Conditions: Asthma
Keywords: pharmacokinetics pediatric Mepolizumab subcutaneous eosinophilic asthma pharmacodynamics
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 36
Healthy volunteers: no

Brief summary:
Mepolizumab is a humanized immunoglobulin G (IgG1) monoclonal antibody (mAb) that exhibits dose proportional and time-independent pharmacokinetics. The study will be conducted in 2 parts. Part A: it will be pharmacokinetic (PK) and pharmacodynamic (PD) study conducted to support the use of mepolizumab in children aged 6 to 11 years with severe eosinophilic asthma and characterize the PK/PD of mepolizumab 40 milligrams (mg) or 100 mg administered subcutaneously depending on participant body weight. Part B: It is a long-term safety / pharmacodynamic phase in which extended treatment for a further 52 weeks will be offered on an optional basis to those subjects eligible for continued treatment. Participants with bodyweight \<40 kilogram (kg) will be dosed with mepolizumab 40 mg and participants with body weight \>=40 kg will be dosed with mepolizumab 100 mg subcutaneously in upper arm or thigh at Visit 2 (Week 0). Approximately 40 male or female participants aged 6 to 11 years will be screened to achieve approximately 28 eligible participants entering the treatment phase to allow availability of 20 evaluable participants, with a minimum of six participants enrolled in the \<40 kg bodyweight group. The total duration of the study will be 22 weeks and will include a run-in period of 1-2 weeks, a treatment period of 12 weeks and a follow-up phase of 8 weeks. A participant will be considered having completed the study if the participant completes all phases of the study including the follow-up phase (Week 20 \[visit 8\]).

Detailed description:

Arms:
arm 1: Participants with bodyweight \< 40 kg will receive 0.4 milliliter (mL) of reconstituted mepolizumab subcutaneously, in upper arm or thigh. arm 2: Participants with bodyweight \>= 40 kg will receive 1.0 mL of reconstituted mepolizumab subcutaneously, in upper arm or thigh.

Interventions: intervention 1: Mepolizumab
Intervention descriptions: intervention 1: Mepolizumab is supplied as 100 mg lyophilised cake in sterile vials for subcutaneous administration in upper arm or thigh. The vial will be reconstituted with sterile water for injection prior to individual use.

Protocol document:
Prot_000.pdf: 
2014N216964_05
CONFIDENTIAL
The GlaxoSmithKline group of companies
200363
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
An open-label study to characterize the pharmacokinetics and 
pharmacodynamics of mepolizumab administered 
subcutaneously in children from 6 to 11 years of age with severe 
eosinophilic asthma
Compound Number:
SB-240563
Development Phase:
II
Effective Date:
18-JAN-2017
Protocol Amendment Number:  05
Author (s):
 
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
2017N314087_00
PPD


2014N216964_05
CONFIDENTIAL
The GlaxoSmithKline group of companies
200363
2
Revision Chronology
GlaxoSmithKline 
Document Number
Date
Version
2014N216964_00
2014-DEC-14
Original
2014N216964_01
2015-JUN-10
Amendment No. 1
1. Addition of the C-ACT questionnaire to assess asthma control
2.  To allow of the use of the ACQ tool to be administered in each country for which 
there is a validated translation available
3.  Use of the Global Lung Function Initiative 2012 equations by Quanjer (2012) to 
estimate FEV1 predicted values in place of NHANES III
4.  To correct typographical errors in the Time and Events Table 3, to remove the 
reference to “fasting” in Table 4 and to update the name of the central laboratory manual 
in Section 7.2.6
5.  To remove reference to the “pharmacy manual” and to clarify that all instructions for 
preparing Investigational Product are provided in the “Study Reference Manual”
6.  To add a copy of the ACQ-7 questionnaire to Appendix 12.5
7. To add a copy of the ACQ-IA questionnaire to Appendix 12.6
8.  To add a copy of the C-ACT questionnaire to Appendix 12.9
9.  To clarify that a draft version of the ACQ-IA may be used until a final linguistically 
validated version becomes available
10. To clarify that blood samples will be stored for up to 15 years after the end of the 
study.
2014N216964_02
2015-SEP-30
Amendment No. 2
1.  To change the details of the Primary and Secondary Medical Monitors for the study.
2.  To permit extended mepolizumab treatment for a minimum of 52 weeks upon 
completion of the pharmacokinetic/pharmacodynamic phase (Part A) of the protocol.
3.  To add long-term safety (52 weeks) as the primary objective for the extended 
treatment phase (Part B). 
4.  To add long-term pharmacodynamic response as a secondary objective for the 
extended treatment phase. 
5.  To add a Time & Events table (Table 4) to specify assessments and procedures to be 
conducted during the extended treatment phase. 
6.  To amend Section 9.3.2 to specify a pre-planned interim analyses to report results of 
the initial pharmacokinetic/pharmacodynamic phase upon completion of all required 
assessment for all subjects. 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
The GlaxoSmithKline group of companies
200363
3
7.  To add Section 9.5 to define the primary and secondary analysis plans for the 
extended treatment phase.
2014N216964_03
2016-MAR-30
Amendment No. 3
1.
Protocol Synopsis, Treatment Arms and Duration, Part A Treatment:  To add 
guidance regarding the capabilities required at site during post-SC administration 
monitoring of subjects.
2.
Protocol Synopsis, Treatment Arms and Duration, Part A Treatment:  to clarify that 
subjects will receive either 40mg or 100mg study medication during Part A
3.
Protocol Synopsis, Treatment Arms and Duration, Part B Treatment:  to clarify that 
subjects will have their treatment dose adjusted to 100mg from the time their bodyweight 
reaches 40kg
4.
Section 4, Study Design Part A Treatment:  to clarify that subjects will receive either 
40mg or 100mg study medication during Part A
5.
Section 4:  Study Design.  To clarify that the Time and Events Table includes both 
Table 3 and Table 4
6.
Section 4 Part A Follow-up:  To change “positive neutralizing antibody” to “positive 
anti-mepolizumab antibody” and to clarify the timeline for obtaining a repeat sample
7.
Section 4:  To clarify that subjects should be monitored for 1 hour post-dose during 
Part A only and thereafter monitoring in Part B will be according to standard practice at 
the site and to give guidance regarding the capability requirements at site during this 
monitoring.
8.
Section 4.3:  Type and number of subjects. To clarify that sample size is not 
determined for Part B and that all subjects completing Part A are eligible for Part B.
9.
Section 5.1 Inclusion Criteria for Part A:  To clarify the inclusion criterion 4 in-line 
with GINA 2015 guidelines for treatment of 6-11 year olds.
10. Section 5.1  Inclusion Criteria for Part A: To update inclusion criterion 7 in-line with 
inclusion criterion 4
11. To include an exclusion criterion for Positive Hepatitis B Surface Antigen or positive 
Hepatitis C antibody at Visit 1
12. Section 5.1:  To correct an omission in inclusion criterion 9 and add the “Exit Visit” 
for Part A to the list of visits at which a urine pregnancy test is performed
13. Section 5.1:  Inclusion Criteria Part A:  To clarify that FEV1 predicted should be 
calculated using the Quanjer 2012 equations.
14. Section 5.5 Withdrawal/Stopping Criteria:  To clarify that the Early Withdrawal Visit 
should be completed for subjects withdrawing from the study.
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
The GlaxoSmithKline group of companies
200363
4
15. Section 6.2:  Preparation of Investigational Product (Part A and Part B):  To clarify 
that the assigned dose will remain the same throughout Part A only.
16. Section 6.2 Dosage and Administration:  To clarify that treatment numbers will not 
be generated for this study
17. Section 6.8, Treatment after completion of Part A and Part B:  To remove the 
reference to approval needed from GSK for subjects to continue into Part B
18. Section 6.9.1:  Permitted Medications and Non-Drug Therapies:  To clarify that time
of administration of concomitant medications is not required in the eCRF.  To clarify that 
rescue medication will be provided for the study.  To clarify that oral corticosteroids are 
permitted during this study and to clarify that baseline ICS and Baseline controller levels 
should not be changed between screening and Visit 2.
19. Section 7, Table 3 Time and Events Table Footnotes 2, 3, 7 and 8:    To clarify that 
the Exit Visit date should be conducted as close as possible to the planned visit date 
(Week 12), to clarify that footnote 7 is applicable to subjects withdrawn, and to clarify 
that Visit 8 assessments should not be duplicated at Visit 9 if the visits are performed on 
the same day.
20. Section 7.7:  Correct “ACQ” to “ACQ-IA”.
21. Section 7.8:  The Childhood Asthma Control Test:  One sentence removed for 
incorrectness and one duplicate sentence removed.
22. Section 9.2 Sample Size Assumptions:  To correct sample size assumptions
23. Section 9.3.1.1 and Section 9.3.1.5:  To correct the Safety Populations for Part A and 
Part B.
24. Section 9.5.2 and Section 9.5.3:  To correct the Secondary and Exploratory Analyses 
assumptions for Part B.
2014N216964_04
2016-MAY-05
Amendment No. 4
1. Section 5.1 Inclusion Criteria for Part A:   To correct an error in Protocol 
Amendment 03 when text was deleted from Inclusion Criterion 4 in error.
2014N216964_05
2017-JAN-18
Amendment No. 5
1. Section 1, Protocol Synopsis, Rationale:  To clarify that Part B follow-up is not 
required for subjects transitioning to the long-term access program.
2. Section 1, Protocol Synopsis, Objective(s)/Endpoint(s): Secondary and Exploratory 
Endpoints will be measured from Week 0 in Part A instead of Week 20 in Part B:  
“Change from Week 20 (Visit 9)” is amended to “Change from Week 0 (Visit 2)”
and that Secondary and Exploratory Endpoints will be measured at Week 80 only 
for subjects that will not transition to the long-term access program.
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
The GlaxoSmithKline group of companies
200363
5
3. Section 1, Protocol Synopsis, Overall Design:  Long Term 
Safety/Pharmacodynamic Phase (Part B) updated to clarify that Part B follow-up is 
only required for subjects not transitioning to the long-term access program.
4. Section 1, Protocol Synopsis, Treatment Arms and Duration:  Part B Follow-up
paragraph is updated to clarify that Part B follow-up is only required for subjects 
not transitioning to the long-term access program.
5. Section 3, Objectives and Endpoints, Part B:  Secondary and Exploratory 
Endpoints will be measured from Week 0 in Part A instead of Week 20 in Part B:  
“Change from Week 20 (Visit 9)” is amended to “Change from Week 0 (Visit 2)”
6. Section 3, Objectives and Endpoints, Part B:  Secondary and Exploratory 
Endpoints will be measured at Week 80 only for subjects that will not transition to 
the long-term access program.
7. Section 4, Study Design:  Sentence added to clarify that Part B follow-up is not 
required for subjects transitioning to the long term access program.
8. Section 4, Long-Term Safety/Pharmacodymamic Phase (Part B), Follow-up section 
updated to clarify that Part B follow-up is only required for subjects not 
transitioning to the long-term access program and to add the duration of Part B for 
subjects transitioning to the long-term access program.
9. Section 4, Long-Term Safety/Pharmacodynamic Phase (Part B), Follow-up section 
updated to clarify the definition of “completed subject” for subjects transitioning to 
the long-term access program and for those that do not transition.
10. Section 4.1, Overall Design, Long-Term Safety/Pharmacodymamic Phase (Part B): 
updated to clarify that Part B follow-up is only required for subjects not 
transitioning to the long-term access program
11. Section 4.2, Treatment Arms and Duration, Long-Term Safety/Pharmacodynamic 
Phase (Part B):  Updated to add the duration of Part B for subjects transitioning to 
the long-term access program.
12. Section 4.4, Design Justification:  Updated to clarify that Part B follow-up is only 
required for subjects not transitioning to the long-term access program
13. Section 5.6, Subject and Study Completion:  Updated to clarify the definition of 
“completed subject” for subjects transitioning to the long-term access program and 
for those that do not transition.
14. Section 6.8, Treatment After the Completion of Part A and Part B:  Updated to 
include the long-term access program as an option for treatment of subjects after 
the end of Part B.
15. Section 7, Study Assessments and Procedures, Table 3:  Updated to clarify that IgE 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
The GlaxoSmithKline group of companies
200363
6
“total” only will be measured for this study.
16. Section 7, Study Assessments and Procedures, Table 4:  Footnote added to Table 4 
to clarify that Visit 23 (Week 80) is only applicable for subjects not transitioning to 
the long term access program.
17. Section 7.2.6, Clinical Safety Laboratory Assessments:  Updated to clarify that 
instructions for preparing all laboratory samples may be found in the Q2 Solutions, 
Investigator Manual instead of the Study reference Manual (SRM)
18. Section 7.3, Pharmacokinetics:  Updated to clarify that instructions for preparing 
all laboratory samples may be found in the Q2 Solutions Investigator Manual 
instead of the Study reference Manual (SRM)
19. Section 7.5, Immunogenicity:  Updated to clarify that instructions for preparing all 
laboratory samples may be found in the Q2 Solutions Investigator Manual instead 
of the Study reference Manual (SRM).
20. Section 9.2, Sample Size Considerations:  Updated to clarify that the clearance
mentioned in the section refers to apparent clearance.
21. Section 9.4.2, Secondary Analyses:  Updated to quote the body-weight adjusted 
clearance value in adults (instead of the bodyweight-adjusted apparent clearance) 
and the 80-125% interval around this value, and to provide as additional 
information the value of the corresponding apparent clearance.  
22. Section 12.1, Abbreviations and Trademarks: Apparent clearance after 
extravascular (e.g., subcutaneous) administration (CL/F) added.
23. Section 12.2, Appendix 2:  Footnote updated to clarify that instructions for 
preparing all laboratory samples may be found in the Q2 Solutions Investigator 
Manual instead of the Study reference Manual (SRM).
24. Section 12.3.6, Reporting of SAEs to GSK:  Clarification made to the second bullet 
point regarding reporting SAEs when the electronic system is down.  
 
2017N314087_00


 
2017N314087_00
PPD
PPD
PPD


2014N216964_05
CONFIDENTIAL
200363
8
MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information: 
Role
Name
Day Time Phone 
Number and email 
address
After-hours 
Phone/Cell/
Pager Number
Site Address
Primary Medical 
Monitor 
MD
709 Swedeland 
Road, UW25-3077B
King of Prussia, PA 
19406
Secondary 
Medical Monitor
MD
Stockley Park 
West,United 
Kingdom
SAE contact  
information 
 
MD
5 Moore Dr , RTP 
NC 27709
Sponsor Legal Registered Address:
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Sponsor Contact Address:
GlaxoSmithKline Research & Development Limited
Five Moore Drive 
P.O. 13398
Research Triangle Park, NC 27709-3398, USA
Telephone: 
Sponsor Global Medical Monitor Contact Information:  
 MD (Director, Respiratory Research and Development)
Tel: 
Mobile: 
Email:  
Sponsor Back-up Global Medical Monitor Contact Information:  
 MD (Medical Monitor, Respiratory Research and Development)
Mobile: 
Sponsor Serious Adverse Events (SAE) Co-ordinator: 
 MD (Director, Respiratory Research and Development)
Tel: 
Mobile: 
Regulatory Agency Identifying Number(s): 
IND No. 006971
EudraCT number: 2014-002666-76
 
2017N314087_00
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


2014N216964_05
CONFIDENTIAL
200363
9
INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number: 200363
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
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
10
TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 200363......................................................13
2.
INTRODUCTION....................................................................................................19
2.1.
Study Rationale ..........................................................................................20
2.2.
Brief Background ........................................................................................20
2.2.1.
Severe Eosinophilic Asthma in Children ......................................20
2.2.2.
Pharmacokinetics of mepolizumab...............................................21
2.2.3.
Pharmacodynamics of mepolizumab ...........................................22
2.2.4.
Safety of mepolizumab following administration in Children 
and Adolescents ..........................................................................22
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................23
4.
STUDY DESIGN ....................................................................................................25
4.1.
Overall Design ............................................................................................27
4.2.
Treatment Arms and Duration.....................................................................28
4.3.
Type and Number of Subjects.....................................................................29
4.4.
Design Justification.....................................................................................29
4.5.
Dose Justification........................................................................................30
4.6.
Benefit:Risk Assessment ............................................................................31
4.6.1.
Risk Assessment .........................................................................32
4.6.2.
Benefit Assessment.....................................................................38
4.6.3.
Overall Benefit: Risk Conclusion..................................................38
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............38
5.1.
Inclusion Criteria for Part A.........................................................................39
5.2.
Exclusion Criteria for Part A........................................................................40
5.3.
Eligibility Criteria for Part B .........................................................................41
5.4.
Pre-Screening/Screening/Run-in Failures...................................................41
5.5.
Withdrawal/Stopping Criteria.......................................................................42
5.5.1.
Liver Chemistry Stopping Criteria ................................................42
5.5.1.1.
Study Treatment Restart or Rechallenge....................43
5.6.
Subject and Study Completion....................................................................43
6.
STUDY TREATMENT ............................................................................................44
6.1.
Investigational Product................................................................................44
6.2.
Dosage and Administration.........................................................................44
6.3.
Compliance with Study Treatment Administration.......................................45
6.4.
Blinding.......................................................................................................45
6.5.
Packaging and Labeling..............................................................................46
6.6.
Preparation/Handling/Storage/Accountability..............................................46
6.7.
Treatment of Study Treatment Overdose....................................................47
6.8.
Treatment after the Completion of Part A and Part B..................................47
6.9.
Concomitant Medications and Non-Drug Therapies....................................47
6.9.1.
Permitted Medications and Non-Drug Therapies..........................47
6.9.2.
Prohibited Medications and Non-Drug Therapies.........................48
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................48
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
11
7.1.
Screening and Critical Baseline Assessments ............................................53
7.1.1.
Pre-Screening Failures (Visit 0) ...................................................53
7.1.2.
Screening (Visit 1) .......................................................................53
7.2.
Safety .........................................................................................................53
7.2.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........53
7.2.1.1.
Definition of an Adverse Event (AE) ...........................54
7.2.1.2.
Definition of a Serious Adverse Event (SAE) ..............54
7.2.1.3.
Time period and Frequency for collecting AE 
and SAE information...................................................56
7.2.1.4.
Method of Detecting AEs and SAEs ...........................56
7.2.1.5.
Follow-up of AEs and SAEs........................................56
7.2.1.6.
Regulatory Reporting Requirements for SAEs............57
7.2.2.
Pregnancy ...................................................................................57
7.2.3.
Physical Exams ...........................................................................57
7.2.4.
Vital Signs....................................................................................58
7.2.5.
Electrocardiogram (ECG).............................................................58
7.2.6.
Clinical Safety Laboratory Assessments ......................................58
7.3.
Pharmacokinetics .......................................................................................59
7.4.
Pharmacodynamics ....................................................................................59
7.5.
Immunogenicity...........................................................................................59
7.6.
Forced Expiratory Volume-1 (FEV1)............................................................60
7.7.
Asthma Control Questionnaire-7 (ACQ-7)...................................................60
7.8.
Childhood Asthma Control Test (C-ACT) ....................................................61
7.9.
Asthma Exacerbations................................................................................61
8.
DATA MANAGEMENT ...........................................................................................61
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................62
9.1.
Hypotheses.................................................................................................62
9.2.
Sample Size Considerations.......................................................................62
9.2.1.
Sample Size Assumptions ...........................................................63
9.2.2.
Sample Size Sensitivity................................................................63
9.2.3.
Sample Size Re-estimation or Adjustment...................................63
9.3.
Data Analysis Considerations .....................................................................63
9.3.1.
Analysis Populations Part A.........................................................63
9.3.1.1.
Safety Population Part A ............................................63
9.3.1.2.
Pharmacokinetic Population Part A ............................63
9.3.1.3.
Pharmacodynamic Population (Blood 
Eosinophils) Part A.....................................................63
9.3.1.4.
Pharmacodynamic Population (Outcome 
Assessments) Part A..................................................63
9.3.1.5.
Safety Population Part B ............................................64
9.3.1.6.
Pharmacodynamic Population (Blood 
Eosinophils) Part B.....................................................64
9.3.1.7.
Pharmacodynamic Population (Outcome 
Assessments) Part B..................................................64
9.3.2.
Interim Analysis ...........................................................................64
9.4.
Key Elements of Analysis Plan (Part A) ......................................................64
9.4.1.
Primary Analyses.........................................................................64
9.4.2.
Secondary Analyses ....................................................................64
9.4.3.
Exploratory Analyses ...................................................................65
9.5.
Key Elements of Analysis Plan (Part B) ......................................................65
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
12
9.5.1.
Primary Analysis..........................................................................65
9.5.2.
Secondary Analyses ....................................................................65
9.5.3.
Exploratory Analyses ...................................................................65
10. STUDY GOVERNANCE CONSIDERATIONS........................................................65
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............65
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................65
10.3.
Quality Control (Study Monitoring) ..............................................................66
10.4.
Quality Assurance.......................................................................................66
10.5.
Study and Site Closure ...............................................................................67
10.6.
Records Retention......................................................................................67
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................68
11. REFERENCES.......................................................................................................69
12. APPENDICES........................................................................................................73
12.1.
Appendix 1: Abbreviations and Trademarks................................................73
12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................76
12.3.
Appendix 3: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................79
12.3.1.
Definition of Adverse Events........................................................79
12.3.2.
Definition of Serious Adverse Events...........................................80
12.3.3.
Definition of Cardiovascular Events .............................................81
12.3.4.
Recording of AEs and SAEs ........................................................82
12.3.5.
Evaluating AEs and SAEs............................................................82
12.3.6.
Reporting of SAEs to GSK...........................................................84
12.4.
Appendix 4:  Collection of Pregnancy Information.......................................85
12.5.
Appendix 5: Sample ACQ-7 Questionnaire.................................................86
12.6.
Appendix 6: Sample ACQ-IA Questionnaire................................................89
12.7.
Appendix 7: Acceptable Birth Control..........................................................94
12.8.
Appendix 8: Country Specific Requirements...............................................96
12.9.
Appendix 9: Anaphylaxis Criteria ................................................................97
12.10. Appendix 10:  Childhood Asthma Control Test (C-ACT)..............................98
12.11. Appendix 11:  Protocol Amendment Changes.............................................99
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
13
1.
PROTOCOL SYNOPSIS FOR STUDY 200363
Rationale
This pharmacokinetic/pharmacodynamic study is being conducted as part of an 
extrapolation strategy to support the use of mepolizumab in the 6-11 pediatric population 
with severe eosinophilic asthma.  This study will provide pharmacokinetic and 
pharmacodynamic data for mepolizumab at 40 or 100mg SC, depending on subject 
bodyweight, when administered to children aged 6-11 who have severe eosinophilic 
asthma that are expected to support the extrapolation of safety and efficacy data observed 
in the adult population to this pediatric population.  This study will also assess safety, 
tolerability, and immunogenicity of mepolizumab in this population along with clinical 
outcome measures, the ACQ-7 and the C-ACT.  
Following the main study (Part A), subjects will be evaluated for eligibility to continue 
into the optional long-term extension phase (Part B) of this study.  For those subjects 
determined to be eligible and for whom appropriate informed consent/assent has been 
obtained there will be the option of continuing to receive treatment with mepolizumab 
during a Long-Term Safety / Pharmacodynamic Phase (Part B) which will include 
Treatment and Follow-up phases (Part B Follow-up is not required for subjects 
transitioning to the long term access program at the end of Part B).  Part B will provide 
data to assess the long-term safety and tolerability of mepolizumab in this paediatric 
population and will also provide data to assess the durability of the pharmacodynamic 
response to mepolizumab.
Objective(s)/Endpoint(s)
Pharmacokinetic/Pharmacodynamic Phase (Part A)
Objectives
Endpoints
Primary

To characterize the pharmacokinetics of 
mepolizumab administered 
subcutaneously to subjects aged 6 to 11 
years old with severe eosinophilic 
asthma

To characterize the pharmacodynamics 
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 
(AUC(0-inf), maximum plasma 
concentration (Cmax), and terminal 
phase elimination half-life (t1/2) of 
mepolizumab

Change from baseline in absolute 
blood eosinophil count at week 12
Secondary

To compare the bodyweight-adjusted 
clearance between adults and subjects 

Bodyweight-adjusted clearance 
estimates obtained by population PK 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
14
Objectives
Endpoints
aged 6 to 11 years old with severe 
eosinophilic asthma when 
mepolizumab is administered 
subcutaneously

To characterize asthma control 
following subcutaneous administration 
of mepolizumab to subjects aged 6 to 
11 years old with severe eosinophilic 
asthma 

To assess the safety and tolerability of 
mepolizumab when administered 
subcutaneously to subjects aged 6 to 11 
years old with severe eosinophilic 
asthma  
methods. 

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 week 4,8, 16 and 20

Incidence of Adverse Events

Incidence of clinically significant  
changes in clinical laboratory 
parameters

Frequency of positive anti-
mepolizumab binding antibodies and 
neutralizing antibodies

Incidence of clinically significant 
changes in vital sign measurements
Exploratory 

To assess the number of asthma 
exacerbations that occur during the 
study following subcutaneous 
administration of mepolizumab to 
subjects aged 6 to 11 years old with 
severe eosinophilic asthma

To assess Forced expiratory volume in 
1 second (FEV1) following 
subcutaneous 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-
week 12).

Number of asthma exacerbations that 
occur on- treatment and post-
treatment (week 0 - week 20)

Change from Baseline in FEV1  
measured at week 12
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
15
Long-Term Safety / Long-Term Pharmacodynamic Phase (Part B)
Objectives
Endpoints
Primary

To assess the long-term (52 weeks) 
safety and tolerability of 
mepolizumab when administered 
subcutaneously to subjects aged 6 to 
11* years old with severe 
eosinophilic asthma  

Incidence of Adverse Events

Frequency of positive anti-
mepolizumab binding antibodies and 
neutralizing antibodies

Incidence of clinically significant 
changes in vital sign measurements

Incidence of clinically significant  
changes in clinical laboratory 
parameters
Secondary

To characterize the long-term (52 
weeks) durability of 
pharmacodynamics of mepolizumab 
administered subcutaneously to  
subjects aged 6 to 11* 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 80**.

