*complete removal of patient data listings may …...*complete removal of patient data listings may...
TRANSCRIPT
-
In February 2013, GlaxoSmithKline (GSK) announced a commitment to further clinical transparency through the public disclosure of GSK Clinical Study Reports (CSRs) on the GSK Clinical Study Register.
The following guiding principles have been applied to the disclosure: Information will be excluded in order to protect the privacy of patients and all named
persons associated with the study Patient data listings will be completely removed* to protect patient privacy. Anonymized
data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the GSK Clinical Study Register.
Aggregate data will be included; with any direct reference to individual patients excluded
*Complete removal of patient data listings may mean that page numbers are no longer consecutively
numbered
-
CONFIDENTIAL 2018N355937_00The GlaxoSmithKline group of companies 200363
1
Division: Worldwide DevelopmentInformation Type: Clinical Study ReportControl: None
Title: An open-label study to characterise the pharmacokinetics and pharmacodynamics of mepolizumab administered subcutaneously in children from 6 to 11 years of age with severe eosinophilic asthma (Parts A and B)
Additional Study Design Information: This was a multi-centre, 2-part study: Part A (completed): pharmacokinetic/pharmacodynamic phase (12 week treatment period), mepolizumab 40 or 100 mg subcutaneously depending on bodyweightPart B (completed): 52 week treatment period, long-term safety/pharmacodynamic phase
Phase: II
Compound Number: SB-240563
Effective Date: 16-JUL-2018
Keywords: Severe asthma, blood eosinophil count, effectiveness, pharmacokinetics, pharmacodynamics, safety, dose by bodyweight category.
Authors:
Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised copying or use of this information is prohibited
1
PPD
-
CONFIDENTIAL 2018N355937_00The GlaxoSmithKline group of companies 200363
2
Indication Studied: Severe Eosinophilic Asthma
Initiation Date: 25-AUG-2015
Part A Completion Date: 07-DEC-2016
Part B Completion Date: 31-JAN-2018
Earlier CSRs An open-label study to characterise the pharmacokinetics and pharmacodynamics of mepolizumab administered subcutaneously in children from 6 to 11 years of age with severe eosinophilic asthma (Interim report; final Part A results only). GSK Document Number 2017N314087_00. Effective Date 07-AUG-2017.
Sponsor Signatory:(and Medical Officer)
Eric Bradford, MDProject Physician LeadDirector, Clinical DevelopmentRespiratory R&D
This study was performed in compliance with Good Clinical Practices and GlaxoSmithKline Standard Operating Procedures for all processes involved, including the archiving of essential documents. This study complies with US 21 CFR 312.120.
.
2
-
Table of Contents Page TITLE PAGE .......................................................................................................... ABBREVIATIONS .................................................................................................. ETHICS AND GOOD CLINICAL PRACTICE ......................................................... 1. INTRODUCTION ................................................................................................ 2. STUDY OBJECTIVES & ENDPOINTS .............................................................. 3. INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE .................. 4. INVESTIGATIONAL PLAN ................................................................................
4.1. Study Design ................................................................................................... 4.1.1. Pharmacokinetic/Pharmacodynamic Design (Part A) .................................. 4.1.2. Long-Term Safety/Pharmacodynamic Phase (Part B) ................................. 4.1.3. Analysis .......................................................................................................
4.2. Discussion of Study Design ............................................................................. 4.3. Protocol Amendments ..................................................................................... 4.4. Selection of Study Population ..........................................................................
4.4.1. Inclusion/Exclusion Criteria ......................................................................... 4.4.2. Withdrawal Criteria ......................................................................................
4.5. Treatments ...................................................................................................... 4.5.1. Investigational Product ................................................................................ 4.5.2. Treatment Assignment ................................................................................ 4.5.3. Blinding ........................................................................................................ 4.5.4. Prior and Concomitant Medications and Non-Drug Therapies .................... 4.5.5. Compliance .................................................................................................
4.6. Study Assessments and Procedures ............................................................... 4.6.1. Pharmacokinetic Assessments (Part A only) ............................................... 4.6.2. Pharmacodynamic and Clinical Assessments ............................................. 4.6.3. Safety Assessments ....................................................................................
4.7. Data Quality Assurance ................................................................................... 4.8. Statistical Analyses ..........................................................................................
4.8.1. Sample Size Considerations ....................................................................... 4.8.2. Analysis Populations ................................................................................... 4.8.3. Part A Analyses ........................................................................................... 4.8.4. Part B Analyses ........................................................................................... 4.8.5. Changes in Conduct of the Study or Planned Analyses ..............................
5. RESULTS (PART A) .......................................................................................... 5.1. Study Population Results .................................................................................
5.1.1. Subject Disposition ...................................................................................... 5.1.2. Protocol Deviations...................................................................................... 5.1.3. Demographics and Baseline Characteristics ............................................... 5.1.4. Prior and Concomitant Medications .............................................................
5.2. Pharmacokinetic and Pharmacodynamic Results ............................................ 5.2.1. Pharmacokinetics ........................................................................................ 5.2.2. Pharmacodynamics .....................................................................................
5.3. Relationship Between Pharmacokinetic and Pharmacodynamic Parameters ..
1161819202225252527282829313134343435363637373738404243434446494951515153545757576265
3
CONFIDENTIAL 2018N355937_00200363
-
5.3.1. Analysis Dataset .......................................................................................... 5.3.2. Demographics and Covariates .................................................................... 5.3.3. Population Pharmacokinetic/Pharmacodynamic Analysis ...........................
5.4. Clinical Assessments ....................................................................................... 5.4.1. Asthma Control Questionnaire .................................................................... 5.4.2. Childhood Asthma Control Test ................................................................... 5.4.3. Forced Expiratory Volume in 1 Second ....................................................... 5.4.4. Asthma Exacerbations .................................................................................
5.5. Safety Results ................................................................................................. 5.5.1. Extent of Exposure ...................................................................................... 5.5.2. Adverse Events ........................................................................................... 5.5.3. Serious and Other Significant Adverse Events ............................................ 5.5.4. Immunogenicity ........................................................................................... 5.5.5. Clinical Laboratory Evaluations ................................................................... 5.5.6. Other Safety Evaluations ............................................................................. 5.5.7. Pregnancies ................................................................................................
6. RESULTS (PART B) .......................................................................................... 6.1. Study Population..............................................................................................
6.1.1. Subject Disposition ...................................................................................... 6.1.2. Protocol Deviations...................................................................................... 6.1.3. Demographics and Baseline Characteristics ............................................... 6.1.4. Prior and Concomitant Medications .............................................................
6.2. Safety Results ................................................................................................. 6.2.1. Extent of Exposure ...................................................................................... 6.2.2. Adverse Events ........................................................................................... 6.2.3. Serious and Other Significant Adverse Events ............................................ 6.2.4. Immunogenicity ........................................................................................... 6.2.5. Clinical Laboratory Evaluations ................................................................... 6.2.6. Other Safety Evaluations ............................................................................. 6.2.7. Pregnancies ................................................................................................
6.3. Pharmacodynamic Results .............................................................................. 6.3.1. Blood Eosinophil Count ...............................................................................
6.4. Clinical Assessments ....................................................................................... 6.4.1. Asthma Control Questionnaire .................................................................... 6.4.2. Childhood Asthma Control Test ................................................................... 6.4.3. Forced Expiratory Volume in 1 Second ....................................................... 6.4.4. Asthma Exacerbations .................................................................................
7. DISCUSSION AND CONCLUSIONS (PART A) ................................................ 7.1. Discussion ....................................................................................................... 7.2. Conclusions .....................................................................................................
8. DISCUSSION AND CONCLUSIONS (PART B) ................................................ 8.1. Discussion ....................................................................................................... 8.2. Conclusions .....................................................................................................
9. REFERENCES ................................................................................................... 10. CASE NARRATIVES .......................................................................................
10.1. Serious Adverse Events (Part A) ...................................................................
65656566666970717272737882838890919191929395969696102106107112115115115119120121121122126126129130130131133136136
4
CONFIDENTIAL 2018N355937_00200363
-
10.2. Serious Adverse Events (Part B) ................................................................... 10.3. Adverse Event Leading to Withdrawal (Part A) .............................................. 10.4. Adverse Event Leading to Withdrawal (Part B) ..............................................
11. CHANGES IN PART A DATABASE FOLLOWING PART A DATABASE FREEZE .................................................................................................................
11.1. Adverse Event Changes Following Part A Database Freeze ......................... 11.2. Electrocardiogram Changes Following Part A Database Freeze ................... 11.3. Protocol Deviation Changes Following Part A Database Freeze ................... 11.4. Concomitant Medication Changes Following Part A Database Freeze ..........
