT 8xULN.







Complete the liver event CRF and SAE data collection tool if the event also meets the criteria for an SAE. All events of ALT 3xULN and bilirubin 2xULN (>35% direct) (or ALT 3xULN and INR>1.5, if INR measured); INR measurement is not required and the threshold value stated will not apply to patients receiving


62

anticoagulants), termed ‘Hy’s Law’, must be reported as an SAE (excluding studies of hepatic impairment or cirrhosis).
















Must return weekly for repeat liver chemistries (ALT, AST, alkaline phosphatase,bilirubin) until they resolve, stabilise or return to within baseline



63






Hepatitis C RNA;







Collect sample for measurement of complete blood count with differential to enable future assessment of eosinophilia. Note: To ensure investigators remain blinded to eosinophil count, as for all other blood count tests post-baseline, sites will only be sent absolute neutrophil, lymphocyte, monocyte, and basophil counts. The full blood count data including eosinophil result will be available after the subject’s treatment has been unblinded.






64

















65








a) Results in death




NOTE: In general, hospitalisation signifies that the subject has been detained (usually involving at least an overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have been appropriate in the physician’s office or out-patient setting. Complications that occur during hospitalisation are AEs. If a complication prolongs hospitalisation or fulfills any other serious criteria, the event is serious. When in doubt as to whether “hospitalisation” occurred or wasnecessary, the AE should be considered serious.





f) Medical or scientific judgment should be exercised in deciding whether reporting is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalisation but may jeopardise the subject or may require medical or surgical intervention to prevent one of the other


66

outcomes listed in the above definition. These should also be considered serious. Examples of such events are invasive or malignant cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation, or development of drug dependency or drug abuse.

g) All events of possible drug-induced liver injury with hyperbilirubinaemia defined as ALT 3xULN and bilirubin 2xULN (>35% direct) (or ALT 3xULN and INR>1.5, if INR measured) termed ‘Hy’s Law’ events (INR measurement is not required and the threshold value stated will not apply to patients receiving anticoagulants).








Arrhythmias

Valvulopathy





Revascularisation


67


6.3.6. Death Events



6.3.7. Pregnancy











68












applicable





measured)1












(defined above)3



69








for 2 weeks3


if applicable3


persists 2 weeks


(defined above)3



<2xULN





for 4 weeks3


if applicable3









70















71














72
















73









SF-36

WPAI index.


6.4.1.1. Short Form-36 (SF-36)




The WPAI (General Health version 2.0) is a self or interviewer administered tool comprised of 6 questions which address absenteeism, presenteeism (reduced effectiveness while working), overall work productivity loss (absenteeism plus presenteeism), and activity impairment. This validated tool captures data from the past 7 days. WPAI outcomes are scored as impairment percentages, with a higher percentageindicating greater impairment and less productivity [Reilly Associates, 2012].


74














6.6. Immunogenicity



75


6.7. Biomarkers







7. DATA MANAGEMENT





76


8.1. Hypotheses










77












78



Percent Success

(For either Subjects with Accrued Remission ≥ 24 weeks or Subjects in Remission at Weeks 36 and 48)


15% 44% 29% 4.5 93%

20% 49% 29% 3.8 91%

25% 54% 29% 3.5 90%

30% 59% 29% 3.4 89%

16% 40% 24% 3.5 82%

40% 70% 30% 3.5 91%

72% 90% 18% 3.5 66%










79



Safety Population:


PK Population:


PD Population:









Other comparisons of interest are mepolizumab versus placebo for each of the 3 secondary endpoints. In order to make inferences for the pre-defined secondary endpoints while controlling the overall type I error, multiplicity across these comparisons


80

will be controlled using a closed testing procedure where the secondary endpoints will be nested under the primary efficacy endpoint, followed by a further hierarchical procedure within the secondary endpoints, in the order of: i) time to relapse, ii) prednisolone/prednisone dose followed by, iii) proportion of subjects who achieve remission within the first 24 weeks of the study and then remain in remission. That is:
















81

The primary analysis of co-primary endpoint ’1’ will use a logistic proportional odds regression model for ordered categorical data for the proportion of subjects who achieve remission categorised, as above, for the ITT population. Baseline covariates to be included in the model are: i) baseline steroid dose, ii) ANCA status (due to potential for association with risk of relapse [Sablé-Fourtassou, 2005; Sinico, 2005]) and iii) region, i.e., i) subjects participating in the US ‘Mechanistic’ sub-study, ii) Japan (for administrative reasons) and iii) the remainder of recruited subjects.













82














83


Secondary Endpoints









c. Subjects who withdraw prematurely from study treatment and continue to be followed in the study will be deemed to have an event at the time an event is observed. As in the planned analysis for time to observed relapse, subjects thatwithdraw from the study are censored at the time of withdrawal.

The proportion of subjects with an average daily prednisolone/prednisone dose during the last 4 weeks of the treatment period (Weeks 48 through 52) will be analysed in the same way as the primary endpoint, i.e. using a logistic proportional odds regression model using similar covariates. For subjects who withdraw prematurely from study treatment it will be assumed that their final average daily OCS dose was the average during the 4 weeks immediately following the last dose of study medication. If this is not available, then it will be assumed that their final average daily OCS dose was the average of the last 4 weeks available. Sensitivity analysis will be conducted as follows:

a. The analysis will be replicated using observed data for subjects who prematurely withdraw from treatment, assuming that their final average daily


84

OCS dose was the average during the last 4 weeks of observation while still in the study








AEs will be coded using the MedDRA coding dictionary and summarised by preferred term and treatment group. Adverse events and SAEs occurring pre-treatment, during active treatment and post-treatment will be summarised separately. Separate summaries will be provided for all AEs, investigational product-related AEs, SAEs, events of special interest (including systemic [non-IgE-mediated] and hypersensitivity [IgE-mediated]reactions and local site reactions) and for AEs leading to permanent discontinuation of investigational product or withdrawal from the study. All laboratory parameters for clinical chemistry and haematology will be summarised and tabulated.





85














86







The study will be conducted in accordance with ICH GCP, all applicable subject privacyrequirements, and the ethical principles that are outlined in the Declaration of Helsinki 2008, including, but not limited to:










87














88












89






90

10. REFERENCES









GlaxoSmithKline Document Number 2014N200212 Supplement to Mepolizumab (SB-240563) Investigator's Brochure. Supplement No.: 01 IB Version 12. Date: 22 May 2014.






91

















92

















93









94

11. APPENDICES





[Hetherington, 2002;Mallal, 2002; Mallal, 2008]



Carbamazepine

Seizure, Bipolar disorders & AnalgesiaChung, 2010;

Ferrell, 2008



95

Irinotecan Cancer [Innocenti,2004; Liu, 2008; Schulz, 2009]






96






Efficacy

Study Population









97











If a blood sample for Genetics or PGx research has been collected and it is determined that the subject does not meet the entry criteria for participation in the clinical study, thenthe investigator should instruct the participant that their Genetics/PGx sample will be destroyed. No forms are required to complete this process as it will be completed as part of the consent and sample reconciliation process. In this instance a sample destruction form will not be available to include in the site files.




98






Informed Consent






99

References















100







Inclusion criterion 4:

Japan only definition of Relapsing disease:Subject must have a past history of at least one confirmed EGPA relapse (i.e., requiring increase in OCS dose, initiation of IV prednisolone (or equivalent), initiation/increased dose of immunosuppressive therapy, initiation/increased dose of intravenous immunoglobulin (IVIG) or hospitalisation) within the past 2 years which occurred at least 12 weeks prior to Screening (Visit 1) whilst receiving a dose of prednisolone (or equivalent) of ≥7.5 mg/day.

Rationale: Intravenous immunoglobulin (IVIG) therapy is licensed in Japan for the improvement of neuropathy associated with EGPA and allergic Granulomatous Angiitis in patients not responding to steroid therapy. IVIG is therefore included in the definition of relapsing disease. IV prednisolone (or equivalent) commonly used to manage relapse in Japan.


101





102




















103




104










105














106




107




108




109





110















111



ALT>3xULN



No

Yes






No

Able to monitor

weekly for 4 weeks?

Yes

No**

Yes




Yes

Yes


wks?

Yes

ALT >5xULN

but <8xULN

NoALT >8xULN

Yes

ALT >5 and

<8xULN for > 2

wksYes No



No

Able to monitor

weekly for

> 2 wks?

No

No


Yes No



112


11.13.1. Protocol Amendment 01






Added:







Change from:


Change to:





113






Change from:


Change to:





Change from:


Change to:




114




Change from:


Change to:




Change from:


Change to:




Change from:


Change to:

Hepatitis status: No diagnosis of chronic hepatitis B, as evidenced by positive HBsAg at Screening (Visit 1). Japan only: Subjects positive for


115


HBsAg or antibodies to HBsAg, i.e., HBsAb, or Hepatitis B core antigen, i.e., HBcAb, at Screening (Visit 1) are excluded. Note: Subjects with antibodies to HBsAg, i.e., HBsAb positive, only (i.e., negative for HBsAg and HBcAb) with a history of hepatitis B vaccination can be included.



Added:




Change from:


Change to:




Change from:



116


Change to:




Deleted :







Change from:


Change to:




Added:


Rationale: For consistency with changes to protocol text regarding hepatitis


117


screening for subjects in Japan (see Appendix 2 for additional information).


Change from:

Biomarker samples: Blood and sputum samples to be collected from consenting subjects participating at US sites in the ‘mechanistic/biomarker’ sub-study only. Where possible, blood and sputum samples also to be collected in the event of relapse. Blood samples to be collected from consenting subjects at sites participating in the European ‘mechanistic/biomarker’ sub-study.

Change to:




Change from:


Change to:



Change from:




Change from:

The time of onset of a relapse will be defined as time to change BVAS,


118


asthma or sino-nasal signs and/or symptoms that warranted increase in corticosteroid therapy, increase in dose or addition of immunosuppressive therapy or hospitalisation.

Change to:






Change from:


Change to:

For consenting subjects participating in the US ‘mechanistic’ sub-study, where possible, a blood, urine, sputum and tissue (biopsy) sample should be collected in the event of relapse. In addition, where possible, (i.e., as part of standard of care management), a tissue (biopsy) sample should be collected.



119



Deleted:

Reticulocytes



Added:




Change from:


Change to:




Change from:



120


Change to:




Change from:

Reily Associates. Scoring of WPAI. Available at: http://www.reillyassociates.net/WPAI_Scoring.html. Accessed on May 16,2012.


Change to:





Change from:


Change to:




Added:

Amendment 01 includes a country-specific local amendment generated for


121


Japan.




11.13.2. Protocol Amendment 02


List of protocol changes:



1. SPONSOR INFORMATION PAGE


Change from:


Tel:

Mobile:


122


Change to:


Tel:

Mobile:


Change from:

Tel:

Mobile:

FAX: +

Change to:


Tel:

Mobile:

FAX:

email:

Rationale: Administrative change


Added:

LAMA – long-acting muscarinic adrenoreceptor antagonist


123


SAMA - short-acting muscarinic adrenoreceptor antagonist

Rationale: SAMA and LAMA included in amendment.



Section 3.2, Discussion of Design, paragraph 5

Added:

Note, where the BVAS ≠ 0, the investigator may taper the subject’s OCS downwards at his/her clinical discretion.

Rationale: Clarification that with OCS tapering being as per standard of care that the investigator may taper oral corticosteroids downwards if BVAS ≠ 0.

4. Section 1.4.1 Risk Assessment, Table 1: Risk Assessment for Mepolizumab: bullet 4: Potential risk for adverse cardiovascular (CV) effects

Added:

Data from 2 subsequently completed placebo-controlled severe asthma trials did not show an increased risk of serious ischemic cardiac events; there were no new reports in any treatment groups including placebo.

Rationale: To include updated information from completed placebo-controlled trials in severe asthma.