Exploratory

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 11* years old with 
severe eosinophilic asthma

To characterize the long-term (52 
weeks) asthma control following 
subcutaneous administration of 
mepolizumab to subjects aged 6 to 
11* years old with severe 
eosinophilic asthma 

Incidence of asthma exacerbations

Change from Week 0 (Visit 2) in 
ACQ-7 and C-ACT at weeks 32, 44, 
56, 68, 72 and 80**.
*Subjects who reach their 12th birthday during Part A may participate in Part B
**Week 80 is not applicable to subjects transitioning to the long-term access program
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
16
Overall Design
Pharmacokinetic/Pharmacodynamic Phase (Part A)
This is a multi-centre, open-label study that will assess the pharmacokinetics and 
pharmacodynamics of three 4-weekly doses of mepolizumab, either 40 or 100mg 
depending on subject bodyweight, administered SC to subjects with severe eosinophilic 
asthma aged 6-11 years.
Long-Term Safety / Pharmacodynamic Phase (Part B)
This is a long-term safety / pharmacodynamic phase in which extended treatment for a 
further 52 weeks will be offered on an optional basis to those subjects eligible for 
continued treatment.  Subjects will receive either 40 or 100mg depending on subject 
bodyweight, administered SC every 4 weeks to subjects with severe eosinophilic asthma 
aged 6-11 years.  At the end of the 52 weeks extended treatment in Part B, subjects will 
have an Exit Visit 4 weeks after last dose.  Subjects not transitioning to the long-term 
access program will also have a Follow-Up visit 12 weeks after last dose.
Treatment Arms and Duration
Pharmacokinetic/Pharmacodynamic Phase (Part A)
Enrolled subjects in this study will be assigned to receive one of the following treatments:
Treatment Arm
SC dose
Mepolizumab 40mg SC upper arm or thigh
Mepolizumab 40 mg SC
For subjects <40 kg bodyweight at Visit 2 
(Week 0)
Mepolizumab 100mg SC upper arm or 
thigh
Mepolizumab 100mg SC
For subjects ≥40 kg bodyweight at Visit 2 
(Week 0)
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
17
This Pharmacokinetic/Pharmacodynamic Phase (Part A) study will consist of three 
stages: Pre-Screening/Screening/Run-in, Treatment and Follow-up. 
Pre-Screening/Screening/Run-in:  Subjects will attend an initial Pre-screening visit to 
assess their willingness and eligibility to participate in the study.  The Pre-screening visit 
will include: informed consent, demography, exacerbations and concomitant medications.  
Visit 1(Screening) will include a physical exam, screening laboratory tests, screening 
ECG and other assessments to determine suitability to participate in this study.  The Pre-
screening visit may be conducted at the same clinic visit as Visit 1(Screening).  Subjects 
meeting the Visit 1(Screening) eligibility criteria will enter a Run-in period of up to 2 
weeks to allow for receipt and review of the lab results and ECG. 
Part A Treatment:  Those subjects meeting all of the inclusion/exclusion criteria by 
Visit 2 will receive mepolizumab 40 or 100 mg SC, depending on subject bodyweight (40 
mg for subjects <40 kg and 100 mg for subjects ≥ 40 kg). Subjects will receive their first 
dose of mepolizumab at Visit 2 and enter into the Treatment phase of the study.  Subjects 
shall be observed for a minimum of 60 minutes in the clinic following each injection.  
Safety monitoring of subjects will occur during SC administration and for 1 hour after the 
three administrations in Part A and then follow monitoring policies for the center in Part 
B.  Such monitoring will include general safety monitoring including monitoring for both 
systemic hypersensitivity (i.e., allergic/IgE-mediated and non-allergic) and local site 
reactions.  In the event of an acute severe reaction (e.g., anaphylaxis) following 
administration of mepolizumab, there are personnel/staff onsite at the treatment facility 
who are appropriately trained in basic life support to manage the patient including 
administration of medications (e.g., epinephrine) and have access to a system that can 
promptly transport the patient to another facility for additional care if appropriate.
Those subjects who enter the run-in period but do not meet all inclusion/exclusion criteria 
will be deemed Run-in failures and will not be dosed in the study. The reason for any 
Run-in failure will be recorded in the eCRF.
During the Part A Treatment phase, all subjects will receive mepolizumab either 40mg 
(subjects <40kg at Visit 2) or 100 mg SC (subjects ≥40kg at Visit 2) at week 0 (Visit 2), 
week 4 (Visit 3) and week 8 (Visit 4) which will provide therapeutic coverage through to 
week 12 (Visit 6/End of Therapy Visit).  Visit 6 will mark the end of the treatment phase.
Subjects will visit the clinic at week 9 (Visit 5) to allow for measurement of the 
approximate peak mepolizumab concentration.  
Part A Follow-up:  Following completion of Visit 6, subjects will enter into the Follow-
up phase which will consist of two additional visits at weeks 16 (Visit 7) and 20 (Visit 8).
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
18
Long-Term Safety / Long Term Pharmacodynamic Phase (Part B)
Treatment Arm
SC dose
Mepolizumab 40mg SC upper arm or thigh
Mepolizumab 40 mg SC
For subjects with bodyweight <40 kg at 
Visit 9 (Week 20).  From visit 10, subjects
should be weighed at each visit until 
bodyweight reaches 40kg when the dose 
should be adjusted to 100mg.  From this 
time onwards, the dose will not be adjusted 
again.
Mepolizumab 100mg SC upper arm or 
thigh
Mepolizumab 100mg SC
For subjects with a bodyweight ≥40 kg at 
Visit 9 (Week 20) or from the time that 
bodyweight reaches 40kg.
Part B Treatment:  Those subjects meeting the eligibility criteria for the long-term 
phase of the study at Visit 9 will receive mepolizumab 40 or 100 mg SC, (depending on 
subject bodyweight measured at Visit 9;  40 mg for subjects <40 kg and 100 mg for 
subjects ≥ 40 kg).  Subjects should be monitored post-SC administration according to 
standard practice at the site.  From Visit 10 onwards subjects will receive mepolizumab at 
4-weekly intervals for a total of 48 weeks.  Subjects with bodyweight <40 kg at Visit 9 
should be weighed at each subsequent visit and have their dose adjusted to 100mg once 
their bodyweight reaches 40 kg.  Subjects weighing ≥40kg at Visit 9 will receive the 
100mg dose at all subsequent treatment visits and will not be weighed again.
Part B Follow-up:  Following completion of Visit 22, subjects not transitioning to the 
long term access program will enter into the Follow-up phase which will consist of one 
additional follow-up visit at week 80 (Visit 23).
Type and Number of Subjects
For Part A, approximately 40 male or female subjects with severe eosinophilic asthma, 
aged 6 to 11 years inclusive at screening (Visit 1), will be screened to achieve 
approximately 28 eligible subjects entering the treatment phase to allow for availability 
of 20 evaluable subjects; with a minimum of six subjects enrolled in the < 40 kg 
bodyweight group. An evaluable subject is defined to be a subject who has received all 
three doses of mepolizumab and has had all PK and PD assessments completed through 
to Visit 6 (week 12).
Sample size is not determined for Part B.   All subjects who completed Part A and meet 
the eligibility criteria for Part B will be allowed to participate in Part B.
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
19
Analysis
Population-PK (Pop-PK) parameter estimates will be presented (AUC(0-inf), clearance, 
Cmax, t1/2) for Part A. Descriptive statistics will be used to present the subject 
demographics, subject study accountability, post-hoc individual pharmacokinetic 
parameter estimates (e.g. AUC(0-inf), clearance, Cmax, t1/2), blood eosinophil count and  
ratio of blood eosinophil count to baseline at week 12, IL5 levels, selected clinical 
outcome measures (FEV1, ACQ-7, C-ACT, asthma exacerbations), and safety 
assessments (adverse events, vital signs, ECGs and laboratories) and immunogenicity.  
Confidence intervals may be applied where appropriate.  In addition a pre-planned 
analysis comparing the bodyweight-adjusted clearance between adults and subjects 6-11 
years with severe eosinophilic asthma will be conducted, with appropriate confidence 
intervals applied.  
Safety and Pharmacodynamic data for Parts A and B will be summarized descriptively 
and 95% CIs will be presented where appropriate.
2.
INTRODUCTION
Three randomized, double-blind, placebo-controlled trials have investigated the efficacy, 
tolerability, pharmacokinetics and pharmacodynamics of mepolizumab administered IV 
or SC in subjects 12 and older with severe eosinophilic asthma (Pavord, 2012, Ortega,
2014, Bel, 2014).  Additionally, a randomized, double-blind trial with IV mepolizumab 
administration to treat eosinophilic esophagitis in children ages 2-17 years of age has 
been conducted. However, no trial for children aged less than 12 years old with severe 
eosinophilic asthma or with the SC route has been conducted.  
The generated data from the current study will be used to support the extrapolation of the 
safety and efficacy results from the 3 randomized trials in adolescents and adults to 
children ages 6-11 and ultimately an alternative therapeutic option to treat school-age 
children with severe eosinophilic asthma.  With therapeutic proteins, such as the 
monoclonal antibody mepolizumab, it is common to extrapolate the results of adult 
studies to pediatric subjects in consideration of the pharmacokinetic properties of such 
molecules (Xu, 2013). It is suggested that a principal reason this extrapolation is possible 
is that for monoclonal antibodies targeting a soluble ligand, such as mepolizumab, 
metabolism and clearance are unlikely to be affected by developmental differences in the 
major metabolic pathways.  Monoclonal antibodies (mAbs) tend to be highly specific and 
therefore less likely to present off-target toxicity resulting in wider therapeutic index.  
The pharmacokinetics across age-groups is generally consistent once body-size is taken 
into account (Xu, 2013).  Taking into account these characteristics, mAbs are an ideal 
class of medications for the extrapolation of safety and efficacy data from adults and 
adolescents to children.  This approach permits a more efficient, stream-lined 
development program for this age-group and minimizes the need for large, redundant 
clinical trials in this sub-set of patients.
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
20
2.1.
Study Rationale
Collecting information to provide access to as well as safe and efficacious use of new 
medicines to the pediatric population is of utmost importance. However the conduct of 
large efficacy trials might prove challenging in particular if the prevalence of disease 
particular phenotype (e.g., severe eosinophilic asthma) in the pediatric population is quite 
low. Nonetheless it remains equally important to provide alternative therapeutic options 
to the pediatric population.  This pharmacokinetic/pharmacodynamic study is conducted 
to support the use of mepolizumab in children aged 6-11 with severe eosinophilic asthma. 
This study will provide pharmacokinetic and pharmacodynamic data for mepolizumab 40 
or 100mg SC, depending on subject bodyweight, when administered to children ages 6-
11 that have severe eosinophilic asthma and will ultimately support an extrapolation 
strategy of the safety and efficacy data observed in the adult population with severe 
eosinophilic asthma to this pediatric population. This study will also assess safety, 
tolerability, and immunogenicity of mepolizumab in this population along with clinical 
outcome measures, including the ACQ-7 (Juniper, 1999, Juniper, 2005, Juniper, 2006) 
and the C-ACT.  
In addition a pre-planned analysis comparing the bodyweight-adjusted clearance between 
adults and subjects 6-11 years with severe eosinophilic asthma will be conducted.  The 
goal of this analysis is to demonstrate that the PK in pediatric subjects would be 
predictable from the adult PK model. This study will also collect information on the 
blood eosinophil reduction afforded by mepolizumab 40 or 100 mg SC in this age group 
that can be compared to the adult and adolescent population. A Population-PK (Pop-PK) 
analysis of IV data from pediatric patients 2 to 17 years of age with eosinophilic 
esophagitis using the previous adult meta-analysis IV model showed that the adult IV 
pharmacokinetics model from multiple studies, diseases and populations, predicts 
pediatric IV pharmacokinetics (Assa'ad, 2011). This study aims to demonstrate this is 
also valid following SC administration. 
2.2.
Brief Background
2.2.1.
Severe Eosinophilic Asthma in Children
In the western world, asthma is the most prevalent disorder in school-age children with 
an incidence of 5-8%. (CDC, 2013)  A small subset of this population, approximately 5% 
(Bossley, 2012) are considered to have severe asthma, which is defined as patients with a 
lack of control despite step 4 or 5 of the Global Initiative for Asthma (GINA) guidelines 
or patients that will lose asthma control if they are stepped down from this treatment. 
(GINA, 2015).  These children are often unable to lead a normal life and have an affected 
quality of life due to missed school days and limited ability to participate in physical 
activities due to persistent symptoms and the high frequency of exacerbations. (GINA, 
2015). According to the Center for Disease Control and Prevention (CDC, 2013), 
children ages 5-17 with at least one asthma exacerbation per year miss a combined total 
of 10.5 million days of school (CDC, 2013).  Significant asthma exacerbations also carry 
increased healthcare costs.  In fact, patients who experience an exacerbation are three 
times more costly per year to treat compared to patients who remain exacerbation free 
(Lane, 2006).  Another deleterious outcome for children with severe asthma is a 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
21
progressive loss of lung function. (Szefler, 2014).  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.  In the past decade, only 2 new classes of 
medications have been introduced: anti-leukotrienes and anti-IgE.  There is a significant 
unmet need for new medications to provide asthma control in severe childhood asthma.
Three key efficacy studies support the efficacy and safety of mepolizumab in severe 
eosinophilic asthma in adults and adolescents (Pavord, 2012, Ortega, 2014, Bel, 2014). In 
addition a Dose-ranging Pharmacokinetic (PK)/Pharmacodynamic (PD) Study 
(MEA114092) characterized the dose response for blood eosinophil reduction.
The exacerbation studies and the OCS reduction study were randomized, double-blind, 
parallel-group, placebo-controlled designs.  In addition to frequent exacerbations, the 
subjects in the severe eosinophilic asthma program have a significant burden of steroid 
use, thus reduction of OCS use while maintaining asthma control is an additional key 
treatment outcome.  Since the exacerbation studies required maintenance of standard of 
care (no dose adjustments), the ability of mepolizumab to reduce OCS use was studied in 
a specific study (Bel, 2014).
2.2.2.
Pharmacokinetics of mepolizumab
Mepolizumab is a humanized IgG1 monoclonal antibody (mAb) that exhibits dose-
proportional and time-independent pharmacokinetics. After SC administration to adults 
and adolescents mepolizumab is absorbed slowly, with an absolute bioavailability in the 
arm of 74–80% and median time to maximum concentration (Tmax) values ranging from 
4–8 days. Mepolizumab distributes into a central volume of distribution (Vc) similar to 
plasma volume with a distribution half-life of 1–2 days, and has a steady-state volume of 
distribution (Vss) of 1.5–2 times plasma volume (55–85 mL/kg). Mepolizumab is
catabolized by ubiquitous proteolytic enzymes, not restricted to hepatic tissue, and is 
cleared slowly with a terminal-phase elimination half-life of approximately 20 days, 
irrespective of the route of administration, and mean systemic clearance (CL) of 1.9–3.3 
mL/day/kg. Mepolizumab does not undergo target-mediated clearance. When dosed 
every four weeks, mepolizumab shows two-fold steady-state accumulation, irrespective 
of route of administration, consistent with the terminal-phase elimination half-life of 20 
days.
The pharmacokinetics of IV mepolizumab are well-described using a two-compartment 
model with first-order distribution and elimination and the population PK parameter 
estimates consistent across analyses. Although bodyweight was found to have a 
statistically significant effect on both clearance and volume, the overall magnitude of the 
effect of body weight on mepolizumab exposure was not deemed clinically relevant. The 
pharmacokinetics of mepolizumab is consistent across studies, diseases and ethnicities, 
with pediatric pharmacokinetics predictable from adults. Of note, a previous study was 
conducted with mepolizumab IV in pediatric subjects 2-17 years old with eosinophilic 
esophagitis (Assa'ad, 2011). After adjusting for bodyweight via weight-based dosing, age 
was not a determinant of exposure. A population PK analysis of the data using the 
previous adult meta-analysis IV model described the data adequately without parameter 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
22
estimation or bias, implying that adult pharmacokinetics, estimated from multiple studies, 
diseases and populations, predicts pediatric pharmacokinetics.
2.2.3.
Pharmacodynamics of mepolizumab
Mepolizumab pharmacodynamics has been studied in multiple Clinical Pharmacology 
and efficacy studies in multiple diseases. Mepolizumab treatment produces a consistent 
and sustained reduction in blood eosinophil count relative to baseline whose magnitude 
and duration is dose-dependent, implying that full saturation of IL-5 target can be 
achieved. There are non-linear dose- and concentration-responses to blood eosinophil 
reduction. Dose-response is unchanged by administration route, after adjusting for 
bioavailability. An inhibitory Imax model estimated the SC doses resulting in 50% and 
90% of the maximum effect (ID50 and ID90) to be 11 and 99 mg, respectively, 
corresponding to IV doses of 8 and 74 mg. This finding was further confirmed by the 
severe asthma phase 3 study MEA115588 where similar blood eosinophil reductions 
were observed at corresponding doses of mepolizumab IV 75 mg and SC 100 mg.
Mepolizumab also reduces eosinophils in sputum and bone marrow (Pavord, 2012, 
Flood-Page, 2007).
Blood eosinophil counts assessed in a pediatric population aged 2–17 years with 
eosinophilic esophagitis (EoE) (Assa'ad, 2011) following IV administration showed the 
magnitude of the eosinophil reduction and time to return towards baseline were dose-
dependent. At Week 12, following mepolizumab IV 0.55, 2.5 and 10 mg/kg eosinophil 
reductions were 77%, 69%, and 81%, respectively; similar to adult data at corresponding 
doses.
2.2.4.
Safety of mepolizumab following administration in Children and 
Adolescents
Although no data are available in pediatric patients with severe asthma (aged 6- 11 
years), pediatric subjects 2-17 years with EoE (Assa'ad, 2011) received one of three 
intravenous doses of mepolizumab (0.55, 2.5 or 10mg/kg) every 4 weeks for 12 weeks.  
With regards to safety, the most common AEs were vomiting, diarrhea, oropharyngeal 
pain, upper abdominal pain, symptoms known to be associated with the disease state 
(Sorser, 2013), and nasopharyngitis, headache, cough, and pyrexia.   No AEs appeared to 
be dose-related.   SAEs were reported for 3 subjects: chest discomfort, esophageal injury 
(occurred during esophagogastroduodenoscopy (EGD) study procedure), and foreign 
body trauma; none were considered related to mepolizumab by the investigator.  
Immunogenicity was conducted with the former analytical assay, which showed some 
transient positive anti-drug antibodies; however, there were no neutralizing antibodies 
detected. Furthermore, there was no apparent impact on the clinical, pharmacodynamic or 
pharmacokinetic profiles. These findings indicated low risks and/or concerns associated 
with the immunogenicity profile. Detailed electrocardiogram data showed no clinically 
relevant trends related to prolongation of the QT/QTc interval; no cardiac or ECG-related 
adverse events were reported.  No clinically relevant trends in vital signs or laboratory 
data were observed.  In summary, all doses of mepolizumab demonstrated a favorable 
safety profile; common adverse events were non-serious, not-unexpected with this 
disease, and manageable with minimal supportive care.
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
23
3.
OBJECTIVE(S) AND ENDPOINT(S)
Pharmacokinetic/Pharmacodynamic Phase (Part A)
Objectives
Endpoints
Primary

To characterize the pharmacokinetics 
of mepolizumab administered 
subcutaneously to subjects aged 6 to 
11 years old with severe eosinophilic 
asthma

To characterize the pharmacodynamics 
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 
(AUC(0-inf), maximum plasma 
concentration (Cmax), and terminal 
phase elimination half-life (t1/2) of 
mepolizumab

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

To characterize asthma control 
following subcutaneous administration 
of mepolizumab to subjects aged 6 to 
11 years old with severe eosinophilic 
asthma 

To assess the safety and tolerability of 
mepolizumab when administered 
subcutaneously to subjects aged 6 to 11 
years old with severe eosinophilic 
asthma  

Bodyweight-adjusted clearance 
estimates obtained by population PK 
methods. 

Change from Baseline in ACQ-7  
measured at week 12 

Change from Baseline in ACQ-7 
measured at week 4,8,16 and 20

Change from Baseline in C-ACT  
measured at week 12

Change from Baseline in C-ACT 
measured at week 4,8, 16 and 20

Incidence of Adverse Events

Incidence of clinically significant  
changes in clinical laboratory 
parameters

Frequency of positive anti-
mepolizumab binding antibodies and 
neutralizing antibodies

Incidence of clinically significant 
changes in vital sign measurements
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
24
Objectives
Endpoints
Exploratory 

To assess the number of asthma 
exacerbations that occur during the 
study following subcutaneous 
administration of mepolizumab to 
subjects aged 6 to 11 years old with 
severe eosinophilic asthma

To assess Forced expiratory volume in 
1 second (FEV1) following 
subcutaneous 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-
week 12).

Number of asthma exacerbations that 
occur on- treatment and post-
treatment (week 0 - week 20)

Change from Baseline in FEV1  
measured at week 12
Long-Term Safety / Long-Term Pharmacodynamic Phase (Part B)
Objectives
Endpoints
Primary

To assess the long-term (52 weeks) 
safety and tolerability of mepolizumab 
when administered subcutaneously to 
subjects aged 6 to 11* years old with 
severe eosinophilic asthma  

Incidence of Adverse Events

Frequency of positive anti-
mepolizumab binding antibodies and 
neutralizing antibodies

Incidence of clinically significant 
changes in vital sign measurements

Incidence of clinically significant  
changes in clinical laboratory 
parameters
Secondary

To characterize the long-term (52 
weeks) durability of 
pharmacodynamics of mepolizumab 
administered subcutaneously to  
subjects aged 6 to 11* 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 80**.

Exploratory

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 
11* years old with severe eosinophilic 
asthma

Incidence of asthma exacerbations
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
25
Objectives
Endpoints

To characterize the long-term (52 
weeks) asthma control following 
subcutaneous administration of 
mepolizumab to subjects aged 6 to 11* 
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 80**.
*Subjects who reach their 12th birthday during Part A may continue into Part B
** Week 80 is not applicable to subjects transitioning to the long-term access program
4.
STUDY DESIGN
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Tables (Table 3 and Table 4), 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 Reference Manual (SRM). The SRM will provide 
the site personnel with administrative and detailed technical information that does not 
impact subject safety.
This is a multi-centre, open-label study that will assess the pharmacokinetics and 
pharmacodynamics of three (4-weekly) doses of mepolizumab 40 or 100 mg SC, 
depending on subject bodyweight, administered to subjects with severe eosinophilic 
asthma ages 6-11 years.  
This study will consist of two phases: Part A will consist of Pre-
Screening/Screening/Run-in, Treatment, and Follow-up.  Part B will consist of Long-
Term Treatment and Follow-up.  The Part B follow-up phase is not required for subjects 
transitioning to the long term access program.
Pharmacokinetic/Pharmacodynamic Phase (Part A)
Pre-Screening/Screening/Run-in:  Subjects will attend an initial Pre-screening visit to 
assess their willingness and eligibility to participate in the study.  The Pre-screening visit 
will include: informed consent; demography exacerbations and concomitant medications.  
Visit 1(Screening) will include a physical exam, screening laboratory test, screening ECG 
and other assessments to determine suitability to participate in this study.  The pre-
screening visit may be conducted at the same clinic visit as Visit 1(Screening).  Subjects 
meeting the Visit 1(Screening) eligibility criteria will enter a Run-in period of up to 2 
weeks to allow for receipt and review of the lab results and ECG.  
Treatment:  Those subjects meeting all of the inclusion/exclusion criteria by Visit 2 will 
receive mepolizumab 40 or 100 mg SC, depending on subject bodyweight (40 mg for 
subjects <40 kg and 100 mg for subjects ≥ 40 kg). Subjects will receive their first dose of 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
26
mepolizumab at Visit 2 and enter into the Treatment phase of the study.  Subjects shall be 
observed for a minimum of 60 minutes in the clinic following each injection.  Safety 
monitoring of subjects will occur during SC administration and for 1 hour after the three 
administrations in Part A and then follow monitoring policies for the center in Part B.  
Such monitoring will include general safety monitoring including monitoring for both 
systemic hypersensitivity (i.e., allergic/IgE-mediated and non-allergic) and local site 
reactions.  In the event of an acute severe reaction (e.g., anaphylaxis) following 
administration of mepolizumab, there are personnel/staff onsite at the treatment facility 
who are appropriately trained in basic life support to manage the patient including 
administration of medications (e.g., epinephrine) and have access to a system that can 
promptly transport the patient to another facility for additional care if appropriate.
Those subjects who enter the run-in period but do not meet all inclusion/exclusion criteria 
will be deemed Run-in failures and will not be dosed in the study. The reason for any 
Run-in failure will be recorded in the eCRF.
During the Treatment phase, all subjects will receive mepolizumab either 40mg SC 
(subjects <40kg at Visit 2) or 100 mg SC (subjects ≥40kg at Visit 2) at week 0 (Visit 2), 
week 4 (Visit 3) and week 8 (Visit 4). These doses should provide therapeutic coverage 
through to week 12 (Visit 6/End of Therapy Visit).  Visit 6 will mark the end of the 
treatment phase. 
Subjects will visit the clinic at week 9 (Visit 5) to provide a blood sample to measure the 
approximate peak mepolizumab concentration.  
Study visits will have a window of 3 days; except for Visit 5 which should be 
scheduled 1 day.
Follow-up: Following completion of Visit 6, subjects will enter into the Follow-up phase 
which will consist of two additional visits at weeks 16 (Visit 7) and 20 (Visit 8).For 
subjects who had a positive anti-mepolizumab antibody response at the Follow-up (Visit 
8) (or last study visit at which immunogenicity was assessed if the Follow-up (Visit 8) 
immunogenicity sample is not available), an attempt will be made to obtain a serum 
sample for anti-mepolizumab antibodies at least 4 months after the last dose of study drug
in Part A or upon completion of Part A, whichever is later.
A subject will be regarded as having completed Part A if they complete all phases of Part 
A (Pre-Screening/Screening/Run-in, Treatment, and Follow-up).  Subjects who complete 
Part A will participate for approximately 22 weeks.
Long-Term Safety / Pharmacodynamic Phase (Part B)
At the end of Part A, a benefit/risk assessment will be performed by the Investigator and 
if this assessment supports continued therapy with mepolizumab the subject can continue 
into Part B following the Part A Follow-up (Visit 8).
Long-Term Treatment:  Those subjects meeting the eligibility criteria for the long-term 
phase of the study at Visit 9 will receive mepolizumab 40 or 100 mg SC, (depending on 
subject bodyweight measured at Visit 9;  40 mg for subjects <40 kg and 100 mg for 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
27
subjects ≥ 40 kg).  Subjects should be monitored post-SC administration according to 
standard practice at the site.  
From Visit 10 onwards subjects will receive mepolizumab at 4-weekly intervals for a 
total of 48 weeks.  Subjects with bodyweight <40 kg at Visit 9 should be weighed at each 
subsequent visit and have their dose adjusted once their bodyweight exceeds ≥40 kg.
Follow-up:  Following completion of Visit 22, subjects not transitioning to the long term 
access program will enter into the Follow-up phase which will consist of one additional 
follow-up visit at week 80 (Visit 23).
Study visits in Part B will have a window of 5 days.  The total duration of Part B is
approximately 60 weeks (52 weeks for subjects transitioning to the long-term access 
program).  A subject not transitioning to the long term access program will be regarded as 
having completed Part B if they complete all phases of Part B (Long-Term Treatment and
Follow-up). A subject transitioning to the long term access program will be regarded as 
having completed Part B if they complete all the Treatment phase of Part B.
4.1.
Overall Design
Pharmacokinetic/Pharmacodynamic Phase (Part A)
This is a multi-centre, open-label study that will assess the pharmacokinetics 
pharmacodynamics of three 4-weekly doses of mepolizumab, either 40 or 100mg 
depending on subject bodyweight, administered SC to subjects with severe eosinophilic 
asthma aged 6-11 years.
Long-Term Safety / Pharmacodynamic Phase (Part B)
This is a long-term safety / pharmacodynamic phase in which extended treatment for a 
further 52 weeks will be offered on an optional basis to those subjects eligible for 
continued treatment. Subjects will receive either 40 or 100mg depending on subject 
bodyweight, administered SC every 4 weeks to subjects with severe eosinophilic asthma 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
28
aged 6-11 years.  At the end of the 52 weeks extended treatment in Part B, subjects will 
have an Exit Visit 4 weeks after last dose.  Subjects not transitioning to the long term 
access program will have a Follow-Up visit 12 weeks after last dose.
4.2.
Treatment Arms and Duration
Pharmacokinetic/Pharmacodynamic Phase (Part A)
Enrolled subjects in this study will be assigned to receive one of the following treatments:
Treatment Arm
SC dose
Mepolizumab 40 mg SC upper arm or thigh
Mepolizumab 40 mg SC
For subjects <40 kg bodyweight at Visit 2 
(Week 0)
Mepolizumab 100 mg SC upper arm or 
thigh
Mepolizumab 100mg SC
For subjects ≥40 kg bodyweight at Visit 2 
(Week 0)
The total duration of Part A will be 22 weeks and will include a run-in period of 1-2 
weeks, a treatment period of 12 weeks and a follow-up phase of 8 weeks. 
Long-Term Safety / Long Term Pharmacodynamic Phase (Part B)
Treatment Arm
SC dose
Mepolizumab 40mg SC upper arm or thigh
Mepolizumab 40 mg SC
For subjects <40 kg bodyweight at Visit 9 
(Week 20).  From visit 10, subjects should 
be weighed at each visit until bodyweight 
reaches 40kg when the dose should be
adjusted to 100mg.  From this time 
onwards, the dose will not be adjusted 
again.
Mepolizumab 100mg SC upper arm or 
thigh
Mepolizumab 100mg SC
For subjects bodyweight at Visit 9 (Week 
20) or from the time that bodyweight 
reaches 40 kg
Following completion of Part A subjects will be evaluated for eligibility to continue into 
Part B of this study.  For those subjects determined to be eligible and for whom 
appropriate informed consent/assent has been obtained there will be a Long-Term Safety 
/ Pharmacodynamic Phase (Part B).  The total duration of Part B is approximately 60 
weeks (52 weeks for subjects transitioning to the long-term access program).
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
29
4.3.
Type and Number of Subjects
Approximately 40 male or female subjects with severe eosinophilic asthma, aged 6 to 11 
years inclusive at screening (Visit 1), will be screened to achieve approximately 28 
eligible subjects entering the Part A treatment phase to allow availability of 20 evaluable 
subjects, with a minimum of six subjects enrolled in the < 40 kg bodyweight group.  An 
evaluable subject is defined to be a subject who has received all three doses of 
mepolizumab and has all PK and PD assessments completed through to Visit 6 (week 
12).
Sample size is not determined for Part B.   All subjects who completed Part A and meet 
the eligibility criteria for Part B will be allowed to participate in Part B.
4.4.
Design Justification
This study is designed to characterize the pharmacokinetics and pharmacodynamics of
mepolizumab as add-on to best standard of care in children with severe eosinophilic 
asthma aged 6 to 11 years to support the extrapolation of the safety and efficacy data 
observed in the adult/adolescent population to this pediatric population. The design of the 
study aims to balance the challenging access to the target pediatric population and the 
study constraints with the scientific evidence to support the use of mepolizumab in this 
population. 
An additional secondary objective of the study is to compare the bodyweight-adjusted 
clearance between adults and subjects aged 6 to 11 years old. Three repeat doses of 
mepolizumab administered every 4 weeks subcutaneously to subjects aged 6 to 11 years 
is considered adequate to achieve the PK and PD objectives of the study.  Blood 
eosinophil count is consistently reduced following mepolizumab administration, which 
make blood eosinophils a suitable PD endpoint for evaluation.
The study population reflects the intended population for therapeutic use to support the 
extrapolation strategy. 
A treatment phase duration of 12 weeks is considered sufficient to support the primary 
PK and PD endpoint of the study. A dose ranging PK/PD study (MEA114092) of 
mepolizumab administered intravenously (75 mg) or subcutaneously (12.5, 125 and 250 
mg) with a similar duration was conducted in adult asthmatic subjects with elevated 
blood eosinophil levels. Concordance in the blood eosinophil reduction at 75 mg IV 
between this study and the 12-month duration phase 2/3 study (Pavord, 2012) confirms 
suitability of the 12 weeks duration treatment for the chosen endpoint. Furthermore, 
comparable blood eosinophil count reduction was observed at 75 mg IV and 100 mg SC 
in a phase 3 study (MEA115588) with consistent blood eosinophil reduction observed 
from 12 weeks onwards. These data support conducting a study of 12 weeks duration  
and will allow comparison with adult/adolescent data to support the extrapolation of the 
safety and efficacy data observed in adults/adolescents in the severe asthma phase 3 
program to the 6-11 pediatric population. Subjects will be followed-up for a total of 12 
weeks after the last dose in Part A, which is consistent with the follow-up duration in 
adult studies. 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
30
To minimise the blood sample collection in this pediatric population and to take into 
consideration the constraint of the trial, sparse blood sampling collection has been 
implemented. It is therefore important to assess the operational characteristics of the 
design in order to meet the primary objective of the study. To this effect, simulations of 
different scenario varying the number of subjects included in the trial and evaluating 
different PK sampling schemes were conducted to test the robustness of the study design.  
A sample on week 9 (Visit 5) was included to collect information close to mepolizumab 
Tmax following SC administration (see Section 9.2 for further details).
The assumption is the PK in pediatric subjects 6-11 years old is comparable to the PK in 
adults therefore the adult PK model was used to generate a database of pediatric subjects 
from which random subjects with clinical trial characteristics were selected. Data from 
the different trials were then fitted, bodyweight-adjusted clearance estimated and 
compared to the known value (i.e. the true value from which the pediatric subjects were 
simulated from) (see Section 9.2 for further details).
No long-term data (up to 52 weeks) documenting the safety and tolerability of 
mepolizumab in children aged 6 to 11 years with severe eosinophilic asthma are currently 
available.  As it is expected that treatment with mepolizumab in this population may be 
long-term it is essential that such data be collected.  Extended treatment with 
mepolizumab during Part B of this protocol also permits an assessment of the durability 
of the pharmacodynamic response to mepolizumab in this population.
4.5.
Dose Justification
Doses of 40 mg or 100 mg SC, depending on the subject bodyweight, administered every 
4 weeks has been selected for this 6-11 years old pediatric population which is predicted 
to provide similar exposure to the SC dose that was investigated in the adult/adolescent 
population in the phase 3 program. This dose was shown to be efficacious and well 
tolerated and therefore the doses selected in this study are expected to confer clinical 
activity in the 6-11 years old age group. A non-linear inhibitory dose-response model
identified 99 mg administered SC as providing 90% of the maximum achievable blood 
eosinophil reduction in the adult program. A similar baseline blood eosinophil count is 
anticipated in the severe eosinophilic asthma pediatric population, as was seen in adults 
(Giubergia, 2012; Jenkins, 2003), hence a similar magnitude of blood eosinophil 
reduction is also expected. 
An extrapolation of exposure (AUC(0-inf) ) using allometric principles confirmed from 
pediatric subjects with EoE in study MEE103219 (Assa'ad, 2011) showed that for the 
weight range to be studied, (15 kg and upwards), two weight bands of 15 to less than 40 
and ≥40 kg provided a mean exposure within 25% of the adult 100 mg SC target 
exposure across the entire weight range. This precision compares very favourably with an 
optimal solution of 21% across the wider weight range 1 – 100 kg based on five weight 
bands (GSK Document Number 2014N223495_00).
These proposed doses are further supported by the safety data collected in the previously 
conducted study MEE103219 in which intravenous doses up to 10 mg/kg were 
investigated in pediatric subjects 2-17 years old with eosinophilic esophagitis, from 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
31
pediatric patients in the on-going hypereosinophilic syndrome (HES) compassionate use 
program and the extensive safety database in adults. 
4.6.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
mepolizumab (SB240563) can be found in the Investigator’s Brochure.
Serious adverse events (SAEs) reported from ongoing clinical studies with mepolizumab 
are reviewed daily by the Serious Adverse Events (SAE) Co-ordinator (project Medical 
Monitor. Additionally, regular, systematic reviews of emerging safety data from all 
clinical studies are conducted by an in-house multi disciplinary Safety Review Team 
(SRT) which provides a central and dedicated forum for review of emerging data which 
could impact subject safety. The SRT, which includes the project Medical Monitor, other 
physicians assigned to the project, clinical scientists and a statistician reviews blinded 
and unblinded (i.e., from open-label trials) safety data from ongoing clinical studies with 
mepolizumab on a regular basis and conducts a comprehensive evaluation of the safety 
data upon completion of each study. Moreover, an integrated analysis of safety across the 
program is completed annually when additional safety data are available from completed 
studies. A reassessment of benefit risk and the current Developmental Core Safety 
Information (DCSI) is completed at each SRT meeting subsequent to review of new data. 
There is also a standard and comprehensive process for the reporting and management of 
Sentinel Events at GSK. (A Sentinel Event is an SAE that is not necessarily drug-related, 
but that has been associated historically with adverse reactions for other drugs, and is 
therefore worthy of heightened pharmacovigilance. At GSK Sentinel Events include 
acquired long QT syndrome, agranulocytosis, anaphylactic and anaphylactoid reactions, 
hepatotoxicity, renal failure, seizures, and Stevens Johnson syndrome/toxic epidermal 
necrolysis.) Subsequent to the reporting of a Sentinel Event, the Medical Monitor 
promptly notifies the SRT and the GSK Global Safety Board and leads a thorough and 
comprehensive follow-up of the Sentinel Event with collection of all relevant data. 
The following section outlines the risk assessment and mitigation strategy for this 
protocol: 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
32
4.6.1.
Risk Assessment
Table 1
Assessment of Risk
Potential Risk of Clinical Significance
Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) SB 240563
Risk of Systemic Allergic and Non-allergic 
Reactions, including Anaphylaxis and local 
injection site reactions
Based on data from the completed Ph 3 program 
in severe eosinophilic asthma, incidence rates of 
systemic reactions were low and similar 
between mepolizumab and placebo treatment 
groups.
Acute and delayed systemic reactions, including 
hypersensitivity, have occurred following 
mepolizumab administration; most reactions 
have been non-serious and resolved without 
sequelae.  These reactions generally occur 
within hours of administration, but in some 
instances had a delayed onset (i.e., days).  
An increase in the incidence of local site 
reactions was observed with SC administration 
of mepolizumab compared with placebo, but the 
overall incidence was low.   The most common 
symptoms associated with subcutaneous 
injections included: pain, erythema, swelling, 
itching, and burning sensation.
Reactions reported to date across the 
mepolizumab program are summarized in the 
IB; see ‘Special Warnings and Special 
Daily monitoring of serious adverse events 
(SAEs) by Serious Adverse Events (SAE) Co-
ordinator (project Medical Monitor); regular 
systematic review of adverse event (AE)/SAE 
data from ongoing studies by a GSK safety 
review team. 
Specific case report form (eCRF) pages utilized 
for targeted collection of reactions data.
Use of Joint NIAID/FAAN 2nd Symposium on 
Anaphylaxis to collect data on reports of 
anaphylaxis (Appendix 9: Anaphylaxis 
Criteria).
In addition to normal institutional practices, 
subjects will be observed for a minimum of 60 
minutes in the clinic following each injection 
up-to and including Visit 4.  From Visit 9
onwards, monitoring post-injection should be 
according to the standard procedure at each site.
 