STUDY POPULATION DATA SOURCE TABLES-PART A .................................. Table 1.1 Summary of Subject Populations (Part A) (All Subjects Enrolled
Population) ............................................................................................... Table 1.2 Summary of Reasons for Screening or Run-In Failure (Part A) (All
Subjects Enrolled Population) .................................................................. Table 1.3 Summary of Failed Inclusion/Exclusion Criteria for Screening or Run-in
Failures (Part A) (All Subjects Enrolled Population) ................................. Table 1.4 Summary of Failed Inclusion/Exclusion Criteria for Subjects within the
Safety Population (Part A) (Safety Population) ........................................ Table 1.5 Summary of Number of Subjects Dosed by Country and Site (Part A)
(Safety Population) .................................................................................. Table 1.6 Summary of Subject Disposition (Part A) (Safety Population) ................ Table 1.7 Summary of Demographic Characteristics (Part A) (Safety Population) . Table 1.8 Summary of Derived Age Ranges (Part A) (All Subjects Enrolled
Population) ............................................................................................... Table 1.9 Summary of Race and Racial Combinations (Part A) (Safety
Population) ............................................................................................... Table 1.10 Summary of Race and Racial Combinations Details (Part A) (Safety
Population) ............................................................................................... Table 1.11 Summary of Past Medical Conditions (Part A) (Safety Population) ...... Table 1.12 Summary of Current Medical Conditions (Part A) (Safety Population) .. Table 1.13 Summary of Cardiovascular Assessments - Family History (Part A)
(Safety Population) .................................................................................. Table 1.14 Summary of Asthma Exacerbation History (Part A) (Safety Population)
................................................................................................................. Table 1.15 Summary of Asthma History and Baseline Disease Characteristics
(Part A) (Safety Population) ..................................................................... Table 1.16 Summary of Screening and Baseline Lung Function Results (Part A)
(Safety Population) .................................................................................. Table 1.17 Summary of Asthma Concomitant Medication Taken Before the Run-
In by Respiratory Medication Class (Part A) (Safety Population) ............. Table 1.18 Summary of Asthma Concomitant Medication Taken During the Run-
In by Respiratory Medication Class (Part A) (Safety Population) ............. Table 1.19 Summary of Asthma Concomitant Medication Taken During Treatment
by Respiratory Medication Class (Part A) (Safety Population) ................. Table 1.20 Summary of Asthma Concomitant Medication Taken Post-Treatment
by Respiratory Medication Class (Part A) (Safety Population) .................
152163163
164164166168170178
178
179
180
181
182183184
186
187
188189190
191
192
194
196
198
202
206
210
5
CONFIDENTIAL 2018N355937_00200363
-
Table 1.21 Summary of non-Asthma Concomitant Medication Taken During Treatment (Part A) (Safety Population) ....................................................
Table 1.22 Summary of Important Protocol Deviations (Part A) (Safety Population) ...............................................................................................
Table 1.23 Summary of Study Efficacy Endpoints at Baseline (Part A) (Safety Population) ...............................................................................................
Table 1.24 Summary of Asthma Inhaled Corticosteroid (ICS) Dose (mcg/day) at Screening (Part A) (Safety Population) ....................................................
STUDY POPULATION DATA SOURCE TABLES-PART B .................................. Table 1.25 Summary of Subject Populations (Part B) (Safety Population) ............ Table 1.26 Summary of Subject Disposition (Part B) (Safety Population) ............. Table 1.27 Summary of Asthma Concomitant Medication Taken During
Treatment by Respiratory Medication Class (Part B) (Safety Population) .............................................................................................
Table 1.28 Summary of Asthma Concomitant Medication Taken Post-Treatment by Respiratory Medication Class (Part B) (Safety Population) .............................................................................................
Table 1.29 Summary of Non-Asthma Concomitant Medication Taken During Treatment (Part B) (Safety Population) ..................................................
Table 1.30 Summary of Important Protocol Deviations (Part B) (Safety Population) .............................................................................................
Table 1.31 Summary of Demographic Characteristics (Part B) (Safety Population) .............................................................................................
Table 1.32 Summary of Race and Racial Combinations (Part B) (Safety Population) .............................................................................................
Table 1.33 Summary of Race and Racial Combinations Details (Part B) (Safety Population) .............................................................................................
Table 1.34 Summary of Asthma Exacerbation History (Part B) (Safety Population) .............................................................................................
Table 1.35 Summary of Asthma Exacerbation History (Part B) [Excluding Subject (Safety Population) .........................................
PHARMACOKINETIC DATA SOURCE FIGURES ................................................ Figure 2.1 Model predicted mepolizumab individual time profiles by Treatment ..... Figure 2.2 Model predicted mepolizumab individual time profiles by subject .......... Figure 2.3 Goodness of Fit Plots ............................................................................ Figure 2.4 Plasma Mepolizumab Observed Concentration-Time Profiles (ADA
Positive versus ADA Negative Subjects) ................................................. Figure 2.5 Plasma Mepolizumab Observed Concentration-Time Profiles
(Japanese versus Non-Japanese Subjects) ............................................ Figure 2.6 Model Visual Predictive Check .............................................................. Figure 2.7 Observed/Indiv. Predicted Mepolizumab Plasma Concentration-Time
Profile (Geometric Mean (95%CI)) ........................................................... Figure 2.8 Goodness of Fit Plots ............................................................................ Figure 2.9 Plasma Mepolizumab Observed/Predicted Concentration-Time Profiles
(by Subject) .............................................................................................. Figure 2.10 PK NONMEM Model Visual Predictive Check .....................................
215
223
224
226227227228
229
233
237
246
247
249
250
251
253255255256258
262
263264
267268
272274
6
CONFIDENTIAL 2018N355937_00200363
PPD
-
Figure 2.11 Observed/Indiv. Predicted Blood Eosinophil Count-Time Profile (Geometric Mean (95%CI)) ......................................................................
Figure 2.12 Goodness of Fit Plots .......................................................................... Figure 2.13 Observed/Predicted Blood Eosinophil Count-Time Profiles (by
Subject) .................................................................................................... Figure 2.14 PKPD NONMEM Model Visual Predictive Check ................................ Figure 2.15 Observed Blood Eosinophil Count-Time Profiles (Japanese versus
Non-Japanese Subjects) .......................................................................... Figure 2.23 Standardized PK Parameter Correlation Plot: Continuous Covariates Figure 2.24 Standardized PK Parameter Correlation Plot: Categorical Covariates Figure 2.25 Automated Covariate Selection Models ............................................... Figure 2.26 Observed Blood Eosinophil Count-Time Profiles (ADA Positive versus
ADA Negative Subjects) .......................................................................... Figure 2.27 Standardized PD Parameter Correlation Plot: Continuous Covariates Figure 2.28 Standardized PD Parameter Correlation Plot: Categorical Covariates Figure 2.29 Automated Covariate Selection Models ............................................... Figure 2.30 Standardized PK Parameter Correlation Plot: Continuous Covariates Figure 2.31 Box Plot of Systemic Clearance versus Categorical Covariates of
Interest ..................................................................................................... PHARMACOKINETIC DATA SOURCE TABLES ..................................................
Table 2.1 Summary of Plasma Mepolizumab Pharmacokinetic Concentration-Time Data (observed and predicted) (Pharmacokinetic Population) ........
Table 2.2 Summary Statistics of Individual Model Predicted and Plasma Mepolizumab Pharmacokinetic Parameters (non-transformed and log-transformed) (Pharmacokinetic Population) .............................................
Table 2.3 Description and Evaluation of Key PK Models Tested ............................ Table 2.4 Final Population PK Model Parameters and Exposure Estimates .......... Table 2.5 Summary Statistics for Categorical/Continuous Covariates .................... Table 2.6 Summary of Number of Subjects and PK Samples by Visit .................... Table 2.7 Bodyweight-adjusted Apparent Clearance (mean and 90% CI) .............. Table 2.8 Two-sample Non-parametric Goodness of Fit Test Statistics
(Pharmacokinetics) .................................................................................. Table 2.9 Summary Statistics for Categorical/Continuous Covariates .................... Table 2.10 Summary of Number of Subjects and PD Samples by Visit .................. Table 2.11 Two-sample Non-parametric Goodness of Fit Test Statistics
(Pharmacodynamics) ............................................................................... Table 2.24 Two-sample Non-parametric Goodness of Fit Test Statistics SAS
Model(Primary Pharmacokinetic Analysis) ............................................... EFFICACY DATA SOURCE FIGURES-PART A ...................................................
Figure 2.16 Figure of Absolute Blood Eosinophil Count (10^9/L) (Geometric Mean at Each Visit by Treatment Group) (Part A) (Pharmacodynamic Eosinophils (PDe) Population) .................................................................
Figure 2.17 Figure of Ratio of Blood Eosinophil Count to Baseline (Geometric Mean at Each Visit by Treatment Group) (Part A) (Pharmacodynamic Eosinophils (PDe) Population) .................................................................
277278
282284
286287290292
294295298300302
305306
306
309313314317328329
330332343
344
346348
348
349
7
CONFIDENTIAL 2018N355937_00200363
-
Figure 2.18 Figure of Change from Baseline in Overall ACQ-7 score (Mean Change from Baseline at Each Visit by Treatment Group) (Part A) (Pharmacodynamic Outcome (PDo) Population) .....................................