5. Section 4.2, Inclusion Criterion number 4

Added:


Rationale: Intravenous immunoglobulin (IVIG) therapy is licensed in Japan for the improvement of neuropathy associated with EGPA and allergic Granulomatous Angiitis in patients not responding to steroid therapy. IVIG is therefore included in the definition of relapsing disease.


124


6. Section 4.5.1, Withdrawal from Study Treatment, paragraph 2

Added:

Pregnancy

Rationale: Clarification that, in accordance with Exclusion criterion 16,subjects who are pregnant are excluded from participation.

7. Section 4.5.1, Withdrawal from Study Treatment, paragraph 2, bullet 3

Added and Deleted:

Concurrent medication: Use of prohibited concurrent medication (i.e., as noted in Exclusion Criterion #14 (Prohibited Medications) Section 5.7.2 -Prohibited Medications and Non-Drug Therapies) including cyclophosphamide.

Rationale: Link to Section 5.7.2 – Prohibited Medications and Non-Drug Therapies rather than Exclusion Criterion #14 replaced for clarification.

8. Section 5.7.1 Permitted Medications and Non-Drug Therapies.

Added:

In the event immunosuppressive therapy is initiated or the dose increased (e.g., in the event of relapse) study treatment should be withdrawn and, where possible, the subject continue to be followed up as per protocol until the end of follow-up at Week 60 (see Section 4.5.1- Withdrawal from Study Treatment).

Rationale: Clarification that, as indicated in Section 4.5.1, subjects who withdraw from study treatment prematurely (for any reason including initiation or increased dose of immunosuppressive therapy) should, where possible, continue to be followed up as per protocol until the end of follow-up at Week 60.

9. Section 5.7.2 Prohibited Medications and Non-drug Therapies

Added:

In the event a prohibited medication is used (e.g., in the event of relapse) study treatment should be withdrawn and, where possible, the subject continue to be followed up as per protocol until the end of follow-up at Week 60 (see Section 4.5.1 Withdrawal from Study Treatment). Note, this does not include use of any other investigational agent (biologic or non-biologic) where, if used, the subject should be withdrawn from the study.

Rationale: Clarification that, as indicated in Section 4.5.1, subjects who


125


withdraw from study treatment prematurely (for any reason including initiation of a prohibited medication [except another investigational agent]) should, where possible, continue to be followed up as per protocol until the end of follow-up at Week 60.

10. Section 6, Table 2, Biomarker Sub-studies, Sputum sample

Deleted:

‘X’ in column Week 24 (Visit 9) and Week 52 (Visit 17)

Added:


Rationale: Correction to sub-study sputum sample schedule.


Added:

The period of fasting may be adjusted at the discretion of the investigator for subjects with relevant metabolic conditions (e.g., diabetes mellitus).

Rationale: Clarification provided regarding requirement for fasting in diabetic subjects.


Added:

At Weeks 1 and 29, where practical, an optional PK sample is to be collected (although, where possible, every effort should be made to collect these samples).

Rationale: Clarification that collection of a PK sample at Weeks 1 and 29 is optional.

13. Section 6.2.1.6 Spirometry

Added:

Prior to the Baseline visit (Visit 2) subjects should withhold short-acting beta-2-agonists (SABAs) and short-acting muscarinic adrenoreceptor antagonists (SAMAs) for at least 6 hours and long-acting beta-2-agonists (LABAs) and long-acting muscarinic adrenoreceptor antagonists (LAMAs) for at least 12 hours to enable reversibility testing to be performed. Specifically, FEV1 will be measured pre-salbutamol/albuterol and within 30 minutes [±15 minutes] following up to 4 inhalations of


126


salbutamol/albuterol (a spacer device may be used if required) or equivalent nebulised treatment with salbutamol/albuterol solution. The reversibility test must be performed in the morning only at Baseline (Visit 2).

Rationale: Inclusion of SAMAs and LAMAs as bronchodilators in addition to SABAs and LABAs.

14. Section 6.3.2, Liver Event Follow-up Assessments, 5th bullet

Deleted:


Added:


Rationale: Consistent with the requirement for investigators to be blinded to eosinophil counts for the duration of the study, requirement for assessment of eosinophilia as part of follow-up requirements following a liver event is deleted and is not considered essential for evaluation of a hypersensitivity reaction.

15. Section 10, References and associated cross-references in Section 1.3, Section 1.4 (including in Table 1) and Section 4.2

Added:

GlaxoSmithKline Document Number 2014N200212_Supplement to Mepolizumab (SB-240563) Investigator's Brochure. Supplement No.: 01 IB Version 12. Date: 22 May 2014.

Rationale: Inclusion of Supplement to Investigator’s Brochure Version 12.

16. Section 11.2, Appendix 2: Country Specific Requirements

Added:

Amendment 02 includes a country-specific local amendment generated for Japan.Inclusion criterion 4:

Japan only definition of Relapsing disease:Subject must have a past history of at least one confirmed EGPA relapse


127


(i.e., requiring increase in OCS dose, initiation of IV prednisolone (or equivalent), initiation/increased dose of immunosuppressive therapy, initiation/increased dose of intravenous immunoglobulin (IVIG) or hospitalisation) within the past 2 years which occurred at least 12 weeks prior to Screening (Visit 1) whilst receiving a dose of prednisolone (or equivalent) of ≥7.5 mg/day.



1

TITLE PAGE


Title: A Double-blind, Randomised, Placebo-controlled Study to Investigate the Efficacy and Safety of Mepolizumab in the Treatment of Eosinophilic Granulomatosis with Polyangiitis in Subjects Receiving Standard of Care Therapy


Development Phase: III

Effective Date: 24-JUN-2016


Author (s):



2

Revision Chronology

GlaxoSmithKlineDocument Number

Date Version

2012N142276_00 2013-AUG-29 Original

2012N142276_01 2013-OCT-15 Amendment No. 1

Amendment No.:01 Generated to remove evaluation of ACQ-6 and sino-nasal symptoms at the time of relapse and to clarify the definition of time of onset of relapse; country-specific requirements for Japan regarding hepatitis B screening added as well as clarification to text as needed and administrative changes. A detailed list of changes is provided in Appendix 13

2012N142276_02 2014-AUG-27 Amendment No. 2

Amendment No.:02 Generated to clarify investigators can taper oral corticosteroids downward when BVAS≠0; to include additional statement in risk assessment table; to clarify that subjects who become pregnant must be withdrawn from study treatment; to clarify requirements for collection of a fasting blood sample in diabetic subjects; to clarify that collection of PK samples at Weeks 1 and 29 is optional; to delete requirement for measurement of eosinophil count as a liver event follow-up assessment; to amend the schedule for sputum sampling in the biomarker sub-study; to add country-specific change for Japan regarding definition of relapsing disease in inclusion criteria; to include SAMAs and LAMAs as bronchodilator to be withheld prior to reversibility testing; to clarify requirements for subject follow-up in the event study treatment is discontinued; to include reference to the Supplement to Version 12 of the Investigator’s Brochure and other administrative changes. A detailed list of changes is provided in Appendix 13.

2012N142276_03 2016-JUN-24 Amendment No. 3

Amendment No.:03 Generated to add secondary endpoints including the remission definition as per the EULAR recommendations for conducting clinical trials in systemic vasculitis, i.e., BVAS=0 and prednisolone/prednisone dose ≤7.5 mg/day, to clarify relapse definition, to amend the statistical analysis plan in accordance with the addition of the new secondary endpoints, to clarify specific aspects of the Data Analysis and Statistical Considerations section and to include some administrative updates. A detailed list of changes is provided in Appendix 13.


4










MD (Clinical Development Director)

Mobile:

Email:


MD

Phone:

Mobile:

Email:


5



Mobile:

Email:



IND No. 006971


6


For protocol number MEA115921


I acknowledge that I am responsible for overall study conduct. I agree to personally conduct or supervise the described study.


Investigator Name:

Investigator Address:

Investigator Phone Number:



7

TABLE OF CONTENTS

PAGE

LIST OF ABBREVIATIONS...........................................................................................10




2. OBJECTIVES.........................................................................................................31










6.2. Efficacy.......................................................................................................56


8















7. DATA MANAGEMENT ...........................................................................................77




9








10. REFERENCES.......................................................................................................91

11. APPENDICES ........................................................................................................9511.1. Appendix 1: Genetics/Pharmacogenetics Research ...................................9511.2. Appendix 2: Country Specific Requirements .............................................10111.3. Appendix 3: Recommended Prednisolone/Prednisone Tapering




10




11

IL InterleukinINR International normalised ratioIRB Institutional review BoardITT Intent-to-TreatIUD Intrauterine deviceIV Intravenous(ly)IVRS Interactive Voice Response Systemkg kilogramLABA Long acting beta2 agonistLAMA Long-acting muscarinic adrenoreceptor antagonistsmAb Monoclonal antibodyMedDRA Medical Dictionary for Regulatory Activitiesmg milligramsMPA Microscopic polyangiitis MRI Magnetic resonance imagingMSDS Material Safety Data Sheetmsec millisecondNAB Neutralizing antibodiesOCS Oral CorticosteroidPBMC Peripheral blood mononuclear cellsPCR Polymerase chain reactionPD PharmacodynamicsPEF Peak expiratory flowPGx PharmacogeneticsPK PharmacokineticsPMDA Pharmaceuticals and Medical Devices Agency (Japan)PP Per protocolQTcB QT interval corrected for heart rate according to Bazett’s


formulaRAP Reporting and Analysis PlanRBC Red blood cellRNA Ribonucleic acidRPGN Rapidly progressive glomerulonephritis SABA Short acting beta-agonistSAMA Short-acting muscarinic adrenoreceptor antagonistsSAE Serious Adverse EventSC Subcutaneous(ly)SF-36 Short-form 36SNOT-22 Sino-nasal Outcome Test-22SOC System organ classSPM Study procedures manualSRT Safety review teamTNF Tumour necrosis factorULN Upper limit of normalUS United StatesVDI Vasculitis Damage Index


12

WBC White blood cellWPAI Work Productivity Activity Impairment




VENTOLIN NONMEM 7


13

PROTOCOL SUMMARY

Rationale


The purpose of this randomised, double-blind study is to investigate the efficacy and safety of mepolizumab (300 mg subcutaneously [SC] every 4 weeks) compared with placebo over a 52-week study treatment period in subjects with relapsing or refractory EGPA receiving standard of care therapy including background corticosteroid therapy with or without immunosuppressive therapy. During the treatment period, in accordance with standard of care, corticosteroid dose will be tapered. The key outcomes in the study focus on evaluation of clinical remission, reduction in disease relapse and reduction in corticosteroid requirement.


Objectives

Primary

To investigate the efficacy of mepolizumab plus standard of care compared with placebo plus standard of care on accrued duration of clinical remission, in subjects with relapsing or refractory eosinophilic granulomatosis with polyangiitis (EGPA) receiving standard of care therapy including corticosteroid therapy reduction/withdrawal.


Secondary




14



Other








Study Design




15





Between baseline (randomisation) and Week 4, subjects will be required to continue on their stable OCS (prednisolone/prednisone) dose (if necessary, upward adjustments are permitted for clinical management of the patient). From Week 4 post-baseline onwards, if the subject’s BVAS=0 their OCS dose should be tapered downwards according to standard of care practice. A recommended tapering schedule provided in the protocol enables a reduction in OCS dose every 2 weeks, with the intention of achieving a prednisolone/prednisone dose of 4 mg/day or less. Note, where the BVAS ≠ 0, the investigator may taper the subject’s OCS downwards at his/her clinical discretion. Once a subject has achieved a dose of 4 mg/day prednisolone/prednisone, the investigator is encouraged to continue tapering downwards, if clinically warranted, at dose increments of 0.5-1.0 mg every 2 weeks.

