2014N192079_03 CONFIDENTIALThe GlaxoSmithKline group of companies 201317

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TITLE PAGE

Division: Worldwide DevelopmentInformation Type: Protocol Amendment

Title: A Randomized, Double-Blind, Placebo-Controlled Evaluation of the Effect of the Combination of Umeclidinium and Vilanterol on Exercise Endurance Time in Subjects with COPD

Compound Number: GSK573719+GW642444

Development Phase: IV

Effective Date: 06-MAY-2015

Protocol Amendment Number: 02

Author (s):

Copyright 2015 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised copying or use of this information is prohibited.

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Revision Chronology

GlaxoSmithKlineDocument Number

Date Version

2014N192079_00 2014-JUL-29 Original

2014N192079_01 2014-SEP-15 Re-publishing

The Original was republished to provide clarification on the statistical methods that will be used for the study.

2014N192079_02 2014-OCT-06 Amendment No. 1

Amendment No.1 provides clarification on the efficacy endpoints listed as ‘other endpoints’ and clarification on the order of administration of study procedures shown in Table 5 and correction of typographical errors.

2014N192079_03 2015-MAY-06 Amendment No. 2

Amendment No. 2 includes a change to the wording of the last Exclusion criterion in Section 4.3 to indicate that subjects are not eligible to participate in study 201317 if the subject was randomized to study medication in studies DB2114417 or DB2114418 rather than previously enrolled in these studies. The numbering in Section 4.3 was also re-formatted to show sequential numbering of the Exclusion Criteria.

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SPONSOR INFORMATION PAGE

Clinical Study Identifier: 201317

Sponsor Legal Registered Address:

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

Sponsor Contact Address

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 Medical Monitor Contact Information:

MDGlaxoSmithKlineStockley Park West1-3 Ironbridge Road, Uxbridge, Middlesex, UB11 1 BT, United KingdomEmail: Office Tel:

Back-up Medical Monitor:

MDGlaxoSmithKline5 Moore DriveResearch Triangle Park, NC 27709-3398, USAEmail: Office Tel: Mobile Tel:

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Sponsor Serious Adverse Events (SAE) Contact Information:

MDGlaxoSmithKlineStockley Park West1-3 Ironbridge Road, Uxbridge, Middlesex, UB11 1 BT, United KingdomEmail: Office Tel:

Back-up:

MDGlaxoSmithKline5 Moore DriveResearch Triangle Park, NC 27709-3398, USAEmail: Office Tel: Mobile Tel:

Regulatory Agency Identifying Number(s):

IND No. 106,616

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INVESTIGATOR PROTOCOL AGREEMENT PAGE

For protocol number 201317

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 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 Address:

Investigator Phone Number:

Investigator Signature Date

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TABLE OF CONTENTS

PAGE

LIST OF ABBREVIATIONS...........................................................................................10

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

1. INTRODUCTION....................................................................................................161.1. Background ................................................................................................161.2. Rationale ....................................................................................................161.3. Benefit:Risk Assessment ............................................................................17

1.3.1. Risk Assessment .........................................................................181.3.2. Benefit Assessment .....................................................................211.3.3. Overall Benefit:Risk Conclusion...................................................21

2. OBJECTIVE(S) ......................................................................................................22

3. INVESTIGATIONAL PLAN.....................................................................................223.1. Study Design ..............................................................................................223.2. Discussion of Design ..................................................................................24

4. SUBJECT SELECTION AND WITHDRAWAL CRITERIA.......................................244.1. Number of Subjects ....................................................................................244.2. Inclusion Criteria .........................................................................................254.3. Exclusion Criteria........................................................................................264.4. Randomization Criteria ...............................................................................294.5. Investigational Product (IP) Discontinuation Criteria ...................................30

4.5.1. Protocol defined IP Discontinuation Criteria .................................304.5.2. Study Participation Post IP Discontinuation .................................304.5.3. IP Discontinuation Study Assessments........................................314.5.4. Reasons for Permanent Discontinuation of IP..............................31

4.6. Study Withdrawal Criteria ...........................................................................324.6.1. Study Withdrawal Assessments...................................................324.6.2. Lost to follow up...........................................................................324.6.3. Reasons for Study Withdrawal.....................................................33

4.7. Follow-up Contact.......................................................................................344.8. Pre-Screening Failures ...............................................................................344.9. Screen Failures...........................................................................................354.10. Run-in Failures ...........................................................................................35

5. STUDY TREATMENTS..........................................................................................355.1. Investigational Product and Other Study Treatment....................................35

5.1.1. Storage........................................................................................365.1.2. Study Drug Return .......................................................................37

5.2. Treatment Assignment and Study Drug Administration...............................375.3. Blinding.......................................................................................................385.4. Product Accountability ................................................................................385.5. Treatment Compliance................................................................................395.6. Concomitant Medications and Non-Drug Therapies....................................39

5.6.1. Permitted Medications and Non-Drug Therapies..........................395.6.2. Prohibited Medications and Non-Drug Therapies.........................40

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5.7. Treatment after IP Discontinuation or End of the Study...............................415.8. Treatment of Study Treatment Overdose....................................................42

6. STUDY ASSESSMENTS AND PROCEDURES .....................................................426.1. Critical Baseline Assessments ....................................................................48

6.1.1. Modified Medical Research Council Grading System (mMRC).......................................................................................48

6.1.2. Primary Efficacy Endpoint............................................................496.1.3. Secondary Efficacy Endpoint .......................................................496.1.4. Other Endpoints...........................................................................496.1.5. Incremental Shuttle Walk Test .....................................................496.1.6. Endurance Shuttle Walk Test and Exercise Endurance

Time ............................................................................................506.1.7. Exercise Dyspnea Scale (EDS) ...................................................506.1.8. Reasons for stopping the ESWT..................................................506.1.9. Pulse Oximetry and Heart Rate Monitoring during ISWT

and ESWT ...................................................................................506.1.10. Lung Volumes..............................................................................516.1.11. Spirometry and Responsiveness Testing.....................................51

6.1.11.1. Spirometry..................................................................516.1.11.2. Bronchodilator Responsiveness Testing.....................51

6.1.12. Daily Diary Assessments .............................................................526.1.13. COPD Assessment Test (CAT)....................................................52

6.2. Safety .........................................................................................................526.2.1. Vital Signs....................................................................................536.2.2. COPD Exacerbations...................................................................536.2.3. Liver chemistry stopping and follow up criteria.............................536.2.4. Adverse Events............................................................................56

6.2.4.1. Definition of an AE......................................................566.2.4.2. Definition of an SAE ...................................................576.2.4.3. Sentinel Events ..........................................................58

6.2.5. Laboratory and Other Safety Assessment Abnormalities Reported as AEs and SAEs.........................................................59

6.2.6. Cardiovascular Events .................................................................596.2.7. Pneumonia Events.......................................................................596.2.8. Death Events ...............................................................................606.2.9. Disease-Related Events and/or Disease-Related

Outcomes Not Qualifying as SAES..............................................606.2.10. Pregnancy ...................................................................................606.2.11. Medical Devices...........................................................................606.2.12. Time Period and Frequency of Detecting AEs and SAEs.............606.2.13. Method of Detecting AEs and SAEs.............................................616.2.14. Prompt Reporting of Serious Adverse Events and Other

Events to GSK .............................................................................616.2.14.1. Regulatory Reporting Requirements for SAEs............64

6.3. Pharmacogenetic Research........................................................................65

7. DATA MANAGEMENT ...........................................................................................65

8. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS...................................658.1. Hypotheses.................................................................................................658.2. Study Design Considerations......................................................................65

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8.2.1. Sample Size Assumptions ...........................................................658.2.2. Sample Size Sensitivity................................................................668.2.3. Sample Size Re-estimation..........................................................67

8.3. Data Analysis Considerations .....................................................................688.3.1. Analysis Populations....................................................................688.3.2. Analysis Data Sets.......................................................................688.3.3. Treatment Comparisons ..............................................................68

8.3.3.1. Primary Comparison of Interest ..................................688.3.3.2. Other Comparisons of Interest....................................69

8.3.4. Interim Analysis ...........................................................................698.3.5. Key Elements of Analysis Plan ....................................................69

8.3.5.1. Efficacy Analyses .......................................................708.3.5.2. Safety Analyses..........................................................728.3.5.3. Pharmacogenetic Analyses ........................................72

9. STUDY CONDUCT CONSIDERATIONS ...............................................................729.1. Posting of Information on Publicly Available Clinical Trial Registers............729.2. Regulatory and Ethical Considerations, Including the Informed

Consent Process ........................................................................................739.3. Quality Control (Study Monitoring) ..............................................................739.4. Quality Assurance.......................................................................................749.5. Study and Site Closure ...............................................................................749.6. Records Retention ......................................................................................749.7. Provision of Study Results to Investigators, Posting of Information

on Publicly Available Clinical Trials Registers and Publication ....................75

10. REFERENCES.......................................................................................................76

11. APPENDICES ........................................................................................................7911.1. Appendix 1: Pharmacogenetic Research ....................................................7911.2. Appendix 2: Liver Chemistry Stopping and Follow-up Criteria.....................8411.3. Appendix 3: Country Specific Requirements ...............................................8511.4. Appendix 4: Protocol Changes....................................................................86

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LIST OF ABBREVIATIONS

AEATSCATCICOPDCRDPIDREECGeCRFEDSEETESWTFEV1

FRCFSHFVCGCPGCSPGSKHRIBICICFICHICSIECINRIPIRBISWTITTIVRIWRJ2RLABALAMALTOTMcgMCIDMDIMedDRAMImMRC

MMRM

Adverse EventAmerican Thoracic SocietyCOPD Assessment TestConfidence IntervalChronic Obstructive Pulmonary DiseaseCopy ReferenceDry Powder InhalerDisease-Related EventElectrocardiogramElectronic Case Report FormExercise Dyspnea ScaleExercise endurance timeEndurance Shuttle Walk TestForced Expiratory Volume in One SecondFunctional Residual CapacityFollicle stimulating hormoneForced Vital CapacityGood Clinical PracticeGlobal Clinical Safety and PharmacovigilanceGlaxoSmithKlineHeart RateInvestigator BrochureInspiratory capacityInformed Consent FormInternational Conference on HarmonisationInhaled CorticosteroidIndependent Ethics CommitteeInternational Normalized ratioInvestigational ProductInstitutional Review BoardIncremental Shuttle Walk TestIntent to TreatInteractive Voice Response Interactive Web ResponseJump to ReferenceLong-Acting Beta AgonistLong-Acting Muscarinic AntagonistLong-Term Oxygen TherapyMicrogramMinimal clinically important differenceMetered Dose InhalerMedical Dictionary for Regulatory ActivitiesMultiple ImputationModified Medical Research Council Dyspnea ScaleMixed Model Repeated Measures

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MSDSPGxPPCPRN

Material Safety Data SheetPharmacogeneticsPer Protocol CompleterAs needed

RAPRVSAESPMSPO2TLCULNUSVI

Reporting and Analysis PlanResidual VolumeSerious Adverse EventStudy Procedures ManualArterial oxygen saturationTotal Lung CapacityUpper Limit of NormalUnited StatesVilanterol

Trademark Information

Trademarks of the GlaxoSmithKline group of companies

Trademarks not owned by the GlaxoSmithKline group of companies

ANORO SASELLIPTA

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PROTOCOL SUMMARY

Expiratory airflow limitation is the hallmark physiological change associated with chronic obstructive pulmonary disease (COPD). A consequence of airflow limitation is gas trapping as expiration becomes flow limited. This may occur at rest with more severe airway obstruction and is most evident during exercise as lung emptying is reduced and increased ventilation does not allow full expiration. This increased gas trapping or hyperinflation is the cause of much of the increased work of breathing, dyspnea, and exercise intolerance in subjects with COPD [O'Donnell, 1997; O'Donnell, 1993].

Spirometric measurement of airflow limitation, particularly as assessed by forced expiratory volume in one second (FEV1), is commonly used for the diagnosis of and assessment of response to pharmacotherapeutic intervention in COPD. However, changes in FEV1 may not fully predict symptomatic responses and alternative measures such as exercise tolerance and exertional dyspnea may be more sensitive to therapeutic intervention and/or more clinically relevant than FEV1 [O'Donnell, 1999; Bauerle, 1998; O’Donnell, 1998; Officer, 1998].

Umeclidinium/vilanterol (UMEC/VI) Inhalation Powder is a combination of the long-acting muscarinic antagonist (LAMA) umeclidinium (UMEC) and the long-acting beta2-agonist (LABA) vilanterol (VI) delivered via a multi-dose dry powder inhaler (DPI). UMEC/VI at a dose of 62.5/25mcg once-daily is marketed in the United States (US) under the trade name ANORO™ ELLIPTA™. In a previous 6 month randomized, double-blind, placebo controlled study, UMEC/VI 62.5/25 mcg once-daily demonstrated significantly greater improvements in the primary and secondary efficacy endpoints of trough FEV1 and 0 to 6 hour weighted mean FEV1 compared with UMEC 62.5 mcg, VI 25 mcg and placebo [Donohue, 2013]. The benefit of UMEC/VI on dyspnea symptoms and health-related quality of life was supported by clinically meaningful improvements in transition dyspnea index [TDI], rescue use, and St. George’s Respiratory Questionnaire (SGRQ) total scores compared to placebo [Donohue, 2013].

The effect of UMEC/VI 62.5/25mcg on exercise endurance as measured by the endurance shuttle walk test (ESWT) was investigated in two 12-week, randomized, double-blind, placebo-controlled, incomplete block cross over studies [Maltais, 2013]. A statistically significant and clinically meaningful increase in 3-hour post-dose exercise endurance time (EET) was demonstrated for UMEC/VI 62.5/25mcg compared with placebo at Week 12 in one of the studies. In the second study, the comparison of UMEC.VI 62.5/25 compared to placebo in 3-hour post-dose EET did not reach statistical significance. Additionally in both studies, greater improvements were observed with UMEC/VI 62.5/25 mcg compared to placebo for lung function as measured by trough FEV1 and lung volumes including 3 hours post-dose inspiratory capacity (IC), functional residual capacity (FRC) and residual volume (RV).

Rationale

The purpose of this study is to further evaluate the effect of UMEC/VI 62.5/25mcg on exercise endurance time as measured by the ESWT. Additionally, the effect of

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UMEC/VI 62.5/25 on lung function and lung volumes in COPD patients compared to placebo will be characterized.

Objective(s)

Primary

To evaluate the effect of UMEC/VI 62.5/25mcg on exercise endurance time over 12 weeks in subjects with COPD.

Secondary

To evaluate the effect of UMEC/VI 62.5/25mcg on measures of lung function and lung hyperinflation over 12 weeks in subjects with COPD.

Study Design

This is a multicenter, randomized, double-blind, placebo-controlled, 2-period, complete block design cross-over study.

Approximately 298 subjects will be screened and, assuming 35% of these will not be eligible for randomization; approximately 194 subjects will be randomized.

Eligible subjects will be randomized to receive a sequence consisting of UMEC/VI 62.5/25mcg and placebo once-daily via a Dry Powder Inhaler (DPI). Each treatment will be administered for 12 weeks.

There will be a total of 13 study clinic visits conducted on an outpatient basis. At Pre-Screen (Visit 0), subjects will provide consent by signing the Informed Consent Form (ICF), prior to undertaking any study procedures, and a review of their demography, medical history, concomitant medications, and a COPD exacerbation assessment will be performed. Once the ICF is signed, subjects will receive a subject identifier. Pre-screening and Screening may occur on the same day, if appropriate. Subjects who meet the eligibility criteria at Screening (Visit 1) will complete an 11 to 25 day run-in period followed by two 12-week treatment periods that are separated by a 12 to 17 day washout.

The total duration of subject participation, including the Follow-Up will be approximately 30 weeks. All subjects will be provided with albuterol for use on an “as needed” basis throughout the run-in, washout and study treatment periods while on IP.

Clinic visits will be conducted at Pre-Screening (Visit 0), and at Screening (Visit 1) during which the incremental shuttle walk test (ISWT) will be demonstrated to the subjects. At Visit 2, an ISWT will be performed after subjects view a video of the ISWT to determine the walking speed of the ESWT during Treatment Period 1. After performing the ISWT, the ESWT will be demonstrated to the subjects. At Visit 3, and at any visit where the ESWT is performed, subjects will first view a video of the ESWT before the actual ESWT is performed. At randomization (Visit 4), subjects will perform a pre-dose ESWT for baseline for the first treatment period. At Visits 5, 6, and 7, the

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ESWT will be performed 3 hours post-dose. After Visit 7, there will be a washout of 10 to12 days before Visit 8. At Visit 8, the subject will watch a video of the ISWT and then perform an ISWT to determine the walking speed of the ESWT for Treatment Period 2. Visit 9 will occur 2 to 5 days from Visit 8 and is Day 1 of the second treatment period during which a pre-dose ESWT will be performed for baseline. At Visits 10, 11, and 12, the ESWT will be performed 3 hours post-dose. A Safety Follow-Up assessment to record adverse events will be conducted by telephone approximately 7 days after the end of the second treatment period.

Spirometry will be conducted at Screening and at each on-treatment clinic visit. Pre- and post-albuterol spirometry will be conducted at Screening (Visit 1) for determination of eligibility and calculation of reversibility. Baseline spirometry will be conducted at Visit 4 prior to randomization and at Visit 9 prior to dosing. Pre- dose spirometry (trough) will be conducted at every other on-treatment clinic visit after randomization.

Body plethysmography (for lung volumes) will be performed at Screening and at every on-treatment clinic visit except Visit 6 and Visit 11. Baseline plethysmography will be conducted at Visit 4 prior to randomization and at Visit 9 prior to dosing. Pre- and 3 hour post-dose plethysmography will be conducted at every other on-treatment clinic visit after randomization except Visit 6 and Visit 11.

For determination of subject disposition, subjects will be considered to have completed the study upon completion of Visit 12. There are no plans for compassionate use of the study medications.

Subjects who permanently stop IP are not required to withdraw from the study.