 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
33
Potential Risk of Clinical Significance
Data/Rationale for Risk
Mitigation Strategy
Precautions for Use’ section located in Section 6 
titled ‘Summary of Data and Guidance for the 
Investigator’.
Risk of Immunogenicity
Biopharmaceutical products may elicit anti-drug 
antibody (ADA) and neutralizing antibody 
(NAB), which have the potential to modulate 
pharmacokinetic (PK), pharmacodynamic (PD) 
or produce adverse reactions. However, 
humanized and fully human antibodies are less 
immunogenic than mouse or chimeric 
monoclonal antibodies.
Mepolizumab has low immunogenic potential
and anti-mepolizumab antibody formation is not 
expected to impact the overall clinical benefit of 
mepolizumab treatment.  Both incidence and 
titer data from completed studies demonstrate a 
low risk for loss of efficacy associated with AEs 
and/or altered PK/PD.  
Immunogenicity data reported to date across the 
mepolizumab development program are 
summarized in the IB; See Section 5.4 ‘Clinical 
Immunogenicity’ and a summary of 
immunogenicity findings in Section 6 ‘Other 
Potentially Clinically Relevant Information for 
the Investigator’.
Blood samples are collected in clinical studies 
for detection of both ADA and Nab.
See previous risk for mitigation strategy related 
to clinical safety risks.
 
 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
34
Potential Risk of Clinical Significance
Data/Rationale for Risk
Mitigation Strategy
Potential risk for adverse cardiovascular (CV) 
effects
Mepolizumab binding was restricted to human 
lymphoid tissues in an immunohistochemistry 
tissue binding study suggesting a low likelihood 
of non-pharmacologic effects on cardiovascular 
(CV) function. 
No AEs concerning cardiac conduction or 
repolarization evident in cynomolgus monkeys 
at doses at least 10-fold in excess of humans 
dosed at 10 mg/kg or 750 mg.
No clinically relevant trends observed in ECG 
data in humans.
In one study in subjects with severe refractory 
asthma, cardiac events were reported in similar 
frequencies across treatment groups with a small 
numerical increase observed in serious ischemic 
cardiac events in the mepolizumab-treated 
groups. However, an integrated safety analysis 
of all placebo-controlled multiple dose asthma 
trials showed similar frequency of SAEs 
reported overall from the cardiac and vascular 
system organ class (SOC). Additionally, similar 
findings were observed in other SOCs with 
thrombotic events (e.g., stroke in the Nervous 
System SOC). Data from 2 subsequently 
completed placebo-controlled severe asthma 
trials did not show an increased risk of serious 
ischemic cardiac events; there were no new 
reports in any treatment groups including 
Daily monitoring of SAE Serious Adverse 
Events (SAE) Co-ordinator (project Medical 
Monitor); regular systematic review of AE/SAE 
data from ongoing studies by a GSK safety 
review team.
CV monitoring for study includes:

ECG 

Use of standardized CRFs to collect 
relevant data on CV events of interest (i.e., 
myocardial infarction, hospitalization for 
unstable angina and congestive heart failure, 
arterial thrombosis, pulmonary embolism 
and deep vein thrombosis).
 
 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
35
Potential Risk of Clinical Significance
Data/Rationale for Risk
Mitigation Strategy
placebo.  Based on these data, the overall risk of 
cardiotoxicity associated with mepolizumab 
treatment is low.
Potential risk for increase in infections – a 
theoretical concern with biologics; however, the 
pharmacological properties of mepolizumab 
suggest the risk is low.
No evidence of increased incidence of infections 
in any preclinical studies.
Murine data demonstrate that IL-5 antagonism 
is unlikely to influence cellular or humoral 
immunity, particularly in response to parasitic 
infections.  
No mepolizumab-related effects on lymphocyte 
Immunophenotyping in monkeys or humans, 
including T-cell activation, distribution of 
CD4/CD8 subtypes or Th1/Th2 cytokine 
patterns, B-cells, NK cells or γδ-T-cells. 
In studies completed to date in severe 
eosinophilic asthma patients, reports of overall, 
serious and opportunistic infections were similar 
across treatment groups. Based on these data, 
the overall risk of infections associated with 
mepolizumab treatment is low.
Infections reported to date across the 
mepolizumab development program are 
summarized in the IB; see ‘Special Precautions 
and Warnings’ (for exclusion of subjects with 
underlying parasitic infections) and 
‘Undesirable Effects’ (for  common infections 
Daily monitoring of SAE by Serious 
Adverse Events (SAE) Co-ordinator (project 
Medical Monitor); regular systematic 
review of AE/SAE data from ongoing 
studies by a GSK safety review team. 
Safety assessments to be conducted as outlined 
in protocols.
 
 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
36
Potential Risk of Clinical Significance
Data/Rationale for Risk
Mitigation Strategy
of pharyngitis, lower respiratory tract infection 
and  urinary tract infection reported in  patients 
with severe asthma) sections located in Section 
6 titled ‘Summary of Data and Guidance for the 
Investigator’
Potential risk for increase in malignancies -
theoretical concern with biologics; however, 
blockade of IL-5 is not associated with 
generalized immuno-suppression or impaired 
host resistance.
Role of IL-5 and eosinophils in tumor 
surveillance is not fully characterised in the 
literature. 
No evidence of defective tumor surveillance in 
IL-5 or eosinophil-deficient mice. 
Direct assessment of the carcinogenic potential 
of long-term IL-5 blockade in rodent models not 
technically feasible. 
Based on data from the completed severe 
eosinophilic asthma Phase 3 clinical program, 
both benign and malignant neoplasms were 
reported with a similar frequency across 
treatment groups.  Non-clinical and clinical 
experience does not support a role for 
mepolizumab in the development of 
malignancies.
Malignancies reported to date across the 
mepolizumab development program are 
summarized in the IB.
Daily monitoring of SAE by Serious Adverse 
Events (SAE) Co-ordinator (project Medical 
Monitor); regular systematic review of AE/SAE 
data from ongoing studies by a GSK safety 
review team. 
Standard safety assessments to be conducted as 
outlined in protocols.
 
 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
37
Potential Risk of Clinical Significance
Data/Rationale for Risk
Mitigation Strategy
Potential risk for rebound eosinophilia with 
associated clinical consequences
Early published data with Schering-Plough anti-
IL5 mAb suggested potential for rebound 
eosinophilia and disease exacerbation when 
treatment was stopped in patients with 
hypereosinophilic syndromes [Kim, 2004; 
Gevaert, 2006]; however, no standard definition 
of rebound was used and criteria for reporting 
were variable. 
There have been no verbatim reports of 
‘rebound’ from completed clinical trials of 
subjects with asthma, atopic dermatitis and 
eosinophilic esophagitis. Furthermore, based on 
results from the completed severe eosinophilic 
asthma Phase 3 clinical program the data do not 
support an exaggerated return of symptoms after 
cessation of treatment.
Daily monitoring of SAE by Serious Adverse 
Events (SAE) Co-ordinator (project Medical 
Monitor); regular systematic review of AE/SAE 
data from ongoing studies by a GSK safety 
review team. 
Standard safety assessments to be conducted as 
outlined in protocols.
Study Procedures
Potential risk for injury with phlebotomy 
Risks with phlebotomy include bruising, 
bleeding, infection, nerve damage.
Procedures to be performed by trained personnel 
(i.e., study nurse). Local anaesthetic will be 
recommended at phlebotomy site.
 
 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
38
4.6.2.
Benefit Assessment
Study 200363 will characterize the pharmacokinetics and pharmacodynamics of 
mepolizumab administered subcutaneously to subjects aged 6 to 11 years old with severe 
eosinophilic asthma. This pediatric population of asthma subjects has not been evaluated 
as having received benefit from treatment with mepolizumab.  However, GSK conducted 
a randomized, double-blind, parallel group clinical trial to evaluate the safety, 
tolerability, pharmacokinetics and pharmacodynamics of mepolizumab in 59 children and 
adolescents 2 to 17 years old with eosinophilic esophagitis (Assa'ad, 2011).  Each subject 
received one of three intravenous doses (0.55, 2.5 or 10mg/kg) every 4 weeks for 12 
weeks.  The pharmacodynamic effect observed (reduction of blood eosinophils) was 
consistent with phase 3 studies (Bel, 2014 and Ortega, 2014).  In addition to investigating 
the pharmacokinetics and pharmacodynamics of mepolizumab in a pediatric population 
with severe asthma, this study 200363 will assess the incidence of adverse events and the 
rate of exacerbations to assess safety and efficacy of the treatment in this population.
Exacerbations are a major concern to asthma patients and lead to a worsening of the 
quality of life for subjects. Interventions in at risk populations that can reduce or 
eliminate serious exacerbations will improve a patient’s quality of life and may reduce 
hospitalizations. Subjects participating in this study will be required to attend visits 
approximately every 4 weeks and therefore may benefit from the additional monitoring to 
their current standard asthma care.
4.6.3.
Overall Benefit: Risk Conclusion
Data from mepolizumab preclinical and clinical development demonstrate the ability of 
mepolizumab to inhibit IL-5 and, consequently, treat inflammatory conditions linked to 
an eosinophilic signal, such as asthma subjects predisposed to exacerbations. To date, the 
safety profile of mepolizumab across other mepolizumab studies has been favorable for 
all the patient populations studied. Adverse events (AEs) reported commonly have been 
manageable with minimal medical intervention. Furthermore, preclinical data and the 
observed safety profile to date in over 2000 clinical trial subjects, as well as the history of 
mepolizumab use for at least one year in the severe asthma patient population, has not 
identified a safety concern that would preclude continued use. Therefore, investigation of 
the pharmacokinetics, pharmacodynamics, safety, efficacy, and tolerability of 
mepolizumab in this pediatric population with severe asthma and a continuing unmet 
need is thereby justified in Study 200363.
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL 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 IB.
Deviations from inclusion and exclusion 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.
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
39
5.1.
Inclusion Criteria for Part A
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
[1] AGE
1. Between 6 and 11 years of age inclusive, at the time of screening.
[2] TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. Diagnosis of severe asthma, defined by the regional asthma guidelines (i.e., NIH, 
GINA, etc.), for at least 12 months prior to Visit 1. If the subject is naïve to the study 
site, the subject/guardian must self-report a physician diagnosis of asthma and the 
investigator must confirm by review of medical history with the subject/guardian. 
3. Eosinophilic airway inflammation that is related to asthma characterized as 
eosinophilic in nature as indicated by: 

elevated peripheral blood eosinophil count of ≥300 cells/µL demonstrated in 
the past 12 months OR

elevated peripheral blood eosinophil count of 150/L at visit 1.
4. A well-documented requirement for regular treatment with inhaled corticosteroid 
(>200 μg/day fluticasone propionate (DPI) or equivalent daily) in the 12 months prior 
to Visit 1 with or without maintenance oral corticosteroids (OCS).  The ICS dose 
should represent medium or high dose in children aged 6-11 years of age [GINA, 
2015].
5. Current treatment with an additional controller medication for at least 3 months or a 
documented failure in the past 12 months of an additional controller medication for at 
least 3 successive months.  [e.g., long-acting beta-2-agonist (LABA), leukotriene 
receptor antagonist (LTRA), or theophylline.]
6. FEV1: Persistent airflow obstruction at either visit 1 or Visit 2 (FEV1 performed prior 
to first dose of study medication) as indicated by:

A pre-bronchodilator FEV1 <110% predicted (Quanjer, 2012)  OR

FEV1:FVC ratio < 0.8
7. Previously confirmed history of two or more exacerbations requiring treatment with 
systemic CS (intramuscular (IM), intravenous, or oral), in the 12 months prior to visit 
1, despite the use of inhaled corticosteroids (ICS). For subjects receiving 
maintenance OCS, treatment for the exacerbations must have been a two-fold 
increase or greater in the CS dose.   
8. No changes in the dose or regimen of baseline ICS and/or additional controller 
medication during the run-in period.
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
40
[3] SEX
9. Male or female: Females of childbearing potential must commit to consistent and 
correct use of an acceptable method of contraception (see Appendix 7) for the 
duration of the trial and for 4 months after the last dose of investigational product. A 
urine pregnancy test is required of girls of childbearing potential. This test will be 
performed at the initial screening visit (Visit 1) and will be performed at each 
scheduled treatment visit prior to the administration of investigational product, and 
during the Exit Visit, Early Withdrawal and Follow-up Visits.
[4] INFORMED CONSENT
10. Parent(s)/guardian able to give written informed consent prior to participation in the 
study, which will include the ability to comply with the requirements and restrictions 
listed in the consent form. If applicable, the subject must be able and willing to give 
assent to take part in the study according to the local requirement.
5.2.
Exclusion Criteria for Part A
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
[1]  CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND ECG) 
1.
Subjects with any history of life threatening asthma (e.g. requiring intubation), 
immunosuppressive medications intake or immunodeficiency disorder
2.
Subjects with any medical condition or circumstance making the volunteer 
unsuitable for participation in the study.
3.
Significant abnormality of rate, interval, conduction or rhythm in the 12-lead ECG, 
determined by the investigator in conjunction with the age and gender of the child at 
Visit 1.   
4.
ALT, and bilirubin > 2xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin 
is fractionated and direct bilirubin <35%) at Visit 1.
5.
Positive Hepatitis B Surface Antigen or positive Hepatitis C antibody at Visit 1
6.
Parent/guardian has a history of psychiatric disease, intellectual deficiency, 
substance abuse, or other condition (e.g. inability to read, comprehend and write) 
which will limit the validity of consent to participate in this study.
7.
Unwillingness or inability of the subject or parent/guardian to follow the procedures 
outlined in the protocol.
8.
Subject who is mentally or legally incapacitated.
9.
Children who are wards of the state or government.
10. A subject will not be eligible for this study if he/she is an immediate family member 
of the participating investigator, sub-investigator, study coordinator, or employee of 
the participating investigator.
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
41
[2] CONCOMITANT MEDICATIONS
11. Xolair: Subjects who have received omalizumab [Xolair] within 130 days of Visit 1.
12. Other Biologics: Subjects who have received any biological (other than Xolair) to 
treat inflammatory disease within 5 half-lives of visit 1.
[3]  CONTRAINDICATIONS 
13. History of sensitivity to any of the study medications, or components thereof or a 
history of drug or other allergy that, in the opinion of the investigator or Medical 
Monitor, contraindicates their participation.
14. Hypersensitivity: Subjects with allergy/intolerance to a monoclonal antibody or 
biologic.
[4]  DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
15. The subject has participated in a clinical trial and has received an investigational 
product within the following time period prior to the first dosing day in the current 
study: 30 days, 5 half-lives or twice the duration of the biological effect of the 
investigational product (whichever is longer).
5.3.
Eligibility Criteria for Part B

The subject has completed all study assessments up-to and including Visit 8 and 
received all 3 doses of IP in Part A

The PI has performed a benefit/risk assessment and this assessment supports
continued therapy with mepolizumab. 

The subject’s parents (or guardian) have given consent and the subject has given 
assent for continued treatment
5.4.
Pre-Screening/Screening/Run-in Failures
Subjects will be assigned a study number at the time of signing the consent (Pre-
screening Visit 0).  Subjects who do not progress to the screen visit will be deemed a Pre-
screen Failure.  The reason for screen failure will be captured in the eCRF for these 
subjects.  Rescreen will be permitted with approval of the GSK Medical Monitor. Any 
subject rescreened will be assigned a new subject number and this will be recorded in the 
eCRF.
Those subjects that complete at least one additional visit 1 (screen) procedure, but do not 
enter the run-in period will be designated as screen failures.
Those subjects that enter the run-in period, but are not dosed, will be designated as run-in 
failures.
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
42
Information to be collected for screen failure and run-in failures will be detailed in the 
eCRF completion guidelines, and any Serious Adverse Events reported as associated with 
study procedures will be recorded in the eCRF.
5.5.
Withdrawal/Stopping Criteria
Subjects may be withdrawn from study treatment at anytime by the Investigator if it is 
considered to be detrimental for them to continue in the study.  Reasons for withdrawal 
can include: an adverse event (including abnormal liver function test or abnormal 
laboratory results), lost to follow-up, protocol violation, lack of efficacy, sponsor 
terminated study, non-compliance, pregnancy, or for any other reason.  
Liver chemistry stopping criteria are detailed in Section 5.5.1
Subjects are also free to withdraw consent to participate in the study at anytime. Every 
effort should be made to have them return to the clinic for an Early Withdrawal Visit (See
Table 3 and Table 4) and to return all study related materials.  In those instances where 
the subject specifies the reason for withdrawal of consent, this information will be 
captured in the eCRF.
A subject should only be designated as lost to follow-up if the site is unable to establish 
contact with the subject after 3 documented attempts via 2 different methods (phone, text, 
e-mail, certified letter, etc).
For both Part A and Part B of this study an Exit Visit should be conducted within 4 weeks 
of the last dose received.  In the event that a subject withdraws at, or during, a scheduled 
visit, an Early Withdrawal Visit should be performed at this visit instead.  A Follow-up 
Visit should then be scheduled 12 weeks after the last dose of investigational product
(Visit 8 or Visit 23 for subjects withdrawing from study Parts A or B, respectively).
Any data collected up until the point of withdrawal will be used in the analyses. 
5.5.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology (Food and Drug Administration
Guidance for Industry: Drug-Induced Liver Injury: Premarketing Clinical Evaluation 
2009). 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
43
Phase II Liver Chemistry Stopping and Increased Monitoring Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus
Bilirubin≥2x
ULN (>35% 
direct) 
or plus
INR>1.5, if 
measured*
Possible
Hy’s Law
ALT≥3xULN
ALT≥5xULN
ALT≥3xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
ALT≥3xULN
but able to 
monitor 
weekly for 
4 weeks
No
Yes
Yes
Yes
Yes
No
No
No
No
Yes
ALT≥3xULN
persist for
4 weeks or 
stopping 
criteria 
met
Yes
No
*INR value not applicable to subjects on anticoagulants
Yes
If subject to be monitored weekly must refer to Liver Safety Required  Actions and  Follow  up 
Assessments  section  in  the  Appendix
Must refer to Liver Safety Required Actions and Follow  up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 2
5.5.1.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any subject participating in this study is not permitted.
5.6.
Subject and Study Completion
In Part A, a completed subject is one who has completed all phases of the study including 
the Part A follow-up visit.  In Part B, for subjects not transitioning to the long-term 
access program, a completed subject is one who has completed all phases of Part B 
(including the Part B follow-Up Visit) and for subjects transitioning to the long term 
access program a completed subject is one who has completed the Treatment Phase of 
Part B.
The end of the study is defined as the last subject’s last visit.
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
44
6.
STUDY TREATMENT
6.1.
Investigational Product
Study Treatment
Product name:
Mepolizumab
Dosage form:
Mepolizumab (SB240563) 100 mg vial
Lyophile for reconstitution
Unit dose strength(s)/Dosage 
level(s):
40 and 100 mg
Route of Administration
Subcutaneous, upper arm or thigh.
Dosing instructions:
For subcutaneous injection only
Mepolizumab (SB-240563) is a humanised monoclonal antibody (IgG1, kappa) with 
human heavy and light chain frameworks.  Mepolizumab will be provided as a 
lyophilised cake in sterile vials for individual use.  The vial will be reconstituted with 
Sterile Water for Injection, just prior to use.  Further details of dose preparation and 
administration can be found in the Clinical Investigator’s Brochure (CIB), and the Study 
Reference Manual (SRM). 
The contents of the label will be in accordance with all applicable regulatory 
requirements.
6.2.
Dosage and Administration
Pharmacokinetic/Pharmacodynamic Phase (Part A)
Enrolled subjects in this study will be dosed with the following treatment:
Treatment Arm
SC dose
Mepolizumab 40 mg SC upper arm or thigh
Mepolizumab 40 mg SC
For subjects < 40 kg bodyweight at Visit 2 
(Week 0)
Mepolizumab 100 mg SC upper arm or 
thigh
Mepolizumab 100mg SC
For subjects ≥ 40 kg bodyweight at Visit 2 
(Week 0)
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
45
Long-Term Safety / Long-Term Pharmacodynamic Phase (Part B)
Treatment Arm
SC dose
Mepolizumab 40mg SC upper arm or thigh
Mepolizumab 40 mg SC
For subjects with bodyweight <40 kg at 
Visit 9 (Week 20) and at any subsequent 
visits
Mepolizumab 100mg SC upper arm or 
thigh
Mepolizumab 100mg SC
For subjects with bodyweight ≥40kg at 
Visit 9 (Week 20) or from the visit at 
which bodyweight reaches 40 kg)
Preparation of Investigational Product (Part A and Part B)
Site staff member assigned to the study will be required to prepare the appropriate 
medication according to the study subject’s treatment assignment. Subjects eligible to 
enter the study will be assigned to treatment based on bodyweight at Visit 2. Assigned 
dose will remain the same irrespective of bodyweight changes during the treatment phase
of Part A.   Within Part B the subject’s dose will be adjusted to 100mg SC from the time 
the subject’s bodyweight reaches 40 kg.
Prior to administration, each vial of mepolizumab will need to be reconstituted and 
swirled gently to enable complete dissolution of the product.  Detailed instructions can be 
found within the Study Reference Manual (SRM).  Subjects assigned to the 40 mg 
treatment group will receive 0.4 mL of reconstituted mepolizumab.  Subjects assigned to 
the 100 mg treatment group will receive 1.0 mL of reconstituted mepolizumab.  Injected 
volume may be split between two injection sites for subjects receiving 100 mg (1.0 mL) 
and given as 2x0.5mL injections.  Investigator should consider the use of a local 
anaesthetic at the injections sites.
6.3.
Compliance with Study Treatment Administration
All study treatment will be administered at a clinic visit. The dose will be administered 
by clinic staff in accordance with specific guidance in the Study Reference Manual. 
When the individual SC dose for a subject is prepared from a bulk supply, the preparation 
of the dose will be confirmed by a second member of the study site staff. Subjects will 
receive study treatment directly from the investigator or designee, under medical 
supervision.  The injection volume (mL); and date and time of each dose administered in 
the clinic will be recorded in the source documents.  The dose of study treatment and 
study subject identification will be confirmed at the time of dosing by a member of the 
study site staff other than the person administering the study treatment.  Study drug 
administration (injection volume, date, and time) will be reported in the eCRF.
6.4.
Blinding
This will be an open-label study; therefore, investigators have direct access to the 
subject’s individual study treatment. 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
46
6.5.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
6.6.
Preparation/Handling/Storage/Accountability
Mepolizumab must be stored in a refrigerator or at a temperature of 2-8C and protected 
from light. Maintenance of a temperature log (manual or automated) is required. 
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 
be dispensed or administered only to subjects enrolled in the study and in accordance 
with the protocol.
Under normal conditions of handling and administration, investigational product is not 
expected to pose significant safety risks to site staff.  Take adequate precautions to avoid 
direct eye or skin contact and the generation of aerosols or mists. Notify the monitor of 
any unintentional occupational exposure.  A Material Safety Data Sheet (MSDS) 
describing the occupational hazards of mepolizumab and recommended handling 
precautions will be provided to site staff if required by local laws or will otherwise be 
available from GSK upon request.
A description of the methods and materials required for mepolizumab will be detailed in 
the Study Reference Manual (SRM).

Only subjects enrolled in the study may receive study treatment and only authorized 
site staff may supply or administer study treatment.  All study treatments must be 
stored in a secure environmentally controlled and monitored (manual or automated) 
area in accordance with the labelled storage conditions with access limited to the 
investigator and authorized site staff. 

The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation and final disposition records).  

Further guidance and information for final disposition of unused study treatment are 
provided in the SRM. 

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.  

A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from 
GSK.
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
47
6.7.
Treatment of Study Treatment Overdose
The dose of mepolizumab considered to be an overdose has not been defined. There are 
no known antidotes and GSK does not recommend a specific treatment in the event of a 
suspected overdose. The investigator will use clinical judgement in treating the symptoms 
of a suspected overdose.
6.8.
Treatment after the Completion of Part A and Part B
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the patient’s medical condition whether or not GSK is providing specific 
continuing study treatment under Part B of this study.
At the end of Part A, a benefit/risk assessment will be performed by the Investigator and 
if this assessment supports continued therapy with mepolizumab the subject will be 
offered the opportunity to enrol in Part B following the Part A Follow-up visit (Visit 8).  
Part B will continue for 52 weeks of additional mepolizumab treatment.  
At the end of Part B, when feasible, subjects will transition to a long term access
program.  At the end of the Treatment Phase of Part B, subjects that are not able to 
transition to the long term access program will return to usual care and will be prescribed 
appropriate alternative asthma therapy, as required.  
6.9.
Concomitant Medications and Non-Drug Therapies
6.9.1.
Permitted Medications and Non-Drug Therapies
All concomitant medications taken during the study will be recorded on the electronic 
Case Report Form (eCRF).  Asthma medications taken during the 12 months prior to 
Visit 1 should be recorded in the eCRF.  The minimum requirement is that drug name 
and all dates of administration are to be recorded.  Permitted medications include:

Existing stable asthma therapy (inhaled fluticasone propionate (DPI) or equivalent, 
total daily dose greater than or equal to 200 mcg or equivalent daily) will be 
permitted during the run-in and active treatment period.  Current treatment with an 
additional controller medication [e.g., long-acting beta-2-agonist (LABA), 
leukotriene receptor antagonist (LTRA), or theophylline] will be permitted during 
the run-in and active treatment period.

Short acting beta 2 agonist inhalation aerosol (albuterol/salbutamol) will be 
permitted as rescue medication for symptomatic relief of asthma symptoms.  
Albuterol/salbutamol will be provided locally (except for US sites where it will be 
provided by the GSK Global Supply Organisation) and dispensed at each visit from 
Screening Visit 1, as required.

Oral corticosteroids

Low potency topical corticosteroids (≤1% hydrocortisone).