In this study two definitions of EGPA remission will be investigated defined as i) BVAS=0 plus OCS dose of prednisolone/prednisone 4 mg/day and ii) BVAS=0 plus OCS dose of prednisolone/prednisone 7.5 mg/day. In defining EGPA remission, asthma and sino-nasal symptoms /signs related to EGPA activity, if not specifically covered by the BVAS assessment, will be considered to be controlled by virtue of the low OCS dose and are therefore not included in the remission definition.

EGPA relapse will be defined as worsening or persistence of active disease since the last visit characterised by: a) active vasculitis (BVAS >0); OR b) active asthma symptoms and/or signs with a corresponding worsening in ACQ-6 score (compared to the most recent previous score); OR c) active nasal and/or sinus disease with a corresponding worsening in at least one of the sino-nasal symptom questions (compared to the most recent previous assessment) warranting: i) an increased dose of OCS therapy (or other systemic corticosteroid therapy) to >4 mg/day prednisolone total daily dose or equivalent;OR ii) an increased dose or addition of immunosuppressive therapy; OR iii) hospitalisation related to EGPA worsening. A BVAS evaluation will be conducted at the time of a relapse, or as soon as possible afterwards. The time of onset of a relapse will be defined as i) the time of increase in dose of OCS therapy, and/or ii) increase in dose or addition of immunosuppressive therapy, and/or iii) hospitalisation, in association with the worsening in BVAS, asthma or sino-nasal symptoms. In the event a subject has achieved remission and at any subsequent visit has a BVAS = 1 which does not require an increase in corticosteroid dose above 4 mg/day or 7.5 mg/day (in accordance with the relevant


16

remission definition), or any other significant clinical intervention or investigation, the subject will be considered to be in continued remission.

A major relapse (a sub-set of the total relapse events) will be defined as: any organ or life-threatening EGPA event; OR BVAS ≥6 (involving at least two organ systems in addition to any general symptoms where present [myalgia, arthralgia/arthritis, fever >38ºC or weight loss >2 kg]); OR an asthma relapse requiring hospitalisation; OR sino-nasal relapse requiring hospitalisation.

The minimally effective dose of OCS (prednisolone/prednisone) for each subject will be defined as the dose of OCS one step above the OCS dose at which the first relapse occurred. Where the subject has achieved a dose of OCS of 0-3.5 mg prednisolone/prednisone, the minimally effective dose will be defined as 4.0 mg/day. Upwards dose adjustments within the 0-4.0 mg range are permitted without being considered a relapse.

The management of subjects who relapse will be according to standard of care and may involve increasing the dose of corticosteroids or adjustment in immunosuppressive therapy.







17

Research-supported ‘mechanistic/biomarker’ sub-studies will be conducted at selected sites in the United States (US) and Europe using samples collected from consenting subjects participating in the study. The objective of these studies will include examination of molecular profiles and biomarkers associated with EGPA and response to anti-IL-5 therapy. Specific details of the planned analyses will be outlined in the individual protocols and/or analysis plans for these sub-studies.



the total accrued duration of remission, i.e., the accrued number of weeks where BVAS=0 plus prednisolone/prednisone dose 4 mg/day over the 52 week study treatment period reported as proportion of subjects achieving remission in the following categories: Zero; >0 to <12 weeks; 12 to <24 weeks; 24 to <36 weeks and ≥36 weeks, and

the proportion of subjects who are in remission (i.e., BVAS=0 and prednisolone/prednisone 4 mg/day) at both Weeks 36 and 48 of the study treatment period.





iv. the total accrued duration of remission, i.e., the accrued number of weeks where BVAS=0 plus prednisolone/prednisone dose 7.5 mg/day over the 52 week study treatment period reported as the proportion of subjects achieving remission in the following categories: Zero; >0 to <12 weeks; 12 to <24 weeks; 24 to <36 weeks and ≥36 weeks.

v. the proportion of subjects who are in remission (defined as BVAS=0 plus prednisolone/prednisone dose 7.5 mg/day) at both Weeks 36 and 48 of the study treatment period.

vi. the proportion of subjects who achieve remission (BVAS=0 and prednisolone/prednisone 7.5 mg/day) within the first 24 weeks of the study and remain in remission for the remainder of the study treatment period.


18







19

1. INTRODUCTION

1.1. Background

Eosinophilic Granulomatosis with Polyangiitis (EGPA), also referred to as Churg-Strauss syndrome (CSS), is a rare hypereosinophilic syndrome characterised by small vessel vasculitis in association with asthma, sinusitis, and pulmonary infiltrates. Multiple organs can be affected including the heart, lungs, skin, gastrointestinal tract, kidneys, and nervous system [Keogh, 2006; Vaglio, 2012; Holle, 2009]. The mean age of diagnosis of EGPA is 48 years, with a gender ratio of approximately 1:1 [Pagnoux, 2007]; the incidence has been estimated as 1-4 per million per year [Lane, 2005]. EGPA is associated with a positive status for anti-neutrophil cytoplasmic antibodies (ANCAs), typically ANCA-Myeloperoxidase (MPO) and ANCA-Proteinase 3 (PR3), in approximately 40% of patients [Holle, 2009; Sinico, 2005]. In addition, the role of allergy in EGPA is widely acknowledged, especially in the prodromal disease phase that is characterized by typical allergic manifestations such as asthma, sinusitis, and nasal polyposis with raised serum IgE levels observed in approximately 90% of EGPA patients [Vaglio, 2012]. In recent proposed classification systems for eosinophil disorders, EGPA has been described as being associated with Hypereosinophilic Syndrome (HES) [Simon, 2010], although it should nevertheless be distinguished from true HES [Valent, 2012].



20


Mepolizumab is a fully humanized monoclonal antibody (IgG1, kappa, mAb) which is specific for human IL-5 and which blocks binding of human IL-5 (hIL-5) to the alpha chain of the IL-5 receptor complex expressed on the eosinophil cell surface. In patients with conditions where eosinophilia is considered to play an important part in the pathology, a consistent reduction in eosinophil number is observed in association with mepolizumab administration, with concomitant clinical improvement [Haldar, 2009; Pavord, 2012; Stein 2006, Rothenberg 2008; Nair, 2009].



21

1.2. Rationale


The purpose of this randomised, double-blind study is to investigate the efficacy and safety of mepolizumab (300 mg subcutaneously [SC] every 4 weeks) compared with placebo over a 52-week study treatment period in subjects with relapsing or refractory EGPA receiving standard of care therapy including background corticosteroid therapy with or without immunosuppressive therapy. In accordance with standard of care, corticosteroid dose tapering will be permitted during the study. The key outcomes of this study focus on evaluation of clinical remission, reduction in disease relapse and reduction in corticosteroid requirement.

1.3. Dose Rationale



Mepolizumab (750 mg IV every 4 weeks) was shown to be well-tolerated in studies CRT109797 and MHE109435 consistent with the overall safety profile previously demonstrated in over 1300 subjects treated with mepolizumab across different eosinophilic conditions (i.e., severe asthma, HES, eosinophilic esophagitis, atopic dermatitis and nasal polyposis). For details see the Investigator’s Brochure and Supplement (GlaxoSmithKline Document Number: CM2003/00010/08 and GlaxoSmithKline Document Number 2014N200212_00).


A non-linear inhibition dose-response model based on blood eosinophil counts,developed from a pharmacokinetic/pharmacodynamic (PK/PD) study of mepolizumab in adult subjects with asthma and elevated blood eosinophil levels (study MEA114092), has identified 75 mg IV every 4 weeks as the ID90 (i.e., dose providing 90% of the maximum blood eosinophil reduction achievable by the drug) for blood eosinophil reduction. The estimated absolute bioavailability


22

for SC route of administration in the upper arm in this study was approximately 75% [IB; GlaxoSmithKline Document Number: CM2003/00010/08]. Therefore a dose of 100 mg SC is anticipated to provide similar exposure to a 75mg IV dose. A 100 mg SC dose every 4 weeks is therefore being investigated in confirmatory studies in severe asthma as the SC route is more convenient compared with IV and is generally preferred by patients.










Summaries of findings from both clinical and non-clinical studies conducted with mepolizumab can be found in the Investigator Brochure and Supplement (GlaxoSmithKline Document Number: CM2003/00010/08 and GlaxoSmithKline


23

Document Number: 2014N200212_00). Table 1 summarises the risk assessment and mitigation strategy for this protocol.


24







Reactions reported to date across the mepolizumab program are summarized in the IB and IB supplement; see ‘Special Warnings and Special Precautions for Use’ section located in Section 6 titled ‘Summary of Data and Guidance for the Investigator’. (GlaxoSmithKline Document Number: CM2003/00010/08 and GlaxoSmithKline Document Number: 2014N200212_00).











25







In one study in subjects with severe refractory asthma, cardiac events were reported in similar frequencies across treatment groups with a small numerical increase observed in serious ischemic cardiac events in the mepolizumab-treated groups. However, an integrated safety analysis of all placebo-controlled multiple-dose asthma trials showed a similar frequency of SAEs reported overall from the cardiac and vascular system organ class (SOC). Additionally, similar findings were observed in other SOCs with thrombotic events (e.g., stroke in the Nervous System SOC). Data from 2 subsequently completed placebo-controlled severe asthma trials did not show an increased risk of serious ischemic cardiac events; there were no new reports in any treatment groups including placebo.










26








Infections reported to date across the mepolizumab development program are summarized in the IB and IB supplement; see ‘Special Precautions and Warnings’ (for exclusion of subjects with underlying parasitic infections) and ‘Undesirable Effects’ (for very common infections of nasopharyngitis, URTI, rhinitis and bronchitis reported in other patient populations) sections located in Section 6 titled ‘Summary of Data and Guidance for the Investigator’ (GlaxoSmithKline Document Number: CM2003/00010/08 and GlaxoSmithKline Document Number: 2014N200212_00).





27


















28



Study Procedures










29









30









31

2. OBJECTIVES

Primary

To investigate the efficacy of mepolizumab plus standard of care compared with placebo plus standard of care on accrued duration of clinical remission in subjects with relapsing or refractory eosinophilic granulomatosis with polyangiitis (EGPA) receiving standard of care therapy including corticosteroid therapy reduction/withdrawal.


Secondary





Other









32


3.1. Study Design

Protocol waivers or exemptions are not allowed with the exception of immediate safety concerns. Therefore, adherence to the study design requirements, including those specified in the Time and Events Table (Table 2), are essential and required for study conduct.






33


Between baseline (randomisation) and Week 4, subjects will be required to continue on their stable OCS (prednisolone/prednisone) dose (if necessary, upward adjustments are permitted for clinical management of the patient). From Week 4 post-baseline (Visit 4) onwards, if the subject’s BVAS = 0 their OCS dose should be tapered downwards according to standard of care practice. A recommended tapering schedule for this purpose is provided in Appendix 3 (see Section 11.3). The recommended tapering schedule enables a reduction in OCS dose every 2 weeks, with the intention of achieving a prednisolone/prednisone dose of 4 mg/day or less. Note, where the BVAS ≠ 0, the investigator may taper the subject’s OCS downwards at his/her clinical discretion. Once a subject has achieved a dose of 4 mg/day prednisolone/prednisone, the investigator is encouraged to continue tapering downwards, if clinically warranted, at dose increments of 0.5-1.0 mg every 2 weeks.

In this study two definitions of EGPA remission will be investigated defined as i) BVAS = 0 plus OCS dose of prednisolone/prednisone 4 mg/day and ii) BVAS = 0 plus OCS dose of prednisolone/prednisone 7.5 mg/day. In defining EGPA remission, asthma and sino-nasal symptoms /signs related to EGPA activity, if not specifically covered by the BVAS assessment, will be considered to be controlled by virtue of the low OCS dose and are therefore not included in the remission definition. EGPA relapse will be defined as worsening or persistence of active disease since the last visit characterised by:





34

warranting:

an increased dose of OCS therapy (or other systemic corticosteroid therapy) to >4 mg/day prednisolone total daily dose or equivalent; OR





In the event a subject has achieved remission and at any subsequent visit has a BVAS=1 which does not require an increase in prednisolone/prednisone dose above 4 mg/day or 7.5 mg/day (in accordance with the relevant remission definition), or any other significant clinical intervention or investigation, the subject will be considered to be in continued remission.