Study Endpoints/Assessments

Primary

Exercise endurance time (EET) post-dose at Week 12, defined as the EET obtained 3 hours after dosing at Week 12

Secondary

Trough FEV1 at Week 12, defined as the mean of FEV1 values obtained 23 and 24 hours after dosing on the previous day

Functional residual capacity (FRC) 3 hours post-dose at Week 12

Inspiratory capacity (IC) 3 hours post-dose at Week 12

Other(s)

Post-dose EET and trough FEV1 at other visits

Functional residual capacity (pre-dose and post-dose at other visits)

Inspiratory capacity (pre-dose and post-dose at other visits)

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Residual volume (RV) (pre-dose and post-dose at each visit)

Pre-dose FVC

Rescue albuterol use over Weeks 1-12 (mean number of puffs/day and percentage of rescue-free days)

CAT

Exercise Dyspnea Scale (EDS; modified Borg scale)

Safety

Incidence of adverse events

Vital signs (pulse rate and systolic and diastolic pressure)

Incidence of COPD exacerbations

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1. INTRODUCTION

1.1. Background

COPD is a disorder characterized by airflow obstruction and reduced maximum expiratory flow from the lungs that are not fully reversible [Celli, 2004]. Symptoms of the disease can range from chronic cough and sputum production to severe shortness of breath. COPD is a major cause of poor health, resulting in millions of deaths annually worldwide [GOLD, 2014] and contributing significantly to health care costs and morbidity [Chapman, 2006; Lopez, 2006]. As of 2001, COPD was the fifth leading cause of death and the eleventh leading cause of disability worldwide. By the year 2020, COPD is expected to be the third leading cause of death and the fifth leading cause of disability [Rennard, 2002].

Umeclidinium/vilanterol (UMEC/VI) Inhalation Powder is a combination of the long-acting muscarinic antagonist (LAMA) umeclidinium (UMEC) and the long-acting beta2-agonist (LABA) vilanterol (VI) delivered via a multi-dose dry powder inhaler (DPI). UMEC/VI at a dose of 62.5/25mcg once-daily is marketed under the trade name ANORO ELLIPTA in the US. In a previous 6 month randomized, double-blind, placebo controlled study, UMEC/VI 62.5/25 mcg once-daily demonstrated significantly greater improvements in the primary and secondary efficacy endpoints of trough FEV1 and 0 to 6 hour weighted mean FEV1 compared with UMEC 62.5 mcg, VI 25 mcg and placebo [Donohue, 2013] The benefit of UMEC/VI on dyspnea symptoms and health-related quality of life was supported by clinically meaningful improvements in transition dyspnea index [TDI], rescue use, and St. George’s Respiratory Questionnaire (SGRQ) total scores compared to placebo [Donohue, 2013].

The effect of UMEC/VI 62.5/25mcg on exercise endurance as measured by the endurance shuttle walk test (ESWT) was investigated in two 12-week, randomized, double-blind, placebo-controlled, incomplete block cross over studies [Maltais, 2013]. A statistically significant and clinically meaningful increase in 3-hour post-dose exercise endurance time (EET) was demonstrated for UMEC/VI 62.5/25mcg compared with placebo at Week 12 in of the studies. In the second study, the comparison of UMEC/VI 62.5/25 compared to placebo in 3-hour post-dose EET did not reach statistical significance. Additionally, in both studies, greater improvements were observed with UMEC/VI 62.5/25 mcg compared to placebo for lung function as measured by trough FEV1 and lung volumes including 3 hours post dose inspiratory capacity (IC), functional residual capacity (FRC) and residual volume (RV).

1.2. Rationale

This purpose of this study is to further evaluate the effect of UMEC/VI 62.5/25mcg on exercise endurance time as measured by the ESWT. Additionally, the effect of UMEC/VI 62.5/25 compared to placebo on lung function and lung volumes in COPD patients will be characterized.

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1.3. Benefit:Risk Assessment

Summaries of findings from both clinical and non-clinical studies conducted with UMEC/VI can be found in the respective product label. The current safety profile for the UMEC/VI combination based on data to date is comparable with other LABAs and LAMAs.

The following section outlines the risk assessment and mitigation strategy for this protocol:

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1.3.1. Risk Assessment

Potential Risk of Clinical

Significance

Data/Rationale for Risk Mitigation Strategy

Investigational Product (IP) [e.g.,UMEC/VI]

Cardiovascular effects such as cardiac arrhythmias e.g.supraventricular tachycardia andextrasystoles.

Class effects associated with LABAs and LABA containing therapy. The clinical significance of these arrhythmias is unknown. Clinical experience with UMEC/VI to date in completed studies did not show any association with major cardiovascular events.

Data available in the product label for UMEC/VI

Exclusion criteria have been set for subjects with uncontrolled or severe cardiovascular disease according to the PI’s opinion where the potential risk may outweigh the benefit. The Investigator should also determine the clinical significance of abnormal ECG findings at screening and exclude subjects who would be at undue risk by participating in the trial. Patients with the following abnormalities will be excluded from participation: atrial fibrillation with rapid ventricular rate >120bpm, sustained or nonsustained ventricular tachycardia, or second degree heart block Mobitz type II and third degree heart block (unless pacemaker or defibrillator had been inserted).

Beta agonists and risk of asthma-related death

Long-acting beta agonists such as vilanterol, increase the risk of asthma-related death. A placebo-controlled trial with another LABA (salmeterol) showed an increase in asthma-related deaths in subjects receiving salmeterol. This findng with salmeterol is considered a class effect of all LABAs, including vilanterol. Data are not available to determine whether the rate of death in patients with COPD is increased by LABA.

Subjects with a current diagnosis of asthma are excluded from participation in the study.

Paradoxical bronchospasm

As with other inhaled medicines, UMEC/VI can produce paradoxical bronchospasm which may be life threatening.

If paradoxical bronchospasm occurs following dosing with UMEC/VI, this treatment should be discontinued immediately and alternative therapy should be instituted.

Use in patients with narrow-angle glaucoma or urinary retention

No association has been found to date, in completed studies with UMEC/VI or UMEC monotherapy, on glaucoma or urinary retention. However, glaucoma or urinary retention have been observed with other antimuscarinic agents, and could potentially be due to the pharmacology.

Exclusion criterion states that subjects with medical conditions such as narrow-angle glaucoma, prostatic hypertrophy, or bladder neck obstruction should only be included if, in the opinion of the principal investigator, the benefit outweighs the risk.

Use of inhaled beta agonists and beta blockers

Beta-adreneric blockers may weaken or antagonize the effect of beta2-agonists such as vilanterol.

The study exclusion criteria states that concomitant administration with beta-blockers or strong CYP3A4 inhibitors is only permitted if, in the Investigator’s opinion, the likely benefit outweighs the potential risk.

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Potential Risk of Clinical

Significance

Data/Rationale for Risk Mitigation Strategy

Use of strong cytochrome P450 3A4 inhibitors

Co-administration of UMEC/VI with strong CYP3A4 inhibitors (e.g., ketoconazole) has a potential to increase systemic exposure to vilanterol, which could lead to an increase in the potential for adverse reactions.

1. The study exclusion criteria states that concomitant administration with beta-blockers or strong CYP3A4 inhibitors is only permitted if, in the Investigator’s opinion, the likely benefit outweighs the potential risk.

Pregnancy There is no experience to date of pregnancy during the use of UMEC/VI.

The study inclusion criteria ensures that female subjects of child bearing potential, must have a negative pregnancy test at screening, and agree to a reliable contraceptive method, used consistently and correctly (i.e. in accordance with the approved product label and the instructions of the physician for the duration of the study). Exclusion criteria includes Pregnancy: Women who are pregnant or lactating or are planning on becoming pregnant during the study.

Severe hepatic impairment

UMEC/VI has not been studied in severe hepatic impairment. Exclusion criterion states that subjects severe hepatic impairment should only be included if, in the opinion of the study physician, the benefit outweighs the risk.

Study Procedures

Incremental and Endurance Shuttle Walk procedures

This may cause difficulty breathing, cardiovascular complications including changes in pulse rate and blood pressure, oxygen desaturation, chest pain, palpitations, coughing, wheezing, chest tightness or fainting.

Subjects will be monitored during the procedure for these effects. Specific safety evaluations to be obtained during exercise challenge testing will include heart rate monitoring and blood oxygen monitoring via pulse oximetry.

Spirometry and plethysmography procedures

This may cause difficulty breathing, changes in pulse rate and blood pressure, coughing, wheezing, chest tightness or fainting.

Subjects will be monitored during the procedure for these effects.

ECG lead placement This may cause skin irritation. It may be necessary to have small patches (about a centimetre in diameter) of hair on the chest shaved to properly attach electrodes to the chest.

Other

Side effects of rescue albuterol

Class effects associated with SABAs Subjects should call their study doctor if they experience any of these symptoms

Adverse events seen in clinical studies to date are consistent for the beta2-adrenergic class of compounds

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Potential Risk of Clinical

Significance

Data/Rationale for Risk Mitigation Strategy

Placebo arm Subjects’ condition may worsen since not on active treatment Subjects will be provided with rescue albuterol/ use throughout the study and will be allowed to use a stable dose of ICS throughout the study. Subjects with poorly controlled COPD or who experience an exacerbation of COPD during the run-in period will not be randomized. In addition, patients with very severe COPD (FEV1 <30%) will be excluded from participation in this study.

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1.3.2. Benefit Assessment

Subjects will have the potential of receiving the new combination long-acting bronchodilator therapy UMEC/VI for COPD which may provide benefit to the subjects to improve airflow obstruction and exercise capacity. Subjects who participate in this study will contribute to the process of further characterizing the benefit of combination long-acting bronchodilator therapy for the treatment of COPD.

Specific benefits associated with the study design and procedures include the following:

All subjects will receive albuterol for use “as needed” for relief of COPD symptoms.

Subjects will be able to use a stable dose of an inhaled corticosteroid (ICS) throughout the study for the treatment of COPD.

Study procedures of spirometry, exercise testing, physical examination, and Electrocardiogram (ECG) and vital signs will provide the study subjects with a comprehensive evaluation of their health and COPD disease severity. Smoking cessation counselling will also be provided.

1.3.3. Overall Benefit:Risk Conclusion

The potential risks identified in association with UMEC/VI and with study procedures are justified by the anticipated benefits from active treatments that may be afforded to patients with COPD.

Specific safeguards that will reduce the risk associated with placebo treatment will include the following:

A treatment duration of 12 weeks. This duration is adequate to measure the sustained effects of treatment, while not of excessive duration to withhold maintenance medications.

Subjects with poorly controlled COPD, based on hospitalization for COPD within 12 weeks of screening and/or use of antibiotics for a lower respiratory tract infection or COPD exacerbation or systemic corticosteroids within 6 weeks of screening, are excluded from participating. Additionally, subjects with unstable disease based on an exacerbation of their COPD during the Run-In period will not be randomized into the study.

Subjects with severe COPD requiring LTOT or those with lung resection surgery within 12 months of screening are excluded from participating.

Subjects with very severe COPD (FEV1<30%) are excluded from participating.

Concurrent use of inhaled corticosteroids will be allowed, and subjects will be provided with supplemental albuterol for use on an as-needed basis.

All subjects will be closely followed during the study and subjects will be instructed to contact their Investigator at any time if he/she feels that their COPD symptoms are worsening.

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At any time during the study, the subject and/or the Investigator can decide if additional treatment for the subject’s COPD is needed and subjects may discontinue investigational product or may withdraw from the study at any point without giving a reason, and without affecting their continued medical care.

2. OBJECTIVE(S)

Primary

To evaluate the effect of UMEC/VI 62.5/25mcg on exercise endurance time over 12 weeks in subjects with COPD.

Secondary

To evaluate the effect of UMEC/VI 62.5/25mcg on measures of lung function and lung hyperinflation over 12 weeks in subjects with COPD.

3. INVESTIGATIONAL PLAN

3.1. Study Design

This is a multicenter, randomized, double-blind, placebo-controlled, 2-period, complete block design cross-over study.

Approximately 298 subjects will be screened and, assuming 35% of these will not be eligible for randomization; approximately 194 subjects will be randomized.

Eligible subjects will be randomized to receive a sequence consisting of UMEC/VI 62.5/25mcg and placebo once-daily via a Dry Powder Inhaler (DPI). Each treatment will be administered for 12 weeks.

There will be a total of 13 study clinic visits conducted on an outpatient basis (Figure 1). At Pre-Screen (Visit 0), subjects will provide consent by signing the Informed Consent Form (ICF), prior to undertaking any study procedures, and a review of their demography, medical history, concomitant medications, and a COPD exacerbation assessment will be performed. Once the ICF is signed, subjects will receive a subject identifier. Pre-screening and Screening may occur on the same day, if appropriate. Subjects who meet the eligibility criteria at Screening (Visit 1) will complete an 11 to 25 day run-in period followed by two 12-week treatment periods that are separated by a 12 to 17 day washout.

The total duration of subject participation, including the Follow-Up will be approximately 30 weeks. All subjects will be provided with albuterol for use on an “as needed” basis throughout the run-in, washout and study treatment periods while on IP.

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Figure 1 Study Schematic

Clinic visits will be conducted at Pre-Screening (Visit 0) and at Screening (Visit 1) during which the incremental shuttle walk test (ISWT) will be demonstrated to the subjects. At Visit 2, an ISWT will be performed after subjects view a video of the ISWT to determine the walking speed of the ESWT during Treatment Period 1. After performing the ISWT, the ESWT will be demonstrated to the subjects. At Visit 3, and at any visit where the ESWT is performed, subjects will first view a video of the ESWT before the actual ESWT is performed. At randomization (Visit 4), subjects will perform a pre-dose ESWT for baseline for the first treatment period. At Visits 5, 6, and 7, the ESWT will be performed 3 hours post-dose. After Visit 7, there will be a washout of 10 to12 days before Visit 8. At Visit 8, the subject will watch a video of the ISWT and then perform an ISWT to determine the walking speed of the ESWT for Treatment Period 2. Visit 9 will occur 2 to 5 days from Visit 8 and is Day 1 of the second treatment period during which a pre-dose ESWT will be performed for baseline. At Visits 10, 11, and 12, the ESWT will be performed 3 hours post-dose. A Safety Follow-Up assessment to record adverse events will be conducted by telephone approximately 7 days after the end of the second treatment period.

Spirometry will be conducted at Screening and at each on-treatment clinic visit. Pre- and post-albuterol spirometry will be conducted at Screening (Visit 1) for determination of eligibility and calculation of reversibility. Baseline spirometry will be conducted at Visit 4 prior to randomization and at Visit 9 prior to dosing. Pre- dose spirometry (trough) will be conducted at every other on-treatment clinic visit after randomization.

Body plethysmography (for lung volumes) will be performed at Screening and every on-treatment clinic visit except Visit 6 and Visit 11. Baseline plethysmography will be conducted at Visit 4 prior to randomization and at Visit 9 prior to dosing. Pre- and 3 hour post-dose plethysmography will be conducted at every other on-treatment clinic visit after randomization except Visit 6 and Visit 11.

For determination of subject disposition, subjects will be considered to have completed the study upon completion of Visit 12. There are no plans for compassionate use of the study medications.

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Subjects who permanently stop IP are not required to withdraw from the study.

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, 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.

3.2. Discussion of Design

The cross-over design is well suited to achieve the objectives of this study primarily because UMEC/VI does not result in disease cure and COPD is a chronic disease with little day to day variability. In the two previously performed crossover exercise studies, Study DB2114417 and Study DB2114418, there was no evidence that the treatment effect was different in different periods for the EET or for trough FEV1. A complete block design will allow for within-subject treatment comparisons which will reduce variability in the response as each subject acts as their own control.

A placebo arm will be included to enable the measurement of the absolute effect of UMEC/VI 62.5/25mcg on EET thereby allowing a robust determination of the response to active treatment.

The treatment period of 12 weeks was chosen, because bronchodilators have been shown to give stabilised results over this period of time. In previous studies, a consistent effect of UMEC/VI 62.5/25mcg on lung function and EET was observed over 12 weeks [Donohue, 2013; Maltais, 2013]. The 2 week period between the two treatment periods is considered sufficient to enable washout of the effects of UMEC/VI on the EET and lung function measures.

4. SUBJECT SELECTION AND WITHDRAWAL CRITERIA

4.1. Number of Subjects

The primary analysis will be performed on the Intent-to-treat (ITT) population including data from subjects who discontinued treatment. The impact of including off treatment data on the estimate of variability and effect size has not been investigated in previous trials and therefore the study has been designed to give sufficient power for the analysis of EET in the Per Protocol Completer (PPC) population (the subset of subjects who adhere to both treatments and to the protocol). A total of 194 subjects will be randomized to ensure that at least 126 subjects complete both treatment periods (i.e., assuming 35% of subjects do not adhere to both treatments).

Assuming a 35% screen failure rate, approximately 298 subjects will be screened.

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4.2. Inclusion Criteria

Specific information regarding warnings, precautions, contraindications, adverse events, and other pertinent information on the GSK investigational product or other study treatment that may impact subject eligibility is provided in the product label.

Deviations from inclusion criteria are not allowed because they can potentially jeopardize 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. Type of subject: Outpatient.

2. Informed Consent: A signed and dated written informed consent prior to study participation.

3. Age: 40 years of age or older at Visit 1.

4. Gender: Male or female subjects.

A female is eligible to enter and participate in the study if she is of:

Non-child bearing potential (i.e. physiologically incapable of becoming pregnant, including any female who is post-menopausal or surgically sterile). Surgically sterile females are defined as those with a documented hysterectomy and/or bilateral oophorectomy or tubal ligation. Post-menopausal females are defined as being amenorrhoeic for greater than 1 year with an appropriate clinical profile, e.g. age appropriate, > 45 years, in the absence of hormone replacement therapy.

OR

Child bearing potential, has a negative pregnancy test at screening, and agrees to one of the following acceptable contraceptive methods used consistently and correctly (i.e. in accordance with the approved product label and the instructions of the physician for the duration of the study – screening to follow-up contact):

Abstinence

Oral Contraceptive, either combined or progestogen alone

Injectable progestogen

Implants of levonorgestrel

Estrogenic vaginal ring

Percutaneous contraceptive patches

Intrauterine device (IUD) or intrauterine system (IUS) that meets the SOP effectiveness criteria as stated in the product label

Male partner sterilization (vasectomy with documentation of azoospermia) prior to the female subject's entry into the study, and this male is the sole partner for

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that subject. For this definition, “documented” refers to the outcome of the investigator's/designee’s medical examination of the subject or review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject’s medical records.

Double barrier method: condom and an occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository)

5. Diagnosis: A diagnosis of COPD in accordance with the definition by the American Thoracic Society/European Respiratory Society [Celli, 2004].

6. Smoking History: Current or former cigarette smokers with a history of cigarette smoking of 10 pack-years [number of pack years = (number of cigarettes per day / 20) x number of years smoked (e.g., 20 cigarettes per day for 10 years, or 10 cigarettes per day for 20 years]. Former smokers are defined as those who have stopped smoking for at least 6 months prior to Visit 1.