Figure 2.19 Figure of Change from Baseline in Overall ACQ-5 score (Mean Change from Baseline at Each Visit by Treatment Group) (Part A) (Pharmacodynamic Outcome (PDo) Population) .....................................
Figure 2.20 Figure of Change from Baseline in C-ACT Total score (Mean Change from Baseline at Each Visit by Treatment Group) (Part A) (Pharmacodynamic Outcome (PDo) Population) .....................................
Figure 2.21 Figure of Change from Baseline in Pre-Bronchodilator FEV1 (mL) (Mean Change from Baseline at Each Visit by Treatment Group) (Part A) (Pharmacodynamic Outcome (PDo) Population) ................................
Figure 2.22 Kaplan-Meier Cumulative Incidence Curve for Time to First Exacerbation (Part A) (Pharmacodynamic Outcome (PDo) Population) ..
EFFICACY DATA SOURCE FIGURES-PART B ................................................... Figure 2.32 Figure of Absolute Blood Eosinophil Count (10^9/L) (Geometric
Mean at Each Visit) (Part B) (Pharmacodynamic Eosinophils (PDe) Population) .............................................................................................
Figure 2.33 Figure of Ratio of Blood Eosinophil Count to Baseline (Geometric Mean at Each Visit) (Part B) (Pharmacodynamic Eosinophils (PDe) Population) .............................................................................................
Figure 2.34 Figure of Absolute Blood Eosinophil Count (10^9/L) (Geometric Mean at Each Visit) (Part B) [Excluding Subject (Pharmacodynamic Eosinophils (PDe) Population) ................................
Figure 2.35 Figure of Ratio of Blood Eosinophil Count to Baseline (Geometric Mean at Each Visit) (Part B) [Excluding Subject (Pharmacodynamic Eosinophils (PDe) Population) ................................
Figure 2.36 Figure of Absolute Blood Eosinophil Count (10^9/L) (Geometric Mean at Each Visit) (Part A and Part B) (Pharmacodynamic Eosinophils (PDe) Population) ................................................................
Figure 2.37 Figure of Ratio of Blood Eosinophil Count to Baseline (Geometric Mean at Each Visit) (Part A and Part B) (Pharmacodynamic Eosinophils (PDe) Population) ................................................................
Figure 2.38 Figure of Ratio of Blood Eosinophil Count to Baseline Profiles in Subjects Switching from 40mg SC to 100 mg SC (Subject
(Pharmacodynamic Eosinophils (PDe) Population) ..... Figure 2.39 Figure of Ratio of Blood Eosinophil Count to Baseline Profiles in
Subjects Switching from 40mg SC to 100 mg SC (Subject (Pharmacodynamic Eosinophils (PDe) Population) .....
Figure 2.40 Figure of Ratio of Blood Eosinophil Count to Baseline Profiles in Subjects Switching from 40mg SC to 100 mg SC (Subject
(Pharmacodynamic Eosinophils (PDe) Population) ..... Figure 2.41 Figure of Ratio of Blood Eosinophil Count to Baseline Profiles in
Subjects Switching from 40mg SC to 100 mg SC (Subject (Pharmacodynamic Eosinophils (PDe) Population) .....
350
351
352
353
354355
355
356
357
358
359
360
361
362
363
364
8
CONFIDENTIAL 2018N355937_00200363
PPD
PPD
PPD
PPD
PPD
PPD
-
EFFICACY DATA SOURCE TABLES-PART A ..................................................... Table 2.12 Summary of Blood Eosinophil Count (Part A) (Pharmacodynamic
Eosinophils (PDe) Population) ................................................................. Table 2.13 Summary of ACQ-7 Score (Part A) (Pharmacodynamic Outcome
(PDo) Population) .................................................................................... Table 2.14 Summary of 0.5 Point or More Reduction in ACQ-7 Score from
Baseline (Part A) (Pharmacodynamic Outcome (PDo) Population) ......... Table 2.15 Summary of ACQ-5 Score (Part A) (Pharmacodynamic Outcome
(PDo) Population) .................................................................................... Table 2.16 Summary of 0.5 Point or More Reduction in ACQ-5 Score from
Baseline (Part A) (Pharmacodynamic Outcome (PDo) Population) ......... Table 2.17 Summary of C-ACT Score (Part A) (Pharmacodynamic Outcome
(PDo) Population) .................................................................................... Table 2.18 Summary of Clinic Pre-Bronchodilator FEV1 (mL) (Part A)
(Pharmacodynamic Outcome (PDo) Population) ..................................... Table 2.19 Overview of Asthma Exacerbations (Part A) (Pharmacodynamic
Outcome (PDo) Population) ..................................................................... Table 2.20 Summary of Frequency of Exacerbations (Week 0 - Week 12) (Part A)
(Pharmacodynamic Outcome (PDo) Population) ..................................... Table 2.21 Summary of Frequency of Exacerbations (Week 0 - Week 20) (Part A)
(Pharmacodynamic Outcome (PDo) Population) ..................................... Table 2.22 Summary of Time to First Asthma Exacerbation (Part A)
(Pharmacodynamic Outcome (PDo) Population) ..................................... Table 2.23 Summary of IL-5 (Part A) (Pharmacodynamic Outcome (PDo)
Population) ............................................................................................... EFFICACY DATA SOURCE TABLES-PART B .....................................................
Table 2.25 Summary of Blood Eosinophil Count (Part B) (Pharmacodynamic Eosinophils (PDe) Population) ................................................................
Table 2.26 Summary of ACQ-7 Score (Part B) (Pharmacodynamic Outcome (PDo) Population) ...................................................................................
Table 2.27 Summary of 0.5 Point or More Reduction in ACQ-7 Score from Baseline (Part B) (Pharmacodynamic Outcome (PDo) Population) ........
Table 2.28 Summary of ACQ-5 Score (Part B) (Pharmacodynamic Outcome (PDo) Population) ...................................................................................
Table 2.29 Summary of 0.5 Point or More Reduction in ACQ-5 Score from Baseline (Part B) (Pharmacodynamic Outcome (PDo) Population) ........
Table 2.30 Summary of C-ACT Score (Part B) (Pharmacodynamic Outcome (PDo) Population) ...................................................................................
Table 2.31 Summary of Clinic Pre-Bronchodilator FEV1 (mL) (Part B) (Pharmacodynamic Outcome (PDo) Population) ....................................
Table 2.32 Overview of Asthma Exacerbations (Part B) (Pharmacodynamic Outcome (PDo) Population) ....................................................................
Table 2.33 Summary of Frequency of Exacerbations (Week 20 - Week 72) (Part B) (Pharmacodynamic Outcome (PDo) Population) .......................
Table 2.34 Summary of Time to First Asthma Exacerbation (Part B) (Pharmacodynamic Outcome (PDo) Population) ....................................
365
365
371
376
381
386
391
396
401
403
404
405
406407
407
413
419
425
431
437
443
449
451
452
9
CONFIDENTIAL 2018N355937_00200363
-
Table 2.35 Summary of Blood Eosinophil Count (Part B) [Excluding Subject (Pharmacodynamic Eosinophils (PDe) Population) .....
Table 2.36 Summary of ACQ-7 Score (Part B) [Excluding Subject (Pharmacodynamic Outcome (PDo) Population) .........
Table 2.37 Summary of 0.5 Point or More Reduction in ACQ-7 Score from Baseline (Part B) [Excluding Subject (Pharmacodynamic Outcome (PDo) Population) ....................................
Table 2.38 Summary of ACQ-5 Score (Part B) [Excluding Subject (Pharmacodynamic Outcome (PDo) Population) .........
Table 2.39 Summary of 0.5 Point or More Reduction in ACQ-5 Score from Baseline (Part B) [Excluding Subject (Pharmacodynamic Outcome (PDo) Population) ....................................
Table 2.40 Summary of C-ACT Score (Part B) [Excluding Subject (Pharmacodynamic Outcome (PDo) Population) .........
Table 2.41 Summary of Clinic Pre-Bronchodilator FEV1 (mL) (Part B) [Excluding Subject (Pharmacodynamic Outcome (PDo) Population) ...................................................................................
Table 2.42 Overview of Asthma Exacerbations (Part B) [Excluding Subject (Pharmacodynamic Outcome (PDo) Population) .........
Table 2.43 Summary of Frequency of Exacerbations (Week 20 - Week 72) (Part B) [Excluding Subject (Pharmacodynamic Outcome (PDo) Population) ....................................................................
Table 2.44 Summary of Time to First Asthma Exacerbation (Part B) [Excluding Subject (Pharmacodynamic Outcome (PDo) Population) .............................................................................................
Table 2.45 Annualised Rate of On-Treatment Exacerbations (Part B) (Pharmacodynamic Outcome (PDo) Population) ....................................
Table 2.46 Summary of Reduction in On-Treatment Exacerbations from Year Prior to Study (Part B) (Pharmacodynamic Outcome (PDo) Population) .............................................................................................