A major relapse (a sub-set of the total relapse events) will be defined as: any organ or life-threatening EGPA event; OR BVAS ≥6 (involving at least two organ systems in addition to any general symptoms where present [myalgia, arthralgia/arthritis, fever >38ºC or weight loss >2 kg]); OR an asthma relapse requiring hospitalisation; OR sino-nasal relapse requiring hospitalisation.

The minimally effective dose of OCS (prednisolone/prednisone) for each subject will be defined as the dose of OCS one step above the OCS dose at which the first relapse occurred. Where the subject has achieved a dose of OCS of 0-3.5 mg prednisolone/prednisone, the minimally effective dose will be defined as 4.0 mg/day. Upwards dose adjustments within the 0-4.0 mg range are permitted without being considered a relapse.

The management of subjects who relapse will be according to standard of care and may involve increasing the dose of corticosteroids or adjustment in immunosuppressive therapy.

If the subject’s first relapse is managed with the use of an increase in corticosteroid dose, tapering should be recommenced as soon as the relapse has been appropriately controlled, as per standard of care practice. As stated above, the recommended tapering schedule is provided in Appendix 3 (see Section 11.3), although after the first relapse the investigator may opt to use larger dose increments and shorter dose intervals than outlined in the schedule, if clinically indicated. Once the minimally effective dose of OCS is achieved, any down-tapering below this dose level will be at the discretion of the investigator,


35

based on the clinical condition of the subject. In the event of a second or subsequent relapse, any further OCS tapering, post-relapse, will be conducted at the discretion of the investigator.






Research-supported ‘mechanistic/biomarker’ sub-studies will be conducted at selected sites in the United States (US) and Europe using samples collected from consenting subjects participating in the study. The objective of these studies will include


36

examination of molecular profiles and biomarkers associated with EGPA and response to anti-IL-5 therapy. Specific details of the planned analyses will be outlined in the individual protocols and/or analysis plans for these studies.





European League Against Rheumatism (EULAR) recommendations for clinical studies in systemic vasculitis encourage demonstration of corticosteroid-sparing as a trial outcome with a proposed definition of remission including disease control (i.e., BVAS=0) with prednisolone dose of ≤7.5 mg/day for a prolonged period [Hellmich, 2007]. In this study,this definition will be investigated in addition to a second, more stringent definition,requiring a BVAS=0 with prednisolone/prednisone dose of ≤4.0 mg/day. This more stringent requirement reflects the evidence that doses in excess of 7.5 mg/day prednisolone (or equivalent) are associated with an increased risk of long-term complications [Sarnes, 2011].

The total study treatment duration is 52 weeks. This duration permits downwards tapering of OCS dose to a target of 4 mg/day prednisolone/prednisone and evaluation of


37

disease control over an extended period, and balances the need to assess the experimental therapy for at least 12 months and the feasibility of retaining subjects in a clinical trial over a prolonged period of time. The protocol provides a recommended schedule from Week 4 for gradual tapering of corticosteroids down to 4 mg/day prednisolone/prednisone where the subject’s BVAS=0 (Appendix 3; see Section 11.3). Note, where the BVAS ≠ 0, the investigator may taper the subject’s OCS downwards at his/her clinical discretion. Once subjects have reached a dose of 4 mg/day prednisolone/prednisone, further tapering downwards may be continued. However, upward adjustment in the dose of OCS is permitted within the 0-4.0 mg range without necessarily being defined as a relapse. This approach recognises that some subjects on long-term OCSs are relatively resistant to complete discontinuation of therapy, and are vulnerable to precipitation of Addisonian symptoms.






Specific information regarding warnings, precautions, contraindications, AEs, and other pertinent information on the GSK investigational product or other study treatment that may impact subject eligibility is provided in the mepolizumab IB and Supplement (GlaxoSmithKline Document Number: CM2003/00010/08 and GlaxoSmithKline Document Number: 2014N200212_00).





38










palpable purpura;





Refractory disease:


a. Subjects who have received a cyclophosphamide (CYC) induction regimen may be included a minimum of 2 weeks after the last dose of daily oral CYC, or 3 weeks after the last dose of pulsed IV CYC prior to


39

Baseline (Visit 2), if their total WBC is ≥4x109/L (tested at the local laboratory, if necessary) prior to randomisation.
















40


















7. Other concurrent medical conditions: Subjects who have known, pre-existing, clinically significant endocrine, autoimmune, metabolic, neurological, renal, gastrointestinal, hepatic, haematological, respiratory or any other system


41

abnormalities that are not associated with EGPA and are uncontrolled with standard treatment.



10. Hepatitis status: Diagnosis of chronic hepatitis B, as evidenced by positive Hepatitis B surface antigen (HBsAg) at Screening (Visit 1). Japan only: Subjects positive for HBsAg , antibodies to HBsAg, i.e., HBsAb, or Hepatitis B core antigen, i.e., HBcAb, at Screening (Visit 1). Note: Subjects with antibodies to HBsAg, i.e., HBsAb positive, only (i.e., negative for HBsAg and HBcAb) with a history of hepatitis B vaccination can be included.
















WBC < 4 x109/L



42












Laboratory abnormality: No evidence of clinically significant abnormality in the haematological, biochemical or urinalysis screen at Screening (Visit 1), as judged by the investigator. Exception: Subjects who have received a CYC induction regimen may be randomised a minimum of 2 weeks after the last dose of daily oral CYC, or 3 weeks after the last dose of pulsed IV CYC, if their total WBC is ≥4x109/L (tested at the local laboratory if necessary).

Hepatitis status: No diagnosis of chronic hepatitis B, as evidenced by positive HBsAg at Screening (Visit 1). Japan only: Subjects positive for HBsAg or antibodies to HBsAg, i.e., HBsAb, or Hepatitis B core antigen, i.e., HBcAb, at Screening (Visit 1) are excluded. Note: Subjects with antibodies to HBsAg, i.e., HBsAb positive, only (i.e., negative for HBsAg and HBcAb) with a history of hepatitis B vaccination can be included.


43

Liver Function Tests: obtained at Screening (Visit 1):





ECG over-read: No evidence of significant abnormality in the 12-lead ECG over-read from the Screening visit (Visit 1).




Reasons for premature discontinuation of study treatment must be captured in the electronic case report form (eCRF), e.g., AE, lack of efficacy, protocol deviation, pregnancy, investigator discretion, consent withdrawn etc. In addition, subjects will be withdrawn from study treatment for any of the following reasons:



Concurrent medication: Use of prohibited concurrent medication (i.e., as noted in Section 5.7.2 - Prohibited Medications and Non-Drug Therapies) including cyclophosphamide.


ECG abnormalities:

QTc >500 msec



These criteria should be based on the average QTc value of triplicate ECGs. For example, if an ECG demonstrates a prolonged QT interval, obtain two more ECGs over a brief


44

period, and then use the averaged QTc values of the three ECGs to determine whether the patient should be discontinued from the study.




<450 msec >500 msec

450-480 msec ≥530 msec









Those subjects who complete at least one procedure at the Screening Visit (Visit 1) but do not complete the Baseline Visit (Visit 2) will be designated as screen failures. Subjects


45

who fail to meet the randomisation criteria at the Baseline Visit (Visit 2) will be designated as run-in failures.



5. STUDY TREATMENTS








A unique Subject Number will be assigned to any subject who is consented. This unique subject number will be used to identify the individual subject throughout the study and will not be re-assigned to any other subject. Randomisation will be stratified by; i) subjects in the US participating in the US ‘mechanistic/biomarker’ sub-study


46

(approximately 50 subjects), ii) subjects recruited in Japan and iii) the remainder of the recruited subjects.














47


Safety monitoring of subjects will occur during SC administration and for 1 hour after the end of injection. Such monitoring will include general safety monitoring including monitoring for both systemic hypersensitivity (i.e., allergic/IgE-mediated and non-allergic) and local site reactions. Trained rescue personnel and rescue medications/equipment must be available for use at all times. See Appendix 11(Section 11.11) for additional information.

5.4. Blinding








48






In the event immunosuppressive therapy is initiated or the dose increased (e.g., in the event of relapse) study treatment should be withdrawn and, where possible, the subject continue to be followed up as per protocol until the end of follow-up at Week 60 (see Section 4.5.1 - Withdrawal from Study Treatment).





Omalizumab 130 days




Anti-TNF 12 weeks






49



In the event a prohibited medication is used (e.g., in the event of relapse) study treatment should be withdrawn and, where possible, the subject continue to be followed up as per protocol until the end of follow-up at Week 60 (see Section 4.5.1 - Withdrawal from Study Treatment). Note, this does not include use of any other investigational agent (biologic or non-biologic) where, if used, the subject should be withdrawn from the study.








Throughout the study subjects will be required to complete the following paperquestionnaires at the study site: Sino-nasal Outcome Test-22 (SNOT-22), the Short Form-36 (SF-36), and the Work Productivity and Activity Impairment (WPAI) Index.


50



period


18 19Early W/D (2)


Pre-screen


BASE LINE

13

47

87

127

167

207

247

287

293

327

367

407

447

487

527

567

607


X




X



51


period


18 19Early W/D (2)


Pre-screen


BASE LINE

13

47

87

127

167

207

247

287

293

327

367

407

447

487

527

567

607







52


period


18 19Early W/D (2)


Pre-screen


BASE LINE

13

47

87

127

167

207

247

287

293

327

367

407

447

487

527

567

607





Complete eCRF X X X X X X X X X X X X X X X X X X X X X




possible. The period of fasting may be adjusted at the discretion of the investigator for subjects with relevant metabolic conditions (e.g., diabetes mellitus).15. Urinalysis Screen sample (Visit 1) to be analysed by the central laboratory; all other tests to be conducted using by dipstick.16. Hepatitis B Surface Antigen and Hepatitis C antibody (if hepatitis C antibody positive, a HCV RNA test (either quantitative or qualitative) should be performed). Japan only:


53

Antibodies to Hepatitis B Surface Antigen and Hepatitis B Core Antigen, i.e., HBsAb and HBcAb, respectively.17. Serum pregnancy test (S) to be conducted in women of childbearing potential at Screening (Visit 1) and Week 52 (or early withdrawal); urine pregnancy tests (U) to be conducted

at all other indicated visits.18. PK sampling: At Baseline and Weeks 4, 28 and 48 the PK sample should be taken pre-dose. At Weeks 1 and 29, where practical, an optional PK sample is to be collected

(although, where possible, every effort should be made to collect these samples).19. In the event of premature discontinuation of study medication, a sample for measurement of anti-drug antibodies should be collected at the nearest scheduled study visit


at US sites in the ‘mechanistic/biomarker’ sub-study only. Where possible, blood, sputum and urine samples also to be collected in the event of relapse. Blood samples to becollected as indicated from Baseline (Visit 1) to Week 60 (or early withdrawal) from consenting subjects at sites participating in the European ‘biomarker’ sub-study.




54


























55

Urinalysis.




ANCA (MPO and PR3).



Weight.



















Clinical chemistry.

Urinalysis.


IL-5.


56

CRP and ESR.

IgE.





6.2. Efficacy


Primary


Zero

>0 to <12 weeks

12 to <24 weeks

24 to <36 weeks

≥36 weeks

The proportion of subjects who are in remission (i.e., BVAS=0 and prednisolone/prednisone ≤4 mg/day) at both Weeks 36 and 48 of the study treatment period.