Acetaminophen. 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
48
Other concomitant medication may be considered on a case by case basis by the GSK 
Medical Monitor.
No changes in the dose or regimen of baseline ICS and/or additional controller 
medication are permitted during the run-in period.
6.9.2.
Prohibited Medications and Non-Drug Therapies
Table 2 lists those medications that are prohibited from use during the study.
Table 2
Prohibited Medications
Medication

Investigational drugs other than mepolizumab

Antibody asthma therapeutics (e.g. Xolair)

Experimental anti-inflammatory drugs (non biologicals)

Immunosuppressive medications1

Methotrexate, troleandomycin, cyclosporin, azathioprine 

Oral gold

Chemotherapy used for conditions other than asthma

Regular systemic (oral or parenteral) corticosteroids for the treatment of 
conditions other than asthma or for treatment of hypoadrenalism
1.
The list of immunosuppressives provided contains commonly used example medications. The list is 
not all-inclusive and other known immunosuppressive medications not listed are also prohibited.
7.
STUDY ASSESSMENTS AND PROCEDURES
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.
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Tables (Table 3 and 
Table 4).
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
49
Table 3
Time and Events Table - Pharmacokinetic/Pharmacodynamic Phase (Part A)
Procedure
Pre-Screen1
Screening
Treatment Period
Exit 
Visit3
Follow-up 
Early 
Withdrawal
Visit Number 
0
1
2
3
4
5
6
7
88
Week of Study 
(visit window   3 days, ±1 day Visit 5))
Prior to or same 
day as Visit 1
(up to 14 days 
prior to Visit 2)
0
4
8
9
12
16
20
Subject Screen
Informed consent
X
Inclusion and exclusion criteria
X
X
Demography
X
Medical history, including bronchodilator 
reversibility history4
X
Past and current medical conditions 
X
Asthma exacerbation history 
X
Safety Assessments
Concomitant medications
X
X
X
X
X
X
X
X
X
X
Hematology (including eosinophils)
X
X
X
X
X
X
X
X
X
Clinical Chemistry
X
X
X
X
X
X
12-lead ECG
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
Bodyweight
X
Brief physical examination
X
Adverse events
X
X
X
X
X
X
X
X
X
Cardiovascular events
X
X
X
X
X
X
X
X
X
Liver events
X
X
X
X
X
X
X
X
X
Laboratory Assessments
Urinalysis
X
X
X
Pregnancy Test
U
U5
U5
U5
U
U
U
U
HBsAg and hepatitis C antibody
X6
Serum IgE (total)
X5
PK blood sample
X5
X5
X
X
X
X
X
 
 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
50
Procedure
Pre-Screen1
Screening
Treatment Period
Exit 
Visit3
Follow-up 
Early 
Withdrawal
Visit Number 
0
1
2
3
4
5
6
7
88
Week of Study 
(visit window   3 days, ±1 day Visit 5))
Prior to or same 
day as Visit 1
(up to 14 days 
prior to Visit 2)
0
4
8
9
12
16
20
IL5 serum sample
X5
X
Blood sample for immunogenicity2,7
X5
X
X2
X
Outcomes Assessments
FEV1
X
X
X
X
X
X
X
X
ACQ-7
X
X
X
X
X
X
X
C-ACT
X
X
X
X
X
X
X
Assessment of exacerbation
X
X
X
X
X
X
X
X
X
X
Investigational Product
Mepolizumab SC dose administered
X
X
X
Study Administration
Email to GSK Operational Lead
X
X
X
X
X
X
X
X
X
X
Complete eCRF
X
X
X
X
X
X
X
X
X
X
1.
Pre-screen must be completed prior to or on the same day as Screen Visit. 
2.
For subjects who had a positive anti-mepolizumab antibody response at the 12 week post-last-dose follow-up assessment (Visit 8) (or last study visit at which immunogenicity was 
assessed if the Follow-up (Visit 8) immunogenicity sample is not available) an attempt will be made to obtain a serum sample for anti-mepolizumab antibodies at least 4 months 
after the last dose of study drug in Part A or upon completion of Part A, whichever is later.
3.
Exit visit should be performed as close as possible to the planned week 12 visit date.
4.
Therapy history to include a detailed review of prior biologics received for treatment of asthma, including prior investigational anti-IL5 or anti-IL13 preparations.
5.
During the treatment period, all lab samples and procedures should be obtained prior to study treatment administration.
6.
A positive Hepatitis B Surface Antigen and Hepatitis C antibody is exclusionary
7.
This immunogenicity sample must always be collected 12 weeks (7 days) post-last-dose of study treatment; therefore, for subjects who withdraw from study treatment early, this 
sample must be collected 12 weeks (7 days) after their confirmed last dose of study treatment (i.e., prior to Visit 8). In the event that this sample collection date coincides with an 
Early Withdrawal Visit, only one immunogenicity sample should be collected.
8.
Visit 8 to be performed 12 weeks post last dose. For subjects continuing into the long-term extension phase Part B, Visit 9 should be conducted on the same day as Visit 8 once 
all of the visit 8 assessments have been completed.  Assessments performed at Visit 8 that are also listed for Visit 9 should not be duplicated if Visit 8 and Visit 9 are performed on 
the same day.
 
 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
51
Table 4
Time and Events Table Long-Term Safety / Pharmacodynamic Phase (Part B)
Procedure
Eligibility 
Check / 
First 
Dose
Treatment Period
Exit 
Visit
Follow-up3
Early 
Withdrawal
Visit
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Week of Study 
(visit window 5 days)
20
24
28
32
36
40
44
48
52
56
60
64
68
72
80
Subject Screen
Informed consent
X1
Inclusion and exclusion criteria
X1
Safety Assessments
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology (including 
eosinophils) 2
X
X
X
X
X
X
X
X
Clinical Chemistry2
X
X
X
X
X
X
X
12-lead ECG
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Bodyweight
X
X1
X1
X1
X1
X1
X1
X1
X1
X1
X1
X1
X1
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Cardiovascular events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Liver events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments2
Urinalysis
X1
X
X
X
Pregnancy Test
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
Blood sample for 
immunogenicity2
X
X
X
X
Outcomes Assessments
FEV1
X1
X
X
X
X
X
X
X
ACQ-7
X1
X
X
X
X
X
X
X
C-ACT
X1
X
X
X
X
X
X
X
 
 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
52
Procedure
Eligibility 
Check / 
First 
Dose
Treatment Period
Exit 
Visit
Follow-up3
Early 
Withdrawal
Visit
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Week of Study 
(visit window 5 days)
20
24
28
32
36
40
44
48
52
56
60
64
68
72
80
Assessment of exacerbation
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Investigational Product
Mepolizumab SC dose 
administered
X
X
X
X
X
X
X
X
X
X
X
X
X
Study Administration
Email to GSK Operational Lead
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete eCRF
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
1.
Bodyweight will be measured at Visit 9 and at each visit until such time as the subject reaches 40kg in weight. Subjects with bodyweight ≥40Kg at Visit 9 will not be weighed again 
during Part B.
2.
All laboratory samples should be collected prior to the administration of study medication
3.
The 12-week post-dose follow-up visit (Visit 23) is not required for subjects transitioning to the long-term access program.
 
 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
53
7.1.
Screening and Critical Baseline Assessments
7.1.1.
Pre-Screening Failures (Visit 0)
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 further will be considered a 
pre-screen failure.  Note:  Visit 0 (Pre-Screening) and Visit 1 (Screening) may be 
conducted on the same day as part of the same clinic visit.  Visit 0 is required to ensure 
full accountability of eligible and non-eligible subjects offered participation in this study.
The following information will be collected for subjects who are pre-screen failures:
a.
Date of ICF signature
b.
Details of asthma medications within 30 days of Visit 0
c.
Details of asthma exacerbation between date of  informed consent and pre-screening, 
if applicable
d.
Serious adverse events (SAEs) that occur between the date of informed consent form  
and  Screening Visit  if related to study participation are recorded in inform and on a 
paper SAE form and sent to GSK safety within 24 hours
e.
Demographic information including age, gender, race and ethnicity
f.
Subject number
g.
Investigator signature page
7.1.2.
Screening (Visit 1)
A subject not considered a Pre-Screen Failure will continue further with the assessments 
for Visit 1 per Table 3
7.2.
Safety
Planned time points for all safety assessments are listed in the Time and Events Tables
(Table 3 and Table 4).  Additional time points for safety tests may be added during the 
course of the study based on newly available data to ensure appropriate safety 
monitoring.
7.2.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 
In line with clinical practice, monitoring of patients following administration of a 
biologic agent including mepolizumab should be done to detect and report the occurrence 
of systemic (i.e., allergic/hypersensitivity and non-allergic) reactions.  Hypersensitivity 
reactions will be monitored using the diagnostic criteria for anaphylaxis as outlined by 
the 2006 Joint NIAID/FAAN Second Symposium on Anaphylaxis [Sampson, 2006] 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
54
(Appendix 9). Information will be also collected on the occurrence of local injection site 
reactions.
7.2.1.1.
Definition of an Adverse Event (AE)
Any untoward medical occurrence in a patient or clinical investigation subject, 
temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product.
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.  For marketed medicinal products, this 
also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse.
Events meeting the definition of an AE include:

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study

Signs, symptoms, or the clinical sequelae of a suspected interaction

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE) unless this is an intentional overdose taken with possible suicidal/self-
harming intent. This should be reported regardless of sequelae.
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. However, the signs and symptoms and/or clinical sequelae 
resulting from lack of efficacy will be reported if they fulfil the definition of an AE or 
SAE.  
Events that do not meet the definition of an AE include:

Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that 
leads to the procedure is an AE

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital)

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen

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
7.2.1.2.
Definition of a Serious Adverse Event (SAE)
A serious adverse event is any untoward medical occurrence that, at any dose:
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
55
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 hospitalization or prolongation of existing hospitalization
NOTE:  In general, hospitalization 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 hospitalization are 
AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.
Hospitalization 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 hospitalization but may jeopardize 
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 hospitalization, 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 urinary bilirubin detectable 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.   
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
56
7.2.1.3.
Time period and Frequency for collecting AE and SAE information

AEs and SAEs will be collected from the start of Study Treatment until the follow-
up contact (see Section 7.2.1.5), at the timepoints specified in the Time and Events 
Table (Table 3 and Table 4).

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the eCRF.

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK product 
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 recorded and reported to GSK within 24 hours, as indicated in 
Appendix 3.

Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the study treatment or study participation, the investigator 
must promptly notify GSK.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 3.
7.2.1.4.
Method of Detecting AEs and SAEs
Care will 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 does your child seem to feel?”

“Has your child had any (other) medical problems or seem to act differently in any 
way since his/her last visit/contact?”

“Has your child needed to take any medicines, other than those provided in this 
study, since his/her last visit/contact?”
7.2.1.5.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All SAEs and non-serious AEs of special interest 
will be followed until resolution, until the condition stabilizes, until the event is otherwise 
explained, or until the subject is lost to follow-up (as defined in Section 5.5). Further 
information on follow-up procedures is given in Appendix 3.
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
57
7.2.1.6.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK of SAEs and non-serious AEs related to 
study treatment (even for non- interventional post-marketing studies) is essential so that 
legal obligations and ethical responsibilities towards the safety of subjects and the safety 
of a product under clinical investigation are met. 
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
7.2.2.
Pregnancy
The investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study.  The investigator will record pregnancy 
information on the appropriate form and submit it to GSK within 2 weeks of learning of a 
subject's pregnancy.  The subject will also be followed to determine the outcome of the 
pregnancy.  Information on the status of the mother and child will be forwarded to GSK.  
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery 
date.  Any premature termination of the pregnancy will be reported.
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be recorded 
as an AE or SAE.
A spontaneous abortion is always considered to be an SAE and will be reported as such.  
Furthermore, any SAE occurring as a result of a post-study pregnancy and is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK as 
described in Section 12.3.6. While the investigator is not obligated to actively seek this 
information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.
Any female subject who becomes pregnant while participating will have study treatment 
discontinued, but will be requested to continue study visits through the Follow-up phase. 
7.2.3.
Physical Exams

A brief physical examination will include, at a minimum assessments of the lungs, 
cardiovascular system, and abdomen (liver and spleen).
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
58

Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
7.2.4.
Vital Signs
Sitting pulse rate and blood pressure measurements will be performed by the investigator 
or qualified site staff, as outlined in Time and Events schedule (Table 3 and Table 4). 
Measurements will be done pre-infusion/injection with the subject sitting, having rested 
in this position for at least 5 minutes before each reading.  They will be taken before 
measurement of any clinic lung function tests or ECGs at the specified time point.
7.2.5.
Electrocardiogram (ECG)
Twelve-lead ECGs will be performed at the visits specified in the Time and Events 
schedule (Table 3 and Table 4).  
Electrocardiogram measurements will be made after the subject has rested in the supine 
position for 5 minutes.  The ECG should be obtained before lung function testing
followed by other study procedures.  Collection shortly after a meal or during sleep 
should be avoided since QT prolongation can occur at these times.
Investigators will be provided with ECG machines by GSK through a designated central 
laboratory. Paper ECG traces will be recorded at a standard paper speed of 25 mm/sec 
and gain of 10mm/mV, with a lead II rhythm strip. There will be electronic capture and 
storage of the data by a validated method, with subsequent transferral to the central 
laboratory for manual reading and calculation of the electrocardiographic parameters.  
Subjects with evidence of significant abnormality in the 12-lead at screening will be 
excluded from enrolment into the Part A treatment phase.
Paper traces are required to be maintained at the site with other source documents.
7.2.6.
Clinical Safety Laboratory Assessments
Clinical laboratory tests will be conducted at the visits specified in the Time and Events 
schedule (Table 3 and Table 4).  Hematology, clinical chemistry, urinalysis and 
additional parameters to be tested are listed below:
Table 5
Laboratory Evaluations
Hematology
Platelet Count
RBC Indices:
Automated WBC Differential:
RBC Count
MCV
Neutrophils
WBC Count (absolute) 
MCH
Lymphocytes
Reticulocyte Count
MCHC
Monocytes
Hemoglobin
Eosinophils
Hematocrit
Basophils
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
59
Clinical Chemistry
BUN
Potassium
AST (SGOT)
Total and direct bilirubin
Creatinine
Chloride
ALT (SGPT)
Uric Acid
Glucose, 
Total CO2
GGT
Albumin
Sodium
Calcium
Alkaline phosphatase
Total Protein
Routine Urinalysis
Specific gravity, pH, glucose, protein, blood and ketones by dipstick
Microscopic examination (if blood or protein is abnormal)
All blood samples which will be taken prior to each administration of study medication 
will be sent to a central laboratory for analysis (details provided in the Q2 Solutions 
Investigator Manual). Standard reference ranges will be used.  
Full details of the collection and shipping requirements for the central laboratory are 
provided in the Quest Diagnostics Clinical Trials Investigator Manual.  The central 
laboratory will fax laboratory results to the Investigator and will transmit the results 
electronically to GlaxoSmithKline. 
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 only use samples collected from the study 
for the purpose stated in this protocol and in the informed consent form.  Subjects may 
request that their samples are destroyed at any time.
7.3.
Pharmacokinetics
Blood samples for analysis of mepolizumab plasma concentration will be obtained as per 
the Part A Time and Events table (Table 3).  Samples obtained at visit 3 and 4 must be 
drawn prior to mepolizumab dosing.  The date and exact time of collection for each 
sample will be documented in the eCRF.
Details for collection and processing of samples may be found in the Q2 Solutions 
Investigator Manual.
7.4.
Pharmacodynamics
Blood eosinophil counts will be recorded as part of the standard haematological 
assessments performed at the visits specified in the Time and Events table (Table 3 and 
Table 4).  
7.5.
Immunogenicity
Blood samples will be collected for the determination of anti-mepolizumab antibodies, 
prior to dosing at Visit 2 (Week 0), and subsequently at Visit 7 (Week 16), and at Visit 8 
(Week 20) and Early Withdrawal. 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
60
For subjects who had a positive anti-mepolizumab antibody response at the Follow-up 
(Visit 8) (or last study visit at which immunogenicity was assessed if the Follow-up (Visit 
8) immunogenicity sample is not available), an attempt will be made to obtain a serum 
sample for anti-mepolizumab antibodies at least 4 months after the last dose of study drug 
in Part A or upon completion of Part A, whichever is later.
In Part B, immunogenicity samples will be collected prior to dosing at Visit 15 (week 
44), Visit 21 (week 68) and, when applicable, at Follow-up Visit 23 (week 80) and Early 
Withdrawal.
Details for sample collection and processing may be found in the Q2 Solutions 
Investigator Manual.
7.6.
Forced Expiratory Volume-1 (FEV1)
To permit investigator staff completion of the ACQ-7 questionnaire (Section 7.7 below) 
spirometry will be conducted, using the site’s own equipment at the visits specified in the 
Time and Events schedule (Table 3 and Table 4).  The spirometer should meet American 
Thoracic Society standards and produce a printout of all data generated, which should be 
stored in the subject’s notes.  The spirometer should be calibrated in accordance with the 
manufacturer’s instructions and a calibration log maintained. Spirometry must be 
performed at the same time (1 hour) of the Visit 2 spirometry. Subjects should try to 
withhold short-acting beta-2-agonists (SABAs) for ≥6 hours and LABAs for 12 hours 
prior to clinic visit, if possible. Assessments to be recorded will include FEV1, and FVC.   
For predicted FEV1 values, reference is made to the multi-ethnic reference values for 
spirometry for the 3-95-yr age range: using the Global Lung Function Initiative 2012 
equations and look-up tables (Quanjer, 2012).  See the Study Reference Manual (SRM)
for further details
7.7.
Asthma Control Questionnaire-7 (ACQ-7)
The ACQ-7 (Juniper, 1999, Juniper, 2005, Juniper, 2006, Juniper, 2010) will be 
administered by a trained clinic staff member at each visit indicated in the Time and 
Events schedule (Table 3 and Table 4).  The ACQ-7 is a simple questionnaire to measure 
the adequacy of asthma control and change in asthma control which occurs either 
spontaneously or as a result of treatment (Appendix 5).  The questionnaire includes 7 
items; and requires a 1 week recall (for items on symptoms and rescue inhaler use).  The 
ACQ-IA has a multidimensional construct assessing symptoms (5 items administered by 
clinic staff to the child using the interviewer administer format) and rescue 
bronchodilator use (query to child or parent), and FEV1% (1 item) completed by clinic 
staff (Appendix 6).  The ACQ-7 uses a 7-point scale (0=no impairment, 6= maximum 
impairment for symptoms and rescue use; and 7 categories for FEV1%).  The instrument 
has a reported high test-retest reproducibility with an intraclass correlation coefficient 
=0.90.  The minimally important change in score is 0.5. The ACQ-IA will be 
administered to subjects for whom an appropriate translation is available. If necessary, 
the draft ACQ-IA will be administered until a final linguistically validated version 
becomes available. The draft version of the ACQ-IA includes the linguistically validated 
ACQ-7 items, final instructions for each language and draft alternative item prompts to 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
61
facilitate administration to children.  Use of the ACQ-7 is authorized by permission of the 
author.
7.8.
Childhood Asthma Control Test (C-ACT)
The Childhood Asthma Control Test (C-ACT) assesses asthma control in children 4-11 
years of age (Liu, 2007, Liu, 2010). The ACT will be completed on paper. The C-ACT 
should be completed prior to other study procedures to ensure that responses are not 
influenced by interactions with study site staff.  The C-ACT is a 7-question, 2-part 
questionnaire, with items one through 4 to be completed by the child (with assistance 
from a caregiver, as needed) and items 5 to 7 to be completed by the caregiver (Appendix 
10).   A total sum score based upon responses to all items is calculated to provide an 
overall measure of asthma control. 
7.9.
Asthma Exacerbations
At each study visit the investigator will make an assessment of the occurrence of an 
asthma exacerbation.  Any asthma exacerbation will be recorded on the appropriate eCRF 
page.
An exacerbation of asthma as defined as:
Worsening of asthma which requires use of systemic corticosteroids1and/or 
hospitalisation and/or Emergency Department (ED) visits.
1For all subjects, i.v. or oral steroid (e.g., prednisone) for at least 3 days or a single IM 
CS dose is required. For subjects on maintenance systemic corticosteroids, at least 
double the existing maintenance dose for at least 3 days is required. 
8.
DATA MANAGEMENT

For this study subject data will be entered into GSK defined CRFs, transmitted 
electronically to GSK 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 MedDRA 
(Medical Dictionary for Regulatory Activities) and an internal validated medication 
dictionary, GSKDrug.  

CRFs (including queries and audit trails) will be retained by GSK, and copies will be 
sent to the investigator to maintain as the investigator copy.  Subject initials will not 
be collected or transmitted to GSK according to GSK policy.
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
62
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
No formal hypothesis will be tested.  
Population-PK (Pop-PK) parameter estimates will be presented (AUC(0-inf), clearance, 
Cmax, t1/2).  Descriptive statistics will be used to present the subject demographics, 
subject study accountability, post-hoc individual pharmacokinetic parameter estimates 
(e.g. AUC(0-inf), clearance, Cmax, t1/2), blood eosinophil count and ratio of blood eosinophil 
count to baseline at week 12, IL5 levels, selected clinical outcome measures (FEV1, 
ACQ-7, C-ACT, asthma exacerbations), and safety assessments (adverse events, vital 
signs, ECGs and laboratories) and immunogenicity.  Confidence intervals may be applied 
where appropriate.  In addition a pre-planned analysis comparing the bodyweight-
adjusted clearance between adults and subjects 6-11 years with severe eosinophilic 
asthma will be conducted, with appropriate confidence intervals applied.
Details of the statistical considerations and data analyses will be detailed in the Reporting 
and Analysis Plan (RAP). 
9.1.
Hypotheses
Formal hypothesis testing will not be performed.
9.2.
Sample Size Considerations
The sample size was determined by the number of subjects needed for the PK and PD 
evaluations of Part A of the study, based on previous PK/PD studies. A pediatric 
population-PK trial simulation (GSK Document Number 2014N223495_00) was used to 
determine the Root Mean Square Error (RMSE, i.e. standard deviation) in estimated 
exposure (AUC(0-inf) ) as a function of sample size, pharmacokinetic sampling scheme and 
model assumptions. Based on 1000 trial simulations per scenario, a sample size of 16-32 
subjects is sufficient to maintain precision in exposure estimation (and hence 
bodyweight-adjusted clearance) below 20%, (as compared with the  guideline 40%), 
providing five pharmacokinetic samples (including one close to Tmax) are collected and 
four parameters are fixed from adult values in the population-PK model.
For blood eosinophils it is expected that this trial will have a similar residual variance to 
that observed in the MEA115588 trial, where a residual SD of 0.7867 on the log 
transformed scale was observed. Based on this assumption, a total of 20 subjects should 
provide sufficient precision for the 95% confidence interval for the ratio to baseline to lie 
within a ratio of 50% of the observed value. For example if the observed ratio to baseline 
for blood eosinophils is 0.14, the reduction observed in trial MEA115588, the 95% 
confidence interval is expected to be from 0.09 to 0.20.
With regards to the pre-planned secondary analysis, the trial simulations also showed that 
for the proposed sample size and sampling scheme, 80% of simulated trials yielded a 
bodyweight-adjusted apparent clearance with 90% confidence limits falling within the 
bounds 0.8 – 1.25 of the adult apparent clearance value (CL/F of 0.29 L/day). This 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
63
precision is deemed sufficient for extrapolation purposes from adults to pediatric subjects 
aged 6 to 11 years supported by this study (GSK Document Number 2014N223495_00).
Patients who complete Part A and who meet the eligibility criteria for Part B will be 
allowed to participate in Part B and no specific sample size requirements are defined.
9.2.1.
Sample Size Assumptions
No sample size assumptions are assumed beyond the demonstrated comparability 
between adult pharmacokinetic parameters and those observed in an intravenous study in 
children aged 2-17 years with eosinophilic esophagitis.
9.2.2.
Sample Size Sensitivity
Further details of the PK trial simulation sample size estimation methodology are 
provided in GSK Document Number 2014N223495_00. 
9.2.3.
Sample Size Re-estimation or Adjustment
No sample size re-estimation or adjustment will be performed.
9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations Part A
9.3.1.1.
Safety Population Part A
All subjects receiving at least one dose of mepolizumab beginning at Visit 2 will be 
included in the safety population for Part A analyses.
9.3.1.2.
Pharmacokinetic Population Part A
All subjects receiving at least one dose of mepolizumab beginning at Visit 2 and having 
at least one blood sample taken at Visit 3 or thereafter with measurable mepolizumab 
plasma concentration will be included in the pharmacokinetic population for Part A 
analyses.  
9.3.1.3.
Pharmacodynamic Population (Blood Eosinophils) Part A
All subjects receiving at least one dose of mepolizumab beginning at Visit 2 and having 
at least one blood sample taken for blood eosinophil count post dosing at Visit 2 will be 
included in the pharmacodynamic population (blood eosinophils) for Part A analyses.
9.3.1.4.
Pharmacodynamic Population (Outcome Assessments) Part A
All subjects receiving at least one dose of mepolizumab beginning at Visit 2  and having 
at least one assessment of pharmacodynamic outcomes (ACQ-7, ACT, asthma 
exacerbation, or FEV1,) post dosing at Visit 2 will be included in the pharmacodynamic 
population (outcomes) for Part A analyses.
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
64
9.3.1.5.
Safety Population Part B
All subjects receiving at least one dose of study medication beginning at Visit 9 will be 
included in the safety population for Part B analyses.
9.3.1.6.
Pharmacodynamic Population (Blood Eosinophils) Part B
All subjects receiving at least one dose of mepolizumab beginning at Visit 9 and having 
at least one blood sample taken for blood eosinophil count post dosing at Visit 9 will be 
included in the pharmacodynamic population (blood eosinophils) for Part B analyses.  
9.3.1.7.
Pharmacodynamic Population (Outcome Assessments) Part B
All subjects receiving at least one dose of mepolizumab beginning at Visit 9 and having 
at least one assessment of pharmacodynamic outcomes (ACQ-7, ACT, asthma 
exacerbation, or FEV1,) post dosing at Visit 9 will be included in the pharmacodynamic 
population (outcomes) for Part B analyses.
9.3.2.
Interim Analysis
A full interim analysis is planned at the completion of the 
Pharmacokinetic/Pharmacodynamic Phase (Part A) of this study.  All eCRF data will be 
monitored, queried, and a soft-database lock will be performed on all subject data 
through Visit 8 following last subject achieving Visit 8.  A statistical output will be 
prepared in accordance with all study objectives and endpoints for Part A.
9.4.
Key Elements of Analysis Plan (Part A)
9.4.1.
Primary Analyses
The primary endpoints of plasma mepolizumab PK parameters will be evaluated by 
population PK methods. A number of pharmacokinetic parameters will be fixed from 
adult values in support of the sparse sampling, and estimated population-PK parameter 
estimates will be provided. Additionally, the post-hoc individual PK parameter estimates 
(including the derived parameters e.g. AUC(0-inf), clearance, Cmax and t1/2) will be 
summarised using descriptive statistics, when appropriate. 
Blood eosinophil count, the primary pharmacodynamic endpoint, will be log transformed 
prior to analysis and will also be summarised using descriptive statistics.  
Confidence intervals will be presented when appropriate. The analysis schema will be 
outlined in the RAP.
9.4.2.
Secondary Analyses
Secondary endpoints including ACQ-7, C-ACT, incidence in adverse events, frequency 
of positive anti-mepolizumab antibodies, and clinically significant changes in laboratory 
parameters and vital signs will be summarised using descriptive statistics. Formal 
hypothesis testing will not be performed. 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
65
The comparison of bodyweight-adjusted clearance between the 6-11 year olds and adults 
will be made by comparing the point estimate and 90% CI of bodyweight-adjusted 
clearance in this study with the historic value in adults of L/day (corresponding to an 
apparent clearance of 0.29 L/day assuming an absolute bioavailability of 75%) along with 
a proposed 80-125% interval around this estimate (i.e., 0.18-0.28 L/day).
Confidence intervals will be presented when appropriate. The analysis schema will be 
outlined in the RAP.
9.4.3.
Exploratory Analyses
Exploratory endpoints of number of asthma exacerbations both on- and post-
mepolizumab treatment and FEV1 will be summarised using descriptive statistics.  
Confidence intervals will be presented when appropriate. The analysis schema will be 
outlined in the RAP.
9.5.
Key Elements of Analysis Plan (Part B)
9.5.1.
Primary Analysis
The incidence in adverse events, frequency of positive anti-mepolizumab antibodies, and 
clinically significant changes in laboratory parameters and vital signs will be summarised 
using descriptive statistics. 
9.5.2.
Secondary Analyses
Blood eosinophil count will be log transformed prior to analysis and will also be 
summarised using descriptive statistics.  
9.5.3.
Exploratory Analyses
Exploratory endpoints including ACQ-7, C-ACT and number of exacerbations will be 
summarised using descriptive statistics, Confidence intervals will be presented when 
appropriate. The analysis schema will be outlined in the RAP.
10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a site, GSK will obtain favorable 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.
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
66
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki.  This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable

Signed informed consent  to be obtained for each subject before participation in the 
study (and for amendments as applicable)

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol deviations 
to IRB/IEC)

GSK will provide full details of the above procedures, either verbally, in writing, or 
both.
10.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including 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 also include 
identification, agreement and documentation of data items for which the CRF will 
serve as the source document.
GSK will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and 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
10.4.
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.
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
67
10.5.
Study and Site Closure

Upon completion or premature discontinuation of the study, the GSK monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and GSK Standard Operating 
Procedures.

GSK reserves the right to temporarily suspend or prematurely discontinue this study 
at any time for reasons including, but not limited to, safety or ethical issues or severe 
non-compliance. For multicenter studies, this can occur at one or more or at all sites.  

If GSK determines such action is needed, GSK will discuss the reasons for taking 
such action with the investigator or the head of the medical institution (where 
applicable).  When feasible, GSK will provide advance notification to the 
investigator or the head of the medical institution, where applicable, of the 
impending action.

If the study is suspended or prematurely discontinued for safety reasons, GSK will 
promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action.  

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation.
10.6.
Records Retention

Following closure of the study, the investigator or the 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 maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review in 
conjunction with assessment of the facility, supporting systems, and relevant site 
staff.  

Where permitted by local laws/regulations or institutional policy, some or all of these 
records can be maintained in a format other than hard copy (e.g., microfiche, 
scanned, electronic); however, caution needs to 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 and meet accessibility and retrieval standards, including 
re-generating a hard copy, if required.  Furthermore, the investigator must ensure 
there is an acceptable back-up of these reproductions and that an acceptable quality 
control process exists for making these reproductions.

GSK will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements.  The minimum retention time 
will meet the strictest standard applicable to that site for the study, as dictated by any 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
68
institutional requirements or local laws or regulations, GSK standards/procedures, 
and/or institutional requirements.  