7. Severity of Disease: A pre- and post-albuterol FEV1/FVC ratio of <0.70 and a post-albuterol FEV1 of 30% and 70% of predicted normal values [Hankinson, 1999; Hankinson, 2010].

8. Dyspnea: A score of ≥2 on the Modified Medical Research Council Dyspnea Scale (mMRC) at Visit 1.

9. Resting Lung Volumes: A resting FRC of 120% of predicted normal FRC at Visit 1. Predicted values for FRC will be obtained using predicted normal values [Stocks, 1995].

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. Pregnancy: Women who are pregnant or lactating or are planning on becoming pregnant during the study.

2. Asthma: A current diagnosis of asthma.

3. Other Respiratory Disorders Known -1 antitrypsin deficiency, active lung infections (such as tuberculosis), and lung cancer in remission for <5 years are absolute exclusionary conditions. A subject who, in the opinion of the investigator, has any other significant respiratory conditions in addition to COPD should be excluded. Examples may include clinically significant bronchiectasis, pulmonary hypertension, sarcoidosis, or interstitial lung disease. Allergic rhinitis is not exclusionary.

4. Other Diseases/Abnormalities: Any subject who is considered unlikely to survive the duration of the study period or has any rapidly progressing disease or immediate life-threatening illness (e.g. cancer). In addition, any subject who has any condition

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besides COPD that is likely to affect respiratory function or the ability to perform exercise testing such as peripheral vascular disease should not be included in the study.

5. Severe Hepatic Impairment: Patients with severe hepatic impairment (Child-Pugh class C) should be excluded unless, in the opinion of the investigator, the benefit is likely to outweigh the risk.

6. Unstable or life threatening cardiac disease: Umeclidinium/vilanterol should be used with caution in subjects with severe cardiovascular disease. In the opinion of the investigator, use should only be considered if the benefit is likely to outweigh the risk in conditions such as:

Myocardial infarction or unstable angina in the last 6 months

Unstable or life threatening cardiac arrhythmia requiring intervention in the last 3 months

NYHA Class IV heart failure

7. Contraindications: Any history of allergy or hypersensitivity to any anticholinergic/muscarinic receptor antagonist, beta2-agonist, sympathomimetic, lactose/milk protein or magnesium stearate.

8. Antimuscarinic effects: Subjects with medical conditions such as narrow-angle glaucoma, urinary retention, prostatic hypertrophy, or bladder neck obstruction should only be included if, in the opinion of the study physician, the benefit outweighs the risk.

9. Hospitalization: Hospitalization for COPD or pneumonia within 12 weeks prior to Visit 1

10. Lung Resection: Subjects with lung volume reduction surgery within the 12 months prior to Screening (Visit 1).

11. 12-Lead ECG: Investigators will be provided with ECG reviews conducted by a centralized independent cardiologist to assist in evaluation of subject eligibility. The Investigator will determine the clinical significance of each abnormal ECG finding in relation to the subject’s medical history and exclude subjects who would be at undue risk by participating in the trial. Subjects with the following abnormalities are excluded from participation in the study:

Atrial fibrillation with rapid ventricular rate >120 bpm

Sustained or nonsustained ventricular tachycardia

Second degree heart block Mobitz type II and third degree heart block (unless pacemaker or defibrillator had been inserted)

12. Medication Prior to Spirometry: Unable to withhold albuterol for the 4 hour period required prior to spirometry testing at each study visit

13. Interactions: Concomitant administration with beta-blockers or strong CYP3A4 inhibitors is only permitted if, in the Investigator’s opinion, the likely benefit outweighs the potential risk

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14. Medications prior to Screening: Use of the following medications according to the following defined time intervals prior to Visit 1:

Medication Time intervalDepot corticosteroids 12 weeksSystemic, oral or parenteral corticosteroids1 6 weeks

Antibiotics (for lower respiratory tract infection and/or COPD exacerbation)

6 weeks

LABA/ICS combination products if LABA/ICS therapy is discontinued completely

30 days

LABA/ICS combination products only If discontinuing LABA therapy and switching to ICS monotherapy2

48 hours for the salmeterol or formoterol component

14 days for the vilanterol component

Use of ICS at a dose >1000 mcg/day of fluticasone propionate or equivalent3

30 days

Initiation or discontinuation of ICS use3 30 daysPhosphodiesterase 4 (PDE4) inhibitor (roflumilast) 14 daysInhaled long acting beta2 agonists (LABA):

salmeterol, formoterol 48 hoursolodaterol, indacaterol 14 days

Long-acting muscarinic antagonists (tiotropium, aclidinium, glycopyrronium, umeclidinium)

7 days

LAMA/LABA combination products Apply whichever mono component has the longest washout

Theophyllines 48 hoursOral beta2-agonists

long-acting 48 hoursshort-acting 12 hours

Inhaled short acting beta2-agonists4 4 hoursInhaled short-acting anticholinergics5 4 hoursInhaled short-acting anticholinergic/short-acting beta2-agonist combination products

4 hours

Any other investigational medication 30 days or within 5 drug half-lives (whichever is longer)

1. Intra-articular and epidural corticosteroid injections are permitted.2. The dose of ICS that is switched to must not exceed 1000mcg of fluticasone propionate or equivalent.3. Use of ICS is permitted provided the dose does not exceed 1000mcg of fluticasone propionate or equivalent; ICS

use not to be initiated or discontinued within 30 days prior to Visit 1 except for subjects on LABA/ICS therapy who may discontinue LABA/ICS therapy as indicated and switch to ICS monotherapy.

4. Use of study provided prn albuterol/ is permitted during the study, except in the 4-hour period prior to spirometry testing

5. Use of inhaled short-acting anticholinergics is permitted during the run-in period between Visits 1 and 4 and washout period between Visits 7 and 9. Subjects must discontinue use of short-acting anticholinergics at least 4 hours before Visit 4 and Visit 9. Subjects should not use short acting anticholinergics during the double-blind treatment periods.

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15. Oxygen: Use of long-term oxygen therapy (LTOT) described as oxygen therapy prescribed for greater than 12 hours a day. As-needed oxygen use (i.e., 12 hours per day) is not exclusionary.

16. Nebulized Therapy: Regular use (prescribed for use every day, not for as-needed use) of short-acting bronchodilators (e.g., albuterol) via nebulized therapy

17. Pulmonary Rehabilitation Program: Participation in the acute phase of a pulmonary rehabilitation program within 4 weeks prior to Visit 1. Subjects who are in the maintenance phase of a pulmonary rehabilitation program are not excluded.

18. Drug or Alcohol Abuse: A known or suspected history of alcohol or drug abuse within 2 years prior to Visit 1.

19. Affiliation with Investigator Site: Is an investigator, sub-investigator, study coordinator, employee of a participating investigator or study site, or immediate family member of the aforementioned that is involved in this study.

20. Inability to read: In the opinion of the Investigator, any subject who is unable to read and/or would not be able to complete a questionnaire

21. Participation in Previous Exercise Studies: Subjects who have previously beenrandomized to study medication in GlaxoSmithKline studies DB2114417 or DB2114418.

4.4. Randomization Criteria

In order to be randomized to double-blind study drug the subject must meet the following randomization criteria at Visit 4:

1. COPD Exacerbation: Subject must not have experienced a moderate or severe COPD exacerbation or a lower respiratory tract infection during run-in or at Visit 4. A moderate exacerbation is defined as worsening of symptoms of COPD requiring the use of antibiotics or systemic corticosteroids. A severe exacerbation is defined as worsening symptoms of COPD requiring hospitalization.

2. Inhaled Corticosteroids: Subjects using inhaled corticosteroids (ICS) must have maintained use of ICS during the run-in period at a dose 1000mcg/day fluticasone propionate or equivalent.

3. ESWT: Demonstrate the ability to properly perform the ESWT at Visit 3 and Visit 4.

4. ESWT Duration: The exercise endurance time for the ESWT conducted at Visit 3 and 4 must be 15 minutes.

5. ESWT Variation: The exercise endurance times for the ESWT conducted at Visit 3 and 4 must not vary by > 2 minutes.

6. Oxygen Saturation: An SpO2 of 85 % during the ESWT at Visit 3 as measured by pulse oximeter.

7. Oxygen Use during ESWT: Must be able to complete the ESWT without the need for supplemental oxygen.

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8. Prohibited Medications: No use of prohibited COPD medications during the run-in period or at Visit 4.

4.5. Investigational Product (IP) Discontinuation Criteria

Subjects who permanently discontinue IP are not required to withdraw from the study. If for any reason a subject must permanently discontinue IP every effort should be made by the investigator/staff to keep the subject in the study to collect important efficacy and safety data, as detailed in Section 4.5.3.

4.5.1. Protocol defined IP Discontinuation Criteria

A subject must be permanently discontinued from IP if any of the following stopping criteria are met:

Liver Chemistry: Meets any of the protocol-defined liver chemistry stopping criteria as defined in Section 6.2.3.

Pregnancy: Positive pregnancy test

COPD exacerbation: >1 moderate to severe COPD exacerbation throughout the study. A moderate exacerbation is defined as worsening of symptoms of COPD requiring the use of antibiotics or systemic corticosteroids. A severe exacerbation is defined as worsening symptoms of COPD requiring hospitalization.

4.5.2. Study Participation Post IP Discontinuation

Subjects have the right to discontinue IP before the end of the study. A subject may also be asked to discontinue IP at the investigator’s discretion or because the subject met the protocol defined IP discontinuation criteria detailed above.

Subjects who have permanently discontinued IP are not required to withdraw from the study. Subjects who have permanently discontinued IP and have not withdrawn consent may continue in the study and complete all remaining protocol specified visits.After permanent discontinuation of IP, subjects can resume conventional COPD therapy as prescribed by the Investigator.

The Investigator must document the reason for discontinuation of IP in the electronic Case Report Form (eCRF).

Subjects who have permanently discontinued IP and have not withdrawn consent will continue to attend the clinic at the protocol designated time intervals and complete important efficacy and safety assessments. However, if this is not possible then the investigator will encourage the subject to participate in as much of the study as they are willing (or able) to. Guidance is provided in the SPM and can be used by the investigator to discuss and agree the appropriate level of ongoing study participation with subjects, after they have discontinued IP.

If the subject is unable to visit the clinic to complete any study assessments which require physical presence of the subject (e.g., CAT, vital signs, plethysmography, spirometry,

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exercise testing,), the subject visits will occur by telephone contact to review the following:

COPD exacerbations

Adverse Event (AE)/Serious Adverse Events (SAEs)

Concomitant medications

4.5.3. IP Discontinuation Study Assessments

The Investigator must make every effort to have the subject return to the clinic as soon as possible after the subject permanently discontinues IP in order to complete the IP Discontinuation Visit. The following evaluations and procedures as outlined in the Time and Events table should be completed and recorded in the eCRF as required:

Smoking status

Smoking cessation counselling

Physical examination

Vital signs

AE/SAE assessment

COPD exacerbation assessment

Urine pregnancy test

Concomitant medication assessment

Collect albuterol

Collect IP

Assess IP compliance

A safety follow-up phone call should be conducted approximately 7 days following the IP Discontinuation Visit.

4.5.4. Reasons for Permanent Discontinuation of IP

The primary reason for permanent discontinuation of IP will be recorded in the eCRF. Specific regard should be given to distinguishing permanent discontinuation of IP due to an adverse event from other reasons for permanent discontinuation of IP.

Primary reasons and sub-reasons for discontinuation of IP will be categorised as follows:

adverse event

lack of efficacy

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COPD exacerbation

protocol deviation

subject reached protocol-defined stopping criteria

Liver chemistry

Pregnancy

Study closed/terminated

Lost to follow-up

Investigator discretion

Decision by subject or proxy

Investigator site closed

4.6. Study Withdrawal Criteria

For this study there are no pre-determined protocol specific study withdrawal criteria (see Section 4.5.1. for protocol defined IP discontinuation criteria). Patients may discontinue IP and remain in the study. Every effort should be made by the investigator to keep the subject in the study even if IP is discontinued. However, a subject may voluntarily withdraw from participation in this study at any time. The investigator may also, at his or her discretion, withdraw a subject from further study participation. Subjects who are withdrawn from the study will not be replaced.

4.6.1. Study Withdrawal Assessments

Subjects have the right to withdraw from the study and to withdraw their consent for further participation in the study (i.e. this precludes continued data collection).

Subjects who are on IP and wish to discontinue IP and withdraw from further participation in the study should be encouraged to return to the clinic as soon as possible to complete the IP Discontinuation Visit assessments and to complete the safety follow-up contact approximately 7 days later.

Subjects who have previously discontinued IP (and have already completed their IP Discontinuation Visit and safety follow-up contact) but then decide at a later date that they no longer wish to participate in the study, may withdraw from the study by contacting the site by telephone to notify the site of their intention to withdraw; no additional safety follow-up visit is required.

4.6.2. Lost to follow up

If a subject fails to attend the clinic for a required study visit, the site should attempt to contact the subject and re-schedule the missed visit as soon as possible. The site should

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also counsel the subject on the importance of maintaining the assigned visit schedule and ascertain whether or not the subject wishes to and/or should continue in the study based on previous non-compliance. In cases where the subject does not return for the rescheduled visit or cannot be reached to reschedule the missed visit, the site should make every effort to regain contact with the subject (3 telephone calls and if necessary a certified letter to the subject’s last known mailing address) so that they can appropriately be withdrawn from the study. These contact attempts should be documented in the subject’s medical record. If the subject continues to be unreachable, only then will he/she be considered to have withdrawn from the study with a primary reason of “Lost to Follow-up”. For all other subjects withdrawing from the study, an alternative reason for discontinuation should be recorded in the eCRF.

4.6.3. Reasons for Study Withdrawal

The primary reason for study withdrawal will be recorded in the electronic Case Report Form (eCRF). When a subject withdraws consent, the investigator must document the reason (if specified by the subject) in the eCRF. If subjects discontinue IP (and have already completed their IP Discontinuation Visit and safety follow-up contact) but then decide at a later date that they no longer wish to participate in the study, the reason for withdrawal will be recorded in the eCRF.

The primary reason for study withdrawal will be categorized as:

Adverse event

Lost to follow-up

Withdrew consent

subject relocated

frequency of visits

burden of procedures

other (specify)

Protocol deviation

Lack of efficacy

COPD exacerbation

Study closed/terminated

Subject reached protocol-defined stopping criteria

Liver event

Pregnancy

Investigator discretion

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4.7. Follow-up Contact

A safety follow-up contact will be conducted 72 days following the completion of the randomized treatment period (Visit 12) or following the IP Discontinuation Visit.

The following procedures will be performed:

AE/SAE assessment

Concomitant medication assessment (used to treat a COPD exacerbation or SAE); All concomitant medications will be collected for subjects who discontinue IP and continue in the study.

COPD exacerbation assessment

Call Interactive Voice Response(IVR)/Interactive Web Response (IWR) to report safety follow-up contact

Subjects who have successfully completed all on-treatment randomized visits (including Visit 12) will be discharged from the study upon completion of the safety follow-up contact.

Subjects who have discontinued IP will complete the IP Discontinuation Visit followed 7 2 days later by the safety follow-up contact and then will continue in the study to complete all remaining visits and will be discharged from the study once they complete Visit 12.

Subjects who are on IP and wish to discontinue IP and withdraw from further participation in the study will complete the IP Discontinuation/Visit followed 7 2 days later by the safety follow-up contact.

Subjects who have discontinued IP and are continuing in the study (after completing the IP Discontinuation Visit and safety follow-up phone call), but who decide at a later date to withdraw from the study, should contact the site by phone to notify the site of their intention to withdraw. No additional safety follow-up visit is required.

4.8. Pre-Screening Failures

A subject will be assigned a subject number at the time the informed consent is signed.

A subject who is assigned a subject number but is not screened will be considered a pre-screen failure.

The study (IVR/IWR) will be contacted to report pre-screen failures. The following information will be collected for subjects who are pre-screen failures:

Date of ICF signature

Details of COPD medications within 30 days of Visit 0

COPD exacerbation status, if applicable

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Serious Adverse Events information, if applicable, only for any SAE considered 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

Demographic information including race, age and gender

Subject number

Investigator signature page

4.9. Screen Failures

A screen failure is defined as any subject who has been assigned a subject identifier, but does not continue in the study beyond Visit 1 (Screening) or any subject who completes Visit 1 and enters the run-in period but is subsequently found to be ineligible for the study based on procedures (e.g., ECG, or spirometry) conducted at Visit 1.

The IVR/IWR will be contacted to report screen failures. Additionally, the following information will be collected in the eCRF for screen failures:

Date of screening visit

Reason subject failed screening

4.10. Run-in Failures

Subjects who meet all the Visit 1 eligibility criteria, but are not randomized will be considered run-in failures. In addition to the information described in Section 4.8 and Section 4.9, the reason for the run-in failure will be recorded in the eCRF as well as information for any SAE as that occurred during the run-in period prior to the planned Visit 4 date.

5. STUDY TREATMENTS

5.1. Investigational Product and Other Study Treatment

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. Site staff should take adequate precautions to avoid direct eye or skin contact and the generation of aerosols or mists. Site staff should 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. Investigational product must be stored in a secure area under the appropriate physical conditions for the product. Access to and administration of the investigational product will be limited to the investigator and

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authorised site staff. Investigational product must be dispensed or administered only to subjects enrolled in the study and in accordance with the protocol.

GSK will provide the following double-blind medications for use in this study.

UMEC/VI 62.5/25mcg via a DPI once-daily

Placebo via a DPI once-daily

The DPI contains a total of 30 doses. Each DPI will be comprised of two double-foil, laminate blister strips. Descriptions of the double-blind investigational products for this study are provided in Table 1 (UMEC/VI) and Table 2 (placebo).The DPIs containing investigational product and matching placebo will be identical in appearance. Subjects will be instructed to take one inhalation each morning from the DPI. Subject instructions and details on how to use the DPI are provided in the SPM.

Table 1 Description of UMEC/VI Inhalation Powder

Formulation First strip Second stripUMEC blended with lactose and

magnesium stearateVI blended with lactose and

magnesium stearate

Dosage Form DPI with 30 doses (2 strips with 30 blisters per strip)Unit Dose Strengths 62.5mcg per blister 25 mcg per blisterPhysical description Dry white powder Dry white powderRoute of Administration Inhaled

Table 2 Description of Placebo Inhalation Powder DPI

Formulation First strip Second stripLactose with magnesium stearate Lactose with magnesium stearate

Dosage Form DPI with 30 doses (2 strips with 30 blisters per strip)Unit Dose Strengths N/A1 N/A1

Physical description Dry white powder Dry white powderRoute of Administration Inhaled1. N/A= not applicable

Albuterol via metered-dose-inhaler (MDI) will be issued for reversibility testing at Visit 1. Albuterol MDI will be issued throughout the study for use as-needed (prn). GSK will not continue to supply albuterol to subjects who stop IP but continue in the study. GSK will not supply nebules but these are allowed for use throughout the study. Albuterol will be sourced from local commercial stock. If not available locally, GSK will source centrally.