Secondary



Zero

>0 to ≤4.0 mg

>4.0 to ≤7.5 mg

>7.5 mg


57


The total accrued duration of remission, i.e., the accrued number of weeks where BVAS=0 plus prednisolone/prednisone dose 7.5 mg/day over the 52 week study treatment period reported as the proportion of subjects achieving remission in the following categories: Zero; >0 to <12 weeks; 12 to <24 weeks; 24 to <36 weeks and ≥36 weeks,

The proportion of subjects who are in remission (defined as BVAS=0 plus prednisolone/prednisone dose 7.5 mg/day) at both Weeks 36 and 48 of the study treatment period.

The proportion of subjects who achieve remission (BVAS=0 and prednisolone/prednisone 7.5 mg/day) within the first 24 weeks of the study and remain in remission for the remainder of the study treatment period.

Other


Zero

>0 to <12 weeks

12 to <24 weeks

24 to <36 weeks

≥36 weeks

Total duration of sustained remission, i.e., longest uninterrupted period of weeks where BVAS=0 plus prednisolone/prednisone ≤7.5 mg/day over the 52 week study treatment period, reported as proportion of subjects achieving sustained remission in the following categories:

Zero

>0 to <12 weeks

12 to <24 weeks

24 to <36 weeks

≥36 weeks





58




<25%

25 to <50%

50 to <75%

75 to <100%

100%















The BVAS form is divided into 9 organ-based systems, with each section including symptoms/signs that are typical of that particular organ involvement in systemic vasculitis. The form is designed to record features that are attributable to current vasculitis, after exclusion of other causes such as infection, hypertension etc. The scoring sheet records the presence or absence of each item. Each item is weighted and a


59

maximum total score applied to each system. The total score on all 9 organ systems gives an indication of the disease activity of each patient at the time of scoring and reflects the need for therapy.


6.2.1.2. Relapse





warranting:

An increased dose of OCS therapy (or other systemic corticosteroid therapy) to >4 mg/day prednisolone total daily dose or equivalent OR








60








Runny nose








61




6.2.1.6. Spirometry



Prior to the Baseline visit (Visit 2) subjects should withhold short-acting beta-2-agonists (SABAs) and short-acting muscarinic adrenoreceptor antagonists (SAMAs) for at least 6 hours and long-acting beta-2-agonists (LABAs) and long-acting muscarinic adrenoreceptor antagonists (LAMAs) for at least 12 hours to enable reversibility testing to be performed. Specifically, FEV1 will be measured pre-salbutamol/albuterol and within 30 minutes [±15 minutes] following up to 4 inhalations of salbutamol/albuterol (a spacer device may be used if required) or equivalent nebulised treatment with salbutamol/albuterol solution. The reversibility test must be performed in the morning only at Baseline (Visit 2).







62

6.3. Safety


















63




ALT 8xULN.

ALT 5xULN but <8 xULN persists for 2 weeks

ALT 3xULN if associated with symptoms (new or worsening) believed to be related to hepatitis (such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, or jaundice) or hypersensitivity (such as fever, rash or eosinophilia).

ALT 5xULN but <8 xULN and cannot be monitored weekly for 2 weeks











64


















Hepatitis C RNA;





65
















66

















a) Results in death



67








f) Medical or scientific judgment should be exercised in deciding whether reporting is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalisation but may jeopardise the subject or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition. These should also be considered serious. Examples of such events are invasive or malignant cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation, or development of drug dependency or drug abuse.

g) All events of possible drug-induced liver injury with hyperbilirubinaemia defined as ALT 3xULN and bilirubin 2xULN (>35% direct) (or ALT 3xULN and INR>1.5, if INR measured) termed ‘Hy’s Law’ events (INR measurement is not required and the threshold value stated will not apply to patients receiving anticoagulants).



68







Arrhythmias

Valvulopathy





Revascularisation


6.3.6. Death Events



6.3.7. Pregnancy



69














70








applicable





measured)1












(defined above)3







for 2 weeks3


if applicable3


persists 2 weeks


(defined above)3



71




<2xULN





for 4 weeks3


if applicable3











72















73












74
















75









SF-36

WPAI index.


6.4.1.1. Short Form-36 (SF-36)




The WPAI (General Health version 2.0) is a self or interviewer administered tool comprised of 6 questions which address absenteeism, presenteeism (reduced effectiveness while working), overall work productivity loss (absenteeism plus presenteeism), and activity impairment. This validated tool captures data from the past 7 days. WPAI outcomes are scored as impairment percentages, with a higher percentage indicating greater impairment and less productivity [Reilly Associates, 2012].


76














6.6. Immunogenicity




77

6.7. Biomarkers



US: Samples (blood, urine and sputum, and in case of relapse, where possible [i.e., if as part of standard of care management] a tissue sample) for the research-supported, ‘mechanistic’ sub-study, will be collected from specified US sites only at the visits specified in the Time and Events table (Table 2). Procedures for sample management and shipment for this sub-study will be provided to the relevant sites.

Europe: Blood samples for the research-supported ‘biomarker’ sub-study will be collected from participating EU sites only at the visits specified in the Time and Events table (Table 2). Procedures for sample management and shipment for this sub-study will be provided to the relevant sites.



7. DATA MANAGEMENT





78


8.1. Hypotheses










79












80



Percent Success(For either Subjects with Accrued Remission ≥

24 weeks or Subjects in Remission at Weeks 36 and 48)Placebo Mepolizumab Difference Odds Ratio Power15% 44% 29% 4.5 93%20% 49% 29% 3.8 91%25% 54% 29% 3.5 90%30% 59% 29% 3.4 89%16% 40% 24% 3.5 82%40% 70% 30% 3.5 91%72% 90% 18% 3.5 66%










The Per Protocol (PP) population will consist of all subjects in the Intent-to-Treat population not identified as full protocol deviators with respect to criteria that are considered to impact the primary efficacy analysis. The decision to exclude a subject from the PP population or exclude part of their data from the PP population analyses will


81

be made prior to breaking the blind. The PP population will be used for a supplementary analysis of the primary endpoint.

Safety Population:


PK Population:


PD Population:









Other comparisons of interest are mepolizumab versus placebo for each of the secondary endpoints. When strong control of the overall type I error is required, adjustment for multiplicity will be achieved using a closed testing procedure with the secondary endpoints nested under the primary efficacy endpoint, followed by a further hierarchical procedure within the secondary endpoints. The hierarchy of the secondary endpoints is defined as follows:

Time to first confirmed EGPA relapse


82

Average daily prednisolone/prednisone dose during the last 4 weeks of the study.

The proportion of subjects who achieve remission (defined as BVAS=0 plus prednisolone/prednisone dose 4 mg/day) within the first 24 weeks of the study and then remain in remission for the remainder of the study treatment period.

Total accrued duration of remission, (defined as BVAS=0 plus prednisolone/prednisone dose 7.5 mg/day) over the 52 week study.

The proportion of subjects who are in remission (defined as BVAS=0 plus prednisolone/prednisone dose 7.5 mg/day) at both Weeks 36 and 48 of the study.

The proportion of subjects who achieve remission (defined as BVAS=0 plus prednisolone/prednisone dose 7.5 mg/day) within the first 24 weeks of the study and then remain in remission for the remainder of the study treatment period











83

The proportion of subjects who are in remission (i.e. BVAS=0 plus prednisolone/prednisone dose 4 mg/day) at both Weeks 36 and 48 of the study treatment period

The primary analysis of co-primary endpoint ’1’ will use a proportional odds regression model for ordered categorical data for the proportion of subjects who achieve remission,categorised as above, for the ITT population. Baseline covariates to be included in the model are: baseline prednisone/prednisolone daily dose, baseline BVAS score and region (North America/European Union/Japan).






A sensitivity analysis will be performed, using the actual accrued duration of remission inweeks, rather than in categories, using a Wilcoxon-Mann-Whitney test.


The primary analyses for the co-primary endpoints will address a de facto estimand and use all observed remission data. For subjects withdrawing prematurely from randomised treatment, remission status over the remainder of the study will be included in the analysis where this is available. Subjects who withdraw from the study and where no remission status is available will be included in the analysis as not in remission for the duration of the missing period.

A sensitivity analysis will be performed for the co-primary endpoints whereby subjectswithdrawn from randomised treatment will be assumed to be no longer in remission after the time of withdrawal from randomised treatment. Additional sensitivity analyses will be described in the analysis plan.A supporting analysis of the PP population will also be performed.


Interactions of treatment with subgroups and covariates of specific clinical interest will also be explored; these will be defined in the RAP.


84

Secondary Endpoints




iv. The total accrued duration of remission, i.e., the accrued number of weeks where BVAS=0 plus prednisolone/prednisone dose ≤7.5 mg/day over the 52 week study treatment period reported as the proportion of subjects achieving remission in the following categories: Zero; >0 to <12 weeks; 12 to <24 weeks; 24 to <36 weeks and ≥36 weeks

v. The proportion of subjects who are in remission (defined as BVAS=0 plus prednisolone/prednisone dose ≤7.5 mg/day) at both Weeks 36 and 48 of the study treatment period.

vi. The proportion of subjects who achieve remission (BVAS=0 and prednisolone/prednisone ≤7.5 mg/day) within the first 24 weeks of the study and remain in remission for the remainder of the study treatment period.

Time to first EGPA relapse will be analysed using a Cox proportional hazards regression model using the same covariates as those specified for analysis of the primary endpoints. The hazard ratio will be derived along with 95% confidence limits. Cumulative event rates will be calculated using the Kaplan-Meier method. The proportional hazards assumption will be assessed, with details to be provided in the RAP. If the validity of the proportional hazards assumption is not acceptable, the treatment effect will be assessed using the Log-Rank Test.

The analysis of time to first EGPA relapse will address a de facto estimand and use all observed relapse data. The analysis will be performed for the time to first relapse, considering all relapse events regardless of whether the subject had withdrawn from study treatment at the time of the relapse. Subjects will be censored at the time of study completion or withdrawal from the study. The following sensitivity analyses will be performed for the time to first relapse:

Assuming subjects who withdrew prematurely from study treatment had an event at the time of withdrawal.

Assuming subjects who withdrew prematurely from study treatment due to a treatment-related reason (i.e. ‘Adverse event’ or ‘Lack of efficacy’) had an event at the time of withdrawal.

The proportion of subjects in each category of average daily prednisolone/prednisone dose during the last 4 weeks of the treatment period (Weeks 48 through 52) will be analysed in the same way as the primary endpoint, i.e. using a proportional odds regression model using the same covariates. The analysis will address a de facto estimand, and sensitivity analyses will be conducted as specified in the analysis plan.


85

The proportion of subjects who achieve remission within the first 24 weeks of the study and then remain in remission for the remainder of the treatment period will be analysed using a logistic regression model, using the same covariates as those used for the co-primary endpoints. The analysis will address a de facto estimand, and sensitivity analyses will be conducted as specified in the analysis plan.

The following endpoints will be analysed using the two remission definitions, i.e., BVAS=0 plus prednisolone/prednisone dose 4 mg/day and BVAS=0 plus prednisolone/prednisone dose 7.5 mg/day:

Total accrued duration of remission.

Proportion of subjects who are in remission at both Weeks 36 and 48 of the study.

Proportion of subjects who achieve remission within the first 24 weeks of the study and then remain in remission until the end of the study.











86











87







The study will be conducted in accordance with ICH GCP, all applicable subject privacy requirements, and the ethical principles that are outlined in the Declaration of Helsinki 2008, including, but not limited to:










88














89












90






91

10. REFERENCES








GlaxoSmithKline Document Number 2014N200212_00Supplement to Mepolizumab (SB-240563) Investigator's Brochure. Supplement No.: 01 IB Version 12. Date: 22 May 2014.







92

















93










Rochon J, Kieser M. A closer look at the effect of preliminary goodness of fit testing for normality for the one sample t test. British Journal of Mathematical and Statistical Psychology. 2011 Nov 1;64(3):410-26.