Table 2.47 Annualised Rate of On-Treatment Exacerbations Requiring Hospitalisation (Part B) (Pharmacodynamic Outcome (PDo) Population) .............................................................................................
Table 2.48 Annualised Rate of On-Treatment Exacerbations (Part B) [Excluding Subject (Pharmacodynamic Outcome (PDo) Population) ...................................................................................
Table 2.49 Summary of Reduction in On-Treatment Exacerbations from Year Prior to Study (Part B) [Excluding Subject (Pharmacodynamic Outcome (PDo) Population) ....................................
Table 2.50 Annualised Rate of On-Treatment Exacerbations Requiring Hospitalisation (Part B) [Excluding Subject (Pharmacodynamic Outcome (PDo) Population) ....................................
453
459
465
471
477
483
489
495
497
498
499
500
501
502
503
504
10
CONFIDENTIAL 2018N355937_00200363
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
-
SAFETY DATA SOURCE FIGURES-PART A ....................................................... Figure 3.1 Scatter Plot of Maximum Post-Baseline vs. Baseline for ALT (Part A)
(Safety Population) .................................................................................. Figure 3.2 Scatter Plot of Maximum ALT vs. Maximum Total Bilirubin (Part A)
(Safety Population) .................................................................................. SAFETY DATA SOURCE FIGURES-PART B .......................................................
Figure 3.3 Scatter Plot of Maximum Post-Baseline vs. Baseline for ALT (Part B) (Safety Population) ............................................................................
Figure 3.4 Scatter Plot of Maximum Post-Baseline ALT vs. Maximum Post-Baseline Total Bilirubin (Part B) (Safety Population) ..............................
SAFETY DATA SOURCE TABLES-PART A ........................................................ Table 3.1 Summary of Number of Treatments Administered and Time On-
Treatment (Part A) (Safety Population) .................................................... Table 3.2 Overview of All Adverse Events (Part A) (Safety Population) ................. Table 3.3 Summary of All On-Treatment Adverse Events by System Organ Class
(Part A) (Safety Population) ..................................................................... Table 3.4 Summary of All On-Treatment Adverse Events by System Organ Class
and Maximum Intensity (Part A) (Safety Population) ............................... Table 3.5 Summary of All Post-Treatment Adverse Events by System Organ
Class (Part A) (Safety Population) ........................................................... Table 3.6 Summary of All Post-Treatment Adverse Events by System Organ
Class and Maximum Intensity (Part A) (Safety Population) ..................... Table 3.7 Summary of On-Treatment Adverse Events by Overall Frequency (Part
A) (Safety Population) .............................................................................. Table 3.8 Summary of All On-Treatment Drug-Related Adverse Events by System
Organ Class (Part A) (Safety Population) ................................................ Table 3.9 Summary of All On-Treatment Drug-Related Adverse Events by System
Organ Class and Maximum Intensity (Part A) (Safety Population) .......... Table 3.10 Summary of On-Treatment Adverse Events by Highest Anti Drug
Antibody Result At Any Time Post Baseline (Part A) (Safety Population) Table 3.11 Summary of Post-Treatment Adverse Events by Highest Anti Drug
Antibody Result At Any Time Post Baseline (Part A) (Safety Population) .................................................................................................................
Table 3.12 Summary of Number of Subjects and Occurrences of Common On-Treatment Non-Serious Adverse Events by System Organ Class (Part A) (Safety Population) ..............................................................................
Table 3.13 Summary of Fatal Serious Adverse Events by System Organ Class (Part A) (Safety Population) .....................................................................
Table 3.14 Summary of Non-Fatal Serious On-Treatment Adverse Events by System Organ Class (Part A) (Safety Population) ...................................
Table 3.15 Summary of Non-Fatal Serious Post-Treatment Adverse Events by System Organ Class (Part A) (Safety Population) ...................................
Table 3.16 Summary of On-Treatment Serious Adverse Events by System Organ Class (Part A) (Safety Population) ...........................................................
Table 3.17 Summary of Post-Treatment Serious Adverse Events by System Organ Class (Part A) (Safety Population) ................................................
505
505
506507
507
508509
509510
511
515
526
528
534
537
539
545
551
554
562
563
564
565
566
11
CONFIDENTIAL 2018N355937_00200363
-
Table 3.18 Summary of Drug-Related Serious Adverse Events by System Organ Class (Part A) (Safety Population) ...........................................................
Table 3.19 Summary of Drug-Related Serious Adverse Events by System Organ Class and Maximum Intensity (Part A) (Safety Population) .....................
Table 3.20 Summary of Adverse Events Leading to Permanent Discontinuation of Study Treatment or Withdrawal from Study by Overall Frequency (Part A) (Safety Population) ..............................................................................
Table 3.21 Summary of Number of Subjects and Occurrences of On-Treatment Serious Adverse Events by System Organ Class and Preferred Term (Part A) (Safety Population) .....................................................................
Table 3.22 Summary of Systemic (non-allergic or allergic/hypersensitivity) Reactions (On-Treatment) (Part A) (Safety Population) ...........................
Table 3.23 Summary Profile of Systemic (non-allergic or allergic/hypersensitivity) Reactions (On-Treatment) (Part A) (Safety Population) ...........................
Table 3.24 Summary Profile of Systemic Allergic Reactions (On-Treatment) (Part A) (Safety Population) ..............................................................................
Table 3.25 Summary Profile of Systemic Non-Allergic Reactions (On-Treatment) (Part A) (Safety Population) .....................................................................
Table 3.26 Summary of Local Injection Site Reactions (On-Treatment) (Part A) (Safety Population) ..................................................................................
Table 3.27 Summary of Local Injection Site Reactions by Relation to IP (On-Treatment) (Part A) (Safety Population) ...................................................
Table 3.28 Summary Profile of Local Injection Site Reactions (On-Treatment) (Part A) (Safety Population) .....................................................................
Table 3.29 Summary of AEs meeting Anaphylaxis Criteria (On-Treatment) (Part A) (Safety Population) ..............................................................................
Table 3.30 Summary Profile of AEs meeting Anaphylaxis Criteria (On-Treatment) (Part A) (Safety Population) .....................................................................
Table 3.31 Summary of Serious Cardiac, Vascular and Thromboembolic Adverse Events (On-Treatment) (Part A) (Safety Population)................................
Table 3.32 Summary Profile of Serious Cardiac, Vascular and Thromboembolic Adverse Events (On-Treatment) (Part A) (Safety Population) .................
Table 3.33 Summary of Serious Ischemic AEs (On-Treatment) (Part A) (Safety Population) ...............................................................................................
Table 3.34 Summary Profile of Serious Ischemic AEs (On-Treatment) (Part A) (Safety Population) ..................................................................................
Table 3.35 Summary of Malignancies (On-Treatment) (Part A) (Safety Population) .................................................................................................................
Table 3.36 Summary Profile of Malignancies (On-Treatment) (Part A) (Safety Population) ...............................................................................................
Table 3.37 Summary of Opportunistic Infections (On-Treatment) (Part A) (Safety Population) ...............................................................................................
Table 3.38 Summary Profile of Opportunistic Infections (On-Treatment) (Part A) (Safety Population) ..................................................................................
Table 3.39 Summary of On-Treatment Serious AEs and AEs of Special Interest (Part A) (Safety Population) .....................................................................
567
568
570
571
574
575
578
581
582
583
584
587
588
589
590
591
592
593
594
595
596
597
12
CONFIDENTIAL 2018N355937_00200363
-
Table 3.40 Summary of All Cardiovascular Events Reported by the Investigator (Part A) (Safety Population) .....................................................................
Table 3.41 Summary of ADA Assay Results (Part A) (Safety Population) .............. Table 3.42 Summary of NAb Assay Results (Part A) (Safety Population) .............. Table 3.43 Summary of Treatment Emergent ADA Assay Results (Part A) (Safety
Population) ............................................................................................... Table 3.44 Summary of Change From Baseline in Chemistry Data (Part A)
(Safety Population) .................................................................................. Table 3.45 Summary of Chemistry Results (Change from Baseline Relative to the
Normal Range) (Part A) (Safety Population) ............................................ Table 3.46 Summary of Change From Baseline in Haematology Data (Part A)
(Safety Population) .................................................................................. Table 3.47 Summary of Haematology Results (Change from Baseline Relative to
the Normal Range) (Part A) (Safety Population) ...................................... Table 3.48 Summary of Subjects Meeting Emergent Hepatobiliary Laboratory
Abnormality Criteria (Part A) (Safety Population) ..................................... Table 3.49 Summary of ECG Findings (Part A) (Safety Population) ...................... Table 3.50 Summary of Change from Baseline ECG Values by Visit (Part A)
(Safety Population) .................................................................................. Table 3.51 Summary of Actual and Change From Baseline QTc(F) Values by
Category (msec) (Part A) (Safety Population) .......................................... Table 3.52 Summary of Actual and Change From Baseline QTc(B) Values by
Category (msec) (Part A) (Safety Population) .......................................... Table 3.53 Summary of Change from Baseline in Vital Signs (Part A) (Safety
Population) ............................................................................................... SAFETY DATA SOURCE TABLES-PART B ........................................................