5.1.1. Storage

Investigational product must be stored in a secure area under the appropriate physical conditions for the product. Access to and administration of the investigational product will be limited to the investigator and authorised site staff. Investigational product must

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be dispensed or administered only to subjects enrolled in the study and in accordance with the protocol.

The investigation product (i.e., DPIs) should be stored up to 25C (77F). The DPIs are packaged in a foil overwrap with enclosed desiccant. The foil overwrap must not be opened until immediately prior to use. Once the foil overwrap has been opened the DPI has a 30-day in-use shelf life.

The sites must maintain a temperature log for the investigational products.

Details of study medication administration oversight are provided in the SPM.

5.1.2. Study Drug Return

At the end of the study, all study supplied study medication (used and unused) will be returned to GSK to be available for disposal. Details for both destruction and return of study medication are provided in the SPM.

For any DPI that fails to function properly, the subject should return to the clinic as soon as possible to obtain a new inhaler. The site will call IVR/IWR to obtain a new replacement medication for the subjects and dispense the new study medication kit from the site’s investigational product supply as instructed by IVR/IWR.

In addition, any DPI that fails to function properly must be identified and returned to GSK for testing. Details of the failure will be documented in the eCRF.

5.2. Treatment Assignment and Study Drug Administration

Subjects will be assigned to study treatment in accordance with the randomization schedule. Once a randomization number has been assigned to a subject, the same number cannot be reassigned to any other subject in the study.

Randomization to blinded study drug will occur at Visit 4 after the spirometry, lung volumes, and ESWT procedures are completed.

All subjects will be dispensed albuterol via MDI and/or nebules during the run-in, washout and treatment periods to use as needed.

At Visit 4 eligible subjects will be randomized 1:1 to one of the sequences shown in Table 3.

Table 3 Treatment Sequences

Sequence Period 1 Period 21 UMEC/VI 62.5/25 Placebo2 Placebo UMEC/VI 62.5/25

The duration of treatment for each subject in each period is 12 weeks. On the morning of each clinic study visit, subjects will refrain from taking their morning dose of study

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medication until instructed to do so by clinic personnel. On the other days during the treatment period (i.e. “non-clinic days”), subjects will be instructed to self-administer one inhalation from the DPI each morning.

During the washout period, subjects will discontinue use of the study DPIs and will continue use of study provided albuterol to manage breakthrough symptoms. Additionally, short-acting anticholinergics will be allowed for use during the washout periods (see Section 5.6.1).

This study will utilize an IVR/IWR which will provide a means for central allocation of drug. Each investigator will be supplied with sufficient supplies to conduct the trial. Additional treatment packs will be supplied as needed to the sites. Details of how to use the IVR/IWR to register and randomize subjects is provided in the SPM.

Study drug will be collected at Visit 7 and Visit 12 or the IP Discontinuation visit.

5.3. Blinding

This will be a double-blind study. Neither the subject nor the study physician will know which study medication the subject is receiving.

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.

A subject may not continue in the study once the treatment code is unblinded. The primary reason for discontinuation (the event or condition that led to the unblinding) will be recorded in the eCRF.

5.4. 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

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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.

5.5. Treatment Compliance

At clinic treatment visits (Visits 4-7 and Visits 9-12) study drug administration will be observed by study personnel to ensure the proper administration of study drug. Subject compliance with double-blind study medication will be assessed at clinic Visit 6 and Visit 7 and Visit 11 and Visit 12 by reviewing the dose counter on each DPI.

If study medication compliance is determined to be < 80% or > 120%, the subject must be re-educated on proper dosing per protocol. This re-education should be documented in the subject’s source document.

If the double-blind study medication is prematurely discontinued during the course of the study or medication compliance repeatedly falls outside of the acceptable range described above, the study sponsor/site monitor must be contacted to discuss whether or not the subject should discontinue IP.

5.6. Concomitant Medications and Non-Drug Therapies

All COPD medications used within 30 days prior to Visit 0 and onwards should be recorded in the eCRF including any changes. Beginning at Visit 1 and throughout the rest of the study, all non-COPD medications should be recorded in the eCRF including any changes. Study provided albuterol and double-blind study drug should not be recorded in the eCRF. The minimum requirement includes but is not limited to drug name, dose, route and the dates of administration.

5.6.1. Permitted Medications and Non-Drug Therapies

The following relevant medications are permitted during this study:

Study-provided albuterol for use as relief medication throughout the run-in and treatment periods, provided the medication is withheld for at least 4 hours prior to spirometry and/or ISWT/ESWT testing.

Short-acting inhaled anticholinergics for relief of symptoms throughout the run period between Visits 1 and 4 and washout period between Visits 7 and 9. Subjects must discontinue use of the short-acting anticholinergics at least 4 hours prior to Visit 4 and Visit 9. Note: Subjects should not use short acting anticholinergics during the double-blind treatment periods.

Inhaled corticosteroids at a dose 1000mcg/day of fluticasone propionate.

Mucolytics such as acetylcysteine

Medications for rhinitis (e.g. intranasal corticosteroids, antihistamines, cromolyn, nedocromil, nasal decongestants)

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Influenza vaccine

Pneumococcal vaccine

Antibiotics for short term treatment (≤14 consecutive days) including treatment for of acute infections and COPD exacerbations

Systemic corticosteroids for short-term (14 consecutive days) treatment of acute conditions and for the treatment of COPD exacerbations

As-needed oxygen use (i.e., 12 hours per day)

Co-administration with beta-blockers or strong CYP3A4 inhibitors is permitted only if, in the Investigator’s opinion, the likely benefit outweighs the potential risk.

Pulmonary rehabilitation program in maintenance phase

Smoking cessation treatment, including a stable regimen of nicotine replacement

Use of positive airway pressure for sleep apnea

Localized corticosteroid injections (e.g., intra-articular and epidural)

Oral muscarinic antagonists for the treatment of overactive bladder are permitted but should be used with caution as they may exacerbate medical conditions that are contraindicated for anticholinergics (e.g., narrow angle glaucoma and bladder outflow obstruction)

Immunotherapy injections

Over-the counter (OTC) cough suppressants

Topical or ophthalmic corticosteroids

Tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs). Administered with caution as they may potentiate the effects of beta-agonists on the vascular system.

Diuretics: Caution is advised in the co-administration of beta-agonists with non-potassium sparing diuretics.

5.6.2. Prohibited Medications and Non-Drug Therapies

Use of the medications listed in Table 4 is not permitted during the study unless the IP discontinuation visit has been completed.

Table 4 Prohibited Medications during the Study

MedicationDepot corticosteroidsSystemic, oral or parenteral corticosteroids1

LABA/ICS combination products Use of ICS at a dose >1000 mcg/day of fluticasone propionate or equivalent2

Initiation or discontinuation of ICS use2

Phosphodiesterase 4 (PDE4) inhibitor Inhaled long acting beta2 agonists (LABA):

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Medicationsalmeterol, formoterololodaterol, indacaterol

Long-acting muscarinic antagonists (tiotropium, aclidinium, glycopyrronium, umeclidinium)

LAMA/LABA combination productsTheophyllinesOral beta2-agonists

long-actingshort-acting

Inhaled short-acting anticholinergics3

Inhaled short-acting anticholinergic/short-acting beta2-agonist combination productsAny other investigational medication1. Intra-articular and epidural corticosteroid injections are permitted2. Use of ICS is permitted provided the dose does not exceed 1000mcg of fluticasone propionate or equivalent; ICS

use not to be initiated or discontinued within 30 days prior to Visit 1. 3. Use of inhaled short-acting anticholinergics is permitted during the run-in period between Visits 1 and 4 and

washout period between Visits 7 and 9. Subjects must discontinue use of short-acting anticholinergics at least 4 hours before Visit 4 and Visit 9. Subjects should not use short acting anticholinergics during the double-blind treatment periods.

The following medications or treatments are also not allowed during the study:

LTOT (defined as oxygen therapy prescribed for great than 12 hours per day)

Regular (prescribed for use every day, not for as-needed use) nebulized therapy with albuterol/salbutamol

Initiation of pulmonary rehabilitation during the study

Acetaminophen is not used in patients with acute viral hepatitis.

5.7. Treatment after IP Discontinuation or End of the Study

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

GSK will not provide post-IP discontinuation treatment or post study treatment. There are no plans to provide study medication for compassionate use following IP discontinuation or study completion.

At the end of the treatment period Visit 12 or after permanent discontinuation of IP, or withdrawal from study, subjects can resume conventional COPD therapy as prescribed by the Investigator.

Post-treatment concomitant medications should not be entered into the eCRF until the safety Follow-up contact for subjects who successfully complete Visit 12 on IP and for subjects who withdraw from the study except for medications used to treat a COPD exacerbation or an SAE.

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For subjects who discontinue IP but continue in the study, all post-treatment concomitant medications should be entered into the eCRF until they complete Visit 12.

5.8. Treatment of Study Treatment Overdose

An overdose is defined as a dose greater than the total doses described above which results in clinical signs and symptoms. These should be recorded by the investigator on the AE/SAE pages. In the event of an overdose of study medication, the investigator should use clinical judgment in treating the overdose and contact the study medical monitor.

GSK is not recommending specific treatment guidelines for overdose and toxicity management. The investigator is advised to refer to the relevant document(s) for detailed information regarding warnings, precautions, contraindications, adverse events, and other significant data pertaining to the study drug being used in this study. Such documents may include, but not be limited to, the approved product label for albuterol and UMEC/VI or equivalent document provided by GSK.

6. STUDY ASSESSMENTS AND PROCEDURES

This section provides an outline of the timing and completion of all study procedures, as well as descriptions of specific procedures. A schedule of Time and Events for all visits is included in Table 5.

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Table 5 Time and Events Table

Procedures Pre-Screen

Screen Run - In Rand Treatment 1 Wash Out

Treatment 2 IP Disontinuation1

Follow-up

Visit Number 0 1 2 3 4 5 6 7 8 9 10 11 12Treatment Day V1

+1 to 7 days

V2 +5 to 9days

Day1V3 +5 to 9 days

Day2 Day 433

Day 853

10 to 12 days from V7

Day1(V8 +2 to 5 days)

Day 2 Day 433

Day 853

72 Days from V12 or IP Discontinuation

Week Designation N/A N/A N/A 1 1 6 12 N/A 1 1 6 12 13

Screening or Baseline AssessmentsWritten informed consent2

X X

Demography X XMedical /COPD History

X

Smoking history/status X X X X X XSmoking cessation counseling3

X X X

Inclusion/exclusion criteria

X

Randomisation criteria XPhysical examination X X XVital signs X X4

Screen12-Lead ECG XmMRC questionnaire X5

Screening lung volumes

X

Screening Spirometry (including bronchodilator responsiveness testing)6

X

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Procedures Pre-Screen

Screen Run - In Rand Treatment 1 Wash Out

Treatment 2 IP Disontinuation1

Follow-up

Visit Number 0 1 2 3 4 5 6 7 8 9 10 11 12Treatment Day V1

+1 to 7 days

V2 +5 to 9days

Day1V3 +5 to9 days

Day2 Day 433

Day 853

10 to 12 days from V7

Day1(V8 +2 to 5 days)

Day 2 Day 433

Day 853

72 Days from V12 or IP Discontinuation

Week Designation N/A N/A N/A 1 1 6 12 N/A 1 1 6 12 13

Register visit in IVR/IWR

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

SafetyAdverse Events X X X X X X X X X X XSerious Adverse Events

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

Vitals pre-and post-walk shuttle walk7

X X X X X X X X X X X

EfficacyCOPD exacerbation assessment

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

Pre-dose baseline spirometry

X X

Trough spirometry8 X X X X X XLung volumes (plethysmography) pre & 3hrs. post-dose

X9 X X X9 X X

ISWT demonstration XISWT video X10 X10

ISWT X X

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Procedures Pre-Screen

Screen Run - In Rand Treatment 1 Wash Out

Treatment 2 IP Disontinuation1

Follow-up

Visit Number 0 1 2 3 4 5 6 7 8 9 10 11 12Treatment Day V1

+1 to 7 days

V2 +5 to 9days

Day1V3 +5 to 9 days

Day2

Day 433

Day 853

10 to 12 days from V7

Day1(V8 +2 to 5 days)

Day 2 Day 433

Day 853

72 Days from V12 or IP Discontinuation

Week Designation N/A N/A N/A 1 1 6 12 N/A 1 1 6 12 13

ESWT demonstration X11

ESWT video12 X X X X X X X X XESWT13 X X X X X X X X XHeart rate/pulse Oximetry14

X X X X X X X X X X X

Exercise Dyspnea Scale (Borg scale)

X15 X X X X X X X X X

LabsPGx Sampling16 XUrine Pregnancy Test17

X X X X X X

DiariesIssue run-in/washout diary

X X X X

Collect run-in/washout diary

X X X X

Issue treatment diary X X X XCollect treatment diary X X X XHealth Outcomes or QuestionnaireCAT18 X X X X

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Procedures Pre-Screen

Screen Run - In Rand Treatment 1 Wash Out

Treatment 2 IP Disontinuation1

Follow-up

Visit Number 0 1 2 3 4 5 6 7 8 9 10 11 12Treatment Day V1

+1 to 7 days

V2 +5 to 9days

Day1V3 +5 to 9 days

Day2

Day 433

Day 853

10 to 12 days from V7

Day1(V8 +2 to 5 days)

Day 2 Day 433

Day 853

72 Days from V12 or IP Discontinuation

Week Designation N/A N/A N/A 1 1 6 12 N/A 1 1 6 12 13

MedicationsConcomitant medication

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

Dispense19, collect albuterol

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

Dispense study medication

X X

Dispense unblinding card

X

Collect Study meds/ assess compliance

X X X X X

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1. IP Discontinuation Visit-The investigator must make every effort to have the subject return to the clinic as soon as possible for an IP discontinuation for subjects who discontinue IP but continue in the study and for subjects who are on IP but wish to withdraw from further study participation. An IP Discontinuation Visit may occur at a regular scheduled clinic visit or between study visits.

2. Written Informed Consent must be signed prior to initiation of study procedures, including changes in COPD medications. Subjects will be assigned a subject number at the time the ICF is signed. Visit 0 and Visit 1 may occur on the same day if applicable. ICF will be singed only once either at Visit 0 or Visit 1. Demography data will be collected at the time the ICF is signed. Consent for PGx testing is optional.

3. Details to be provided in SPM.4. Single set of vitals only.5. mMRC to be completed prior to screening lung volume (plethysmography) and spirometry assessments.6. Spirometry to be conducted as follows: pre-bronchodilator testing following by post-albuterol testing. Post albuterol testing conducted 10 to 30 min after subject self-

administration of 4 puffs of albuterol via MDI. Spirometry to be conducted after lung volume (plethysmography) assessments7. Vital signs pre- and post-walk should be performed at the visits indicated. Details of the timings of these measurements are provided in the SPM. 8. Trough spirometry obtained 23 and 24hrs after the previous day’s dose.9. Lung volumes (plethysmography) performed pre-dose only at these visits.10. Subjects to view ISWT video before performing the ISWT.11. Subjects to have demonstration of ESWT after performing the ISWT.12. Subjects will view the ESWT video prior to performing the ESWT.13. At Visit 3, a pre-randomization ESWT will be performed. At Visits 4 and 9 only pre-dose ESWT will be performed. All other post-randomization visits require 3hr post-dose

ESWT (only).14. Heart rate and pulse oximetry will be monitored before and after exercise and every 30 seconds during exercise test for safety purposes only. 15. The Borg assessment at Visit 2 is for the ESWT demonstration.16. PGx sample collected at Visit 4 or any scheduled clinic visit thereafter. PGx sample collected at IP Discontinuation Visit for subjects who discontinue IP but continue in the study

or for subjects who withdraw from further study participation after Visit 4. PGx consent must be signed prior to PGx sampling. 17. For females of childbearing potential only18. The CAT questionnaire should be administered prior to plethysmography, spirometry, and exercise testing.19. Albuterol to be used and dispensed on an as-needed basis. Use to be recorded daily by subjects in the dairy (puffs per day of MDI and/or nebules used)

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6.1. Critical Baseline Assessments

No study related procedures may be performed until the informed consent form document has been signed by the subject. A pre-screening visit may be required in order to administer the informed consent before any changes are made to the subject’s current medication regimen. The investigator should exercise clinical judgment, and is discouraged from changing medications only for the purposes of the clinical study. The informed consent must be signed before any changes are made to the subject’s current medication regimen. The informed consent may be given at the screening visit if the subject does not take or has not taken any prohibited medications defined by the protocol.

During the pre-screening visit (Visit 0); each subject will have the following demographic information collected:

Demographic information (gender, ethnic origin, date of birth, height and weight)

Concomitant medication review

During the screening visit (Visit 1) each subject will undergo the following assessments:

Cardiovascular medical history/risk factors will be assessed at baseline.

Pre-and post-albuterol spirometry

Medical history including COPD history (comprised of date of diagnosis and COPD type[emphysema and/or chronic bronchitis]), smoking history, COPD exacerbations history, smoking status and previous and/or current medical conditions

Physical examination

Pulse rate and blood pressure measurements

12-lead ECG

Urine pregnancy test (females of childbearing potential only)

mMRC dyspnea scale

Lung volumes (Plethysmography)

The following critical baseline assessments will be conducted at Visit 2 and Visit 8:

ISWT

6.1.1. Modified Medical Research Council Grading System (mMRC)

The subject’s degree of dyspnea to different levels of activity will be rated on the five (0 to 4) point mMRC scale. The mMRC, administered by an interviewer, asks subjects to rate how breathless they are on a 5-point scale as follows:

0 = not troubled by breathlessness except with strenuous exercise

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1 = troubled by shortness of breath when hurrying on the level or walking up a slight hill

2 = Walks slower than people of the same age on the level because of breathlessness or has to stop for breath when walking at own pace on the level

3 = stops for breath after walking about 100 yards or after a few minutes on the level

4 = too breathless to leave the house or breathless when dressing or undressing

Efficacy

6.1.2. Primary Efficacy Endpoint

Exercise endurance time (EET) post-dose at Week 12, defined as the EET obtained 3 hours after dosing at Week 12

6.1.3. Secondary Efficacy Endpoint

Trough FEV1 at Week 12, defined as the mean of FEV1 values obtained 23 and 24 hours after dosing on the previous day.