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Schucany WR, Tony Ng HK. Preliminary goodness-of-fit tests for normality do not validate the one-sample Student t. Communications in Statistics—Theory and Methods. 2006 Dec 1;35(12):2275-86.








Zimmerman DW. A note on preliminary tests of equality of variances. British Journal of Mathematical and Statistical Psychology. 2004 May 1;57(1):173-81.


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11. APPENDICES





[Hetherington, 2002;Mallal, 2002; Mallal, 2008]



Carbamazepine

Seizure, Bipolar disorders & AnalgesiaChung, 2010;

Ferrell, 2008



96

Drug Disease Gene Variant OutcomeIrinotecan Cancer

[Innocenti,2004; Liu, 2008; Schulz, 2009]






97






Efficacy

Study Population









98















99






Informed Consent






100

References















101







Inclusion criterion 4:




102





103




















104




105










106














107




108




109




110


Sino-Nasal Outcome Test-22 Questionnaire




111















112



ALT>3xULN



No

Yes






No

Able to monitor

weekly for 4 weeks?

Yes

No**

Yes




Yes

Yes


wks?

Yes

ALT >5xULN

but <8xULN

NoALT >8xULN

Yes

ALT >5 and

<8xULN for > 2

wksYes No



No

Able to monitor

weekly for

> 2 wks?

No

No


Yes No



113


Protocol Amendment 01






Added:







Change from:


Change to:





114






Change from:


Change to:





Change from:


Change to:

Randomisation will be stratified by; i) subjects in the US participating in the US ‘mechanistic/biomarker’ sub-study (approximately 50 subjects), ii)subjects recruited in Japan and iii) the remainder of the recruited subjects.



115




Change from:


Change to:




Change from:


Change to:




Change from:


Change to:

Hepatitis status: No diagnosis of chronic hepatitis B, as evidenced by positive HBsAg at Screening (Visit 1). Japan only: Subjects positive for


116


HBsAg or antibodies to HBsAg, i.e., HBsAb, or Hepatitis B core antigen,i.e., HBcAb, at Screening (Visit 1) are excluded. Note: Subjects with antibodies to HBsAg, i.e., HBsAb positive, only (i.e., negative for HBsAg and HBcAb) with a history of hepatitis B vaccination can be included.



Added:




Change from:


Change to:




Change from:



117


Change to:




Deleted :







Change from:


Change to:




Added:


Rationale: For consistency with changes to protocol text regarding hepatitis


118


screening for subjects in Japan (see Appendix 2 for additional information).


Change from:

Biomarker samples: Blood and sputum samples to be collected from consenting subjects participating at US sites in the ‘mechanistic/biomarker’ sub-study only. Where possible, blood and sputum samples also to be collected in the event of relapse. Blood samples to be collected from consenting subjects atsites participating in the European ‘mechanistic/biomarker’ sub-study.

Change to:




Change from:


Change to:



Change from:




Change from:

The time of onset of a relapse will be defined as time to change BVAS,


119


asthma or sino-nasal signs and/or symptoms that warranted increase in corticosteroid therapy, increase in dose or addition of immunosuppressive therapy or hospitalisation.

Change to:






Change from:


Change to:

For consenting subjects participating in the US ‘mechanistic’ sub-study, where possible, a blood, urine, sputum and tissue (biopsy) sample should be collected in the event of relapse. In addition, where possible, (i.e., as part of standard of care management), a tissue (biopsy) sample should be collected.



120



Deleted:

Reticulocytes



Added:




Change from:


Change to:




Change from:



121


Change to:




Change from:



Change to:





Change from:


Change to:




Added:

Amendment 01 includes a country-specific local amendment generated for


122


Japan.











Change from:


Tel:

Mobile:


123


Change to:


Tel:

Mobile:


Change from:

Tel:

Mobile:

FAX:

Change to:


Tel:

Mobile:

FAX:

email:



Added:

LAMA – long-acting muscarinic adrenoreceptor antagonist


124


SAMA - short-acting muscarinic adrenoreceptor antagonist

Rationale: SAMA and LAMA included in amendment.



Section 3.2, Discussion of Design, paragraph 5

Added:

Note, where the BVAS ≠ 0, the investigator may taper the subject’s OCS downwards at his/her clinical discretion.

Rationale: Clarification that with OCS tapering being as per standard of care that the investigator may taper oral corticosteroids downwards if BVAS ≠ 0.

4. Section 1.4.1 Risk Assessment, Table 1: Risk Assessment for Mepolizumab: bullet 4: Potential risk for adverse cardiovascular (CV) effects

Added:

Data from 2 subsequently completed placebo-controlled severe asthma trials did not show an increased risk of serious ischemic cardiac events; there were no new reports in any treatment groups including placebo.

Rationale: To include updated information from completed placebo-controlled trials in severe asthma.

5. Section 4.2, Inclusion Criterion number 4

Added:


Rationale: Intravenous immunoglobulin (IVIG) therapy is licensed in Japan for the improvement of neuropathy associated with EGPA and allergic Granulomatous Angiitis in patients not responding to steroid therapy. IVIG is therefore included in the definition of relapsing disease.


125


6. Section 4.5.1, Withdrawal from Study Treatment, paragraph 2

Added:

Pregnancy

Rationale: Clarification that, in accordance with Exclusion criterion 16, subjects who are pregnant are excluded from participation.

7. Section 4.5.1, Withdrawal from Study Treatment, paragraph 2, bullet 3

Added and Deleted:

Concurrent medication: Use of prohibited concurrent medication (i.e., as noted in Exclusion Criterion #14 (Prohibited Medications) Section 5.7.2 -Prohibited Medications and Non-Drug Therapies) including cyclophosphamide.

Rationale: Link to Section 5.7.2 – Prohibited Medications and Non-Drug Therapies rather than Exclusion Criterion #14 replaced for clarification.

8. Section 5.7.1 Permitted Medications and Non-Drug Therapies.

Added:

In the event immunosuppressive therapy is initiated or the dose increased (e.g., in the event of relapse) study treatment should be withdrawn and, where possible, the subject continue to be followed up as per protocol until the end of follow-up at Week 60 (see Section 4.5.1- Withdrawal from Study Treatment).

Rationale: Clarification that, as indicated in Section 4.5.1, subjects who withdraw from study treatment prematurely (for any reason including initiation or increased dose of immunosuppressive therapy) should, where possible, continue to be followed up as per protocol until the end of follow-up at Week 60.

9. Section 5.7.2 Prohibited Medications and Non-drug Therapies

Added:

In the event a prohibited medication is used (e.g., in the event of relapse) study treatment should be withdrawn and, where possible, the subject continue to be followed up as per protocol until the end of follow-up at Week 60 (see Section 4.5.1 Withdrawal from Study Treatment). Note, this does not include use of any other investigational agent (biologic or non-biologic) where, if used, the subject should be withdrawn from the study.

Rationale: Clarification that, as indicated in Section 4.5.1, subjects who


126


withdraw from study treatment prematurely (for any reason including initiation of a prohibited medication [except another investigational agent]) should, where possible, continue to be followed up as per protocol until the end of follow-up at Week 60.

10. Section 6, Table 2, Biomarker Sub-studies, Sputum sample

Deleted:


Added:


Rationale: Correction to sub-study sputum sample schedule.


Added:

The period of fasting may be adjusted at the discretion of the investigator for subjects with relevant metabolic conditions (e.g., diabetes mellitus).

Rationale: Clarification provided regarding requirement for fasting in diabetic subjects.


Added:

At Weeks 1 and 29, where practical, an optional PK sample is to be collected (although, where possible, every effort should be made to collect these samples).

Rationale: Clarification that collection of a PK sample at Weeks 1 and 29 is optional.

13. Section 6.2.1.6 Spirometry

Added:

Prior to the Baseline visit (Visit 2) subjects should withhold short-acting beta-2-agonists (SABAs) and short-acting muscarinic adrenoreceptor antagonists (SAMAs) for at least 6 hours and long-acting beta-2-agonists (LABAs) and long-acting muscarinic adrenoreceptor antagonists (LAMAs) for at least 12 hours to enable reversibility testing to be performed. Specifically, FEV1 will be measured pre-salbutamol/albuterol and within 30 minutes [±15 minutes] following up to 4 inhalations of


127


salbutamol/albuterol (a spacer device may be used if required) or equivalent nebulised treatment with salbutamol/albuterol solution. The reversibility test must be performed in the morning only at Baseline (Visit 2).

Rationale: Inclusion of SAMAs and LAMAs as bronchodilators in addition to SABAs and LABAs.

14. Section 6.3.2, Liver Event Follow-up Assessments, 5th bullet

Deleted:


Added:


Rationale: Consistent with the requirement for investigators to be blinded to eosinophil counts for the duration of the study, requirement for assessment of eosinophilia as part of follow-up requirements following a liver event is deleted and is not considered essential for evaluation of a hypersensitivity reaction.

15. Section 10, References and associated cross-references in Section 1.3, Section 1.4 (including in Table 1) and Section 4.2

Added:

GlaxoSmithKline Document Number 2014N200212_00Supplement to Mepolizumab (SB-240563) Investigator's Brochure. Supplement No.: 01 IB Version 12. Date: 22 May 2014.

Rationale: Inclusion of Supplement to Investigator’s Brochure Version 12.

16. Section 11.2, Appendix 2: Country Specific Requirements

Added:

Amendment 02 includes a country-specific local amendment generated for Japan.Inclusion criterion 4:

Japan only definition of Relapsing disease:Subject must have a past history of at least one confirmed EGPA relapse


128


(i.e., requiring increase in OCS dose, initiation of IV prednisolone (or equivalent), initiation/increased dose of immunosuppressive therapy, initiation/increased dose of intravenous immunoglobulin (IVIG) or hospitalisation) within the past 2 years which occurred at least 12 weeks prior to Screening (Visit 1) whilst receiving a dose of prednisolone (or equivalent) of ≥7.5 mg/day.






1. Author(s):

Change from:

Author (s):

Change to:

Author (s):

Rationale:

Administrative change due to personnel changes.



Change from:

MD, PhD (Head, Clinical Development, Alternative


129


Development Program)

Tel:

Mobile:

Change to:


Mobile:

Email:


Change from:


Tel:

Mobile:


Change to:

MD

Phone:

Mobile:

Email:


Change from:

Tel:


130


Mobile:

FAX:

email:

Change to:


Mobile:

Email:


3. Protocol Summary, Rationale, paragraph 2

Deleted:


Rationale: Specific definition of remission is deleted here since two remission definitions are now being investigated, i.e., BVAS=0 plus OCS dose of prednisolone/prednisone 4 mg/day and BVAS=0 plus OCS dose of prednisolone/prednisone 7.5 mg/day.

4. Protocol Summary, Objectives, Primary, Bullet 1

Section 2, Objectives, Primary, Bullet 1

Change from:

To investigate the efficacy of mepolizumab plus standard of care compared with placebo plus standard of care on duration of clinical remission, defined as accrued duration in weeks where a subject achieves a BVAS=0 and corticosteroid dose ≤4 mg/day prednisolone/prednisone in subjects


131


with relapsing or refractory eosinophilic granulomatosis with polyangiitis (EGPA) receiving standard of care therapy including corticosteroid therapy reduction/withdrawal.

Change to:

To investigate the efficacy of mepolizumab plus standard of care compared with placebo plus standard of care on accrued duration of clinical remission in subjects with relapsing or refractory eosinophilic granulomatosis with polyangiitis (EGPA) receiving standard of care therapy including corticosteroid therapy. reduction/withdrawal.


5. Protocol Summary, Study Design, Paragraph 5, second sentance

Section 3.1, Study Design, Paragraph 6, second sentanceDeleted:

From Week 4 post-baseline onwards, if the subject’s BVAS=0 their oralOCS dose should be tapered downwards according to standard of care practice.