Table 3.54 Summary of Number of Treatments Administered and Time On-Treatment (Part B) (Safety Population) ..................................................
Table 3.55 Overview of All Adverse Events (Part B) (Safety Population) .............. Table 3.56 Summary of All On-Treatment Adverse Events by System Organ
Class (Part B) (Safety Population) .......................................................... Table 3.57 Summary of All On-Treatment Adverse Events by System Organ
Class and Maximum Intensity (Part B) (Safety Population) .................... Table 3.58 Summary of All Post-Treatment Adverse Events by System Organ
Class (Part B) (Safety Population) .......................................................... Table 3.59 Summary of All Post-Treatment Adverse Events by System Organ
Class and Maximum Intensity (Part B) (Safety Population) .................... Table 3.60 Summary of On-Treatment Adverse Events by Overall Frequency
(Part B) (Safety Population) .................................................................... Table 3.61 Summary of All On-Treatment Drug-Related Adverse Events by
System Organ Class (Part B) (Safety Population) .................................. Table 3.62 Summary of All On-Treatment Drug-Related Adverse Events by
System Organ Class and Maximum Intensity (Part B) (Safety Population) .............................................................................................
598599600
601
602
619
653
674
716717
718
722
725
728731
731732
733
738
753
755
761
764
766
13
CONFIDENTIAL 2018N355937_00200363
-
Table 3.63 Summary of On-Treatment Adverse Events by Highest Anti Drug Antibody Result At Any Time Post Baseline (Part B) (Safety Population) .............................................................................................
Table 3.64 Summary of Post-Treatment Adverse Events by Highest Anti Drug Antibody Result At Any Time Post Baseline (Part B) (Safety Population) .............................................................................................
Table 3.65 Summary of Number of Subjects and Occurrences of Common On-Treatment Non-Serious Adverse Events by System Organ Class (Part B) (Safety Population) ....................................................................
Table 3.66 Summary of Fatal Serious Adverse Events by System Organ Class (Part B) (Safety Population) ....................................................................
Table 3.67 Summary of Non-Fatal Serious On-Treatment Adverse Events by System Organ Class (Part B) (Safety Population) ..................................
Table 3.68 Summary of Non-Fatal Serious Post-Treatment Adverse Events by System Organ Class (Part B) (Safety Population) ..................................
Table 3.69 Summary of On-Treatment Serious Adverse Events by System Organ Class (Part B) (Safety Population) ...............................................
Table 3.70 Summary of Post-Treatment Serious Adverse Events by System Organ Class (Part B) (Safety Population) ...............................................
Table 3.71 Summary of Drug-Related Serious Adverse Events by System Organ Class (Part B) (Safety Population) ...............................................
Table 3.72 Summary of Drug-Related Serious Adverse Events by System Organ Class and Maximum Intensity (Part B) (Safety Population) .........
Table 3.73 Summary of Adverse Events Leading to Permanent Discontinuation of Study Treatment or Withdrawal from Study by Overall Frequency (Part B) (Safety Population) ....................................................................
Table 3.74 Summary of Number of Subjects and Occurrences of On-Treatment Serious Adverse Events by System Organ Class and Preferred Term (Part B) (Safety Population) ....................................................................
Table 3.75 Summary of Systemic (Non-Allergic or Allergic/Hypersensitivity) Reactions (On-Treatment) (Part B) (Safety Population) .........................
Table 3.76 Summary Profile of Systemic (Non-Allergic or Allergic/Hypersensitivity) Reactions (On-Treatment) (Part B) (Safety Population) .............................................................................................
Table 3.77 Summary Profile of Systemic Allergic Reactions (On-Treatment) (Part B) (Safety Population) ....................................................................
Table 3.78 Summary Profile of Systemic Non-Allergic Reactions (On-Treatment) (Part B) (Safety Population) .................................................
Table 3.79 Summary of Local Injection Site Reactions (On-Treatment) (Part B) (Safety Population) .................................................................................
Table 3.80 Summary of Local Injection Site Reactions by Relation to IP (On-Treatment) (Part B) (Safety Population) .................................................
Table 3.81 Summary Profile of Local Injection Site Reactions (On-Treatment) (Part B) (Safety Population) ....................................................................
Table 3.82 Summary of AEs Meeting Anaphylaxis Criteria (On-Treatment) (Part B) (Safety Population) ....................................................................
773
780
783
793
794
795
796
797
798
799
800
801
803
804
809
814
815
816
817
818
14
CONFIDENTIAL 2018N355937_00200363
-
Table 3.83 Summary Profile of AEs Meeting Anaphylaxis Criteria (On-Treatment) (Part B) (Safety Population) .................................................
Table 3.84 Summary of Serious Cardiac, Vascular and Thromboembolic Adverse Events (On-Treatment) (Part B) (Safety Population) ................
Table 3.85 Summary Profile of Serious Cardiac, Vascular and Thromboembolic Adverse Events (On-Treatment) (Part B) (Safety Population) ................
Table 3.86 Summary of Serious Ischemic AEs (On-Treatment) (Part B) (Safety Population) .............................................................................................
Table 3.87 Summary Profile of Serious Ischemic AEs (On-Treatment) (Part B) (Safety Population) .................................................................................
Table 3.88 Summary of Malignancies (On-Treatment) (Part B) (Safety Population) .............................................................................................
Table 3.89 Summary Profile of Malignancies (On-Treatment) (Part B) (Safety Population) .............................................................................................
Table 3.90 Summary of Opportunistic Infections (On-Treatment) (Part B) (Safety Population) .................................................................................
Table 3.91 Summary Profile of Opportunistic Infections (On-Treatment) (Part B) (Safety Population) ............................................................................
Table 3.92 Summary of On-Treatment Serious AEs and AEs of Special Interest (Part B) (Safety Population) ....................................................................
Table 3.93 Summary of All Cardiovascular Events Reported by the Investigator (Part B) (Safety Population) ....................................................................
Table 3.94 Summary of ADA Assay Results (Part B) (Safety Population) ............ Table 3.95 Summary of NAb Assay Results (Part B) (Safety Population) ............. Table 3.96 Summary of Treatment Emergent ADA Assay Results (Part B)
(Safety Population) ................................................................................. Table 3.97 Summary of Change From Baseline in Chemistry Data (Part B)
(Safety Population) ................................................................................. Table 3.98 Summary of Chemistry Results (Change from Baseline Relative to
the Normal Range) (Part B) (Safety Population) ..................................... Table 3.99 Summary of Change From Baseline in Haematology Data (Part B)
(Safety Population) ................................................................................. Table 3.100 Summary of Haematology Results (Change from Baseline
Relative to the Normal Range) (Part B) (Safety Population) ................... Table 3.101 Summary of Subjects Meeting Emergent Hepatobiliary Laboratory
Abnormality Criteria (Part B) (Safety Population) ................................... Table 3.102 Summary of ECG Findings (Part B) (Safety Population) ................... Table 3.103 Summary of Change from Baseline ECG Values by Visit (Part B)
(Safety Population) ................................................................................. Table 3.104 Summary of Actual and Change From Baseline QTc(F) Values by
Category (msec) (Part B) (Safety Population) ........................................ Table 3.105 Summary of Actual and Change From Baseline QTc(B) Values by
Category (msec) (Part B) (Safety Population) ........................................ Table 3.106 Summary of Change from Baseline in Vital Signs (Part B) (Safety
Population) .............................................................................................