FRC 3 hours post-dose at Week 12

IC 3 hours post-dose at Week 12

6.1.4. Other Endpoints

Post-dose EET and trough FEV1 at other visits

FRC (pre-dose and post-dose at other visits)

IC (pre-dose and post-dose at other visits)

Residual volume (RV) (pre-dose and post-dose at each visit)

Pre-dose FVC

Rescue albuterol use over Weeks 1-12 (mean number of puffs/day and percentage of rescue-free days)

CAT

Exercise Dyspnea scale (Borg scale)

6.1.5. Incremental Shuttle Walk Test

ISWT will be demonstrated at Visit 1 and performed at Visits 2 and 8 after viewing the ISWT video.

As originally described [Singh, 1992], the ISWT will be performed in an enclosed corridor on a flat 10-meter-long course (about 33 feet). The course will be identified by two cones, each positioned 0.5 meter (about 20 inches) from either end to allow patients to walk in an oval and thereby avoid the need for abrupt changes in direction.

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Patients will walk at a predetermined rhythm, as dictated by an audio signal played from a compact disc. Walking speed will initially be set at 0.50 m/sec and will be increased by 0.17 m/sec every min until the patient reaches maximal capacity. The final measures will be distance, expressed in meters, and peak walking speed, expressed in kilometres per hr. Additional details on the conducted of the ISWT will be provided in the SPM.

6.1.6. Endurance Shuttle Walk Test and Exercise Endurance Time

The ESWT will be performed at time points specified in Table 5. Subjects will view the ESWT video before performing the ESWT at scheduled visits. Post-dose ESWT will be performed after completing scheduled plethysmography and spirometry assessments at that visit.

The ESWT will be performed on the same course as the ISWT as described in Section 6.1.5 [Pepin, 2007; Brouillard, 2008].

Because the effects of encouragement on walking performance have been demonstrated [Pepin, 2007; Brouillard, 2008], no encouragement will be given to patients throughout the test. Walking speed will be set at a speed corresponding to 85% of the maximal oxygen uptake, as predicted from the distance walked in the ISWT. The final measures will be distance, expressed in meters, and EET, expressed in seconds. Additional details on the conducted of the ESWT will be provided in the SPM.

6.1.7. Exercise Dyspnea Scale (EDS)

EDS will be assessed using a 10-point modified Borg scale that will be assessed at two-minute intervals during the ESWT. The subject will indicate the level on the scale correlating with their dyspnea, and the coordinator will confirm this level verbally to the subject during the ESWT. See the SPM for more details.

6.1.8. Reasons for stopping the ESWT

The physical limitation that required the subject to stop walking will be recorded as either dyspnea, leg fatigue or other physical limitations such as headache, dizziness, palpitations etc. See the SPM for more details

6.1.9. Pulse Oximetry and Heart Rate Monitoring during ISWT and ESWT

Heart rate (HR) and arterial oxygen saturation will be monitored for safety using a pulse oximeter/heart rate monitor. Heart rate and arterial oxygen saturation will be measured pre and post the ISWT and ESWT and will also be monitored every 30 seconds during the ISWT and ESWT.

Additional details of the pulse oximetry and heart rate measurements obtained during exercise will be provided in the SPM.

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6.1.10. Lung Volumes

Plethysmography is to be performed before spirometry. Lung volumes will be performed at screening, pre-dose only at Visits 4 and 9, and pre- and 3 hour post-dose at Visits 5 and Visit 7 and Visit 10 and Visit 12. Standard body plethysmography techniques will be used for lung volumes.

6.1.11. Spirometry and Responsiveness Testing

6.1.11.1. Spirometry

Spirometry measurements will be obtained using spirometry equipment that meets or exceeds the minimal performance recommendations of the American Thoracic Society (ATS) [Miller, 2005]. All sites will use standardized spirometry equipment provided by an external vendor.

For FEV1 and FVC determinations, acceptable spirometry efforts should have a satisfactory start of test and end of test (i.e. a plateau in the volume-time curve) and be free from artefacts due to cough, early termination, poor effort, obstructed mouthpiece, equipment malfunction, or other reasons [Miller, 2005].

Spirometry should be performed as follows:

Started between approximately 6:00AM and 11:00AM

After withholding albuterol (all visits) for 4 hours

At Visit 1, after withholding COPD medications as specified in the exclusion criteria (Section 4.3)

Pre-dose at Visit 4, 5, Visit 6, Visit 7, Visit 9, Visit 10, Visit 11 and Visit 12. Pre-dose measurements should be obtained after withholding the morning dose of blinded study drug.

Subjects should refrain from smoking for 1 hour prior to each pulmonary function test

6.1.11.2. Bronchodilator Responsiveness Testing

At Visit 1, both pre- and post-albuterol spirometry will be obtained. Post-albuterol/salbutamol FEV1 and FEV1/FVC findings will be used to determine subject eligibility.

Bronchodilator responsiveness testing will be completed as follows:

Following pre-albuterol spirometry (three acceptable spirometry efforts), the subject will self-administer 4 puffs of albuterol MDI. Acceptable spirometry efforts will be obtained approximately 10 to 30 minutes after albuterol administration.

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6.1.12. Daily Diary Assessments

Subjects will record daily assessments in paper diaries.

Subjects will be instructed to record the following information on the daily paper diary card:

Any medical problems the subject may have experienced and any medications used to treat those medical problems

Date and time of morning study medication taken on the day prior to clinic visits.

Record supplemental albuterol use. Record the number of puffs of rescue inhaler or nebules used. (Subjects should withhold albuterol for 4 hours prior to all visits.)

Subjects will be instructed on how to complete their diary cards and will be asked to return the paper diaries at each clinic visit. The study coordinator will review diaries at each clinic visit for completeness, legibility and consistency with subject-reported AEs. Signs and symptoms of COPD included on the diary card will not be considered AEs and will not be collected in the eCRF.

Details of instructions for completion of the diary cards are provided in the SPM.

6.1.13. COPD Assessment Test (CAT)

The CAT will be completed by subjects at Visits 4, 7, 9, and 12.

The COPD Assessment Test (Jones, 2009; Jones, 2012) is a validated, short and simple patient completed questionnaire which has been developed for use in routine clinical practice to measure the health status of patients with COPD. The CAT is an 8-item questionnaire suitable for completion by all patients diagnosed with COPD. When completing the questionnaire, subjects rate their experience on a 6-point scale, ranging from 0 (no impairment) to 5 (maximum impairment) with a scoring range of 0-40. Higher scores indicate greater disease impact.

6.2. Safety

The following safety endpoints will be evaluated:

Incidence of adverse events

Vital signs (pulse rate and systolic and diastolic pressure)

COPD exacerbations

In addition to these safety endpoints additional information related to liver chemistry stopping criteria, pregnancy, laboratory abnormalities, and medical devices is provide below.

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6.2.1. Vital Signs

Vital sign measurements will include heart rate and systolic and diastolic blood pressure (height and weight will be collected at Visit 1 only). Vital signs will be obtained after subjects have rested for approximately 5 minutes.

Vital signs will be performed at Visit 1 (Screening). On Day 1 of each treatment period (Visits 4 and 9) vital signs will be performed pre-shuttle walk (pre-dose) and post shuttle walk (pre-dose). On subsequent on treatment visits (Day 2/Visits 5 and 10), Week 6/Visits 6 and 11) and Week 12/Visits 7 and 12) vital signs will be performed pre shuttle walk (3 hours post dose) and after shuttle walk. Vital signs will also be performed pre and post shuttle walk at Visits 2, 3 and 8 (no dosing at these visits).

6.2.2. COPD Exacerbations

COPD exacerbations will be defined as moderate or severe in intensity. A moderate exacerbation is defined as worsening of symptoms of COPD requiring the use of antibiotics or systemic corticosteroids. A severe exacerbation is defined as worsening symptoms of COPD requiring hospitalization. If a subject has >1 moderate or severe COPD exacerbation during the study, IP must be discontinued. If a subject discontinues IP due to a COPD exacerbation, the exacerbation section of the eCRF should be completed.

Signs and symptoms of COPD included on the diary cards will not be considered AEs and will not be recorded in the eCRF.

6.2.3. Liver chemistry stopping and follow up criteria

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.

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 2:

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 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.

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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 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.

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:

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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:

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 72 hours of last dose. 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 in the time period indicated above, 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.

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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 inthe preceding week [James, 2009]).

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].

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

6.2.4. 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.

6.2.4.1. 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

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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

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

6.2.4.2. 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.

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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 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).

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.

6.2.4.3. Sentinel Events

A Sentinel Event is a GSK-defined SAE that is not necessarily drug-related but has been associated historically with adverse reactions for other drugs and is therefore worthy ofheightened pharmacovigilance. Medical monitor review of all SAEs for possible Sentinel Events is mandated at GSK. The GSK medical monitor may request additional clinical information on an urgent basis if a possible Sentinel Event is identified on SAE review. The current GSK-defined Sentinel Events are listed below:

Acquired Long QT Syndrome

Agranulocytosis/Severe Neutropenia

Anaphylaxis & Anaphylactoid Reactions

Hepatotoxicity

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Acute Renal Failure

Seizure

Stevens Johnson syndrome/Toxic epidermal necrosis

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

Any abnormal laboratory test results (hematology, 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.

6.2.6. 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 thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularisation

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

6.2.7. Pneumonia Events

Investigators will be required to fill out a pneumonia event specific eCRF within one week of when the pneumonia AE/SAE(s) is first reported.

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6.2.8. 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 noncardiovascular death.

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

6.2.9. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as SAES

The following disease related events (DREs) are common in subjects with COPD and can be serious/life threatening:

COPD exacerbation

COPD exacerbations are associated with the disease to be studied and will not be recorded as AEs unless the exacerbation meets the definition of a ‘serious AE’ as defined in Section 6.2.4.2. Exacerbations that meet the definition of ‘serious’ AEs will be recorded on the appropriate eCRF section and should be reported to GSK for all subjects regardless of whether or not they are randomized to blinded study medication. Signs and symptoms of COPD included on the diary card will not be considered AEs and will not be recorded in the eCRF.

6.2.10. 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.

6.2.11. Medical Devices

No medical devices are being used in this study.

6.2.12. 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 follow up contact.

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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 6.2.14.

6.2.13. 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?”

6.2.14. 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.

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Initial Reports Follow-up Information on a Previous Report

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

collection tool24 hours Updated “SAE”

data collection tool

Cardiovascular, pneumonia and/or

death event4

Initial and follow up

reports to be completed within one

week of when the

cardiovascular, pneumonia

and/or death is reported

CV, pneumonia and/or

“death”events data collection

tool(s) if applicable

Initial and follow up reports to be completed within

one week of when the

cardiovascular, pneumonia, and/or death

event is reported

Updated “CV, pneumonia and/or

“death” data collection tool(s) if

applicable

Pregnancy 2 weeks “Pregnancy Notification Form”

2 weeks “Pregnancy Follow-up Form”

Non-serious adverse events

5 calendar days

“Adverse Reaction” data collection tool

2 weeks Updated “Adverse Reaction” data collection tool

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

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Initial Reports Follow-up Information on a Previous Report

Type of Event Time Frame Documents Time Frame DocumentsRemaining liver chemistry abnormalities for Phase II:

ALT5xULN; ALT3xULN with

hepatitis or rash or 3xULN 4 weeks

24 hours2 “Liver Event” Documents

(defined above) 3

24 hours Updated “Liver Event” Documents3

ALT3xULN and <5xULN and biliribin

<2xULN

24 hours2 “Liver Event” Documents

(defined above) do not need

completing unless elevations persist

for 4 weeks or subject cannot be monitored weekly

for 4 weeks3

24 hours Updated “Liver Event” Documents,

if applicable3

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

24 hours2 “Liver Event” Documents

(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

ALT5xULN and bilirubin <2xULN that

persists 2 weeks

24 hours2 “Liver Event” Documents

(defined above) 3

24 hours Updated “Liver Event” Documents3

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Initial Reports Follow-up Information on a Previous Report

Type of Event Time Frame Documents Time Frame Documents

ALT3xULN and <5x ULN and bilirubin

<2xULN

24 hours2 “Liver Event” Documents

(defined above) do not need

completing unless elevations persist

for 4 weeks or subject cannot be monitored weekly

for 4 weeks3

24 hours Updated “Liver Event” Documents,

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.4. Supplementary information (in addition to SAE report, if applicable) needs to be collected for cardiovascular,

pneumonia and death events. See Section 6.2.6, Section 6.2.7, and Section 6.2.8.

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.

6.2.14.1. 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 Investigator Brochure (IB) and will notify the IRB/IEC, if appropriate according to local requirements.

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6.3. Pharmacogenetic Research

Information regarding pharmacogenetic (PGx) research is included in Appendix 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" In all cases, subject initials will not be collected or transmitted to GSK according to GSK policy.

8. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS

8.1. Hypotheses

The primary endpoint is EET measured 3 hours post-dose following 12 weeks of treatment with UMEC/VI 62.5/25mcg. The null hypothesis is that there is no difference in EET between UMEC/VI and placebo:

H0: T1 – T2 = 0

The alternative hypothesis is there is a difference between treatment groups:

H0: T1 – T2 0

8.2. Study Design Considerations

8.2.1. Sample Size Assumptions

The sample size has been calculated in order to provide sufficient power for the comparison of the primary and secondary endpoints.

The sample size calculations use an estimate of within-subject standard deviation (SD) for EET of 169 seconds. This is the value observed in the previous study evaluating exercise capacity which demonstrated a statistically significant and clinically meaningful increase in 3-hour post-dose EET for UMEC/VI 62.5/25mcg compared with placebo at Week 12.

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A study with 126 evaluable subjects will have 90% power to detect a 70 seconds difference in EET between UMEC/VI and placebo at the two-sided 5% significance level. A recent publication determined the Minimal Clinically Important Difference (MCID) for the ESWT to be 45 to 85 seconds after bronchodilation (Pepin, 2011). A previous study observed a 69.4 second increase in 3-hour post-dose EET for UMEC/VI 62.5/25mcg compared with placebo at Week 12. Therefore a difference of 70 seconds is considered appropriate for the comparison of active treatment with placebo.

For trough FEV1, the sample size calculations use a two-sided 5% significance level and an estimate of residual standard deviation for trough FEV1 of 220mL. An analysis including 104 evaluable subjects will have 90% power to detect a 100mL difference between treatments in trough FEV1. The treatment difference and estimate of SD are taken from previous phase III studies.

For post-dose FRC, the sample size calculations use a two-sided 5% significance level and an estimate of residual standard deviation for post-dose FRC of 532 mL. An analysis including 68 evaluable subjects will have 90% power to detect a 302 mL difference between treatments in post-dose FRC. The treatment difference and estimate of SD are taken from the most conservative values observed between UMEC/VI 62.5/25 and placebo at 12 weeks in the MMRM analysis for the previous phase III exercise studies.

For post-dose IC, the sample size calculations use a two-sided 5% significance level and an estimate of residual standard deviation for post-dose IC of 266 mL. An analysis including 29 evaluable subjects will have 90% power to detect a 238 mL difference between treatments in post-dose IC.

A study with 126 evaluable subjects per treatment arm would provide 95% power to detect a 100 mL difference in trough FEV1 between UMEC/VI and placebo. It would provide >99% power to detect a 302 mL difference in post dose FRC and >99% power to detect a difference of 238 mL in post dose IC using the assumptions above. As statistical inference will be conditional on having achieved statistical significance for the primary efficacy endpoint, post-dose EET, powering post-dose EET, trough FEV1, post-dose FRC and post-dose IC each at >90% provides 85% power (conditional on post-dose EET analysis) for the analysis of trough FEV1, post-dose FRC and post-dose IC.

The primary mixed model repeated measures (MMRM) analysis will be conducted on the ITT population including data from subjects who discontinued treatment. The impact of including off treatment data on the estimate of variability and effect size has not been investigated in previous trials and therefore the study has been designed to give sufficient power for the analysis of EET in the PPC population, a subset of subjects who adhere to both treatment periods and to the protocol. To allow for 35% of subjects to not adhere to both treatments, 194 subjects will be randomised.

8.2.2. Sample Size Sensitivity

The within-subject SD of 169 seconds for EET used for the sample size calculations was obtained from one previous study. In a second study the value was 148 seconds. If the

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standard deviation in this study is different from the estimated value, the power to detect the planned difference in EET will be affected. Table 6 illustrates the power for the comparison of UMEC/VI with placebo which would be obtained with different values of SD, assuming the sample size remains constant at 126 evaluable subjects.

Table 6 Power Calculation for Treatment Differences

Within-subject SD Treatment Difference

(seconds)

Power

148 70 96%

169 70 90%

190 70 83%

If the within subject SD increased to 190 seconds, the study would have 83% power to detect a difference of 70 seconds between UMEC/VI and placebo. If the SD were 148 seconds then the study would have 96% power to detect a difference of 70 seconds.

The treatment difference which can be detected with 90% power will also be affected by changes in the SD; this is shown in Table 7.

Table 7 Treatment Differences Detected with 90% Power

Within-subject SD Power Treatment Difference

(seconds)

148 90% 61

169 90% 70

190 90% 78

If the SD increased to 190 seconds, the study would have 90% power to detect a difference of 78 seconds between UMEC/VI and placebo. If the SD were as low as 148 seconds then the study would have 90% power to detect a difference of 61 seconds.

Based on a SD of 169 seconds and a sample size of 126 evaluable subjects, the study would conclude statistical significance with a treatment difference of 42 seconds [detectable effect].

8.2.3. Sample Size Re-estimation

No sample size re-estimation is planned for this study.

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8.3. Data Analysis Considerations

8.3.1. Analysis Populations

Three subject populations will be identified.

The All Subjects Enrolled Population will comprise all subjects for whom a record exists on the study database, including screen failures and any subject who was not screened but experienced a serious adverse event (SAE) between the date of informed consent and the planned date of the Screening Visit. This population will be used for reporting subject disposition, reasons for withdrawal prior to randomization, and inclusion, exclusion and randomization criteria deviations and SAEs for non-randomized subjects.

The Intent-to-treat (ITT) Population will comprise all subjects randomized to treatment. Outcomes will be reported according to the randomized treatment allocation. Subjects will be included in the analysis of a particular outcome if they provided at least one on-treatment assessment of that outcome. This population will be used for analyses of the primary efficacy endpoint and for all other data analyses and displays. This population will be used for displays including data from subjects who discontinued treatment and also for displays which include only on-treatment data.