Rationale: The word oral is redundant.

6. Protocol Summary, Study Design, Paragraph 6

Section 3.1, Study Design, Paragraph 7

Change from:


Change to:

In this study two definitions of EGPA remission will be investigateddefined as i) BVAS=0 plus OCS dose of prednisolone/prednisone 4 mg/day and ii) BVAS=0 plus OCS dose of prednisolone/prednisone 7.5


132


mg/day. In defining EGPA remission, asthma and sino-nasal symptoms /signs related to EGPA activity, if not specifically covered by the BVAS assessment, will be considered to be controlled by virtue of the low OCS dose and are therefore not included in the remission definition.

Rationale: Text amended to incorporate both definitions of remission, i.e., BVAS=0 plus OCS dose of prednisolone/prednisone 4 mg/day and BVAS=0 plus OCS dose of prednisolone/prednisone 7.5 mg/day.


Section 3.1, Study Design, Paragraph 7, 4th bullet

Section 6.2.1.2, Paragraph 1, 4th bullet

Added:

An increased dose of OCS therapy (or other systemic corticosteroid therapy) to >4 mg/day prednisolone total daily dose or equivalent OR

Rationale: Added to ensure use of any systemic corticosteroid, e.g., including intravenous administration, could constitute a relapse with increase to a dose of >4 mg/day prednisolone total daily dose or equivalent. This >4 mg/day prednisolone total daily dose or equivalent clarification is consistent with the statement that upward dose adjustments within the 0-4.0 mg range are permitted without being considered a relapse.

8. Protocol Summary, Study Design, Paragraph 7 (last sentence)


Change from:

In the event a subject has achieved remission (i.e., BVAS=0 and prednisolone/prednisone dose ≤4 mg/day) and at any subsequent visit has a BVAS = 1 which does not require an increase in corticosteroid dose above 4 mg/day, or any other significant clinical intervention or investigation, the subject will be considered to be in continued remission.

Change to:

In the event a subject has achieved remission and at any subsequent visit has a BVAS = 1 which does not require an increase in corticosteroid dose


133


above 4 mg/day or 7.5 mg/day (in accordance with the relevant remission definition), or any other significant clinical intervention or investigation, the subject will be considered to be in continued remission.




Change from:


Change to:

A major relapse (a sub-set of the total relapse events) will be defined as: any organ or life-threatening EGPA event; OR BVAS ≥6 (involving at least two organ systems in addition to any general symptoms where present[myalgia, arthralgia/arthritis, fever >38ºC or weight loss >2 kg]); OR an asthma relapse requiring hospitalisation; OR sino-nasal relapse requiring hospitalisation.

Rationale:

To ensure major asthma relapses reflect significant clinical events rather than minor clinical worsening.



Deleted:

The minimally effective dose of OCS (prednisolone/prednisone) for each subject will be defined as the dose of OCS one step above the OCS dose at which the first relapse occurred. Where the subject has achieved a dose of OCS of 0-3.5 mg prednisolone/prednisone, the minimally effective dose


134


will be defined as 4.0 mg/day. Upwards dose adjustments within the 0-4.0 mg range are permitted without necessarily being considered a relapse.

Rationale: Since relapse is associated with an increased dose of OCS therapy (or other systemic corticosteroid therapy) to >4 mg/day prednisolone total daily dose or equivalent, the word ‘necessarily’ isredundant.



Deleted:


Rationale: Management of relapse according to standard of care may involve use of any systemic corticosteroids (e.g., oral or intravenous).

12. Protocol Summary, Study Design, Last Paragraph

Section 3.1, Study Design, Last Paragraph

Change from:

Investigator-sponsored ‘mechanistic/biomarker’ sub-studies will be conducted at selected sites in the United States (US) and Europe using samples collected from consenting subjects participating in the study. The objective of these studies will include examination of molecular profiles and biomarkers associated with EGPA and response to anti-IL-5 therapy. Specific details of the planned analyses will be outlined in the individual protocols and/or analysis plans for these sub-studies.

Change to:

Research-supported ‘mechanistic/biomarker’ sub-studies will be conducted at selected sites in the United States (US) and Europe using samples collected from consenting subjects participating in the study. The objective of these studies will include examination of molecular profiles and biomarkers associated with EGPA and response to anti-IL-5 therapy. Specific details of the planned analyses will be outlined in the individual protocols and/or analysis plans for these sub-studies.


135


Rationale: Research-supported, not Investigator-sponsored, is the appropriate description of this collaboration as per GSK procedures.

13. Protocol Summary, Study Endpoints/Assessments, Co-primary endpoints

Section 6.2.1 Efficacy Endpoints, Primary, Bullet 2

Section 8.3.5.1 Efficacy Analyses, Primary Efficacy Endpoints

Added:

The proportion of subjects who are in remission (i.e., BVAS=0 and prednisolone/prednisone 4 mg/day) at both Weeks 36 and 48 of the study treatment period.

Rationale: Since two remission definitions are now being investigated, i.e., BVAS=0 plus OCS dose of prednisolone/prednisone 4 mg/day and BVAS=0 plus OCS dose of prednisolone/prednisone 7.5 mg/day, the specific remission definition for this co-primary endpoint is specified here.

14. Protocol Summary, Study Endpoints/Assessments, Secondary Endpoints

Section 6.2.1, Efficacy Endpoints, Secondary

Section 8.3.5.1, Secondary Endpoints

Section 8.3.5.1 Efficacy Analyses, Secondary Endpoints

Added:

iv. the total accrued duration of remission, i.e., the accrued number of weeks where BVAS=0 plus prednisolone/prednisone dose 7.5 mg/day over the 52 week study treatment period reported as the proportion of subjects achieving remission in the following categories: Zero; >0 to <12 weeks; 12 to <24 weeks; 24 to <36 weeks and ≥36 weeks.

v. the proportion of subjects who are in remission (defined as BVAS=0 plus prednisolone/prednisone dose 7.5 mg/day) at both Weeks 36and 48 of the study treatment period.

vi. the proportion of subjects who achieve remission (BVAS=0 and prednisolone/prednisone 7.5 mg/day) within the first 24 weeks of the study and remain in remission for the remainder of the study treatment period.

Rationale: Following further internal review and consultation with


136


external experts, the remission definition as per the EULAR recommendations for conducting clinical studies or clinical trials in systemic vasculitis (Hellmich, 2007) has been included for investigation in this study in addition to the more stringent definition of BVAS=0 plus OCS dose of prednisolone/prednisone 4 mg/day. As such, additional secondary endpoints reflecting the two co-primary endpoints and third secondary endpoint have been included using this alternative remission definition.

15. Section 1.2, Rationale, paragraph 2

Change from:


Change to:

The purpose of this randomised, double-blind study is to investigate the efficacy and safety of mepolizumab (300 mg subcutaneously [SC] every 4 weeks) compared with placebo over a 52-week study treatment period in subjects with relapsing or refractory EGPA receiving standard of care therapy including background corticosteroid therapy with or without immunosuppressive therapy. In accordance with standard of care, corticosteroid dose tapering will be permitted during the study. The key outcomes of this study focus on evaluation of clinical remission, reduction in disease relapse and reduction in corticosteroid requirement.


16. Section 3.2, Discussion of Design, paragraph 4

Change from:

European League Against Rheumatism (EULAR) recommendations for clinical studies in systemic vasculitis encourage demonstration of


137


corticosteroid-sparing as a trial outcome with a proposed definition of remission including disease control (i.e., BVAS=0) with prednisolone dose of ≤7.5 mg/day for a prolonged period [Hellmich, 2007]. In this study, the definition of remission requires a BVAS=0 with prednisolone/prednisone dose of ≤4.0 mg/day. This more stringent requirement reflects the evidence that doses in excess of 7.5 mg/day prednisolone (or equivalent) are associated with an increased risk of long-term complications [Sarnes, 2011].

Change to:

European League Against Rheumatism (EULAR) recommendations for clinical studies in systemic vasculitis encourage demonstration of corticosteroid-sparing as a trial outcome with a proposed definition of remission including disease control (i.e., BVAS=0) with prednisolone dose of ≤7.5 mg/day for a prolonged period [Hellmich, 2007]. In this study this definition will be investigated in addition to a second, more stringent definition, requiring a BVAS=0 with prednisolone/prednisone dose of ≤4.0 mg/day. This more stringent requirement reflects the evidence that doses in excess of 7.5 mg/day prednisolone (or equivalent) are associated with an increased risk of long-term complications [Sarnes, 2011].

Rationale: Following further internal review and consultation with external expert remission definition as per the EULAR recommendations for conducting clinical studies or clinical trials in systemic vasculitis (Hellmich, 2007) has been included for investigation in this study in addition to the more stringent definition of BVAS=0 plus OCS dose of prednisolone/prednisone 4 mg/day. As such, additional secondary endpoints reflecting the two co-primary endpoints and third secondary endpoint have been included using this alternative remission definition.

17. Section 6.2.1, Efficacy Endpoints, Other

Added:

Total duration of sustained remission, i.e., longest uninterrupted period of weeks where BVAS=0 plus prednisolone/prednisone ≤7.5 mg/day over the 52 week study treatment period, reported as proportion of subjects achieving sustained remission in the following categories:

Zero

>0 to <12 weeks

12 to <24 weeks

24 to <36 weeks


138


≥36 weeks

Rationale: This addition allows investigation of this endpoint using both definitions of remission being investigated in this study, i.e., BVAS=0 plus OCS dose of prednisolone/prednisone 4 mg/day and BVAS=0 plus OCS dose of prednisolone/prednisone 7.5 mg/day.

18. Section 6.7.1, Mechanistic/Biomarker Sub-studies

Change from:



Change to:

US: Samples (blood, urine and sputum, and in case of relapse, where possible [i.e., if as part of standard of care management] a tissue sample) for the research-supported, ‘mechanistic’ sub-study, will be collected from specified US sites only at the visits specified in the Time and Events table (Table 2). Procedures for sample management and shipment for this sub-study will be provided to the relevant sites.

Europe: Blood samples for the research-supported ‘biomarker’ sub-study will be collected from participating EU sites only at the visits specified in the Time and Events table (Table 2). Procedures for sample management and shipment for this sub-study will be provided to the relevant sites.

Rationale: Research-supported, not Investigator-sponsored, is the appropriate description of this collaboration as per GSK procedures.

19. Section 8.3.3.2 Other Comparisons of Interest

Deleted:

Other comparisons of interest are mepolizumab versus placebo for each of the 3 secondary endpoints. In order to make inferences for the pre-defined secondary endpoints while controlling the overall type I error, multiplicity


139


across these comparisons will be controlled using a closed testing procedure where the secondary endpoints will be nested under the primary efficacy endpoint, followed by a further hierarchical procedure within the secondary endpoints, in the order of: i) time to relapse, ii) prednisolone/prednisone dose followed by, iii) proportion of subjects who achieve remission within the first 24 weeks of the study and then remain in remission. That is:





Added:

Other comparisons of interest are mepolizumab versus placebo for each of the secondary endpoints. When strong control of the overall type I error is required, adjustment for multiplicity will be achieved using a closed testing procedure with the secondary endpoints nested under the primary efficacy endpoint, followed by a further hierarchical procedure within the secondary endpoints. The hierarchy of the secondary endpoints is defined as follows:

Time to first confirmed EGPA relapse

Average daily prednisolone/prednisone dose during the last 4 weeks of the study.

The proportion of subjects who achieve remission (defined as BVAS=0 plus prednisolone/prednisone dose 4 mg/day) within the first 24 weeks of the study and then remain in remission for the remainder of the study treatment period.

Total accrued duration of remission, (defined as BVAS=0 plus prednisolone/prednisone dose 7.5 mg/day) over the 52 week study.

The proportion of subjects who are in remission (defined as BVAS=0 plus prednisolone/prednisone dose 7.5 mg/day) at both Weeks 36 and 48 of the study.