819
823
824
825
826
827
828
829
830
834
835836837
838
839
856
890
932
974975
976
982
984
986
15
CONFIDENTIAL 2018N355937_00200363
-
CONFIDENTIAL 2018N355937_00200363
8
ABBREVIATIONS
ACQ Asthma Control QuestionnaireADA Anti-drug antibodyAE(s) Adverse event(s)AESI(s) Adverse event(s) of special interestALT Alanine aminotransferaseASE All Subjects EnrolledAST Aspartate aminotransferaseAUC(0-inf) Area under the concentration-time curve from time zero (pre-
dose) extrapolated to infinite timeBID Twice dailyBSV Between-subject variabilityBWT BodyweightC-ACT Childhood Asthma Control TestCav Average concentrationCFR Code of Federal RegulationsCI Confidence intervalCL Systemic plasma clearanceCL/F Apparent plasma clearance after extravascular (e.g.,
subcutaneous) administrationCmax Maximum plasma concentrationCmax ss Maximum plasma concentration at steady stateCPSR Clinical pharmacology study reportCS CorticosteroidsCVT Cardiac, vascular, thromboembolicDPI Dry powder inhalereCRF(s) Electronic case report form(s)FEV1 Forced expiratory volume in 1 secondfL FemtolitresFOCEI First order conditional estimation with interactionFVC Forced vital capacityGCP(s) Good Clinical Practice(s)GSK GlaxoSmithKlineICH International Council for Harmonisation of Technical
Requirements for Registration of Pharmaceuticals for Human Use
ICS Inhaled corticosteroidsIg ImmunoglobulinIL-5 Interleukin-5IRB Institutional Review BoardIV IntravenousKA Absorption rate constantkg Kilogramµg MicrogramµL MicrolitremAb(s) Monoclonal antibody(ies)mcg Microgram
16
-
CONFIDENTIAL 2018N355937_00200363
9
MedDRA Medical Dictionary for Regulatory Activitiesmg MilligramsmL Millilitremsec MillisecondNPDE Normal Prediction Distribution ErrorOCS Oral corticosteroidsPD Pharmacodynamic(s)PDe Pharmacodynamic (Blood Eosinophils)PDo Pharmacodynamic (Outcome Assessments)pg PicogramPK Pharmacokinetic(s)PK/PD Pharmacokinetic/pharmacodynamicPT Preferred termQC Quality controlQTc corrected QT intervalQTcB QT interval corrected for heart rate according to Bazett’s
formulaQTcF QT interval corrected for heart rate according to Fridericia’s
formulaRAP Reporting and Analysis PlanSAE(s) Serious adverse event(s)SC SubcutaneousSD Standard deviationSOC System Organ Classt½ Terminal-phase elimination half-lifeTmax Time to reach maximum plasma concentrationULN Upper limit of normalUK United KingdomUS United StatesV Volume of distribution
Trademark Information
Trademarks of the GlaxoSmithKline group of companies
Trademarks not owned by the GlaxoSmithKline group of companies
NUCALA™ NONMEMSASXolair
17
-
CONFIDENTIAL 2018N355937_00200363
10
ETHICS AND GOOD CLINICAL PRACTICE
The study protocol, any amendments, the informed consent, and other information that required pre-approval were reviewed and approved by a national, regional, or investigational center ethics committee or institutional review board, in accordancewith the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) and applicable country-specific requirements, including US 21 Code of Federal Regulations (CFR) 312.3(b) for constitution of independent ethics committees. Ethics committee or institutional review board approvals are maintained in the Sponsor’s study file.
Investigators were trained to conduct the study in accordance with GCPs and the study protocol, as defined in ICH E3, Section 9.6. Written commitments were obtained from investigators to conduct the study in accordance with ICH GCP and all applicable subject privacy requirements, and the ethical principles that are outlined in the Declaration of Helsinki (2013), and to conduct the study in accordance with the protocol.
The study was monitored in accordance with ICH E6, Section 5.18. If significant findings (e.g., potential serious misconduct or noncompliance with GCP, including potential Serious Breaches) were identified during monitoring or auditing of a site, these are presented in either Section 5.1.2 (Protocol Deviations [Part A]) or Section 6.1.2(Protocol Deviations [Part B]) of this report.
Written informed consent was obtained from the parent(s)/guardian of each subject prior to the performance of any study-specific procedures. If applicable, informed assent was obtained from the subject. The investigator agreed to provide the parent(s)/guardian and subject as much time as necessary to review the document, to inquire about details of the trial, and to decide whether or not to participate in the study. The informed consent was signed and dated by the parent(s)/guardian of the study subject and by the person who conducted the informed consent discussion. The informed assent was signed and dated by the study subject and by the person who conducted the informed assent discussion, where deemed appropriate and local regulations allowed. Electronic case report forms (eCRFs) were provided for each subject’s data to be recorded.
18
-
CONFIDENTIAL 2018N355937_00200363
11
1. INTRODUCTION
In the western world, asthma is the most prevalent disorder in school-age children, with an incidence of 5% to 8% [CDC, 2013]. A small subset of this population, approximately 5% [Bossley, 2012], are considered to have severe asthma; these children are often unable to lead a normal life (see Protocol Section 2.2.1). Significant asthma exacerbations also carry increased healthcare costs. Despite the significant health and economic impact of severe asthma in children, there has been a paucity of new classes of medications developed for this condition, with only 2 new classes of medications being introduced in the past two decades: anti-leukotrienes and anti-immunoglobulin E. There is, therefore, a significant unmet need for new medications to provide asthma control in severe childhood asthma.
Mepolizumab (Nucala™) is a humanised immunoglobulin (Ig)G1 monoclonal antibody (mAb) that exhibits dose-proportional and time-independent pharmacokinetics (PK) (see Protocol Section 2.2.2). MAbs tend to be highly specific and, therefore, are less likely to present off-target toxicity, resulting in a wide therapeutic index. Their PK across age-groups is generally consistent once body-size is taken into account [Xu, 2013]. Based on these characteristics, mAbs are an ideal class of medication for extrapolation of safety and efficacy data from adults and adolescents to children.
Data from mepolizumab preclinical and clinical development demonstrate the ability of mepolizumab to inhibit interleukin (IL)-5 and, consequently, treat inflammatory conditions linked to an eosinophilic signal, such as asthma in subjects predisposed to exacerbations.
Three randomised, double-blind, placebo-controlled trials have investigated the efficacy, tolerability, PK and pharmacodynamics (PD) of mepolizumab administered intravenously or subcutaneously, in subjects aged 12 years and older with severe eosinophilic asthma [Pavord, 2012, Bel, 2014, Ortega, 2014]. Additionally, a randomised, double-blind trial with IV mepolizumab administration to treat eosinophilic oesophagitis, in children aged 2 to 17 years has been conducted [GlaxoSmithKline Document Number RM2009/00093/00, Study MEE103219]. However, until the conduct of the study described in this report, no trial had been conducted with mepolizumab in children aged less than 12 years old with severe eosinophilic asthma. Futhermore, SC mepolizumab had never been administered to children aged less than 12 years old with any condition.
The primary aim of Part A of this Phase II study was to characterise the PK and PD of mepolizumab and the primary aim of Part B was to assess the long-term (52 weeks) safety and tolerability of mepolizumab, to provide support for its use in children aged 6 to 11 years old with severe eosinophilic asthma.
This study ultimately supports an extrapolation strategy of the safety and efficacy data observed in the adult and adolescent population with severe eosinophilic asthma, in the 3 randomised trials, to this paediatric population. With therapeutic proteins, such as the mAb mepolizumab, it is common to extrapolate the results of adult studies to paediatric subjects in consideration of the PK properties of such molecules [Xu, 2013]. This approach permits a more efficient, streamlined development programme for this age
19
-
CONFIDENTIAL 2018N355937_00200363
12
group and minimises the need for large, redundant clinical trials in this subset of patients, where the prevalence of the disease phenotype is low. This study also assessed the safety, tolerability and immunogenicity of mepolizumab in children aged 6 to 11 years old, along with clinical outcome measures, including the Asthma Control Questionnaire (ACQ)-7 [Juniper, 1999, Juniper, 2005, Juniper, 2006] and the Childhood Asthma Control Test (C-ACT) (see Protocol Section 2.1).
2. STUDY OBJECTIVES & ENDPOINTS
This study was performed in 2 parts; Part A (Week 0 to Week 20) and Part B (Week 20 to Week 80). Part A completed on 07-Dec-2016. Part B completed on 31-Jan-2018.
Pharmacokinetic/pharmacodynamics phase (Part A)
Objectives EndpointsPrimary
To characterise the PK of mepolizumab administered subcutaneously to subjects aged 6 to 11 years old with severe eosinophilic asthma
Population-PK model derived estimates of clearance, area under the plasma-concentration time curve to infinity (AUC[0-inf]), maximum plasma concentration (Cmax), and terminal phase elimination half-life (t½) of mepolizumab
To characterise the PD of mepolizumab administered subcutaneously to subjects aged 6 to 11 years old with severe eosinophilic asthma
Change from baseline in absolute blood eosinophil count at Week 12
Secondary
To compare the bodyweight-adjusted clearance between adults and subjects aged 6 to 11 years old with severe eosinophilic asthma when mepolizumab is administered subcutaneously
Bodyweight-adjusted clearance estimates obtained by population-PK methods.
To characterise asthma control following SC administration of mepolizumab to subjects aged 6 to 11 years old with severe eosinophilic asthma
Change from Baseline in ACQ-7 measured at Week 12
Change from Baseline in ACQ-7 measured at Weeks 4, 8, 16 and 20
Change from Baseline in C-ACT measured at Week 12
Change from Baseline in C-ACT measured at Weeks 4, 8, 16 and 20
20
-
CONFIDENTIAL 2018N355937_00200363
13
Objectives Endpoints
To assess the safety and tolerability of mepolizumab when administered subcutaneously to subjects aged 6 to 11 years old with severe eosinophilic asthma
Incidence of adverse events (AEs)
Incidence of clinically significant changes in clinical laboratory parameters
Frequency of positive anti-mepolizumab binding antibodies and neutralising antibodies
Incidence of clinically significant changes in vital sign measurements
Exploratory
To assess the number of asthma exacerbations that occur during the study following SC administration of mepolizumab to subjects aged 6 to 11 years old with severe eosinophilic asthma
Number of asthma exacerbations that occur while on treatment (Week 0 to Week 12).