The Per Protocol Completer (PPC) Population will comprise all subjects in the ITT Population who complete the study (completed Visit 12), were not identified as protocol deviators and did not discontinue treatment. Subjects with time-point specific protocol deviations will be included in the PPC population only if they have valid assessments at baseline and Week 12 for each period. Subjects who have time-point specific protocol deviations at Day 2 or Week 6 will be included in the PPC Population but will have the affected data excluded from the analysis. The definition of specific deviations will be included in the Reporting and Analysis Plan (RAP) and the decision to exclude a subject from the PPC will be made prior to breaking the blind. This population will be used to analyse completers for the primary and secondary endpoints.

8.3.2. Analysis Data Sets

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

8.3.3. Treatment Comparisons

8.3.3.1. Primary Comparison of Interest

The primary causal estimand of interest is the de facto or intent-to-treat estimand, i.e., evaluation of the comparison of UMEC/VI with placebo for the primary endpoint of post-dose EET at Week 12 in all randomised subjects, regardless of their adherence to treatment or to the protocol which will include data from subjects who discontinue IP treatment.

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8.3.3.2. Other Comparisons of Interest

UMEC/VI and placebo will be compared for the secondary endpoints in the ITT population including data from subjects who discontinued treatment. In order to account for multiplicity across key endpoints, a step-down closed testing procedure will be applied whereby inference for a test in the pre-defined hierarchy is dependent upon statistical significance having been achieved for previous tests in the hierarchy. The hierarchy will consist of the comparison of UMEC/VI versus placebo, performed on the primary and secondary endpoints in the following order:

Exercise endurance time (EET) 3 hours post-dose at Week 12

Trough FEV1 at Week 12

Functional residual capacity (FRC) 3 hours post-dose at Week 12

Inspiratory capacity (IC) 3 hours post-dose at Week 12

UMEC/VI and placebo will also be compared for the primary and secondary endpoints in the ITT population including only on-treatment data and in the PPC population (the subset of subjects who adhere to both treatments and to the protocol). UMEC/VI and placebo will be compared for the other efficacy endpoints in the ITT population including only on-treatment data. No multiplicity adjustment will be applied.

8.3.4. Interim Analysis

No interim analysis is planned.

8.3.5. Key Elements of Analysis Plan

Where possible, data from subjects who withdraw prematurely from the study will be included in any relevant analyses. Specific details for inclusion will be detailed in the RAP, but in general the minimum data required will be a baseline evaluation and at least one on-treatment evaluation.

Data collected during a clinic visit will be reported by the visit at which the data were collected and will not be excluded from any analysis for being collected outside of an assessment window.

For the purposes of analyses, a completed subject is defined as anyone with a valid assessment for the endpoint at Visit 12.

It is anticipated that approximately 10 centers in the U.S. will participate in the study. Centres enrolling a small number of subjects may be pooled with another centre. All amalgamations will be finalised and documented in the RAP prior to unblinding the treatment codes. These amalgamations will be used wherever region is incorporated into the analysis.

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Baseline values for each endpoint will be those used from pre-treatment in period 1 at Visit 4 (randomisation) or pre-treatment in period 2 at Visit 9 or from Visit 1 (screening) and will be defined in the RAP.

8.3.5.1. Efficacy Analyses

All efficacy data will be summarized using means, SDs and ranges for continuous data and frequencies and percentages for categorical data.

Primary Endpoint

The change from baseline in the primary endpoint of EET at Week 12 will be analysed for the ITT population including data from subjects who discontinued treatment using a repeated measures model including data recorded at each of Day 2, Week 6 and Week 12. The following covariates will be included in the model, period walking speed (the difference between a patient’s walking speed for each treatment period, and the mean overall walking speed for that patient), mean walking speed (the mean of the walking speeds in each of the two treatment periods), period, treatment, visit, smoking status, visit by period walking speed, visit by mean walking speed and visit by treatment interactions, where visit is nominal Subject will be fitted as a random effect. Treatment effects will be estimated at each visit separately. The variance-covariance matrix will be assumed unstructured. Missing data are not imputed in this analysis; however, all non-missing data will be used within the analysis to estimate the treatment effect for each endpoint on Week 12.

Estimated treatment differences for UMEC/VI vs. placebo will be presented together with 95% confidence intervals (CIs) for the difference and p-values.

The MMRM analysis of the primary endpoint will be repeated for the ITT Population including only on-treatment data and also in the PPC population.

The impact of missing data due to study withdrawals will be examined further by conducting sensitivity analyses using multiple imputation (MI) methods, for the ITT Population including data from subjects who discontinued treatment.

Firstly, within each treatment arm in each treatment period, a Bayesian multivariate normal model for the data (including covariates of period walking speed and smoking status similarly to the primary MMRM analysis) will be fitted using a Markov Chain Monte Carlo approach and quasi-independent samples drawn from the posterior distributions for the parameters of the multivariate normal distribution for each arm in each period. Non-informative priors will be used. This allows all missing observations to be imputed, whether a subject has a monotone or non-monotone pattern of missingness.

Imputations will be drawn for subsets of subjects in each treatment arm in each treatment period. Within these subsets, the imputations will be drawn separately for each missingness pattern based upon assumptions for the patterns of means post withdrawal using the sampled means for this imputation across all arms, as described below, and conditioning on observed previous observations and also covariate values for the individual subject.

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The following multiple imputation methods are proposed:

1. “Jump to Reference” (J2R). Here the mean is that in the UMEC/VI arm before withdrawal and that in the placebo arm after withdrawal. This is the most extreme method as it is the residuals from before withdrawal that drive the imputation and these are measured against the mean in the UMEC/VI arm.

2. “Copy reference” (CR). Here the means are those from the placebo arm both before and after withdrawal. This is less severe than J2R as any effect of treatment induces positive residuals prior to withdrawal which potentially feed through into the imputed values after withdrawal.

Data from the first imputation of the first treatment period and the first imputation of the second treatment period will be combined to create a single imputation dataset for analysis. This will be repeated for each separate imputation of the first and second treatment periods. For each imputation dataset, an analysis of variance will be carried out using Week 12 data, both actual and imputed, using the same covariates as in the primary analysis. Contrasts of interest will be estimated, and then combined across imputations using standard multiple imputation rules.

Secondary Endpoint

The secondary endpoint of trough FEV1, at Week 12 will be analysed for the ITT Population including data from subjects who discontinued treatment using an MMRM analysis, including covariates of period baseline, mean baseline, period, treatment, visit, smoking status, visit by period baseline interaction, visit by mean baseline interaction and visit by treatment interaction, where visit is nominal. The model will use all available trough FEV1 values recorded on Day 2, Week 6 and Week 12. Missing data are not directly imputed in this analysis; however, all non-missing data for a subject will be used within the analysis to estimate the treatment effect for trough FEV1 at Week 12. Two models will be fitted; one with a response variable of trough FEV1 and one with a response variable of change from baseline in trough FEV1. Estimated treatment differences for UMEC/VI vs. placebo will be presented together with 95% confidence intervals (CIs) for the difference and p-values. This analysis will be repeated for the other secondary endpoints, FRC post dose and IC post dose. Sensitivity analyses using the ITT Population including only on-treatment data and in the PPC population will be performed.

Other Endpoints

Pre-dose FRC, Pre-dose IC, Pre-dose RV and RV post dose will be analysed separately for the ITT Population including only on-treatment data using the same methodology as that for the secondary endpoint. The mean number of puffs of rescue medication per day for Weeks 1-2, 3-4, 5-6, 7-8, 9-10 and 11-12 will be analysed using a mixed model repeated measures analysis including covariates of period baseline, mean baseline, period, treatment, two-weekly period, smoking status, two-weekly period by period baseline interaction and two-weekly period by mean baseline interaction. The model will use all available values recorded during Weeks 1-2, 3-4, 5-6, 7-8, 9-10 and 11-12. Missing data are not directly imputed in this analysis; however, all non-missing data for a subject will be used within the analysis to estimate the treatment effect for the mean

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number of puffs of rescue medication over Weeks 1-12. Two models will be fitted; one with a response variable of mean number of puffs, and one with a response variable of change from baseline in mean number of puffs. The variance-covariance matrix will be assumed unstructured.

Estimated treatment differences for UMEC/VI vs. placebo will be presented together with 95% confidence intervals (CIs) for the difference and p-values.

The percentage of rescue-free days will be analysed similarly.

Full details of the analyses to be performed on primary, secondary and other efficacy endpoints, including Exercise Dyspnea Scale and CAT, will be provided in the Reporting and Analysis Plan (RAP).

8.3.5.2. Safety Analyses

AEs will be coded using the standard GSK dictionary, Medical Dictionary for Regulatory Activities (MedDRA), and grouped by body system. AEs with onset pre-treatment or during active treatment will be summarized separately. The number and percentage of subjects experiencing at least one AE of any type, AEs within each body system and AEs within each preferred term will be presented for each treatment group. Separate summaries will be provided for all AEs, drug related AEs, SAEs and AEs leading to withdrawal.

All SAEs will be tabulated and listed by treatment group. Deaths and SAEs will be documented in case narrative format.

Vital signs (pulse rate, systolic blood pressure and diastolic blood pressure) will be summarized by treatment group for the ITT Population including only on-treatment data.

The proportion of subjects experiencing a COPD exacerbation will be tabulated.

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

8.3.5.3. Pharmacogenetic Analyses

See Appendix 1 for details about the Pharmacogenetics Analysis Plan.

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.

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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 Helsinki 2008, 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., PGx assessments described in Appendix 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 the 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 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.

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Study is conducted in accordance with the currently approved protocol and any other 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.

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.

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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 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.

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10. REFERENCES

Bauerle O., Chrusch C.A., Younes M. Mechanisms by which COPD affects exercise tolerance Am. J.Respir. Crit. Care Med. 1998 157:1 (57-68).

Brouillard C, Pepin V, Milot J, Lacasse Y, Maltais F. Endurance shuttle walk test: Responsiveness to salmeterol in COPD. Eur Respir J. 2008;31:579-84.

Celli BR, MacNee W. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J. 2004; 23:932-946.

Chapman KR, Mannino DM; Soriano JB; Vermeire PA; Buist AS; Thun MJ; Connell C. Epidemiology and costs of Chronic Obstructive Pulmonary Disease. Eur Respir J. 2006;27:188-207.

Donohue JF, Maleki-Yazdi MR, Kilbride S, Mehta R, Kalberg, C, Church A. Efficacy and safety of once-daily umeclidinium/vilanterol 62.5/25mcg in COPD. Respir Med. 2013;107:1538-1546

GOLD. Global Initiative for Chronic Obstructive Lung Disease [GOLD]. Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease. Last Updated 2014. http://www.goldcopd.org.

Hankinson JL, Kawut SM, Shahar E, Smith LJ, MD, Hinckley Stukovsky K, and Barr RG. Performance of American Thoracic Society-Recommended Spirometry Reference Values in a Multiethnic Sample of Adults: The Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study. Chest. 2010;137:138-45

Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of the general U.S. population. Am J Respir Crit Care Med. 1999;159:179-87

James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee WM. Pharmacokinetics of Acetaminophen-Protein Adducts in Adults with Acetaminophen Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37(8): 1779-1784.

Jones, P., Harding, G., Berry, P., Wiklund, I., Chen, W-H., Leidy, N. Development and first validation of the COPD Assessment Test (CAT) Eur Respir J 2009; 34: 648–654

Jones, P., Harding, G., Wiklund, I., Berry, P., Tabberer, M., Yu, R., Leidy, N. Tests of the Responsiveness of the Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT) Following Acute Exacerbation and Pulmonary Rehabilitation Chest 2012; 142: 134-140

Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P, Gault E. 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. J Clin Microbiol. 2005;43(5):2363–2369.

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Lopez AD, Shibuya K, Rao C, Mathers CD, Hansel AL, Held LS, Schmid V, Buist S. Chronic obstructive pulmonary disease: current burden and future projections. Eur Respir J. 2006;27:397-412.

Maltais, F;Singh, S; Donald, AC; Crater, G; Church, A; Goh A; and Riley, JH. Effects of a Combination of Vilanterol and Umeclidinium on Exercise Endurance in COPD Subjects: Two randomized clinical trials. Eur Respir J. 2013;42(Suppl 57):145s.

Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo R, Enright P, van der Grinten CPM, Gustafsson P, Jensen R, Johnson DC, MacIntyre N, McKay R, Navajas D, Pedersen OF, Pellegrino R, Viegi G, Wanger J. Standardization of spirometry. Eur Respir J. 2005;26:319-338.

O’Donnell DE, Lam M, Webb KA. Measurement of Symptoms, Lung Hyperinflation, and Endurance during Exercise in Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 1998;158:1557–1565.

O'Donnell DE, Lam M, Webb KA. Spirometric correlates of improvement in exercise performance after anticholinergic therapy in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1999;160:542-549

O'Donnell, D.E., Bertley, J.C., Chau, L.K.L., Webb, K.A. Qualitative aspects of exertional breathlessness in chronic airflow limitation: Pathophysiologic mechanisms. Am. J.Respir.Crit. Care Med.. 1997; 155,. 109-115

O'Donnell, D.E., Webb, K.A.Exertional breathlessness in patients with chronic airflow limitation: The role of lung hyperinflation. American Review of Respiratory Disease 1993 148, 1351-1357

Officer T.M., Pellegrino R., Brusasco V. and Rodarte J.R. Measurement of pulmonary resistance and dynamic compliance with airway obstruction. Journal of Applied Physiology 1998; 85:5, 1982-1988

Pepin V, Brodeur J, Lacasse Y, Milot J, LeBlanc P, Whittom F, Maltais F. Six-minute walking versus shuttle walking: responsiveness to bronchodilation in chronic obstructive pulmonary disease. Thorax. 2007;62:291-8.

Pepin V, Laviolette L, Brouillard C, Sewell L, Singh S, Revill S, Lacasse Yves, Maltais F. Significance of changes in endurance shuttle walking performance. Thorax. 2011;66:115-120.

Rennard SI, DeCramer M; Calverley PM et al. Impact of COPD in North America and Europe in 2000: subjects' perspective of confronting COPD International Survey. Eur Respir J. 2002;20:799-805.

Singh SJ, Morgan MD, Scott S, Walters D, Hardman AE. Development of a shuttle walking test of disability in patients with chronic airways obstruction. Thorax. 1992;47:1019-24.

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Stocks, J, Quanjer, Ph.H. Reference values for residual volume, functional residual capacity and total lung capacity. Eur Respir. J; 1995, 8, 492-506.

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11. APPENDICES

11.1. Appendix 1: Pharmacogenetic Research

Pharmacogenetics – Background

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 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*57:01positive 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*57:01 screening 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*15:02 are 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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Drug Disease Gene Variant OutcomeIrinotecan 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 PGx research is the collection of samples during the conduct of clinical studies.

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 UMEC/VI.

Pharmacogenetic Research Objectives

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 UMEC/VI. If at any time it appears there is potential variability in response in this clinical study or in a series of clinical studies with UMEC/VI, the following objectives may be investigated – the relationship between genetic variants and study treatment with respect to:

Safety and/or tolerability

Efficacy

Study Population

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

Subject participation in the 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

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

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If taking saliva collections, no additional whole blood samples will be necessary for the PGx analysis. Saliva (2mL) is collected into the DNA self-collection kit. A single sample will be taken but can be duplicated if the first sample is unusable. It is recommended that the saliva sample be collected at Visit 4.

The 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 saliva 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 saliva sample may be subjected to sample quality control analysis. This analysis will involve the genotyping of several genetic markers to confirm the integrity of individual samples. If inconsistencies are noted in the analysis, then those samples may be destroyed.

The need to conduct PGx analysis may be identified after a study (or a set of studies) of UMEC/VI 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 UMEC/VI.

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 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 PGx sample, if already collected:

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

Withdraw from the PGx research and destroy the PGx sample

If a subject withdraws consent for 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 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 PGx research or have their sample destroyed whether during the study or during the retention period following close of the main study.

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Screen and Baseline Failures

If a blood sample for 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 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.

Pharmacogenetics Analyses

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

If applicable and PGx research is conducted, appropriate statistical analysis methods will be used to evaluate pharmacogenetic data in the context of the other clinical data. Results of 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 PGx research may still participate in the clinical study. PGx informed consent must be obtained prior to any saliva being taken for PGx research.

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

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

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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 PGx studies is generally preliminary in nature, and therefore the significance and scientific validity of the results are undetermined.

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, Shortino D, Baker KL, Spreen W, Lai E, Davies K, Handley A, Dow DJ, Fling ME, Stocum M, Bowman C, Thurmond LM, Roses AD. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. Lancet. 2002; 359:1121-1122.

Innocenti F, Undevia SD, Iyer L, Chen PX, Das S, Kocherginsky M, Karrison T, Janisch L, Ramirez J, Rudin CM, Vokes EE, Ratain MJ. 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, Liu JH, Lin JK, Lin TC, Chen WS, Jiang JK, Wang HS, Wang WS. 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.

Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, Sayer D, Castley A, Mamotte C, Maxwell D, James I. 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, Molina JM, Workman C, Tomazic J, Jägel-Guedes E, Rugina S, Kozyrev O, Cid JF, Hay P, Nolan D, Hughes S, Hughes A, Ryan S, Fitch N, Thorborn D, Benbow A; 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, Moosmann N, Zwingers T, Boeck S, Giessen C, Stemmler HJ. UGT1A1 gene polymorphism: Impact on toxicity and efficacy of irinotecan-based regimens in metastatic colorectal cancer. World J. Gastroenterol. 2009; 15: 5058-5066.

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11.2. Appendix 2: 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

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11.3. Appendix 3: Country Specific Requirements

There are no country specific requirements.

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11.4. Appendix 4: Protocol Changes

Protocol Amendment 01

This amendment applies to all study centers participating in study 201317.

Rationale

This protocol amendment is being implemented to clarify the efficacy endpoints designated as ‘other endpoints’, clarify the order of administration of some study procedures shown in Table 5, and correct typographical errors.

Method of Amendment

Original and amended texts are specified as follows:

Original text: as written in the original protocol

Revised text: as written in Amendment No. 01 with revisions in bold font or as strikethrough text to show text deletions.