140


The proportion of subjects who achieve remission (defined as BVAS=0 plus prednisolone/prednisone dose 7.5 mg/day) within the first 24 weeks of the study and then remain in remission for the remainder of the study treatment period.

Rationale: The hierarchical procedure was updated to reflect the addition of three secondary endpoints. The text was also amended to allow more flexibility regarding the strong control of type I error.

20. Section 8.3.5.1 Efficacy Analyses, Primary efficacy endpoints, paragraph 2

Changed from:

The primary analysis of co-primary endpoint ’1’ will use a logisticproportional odds regression model for ordered categorical data for the proportion of subjects who achieve remission categorised, as above, for the ITT population. Baseline covariates to be included in the model are i) baseline steroid dose, ii) ANCA status (due to potential for association with risk of relapse Sable Fourtassour, 2005; Sinico, 2005]) and iii) region, i.e., i) subjects participating in the US ‘Mechanistic’ sub-study, ii) Japan (for administrative reasons) and iii) the remainder of recruited subjects

Changed to:

The primary analysis of co-primary endpoint ’1’ will use a proportional odds regression model for ordered categorical data for the proportion of subjects who achieve remission categorised, as above, for the ITT population. Baseline covariates to be included in the model are: baseline prednisone/prednisolone daily dose, baseline BVAS score and region (North America/European Union/Japan).

Rationale: Baseline prednisone/prednisolone daily dose and baseline BVAS score are considered to be important prognostic factors for efficacy endpoints. The definition of region is considered to reflect potential differences in standard of care between sites. ANCA status is not considered as an important prognostic factor; however an interaction of ANCA status with treatment effect will be investigated in an exploratory analysis.

21. Section 8.3.5.1 Efficacy Analyses, Evaluating Model Assumptions, paragraph 1

Deleted:

The logistic proportional odds regression model for ordered categorical data assumes that the odds are proportional. This assumption will be assessed with a Score Test for the Proportional Odds Assumption. If this test is significant, analysis using a Wilcoxon-Mann-Whitney test will be


141


conducted, adjusting for strata (van Elteren statistic). For this analysis, baseline steroid dose will be categorized as ’low’ versus ‘high’.

Rationale: Conditional tests like this are considered to be problematic and do not preserve type I error. (Rochon , 2011; Zimmerman , 2004;Schucany , 2006).

22. Section 8.3.5.1 Efficacy Analyses, Missing Data in Primary Endpoints,

Deleted:

For both of the co-primary endpoints, in the event of a missing value, the last available observation will be carried forward until a value is observed supporting a change in state. For example, if a subject is in remission, he/she will be assumed to still be in remission until there are data to indicate he/she is not in remission. Similarly, if a subject is not in remission, it will be assumed the subject is not in remission until there are data to indicate that he/she is in remission.




a) Analyses will be replicated using observed data for subjects who withdraw prematurely from study treatment and continue to be followed in the observation period to determine duration of remission. For subjects who withdraw prematurely from the study and are no longer under observation, analyses will be replicated assuming post-withdrawal values are ‘not in remission’.

b) Analyses will be replicated assuming placebo subjects who withdraw prematurely from study treatment are in remission for various percentages of time post-treatment to determine what, if any, assumption around missing data would result in a non-significant p-value.



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a) Analyses will be replicated using observed data for subjects who withdraw prematurely from study treatment and continued to be followed in the observation period to determine remission at Weeks 36 and 48. For subjects who withdraw prematurely from the study and are no longer under observation, analyses will be replicated assuming post-withdrawal values at Weeks 36 and 48 are ‘not in remission’.

b) Analyses will be replicated assuming various percentages of placebo subjects withdrawing prematurely from study treatment are in remission at Weeks 36 and 48, to determine what, if any, assumption around missing data would result in a non-significant p-value


a) Various percentages of on treatment missing values for placebo subjects are always in remission

b) Various percentages of on treatment missing values for mepolizumab subjects are always not in remission.

Added:

The primary analyses for the co-primary endpoints will address a de facto estimand and use all observed remission data. For subjects withdrawing prematurely from randomised treatment, remission status over the remainder of the study will be included in the analysis where this is available. Subjects who withdraw from the study and where no remission status is available will be included in the analysis as not in remission for the duration of the missing period.

A sensitivity analysis will be performed for the co-primary endpoints whereby subjects withdrawn from randomised treatment will be assumed to be no longer in remission after the time of withdrawal from randomised treatment. Additional sensitivity analyses will be described in the analysis plan.

Rationale: The primary analysis has been changed to use a de facto estimand; therefore analyses assuming that subjects withdrawn from randomised treatment are not in remission are now considered to be supportive. Additional details will be specified in the analysis plan.


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23. Section 8.3.5.1 Efficacy Analyses, Subgroups and covariates in Primary Endpoints, paragraph 1

Deleted: Note, this will include investigation of the subgroup of subjects with biopsy-proven EGPA

Rationale: Details of subgroups will be included in the analysis plan.

24. Section 8.3.5.1 Efficacy Analyses, Subgroups and covariates in Primary Endpoints, paragraph 2

Deleted:


Rationale: Removed duplicate text.

25. Section 8.3.5.1 Efficacy Analyses, Secondary Endpoints

Added:

vii. The total accrued duration of remission, i.e., the accrued number of weeks where BVAS=0 plus prednisolone/prednisone dose ≤7.5 mg/day over the 52 week study treatment period reported as the proportion of subjects achieving remission in the following categories: Zero; >0 to <12 weeks; 12 to <24 weeks; 24 to <36 weeksand ≥36 weeks

viii. The proportion of subjects who are in remission (defined as BVAS=0 plus prednisolone/prednisone dose ≤7.5 mg/day) at both Weeks 36 and 48 of the study treatment period.

ix. The proportion of subjects who achieve remission (BVAS=0 and prednisolone/prednisone ≤7.5 mg/day) within the first 24 weeks of the study and remain in remission for the remainder of the study treatment period.

Rationale:

List of secondary endpoints updated to align with Section 8.3.5.1.

26. Section 8.3.5.1 Efficacy Analyses, Secondary Endpoints: Time to first EGPA relapse

Deleted:

Time to first confirmed EGPA relapse will be analysed using a Cox


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proportional hazards regression model allowing for similar covariates as those specified for analysis of the primary endpoints. The hazard ratio will be derived along with 95% confidence limits. Cumulative event rates will be calculated using the Kaplan-Meier method. The proportional hazards assumption will be assessed, with details to be provided in the RAP. If the validity of the proportional hazards assumption is not acceptable, the treatment effect will be assessed using the Log-Rank Test. The analysis will be based on the time to observed relapse. In the event that a subject withdraws prematurely from study treatment or from the study, then the event time for that subject will be censored at the time of withdrawal from treatment





Added:

Time to first EGPA relapse will be analysed using a Cox proportional hazards regression model using the same covariates as those specified for analysis of the primary endpoints. The hazard ratio will be derived along with 95% confidence limits. Cumulative event rates will be calculated using the Kaplan-Meier method. The proportional hazards assumption will be assessed, with details to be provided in the RAP. If the validity of the proportional hazards assumption is not acceptable, the treatment effect will be assessed using the Log-Rank Test. The analysis of time to first EGPA relapse will address a de facto estimand and use all observed relapse data. The analysis will be performed for the time to first relapse, considering all relapse events regardless of whether the subject had withdrawn from study treatment at the time of the relapse. Subjects will be censored at the time of study completion or withdrawal from the study.

The following sensitivity analyses will be performed for the time to first relapse:

Assuming subjects who withdrew prematurely from study treatment had an event at the time of withdrawal.


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Assuming subjects who withdrew prematurely from study treatment due to a treatment-related reason (i.e. ‘Adverse event’ or ‘Lack of efficacy’) had an event at the time of withdrawal.

Rationale:

The primary analysis has been changed to use a de facto estimand.Sensitivity analyses are defined, with further details described in the analysis plan.

27. Section 8.3.5.1 Efficacy Analyses, Secondary Endpoints: The proportion of subjects with an average daily prednisolone/prednisone dose during the last 4 weeks of the treatment period

Deleted :

The proportion of subjects with an average daily prednisolone/prednisone dose during the last 4 weeks of the treatment period (Weeks 48 through 52) will be analysed in the same way as the primary endpoint, i.e. using a logistic proportional odds regression model using similar covariates. For subjects who withdraw prematurely from study treatment it will be assumed that their final average daily OCS dose was the average during the 4 weeks immediately following the last dose of study medication. If this is not available, then it will be assumed that their final average daily OCS dose was the average of the last 4 weeks available.

Sensitivity analysis will be conducted as follows:

a. The analysis will be replicated using observed data for subjects who prematurely withdraw from treatment, assuming that their final average daily OCS dose was the average during the last 4 weeks of observation while still in the study


Added:

The proportion of subjects in each category of average daily prednisolone/prednisone dose during the last 4 weeks of the treatment period (Weeks 48 through 52) will be analysed in the same way as the primary endpoint, i.e. using a proportional odds regression model using the same covariates. The analysis will address a de facto estimand, and sensitivity analyses will be conducted as specified in the analysis plan.


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Rationale: The primary analysis has been changed to use a de facto estimand. Sensitivity analyses will be described in the analysis plan.

28. Section 8.3.5.1 Efficacy Analyses, Secondary Endpoints: The proportion of subjects who achieve remission within the first 24 weeks of the study and then remain in remission for the remainder of the treatment period

Change from:


a) The analysis will be replicated using observed data for subjects who prematurely withdraw from study treatment to determine remission and assuming that all unobserved data have the value of ‘not in remission’.

b) The analysis will be replicated assuming various percentages of placebo subjects who withdraw prematurely from study treatment are in remission for the remainder of the study, to determine what, if any, assumption around missing data would result in a non-significant p-value.

Change to:

The proportion of subjects who achieve remission within the first 24 weeks of the study and then remain in remission for the remainder of the treatment period will be analysed using a regression model, using the same covariates as those used for the co-primary endpoints. The analysis will address a de facto estimand, and sensitivity analyses will be conducted as specified in the analysis plan.

Rationale: The primary analysis has been changed to use a de facto estimand. Sensitivity analyses are defined, with further details described in the analysis plan.

29. Section 8.3.5.1 Efficacy Analyses, Secondary Endpoints

Added:

The following endpoints will be analysed using the two remission definitions, i.e., BVAS=0 plus prednisolone/prednisone dose 4 mg/day


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and BVAS=0 plus prednisolone/prednisone dose 7.5 mg/day:

Total accrued duration of remission

Proportion of subjects who are in remission at both Weeks 36 and 48 of the study,

Proportion of subjects who achieve remission within the first 24 weeks of the study and then remain in remission until the end of the study.

Rationale: Additional endpoints added as per Section 6.2.1 Efficacy Endpoints

30. Section 8.3.5.4 Pharmacokinetic Analyses, Paragraph 2

Deleted:


Rationale: Sentence deleted to allow the use of statistical testing if deemed appropriate.

31. References:

Deleted:


Rationale: ANCA as a covariate and this referral to this reference deleted from Section 8.3.5.1 Efficacy Analyses, Co-primary Efficacy Endpoints.

32. References:

Added:

Rochon J, Kieser M. A closer look at the effect of preliminary goodnessof fit testing for normality for the one sample t test. British Journal of Mathematical and Statistical Psychology. 2011 Nov 1;64(3):410-26.

Schucany WR, Tony Ng HK. Preliminary goodness-of-fit tests for normality do not validate the one-sample Student t. Communications in Statistics—Theory and Methods. 2006 Dec 1;35(12):2275-86.

Zimmerman DW. A note on preliminary tests of equality of variances. British Journal of Mathematical and Statistical Psychology. 2004 May


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1;57(1):173-81.

Rationale:

New references included in to Appendix 11.13 Protocol Amendment 03item 21.