Number of asthma exacerbations that occur on-treatment and post-treatment (Week 0 to Week 20)
To assess forced expiratory volume in 1 second (FEV1) following SC administration of mepolizumab to subjects aged 6 to 11 years old with severe eosinophilic asthma
Change from Baseline in FEV1 measured at Week 12
Long-term safety/long-term pharmacodynamics phase (Part B)
Objectives EndpointsPrimary
To assess the long-term (52 weeks) safety and tolerability of mepolizumab when administered subcutaneously to subjects aged 6 to 111 years old with severe eosinophilic asthma
Incidence of AEs
Frequency of positive anti-mepolizumab binding antibodies and neutralising antibodies
Incidence of clinically significant changes in vital sign measurements
Incidence of clinically significant changes in clinical laboratory parameters
Secondary
To characterise the long-term (52 weeks) durability of PD of mepolizumab administered subcutaneously to subjects aged 6 to 111 years old with severe eosinophilic asthma
Change from Week 0 (Visit 2) in absolute blood eosinophil count at weeks 32, 44, 56, 68, 72 and 802.
21
-
CONFIDENTIAL 2018N355937_00200363
14
Objectives EndpointsExploratory
To assess the number of asthma exacerbations that occur during the long-term (52 weeks) part of the study following subcutaneous administration of mepolizumab to subjects aged 6 to 111 years old with severe eosinophilic asthma
Incidence of asthma exacerbations
To characterise the long-term (52 weeks) asthma control following subcutaneous administration of mepolizumab to subjects aged 6 to 111 years old with severe eosinophilic asthma
Change from Week 0 (Visit 2) in ACQ-7 and C-ACT at weeks 32, 44, 56, 68, 72 and 802.
1. Subjects who reached their 12th birthday during Part A could have participated in Part B. 2. Week 80 was not applicable to subjects transitioning to the long-term access programme.
3. INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE
Part A of this study was conducted at 13 centres; 3 in Japan, 2 in Poland, 6 in the United Kingdom (UK) and 2 in the United States (US) (Source Data: Table 1.5). The first subject was enrolled into Part A on 25-Aug-2015 (first observation on the database) and the last subject completed Part A on 07-Dec-2016 (last observation on the database for Part A).
Part B of this study was conducted at 12 centres; 4 in Japan, 2 in Poland, 4 in the UK and 2 in the US (Source Data: Listing 57). The first subject was enrolled into Part B on 26-Jan-2016 (first observation on the database for Part B) and the last subject completed Part B on 31-Jan-2018 (last observation on the database).
22
-
CONFIDENTIAL 2018N355937_00200363
15
Table 1 Study Conduct
Name and Address Role/ResponsibilitiesEthics Committee/IRB Fukuyama City Hospital, 5-23-1,
Zao-Cho, Fukuyama-City, Hiroshima, 721-8511, JapanNational Hospital Organisation, Central Review Board2-5-21, Higashigaoka, Meguro-ku, Tokyo, 152-8621, JapanKomisja Bioetyczna przy Dolnoslaskiej Izbie Lekarskiej, ul. Kazimierza Wielkiego 45, Wroclaw, 50-077, PolandWestern IRB 1019 39th Avenue SE, Puyallup, Washington, 98374, USChesapeake IRBSuite 110, 6940 Columbia Gateway Drive, Columbia, Maryland, 21046-3431, USCentral London Research Ethics Committee 2Research Ethics Committee Offices, South House, Block A, Room 7-12, Pond Street, London, NW3 2QG, UKNRES Committee London BloomsburyThe Institute of Child Health, The Wolfson Centre, Room D, Mecklenburgh Square, London, WC1N 2AD, UKNRES Committee London BloomsburyHRA NRES Centre Manchester,Barlow House, 3rd Floor, 4 Minshull Street, Manchester, M1 3DZ, UK
Contract Reseach Organisations/Companies and activities outsourced
QuanticateBevan House, Bancroft Court, Bancroft, Hitchin, Hertfordshire, SG5 1LH, UK
Statistics
Focus Diagnostics Incorporated, (d/b/a Quest Diagnostics), 5785 Corporate Avenue, Cypress, California, 90630, US
Laboratory assessments
23
-
CONFIDENTIAL 2018N355937_00200363
16
Name and Address Role/ResponsibilitiesQ Squared Solutions Private Limited, 79 Science Park Drive, #04-08 Cintech IV, Singapore Science Park One, 118264, Singapore
Laboratory assessments
Q2 Solutions125-135 Staines Road, Hounslow, Middlesex, TW3 3JB, UK
Central Laboratory for Part A and laboratory assessments for Part B
Quest Diagnostics Nichols Institute, 33608 Ortega Highway, San JuanCapistrano, California, 92675-2042,US
Laboratory assessments
Quest Diagnostics Nichols Institute, Suite 2E, 27027 Tourney Road, Valencia, California, 91355, US
Laboratory assessments
Tan Tock Seng Hospital, Department of Laboratory Medicine, Level 2, Podium Block,11 Jalan Tan Tock Seng, 308433, Singapore
Laboratory assessments
Quest Diagnostics Limited, Unit B1, Parkway West Industrial Estate, Cranford Lane – Heston, Middlesex, TW5 9QA, United Kingdom
Laboratory assessments
Q Squared Solutions-Edinburgh, The Alba Campus, Rosebank EH54 7EG, Livingston, Scotland
Laboratory assessments
Accenture Life Sciences, 1160 West Swedesford Road, Berwyn, PA 19312
Conversion of data to SDTM
Alliance Pharma, Inc.17 Lee Boulevard, Malvern, PA 19355, US
Plasma analysis, ADA and IL5 analysis for Part A and laboratory assessments for Part B
GSKUpper Merion, 709 Swedeland Road, King of Prussia, PA 19406, USA
NAb analysis
eResearch TechnologyPeterborough Business Park, Lynchwood, Peterborough, Cambridgeshire, PE2 6FZ, UK
Centralised ECG services
TCSMillennium Business Park, Waterfall Plaza, Building No.4/303, Sector 2, Mahape, Navi Mumbai, 400 710
Data management
24
-
CONFIDENTIAL 2018N355937_00200363
17
Name and Address Role/Responsibilities
Complete Regulatory Writing, McCann Complete Medical Group Limited, 19-21 King Edward Street, Macclesfield, SK10 1AQ, UK
Medical writing, CPSR authorship
MonitorUpper Providence UP1210, 1250 South Collegeville Road, Collegeville, PA 19426-0989, US
Medical monitor, clinical expert
Stockley Park West, 1-3 Ironbridge Road, Uxbridge, Middlesex, UB11 1BT, UK
Back-up monitor
See the Modular Appendices for the list of investigators.
4. INVESTIGATIONAL PLAN
4.1. Study Design
This was a multi-centre, open-label, repeat dose study of mepolizumab in subjects with severe eosinophilic asthma, aged 6 to 11 years.
This study consisted of 2 phases:
Part A (pharmacokinetic/pharmacodynamic [PK/PD] phase) consisted of Pre-Screening/Screening/Run-in, 12-week treatment period and 8-week follow-up period;
Part B (long-term safety/PD phase) consisted of a 52-week long-term treatment period and 8-week follow-up period.
On completion of Part B, subjects were offered entry into the long-term access programme until mepolizumab becomes commercially available for this age group, within the subject’s participating country. The Part B follow-up period was not required for subjects transitioning to the long-term access programme.
4.1.1. Pharmacokinetic/Pharmacodynamic Design (Part A)
The PK and PD of either mepolizumab, 40 or 100 mg (depending on subject bodyweight), administered SC once every 4 weeks, for a total duration of 12 weeks, to subjects aged 6 to 11 years with severe eosinophilic asthma, were assessed.
25
PPD
PPD
PPD
-
CONFIDENTIAL 2018N355937_00200363
18
Approximately 40 male or female subjects were to be screened to achieve approximately 28 eligible subjects entering the treatment phase, to allow for availability of 20 evaluable subjects; a minimum of 6 subjects were to be enrolled in the
-
CONFIDENTIAL 2018N355937_00200363
19
Figure 1 Study Design Schematic Pharmacokinetic/Pharmacodynamic Phase (Part A)
4.1.2. Long-Term Safety/Pharmacodynamic Phase (Part B)
This was a long-term safety/PD phase, in which extended treatment for a further 52 weeks was offered on an optional basis to those subjects eligible for continued treatment.
At the end of Part A, a benefit/risk assessment was performed by the Investigator and, if this assessment supported continued therapy with mepolizumab, the subject could continue into Part B of the study following the Part A Follow-up (Visit 8).
Those subjects meeting the eligibility criteria for Part B at Visit 9 received mepolizumab 40 or 100 mg SC, (depending on subject bodyweight measured at Visit 9; 40 mg for subjects
-
CONFIDENTIAL 2018N355937_00200363
20
regarded as having completed Part B if they completed all phases of Part B (Long-Term Treatment and Follow-up). Subjects who transitioned to the long-term access programmewere regarded as having completed Part B if they completed all of the treatment phase of Part B.