Amendment Details:

PROTOCOL SUMMARY

Original text:

Study Endpoints/Assessments

Primary

Exercise endurance time (EET) post-dose at Week 12, defined as the EET obtained 3 hours after dosing at Week 12

Secondary

Trough FEV1 at Week 12, defined as the mean of FEV1 values obtained 23 and 24 hours after dosing on the previous day

Functional residual capacity (FRC) 3 hours post-dose at Week 12

Inspiratory capacity (IC) 3 hours post-dose at Week 12

Other(s)

Post-dose EET and trough FEV1 at other visits

Functional residual capacity (pre-dose and post-dose at other visits)

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Inspiratory capacity (pre-dose and post-dose at other visits)

Residual volume (RV) (pre-dose and post-dose at each visit)

Post-dose FEV1 at each visit

Pre-dose and post-dose FVC at each visit

Rescue albuterol use over Weeks 1-12 (mean number of puffs/day and percentage of rescue-free days)

CAT

Exercise Dyspnea Scale (EDS; modified Borg scale)

Revised text:

Study Endpoints/Assessments

Primary

Exercise endurance time (EET) post-dose at Week 12, defined as the EET obtained 3 hours after dosing at Week 12

Secondary

Trough FEV1 at Week 12, defined as the mean of FEV1 values obtained 23 and 24 hours after dosing on the previous day

Functional residual capacity (FRC) 3 hours post-dose at Week 12

Inspiratory capacity (IC) 3 hours post-dose at Week 12

Other(s)

Post-dose EET and trough FEV1 at other visits

Functional residual capacity (pre-dose and post-dose at other visits)

Inspiratory capacity (pre-dose and post-dose at other visits)

Residual volume (RV) (pre-dose and post-dose at each visit)

Post-dose FEV1 at each visit

Pre-dose FVC

Rescue albuterol use over Weeks 1-12 (mean number of puffs/day and percentage of rescue-free days)

CAT

Exercise Dyspnea Scale (EDS; modified Borg scale)

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3.1 Study Design

Original text:

Clinic visits will be conducted at Pre-Screening (Visit 0) and at Screening (Visit 1) during which the incremental shuttle walk test (ISWT) will be demonstrated to the subjects. At Visit 2, an ISWT will be performed after subjects view a video of the ISWT to determine the walking speed of the ESWT during period 1. After performing the ISWT, the ESWT will be demonstrated to the subjects. At Visit 3, and at any visit where the ESWT is performed, subjects will first view a video of the ESWT before the actual ESWT is performed. At randomization (Visit 4), subjects will perform a pre-dose ESWT for baseline for the first treatment period. At Visits 5, 6, and 7, the ESWT will be performed 3 hours post-dose. After Visit 7, there will be a washout of 10 to12 days before Visit 8. At Visit 8, the subject will watch a video of the ISWT and then perform an ISWT to determine the walking speed of the ESWT for Period 2. Visit 9 will occur 2 to 5 days from Visit 8 and is Day 1 of the second treatment period during which a pre-dose ESWT will be performed for baseline. During Visits 10, 11, and 12, a 3 hour post-dose ESWT will be performed. A Safety Follow-Up assessment to record adverse events will be conducted by telephone approximately 7 days after the end of the second treatment period.

Revised text:

Clinic visits will be conducted at Pre-Screening (Visit 0) and at Screening (Visit 1) during which the incremental shuttle walk test (ISWT) will be demonstrated to the subjects. At Visit 2, an ISWT will be performed after subjects view a video of the ISWT to determine the walking speed of the ESWT during Treatment Period 1. After performing the ISWT, the ESWT will be demonstrated to the subjects. At Visit 3, and at any visit where the ESWT is performed, subjects will first view a video of the ESWT before the actual ESWT is performed. At randomization (Visit 4), subjects will perform a pre-dose ESWT for baseline for the first treatment period. At Visits 5, 6, and 7, the ESWT will be performed 3 hours post-dose. After Visit 7, there will be a washout of 10 to12 days before Visit 8. At Visit 8, the subject will watch a video of the ISWT and then perform an ISWT to determine the walking speed of the ESWT for Treatment Period 2. Visit 9 will occur 2 to 5 days from Visit 8 and is Day 1 of the second treatment period during which a pre-dose ESWT will be performed for baseline. At Visits 10, 11, and 12, the ESWT will be performed 3 hours post-dose. A Safety Follow-Up assessment to record adverse events will be conducted by telephone approximately 7 days after the end of the second treatment period.

6.1.4 Other Endpoints

Original text:

Post-dose EET and trough FEV1 at other visits

FRC (pre-dose and post-dose at other visits)

IC (pre-dose and post-dose at other visits)

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Residual volume (RV) (pre-dose and post-dose at each visit)

Post-dose FEV1 at each visit

Pre-dose and post-dose FVC at each visit

Rescue albuterol use over Weeks 1-12 (mean number of puffs/day and percentage of rescue-free days)

CAT

Exercise Dyspnea scale (Borg scale)

Revised text:

Post-dose EET and trough FEV1 at other visits

FRC (pre-dose and post-dose at other visits)

IC (pre-dose and post-dose at other visits)

Residual volume (RV) (pre-dose and post-dose at each visit)

Post-dose FEV1 at each visit

Pre-dose FVC

Rescue albuterol use over Weeks 1-12 (mean number of puffs/day and percentage of rescue-free days)

CAT

Exercise Dyspnea scale (Borg scale)

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6. STUDY ASSESSMENTS AND PROCEDURES

Original text:

Table 5 Time and Events Table

Procedures Pre-Screen

Screen Run - In Rand Treatment 1 Wash Out

Treatment 2 IP Disontinuation1

Follow-up

Visit Number 0 1 2 3 4 5 6 7 8 9 10 11 12Treatment Day V1

+1 to 7 days

V2 +5 to 9days

Day1V3 +5 to 9 days

Day2

Day 433

Day 853

10 to 12 days from V7

Day1(V8 +2 to 5 days)

Day 2 Day 433

Day 853

72 Days from V12 or IP Discontinuation

Week Designation N/A N/A N/A 1 1 6 12 N/A 1 1 6 12 13

Screening or Baseline AssessmentsWritten informed consent2

X X

Demography X XMedical /COPD History XSmoking history/status X X X X X XSmoking cessation counseling3

X X X

Inclusion/exclusion criteria

X

Randomisation criteria XPhysical examination X X XScreen12-Lead ECG XVital signs X X4

Screening Spirometry (including bronchodilator responsiveness testing)5

X

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Procedures Pre-Screen

Screen Run - In Rand Treatment 1 Wash Out

Treatment 2 IP Disontinuation1

Follow-up

Visit Number 0 1 2 3 4 5 6 7 8 9 10 11 12Treatment Day V1

+1 to 7 days

V2 +5 to 9days

Day1V3 +5 to9 days

Day2

Day 433

Day 853

10 to 12 days from V7

Day1(V8 +2 to 5 days)

Day 2 Day 433

Day 853

72 Days from V12 or IP Discontinuation

Week Designation N/A N/A N/A 1 1 6 12 N/A 1 1 6 12 13

Screening lung volumes

X

mMRC questionnaire XRegister visit in IVR/IWR

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

SafetyAdverse Events X X X X X X X X X X XSerious Adverse Events

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

Vitals pre-and post-walk shuttle walk6

X X X X X X X X X X X

EfficacyCOPD exacerbation assessment

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

Pre-dose baseline spirometry

X X

Trough spirometry7 X X X X X XLung volumes (Pleth) pre & 3hrs. post-dose study med

X8 X X X8 X X

ISWT demonstration XISWT video X9 X9

ISWT X X

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Procedures Pre-Screen

Screen Run - In Rand Treatment 1 Wash Out

Treatment 2 IP Disontinuation1

Follow-up

Visit Number 0 1 2 3 4 5 6 7 8 9 10 11 12Treatment Day V1

+1 to 7 days

V2+5 to 9days

Day1V3 +5 to 9 days

Day2

Day 433

Day 853

10 to 12 days from V7

Day1(V8 +2 to 5 days)

Day 2 Day 433

Day 853

72 Days from V12 or IP Discontinuation

Week Designation N/A N/A N/A 1 1 6 12 N/A 1 1 6 12 13

ESWT demonstration X10

ESWT video11 X X X X X X X X XESWT12 X X X X X X X X XHeart rate/pulse Oximetry13

X X X X X X X X X X X

LabsPGx Sampling14 XUrine Pregnancy Test15

X X X X X X

DiariesIssue run-in/washout diary

X X X X

Collect run-in/washout diary

X X X X

Issue treatment diary X X X XCollect treatment diary X X X XHealth Outcomes or QuestionnaireExercise Dyspnea Scale (Borg scale)

X16 X X X X X X X X X

CAT X X X X

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Procedures Pre-Screen

Screen Run - In Rand Treatment 1 Wash Out

Treatment 2 IP Disontinuation1

Follow-up

Visit Number 0 1 2 3 4 5 6 7 8 9 10 11 12Treatment Day V1

+1 to 7 days

V2 +5 to 9days

Day1V3 +5 to 9 days

Day2

Day 433

Day 853

10 to 12 days from V7

Day1(V8 +2 to 5 days)

Day 2 Day 433

Day 853

72 Days from V12 or IP Discontinuation

Week Designation N/A N/A N/A 1 1 6 12 N/A 1 1 6 12 13

MedicationsConcomitant medication

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

Dispense17, collect albuterol

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

Dispense study medication

X X

Dispense unblinding card

X

Collect Study meds/ assess compliance

X X X X X

1. IP Discontinuation Visit-The investigator must make every effort to have the subject return to the clinic as soon as possible for an IP discontinuation for subjects who discontinue IP but continue in the study and for subjects who are on IP but wish to withdraw from further study participation. An IP Discontinuation Visit may occur at a regular scheduled clinic visit or between study visits.

2. Written Informed Consent must be signed prior to initiation of study procedures, including changes in COPD medications. Subjects will be assigned a subject number at the time the ICF is signed. Visit 0 and Visit 1 may occur on the same day if applicable. ICF will be singed only once either at Visit 0 or Visit 1. Demography data will be collected at the time the ICF is signed. Consent for PGx testing is optional.

3. Details to be provided in SPM.4. Single set of vitals only.5. Spirometry to be conducted as follows: pre-bronchodilator testing following by post-albuterol testing. Post albuterol testing conducted 10 to 30 min after subject self-

administration of 4 puffs of albuterol via MDI 6. Vital signs pre- and post-walk should be performed at the visits indicated. Details of the timings of these measurements are provided in the SPM. 7. Trough spirometry obtained 23 and 24hrs after the previous day’s dose.

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8. Lung volumes (plethysmography) performed pre-dose only at these visits.9. Subjects to view ISWT video before performing the ISWT.10. At Visit 3, subjects to have demonstration of ESWT after performing the ISWT.11. Subjects will view the ESWT video prior to performing the ESWT.12. At Visit 3, an ESWT will be performed. At Visits 4 and 9 only pre-dose ESWT should be performed. All other visits require post-dose ESWT.13. Heart rate and pulse oximetry will be monitored before and after exercise and every 30 seconds during exercise test using a monitor for safety purposes only. 14. PGx sample collected at Visit 4 or any scheduled clinic visit thereafter. PGx sample collected at IP Discontinuation Visit Visit for subjects who discontinue IP but continue in the

study or for subjects who withdraw from further study participation after Visit 4. PGx consent must be signed prior to PGx sampling. 15. For females of childbearing potential only16. The Borg assessment at Visit 2 is for the ESWT demonstration.17. Albuterol to be used and dispensed on an as-needed basis. Use to be recorded daily by subjects in the dairy (puffs per day of MDI and/or nebules used)

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Revised text:

Procedures Pre-Screen

Screen Run - In Rand Treatment 1 Wash Out

Treatment 2 IP Disontinuation1

Follow-up

Visit Number 0 1 2 3 4 5 6 7 8 9 10 11 12Treatment Day V1

+1 to 7 days

V2 +5 to 9days

Day1V3 +5 to 9 days

Day2

Day 433

Day 853

10 to 12 days from V7

Day1(V8 +2 to 5 days)

Day 2 Day 433

Day 853

72 Days from V12 or IP Discontinuation

Week Designation N/A N/A N/A 1 1 6 12 N/A 1 1 6 12 13

Screening or Baseline AssessmentsWritten informed consent2

X X

Demography X XMedical /COPD History XSmoking history/status X X X X X XSmoking cessation counseling3

X X X

Inclusion/exclusion criteria

X

Randomisation criteria XPhysical examination X X XVital signs X X4

Screen12-Lead ECG XVital signs X X4

mMRC questionnaire X5

Screening lung volumes

X

Screening Spirometry (including bronchodilator responsiveness testing)6

X

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Procedures Pre-Screen

Screen Run - In Rand Treatment 1 Wash Out

Treatment 2 IP Disontinuation1

Follow-up

Visit Number 0 1 2 3 4 5 6 7 8 9 10 11 12Treatment Day V1

+1 to 7 days

V2 +5 to 9days

Day1V3 +5 to9 days

Day2

Day 433

Day 853

10 to 12 days from V7

Day1(V8 +2 to 5 days)

Day 2 Day 433

Day 853

72 Days from V12 or IP Discontinuation

Week Designation N/A N/A N/A 1 1 6 12 N/A 1 1 6 12 13

Register visit in IVR/IWR

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

SafetyAdverse Events X X X X X X X X X X XSerious Adverse Events

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

Vitals pre-and post-walk shuttle walk7

X X X X X X X X X X X

EfficacyCOPD exacerbation assessment

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

Pre-dose baseline spirometry

X X

Trough spirometry8 X X X X X XLung volumes (plethysmography) pre & 3hrs. post-dose

X9 X X X9 X X

ISWT demonstration XISWT video X10 X10

ISWT X X

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Procedures Pre-Screen

Screen Run - In Rand Treatment 1 Wash Out

Treatment 2 IP Disontinuation1

Follow-up

Visit Number 0 1 2 3 4 5 6 7 8 9 10 11 12Treatment Day V1

+1 to 7 days

V2 +5 to 9days

Day1V3 +5 to 9 days

Day2

Day 433

Day 853

10 to 12 days from V7

Day1(V8 +2 to 5 days)

Day 2 Day 433

Day 853

72 Days from V12 or IP Discontinuation

Week Designation N/A N/A N/A 1 1 6 12 N/A 1 1 6 12 13

ESWT demonstration X11

ESWT video12 X X X X X X X X XESWT13 X X X X X X X X XHeart rate/pulse Oximetry14

X X X X X X X X X X X

Exercise Dyspnea Scale (Borg scale)

X15 X X X X X X X X X

LabsPGx Sampling16 XUrine Pregnancy Test16

X X X X X X

DiariesIssue run-in/washout diary

X X X X

Collect run-in/washout diary

X X X X

Issue treatment diary X X X XCollect treatment diary X X X XHealth Outcomes or QuestionnaireCAT18 X X X X

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Procedures Pre-Screen

Screen Run - In Rand Treatment 1 Wash Out

Treatment 2 IP Disontinuation1

Follow-up

Visit Number 0 1 2 3 4 5 6 7 8 9 10 11 12Treatment Day V1

+1 to 7 days

V2 +5 to 9days

Day1V3 +5 to 9 days

Day2

Day 433

Day 853

10 to 12 days from V7

Day1(V8 +2 to 5 days)

Day 2 Day 433

Day 853

72 Days from V12 or IP Discontinuation

Week Designation N/A N/A N/A 1 1 6 12 N/A 1 1 6 12 13

MedicationsConcomitant medication

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

Dispense19, collect albuterol

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

Dispense study medication

X X

Dispense unblinding card

X

Collect Study meds/ assess compliance

X X X X X

1. IP Discontinuation Visit-The investigator must make every effort to have the subject return to the clinic as soon as possible for an IP discontinuation for subjects who discontinue IP but continue in the study and for subjects who are on IP but wish to withdraw from further study participation. An IP Discontinuation Visit may occur at a regular scheduled clinic visit or between study visits.

2. Written Informed Consent must be signed prior to initiation of study procedures, including changes in COPD medications. Subjects will be assigned a subject number at the time the ICF is signed. Visit 0 and Visit 1 may occur on the same day if applicable. ICF will be singed only once either at Visit 0 or Visit 1. Demography data will be collected at the time the ICF is signed. Consent for PGx testing is optional.

3. Details to be provided in SPM.4. Single set of vitals only.5. mMRC to be completed prior to screening lung volume (plethysmography) and spirometry assessments6. Spirometry to be conducted as follows: pre-bronchodilator testing following by post-albuterol testing. Post albuterol testing conducted 10 to 30 min after subject self-

administration of 4 puffs of albuterol via MDI. Spirometry to be conducted after lung volume (plethysmography) assessments7. Vital signs pre- and post-walk should be performed at the visits indicated. Details of the timings of these measurements are provided in the SPM.

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8. Trough spirometry obtained 23 and 24hrs after the previous day’s dose.9. Lung volumes (plethysmography) performed pre-dose only at these visits.10. Subjects to view ISWT video before performing the ISWT.11. Subjects to have demonstration of ESWT after performing the ISWT.12. Subjects will view the ESWT video prior to performing the ESWT.13. At Visit 3, a pre-randomization ESWT will be performed. At Visits 4 and 9 only pre-dose ESWT will be performed. All other post-randomization visits require 3hr post-dose

ESWT (only).14. Heart rate and pulse oximetry will be monitored before and after exercise and every 30 seconds during exercise test for safety purposes only.15. The Borg assessment at Visit 2 is for the ESWT demonstration.16. PGx sample collected at Visit 4 or any scheduled clinic visit thereafter. PGx sample collected at IP Discontinuation Visit for subjects who discontinue IP but continue in the study

or for subjects who withdraw from further study participation after Visit 4. PGx consent must be signed prior to PGx sampling. 17. For females of childbearing potential only18. The CAT questionnaire should be administered prior to plethysmography, spirometry, and exercise testing.19. Albuterol to be used and dispensed on an as-needed basis. Use to be recorded daily by subjects in the dairy (puffs per day of MDI and/or nebules used)

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6.2.1 Vital Signs

Original text:

Vital sign measurements will include heart rate and systolic and diastolic blood pressure (height and weight will be collected at Visit 1 only). Vital signs will be obtained after subjects have rested for approximately 5 minutes.

Vital signs will be performed at Visit 1 (Screening). On day 1 of each treatment period vital signs will be performed pre-shuttle walk and post shuttle walk. On subsequent on treatment visits (Day 2, Week 6 and Week 12) vital signs will be performed pre shuttle walk (3 hours post dose) and after shuttle walk. Vital signs will also be performed pre and post shuttle walk at Visits 2, 3 and 8.

Revised text:

Vital sign measurements will include heart rate and systolic and diastolic blood pressure (height and weight will be collected at Visit 1 only). Vital signs will be obtained after subjects have rested for approximately 5 minutes.