The investigator must notify GSK of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of ownership 
of the records in the event the investigator is no longer associated with the site.
10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically 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.
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy.
One or more manuscripts will be progressed for publication in the scientific literature.
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
69
11.
REFERENCES
Assa'ad HA, Gupta KS, Collins HM, Thomson M, Heath TA, Smith AD, Perschy LT, 
Jurgensen HC, Ortega GH, Aceves SS. Treatment of Pediatric Eosinophilic Esophagitis 
with Mepolizumab: A Randomized, Double-blind, Controlled Clinical Trial. 
Gastroenterology. 2011; 141:1593-1604. 
Bel EH, Wenzel SE, Thompson PJ, Prazma CM,  Keene ON, Yancey SW, Ortega HG, 
and Pavord ID, for the SIRIUS Investigators.  Oral Glucocorticoid-Sparing Effect of 
Mepolizumab in Eosinophilic Asthma.  N Engl J Med 2014; 371:1189-1197 September 
25, 2014
Bossley CJ, Fleming L, Gupta A, Regamey N, Frith J, Oates T, et al. Pediatric severe 
asthma is characterized by eosinophilia and remodeling without T(H)2 cytokines. J 
Allergy Clin Immunol. 2012; 129:974-82 e13. 
Carlsen CLK, G. Hedlin G, Bush A, et al. Assessment of problematic severe asthma in 
children.  Eur Respir J 2011; 37: 432–440
Centers for Disease Control and Prevention (CDC). National Center for Health Statistics. 
Health Data Interactive. www.cdc.gov/nchs/hdi.htm. Asthma and Chronic Obstructive 
Pulmonary Disease: US, NHIS 2009-2011. May 15, 2013. 
Clutterbuck EJ, Hirts EME, Sanderson CJ et al. Human interleukin - 5 (IL-5) regulated 
the production of eosinophils in human bone marrow cultures: comparison and 
interaction with IL-1, IL-3, IL-6 and GM-CSF. Blood. 1989; 73:1504-13. 
Fitzpatrick AM, Higgins M., Holguin F, et al. The molecular phenotype of severe asthma 
in children. J Allergy Clin Immunol. 2010;125. 851-857.
Fitzpatrick, A. M., W. G. Teague, et al. Heterogeneity of severe asthma in childhood: 
confirmation by cluster analysis of children in the National Institutes of Health/National 
Heart, Lung, and Blood Institute Severe Asthma Research Program.  J Allergy Clin 
Immunol 2011;127:382-389.
Flood-Page P, Swenson C, Faiferman I, et al. International Mepolizumab Study Group. A 
study to evaluate safety and efficacy of Mepolizumab in patients with moderate persistent 
asthma. Am J Respir Crit Care Med. 2007;176:1062-71. 
Gevaert P, Lang-Loidolt D, Lackner A, et al. Nasal IL5 levels determine the response to 
anti-IL5 treatment in patients with nasal polyps. J Allergy Clin Immunol. 2006;118:1133-
41.
Giubergia V, Fridman N, González Pena H. Healthcare Program for Children with Severe 
Asthma: impact analysis. Arch Argent Pediatr 2012; 110:382-387.
Global Initiative for Asthma (GINA). 2015 GINA Report, Global Strategy for Asthma 
Management and Prevention,  . Available from: http://www.ginasthma.org. 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
70
GSK Document Number 2014N223495_00. Mepolizumab Paediatric Severe Asthma 
Population-Pharmacokinetic Trial Simulation. CPMS Clinical Pharmacology Modelling 
Report (December 2014).
GSK Document Number 2014N223530_00. Mepolizumab Severe Asthma Paediatric and 
Adolescent Dose Extrapolation. CPMS Clinical Pharmacology Modelling Report 
(December 2014).
Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation U.S. 
Department of Health and Human Services Food and Drug Administration Center for 
Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research 
(CBER) July 2009
Haldar P, Brightling CE, Hargadon B, Gupta S, Monteiro W, Sousa A, Marshall R, 
Bradding P, Green RH, Wardlaw AJ, Pavord ID. Mepolizumab and exacerbations of 
refractory eosinophilic asthma. N Engl J Med. 2009; 360:973-984. 
Jenkins HA, Cherniack R, Szefler SJ, Covar R, Gelfand EW, Spahn JD. A comparison of 
the clinical characteristics of children and adults with severe asthma. Chest. 2003; 
124:1318-24. 
Juniper EF, Bousquet J, Abetz L, Bateman ED. Identifying 'well-controlled' and 'not 
well-controlled' asthma using the Asthma Control Questionnaire. Respiratory Medicine 
2006 (100): 616–621.
Juniper EF, Gruffydd-Jones K, Ward S, Svensson K. Validation, measurement properties 
and interpretation of the Asthma Control Questionnaire in children. Eur Respir J 2010: 
36: 1410-1416
Juniper EF, O'Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of 
a questionnaire to measure asthma control. Eur Respir J 1999; 14: 902–907.
Juniper EF, Svensson K, Mork AC, Stahl E. Measurement properties and interpretation of 
three shortened versions of the asthma control questionnaire. Respiratory Medicine 2005 
(99): 553–558.
Kim YJ, Prussin C, Martin B et al. Rebound eosinophilia after treatment of 
hypereosinophilic syndrome and eosinophilic gastroenteritis with monoclonal anti-IL-5 
antibody SCH55700. J Allergy Clin Immunol. 2004;114(6):1449-1455.
Lane S, Molina J, ,Plusa T. An international observational prospective study to determine 
the Cost Of Asthma eXacerbations (COAX). Respiratory Medicine. Volume 100, Issue 3,
March 2006, Pages 434–450.
Liu AH, A, Gilsenan W, Stanford RH,  Lincourt W,  Ziemiecki R, and Ortega H.  Status 
of Asthma Control in Pediatric Primary Care: Results from the Pediatric Asthma Control 
Characteristics and Prevalence Survey Study (ACCESS). J Pediatr 2010;157:276-81.
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
71
Liu AH, Zeiger R, Sorkness C, Mahr T, Ostrom N, Burgess S, et al. Development and 
cross-sectional validation of the Childhood Asthma Control Test. J Allergy Clin Immunol 
2007;119:817-25.
Mepolizumab (SB-240563) Investigator’s Brochure. 2014. CM2003/00010/09 effective 
14Nov2014
O’Byrne PM, Pedersen S, Lamm CJ, et al. Severe exacerbations and decline in lung 
function in asthma. Am J Respir Crit Care Med 2009; 179: 19–24.
Ortega H, Yancy S, Cozens S. Pharmacokinetics and absolute bioavailability of 
mepolizumab following administration at subcutaneous and intramuscular sites. Clinical 
Pharmacology in Drug Development. published online: 13 SEP 2013 DOI: 
10.1002/cpdd.60. 
Ortega, HG, Liu, MC, Pavord ID, Brusselle, GG, FitzGerald JM, Chetta, A, Humbert M, 
Ph.D., n E. Katz, LE, Keene, ON, Yancey SW, and Chanez P, for the MENSA 
Investigators. Mepolizumab Treatment in Patients with Severe Eosinophilic Asthma. N 
Engl J Med 2014; 371:1198-1207September 25, 2014
Pavord ID, Korn S, Howarth P, et al.  Mepolizumab for severe eosinophilic asthma 
(DREAM): a multicentre, double-blind, placebo-controlled trial.  Lancet 2012;380:651-
59.
Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, Enright PL, Hankinson 
JL, Ip MS, Zheng J, Stocks J; ERS Global Lung Function Initiative. Multi-ethnic 
reference values for spirometry for the 3-95-yr age range: the global lung function 2012 
equations. Eur Respir J. 2012 Dec; 40(6):1324-43.
Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, Branum A, 
et al. Second symposium on the definition and management of anaphylaxis: summary 
report--second National Institute of Allergy and Infectious Disease/Food Allergy and 
Anaphylaxis Network symposium. J Allergy Clin Immunol 2006(2);117:391-397.
Sears, M. R., Greene, J. M., Willan, A. R., Wiecek, E. M., Taylor, D. R., Flannery, E. M., 
Cowan, J. O., Herbison, G. P., Silva, P. A. and Poulton, R. A longitudinal, population-
based, cohort study of childhood asthma followed to adulthood. N. Engl. J. Med. 2003; 
349:1414–1422
Sorser AS, Barawi M, Hagglund K, Almojaned M, Lyons H. Eosinophilic esophagitis in 
children and adolescents: epidemiology, clinical presentation and seasonal variation. J 
Gastroenterol (2013) 48:81–85.
Stern, D. A., Morgan, W. J., Halonen, M., Wright, A. L. and Martinez, F. D. Wheezing 
and bronchial hyper-responsiveness in early childhood as predictors of newly diagnosed 
asthma in early adulthood: a longitudinal birth-cohort study. Lancet 2008; 372: 1058–
1064
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
72
Szefler SJ, James F. Chmiel JF, Fitzpatrick AM, George Giacoia G, Green TP,  Jackson 
DJ, Nielsen HC, Phipatanakul W, Raissy HH. Asthma across the ages: Knowledge gaps 
in childhood asthma. Journal of Allergy and Clinical Immunology. Volume 133, Issue 1, 
Pages 3–13, January 2014
Xu Z, Davis HM, Zhou H.  Rational development and utilization of antibody-based 
therapeutic proteins in pediatrics. Pharmacology & Therapeutics (2013) 137:225-247.
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
73
12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
ACQ-7
Asthma Control Questionnaire-7
ADA
Anti-drug Antibody
AE
Adverse Event
ALT
Alanine aminotransferase (SGPT)
AST
Aspartate aminotransferase (SGOT)
AUC
Area under concentration-time curve
AUC(0-inf)
Area under concentration time curve to infinity
-HCG
Beta-Human Chorionic Gonadotropin
BUN
Blood urea nitrogen
C-ACT
Childhood Asthma Control Test 
CC
Cubic Centimeter
CI
Confidence Interval
CL
Systemic clearance of parent drug
CL/F
Apparent clearance after extravascular (e.g., subcutaneous) 
administration
Cmax
Maximum observed concentration 
CDC
Centers for Disease Control (US)
CO2
Carbon dioxide
CPK
Creatine phosphokinase
CPSR
Clinical Pharmacology Study Report
eCRF
Electronic Case Report Form
CS
Corticosteroids
CV
Cardiovascular
DCSI
Developmental Core Safety Information
DPI
Dry Powder Inhaler
ECG
Electrocardiogram
ED
Emergency Department
EGD
Esophagogastroduodenoscopy
EoE
Eosionophilic Esophagitis
FAAN
Food Allergy and Anaphylaxis Network
FEV1
Forced Expiratory Volume in 1 second
FVC
Forced Vital Capacity
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilence
GGT
Gamma glutamyltransferase
GINA
Global Initiative for Asthma
GSK
GlaxoSmithKline
HBsAg
Hepatitis B surface antigen
hCG
Human chorionic gonadotropin
HES
Hypereosinophilic syndrome
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
74
HR
Heart rate
IB
Investigator’s Brochure
ICH
International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for 
Human Use
ICS
Inhaled Corticosteroids
ID50/90
50% or 90% Inhibition of Maximum Effect
IEC
Independent Ethics Committee
IgG
Immunoglobulin
IL-5
Interleukin 5
IM
Intramuscular
Imax
Maximum Inhibition Model
IP
Investigational Product
IRB
Institutional Review Board
IUD
Intrauterine Device
IV
Intravenous
kg
Kilogram
LABA
Long acting inhaled β2 adrenoceptor agonist
LRTA
Leukotriene Receptor Antagonist
µg
Microgram
µL
Microliter
mAb
Monoclonal Antibody
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligrams
mL
Milliliter
MSDS
Material Safety Data Sheet
Nab
Neutralizing Antibody
NIAID
National Institute of Allergy and Infectious Diseases (US)
NIH
National Institute of Health (US)
OCS
Oral Corticosteroids
OLE
Open label extension
PD
Pharmacodynamic
PK
Pharmacokinetic
Pop-PK
Population Pharmacokinetics
QT
The QT interval is measured from the beginning of the QRS 
complex to the end of the T wave
QTc
QT duration corrected for heart rate
RAP
Reporting and Analysis Plan
SAE
Serious adverse event(s)
SAS
Statistical Analysis Software
SC
subcutaneous
SGOT
Serum glutamic-oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
75
SOC
System Organ Class
SOP
Standard Operating Procedure
SRM
Study Reference Manual
SRT
Safety Review Team
SUSAR
Suspected, Unexpected, Serious Adverse drug Reaction
t½
Terminal phase half-life
Tmax
Time of occurrence of Cmax
TTS
Study Specific Technical Agreement Memo
µL
Microliter
ULN
Upper limit of normal
UK
United Kingdom
US
United States
Vc
Central Volume of Distribution
WBC
White blood cells
Vss
Steady State Volume of Distribution
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
QOL Technologies Ltd
SAS
WinNonlin
Xolair
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
76
12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments
Phase II liver chemistry stopping and increased monitoring criteria have been 
designed to assure subject safety and evaluate liver event etiology (in alignment with the 
FDA premarketing clinical liver safety guidance).  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Phase II liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT-absolute
ALT 5xULN
ALT Increase
ALT 3xULN persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin)
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot Monitor
ALT 3xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be 
related to liver injury or hypersensitivity
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
77
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue  study treatment 

Report the event to GSK within 24 hours

Complete the liver event CRF and complete an 
SAE data collection tool if the event also meets 
the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries
resolve, stabilize, or return to within baseline 
(see MONITORING below)

Do not restart/rechallenge subject with study 
treatment 
MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24 hrs

Monitor subjects twice weekly until liver 
chemistries resolve, stabilize or return to within 
baseline 

A specialist or hepatology consultation is 
recommended
For All other criteria: 

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24-72 
hrs 

Monitor subjects weekly until liver chemistries 
resolve, stabilize or return to within baseline

Viral hepatitis serology4

Blood sample for pharmacokinetic (PK) 
analysis5

Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications 
on the concomitant medications report 
form including acetaminophen, herbal 
remedies, other over the counter 
medications.

Record alcohol use on the liver event 
alcohol intake case report form
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG or gamma globulins).

Serum acetaminophen adduct HPLC 
assay (quantifies potential 
acetaminophen contribution to liver 
injury in subjects with definite or likely 
acetaminophen use in the preceding 
week). NOTE: not required in China

Liver imaging (ultrasound, magnetic 
resonance, or computerised 
tomography) and /or liver biopsy to 
evaluate liver disease; complete Liver 
Imaging and/or Liver Biopsy CRF 
forms.
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
78
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN.
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to subjects receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)
4.
Includes: 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 
5.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.)  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment 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 Q2 Solutions Investigator Manual. 
Phase II liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 3xULN and <5xULN and bilirubin 
<2xULN, without symptoms believed to 
be related to liver injury or 
hypersensitivity, 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. 

Subject can continue study 

Subject 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 subject meets 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 normalize or return to within 
baseline.
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
79
12.3.
Appendix 3: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.3.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is 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.
Events meeting AE definition include:

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.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent. This should be reported regardless of sequelae).

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE.  However, the signs and symptoms and/or clinical 
sequelae resulting from lack of efficacy will be reported if they fulfil the definition 
of an AE or SAE.
Events NOT meeting definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
80
the disease/disorder being studied, unless more severe than expected for the subject’s 
condition.

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.
12.3.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
Serious Adverse Event (SAE) is defined as 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 hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization 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 hospitalization are 
AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d. Results in disability/incapacity
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 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
81
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.
Other situations:

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 hospitalization but may jeopardize 
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 hospitalization, or development of drug dependency 
or drug abuse
g. Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** > 1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick.  If fractionation is unavailable and ALT 3xULN 
and total bilirubin 2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.
12.3.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF 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
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
82

Deep venous thrombosis/pulmonary embolism

Revascularization
12.3.4.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the CRF

It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to GSK in lieu of completion of the GSK, AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK.  In this instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to 
submission of to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.

The use of a single question from a multidimensional health survey to designate a 
cause-effect relationship to an AE is inappropriate.
12.3.5.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. An AE that is assessed as 
severe will not be confused with an SAE. Severity is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
83
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of his/her assessment.

For each AE/SAE the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK.  However, it is very important 
that the investigator always make an assessment of causality for every event 
prior to the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.

The investigator is obligated to assist.  This may include additional laboratory tests 
or investigations, histopathological examinations or consultation with other health 
care professionals.

If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide GSK with a copy of any post-mortem findings, 
including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
84
12.3.6.
Reporting of SAEs to GSK
AE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data collection 
tool

If the electronic system is unavailable, the site will use the paper SAE data collection 
tool and fax it to the SAE coordinator within 24 hours.

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) will be taken off-line to prevent the entry of new data or changes to 
existing data

If a site receives a report of a new SAE from a study subject or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, the site can report this information on a paper SAE form or to the SAE 
coordinator by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
85
12.4.
Appendix 4:  Collection of Pregnancy Information

Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study

Information will be recorded on the appropriate form and submitted to GSK within 2 
weeks of learning of a subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on mother and infant, which will be 
forwarded to GSK.  Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date. 

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  

Any SAE occurring as a result of a post-study pregnancy, which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK 
as described in Appendix 3. While the investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.
Any female subject who becomes pregnant while participating 

will be withdrawn from the study
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
86
12.5.
Appendix 5: Sample ACQ-7 Questionnaire
 
2017N314087_00
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third party 
copyright laws and therefore have been excluded.


2014N216964_05
CONFIDENTIAL
200363
89
12.6.
Appendix 6: Sample ACQ-IA Questionnaire
 
2017N314087_00
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third party 
copyright laws and therefore have been excluded.


2014N216964_05
CONFIDENTIAL
200363
94
12.7.
Appendix 7: Acceptable Birth Control
To be eligible for entry into the study, females of childbearing potential must commit to 
consistent and correct use of an acceptable method of birth control from the time of 
consent, for the duration of the trial, and for 4 months after the last study drug 
administration.

Abstinence from penile-vaginal intercourse

Male partner who is sterile prior to the female subject’s entry into the study 
and is the sole sexual partner for that female subject 

Implants of levonorgestrel  or etonogestrel 

Injectable progestogen

Oral contraceptive (either combined or progestogen alone)

Estrogenic vaginal ring

Percutaneous contraceptive patches

Any intrauterine device (IUD) with a documented failure rate of less than 1% 
per year.

Male condom combined with a vaginal spermicide (foam, gel, film, cream, or 
suppository)

Male condom combined with a female diaphragm, either with or without a 
vaginal spermicide (foam, gel, film, cream, or suppository)
Females of childbearing potential are defined as females with functioning ovaries (i.e., 
post-menarche, premenopausal women with no documented impairment of oviductal or 
uterine function that would cause sterility). This category includes females with 
oligomenorrhea, females who are peri-menopausal, and young females who have begun 
to menstruate (adolescents).  The information on the lack of impairment of oviductal or 
uterine function that would cause sterility, can come from the site personnel’s:

Review of subject’s medical records

Medical examination of the subject

Interview with the subject on her medical history.
Menarche is the onset of menses for the first time in a young female and is preceded by 
several changes associated with puberty including breast development and pubic hair 
growth. Menarche usually occurs within 1-2 years of breast development, thelarche. 
However, a young female can become pregnant before her first menses. Thus, a 
conservative definition of non-childbearing potential in a pre-menarcheal female is a 
young female who has not yet entered puberty as evidenced by lack of breast 
development (palpable glandular breast tissue).  
Based on the absence of an identified reproductive hazard from preclinical studies, 
absence of a genotoxic potential, and very low levels of mepolizumab that might be 
present in semen, there is no recognized risk for mepolizumab to affect human sperm or 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
95
the fetus if transferred to a female partner via semen. Therefore, the use of condoms or 
other methods of contraception in the male study subject is not required.
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
96
12.8.
Appendix 8: Country Specific Requirements
No country-specific requirements exist.
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
97
12.9.
Appendix 9: Anaphylaxis Criteria
Hypersensitivity reactions will be monitored using the diagnostic criteria for anaphylaxis 
as outlined by the Joint NIAID/FAAN Second Symposium on Anaphylaxis [Sampson, 
2006]. The criteria do not make a distinction based on underlying mechanism. These 
criteria are summarized as follows:
1.
Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, swollen lips-
tongue-uvula), and at least one of the following:
a.
Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced PEF, hypoxemia) 
b. Reduced BP or associated symptoms of end-organ dysfunction (e.g., 
hypotonia [collapse], syncope, incontinence)
2.
Two or more of the following that occur rapidly after exposure to a likely allergen 
for that patient (minutes to several hours):
a.
Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, 
swollen lips-tongue-uvula)
b. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced PEF, hypoxemia)
c.
Reduced BP or associated symptoms (e.g., hypotonia [collapse], syncope, 
incontinence)
d. Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting)
3.
Reduced BP after exposure to known allergen for that patient (minutes to several 
hours):
a.
Infants and children: low systolic BP (age specific) or greater than 30% 
decrease in systolic BP
b. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from 
that person’s baseline
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
98
12.10.
Appendix 10:  Childhood Asthma Control Test (C-ACT)
 
2017N314087_00
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are 
protected by third party copyright laws and therefore have been excluded.


2014N216964_05
CONFIDENTIAL
200363
99
12.11.
Appendix 11:  Protocol Amendment Changes
Protocol Amendment 01
1. Addition of the C-ACT questionnaire to assess asthma control:
Section 1 and Section 3.  Objective(s)/Endpoint(s), Secondary Endpoints:
Original Text:

Bodyweight-adjusted clearance estimates obtained by population PK methods. 

Change from Baseline in ACQ-7  measured at week 12 

Change from Baseline in ACQ-7 measured at weeks 4,8,16 and 20

Incidence of Adverse Events

Incidence of clinically significant  changes in clinical laboratory parameters

Frequency of positive anti-mepolizumab binding antibodies and neutralizing 
antibodies

Incidence of clinically significant changes in vital sign measurements
Amended Text:

Bodyweight-adjusted clearance estimates obtained by population PK methods. 

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 week 4,8, 16 and 20

Incidence of Adverse Events

Incidence of clinically significant  changes in clinical laboratory parameters

Frequency of positive anti-mepolizumab binding antibodies and neutralizing 
antibodies

Incidence of clinically significant changes in vital sign measurements
Section 7, Table 3 Time and Events Table:
C-ACT added to visits 2, 3, 4, 6, 7, 8 and Early Withdrawal
Section 7.8:  Childhood Asthma Control Test:  A new section describing the C-ACT 
has been added to describe the use of the C-ACT for this study:
Additional Text:
The Childhood Asthma Control Test (C-ACT) assesses asthma control in children 4-11 
years of age with asthma (Liu, 2007, Liu, 2010). The C-ACT was designed to be self-
administered, to incorporate input from parent and child. The C-ACT is a self-
administered questionnaire. It is intended to complement pulmonary function testing and 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
100
other assessments by health care providers. Before seeing the health care provider, 
patients will complete the questionnaire (with help from their custodial caregiver). This 
self administered test is a clinically validated age-specific instrument to assess asthma 
control and can be completed in a short period of time. The C-ACT is a 7-question, 2-part 
questionnaire, with one part to be completed by the child with caregiver assistance and 
the other part to be completed by the caregiver (Appendix 10).
Section 1, Analysis and Section 9 and Section 9.2, :  C-ACT added to the list of 
clinical outcome measures and secondary endpoints.
Appendix 10:  Childhood Asthma Control Test:  A copy of the C-ACT has been 
added to Appendix 10.
2. Inclusion Criteria:  Heading numbers corrected:
Original numbering:
[1] AGE
1. Between 6 and 11 years of age inclusive, at the time of screening.
[2] TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. Diagnosis of severe asthma, defined by the regional asthma guidelines (i.e., NIH, 
GINA, etc.), for at least 12 months prior to Visit 1. If the subject is naïve to the 
study site, the subject/guardian must self-report a physician diagnosis of asthma 
and the investigator must confirm by review of medical history with the 
subject/guardian. 
3. Eosinophilic airway inflammation that is related to asthma characterized as 
eosinophilic in nature as indicated by: 

elevated peripheral blood eosinophil count of ≥300 cells/µL demonstrated in 
the past 12 months OR

elevated peripheral blood eosinophil count of 150/L at visit 1.
4. A well-documented requirement for regular treatment with inhaled corticosteroid 
(≥400 μg/day fluticasone propionate (DPI) or equivalent daily) in the 12 months 
prior to Visit 1 with or without maintenance oral corticosteroids (OCS).
5. Current treatment with an additional controller medication for at least 3 months or 
a documented failure in the past 12 months of an additional controller medication 
for at least 3 successive months.  [e.g., long-acting beta-2-agonist (LABA), 
leukotriene receptor antagonist (LTRA), or theophylline.]
6. FEV1: Persistent airflow obstruction at either visit 1 or Visit 2 (FEV1 performed 
prior to first dose of study medication) as indicated by:

A pre-bronchodilator FEV1 <110% predicted  OR
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
101

FEV1:FVC ratio < 0.8 recorded at visit 1 
7. Previously confirmed history of two or more exacerbations requiring treatment 
with systemic CS (intramuscular (IM), intravenous, or oral), in the 12 months 
prior to visit 1, despite the use of high-dose inhaled corticosteroids (ICS).  For 
subjects receiving maintenance CS, the CS treatment for the exacerbations must 
have been a two-fold increase or greater in the dose.
8.
No changes in the dose or regimen of baseline ICS and/or additional controller 
medication during the run-in period.
[4] SEX
9. Male or female: Females of childbearing potential must commit to consistent and 
correct use of an acceptable method of contraception (see Appendix 7) for the 
duration of the trial and for 4 months after the last dose of investigational product. A 
urine pregnancy test is required of girls of childbearing potential. This test will be 
performed at the initial screening visit (Visit 1) and will be performed at each 
scheduled study visit prior to the administration of investigational product, and during 
the Early Withdrawal and Follow-up Visits.
[5] INFORMED CONSENT
10. Parent(s)/guardian able to give written informed consent prior to participation in the 
study, which will include the ability to comply with the requirements and restrictions 
listed in the consent form. If applicable, the subject must be able and willing to give 
assent to take part in the study according to the local requirement.
Amended numbering:
[1] AGE
1. Between 6 and 11 years of age inclusive, at the time of screening.
[2] TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. Diagnosis of severe asthma, defined by the regional asthma guidelines (i.e., NIH, 
GINA, etc.), for at least 12 months prior to Visit 1. If the subject is naïve to the study 
site, the subject/guardian must self-report a physician diagnosis of asthma and the 
investigator must confirm by review of medical history with the subject/guardian. 
3. Eosinophilic airway inflammation that is related to asthma characterized as 
eosinophilic in nature as indicated by: 

elevated peripheral blood eosinophil count of ≥300 cells/µL demonstrated in 
the past 12 months OR

elevated peripheral blood eosinophil count of 150/L at visit 1.
4. A well-documented requirement for regular treatment with inhaled corticosteroid 
(≥400 μg/day fluticasone propionate (DPI) or equivalent daily) in the 12 months prior 
to Visit 1 with or without maintenance oral corticosteroids (OCS).
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
102
5. Current treatment with an additional controller medication for at least 3 months or a 
documented failure in the past 12 months of an additional controller medication for at 
least 3 successive months.  [e.g., long-acting beta-2-agonist (LABA), leukotriene 
receptor antagonist (LTRA), or theophylline.]
6. FEV1: Persistent airflow obstruction at either visit 1 or Visit 2 (FEV1 performed prior 
to first dose of study medication) as indicated by:

A pre-bronchodilator FEV1 <110% predicted  OR

FEV1:FVC ratio < 0.8 recorded at visit 1 
7. Previously confirmed history of two or more exacerbations requiring treatment with 
systemic CS (intramuscular (IM), intravenous, or oral), in the 12 months prior to visit 
1, despite the use of high-dose inhaled corticosteroids (ICS).  For subjects receiving 
maintenance CS, the CS treatment for the exacerbations must have been a two-fold 
increase or greater in the dose.
8.
No changes in the dose or regimen of baseline ICS and/or additional controller 
medication during the run-in period.
[3] SEX
9. Male or female: Females of childbearing potential must commit to consistent and 
correct use of an acceptable method of contraception (see Appendix 7) for the 
duration of the trial and for 4 months after the last dose of investigational product. A 
urine pregnancy test is required of girls of childbearing potential. This test will be 
performed at the initial screening visit (Visit 1) and will be performed at each 
scheduled study visit prior to the administration of investigational product, and during 
the Early Withdrawal and Follow-up Visits.
[4] INFORMED CONSENT
10. Parent(s)/guardian able to give written informed consent prior to participation in the 
study, which will include the ability to comply with the requirements and restrictions 
listed in the consent form. If applicable, the subject must be able and willing to give 
assent to take part in the study according to the local requirement.
3. Section 7.6:  Forced Expiratory Volume-1 (FEV1).  Change to the predicted values 
from NHANES III to Quanjer (2012).
Original Text:
To permit investigator staff completion of the ACQ-7 questionnaire (Section 7.7 below) 
spirometry will be conducted, using the site’s own equipment at the visits specified in the 
Time and Events schedule (Table 3).  The spirometer should meet American Thoracic 
Society standards and produce a printout of all data generated, which should be stored in 
the subject’s notes.  The spirometer should be calibrated in accordance with the 
manufacturer’s instructions and a calibration log maintained. Spirometry must be 
performed at the same time (1 hour) of the Visit 2 spirometry. Subjects should try to 
withhold short-acting beta-2-agonists (SABAs) for ≥6 hours and LABAs for 12 hours 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
103
prior to clinic visit, if possible. Assessments to be recorded will include FEV1, and FVC.   
For predicted FEV1 values, NHANES III values will be used and adjustments to these 
values will be made for race (Juniper, 1999).  If a subject is recorded as having Hispanic 
or Latino ethnicity, then the Mexican-American equations will be used (irrespective of 
race).  If a subject is recorded as being of African American/African Heritage race, then 
the African American equations will be used. If a subject is recorded as being of Asian 
race, then the Asian equations will be used.  Otherwise, the Caucasian equations will be 
used.
Amended Text:
To permit investigator staff completion of the ACQ-7 questionnaire (Section 7.7 below) 
spirometry will be conducted, using the site’s own equipment at the visits specified in the 
Time and Events schedule (Table 3).  The spirometer should meet American Thoracic 
Society standards and produce a printout of all data generated, which should be stored in 
the subject’s notes.  The spirometer should be calibrated in accordance with the 
manufacturer’s instructions and a calibration log maintained. Spirometry must be 
performed at the same time (1 hour) of the Visit 2 spirometry. Subjects should try to 
withhold short-acting beta-2-agonists (SABAs) for ≥6 hours and LABAs for 12 hours 
prior to clinic visit, if possible. Assessments to be recorded will include FEV1, and FVC.   
For predicted FEV1 values, reference is made to the multi-ethnic reference values for 
spirometry for the 3-95-yr age range: using the Global Lung Function Initiative 2012 
equations and look-up tables (Quanjer, 2012).  A link to a simple online tool for 
calculating the percent predicted FEV1 is provided in the Study Reference Manual. 
4. Section 7.7:  Asthma Control Questionnaire-7 (ACQ-7):  Wording changed to clarify 
that the ACQ-7 will be used in countries where a validated translation is available.
The ACQ-7 (Juniper, 1999, Juniper, 2005, Juniper, 2006) will be administered by a 
trained clinic staff member at each visit indicated in the Time and Events schedule 
(Table 3).  The ACQ-7 is a simple questionnaire to measure the adequacy of asthma 
control and change in asthma control which occurs either spontaneously or as a result 
of treatment (Appendix 5).  The questionnaire includes 7 items; and requires a 1 week 
recall (for items on symptoms and rescue inhaler use).  The ACQ has a 
multidimensional construct assessing symptoms (5 items administered by clinic staff 
to the child) and rescue bronchodilator use (query to child or parent), and FEV1% (1 
item) completed by clinic staff.  The ACQ-7 uses a 7-point scale (0=no impairment, 
6= maximum impairment for symptoms and rescue use; and 7 categories for 
FEV1%).  The instrument has a reported high test-retest reproducibility with an 
intraclass correlation coefficient =0.90.  The minimally important change in score is 
0.5.  The instrument has validated language versions for each country participating in 
this study. Use of the ACQ-7 is authorized by permission of the author.
Amended Text:
The ACQ-7 (Juniper, 1999, Juniper, 2005, Juniper, 2006) will be administered by a 
trained clinic staff member at each visit indicated in the Time and Events schedule 
(Table 3).  The ACQ-7 is a simple questionnaire to measure the adequacy of asthma 
control and change in asthma control which occurs either spontaneously or as a result 
of treatment (Appendix 5).  The questionnaire includes 7 items; and requires a 1 week 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
104
recall (for items on symptoms and rescue inhaler use).  The ACQ has a 
multidimensional construct assessing symptoms (5 items administered by clinic staff 
to the child) and rescue bronchodilator use (query to child or parent), and FEV1% (1 
item) completed by clinic staff.  The ACQ-7 uses a 7-point scale (0=no impairment, 
6= maximum impairment for symptoms and rescue use; and 7 categories for 
FEV1%).  The instrument has a reported high test-retest reproducibility with an 
intraclass correlation coefficient =0.90.  The minimally important change in score is 
0.5.  The instrument will be administered in each country for which there is a 
validated translation. Use of the ACQ-7 is authorized by permission of the author.
5. Section 6.2:  Clarification that the 100mg (1.0ML) injection can be administered as 2 
x 0.5ML injections
Original Text:
  Injected volume may be split between two injection sites for subjects receiving 100 mg 
(1.0 mL ).  Investigator should consider the use of a local anaesthetic at the injections 
sites.
Amended Text:
  Injected volume may be split between two injection sites for subjects receiving 100 mg 
(1.0 mL ) and given as 2x0.5mL injections.  Investigator should consider the use of a 
local anaesthetic at the injections sites.
6. Section 7.2.6 Clinical Safety Laboratory Assessments:  Typographical errors 
corrected in Table 4:
Reference to “fasting” removed as glucose will be tested “non-fasting”.
Specific gravity included in the dipstick test.
The “Central Laboratory Investigator Manual” has been corrected to “Quest 
Diagnostics Clinical Trials Investigator Manual”
7. Section 6.2:  Reference to the “Pharmacy Manual” has been corrected to the “Study 
Procedures Manual (SPM)”
Section 6.6:  Amended to clarify that all instructions for preparing Investigational 
Product may be found in the Study Reference Manual (SRM) instead of the pharmacy 
manual
Original Text:
A description of the methods and materials required for mepolizumab will be 
detailed in a Study Specific Technical Agreement/Memo (TTS) or Pharmacy 
Manual which will be accompanied by a Quality Agreement.
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
105
Amended Text:
A description of the methods and materials required for mepolizumab will be 
detailed in the Study Reference Manual (SRM).
8. Section 7.7:  A sentence has been added to clarify that a draft version of the ACQ-IA 
may be used until a validated translation becomes available.
Original text:
The instrument has a reported high test-retest reproducibility with an intraclass 
correlation coefficient =0.90.  The minimally important change in score is 0.5.  The 
instrument will be administered in subjects for whom an appropriate linguistically valid 
translation is available. Use of the ACQ-7 is authorized by permission of the author.
Amended text:
The instrument has a reported high test-retest reproducibility with an intraclass 
correlation coefficient =0.90.  The minimally important change in score is 0.5.  The 
ACQ-IA will be administered to subjects for whom an appropriate translation is 
available. If necessary, the draft ACQ-IA will be administered until a final linguistically 
validated version becomes available. The draft version of the ACQ-IA includes the 
linguistically validated ACQ-7 items, final instructions for each language and draft 
alternative item prompts to facilitate administration to children.  Use of the ACQ-7 is 
authorized by permission of the author.
9. Section 7.2.6:  A paragraph has been added to clarify that blood samples will be 
stored for up to 15 years after the end of the study.
Amended text:
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 only use samples collected 
from the study for the purpose stated in this protocol and in the informed consent 
form.  Subjects may request that their samples are destroyed at any time.
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
106
Protocol Amendment 02
1.
To change details of the Primary and Secondary Medical Monitors for the study:
Medical Monitor Sponsor Information Page
Original Text:
Role
Name
Day Time Phone 
Number and email 
address
After-hours 
Phone/Cell/
Pager Number
Site Address
Primary Medical 
Monitor 
MD
Stockley Park 
West,United 
Kingdom
Secondary 
Medical Monitor
,MD
5 Moore Dr , RTP 
NC 27709
Amended Text:
Role
Name
Day Time Phone 
Number and email 
address
After-hours 
Phone/Cell/
Pager Number
Site Address
Primary Medical 
Monitor 
MD
709 Swedeland 
Road, UW25-3077B
King of Prussia, PA 
19406
Secondary 
Medical Monitor
MD
Stockley Park 
West,United 
Kingdom
Original Text:
Sponsor Global Medical Monitor Contact Information:  
 MD (Medical Monitor, Respiratory Research and Development)
Mobile: 
Sponsor Back-up Global Medical Monitor Contact Information:  
 MD ScD (Director, Physician Lead, Respiratory Research and 
Development)
Tel: 
Mobile: 
 
2017N314087_00
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


2014N216964_05
CONFIDENTIAL
200363
107
Amended Text:
Sponsor Global Medical Monitor Contact Information:  
 MD (Director, Respiratory Research and Development)
Tel: 
Mobile: 
Email:  
Sponsor Back-up Global Medical Monitor Contact Information:  
 MD (Medical Monitor, Respiratory Research and Development)
Mobile: 
2. To permit extended mepolizumab treatment for a minimum of 52 weeks upon 
completion of the pharmacokinetic/pharmacodynamic phase (Part A) of the protocol.
PROTOCOL SYNOPSIS FOR STUDY 200363
Original Text:
Rationale
This pharmacokinetic/pharmacodynamic study is being conducted as part of an 
extrapolation strategy to support the use of mepolizumab in the 6-11 pediatric population 
with severe eosinophilic asthma.  This study will provide pharmacokinetic and 
pharmacodynamic data for mepolizumab at 40 or 100mg SC, depending on subject 
bodyweight, when administered to children aged 6-11 who have severe eosinophilic 
asthma that are expected to support the extrapolation of safety and efficacy data observed 
in the adult population to this pediatric population.  This study will also assess safety, 
tolerability, and immunogenicity of mepolizumab in this population along with  clinical 
outcome measures, the ACQ-7 and the C-ACT.
Amended Text:
Rationale
This pharmacokinetic/pharmacodynamic study is being conducted as part of an 
extrapolation strategy to support the use of mepolizumab in the 6-11 pediatric population 
with severe eosinophilic asthma.  This study will provide pharmacokinetic and 
pharmacodynamic data for mepolizumab at 40 or 100mg SC, depending on subject 
bodyweight, when administered to children aged 6-11 who have severe eosinophilic 
asthma that are expected to support the extrapolation of safety and efficacy data observed 
in the adult population to this pediatric population.  This study will also assess safety, 
tolerability, and immunogenicity of mepolizumab in this population along with clinical 
outcome measures, the ACQ-7 and the C-ACT.
Following the main study (Part A), subjects will be evaluated for eligibility to continue 
into the optional long-term extension phase (Part B) of this study.  For those subjects 
determined to be eligible and for whom appropriate informed consent/assent has been 
obtained there will be the option of continuing to receive treatment with mepolizumab 
 
2017N314087_00
PPD
PPD
PPD
PPD
PPD
PPD


2014N216964_05
CONFIDENTIAL
200363
108
during a Long-Term Safety / Pharmacodynamic Phase (Part B) which will include 
Treatment and Follow-up phases.  Part B will provide data to assess the long-term safety 
and tolerability of mepolizumab in this paediatric population and will also provide data to 
assess the durability of the pharmacodynamic response to mepolizumab.
3. To add long-term safety (52 weeks) as the primary objective for the extended 
treatment phase (Part B)
To add long-term pharmacodynamic response as a secondary objective for the extended 
treatment phase
Protocol Synopsis and Section 3:  Objective(s)/Endpoint(s)
Additional text:
Long-Term Safety / Long-Term Pharmacodynamic Phase (Part B)
Objectives
Endpoints
Primary

To assess the long-term (52 weeks) 
safety and tolerability of 
mepolizumab when administered 
subcutaneously to subjects aged 6 to 
11* years old with severe 
eosinophilic asthma  

Incidence of Adverse Events

Frequency of positive anti-
mepolizumab binding antibodies and 
neutralizing antibodies

Incidence of clinically significant 
changes in vital sign measurements

Incidence of clinically significant  
changes in clinical laboratory 
parameters
Secondary

To characterize the long-term (52 
weeks) durability of 
pharmacodynamics of mepolizumab 
administered subcutaneously to  
subjects aged 6 to 11* years old with 
severe eosinophilic asthma

Change from Week 20 (Visit 9) in 
absolute blood eosinophil count at 
weeks 32, 44, 56, 68, 72 and 80.
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
109
Objectives
Endpoints

Exploratory

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 11* years old with 
severe eosinophilic asthma

To characterize the long-term (52 
weeks) asthma control following 
subcutaneous administration of 
mepolizumab to subjects aged 6 to 
11* years old with severe 
eosinophilic asthma 

Incidence of asthma exacerbations

Change from Week 20 (Visit 9) in 
ACQ and C-ACT at weeks 32, 44, 
56, 68, 72 and 80.
*Subjects who reach their 12th birthday during Part may continue into Part 
B
Protocol Synopsis 
Additional text:
Long-Term Safety / Pharmacodynamic Phase (Part B)
This is a long-term safety / pharmacodynamic phase in which extended treatment for a 
further 52 weeks will be offered on an optional basis to those subjects eligible for 
continued treatment.  Subjects will receive either 40 or 100mg depending on subject 
bodyweight, administered SC every 4 weeks to subjects with severe eosinophilic asthma 
aged 6-11 years.  At the end of the 52 weeks extended treatment in Part B, subjects will 
have an Exit Visit 4 weeks after last dose and a Follow-Up visit 12 weeks after last dose.
Protocol Synopsis
Treatment Arms and Duration:
Original Text:
This study will consist of three phases: Pre-Screening/Screening/Run-in, Treatment and 
Follow-up. 
Pre-Screening/Screening/Run-in:  Subjects will attend an initial Pre-screening visit to 
assess their willingness and eligibility to participate in the study.  The Pre-screening visit 
will include: informed consent, demography, exacerbations and concomitant medications. 
Visit 1 Screening (which for convenience may be conducted as the same clinic 
attendance) will include a physical exam, screening laboratory tests, screening ECG and 
other assessments to determine suitability to participate in this study.  Subjects meeting 
the Visit 1/Screening eligibility criteria will enter a Run-in period of up to 2 weeks to 
allow for receipt and review of the lab results and ECG. 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
110
Amended text:
This Pharmacokinetic/Pharmacodynamic Phase (Part A) study will consist of three 
stages: Pre-Screening/Screening/Run-in, Treatment and Follow-up. 
Pre-Screening/Screening/Run-in:  Subjects will attend an initial Pre-screening visit to 
assess their willingness and eligibility to participate in the study.  The Pre-screening visit 
will include: informed consent, demography, exacerbations and concomitant medications.  
Visit 1(Screening) will include a physical exam, screening laboratory tests, screening 
ECG and other assessments to determine suitability to participate in this study.  The Pre-
screening visit may be conducted at the same clinic visit as Visit 1(Screening).  Subjects 
meeting the Visit 1(Screening) eligibility criteria will enter a Run-in period of up to 2 
weeks to allow for receipt and review of the lab results and ECG. 
Part A Treatment:  Those subjects meeting all of the inclusion/exclusion criteria by 
Visit 2 will receive mepolizumab 40 or 100 mg SC, depending on subject bodyweight (40 
mg for subjects <40 kg and 100 mg for subjects ≥ 40 kg). Subjects will receive their first 
dose of mepolizumab at Visit 2 and enter into the Treatment phase of the study.  Subjects 
shall be observed for a minimum of 60 minutes in the clinic following each injection.  
Those subjects who enter the run-in period but do not meet all inclusion/exclusion criteria 
will be deemed Run-in failures and will not be dosed in the study. The reason for any 
Run-in failure will be recorded in the eCRF.
During the Part A Treatment phase, all subjects will receive mepolizumab 40 or 100 mg 
SC, depending on subject bodyweight, at week 0 (Visit 2), week 4 (Visit 3) and week 8 
(Visit 4) which will provide therapeutic coverage through to week 12 (Visit 6/End of 
Therapy Visit).  Visit 6 will mark the end of the treatment phase.
Subjects will visit the clinic at week 9 (Visit 5) to allow for measurement of the 
approximate peak mepolizumab concentration.  
Part A Follow-up:  Following completion of Visit 6, subjects will enter into the Follow-
up phase which will consist of two additional visits at weeks 16 (Visit 7) and 20 (Visit 8).
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
111
Long-Term Safety / Long Term Pharmacodynamic Phase (Part B)
Treatment Arm
SC dose
Mepolizumab 40mg SC upper arm or thigh
Mepolizumab 40 mg SC
For subjects with bodyweight <40 kg at 
Visit 9 (Week 20).  From visit 10, subjects
should be weighed at each visit until 
bodyweight reaches 40kg when the dose 
should be adjusted to 100mg.  From this 
time onwards, the dose will not be adjusted 
again.
Mepolizumab 100mg SC upper arm or 
thigh
Mepolizumab 100mg SC
For subjects with a bodyweight ≥40 kg at 
Visit 9 (Week 20) or from the time that 
bodyweight reaches 40kg. 
Part B Treatment:  Those subjects meeting the eligibility criteria for the long-term 
phase of the study at Visit 9 will receive mepolizumab 40 or 100 mg SC, (depending on 
subject bodyweight measured at Visit 9;  40 mg for subjects <40 kg and 100 mg for 
subjects ≥ 40 kg).  Subjects shall be observed for a minimum of 60 minutes in the clinic 
following injection at Visit 9 and at subsequent visits subjects should be monitored 
according to standard practice at the site.  From Visit 10 onwards subjects will receive the 
same dose of mepolizumab at 4-weekly intervals for a total of 48 weeks.  Subjects with 
bodyweight <40 kg at Visit 9 should be weighed at each subsequent visit and have their 
dose adjusted once their bodyweight exceeds 40 kg.
Part B Follow-up:  Following completion of Visit 22, subjects will enter into the 
Follow-up phase which will consist of one additional follow-up visit at week 80 (Visit 
23).
Protocol Synopsis, Type and Number of Subjects:
Original Text:
Approximately 40 male or female subjects with severe eosinophilic asthma, aged 6 to 11 
years inclusive at screening (Visit 1), will be screened to achieve approximately 28 
eligible subjects entering the treatment phase to allow for availability of 20 evaluable 
subjects; with a minimum of six subjects enrolled in the < 40 kg bodyweight group. An 
evaluable subject is defined to be a subject who has received all three doses of 
mepolizumab and has had all PK and PD assessments completed through to Visit 6 (week 
12).
Amended text:
For Part A, approximately 40 male or female subjects with severe eosinophilic asthma, 
aged 6 to 11 years inclusive at screening (Visit 1), will be screened to achieve 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
112
approximately 28 eligible subjects entering the treatment phase to allow for availability 
of 20 evaluable subjects; with a minimum of six subjects enrolled in the < 40 kg 
bodyweight group. An evaluable subject is defined to be a subject who has received all 
three doses of mepolizumab and has had all PK and PD assessments completed through 
to Visit 6 (week 12).
Sample size is not determined for Part B.   All subjects who completed Part A and meet 
the eligibility criteria for Part B will be allowed to participate in Part B.
Protocol Synopsis, Analysis:
Original Text:
Analysis
Population-PK (Pop-PK) parameter estimates will be presented (AUC(0-inf), clearance, 
Cmax, t1/2). Descriptive statistics will be used to present the subject demographics, subject 
study accountability, post-hoc individual pharmacokinetic parameter estimates (e.g. 
AUC(0-inf), clearance, Cmax, t1/2), blood eosinophil count and  ratio of blood eosinophil 
count to baseline at week 12, IL5 levels, selected clinical outcome measures (FEV1, 
ACQ-7, C-ACT, asthma exacerbations), and safety assessments (adverse events, vital 
signs, ECGs and laboratories) and immunogenicity.  Confidence intervals may be applied 
where appropriate.  In addition a pre-planned analysis comparing the bodyweight-
adjusted clearance between adults and subjects 6-11 years with severe eosinophilic 
asthma will be conducted, with appropriate confidence intervals applied.  
Amended Text:
Analysis
Population-PK (Pop-PK) parameter estimates will be presented (AUC(0-inf), clearance, 
Cmax, t1/2) for Part A. Descriptive statistics will be used to present the subject 
demographics, subject study accountability, post-hoc individual pharmacokinetic 
parameter estimates (e.g. AUC(0-inf), clearance, Cmax, t1/2), blood eosinophil count and  
ratio of blood eosinophil count to baseline at week 12, IL5 levels, selected clinical 
outcome measures (FEV1, ACQ-7, C-ACT, asthma exacerbations), and safety 
assessments (adverse events, vital signs, ECGs and laboratories) and immunogenicity.  
Confidence intervals may be applied where appropriate.  In addition a pre-planned 
analysis comparing the bodyweight-adjusted clearance between adults and subjects 6-11 
years with severe eosinophilic asthma will be conducted, with appropriate confidence 
intervals applied.  
Safety and Pharmacodynamic data for Parts A and B will be summarized descriptively 
and 95% CIs will be presented where appropriate.
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
113
opSection 4, Study Design:
Original text:
This study will consist of three phases: Pre-Screening/Screening/Run-in, Treatment, and 
Follow-up. 
Pre-Screening/Screening/Run-in:  Subjects will attend an initial Pre-screening visit to 
assess their willingness and eligibility to participate in the study.  The Pre-screening visit 
will include: informed consent; demography exacerbations and concomitant medications.  
Visit 1 Screening (which for convenience may be conducted as the same clinic 
attendance) will include a physical exam, screening laboratory test, screening ECG and 
other assessments to determine suitability to participate in this study.  Subjects meeting 
the Visit 1/Screening eligibility criteria will enter a Run-in period of up to 2 weeks to 
allow for receipt and review of the lab results and ECG.  
Amended text:
This study will consist of two phases: Part A will consist of Pre-
Screening/Screening/Run-in, Treatment, and Follow-up.  Part B will consist of Long-
Term Treatment and Follow-up.
Pharmacokinetic/Pharmacodynamic Phase (Part A)
Pre-Screening/Screening/Run-in:  Subjects will attend an initial Pre-screening visit to 
assess their willingness and eligibility to participate in the study.  The Pre-screening visit 
will include: informed consent; demography exacerbations and concomitant medications.  
Visit 1(Screening) will include a physical exam, screening laboratory test, screening ECG 
and other assessments to determine suitability to participate in this study.  The pre-
screening visit may be conducted at the same clinic visit as Visit 1(Screening).  Subjects 
meeting the Visit 1(Screening) eligibility criteria will enter a Run-in period of up to 2 
weeks to allow for receipt and review of the lab results and ECG.  
Section 4, Study Design:
Original text:
Follow-up: Following completion of Visit 6, subjects will enter into the Follow-up phase 
which will consist of two additional visits at weeks 16 (Visit 7) and 20 (Visit 8).
Study visits will have a window of 3 days; except for Visit 5 which should be 
scheduled 1 day.
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
114
Study Completion and Open-Label Extension study (OLE)
A subject will be regarded as having completed the study if they complete all phases of 
the study (Pre-Screening/Screening/Run-in, Treatment, and Follow-up).  Subjects who 
complete the study will participate for approximately 22 weeks.
Subjects who are considered to be at risk of experiencing a life-threatening exacerbation 
of their asthma or whose functional health status will become significantly worse on 
regular basis if returned to standard of care may be eligible for an OLE study. If the 
subject is likely to benefit from continued mepolizumab treatment, as judged by the 
investigator and agreed by GSK, the subject will be offered the opportunity to enrol in an 
extended treatment study with mepolizumab following the Follow-up (Visit 8).
For subjects who had a positive neutralizing antibody response at the Follow-up (Visit 8) 
(or last study visit at which immunogenicity was assessed if the Follow-up (Visit 8) 
immunogenicity sample is not available), an attempt will be made to obtain a serum 
sample for anti-mepolizumab antibodies at least 4 months after the last dose of study 
drug. 
Amended text:
Follow-up: Following completion of Visit 6, subjects will enter into the Follow-up phase 
which will consist of two additional visits at weeks 16 (Visit 7) and 20 (Visit 8).For 
subjects who had a positive neutralizing antibody response at the Follow-up (Visit 8) (or 
last study visit at which immunogenicity was assessed if the Follow-up (Visit 8) 
immunogenicity sample is not available), an attempt will be made to obtain a serum 
sample for anti-mepolizumab antibodies at least 4 months after the last dose of study 
drug.
Study visits will have a window of 3 days; except for Visit 5 which should be 
scheduled 1 day.
A subject will be regarded as having completed Part A if they complete all phases of Part 
A (Pre-Screening/Screening/Run-in, Treatment, and Follow-up).  Subjects who complete 
Part A will participate for approximately 22 weeks.
Long-Term Safety / Pharmacodynamic Phase (Part B)
At the end of Part A, a benefit/risk assessment will be performed by the Investigator and 
if this assessment supports continued therapy with mepolizumab the subject can continue 
into Part B, with approval from GSK, following the Part A Follow-up (Visit 8).
Study visits in Part B will have a window of 5 days.  The total duration of Part B is 
approximately 60 weeks.
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
115
Section 4.1, Overall Design ; Section 4.2 Treatment Arms and Duration
Original text:
Overall Design
Treatment Arms and Duration
Enrolled subjects in this study will be assigned to receive one of the following treatments:
Treatment Arm
SC dose
Mepolizumab 40 mg SC upper arm or thigh
Mepolizumab 40 mg SC
For subjects <40 kg bodyweight at Visit 2 
(Week 0)
Mepolizumab 100 mg SC upper arm or 
thigh
Mepolizumab 100mg SC
For subjects ≥40 kg bodyweight at Visit 2 
(Week 0)
The total duration of the study will be 22 weeks and will include a run-in period of 1-2 
weeks, a treatment period of 12 weeks and a follow-up phase of 8 weeks. A subject will 
be considered having completed the study if the subject completes all phases of the study 
including the follow-up phase (Visit 8).  A subject will be defined as evaluable if the 
subject received all 3 planned doses of mepolizumab and has completed all 
pharmacokinetic and pharmacodynamic assessments through to study Visit 6.
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
116
Amended text:
Overall Design
Pharmacokinetic/Pharmacodynamic Phase (Part A)
This is a multi-centre, open-label study that will assess the pharmacokinetics 
pharmacodynamics of three 4-weekly doses of mepolizumab, either 40 or 100mg 
depending on subject bodyweight, administered SC to subjects with severe eosinophilic 
asthma aged 6-11 years.
Long-Term Safety / Pharmacodynamic Phase (Part B)
This is a long-term safety / pharmacodynamic phase in which extended treatment will be 
offered on an optional basis to those subjects eligible for continued treatment.  Subjects 
will receive either 40 or 100mg depending on subject bodyweight, administered 
subcutaneously at 4-weekly intervals for a total of 52 weeks.
Treatment Arms and Duration
Pharmacokinetic/Pharmacodynamic Phase (Part A)
Enrolled subjects in this study will be assigned to receive one of the following treatments:
Treatment Arm
SC dose
Mepolizumab 40 mg SC upper arm or thigh
Mepolizumab 40 mg SC
For subjects <40 kg bodyweight at Visit 2 
(Week 0)
Mepolizumab 100 mg SC upper arm or 
thigh
Mepolizumab 100mg SC
For subjects ≥40 kg bodyweight at Visit 2 
(Week 0)
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
117
Part A Pre-Screening/Screening/Run-in:  Subjects will attend an initial Pre-screening 
visit to assess their willingness and eligibility to participate in the study.  The Pre-
screening visit will include: informed consent, demography, exacerbations and 
concomitant medications.  Visit 1(Screening) will include a physical exam, screening 
laboratory tests, screening ECG and other assessments to determine suitability to 
participate in this study.  The Pre-screening visit may be conducted at the same clinic 
visit as Visit 1 (Screening).  Subjects meeting the Visit 1(Screening) eligibility criteria 
will enter a Run-in period of up to 2 weeks to allow for receipt and review of the lab 
results and ECG. 
Part A Treatment:  Those subjects meeting all of the inclusion/exclusion criteria by 
Visit 2 will receive mepolizumab 40 or 100 mg SC, depending on subject bodyweight (40 
mg for subjects <40 kg and 100 mg for subjects ≥ 40 kg). Subjects will receive their first 
dose of mepolizumab at Visit 2 and enter into the Treatment phase of the study.  Subjects 
shall be observed for a minimum of 60 minutes in the clinic following each injection.  
Those subjects who enter the run-in period but do not meet all inclusion/exclusion criteria 
will be deemed Run-in failures and will not be dosed in the study. The reason for any 
Run-in failure will be recorded in the eCRF.
During the Part A Treatment phase, all subjects will receive mepolizumab 40 or 100 mg 
SC, depending on subject bodyweight measured at Visit 2, at week 0 (Visit 2), week 4 
(Visit 3) and week 8 (Visit 4) which will provide therapeutic coverage through to week 
12 (Visit 6/End of Therapy Visit).  Visit 6 will mark the end of the treatment phase.
Subjects will visit the clinic at week 9 (Visit 5) to allow for measurement of the 
approximate peak mepolizumab concentration.  
Part A Follow-up:  Following completion of Visit 6, subjects will enter into the Follow-
up phase which will consist of two additional visits at weeks 16 (Visit 7) and 20 (Visit 8).
The total duration of Part A will be 22 weeks and will include a run-in period of 1-2 
weeks, a treatment period of 12 weeks and a follow-up phase of 8 weeks. A subject will 
be considered having completed Part A if the subject completes all phases including the 
follow-up phase (Visit 8).  A subject will be defined as evaluable for Part A if the subject 
received all 3 planned doses of mepolizumab and has completed all pharmacokinetic and 
pharmacodynamic assessments through to study Visit 6
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
118
Long-Term Safety / Long Term Pharmacodynamic Phase (Part B)
Treatment Arm
SC dose
Mepolizumab 40mg SC upper arm or thigh
Mepolizumab 40 mg SC
For subjects <40 kg bodyweight at Visit 9 
(Week 20).  From visit 10, subjects should 
be weighed at each visit until bodyweight 
reaches 40kg when the dose should be 
adjusted to 100mg.  From this time 
onwards, the dose will not be adjusted 
again.
Mepolizumab 100mg SC upper arm or 
thigh
Mepolizumab 100mg SC
For subjects bodyweight at Visit 9 (Week 
20) or from the time that bodyweight 
reaches 40 kg
Following Part A subjects will be evaluated for eligibility to continue into Part B of this 
study.  For those subjects determined to be eligible and for whom appropriate informed 
consent/assent has been obtained there will be a Long-Term Safety / Pharmacodynamic 
Phase (Part B).  Part B will include Treatment and Follow-up phases. 
Part B Treatment:  Those subjects meeting all of the Part B eligibility criteria by Visit 9 
will receive mepolizumab 40 or 100 mg SC, depending on subject bodyweight at Visit 9 
(40 mg for subjects <40 kg and 100 mg for subjects ≥ 40 kg). Subjects shall be observed 
for a minimum of 60 minutes in the clinic following injection at Visit 9 and at subsequent 
visits subjects should be monitored according to standard practice at the site.  From Visit 
10 onwards subjects will receive the same dose of mepolizumab at 4-weekly intervals.  
Subjects with bodyweight <40 kg at Visit 9 should be weighed at each visit and have 
their dose adjusted once their bodyweight exceeds 40 kg.  Once a subject starts treatment 
with the 100mg dose, the dose will not be adjusted further even if the subject’s 
bodyweight should drop below 40kg.
Part B Follow-up:  Following completion of Visit 22, subjects will enter into the 
Follow-up phase which will consist of an additional visit at week 80 (Visit 23).
Section 4.4, Design Justification
Additional text:
No long-term data (up to 52 weeks) documenting the safety and tolerability of 
mepolizumab in children aged 6 to 11 years with severe eosinophilic asthma are currently 
available.  As it is expected that treatment with mepolizumab in this population may be 
long-term it is essential that such data be collected.  Extended treatment with 
mepolizumab during Part B of this protocol also permits an assessment of the durability 
of the pharmacodynamic response to mepolizumab in this population.
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
119
Section 4.5.1, Table
Assessment of Risk, Mitigation Strategy:
Original text:
In addition to normal institutional practices, subjects will be observed for a minimum of 
60 minutes in the clinic following each injection.  
Amended text:
In addition to normal institutional practices, subjects will be observed for a minimum of 
60 minutes in the clinic following each injection up-to and including Visit 9.  From Visit 
10 onwards, monitoring post-injection should be according to the standard procedure at 
each site.
Original text:
Safety assessments to be conducted as outlined in protocols.
Amended text:
Daily monitoring of SAE by Serious Adverse Events (SAE) Co-ordinator (project 
Medical Monitor); regular systematic review of AE/SAE data from ongoing studies by a 
GSK safety review team. 
Safety assessments to be conducted as outlined in protocols.
Section 5.3, Eligibility Criteria for Part B
Additional Text:
Eligibility Criteria for Part B

The subject has completed all study assessments up-to and including Visit 8 and 
received all 3 doses of IP in Part A.