4.1.3. Analysis
A complete analysis of Part A data was planned at the completion of the follow-up visit (Week 20) of the PK/PD phase of this study. All electronic case report form (eCRF) data were to be monitored, queried, and a soft-database lock performed on all subject data through Visit 8, following the last subject achieving Visit 8. Statistical outputs were to be prepared in accordance with all study objectives and endpoints for Part A.
A complete analysis of Part B data was planned at the completion of the follow-up visit (Visit 23, Week 80) of the long-term safety/PD phase of this study. All eCRF data were to be monitored, queried, and a database lock performed on all subject data through Visit 23, following the last subject achieving Visit 23. Statistical outputs generated after completion of Part A were not reproduced on completion of Part B.
4.2. Discussion of Study Design
This study was designed to characterise the PK and PD of mepolizumab, as an add-on to best standard of care, in children aged 6 to 11 years with severe eosinophilic asthma. The study also assessed safety, tolerability and immunogenicity of mepolizumab in this population along with clinical outcome measures, the ACQ-7 and the C-ACT. These data will support the extrapolation of the safety and efficacy data observed in the adult/adolescent population to this paediatric population. Due to the low prevalence of this particular disease phenotype, conducting a large efficacy trial would prove challenging. Therefore, the design of this study aimed to balance the challenging access to the target paediatric population, and the study constraints, with the scientific evidence to support the use of mepolizumab in this population.
The study population reflects the intended population for therapeutic use, to support the extrapolation strategy, and a treatment phase duration of 12 weeks was considered sufficient to support the primary PK and PD endpoints of the study. A dose ranging PK/PD study (GlaxoSmithKline Document Number 2011N115942_01, Study MEA114092), of comparable duration, conducted in adult asthmatic subjects with elevated blood eosinophil levels demonstrated concordance in the blood eosinophil reduction at 12 weeks with that observed following a 12-month duration treatment period in a Phase II/III study [Pavord, 2012], thus confirming the suitability of the 12 weeks treatment duration for the chosen endpoints (see Protocol Section 4.4 for more detail). Subjects were followed-up for a total of 12 weeks after the last dose in Part A, which was consistent with the follow-up duration in adult studies.
Based on the subject’s bodyweight, mepolizumab doses of 40 mg (weight
-
CONFIDENTIAL 2018N355937_00200363
21
programme. This SC dose of 100 mg in adults was previously shown to be efficacious and well tolerated, and the bodyweight adjusted doses of 40 mg or 100 mg were expected to confer clinical activity in the 6 to 11 years age group (see Protocol Section 4.5 for more detail).
Since blood eosinophil count is consistently reduced following mepolizumab administration in adults, and in paediatric subjects with eosinophilic oesophagitis, blood eosinophil count was considered a suitable PD endpoint for evaluation.
A secondary objective of the study was to compare the bodyweight-adjusted clearance (CL) between adults and subjects aged 6 to 11 years old, to further support the extrapolation strategy.
To minimise the blood sample collection in this paediatric population and to take into consideration the constraint of the trial, sparse blood sampling collection was implemented (see the Time and Events table [Attachment 1]). The study design robustness was established by conducting simulations of different scenarios, which varied the number of subjects included in the trial and evaluated different PK sampling schemes (see Protocol Section 4.4 and Section 9.2 for more detail).
The long-term safety and tolerability of mepolizumab in children, aged 6 to 11 years, with severe eosinophilic asthma has not been determined in Part A of this study. The extended treatment phase (52 weeks) in Part B of this study collected long-term data, which allowed assessment of the durability of the PD response to mepolizumab in this paediatric population.
4.3. Protocol Amendments
The original protocol was approved on 14 December 2014. To date, there have been 5 amendments to the Protocol (Table 2). All 5 protocol amendments apply to all countries participating in the study. Amendments 1 to 4 became effective during Part A of the study and Amendment 5 became effective after completion of Part A of the study and only applied to Part B.
29
-
CONFIDENTIAL 2018N355937_00200363
22
Table 2 Protocol Amendments
Amendment Number (date)/Study Timing
Changes to the Protocol
Amendment 1(10-Jun-2015)
Initiated before the start of enrolment
C-ACT questionnaire to assess asthma control was added. Permission given to allow the use of the ACQ tool to be administered
in each country for which there was a validated translation available. Use of the National Health and Nutrition Examination Survey III was
replaced with the use of the Global Lung Function Initiative 2012 equations [Quanjer, 2012] to estimate FEV1 predicted values.
Copies of the ACQ questionnaires (ACQ-7 and ACQ-IA) and the C-ACT questionnaire were appended to the Protocol.
Clarification that blood samples will be stored for up to 15 years after the end of the study.
Amendment 2(30-Sep-2015)
Initiated after the start of enrolment
To permit extended mepolizumab treatment for a minimum of 52 weeks upon completion of the PK/PD phase (Part A).
Long-term safety (52 weeks) was added as the primary objective for this extended treatment phase (Part B).
Long-term PD response was added as the secondary objective for Part B.
A Time and Events table was added to specify the assessments and procedures to be conducted during Part B.
Amendment made to Section 9.3.2 of the Protocol to specify a pre-planned analysis to report results of the initial PK/PD phase (Part A) upon completion of all required assessments for all subjects in Part A.
Section 9.5 was added to the Protocol to define the primary and secondary analysis plans for the extended treatment phase (Part B).
Amendment 3(30-Mar-2016)
Initiated after the start of enrolment
Guidance added regarding the post-SC administration monitoring of subjects.
Clarification provided regarding the doses received in the Treatment Arms during Part A (including dose adjustment when subjects exceeded 40 kg in Part B only).
Clarification given that sample size is not determined for Part B and that all subjects completing Part A, who meet the eligibility criteria for Part B, are eligible for Part B.
Inclusion Criteria for Part A amended: To clarify that inclusion criterion 4 is in-line with Global Initiative for Asthma 2015 guidelines for treatment of 6-11 year olds. The 200363 study was designed to assess the PK of mepolizumab in children aged 6-11 years with severe eosinophilic asthma with 2 or more exacerbations in the past year, despite Step 4 therapy, a population similar to the adolescent/adult programme. However, initially the inhaled corticosteroid (ICS) inclusion criteria required high-dose ICS (≥400 µg/day) which, while a similar ICS dose strength category to the adult inclusion criteria in Study MEA115588, was a higher dose strength category than that required for adolescents (at least medium
30
-
CONFIDENTIAL 2018N355937_00200363
23
Amendment Number (date)/Study Timing
Changes to the Protocol
dose ICS plus additional controller). The inclusion criteria were amended to be consistent with the adolescent criteria in Study MEA115588 and require, at a minimum, Step 4 therapy: medium dose ICS (fluticasone proprionate dry powder inhaler [DPI] >200 µg/day in children aged 6 to 11 years) plus an additional controller. With this approach, all children uncontrolled on Step 4 therapy (medium or high dose ICS plus an additional controller) were eligible for mepolizumab in Study 200363.
Inclusion of an exclusion criterion for Positive Hepatitis B Surface Antigen or positive Hepatitis C antibody at Visit 1.
Addition of the “Exit Visit” for Part A to the list of visits at which a urine pregnancy test was performed.
Clarification that FEV1 predicted should be calculated using the Quanjer, 2012 equations.
Clarification that the Early Withdrawal Visit should be completed for subjects withdrawing from the study.
Amendment 4(05-May-2016)
Initiated after the start of enrolment
Correction to an error made in Protocol Amendment 3 when text was deleted from Inclusion Criterion 4 in error.
Amendment 5(18-Jan-2017)
Initiated after the completion of Part A
Clarification that Part B Follow-up was not required for subjects transitioning to the long-term access programme.
Clarification provided for the term ‘completed subject’. Confirmation was provided regarding when the Secondary and
Exploratory Endpoints in Part B were measured from (Visit 2 [Week 0] in Part A instead of Visit 9 [Week 20] in Part B).
Clarification that Secondary and Exploratory Endpoints were to be measured at Week 80 only for subjects that did not transition to the long-term access programme.
Confirmation that only ‘total’ IgE was measured in this study.
4.4. Selection of Study Population
4.4.1. Inclusion/Exclusion Criteria
Key inclusion/exclusion criteria are noted below (see Protocol Section 5.1, Section 5.2and Section 5.3 for additional details).
31
-
CONFIDENTIAL 2018N355937_00200363
24
4.4.1.1. Inclusion Criteria (Part A)
A subject was eligible for inclusion in this study only if all of the following criteria applied:
1. Subjects were between 6 and 11 years of age inclusive, at the time of screening.
2. Subjects had been diagnosed with severe asthma, defined by regional asthma guidelines, for at least 1 year.
3. Subjects had eosinophilic airway inflammation that was related to asthma characterised as eosinophilic in nature, as indicated by:
Elevated peripheral blood eosinophil count of 300 cells/µL demonstrated within 12 months of screening or
Elevated peripheral blood eosinophil