Vital signs will be performed at Visit 1 (Screening). On Day 1 of each treatment period (Visits 4 and 9) vital signs will be performed pre-shuttle walk (pre-dose) and post shuttle walk (pre-dose). On subsequent on treatment visits (Day 2/Visits 5 and 10), Week 6/Visits 6 and 11) and Week 12/Visits 7 and 12) vital signs will be performed pre shuttle walk (3 hours post dose) and after shuttle walk. Vital signs will also be performed pre and post shuttle walk at Visits 2, 3 and 8 (no dosing at these visits).

Original text:

6.2.14 Prompt Reporting of Serious Adverse Events and Other Events to GSK

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Initial Reports Follow-up Information on a Previous Report

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

collection tool24 hours Updated “SAE”

data collection tool

Cardiovascular, pneumonia and/or

death event4

Initial and follow up

reports to be completed within one

week of when the

cardiovascular, pneumonia

and/or death is reported

CV, pneumonia and/or

“death”events data collection

tool(s) if applicable

Initial and follow up reports to be completed within

one week of when the

cardiovascular, pneumonia, and/or death

event is reported

Updated “CV, pneumonia and/or

“death” data collection tool(s) if

applicable

Pregnancy 2 weeks “Pregnancy Notification Form”

2 weeks “Pregnancy Follow-up Form”

Non-serious adverse events

5 calendar days

“Adverse Reaction” data collection tool

2 weeks Updated “Adverse Reaction” data collection tool

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

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Initial Reports Follow-up Information on a Previous Report

Type of Event Time Frame Documents Time Frame DocumentsRemaining liver chemistry abnormalities for Phase II:

ALT5xULN; ALT3xULN with

hepatitis or rash or 3xULN 4 weeks

24 hours2 “Liver Event” Documents

(defined above) 3

24 hours Updated “Liver Event” Documents3

ALT3xULN and <5xULN and biliribin

<2xULN

24 hours2 “Liver Event” Documents

(defined above) do not need

completing unless elevations persist

for 4 weeks or subject cannot be monitored weekly

for 4 weeks3

24 hours Updated “Liver Event” Documents,

if applicable3

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

24 hours2 “Liver Event” Documents

(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

ALT5xULN and bilirubin <2xULN that

persists 2 weeks

24 hours2 “Liver Event” Documents

(defined above) 3

24 hours Updated “Liver Event” Documents3

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Initial Reports Follow-up Information on a Previous Report

Type of Event Time Frame Documents Time Frame Documents

ALT3xULN and <5x ULN and bilirubin

<2xULN

24 hours2 “Liver Event” Documents

(defined above) do not need

completing unless elevations persist

for 4 weeks or subject cannot be monitored weekly

for 4 weeks3

24 hours Updated “Liver Event” Documents,

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.4. Supplementary information (in addition to SAE report, if applicable) needs to be collected for cardiovascular,

pneumonia and death events. See Section 6.3.6, Section 6.3.7, and Section 6.3.8.

Revised text:

Note: footnote text was revised to site the correct reference sections.

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Initial Reports Follow-up Information on a Previous Report

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

collection tool24 hours Updated “SAE”

data collection tool

Cardiovascular, pneumonia and/or

death event4

Initial and follow up

reports to be completed within one

week of when the

cardiovascular, pneumonia

and/or death is reported

CV, pneumonia and/or

“death”events data collection

tool(s) if applicable

Initial and follow up reports to be completed within

one week of when the

cardiovascular, pneumonia, and/or death

event is reported

Updated “CV, pneumonia and/or

“death” data collection tool(s) if

applicable

Pregnancy 2 weeks “Pregnancy Notification Form”

2 weeks “Pregnancy Follow-up Form”

Non-serious adverse events

5 calendar days

“Adverse Reaction” data collection tool

2 weeks Updated “Adverse Reaction” data collection tool

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

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Initial Reports Follow-up Information on a Previous Report

Type of Event Time Frame Documents Time Frame DocumentsRemaining liver chemistry abnormalities for Phase II:

ALT5xULN; ALT3xULN with

hepatitis or rash or 3xULN 4 weeks

24 hours2 “Liver Event” Documents

(defined above) 3

24 hours Updated “Liver Event” Documents3

ALT3xULN and <5xULN and biliribin

<2xULN

24 hours2 “Liver Event” Documents

(defined above) do not need

completing unless elevations persist

for 4 weeks or subject cannot be monitored weekly

for 4 weeks3

24 hours Updated “Liver Event” Documents,

if applicable3

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

24 hours2 “Liver Event” Documents

(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

ALT5xULN and bilirubin <2xULN that

persists 2 weeks

24 hours2 “Liver Event” Documents

(defined above) 3

24 hours Updated “Liver Event” Documents3

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Initial Reports Follow-up Information on a Previous Report

Type of Event Time Frame Documents Time Frame Documents

ALT3xULN and <5x ULN and bilirubin

<2xULN

24 hours2 “Liver Event” Documents

(defined above) do not need

completing unless elevations persist

for 4 weeks or subject cannot be monitored weekly

for 4 weeks3

24 hours Updated “Liver Event” Documents,

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.4. Supplementary information (in addition to SAE report, if applicable) needs to be collected for cardiovascular,

pneumonia and death events. See Section 6.26, Section 6.2.7, and Section 6.2.8.

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Protocol Amendment 02

This amendment applies to all study centers participating in study 201317.

Rationale

This protocol amendment is being implemented to change the wording of the last Exclusion criterion in Section 4.3 to indicate that subjects are not eligible to participate in study 201317 if the subject was randomized to study medication in studies DB2114417 or DB2114418 rather than previously enrolled in these studies. The numbering in Section 4.3 was also re-formatted to show sequential numbering of the Exclusion Criteria.

Method of Amendment

Original and amended texts are specified as follows:

Original text: as written in the original protocol

Revised text: as written in Amendment No. 02 with revisions in bold font.

Amendment Details:

Original text:

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. Pregnancy: Women who are pregnant or lactating or are planning on becoming pregnant during the study.

2. Asthma: A current diagnosis of asthma.

3. Other Respiratory Disorders Known -1 antitrypsin deficiency, active lung infections (such as tuberculosis), and lung cancer in remission for <5 years are absolute exclusionary conditions. A subject who, in the opinion of the investigator, has any other significant respiratory conditions in addition to COPD should be excluded. Examples may include clinically significant bronchiectasis, pulmonary hypertension, sarcoidosis, or interstitial lung disease. Allergic rhinitis is not exclusionary.

4. Other Diseases/Abnormalities: Any subject who is considered unlikely to survive the duration of the study period or has any rapidly progressing disease or immediate life-threatening illness (e.g. cancer). In addition, any subject who has any condition besides COPD that is likely to affect respiratory function or the ability to perform

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exercise testing such as peripheral vascular disease should not be included in the study.

5. Severe Hepatic Impairment: Patients with severe hepatic impairment (Child-Pugh class C) should be excluded unless, in the opinion of the investigator, the benefit is likely to outweigh the risk.

6. Unstable or life threatening cardiac disease: Umeclidinium/vilanterol should be used with caution in subjects with severe cardiovascular disease. In the opinion of the investigator, use should only be considered if the benefit is likely to outweigh the risk in conditions such as:

Myocardial infarction or unstable angina in the last 6 months

Unstable or life threatening cardiac arrhythmia requiring intervention in the last 3 months

NYHA Class IV heart failure

2. Contraindications: Any history of allergy or hypersensitivity to any anticholinergic/muscarinic receptor antagonist, beta2-agonist, sympathomimetic, lactose/milk protein or magnesium stearate.

3. Antimuscarinic effects: Subjects with medical conditions such as narrow-angle glaucoma, urinary retention, prostatic hypertrophy, or bladder neck obstruction should only be included if, in the opinion of the study physician, the benefit outweighs the risk.

4. Hospitalization: Hospitalization for COPD or pneumonia within 12 weeks prior to Visit 1

5. Lung Resection: Subjects with lung volume reduction surgery within the 12 months prior to Screening (Visit 1).

6. 12-Lead ECG: Investigators will be provided with ECG reviews conducted by a centralized independent cardiologist to assist in evaluation of subject eligibility. The Investigator will determine the clinical significance of each abnormal ECG finding in relation to the subject’s medical history and exclude subjects who would be at undue risk by participating in the trial. Subjects with the following abnormalities are excluded from participation in the study:

Atrial fibrillation with rapid ventricular rate >120 bpm

Sustained or nonsustained ventricular tachycardia

Second degree heart block Mobitz type II and third degree heart block (unless pacemaker or defibrillator had been inserted)

7. Medication Prior to Spirometry: Unable to withhold albuterol for the 4 hour period required prior to spirometry testing at each study visit

8. Interactions: Concomitant administration with beta-blockers or strong CYP3A4 inhibitors is only permitted if, in the Investigator’s opinion, the likely benefit outweighs the potential risk

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9. Medications prior to Screening: Use of the following medications according to the following defined time intervals prior to Visit 1:

Medication Time intervalDepot corticosteroids 12 weeksSystemic, oral or parenteral corticosteroids1 6 weeks

Antibiotics (for lower respiratory tract infection and/or COPD exacerbation)

6 weeks

LABA/ICS combination products if LABA/ICS therapy is discontinued completely

30 days

LABA/ICS combination products only If discontinuing LABA therapy and switching to ICS monotherapy2

48 hours for the salmeterol or formoterol component

14 days for the vilanterol component

Use of ICS at a dose >1000 mcg/day of fluticasone propionate or equivalent3

30 days

Initiation or discontinuation of ICS use3 30 daysPhosphodiesterase 4 (PDE4) inhibitor (roflumilast) 14 daysInhaled long acting beta2 agonists (LABA):

salmeterol, formoterol 48 hoursolodaterol, indacaterol 14 days

Long-acting muscarinic antagonists (tiotropium, aclidinium, glycopyrronium, umeclidinium)

7 days

LAMA/LABA combination products Apply whichever mono component has the longest washout

Theophyllines 48 hoursOral beta2-agonists

long-acting 48 hoursshort-acting 12 hours

Inhaled short acting beta2-agonists4 4 hoursInhaled short-acting anticholinergics5 4 hoursInhaled short-acting anticholinergic/short-acting beta2-agonist combination products

4 hours

Any other investigational medication 30 days or within 5 drug half-lives (whichever is longer)

1. Intra-articular and epidural corticosteroid injections are permitted.2. The dose of ICS that is switched to must not exceed 1000mcg of fluticasone propionate or equivalent.3. Use of ICS is permitted provided the dose does not exceed 1000mcg of fluticasone propionate or equivalent; ICS

use not to be initiated or discontinued within 30 days prior to Visit 1 except for subjects on LABA/ICS therapy who may discontinue LABA/ICS therapy as indicated and switch to ICS monotherapy.

4. Use of study provided prn albuterol/ is permitted during the study, except in the 4-hour period prior to spirometry testing

5. Use of inhaled short-acting anticholinergics is permitted during the run-in period between Visits 1 and 4 and washout period between Visits 7 and 9. Subjects must discontinue use of short-acting anticholinergics at least 4 hours before Visit 4 and Visit 9. Subjects should not use short acting anticholinergics during the double-blind treatment periods.

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10. Oxygen: Use of long-term oxygen therapy (LTOT) described as oxygen therapy prescribed for greater than 12 hours a day. As-needed oxygen use (i.e., 12 hours per day) is not exclusionary.

11. Nebulized Therapy: Regular use (prescribed for use every day, not for as-needed use) of short-acting bronchodilators (e.g., albuterol) via nebulized therapy

12. Pulmonary Rehabilitation Program: Participation in the acute phase of a pulmonary rehabilitation program within 4 weeks prior to Visit 1. Subjects who are in the maintenance phase of a pulmonary rehabilitation program are not excluded.

13. Drug or Alcohol Abuse: A known or suspected history of alcohol or drug abuse within 2 years prior to Visit 1.

14. Affiliation with Investigator Site: Is an investigator, sub-investigator, study coordinator, employee of a participating investigator or study site, or immediate family member of the aforementioned that is involved in this study.

15. Inability to read: In the opinion of the Investigator, any subject who is unable to read and/or would not be able to complete a questionnaire

16. Participation in Previous Exercise Studies: Subjects who have previously been assigned a subject number (enrolled) in GlaxoSmithKline studies DB2114417 or DB2114418.

Revised text:

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. Pregnancy: Women who are pregnant or lactating or are planning on becoming pregnant during the study.

2. Asthma: A current diagnosis of asthma.

3. Other Respiratory Disorders Known -1 antitrypsin deficiency, active lung infections (such as tuberculosis), and lung cancer in remission for <5 years are absolute exclusionary conditions. A subject who, in the opinion of the investigator, has any other significant respiratory conditions in addition to COPD should be excluded. Examples may include clinically significant bronchiectasis, pulmonary hypertension, sarcoidosis, or interstitial lung disease. Allergic rhinitis is not exclusionary.

4. Other Diseases/Abnormalities: Any subject who is considered unlikely to survive the duration of the study period or has any rapidly progressing disease or immediate life-threatening illness (e.g. cancer). In addition, any subject who has any condition besides COPD that is likely to affect respiratory function or the ability to perform exercise testing such as peripheral vascular disease should not be included in the study.

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5. Severe Hepatic Impairment: Patients with severe hepatic impairment (Child-Pugh class C) should be excluded unless, in the opinion of the investigator, the benefit is likely to outweigh the risk.

6. Unstable or life threatening cardiac disease: Umeclidinium/vilanterol should be used with caution in subjects with severe cardiovascular disease. In the opinion of the investigator, use should only be considered if the benefit is likely to outweigh the risk in conditions such as:

Myocardial infarction or unstable angina in the last 6 months

Unstable or life threatening cardiac arrhythmia requiring intervention in the last 3 months

NYHA Class IV heart failure

7. Contraindications: Any history of allergy or hypersensitivity to any anticholinergic/muscarinic receptor antagonist, beta2-agonist, sympathomimetic, lactose/milk protein or magnesium stearate.

8. Antimuscarinic effects: Subjects with medical conditions such as narrow-angle glaucoma, urinary retention, prostatic hypertrophy, or bladder neck obstruction should only be included if, in the opinion of the study physician, the benefit outweighs the risk.

9. Hospitalization: Hospitalization for COPD or pneumonia within 12 weeks prior to Visit 1

10. Lung Resection: Subjects with lung volume reduction surgery within the 12 months prior to Screening (Visit 1).

11. 12-Lead ECG: Investigators will be provided with ECG reviews conducted by a centralized independent cardiologist to assist in evaluation of subject eligibility. The Investigator will determine the clinical significance of each abnormal ECG finding in relation to the subject’s medical history and exclude subjects who would be at undue risk by participating in the trial. Subjects with the following abnormalities are excluded from participation in the study:

Atrial fibrillation with rapid ventricular rate >120 bpm

Sustained or nonsustained ventricular tachycardia

Second degree heart block Mobitz type II and third degree heart block (unless pacemaker or defibrillator had been inserted)

12. Medication Prior to Spirometry: Unable to withhold albuterol for the 4 hour period required prior to spirometry testing at each study visit

13. Interactions: Concomitant administration with beta-blockers or strong CYP3A4 inhibitors is only permitted if, in the Investigator’s opinion, the likely benefit outweighs the potential risk

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14. Medications prior to Screening: Use of the following medications according to the following defined time intervals prior to Visit 1:

Medication Time intervalDepot corticosteroids 12 weeksSystemic, oral or parenteral corticosteroids1 6 weeks

Antibiotics (for lower respiratory tract infection and/or COPD exacerbation)

6 weeks

LABA/ICS combination products if LABA/ICS therapy is discontinued completely

30 days

LABA/ICS combination products only If discontinuing LABA therapy and switching to ICS monotherapy2

48 hours for the salmeterol or formoterol component

14 days for the vilanterol component

Use of ICS at a dose >1000 mcg/day of fluticasone propionate or equivalent3

30 days

Initiation or discontinuation of ICS use3 30 daysPhosphodiesterase 4 (PDE4) inhibitor (roflumilast) 14 daysInhaled long acting beta2 agonists (LABA):

salmeterol, formoterol 48 hoursolodaterol, indacaterol 14 days

Long-acting muscarinic antagonists (tiotropium, aclidinium, glycopyrronium, umeclidinium)

7 days

LAMA/LABA combination products Apply whichever mono component has the longest washout

Theophyllines 48 hoursOral beta2-agonists

long-acting 48 hoursshort-acting 12 hours

Inhaled short acting beta2-agonists4 4 hoursInhaled short-acting anticholinergics5 4 hoursInhaled short-acting anticholinergic/short-acting beta2-agonist combination products

4 hours

Any other investigational medication 30 days or within 5 drug half-lives (whichever is longer)

1. Intra-articular and epidural corticosteroid injections are permitted.2. The dose of ICS that is switched to must not exceed 1000mcg of fluticasone propionate or equivalent.3. Use of ICS is permitted provided the dose does not exceed 1000mcg of fluticasone propionate or equivalent; ICS

use not to be initiated or discontinued within 30 days prior to Visit 1 except for subjects on LABA/ICS therapy who may discontinue LABA/ICS therapy as indicated and switch to ICS monotherapy.

4. Use of study provided prn albuterol/ is permitted during the study, except in the 4-hour period prior to spirometry testing

5. Use of inhaled short-acting anticholinergics is permitted during the run-in period between Visits 1 and 4 and washout period between Visits 7 and 9. Subjects must discontinue use of short-acting anticholinergics at least 4 hours before Visit 4 and Visit 9. Subjects should not use short acting anticholinergics during the double-blind treatment periods.

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15. Oxygen: Use of long-term oxygen therapy (LTOT) described as oxygen therapy prescribed for greater than 12 hours a day. As-needed oxygen use (i.e., 12 hours per day) is not exclusionary.

16. Nebulized Therapy: Regular use (prescribed for use every day, not for as-needed use) of short-acting bronchodilators (e.g., albuterol) via nebulized therapy

17. Pulmonary Rehabilitation Program: Participation in the acute phase of a pulmonary rehabilitation program within 4 weeks prior to Visit 1. Subjects who are in the maintenance phase of a pulmonary rehabilitation program are not excluded.

18. Drug or Alcohol Abuse: A known or suspected history of alcohol or drug abuse within 2 years prior to Visit 1.

19. Affiliation with Investigator Site: Is an investigator, sub-investigator, study coordinator, employee of a participating investigator or study site, or immediate family member of the aforementioned that is involved in this study.

20. Inability to read: In the opinion of the Investigator, any subject who is unable to read and/or would not be able to complete a questionnaire

21. Participation in Previous Exercise Studies: Subjects who have previously been randomized to study medication in GlaxoSmithKline studies DB2114417 or DB2114418.

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