The PI has performed a benefit/risk assessment and this assessment supports 
continued therapy with mepolizumab.  The subject’s parents (or guardian) have 
given consent and the subject has given assent for continued treatment
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
120
Section 6.3, Dosage and Administration
Original text:
Dosage and Administration
Enrolled subjects in this study will be dosed with the following treatment:
Treatment Arm
SC dose
Mepolizumab 40 mg SC upper arm or thigh
Mepolizumab 40 mg SC
For subjects < 40 kg bodyweight at Visit 2 
(Week 0)
Mepolizumab 100 mg SC upper arm or 
thigh
Mepolizumab 100mg SC
For subjects ≥ 40 kg bodyweight at Visit 2 
(Week 0)
Site staff member assigned to the study will be required to prepare the appropriate 
medication according to the study subject’s treatment assignment. Subjects eligible to 
enter the study will be assigned to treatment based on bodyweight at Visit 2. Assigned 
dose will remain the same irrespective of bodyweight changes during the treatment 
phase.
Amended text:
Dosage and Administration
Pharmacokinetic/Pharmacodynamic Phase (Part A)
Enrolled subjects in this study will be dosed with the following treatment:
Treatment Arm
SC dose
Mepolizumab 40 mg SC upper arm or thigh
Mepolizumab 40 mg SC
For subjects < 40 kg bodyweight at Visit 2 
(Week 0)
Mepolizumab 100 mg SC upper arm or 
thigh
Mepolizumab 100mg SC
For subjects ≥ 40 kg bodyweight at Visit 2 
(Week 0)
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
121
Long-Term Safety / Long-Term Pharmacodynamic Phase (Part B)
Treatment Arm
SC dose
Mepolizumab 40mg SC upper arm or thigh
Mepolizumab 40 mg SC
For subjects <40 kg bodyweight at Visit 
9 (Week 20)
Mepolizumab 100mg SC upper arm or 
thigh
Mepolizumab 100mg SC
For subjects bodyweight at Visit 9 (Week 
20) or from the time that bodyweight 
reaches 40 kg)
Preparation of Investigational Product (Part A and Part B)
Site staff member assigned to the study will be required to prepare the appropriate 
medication according to the study subject’s treatment assignment. Subjects eligible to 
enter the study will be assigned to treatment based on bodyweight at Visit 2. Assigned 
dose will remain the same irrespective of bodyweight changes during the treatment 
phase.
Section 6.8, Treatment After Completion of Part A
Original Text:
Treatment after the End of the Study
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the patient’s medical condition whether or not GSK is providing specific 
post study treatment.
Subjects who are considered to be at risk of experiencing a life-threatening exacerbation 
of their asthma or whose functional health status will become significantly worse on 
regular basis if returned to standard of care may be eligible for an OLE study. If the 
subject is likely to benefit from continued mepolizumab treatment, as judged by the 
investigator and agreed by GSK, the subject will be offered the opportunity to enrol in an 
extended treatment study with mepolizumab following the Follow-up (Visit 8).
Amended Text:
Treatment after the Completion of Part A
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the patient’s medical condition whether or not GSK is providing specific 
continuing study treatment under Part B of this study.
At the end of Part A, a benefit/risk assessment will be performed by the Investigator and 
if this assessment supports continued therapy with mepolizumab and GSK has given 
approval, the subject will be offered the opportunity to enrol in Part B following the Part 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
122
A Follow-up visit (Visit 8).  Part B will continue for 52 weeks of additional mepolizumab 
treatment.  
At the end of Part B, subjects will return to usual care and will be prescribed appropriate 
alternative asthma therapy, as required.  
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
123
Section 7, Study Assessments and Procedures:
Addition of Time & Events Table 4 for Part B:
Additional text:
Table 4
Time and Events Table Long-Term Safety / Pharmacodynamic Phase (Part B)
Procedure
Eligibility 
Check / 
First 
Dose
Exit 
Visit
Follow-
up
Early 
Withdrawal
Visit
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Week of Study 
(visit window 5 days)
20
24
28
32
36
40
44
48
52
56
60
64
68
72
80
Subject Screen
Informed consent
X1
Inclusion and exclusion criteria
X1
Safety Assessments
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology (including 
eosinophils)
X
X
X
X
X
X
X
X
Clinical Chemistry
X
X
X
X
X
X
X
12-lead ECG
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Bodyweight
X
X1
X1
X1
X1
X1
X1
X1
X1
X1
X1
X1
X1
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Cardiovascular events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Liver events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments
Urinalysis
X1
X
X
X
Pregnancy Test
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
 
 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
124
Procedure
Eligibility 
Check / 
First 
Dose
Exit 
Visit
Follow-
up
Early 
Withdrawal
Visit
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Week of Study 
(visit window 5 days)
20
24
28
32
36
40
44
48
52
56
60
64
68
72
80
Blood sample for immunogenicity
X
X
X6
X5
Outcomes Assessments
FEV1
X1
X
X
X
X
X
X
X
ACQ-7
X1
X
X
X
X
X
X
X
C-ACT
X1
X
X
X
X
X
X
X
Assessment of exacerbation
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Investigational Product
Mepolizumab SC dose 
administered
X
X
X
X
X
X
X
X
X
X
X
X
X
Study Administration
Email to GSK Operational Lead
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete eCRF
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
1.
Bodyweight will be measured at Visit 9 and at each visit until such time as the subject reaches 40kg in weight. Subjects with bodyweight ≥40Kg at Visit 9 will not be weighed again 
during Part B.
 
 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
125
Section 7.5, Immunogenicity
Original Text:
Immunogenicity
Blood samples will be collected for the determination of anti-mepolizumab antibodies, 
prior to dosing at Visit 2 (Week 0), and subsequently at Visit 7 (Week 16), and at Visit 8 
(Week 20). 
Amended Text:
Immunogenicity
Blood samples will be collected for the determination of anti-mepolizumab antibodies, 
prior to dosing at Visit 2 (Week 0), and subsequently at Visit 7 (Week 16), and at Visit 8 
(Week 20). 
For subjects who had a positive neutralizing antibody response at the Follow-up (Visit 8) 
(or last study visit at which immunogenicity was assessed if the Follow-up (Visit 8) 
immunogenicity sample is not available), an attempt will be made to obtain a serum 
sample for anti-mepolizumab antibodies at least 4 months after the last dose of study drug 
in Part A.
In Part B, immunogenicity samples will be collected prior to dosing at Visit 15 (week 
44), Visit 21 (week 68) and at Follow-up Visit 23 (week 80).
Section 7.6, Forced Expiratory Volume (FEV1)
Original Text:
Forced Expiratory Volume-1 (FEV1)
To permit investigator staff completion of the ACQ-7 questionnaire (Section 7.7 below) 
spirometry will be conducted, using the site’s own equipment at the visits specified in the 
Time and Events schedule (Table 3).  The spirometer should meet American Thoracic 
Society standards and produce a printout of all data generated, which should be stored in 
the subject’s notes.  The spirometer should be calibrated in accordance with the 
manufacturer’s instructions and a calibration log maintained. Spirometry must be 
performed at the same time (1 hour) of the Visit 2 spirometry. Subjects should try to 
withhold short-acting beta-2-agonists (SABAs) for ≥6 hours and LABAs for 12 hours 
prior to clinic visit, if possible. Assessments to be recorded will include FEV1, and FVC.   
For predicted FEV1 values, reference is made to the multi-ethnic reference values for 
spirometry for the 3-95-yr age range: using the Global Lung Function Initiative 2012 
equations and look-up tables (Quanjer, 2012).  A link to a simple online tool for 
calculating the percent predicted FEV1 is provided in the Study Reference Manual. 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
126
Amended Text:
Forced Expiratory Volume-1 (FEV1)
To permit investigator staff completion of the ACQ-7 questionnaire (Section 7.7 below) 
spirometry will be conducted, using the site’s own equipment at the visits specified in the 
Time and Events schedule (Table 3 and Table 4).  The spirometer should meet American 
Thoracic Society standards and produce a printout of all data generated, which should be 
stored in the subject’s notes.  The spirometer should be calibrated in accordance with the 
manufacturer’s instructions and a calibration log maintained. Spirometry must be 
performed at the same time (1 hour) of the Visit 2 spirometry. Subjects should try to 
withhold short-acting beta-2-agonists (SABAs) for ≥6 hours and LABAs for 12 hours 
prior to clinic visit, if possible. Assessments to be recorded will include FEV1, and FVC.   
For predicted FEV1 values, reference is made to the multi-ethnic reference values for 
spirometry for the 3-95-yr age range: using the Global Lung Function Initiative 2012 
equations and look-up tables (Quanjer, 2012).  A spreadsheet calculator will be provided 
for calculating percent predicted FEV1
Section 9.2, Sample Size Considerations
Additional paragraph:
Patients who complete Part A and who meet the eligibility criteria for Part B will be 
allowed to participate in Part B and no specific sample size requirements are defined.
Section 9.3 Data Analysis Considerations
Original Text:
Data Analysis Considerations
Analysis Populations
Intent to Treat Population
All subjects receiving at least one dose of study medication will be included in the safety 
population.
Pharmacokinetic Population
All subjects receiving at least one dose of mepolizumab and having at least one blood 
sample with measurable mepolizumab plasma concentration taken will be included in the 
pharmacokinetic population.  
Pharmacodynamic Population (Blood Eosinophils)
All subjects receiving at least one dose of mepolizumab and having at least one blood 
sample taken for blood eosinophil count post dosing will be included in the 
pharmacodynamic population.  
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
127
Interim Analysis
No interim analysis is planned.
Amended Text:
Data Analysis Considerations
Analysis Populations Part A
Safety Population Part A
All subjects receiving at least one dose of study medication beginning at Visit 2 will be 
included in the safety population for Part A analyses.
Pharmacokinetic Population Part A
All subjects receiving at least one dose of mepolizumab beginning at Visit 2 and having 
at least one blood sample taken at Visit 3 or thereafter with measurable mepolizumab 
plasma concentration will be included in the pharmacokinetic population for Part A 
analyses.  
Pharmacodynamic Population (Blood Eosinophils) Part A
All subjects receiving at least one dose of mepolizumab beginning at Visit 2 and having 
at least one blood sample taken for blood eosinophil count post dosing at Visit 2 will be 
included in the pharmacodynamic population (blood eosinophils) for Part A analyses.
Pharmacodynamic Population (Outcome Assessments) Part A
All subjects receiving at least one dose of mepolizumab beginning at Visit 2  and having 
at least one assessment of pharmacodynamic outcomes (ACQ, ACT, asthma 
exacerbation, or FEV1,) post dosing at Visit 2 will be included in the pharmacodynamic 
population (outcomes) for Part A analyses.
Safety Population Part B
All subjects receiving at least one dose of study medication beginning at Visit 9 will be 
included in the safety population for Part B analyses.
Pharmacodynamic Population (Blood Eosinophils) Part B
All subjects receiving at least one dose of mepolizumab beginning at Visit 9 and having 
at least one blood sample taken for blood eosinophil count post dosing at Visit 9 will be 
included in the pharmacodynamic population (blood eosinophils) for Part B analyses.  
Pharmacodynamic Population (Outcome Assessments) Part B
All subjects receiving at least one dose of mepolizumab beginning at Visit 9 and having 
at least one assessment of pharmacodynamic outcomes (ACQ, ACT, asthma 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
128
exacerbation, or FEV1,) post dosing at Visit 9 will be included in the pharmacodynamic 
population (outcomes) for Part B analyses.
Interim Analysis
A full interim analysis is planned at the completion of the 
Pharmacokinetic/Pharmacodynamic Phase (Part A) of this study.  All eCRF data will be 
monitored, queried, and a soft-database lock will be performed on all subject data 
through Visit 8 following last subject achieving Visit 8.  A statistical output will be 
prepared in accordance with all study objective and endpoints for Part A.
Section 9.5, Key Elements of Analysis Plan (Part B):
Additional Text:
Key Elements of Analysis Plan (Part B)
Primary Analysis
The incidence in adverse events, frequency of positive anti-mepolizumab antibodies, and 
clinically significant changes in laboratory parameters and vital signs will be summarised 
using descriptive statistics. 
Secondary Analyses
Blood eosinophil count, the primary pharmacodynamic endpoint, will be log transformed 
prior to analysis and will also be summarised using descriptive statistics.  
Secondary endpoints including ACQ-7, C-ACT will be summarised using descriptive 
statistics, Confidence intervals will be presented when appropriate. The analysis schema 
will be outlined in the RAP.
Section 10.7, Provision of Study Results to Investigators
Original Text:
A manuscript will be progressed for publication in the scientific literature.
Amended Text:
One or more manuscripts will be progressed for publication in the scientific literature.
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
129
Protocol Amendment 03
Section1, Synopsis, Treatment Arms and Duration, Part A:
Original Text:
Part A Treatment:  Those subjects meeting all of the inclusion/exclusion criteria by 
Visit 2 will receive mepolizumab 40 or 100 mg SC, depending on subject bodyweight (40 
mg for subjects <40 kg and 100 mg for subjects ≥ 40 kg). Subjects will receive their first 
dose of mepolizumab at Visit 2 and enter into the Treatment phase of the study.  Subjects 
shall be observed for a minimum of 60 minutes in the clinic following each injection.  
Those subjects who enter the run-in period but do not meet all inclusion/exclusion criteria 
will be deemed Run-in failures and will not be dosed in the study. The reason for any 
Run-in failure will be recorded in the eCRF.
During the Part A Treatment phase, all subjects will receive mepolizumab 40 or 100 mg 
SC, depending on subject bodyweight, at week 0 (Visit 2), week 4 (Visit 3) and week 8 
(Visit 4) which will provide therapeutic coverage through to week 12 (Visit 6/End of 
Therapy Visit).  Visit 6 will mark the end of the treatment phase.
Amended Text:
Part A Treatment:  Those subjects meeting all of the inclusion/exclusion criteria by 
Visit 2 will receive mepolizumab 40 or 100 mg SC, depending on subject bodyweight (40 
mg for subjects <40 kg and 100 mg for subjects ≥ 40 kg). Subjects will receive their first 
dose of mepolizumab at Visit 2 and enter into the Treatment phase of the study.  Subjects 
shall be observed for a minimum of 60 minutes in the clinic following each injection.  
Safety monitoring of subjects will occur during SC administration and for 1 hour after the 
three administrations in Part A and then follow monitoring policies for the center in Part 
B.  Such monitoring will include general safety monitoring including monitoring for both 
systemic hypersensitivity (i.e., allergic/IgE-mediated and non-allergic) and local site 
reactions.  In the event of an acute severe reaction (e.g., anaphylaxis) following 
administration of mepolizumab, there are personnel/staff onsite at the treatment facility 
who are appropriately trained in basic life support to manage the patient including 
administration of medications (e.g., epinephrine) and have access to a system that can 
promptly transport the patient to another facility for additional care if appropriate.
Those subjects who enter the run-in period but do not meet all inclusion/exclusion criteria 
will be deemed Run-in failures and will not be dosed in the study. The reason for any 
Run-in failure will be recorded in the eCRF.
During the Part A Treatment phase, all subjects will receive mepolizumab either 40mg 
(subjects <40kg at Visit 2) or 100 mg SC (subjects ≥40kg at Visit 2) at week 0 (Visit 2), 
week 4 (Visit 3) and week 8 (Visit 4) which will provide therapeutic coverage through to 
week 12 (Visit 6/End of Therapy Visit).  Visit 6 will mark the end of the treatment phase.
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
130
Section1, Synopsis, Treatment Arms and Duration, Part B:
Original Text:
Part B Treatment:  Those subjects meeting the eligibility criteria for the long-term 
phase of the study at Visit 9 will receive mepolizumab 40 or 100 mg SC, (depending on 
subject bodyweight measured at Visit 9;  40 mg for subjects <40 kg and 100 mg for 
subjects ≥ 40 kg).  Subjects shall be observed for a minimum of 60 minutes in the clinic 
following injection at Visit 9 and at subsequent visits subjects should be monitored 
according to standard practice at the site.  From Visit 10 onwards subjects will receive the 
same dose of  mepolizumab at 4-weekly intervals for a total of 48 weeks.  Subjects with 
bodyweight <40 kg at Visit 9 should be weighed at each subsequent visit and have their 
dose adjusted once their bodyweight exceeds 40 kg.
Amended Text:
Part B Treatment:  Those subjects meeting the eligibility criteria for the long-term 
phase of the study at Visit 9 will receive mepolizumab 40 or 100 mg SC, (depending on 
subject bodyweight measured at Visit 9;  40 mg for subjects <40 kg and 100 mg for 
subjects ≥ 40 kg).  Subjects should be monitored post-SC administration according to 
standard practice at the site.  From Visit 10 onwards subjects will receive mepolizumab at 
4-weekly intervals for a total of 48 weeks.  Subjects with bodyweight <40 kg at Visit 9 
should be weighed at each subsequent visit and have their dose adjusted to 100mg once 
their bodyweight reaches 40 kg.  Subjects weighing ≥40kg at Visit 9 will receive the 
100mg dose at all subsequent treatment visits and will not be weighed again.
Section 4 Study Design, Part A Treatment:
Original Text:
Treatment:  Those subjects meeting all of the inclusion/exclusion criteria by Visit 2 will 
receive mepolizumab 40 or 100 mg SC, depending on subject bodyweight (40 mg for 
subjects <40 kg and 100 mg for subjects ≥ 40 kg). Subjects will receive their first dose of 
mepolizumab at Visit 2 and enter into the Treatment phase of the study.  Subjects shall be 
observed for a minimum of 60 minutes in the clinic following each injection.  Those 
subjects who enter the run-in period but do not meet all inclusion/exclusion criteria will 
be deemed Run-in failures and will not be dosed in the study. The reason for any Run-in 
failure will be recorded in the eCRF.
During the Treatment phase, all subjects will receive mepolizumab 40 or 100 mg SC, 
depending on subject bodyweight, at week 0 (Visit 2), week 4 (Visit 3) and week 8 (Visit 
4). These doses should provide therapeutic coverage through to week 12 (Visit 6/End of 
Therapy Visit).  Visit 6 will mark the end of the treatment phase. 
Amended Text:
Treatment:  Those subjects meeting all of the inclusion/exclusion criteria by Visit 2 will 
receive mepolizumab 40 or 100 mg SC, depending on subject bodyweight (40 mg for 
subjects <40 kg and 100 mg for subjects ≥ 40 kg). Subjects will receive their first dose of 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
131
mepolizumab at Visit 2 and enter into the Treatment phase of the study.  Subjects shall be 
observed for a minimum of 60 minutes in the clinic following each injection.  Safety 
monitoring of subjects will occur during SC administration and for 1 hour after the three 
administrations in Part A and then follow monitoring policies for the center in Part B.  
Such monitoring will include general safety monitoring including monitoring for both 
systemic hypersensitivity (i.e., allergic/IgE-mediated and non-allergic) and local site 
reactions.  In the event of an acute severe reaction (e.g., anaphylaxis) following 
administration of mepolizumab, there are personnel/staff onsite at the treatment facility 
who are appropriately trained in basic life support to manage the patient including 
administration of medications (e.g., epinephrine) and have access to a system that can 
promptly transport the patient to another facility for additional care if appropriate.
Those subjects who enter the run-in period but do not meet all inclusion/exclusion criteria 
will be deemed Run-in failures and will not be dosed in the study. The reason for any 
Run-in failure will be recorded in the eCRF.
During the Treatment phase, all subjects will receive mepolizumab either 40mg SC 
(subjects <40kg at Visit 2) or 100 mg SC (subjects ≥40kg at Visit 2) at week 0 (Visit 2), 
week 4 (Visit 3) and week 8 (Visit 4). These doses should provide therapeutic coverage 
through to week 12 (Visit 6/End of Therapy Visit).  Visit 6 will mark the end of the 
treatment phase. 
Section 4 Study Design, Part A Follow-up:
Original Text:
Follow-up: Following completion of Visit 6, subjects will enter into the Follow-up phase 
which will consist of two additional visits at weeks 16 (Visit 7) and 20 (Visit 8).For 
subjects who had a positive neutralizing antibody response at the Follow-up (Visit 8) (or 
last study visit at which immunogenicity was assessed if the Follow-up (Visit 8) 
immunogenicity sample is not available), an attempt will be made to obtain a serum 
sample for anti-mepolizumab antibodies at least 4 months after the last dose of study 
drug.
Amended Text:
Follow-up: Following completion of Visit 6, subjects will enter into the Follow-up phase 
which will consist of two additional visits at weeks 16 (Visit 7) and 20 (Visit 8).For 
subjects who had a positive anti-mepolizumab antibody response at the Follow-up (Visit 
8) (or last study visit at which immunogenicity was assessed if the Follow-up (Visit 8) 
immunogenicity sample is not available), an attempt will be made to obtain a serum 
sample for anti-mepolizumab antibodies at least 4 months after the last dose of study drug
in Part A or upon completion of Part A, whichever is later.
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
132
Section 4 Study Design Long Term treatment:
Original Text:
Long-Term Treatment:  Those subjects meeting the eligibility criteria for the long-term 
phase of the study at Visit 9 will receive mepolizumab 40 or 100 mg SC, (depending on 
subject bodyweight measured at Visit 9;  40 mg for subjects <40 kg and 100 mg for 
subjects ≥ 40 kg).  Subjects shall be observed for a minimum of 60 minutes in the clinic 
following injection at Visit 9 and at subsequent visits subjects should be monitored 
according to standard practice at the site.  
Amended Text:
Long-Term Treatment:  Those subjects meeting the eligibility criteria for the long-term 
phase of the study at Visit 9 will receive mepolizumab 40 or 100 mg SC, (depending on 
subject bodyweight measured at Visit 9;  40 mg for subjects <40 kg and 100 mg for 
subjects ≥ 40 kg).  Subjects should be monitored post-SC administration according to 
standard practice at the site.  
Section 4.1 Overall Design, Part B:
Original Text:
This is a long-term safety / pharmacodynamic phase in which extended treatment will be 
offered on an optional basis to those subjects eligible for continued treatment.  Subjects 
will receive either 40 or 100mg depending on subject bodyweight, administered 
subcutaneously at 4-weekly intervals for a total of 52 weeks.
Amended Text:
This is a long-term safety / pharmacodynamic phase in which extended treatment for a 
further 52 weeks will be offered on an optional basis to those subjects eligible for 
continued treatment.  Subjects will receive either 40 or 100mg depending on subject 
bodyweight, administered SC every 4 weeks to subjects with severe eosinophilic asthma 
aged 6-11 years.  At the end of the 52 weeks extended treatment in Part B, subjects will 
have an Exit Visit 4 weeks after last dose and a Follow-Up visit 12 weeks after last dose.
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
133
Section 4.2, Treatment Arms and Duration:
Original Text:
Pharmacokinetic/Pharmacodynamic Phase (Part A)
Enrolled subjects in this study will be assigned to receive one of the following treatments:
Treatment Arm
SC dose
Mepolizumab 40 mg SC upper arm or thigh
Mepolizumab 40 mg SC
For subjects <40 kg bodyweight at Visit 2 
(Week 0)
Mepolizumab 100 mg SC upper arm or 
thigh
Mepolizumab 100mg SC
For subjects ≥40 kg bodyweight at Visit 2 
(Week 0)
Part A Pre-Screening/Screening/Run-in:  Subjects will attend an initial Pre-screening 
visit to assess their willingness and eligibility to participate in the study.  The Pre-
screening visit will include: informed consent, demography, exacerbations and 
concomitant medications.  Visit 1(Screening) will include a physical exam, screening 
laboratory tests, screening ECG and other assessments to determine suitability to 
participate in this study.  The Pre-screening visit may be conducted at the same clinic 
visit as Visit 1 (Screening).  Subjects meeting the Visit 1(Screening) eligibility criteria 
will enter a Run-in period of up to 2 weeks to allow for receipt and review of the lab 
results and ECG. 
Part A Treatment:  Those subjects meeting all of the inclusion/exclusion criteria by 
Visit 2 will receive mepolizumab 40 or 100 mg SC, depending on subject bodyweight (40 
mg for subjects <40 kg and 100 mg for subjects ≥ 40 kg). Subjects will receive their first 
dose of mepolizumab at Visit 2 and enter into the Treatment phase of the study.  Subjects 
shall be observed for a minimum of 60 minutes in the clinic following each injection.  
Those subjects who enter the run-in period but do not meet all inclusion/exclusion criteria 
will be deemed Run-in failures and will not be dosed in the study. The reason for any 
Run-in failure will be recorded in the eCRF.
During the Part A Treatment phase, all subjects will receive mepolizumab 40 or 100 mg 
SC, depending on subject bodyweight measured at Visit 2, at week 0 (Visit 2), week 4 
(Visit 3) and week 8 (Visit 4) which will provide therapeutic coverage through to week 
12 (Visit 6/End of Therapy Visit).  Visit 6 will mark the end of the treatment phase.
Subjects will visit the clinic at week 9 (Visit 5) to allow for measurement of the 
approximate peak mepolizumab concentration.  
Part A Follow-up:  Following completion of Visit 6, subjects will enter into the Follow-
up phase which will consist of two additional visits at weeks 16 (Visit 7) and 20 (Visit 8).
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
134
The total duration of Part A will be 22 weeks and will include a run-in period of 1-2 
weeks, a treatment period of 12 weeks and a follow-up phase of 8 weeks. A subject will 
be considered having completed Part A if the subject completes all phases including the 
follow-up phase (Visit 8).  A subject will be defined as evaluable for Part A if the subject 
received all 3 planned doses of mepolizumab and has completed all pharmacokinetic and 
pharmacodynamic assessments through to study Visit 6.
Long-Term Safety / Long Term Pharmacodynamic Phase (Part B)
Treatment Arm
SC dose
Mepolizumab 40mg SC upper arm or thigh
Mepolizumab 40 mg SC
For subjects <40 kg bodyweight at Visit 9 
(Week 20).  From visit 10, subjects should 
be weighed at each visit until bodyweight 
reaches 40kg when the dose should be 
adjusted to 100mg.  From this time 
onwards, the dose will not be adjusted
again.
Mepolizumab 100mg SC upper arm or 
thigh
Mepolizumab 100mg SC
For subjects bodyweight at Visit 9 (Week 
20) or from the time that bodyweight 
reaches 40 kg
Following Part A subjects will be evaluated for eligibility to continue into Part B of this 
study.  For those subjects determined to be eligible and for whom appropriate informed 
consent/assent has been obtained there will be a Long-Term Safety / Pharmacodynamic 
Phase (Part B).  Part B will include Treatment and Follow-up phases. 
Part B Treatment:  Those subjects meeting all of the Part B eligibility criteria by Visit 9 
will receive mepolizumab 40 or 100 mg SC, depending on subject bodyweight at Visit 9 
(40 mg for subjects <40 kg and 100 mg for subjects ≥ 40 kg). Subjects should be 
monitored post-SC administration according to standard practice at the site.  From Visit 
10 onwards subjects will receive the same dose of mepolizumab at 4-weekly intervals.  
Subjects with bodyweight <40 kg at Visit 9 should be weighed at each visit and have 
their dose adjusted once their bodyweight exceeds 40 kg.  Once a subject starts treatment 
with the 100mg dose, the dose will not be adjusted further even if the subject’s 
bodyweight should drop below 40kg.
Part B Follow-up:  Following completion of Visit 22, subjects will enter into the 
Follow-up phase which will consist of an additional visit at week 80 (Visit 23).
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
135
Amended Text:
Pharmacokinetic/Pharmacodynamic Phase (Part A)
Enrolled subjects in this study will be assigned to receive one of the following treatments:
Treatment Arm
SC dose
Mepolizumab 40 mg SC upper arm or thigh
Mepolizumab 40 mg SC
For subjects <40 kg bodyweight at Visit 2 
(Week 0)
Mepolizumab 100 mg SC upper arm or 
thigh
Mepolizumab 100mg SC
For subjects ≥40 kg bodyweight at Visit 2 
(Week 0)
The total duration of Part A will be 22 weeks and will include a run-in period of 1-2 
weeks, a treatment period of 12 weeks and a follow-up phase of 8 weeks. 
Long-Term Safety / Long Term Pharmacodynamic Phase (Part B)
Treatment Arm
SC dose
Mepolizumab 40mg SC upper arm or thigh
Mepolizumab 40 mg SC
For subjects <40 kg bodyweight at Visit 9 
(Week 20).  From visit 10, subjects should 
be weighed at each visit until bodyweight 
reaches 40kg when the dose should be 
adjusted to 100mg.  From this time 
onwards, the dose will not be adjusted 
again.
Mepolizumab 100mg SC upper arm or 
thigh
Mepolizumab 100mg SC
For subjects bodyweight at Visit 9 (Week 
20) or from the time that bodyweight 
reaches 40 kg
Following completion of Part A subjects will be evaluated for eligibility to continue into 
Part B of this study.  For those subjects determined to be eligible and for whom 
appropriate informed consent/assent has been obtained there will be a Long-Term Safety 
/ Pharmacodynamic Phase (Part B).  The total duration of Part B is approximately 60 
weeks.
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
136
Section 4.3:  Type and Number of Subjects:
Original Text:
Approximately 40 male or female subjects with severe eosinophilic asthma, aged 6 to 11 
years inclusive at screening (Visit 1), will be screened to achieve approximately 28 
eligible subjects entering the Part A treatment phase to allow availability of 20 evaluable 
subjects, with a minimum of six subjects enrolled in the < 40 kg bodyweight group.  An 
evaluable subject is defined to be a subject who has received all three doses of 
mepolizumab and has all PK and PD assessments completed through to Visit 6 (week 
12).
Amended Text:
Approximately 40 male or female subjects with severe eosinophilic asthma, aged 6 to 11 
years inclusive at screening (Visit 1), will be screened to achieve approximately 28 
eligible subjects entering the Part A treatment phase to allow availability of 20 evaluable 
subjects, with a minimum of six subjects enrolled in the < 40 kg bodyweight group.  An
evaluable subject is defined to be a subject who has received all three doses of 
mepolizumab and has all PK and PD assessments completed through to Visit 6 (week 
12).
Sample size is not determined for Part B.   All subjects who completed Part A and meet 
the eligibility criteria for Part B will be allowed to participate in Part B.Section 5.1:  
Inclusion Criteria for Part A:
Original Text:
4. A well-documented requirement for regular treatment with inhaled corticosteroid 
(≥400 μg/day fluticasone propionate (DPI) or equivalent daily) in the 12 months prior 
to Visit 1 with or without maintenance oral corticosteroids (OCS).
Amended Text:
4. A well-documented requirement for regular treatment with inhaled corticosteroid 
(>200 μg/day fluticasone propionate (DPI) or equivalent daily) with or without 
maintenance oral corticosteroids (OCS).  The ICS dose should represent medium or 
high dose in children aged 6-11 years of age [GINA, 2015].
Section 5.1:  Inclusion Criteria for Part A:
Original Text:
7. Previously confirmed history of two or more exacerbations requiring treatment with 
systemic CS (intramuscular (IM), intravenous, or oral), in the 12 months prior to visit 
1, despite the use of high-dose inhaled corticosteroids (ICS).  For subjects receiving 
maintenance CS, the CS treatment for the exacerbations must have been a two-fold 
increase or greater in the dose.
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
137
Amended Text:
7. Previously confirmed history of two or more exacerbations requiring treatment with 
systemic CS (intramuscular (IM), intravenous, or oral), in the 12 months prior to visit 
1, despite the use of inhaled corticosteroids (ICS). For subjects receiving 
maintenance OCS treatment for the exacerbations must have been a two-fold 
increase or greater in the CS dose.
Section 5.1:  Inclusion Criteria for Part A:
Original Text:
9. Male or female: Females of childbearing potential must commit to consistent and 
correct use of an acceptable method of contraception (see Appendix 7) for the 
duration of the trial and for 4 months after the last dose of investigational product. A 
urine pregnancy test is required of girls of childbearing potential. This test will be 
performed at the initial screening visit (Visit 1) and will be performed at each 
scheduled study visit prior to the administration of investigational product, and during 
the Early Withdrawal and Follow-up Visits.
Amended Text:
9. Male or female: Females of childbearing potential must commit to consistent and 
correct use of an acceptable method of contraception (see Appendix 7) for the 
duration of the trial and for 4 months after the last dose of investigational product. A 
urine pregnancy test is required of girls of childbearing potential. This test will be 
performed at the initial screening visit (Visit 1) and will be performed at each 
scheduled treatment visit prior to the administration of investigational product, and 
during the Exit Visit, Early Withdrawal and Follow-up Visits.
Section 5.1:  Inclusion Criteria Part A
Original Text:
6. FEV1: Persistent airflow obstruction at either visit 1 or Visit 2 (FEV1 performed prior 
to first dose of study medication) as indicated by:

A pre-bronchodilator FEV1 <110% predicted OR

FEV1:FVC ratio < 0.8
Amended Text:
6. FEV1: Persistent airflow obstruction at either visit 1 or Visit 2 (FEV1 performed prior 
to first dose of study medication) as indicated by:

A pre-bronchodilator FEV1 <110% predicted (Quanjer, 2012)  OR

FEV1:FVC ratio < 0.8
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
138
Section 5.2:  Exclusion Criteria for Part A:
Additional exclusion criterion:
5.
A positive Hepatitis B Surface Antigen or Hepatitis C antibody at Visit 1
Section 5.5: Withdrawal/Stopping Criteria
Original Text:
Subjects are also free to withdraw consent to participate in the study at anytime. Every 
effort should be made to have them return to the clinic for an Exit Visit (See Table 3 and 
Table 4) and to return all study related materials.  In those instances where the subject 
specifies the reason for withdrawal of consent, this information will be captured in the 
eCRF.
A subject should only be designated as lost to follow-up if the site is unable to establish 
contact with the subject after 3 documented attempts via 2 different methods (phone, text, 
e-mail, certified letter, etc).
For both Part A and Part B of this study an Exit Visit should be conducted within 4 weeks 
of the last dose received.  In the event a subject withdraws at, or during, a scheduled visit, 
an Exit Visit is not required.  However, all study procedures scheduled at an Exit Visit 
must be performed at this visit instead.  A Follow-up Visit should be scheduled 12 weeks 
after the last dose of investigational product.  
Any data collected up until the point of withdrawal will be used in the analyses.  For 
those subjects completing the follow-up visit, any safety data collected post withdrawal 
through follow-up will be summarised.
Amended Text:
Subjects are also free to withdraw consent to participate in the study at anytime. Every 
effort should be made to have them return to the clinic for an Early Withdrawal Visit (See 
Table 3 and Table 4) and to return all study related materials.  In those instances where 
the subject specifies the reason for withdrawal of consent, this information will be 
captured in the eCRF.
A subject should only be designated as lost to follow-up if the site is unable to establish 
contact with the subject after 3 documented attempts via 2 different methods (phone, text, 
e-mail, certified letter, etc).
For both Part A and Part B of this study an Exit Visit should be conducted within 4 weeks 
of the last dose received.  In the event that a subject withdraws at, or during, a scheduled
visit, an Early Withdrawal Visit should be performed at this visit instead.  A Follow-up 
Visit should then be scheduled 12 weeks after the last dose of investigational product
(Visit 8 or Visit 23 for subjects withdrawing from study Parts A or B, respectively)
Any data collected up until the point of withdrawal will be used in the analyses.  
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
139
Section 6.2:  Dosage and Administration:
Original Text:
Treatment Arm
SC dose
Mepolizumab 40mg SC upper arm or thigh
Mepolizumab 40 mg SC
For subjects <40 kg bodyweight at Visit 
9 (Week 20)
Mepolizumab 100mg SC upper arm or 
thigh
Mepolizumab 100mg SC
For subjects bodyweight at Visit 9 (Week 
20) or from the time that bodyweight 
reaches 40 kg)
Site staff member assigned to the study will be required to prepare the appropriate 
medication according to the study subject’s treatment assignment. Subjects eligible to 
enter the study will be assigned to treatment based on bodyweight at Visit 2. Assigned 
dose will remain the same irrespective of bodyweight changes during the treatment 
phase.
Prior to administration, each vial of mepolizumab will need to be reconstituted and 
swirled gently to enable complete dissolution of the product.  Detailed instructions can be 
found within the Study Reference Manual (SRM).  Subjects assigned to the 40 mg 
treatment group will receive 0.4 mL of reconstituted mepolizumab.  Subjects assigned to 
the 100 mg treatment group will receive 1.0 mL of reconstituted mepolizumab.  Injected 
volume may be split between two injection sites for subjects receiving 100 mg (1.0 mL) 
and given as 2x0.5mL injections.  Investigator should consider the use of a local 
anaesthetic at the injections sites.
All subjects in this open-label, non-randomized study entering the treatment phase will be 
assigned to a unique treatment number in accordance with the schedule generated by 
Clinical Statistics, prior to the start of the study.  
Amended Text:
Treatment Arm
SC dose
Mepolizumab 40mg SC upper arm or thigh
Mepolizumab 40 mg SC
For subjects with bodyweight <40 kg at 
Visit 9 (Week 20) and at any subsequent 
visits
Mepolizumab 100mg SC upper arm or thigh
Mepolizumab 100mg SC
For subjects with bodyweight ≥40kg at 
Visit 9 (Week 20) or from the visit at 
which bodyweight reaches 40 kg
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
140
Site staff member assigned to the study will be required to prepare the appropriate 
medication according to the study subject’s treatment assignment. Subjects eligible to 
enter the study will be assigned to treatment based on bodyweight at Visit 2. Assigned 
dose will remain the same irrespective of bodyweight changes during the treatment phase
of Part A.
Prior to administration, each vial of mepolizumab will need to be reconstituted and 
swirled gently to enable complete dissolution of the product.  Detailed instructions can be 
found within the Study Reference Manual (SRM).  Subjects assigned to the 40 mg 
treatment group will receive 0.4 mL of reconstituted mepolizumab.  Subjects assigned to 
the 100 mg treatment group will receive 1.0 mL of reconstituted mepolizumab.  Injected 
volume may be split between two injection sites for subjects receiving 100 mg (1.0 mL) 
and given as 2x0.5mL injections.  Investigator should consider the use of a local 
anaesthetic at the injections sites.
Section 4:  Study Design:
Original Text:
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table (Table 3), are essential and required for study 
conduct. 
Amended Text:
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table (Table 3 and Table 4), are essential and required 
for study conduct. 
Section 6.8 Treatment After the Completion of Part A and Part B
Original wording
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the patient’s medical condition whether or not GSK is providing specific 
continuing study treatment under Part B of this study.
At the end of Part A, a benefit/risk assessment will be performed by the Investigator and 
if this assessment supports continued therapy with mepolizumab and GSK has given 
approval, the subject will be offered the opportunity to enrol in Part B following the Part 
A Follow-up visit (Visit 8).  Part B will continue for 52 weeks of additional mepolizumab 
treatment.
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
141
Amended wording:
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the patient’s medical condition whether or not GSK is providing specific 
continuing study treatment under Part B of this study.
At the end of Part A, a benefit/risk assessment will be performed by the Investigator and 
if this assessment supports continued therapy with mepolizumab the subject will be 
offered the opportunity to enrol in Part B following the Part A Follow-up visit (Visit 8).  
Part B will continue for 52 weeks of additional mepolizumab treatment.
Section 6.9.1:  Permitted Medications and Non-Drug Therapies:
Original Text:
All concomitant medications taken during the study will be recorded on the electronic 
Case Report Form (eCRF).  The minimum requirement is that drug name and all dates 
and times of administration are to be recorded.
Amended Text:
All concomitant medications taken during the study will be recorded on the electronic 
Case Report Form (eCRF).  The minimum requirement is that drug name and all dates 
and times of administration are to be recorded.
Section 6.9.1:  Permitted Medications and Non-Drug Therapies:
Original Text:
All concomitant medications taken during the study will be recorded on the electronic 
Case Report Form (eCRF).  The minimum requirement is that drug name and all dates 
and times of administration are to be recorded.

Existing stable asthma therapy (inhaled fluticasone propionate (DPI) or equivalent, 
total daily dose greater than or equal to 400 mcg or equivalent daily) will be 
permitted during the run-in and active treatment period.

Current treatment with an additional controller medication for at least 3 months  
[e.g., long-acting beta-2-agonist (LABA), leukotriene receptor antagonist (LTRA), or 
theophylline].

Short acting beta 2 agonist inhalation aerosol (albuterol/salbutamol) will be 
permitted for symptomatic relief of asthma symptoms.

Low potency topical corticosteroids (≤1% hydrocortisone).

Acetaminophen. .
Other concomitant medication may be considered on a case by case basis by the GSK 
Medical Monitor.
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
142
Amended Text:
All concomitant medications taken during the study will be recorded on the electronic 
Case Report Form (eCRF).  Asthma medications taken during the 12 months prior to 
Visit 1 should be recorded in the eCRF.  The minimum requirement is that drug name 
and all dates of administration are to be recorded.  Permitted medications include:

Existing stable asthma therapy (inhaled fluticasone propionate (DPI) or equivalent, 
total daily dose greater than or equal to 200 mcg or equivalent daily) will be 
permitted during the run-in and active treatment period.

Current treatment with an additional controller medication [e.g., long-acting beta-2-
agonist (LABA), leukotriene receptor antagonist (LTRA), or theophylline] will be 
permitted during the run-in and active treatment period..

Short acting beta 2 agonist inhalation aerosol (albuterol/salbutamol) will be 
permitted for symptomatic relief of asthma symptoms.  Albuterol/salbutamol will be 
provided locally (except for US sites where GSK Global Supply Organisation will 
supply the rescue medication) and dispensed at each visit from Screening Visit 1, as 
required.

Oral corticosteroids

Low potency topical corticosteroids (≤1% hydrocortisone).

Acetaminophen. 
Other concomitant medication may be considered on a case by case basis by the GSK 
Medical Monitor.
No changes in the dose or regimen of baseline ICS and/or additional controller 
medication are permitted during the run-in period.
Section 7:  Table 3 Time and Events Table:
Original Text:
Procedure
Pre-
Screen1
Screening
Treatment Period
Exit 
Visit3
Follow-up 
Early 
Withdrawal
Visit Number 
0
1
2
3
4
5
6
77
88
Week of Study 
(visit window   3 days, 
±1 day Visit 5))
Prior to or 
same day 
as Visit 1
(up to 14 
days prior 
to Visit 2)
0
4
8
9
12
16
20
Subject Screen
Informed consent
X
Inclusion and exclusion 
criteria
X
X
Demography
X
Medical history, including 
bronchodilator 
reversibility history4
X
Past and current medical 
X
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
143
Procedure
Pre-
Screen1
Screening
Treatment Period
Exit 
Visit3
Follow-up 
Early 
Withdrawal
Visit Number 
0
1
2
3
4
5
6
77
88
Week of Study 
(visit window   3 days, 
±1 day Visit 5))
Prior to or 
same day 
as Visit 1
(up to 14 
days prior 
to Visit 2)
0
4
8
9
12
16
20
conditions 
Asthma exacerbation 
history 
X
Safety Assessments
Concomitant medications
X
X
X
X
X
X
X
X
X
X
Hematology (including 
eosinophils)
X
X
X
X
X
X
X
X
X
Clinical Chemistry
X
X
X
X
X
X
12-lead ECG
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
Bodyweight
X
Brief physical 
examination
X
Adverse events
X
X
X
X
X
X
X
X
X
Cardiovascular events
X
X
X
X
X
X
X
X
X
Liver events
X
X
X
X
X
X
X
X
X
Laboratory 
Assessments
Urinalysis
X
X
X
Pregnancy Test
U
U5
U5
U5
U
U
U
U
HBsAg and hepatitis C 
antibody
X6
Serum IgE (total and 
specific)
X5
PK blood sample
X5
X5
X
X
X
X
X
IL5 serum sample
X5
X
Blood sample for 
immunogenicity
X5
X7
X2
X
Outcomes 
Assessments
FEV1
X
X
X
X
X
X
X
X
ACQ-7
X
X
X
X
X
X
X
C-ACT
X
X
X
X
X
X
X
Assessment of 
exacerbation
X
X
X
X
X
X
X
X
X
X
Investigational Product
Mepolizumab SC dose 
administered
X
X
X
Study Administration
Email to GSK 
Operational Lead
X
X
X
X
X
X
X
X
X
X
Complete eCRF
X
X
X
X
X
X
X
X
X
X
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
144
9.
Pre-screen must be completed prior to or on the same day as Screen Visit. 
10. For subjects who had a positive anti-mepolizumab antibody response at the 12 week post-last-dose follow-up 
assessment an attempt will be made to obtain a serum sample for anti-mepolizumab antibodies at least 4 months 
after the last dose of study agent or upon completion of the study, whichever is later.
11. Exit visit may be completed 3 to 5 weeks post last dose. If more than 5 weeks has passed since the last dose, 
only perform Follow-up Visit.
12. Therapy history to include a detailed review of prior biologics received for treatment of asthma, including prior 
investigational anti-IL5 or anti-IL13 preparations.
13. During the treatment period, all lab samples and procedures should be obtained prior to study treatment 
administration.
14. A positive Hepatitis B Surface Antigen and Hepatitis C antibody is exclusionary
15. This immunogenicity sample must always be collected 12 weeks (7 days) post-last-dose of study treatment; 
therefore, for subjects who withdraw from study treatment early, this sample must be collected 12 weeks (7 
days) after their confirmed last dose of study treatment (i.e., prior to Visit 8). In the event that this sample 
collection date coincides with an Early Withdrawal Visit, only one immunogenicity sample should be collected.
16. For subjects continuing into the long-term extension phase Part B, Visit 9 should be conducted on the same day 
as Visit 8 once all of the visit 8 assessments have been completed.  .
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
145
Table 4
Time and Events Table Long-Term Safety / Pharmacodynamic Phase (Part B)
Procedure
Eligibility 
Check / First 
Dose
Exit 
Visit
Follow-
up
Early 
Withdrawal
Visit
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Week of Study 
(visit window 5 days)
20
24
28
32
36
40
44
48
52
56
60
64
68
72
80
Subject Screen
Informed consent
X1
Inclusion and exclusion criteria
X1
Safety Assessments
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology (including 
eosinophils) 2
X
X
X
X
X
X
X
X
Clinical Chemistry2
X
X
X
X
X
X
X
12-lead ECG
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Bodyweight
X
X1
X1
X1
X1
X1
X1
X1
X1
X1
X1
X1
X1
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Cardiovascular events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Liver events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments2
Urinalysis
X1
X
X
X
Pregnancy Test
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
Blood sample for 
immunogenicity2
X
X
X
X
Outcomes Assessments
FEV1
X1
X
X
X
X
X
X
X
ACQ-7
X1
X
X
X
X
X
X
X
C-ACT
X1
X
X
X
X
X
X
X
Assessment of exacerbation
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
146
Procedure
Eligibility 
Check / First 
Dose
Exit 
Visit
Follow-
up
Early 
Withdrawal
Visit
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Week of Study 
(visit window 5 days)
20
24
28
32
36
40
44
48
52
56
60
64
68
72
80
Investigational Product
Mepolizumab SC dose 
administered
X
X
X
X
X
X
X
X
X
X
X
X
X
Study Administration
Email to GSK Operational Lead
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete eCRF
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
4.
Bodyweight will be measured at Visit 9 and at each visit until such time as the subject reaches 40kg in weight. Subjects with bodyweight ≥40Kg at Visit 9 will not be weighed again 
during Part B.
All laboratory samples should be collected prior to the administration of study medication
 
 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
147
Amended text:
Procedure
Pre-
Screen1
Screening
Treatment Period
Exit 
Visit3
Follow-up 
Early 
Withdrawal
Visit Number 
0
1
2
3
4
5
6
77
88
Week of Study 
(visit window   3 days, 
±1 day Visit 5))
Prior to or 
same day 
as Visit 1
(up to 14 
days prior 
to Visit 2)
0
4
8
9
12
16
20
Subject Screen
Informed consent
X
Inclusion and exclusion 
criteria
X
X
Demography
X
Medical history, including 
bronchodilator 
reversibility history4
X
Past and current medical 
conditions 
X
Asthma exacerbation 
history 
X
Safety Assessments
Concomitant medications
X
X
X
X
X
X
X
X
X
X
Hematology (including 
eosinophils)
X
X
X
X
X
X
X
X
X
Clinical Chemistry
X
X
X
X
X
X
12-lead ECG
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
Bodyweight
X
Brief physical 
examination
X
Adverse events
X
X
X
X
X
X
X
X
X
Cardiovascular events
X
X
X
X
X
X
X
X
X
Liver events
X
X
X
X
X
X
X
X
X
Laboratory 
Assessments
Urinalysis
X
X
X
Pregnancy Test
U
U5
U5
U5
U
U
U
U
HBsAg and hepatitis C 
antibody
X6
Serum IgE (total and 
specific)
X5
PK blood sample
X5
X5
X
X
X
X
X
IL5 serum sample
X5
X
Blood sample for 
immunogenicity2,7
X5
X
X2
X
Outcomes 
Assessments
FEV1
X
X
X
X
X
X
X
X
ACQ-7
X
X
X
X
X
X
X
C-ACT
X
X
X
X
X
X
X
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
148
Procedure
Pre-
Screen1
Screening
Treatment Period
Exit 
Visit3
Follow-up 
Early 
Withdrawal
Visit Number 
0
1
2
3
4
5
6
77
88
Week of Study 
(visit window   3 days, 
±1 day Visit 5))
Prior to or 
same day 
as Visit 1
(up to 14 
days prior 
to Visit 2)
0
4
8
9
12
16
20
Assessment of 
exacerbation
X
X
X
X
X
X
X
X
X
X
Investigational Product
Mepolizumab SC dose 
administered
X
X
X
Study Administration
Email to GSK 
Operational Lead
X
X
X
X
X
X
X
X
X
X
Complete eCRF
X
X
X
X
X
X
X
X
X
X
1.
Pre-screen must be completed prior to or on the same day as Screen Visit. 
2.
For subjects who had a positive anti-mepolizumab antibody response at the 12 week post-last-dose follow-up 
assessment (Visit 8) (or last study visit at which immunogenicity was assessed if the Follow-up (Visit 8) 
immunogenicity sample is not available) an attempt will be made to obtain a serum sample for anti-mepolizumab 
antibodies at least 4 months after the last dose of study drug in Part A or upon completion of Part A, whichever is 
later.
3.
Exit visit should be performed as close as possible to the planned week 12 visit date.
4.
Therapy history to include a detailed review of prior biologics received for treatment of asthma, including prior 
investigational anti-IL5 or anti-IL13 preparations.
5.
During the treatment period, all lab samples and procedures should be obtained prior to study treatment 
administration.
6.
A positive Hepatitis B Surface Antigen and Hepatitis C antibody is exclusionary
7.
This immunogenicity sample must always be collected 12 weeks (7 days) post-last-dose of study treatment; 
therefore, for subjects who withdraw from study treatment early, this sample must be collected 12 weeks (7 
days) after their confirmed last dose of study treatment (i.e., prior to Visit 8). In the event that this sample 
collection date coincides with an Early Withdrawal Visit, only one immunogenicity sample should be collected.
8.
Visit 8 to be performed 12 weeks post last dose. For subjects continuing into the long-term extension phase Part 
B, Visit 9 should be conducted on the same day as Visit 8 once all of the visit 8 assessments have been 
completed.  Assessments performed at Visit 8 that are also listed for Visit 9 should not be duplicated if Visit 8 and 
Visit 9 are performed on the same day.
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
149
Table4
Time and Events Table Long-Term Safety / Pharmacodynamic Phase (Part B)
3.
Exit visit may be completed 2 to 4 weeks post last dose. If more than 6 weeks has passed since the last dose, only perform Follow-up Visit.
Procedure
Eligibility 
Check / 
First 
Dose
Treatment Period
Exit 
Visit
Follow-
up
Early 
Withdrawal
Visit
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Week of Study 
(visit window 5 days)
20
24
28
32
36
40
44
48
52
56
60
64
68
72
80
Subject Screen
Informed consent
X1
Inclusion and exclusion criteria
X1
Safety Assessments
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology (including 
eosinophils) 2
X
X
X
X
X
X
X
X
Clinical Chemistry2
X
X
X
X
X
X
X
12-lead ECG
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Bodyweight
X
X1
X1
X1
X1
X1
X1
X1
X1
X1
X1
X1
X1
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Cardiovascular events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Liver events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments2
Urinalysis
X1
X
X
X
Pregnancy Test
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
Blood sample for 
immunogenicity2
X
X
X
X
Outcomes Assessments
 
 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
150
Procedure
Eligibility 
Check / 
First 
Dose
Treatment Period
Exit 
Visit
Follow-
up
Early 
Withdrawal
Visit
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Week of Study 
(visit window 5 days)
20
24
28
32
36
40
44
48
52
56
60
64
68
72
80
FEV1
X1
X
X
X
X
X
X
X
ACQ-7
X1
X
X
X
X
X
X
X
C-ACT
X1
X
X
X
X
X
X
X
Assessment of exacerbation
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Investigational Product
Mepolizumab SC dose 
administered
X
X
X
X
X
X
X
X
X
X
X
X
X
Study Administration
Email to GSK Operational Lead
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete eCRF
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
1.
Bodyweight will be measured at Visit 9 and at each visit until such time as the subject reaches 40kg in weight. Subjects with bodyweight ≥40Kg at Visit 9 will not be weighed again 
during Part B.
2.
All laboratory samples should be collected prior to the administration of study medication
 
 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
151
Section 7.5 Immunogenicity
Original Text:
Blood samples will be collected for the determination of anti-mepolizumab antibodies, 
prior to dosing at Visit 2 (Week 0), and subsequently at Visit 7 (Week 16), and at Visit 8 
(Week 20). 
For subjects who had a positive neutralizing antibody response at the Follow-up (Visit 8) 
(or last study visit at which immunogenicity was assessed if the Follow-up (Visit 8) 
immunogenicity sample is not available), an attempt will be made to obtain a serum 
sample for anti-mepolizumab antibodies at least 4 months after the last dose of study drug 
in Part A.
In Part B, immunogenicity samples will be collected prior to dosing at Visit 15 (week 
44), Visit 21 (week 68) and at Follow-up Visit 23 (week 80).
Details for sample collection and processing may be found in the SRM.
Amended Text:
Blood samples will be collected for the determination of anti-mepolizumab antibodies, 
prior to dosing at Visit 2 (Week 0), and subsequently at Visit 7 (Week 16), at Visit 8 
(Week 20) and Early Withdrawal. 
For subjects who had a positive anti-mepolizumab antibody response at the Follow-up 
(Visit 8) (or last study visit at which immunogenicity was assessed if the Follow-up (Visit 
8) immunogenicity sample is not available), an attempt will be made to obtain a serum 
sample for anti-mepolizumab antibodies at least 4 months after the last dose of study drug 
in Part A or upon completion of Part A, whichever is later.
In Part B, immunogenicity samples will be collected prior to dosing at Visit 15 (week 
44), Visit 21 (week 68) and at Follow-up Visit 23 (week 80) and Early Withdrawal.
Details for sample collection and processing may be found in the SRM.
Section 7.6:  Forced Expiratory Volume-1 (FEV1):
Original Text:
A spreadsheet calculator will be provided for calculating percent predicted FEV1
Amended Text:
See the Study Reference Manual (SRM) for further details
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
152
Section 7.7:  Asthma Control Questionnaire-7 (ACQ-7):
Original text:
The ACQ has a multidimensional construct assessing symptoms (5 items administered by 
clinic staff to the child using the interviewer administer format) and rescue 
bronchodilator use (query to child or parent), and FEV1% (1 item) completed by clinic 
staff (Appendix 6).  
Amended Text:
The ACQ-IA has a multidimensional construct assessing symptoms (5 items administered 
by clinic staff to the child using the interviewer administer format) and rescue 
bronchodilator use (query to child or parent), and FEV1% (1 item) completed by clinic 
staff (Appendix 6).  
Section 7.8:  Childhood Asthma Control Test (C-ACT):
Original text:
The Childhood Asthma Control Test (C-ACT) assesses asthma control in children 4-11 
years of age (Liu, 2007, Liu, 2010). The ACT will be completed on paper. The C-ACT 
should be completed prior to other study procedures to ensure that responses are not 
influenced by interactions with study site staff.  The C-ACT is a 7-question, 2-part 
questionnaire, with items one through 4 to be completed by the child (with assistance 
from a caregiver, as needed) and items 5 to 7 to be completed by the caregiver (Appendix 
10).   All items are assessed using a five point descriptive scale. The descriptive response 
options are assigned scores from 1-5 with higher scores representing higher levels of 
asthma control. A total sum score based upon responses to all items is calculated to 
provide an overall measure of asthma control. The C-ACT should be completed prior to 
other study procedures to ensure that responses are not influenced by interactions with 
study site staff. 
Amended Text:
The Childhood Asthma Control Test (C-ACT) assesses asthma control in children 4-11 
years of age (Liu, 2007, Liu, 2010). The ACT will be completed on paper. The C-ACT 
should be completed prior to other study procedures to ensure that responses are not 
influenced by interactions with study site staff.  The C-ACT is a 7-question, 2-part 
questionnaire, with items one through 4 to be completed by the child (with assistance 
from a caregiver, as needed) and items 5 to 7 to be completed by the caregiver (Appendix 
10).   A total sum score based upon responses to all items is calculated to provide an 
overall measure of asthma control. 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
153
Section 9.2 Sample Size Considerations:
Original Text:
The sample size was determined by the number of subjects needed for the PK and PD 
evaluations based on previous PK/PD studies. A pediatric population-PK trial simulation 
(GSK Document Number 2014N223495_00) was used to determine the Root Mean 
Square Error (RMSE, i.e. standard deviation) in estimated exposure (AUC(0-inf) ) as a 
function of sample size, pharmacokinetic sampling scheme and model assumptions. 
Based on 1000 trial simulations per scenario, a sample size of 16-32 subjects is sufficient 
to maintain precision in exposure estimation (and hence bodyweight-adjusted clearance) 
below 20%, (as compared with the  guideline 40%), providing five pharmacokinetic 
samples (including one close to Tmax) are collected and four parameters are fixed from 
adult values in the population-PK model.
Amended Text:
The sample size was determined by the number of subjects needed for the PK and PD 
evaluations of Part A of the study, based on previous PK/PD studies. A pediatric 
population-PK trial simulation (GSK Document Number 2014N223495_00) was used to 
determine the Root Mean Square Error (RMSE, i.e. standard deviation) in estimated 
exposure (AUC(0-inf) ) as a function of sample size, pharmacokinetic sampling scheme and 
model assumptions. Based on 1000 trial simulations per scenario, a sample size of 16-32 
subjects is sufficient to maintain precision in exposure estimation (and hence 
bodyweight-adjusted clearance) below 20%, (as compared with the  guideline 40%), 
providing five pharmacokinetic samples (including one close to Tmax) are collected and 
four parameters are fixed from adult values in the population-PK model.
Section 9.2.1 Sample Size Assumptions
Original Text:
No sample size assumptions are assumed beyond the demonstrated comparability 
between adult pharmacokinetic parameters and those observed in children aged 2-17 
years in an intravenous study of hyper-eosinophilic esophagitis.
Amended text:
No sample size assumptions are assumed beyond the demonstrated comparability 
between adult pharmacokinetic parameters and those observed in an intravenous study in 
children aged 2-17 years with eosinophilic esophagitis.
Section 9.3.1.1 Safety Population Part A:
Original Text:
All subjects receiving at least one dose of study medication beginning at Visit 2 will be 
included in the safety population for Part A analyses.
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
154
Amended Text:
All subjects receiving at least one dose of mepolizumab beginning at Visit 2 will be 
included in the safety population for Part A analyses.
Section 9.3.1.5 Safety Population Part B:
Original Text:
All subjects receiving at least one dose of study medication beginning at Visit 9 will be 
included in the safety population for Part B analyses.
Amended Text:
All subjects receiving at least one dose of mepolizumab beginning at Visit 9 will be 
included in the safety population for Part B analyses.
Section 9.5.2 Secondary Analyses:
Original Text:
Blood eosinophil count, the primary pharmacodynamic endpoint, will be log transformed 
prior to analysis and will also be summarised using descriptive statistics.  
Secondary endpoints including ACQ-7, c-ACT will be summarised using descriptive 
statistics, Confidence intervals will be presented when appropriate. The analysis schema 
will be outlined in the RAP.
Amended Text:
Blood eosinophil count will be log transformed prior to analysis and will also be 
summarised using descriptive statistics.
Section 9.5.3:  Exploratory Analyses:
Exploratory endpoints including ACQ-7, C-ACT and number of exacerbations will be 
summarised using descriptive statistics. Confidence intervals will be presented when 
appropriate. The analysis schema will be outlined in the RAP.
Protocol Amendment 04
Section 5.1:  Inclusion Criteria for Part A:
Original Text:
4. A well-documented requirement for regular treatment with inhaled corticosteroid 
(>200 μg/day fluticasone propionate (DPI) or equivalent daily) with or without 
maintenance oral corticosteroids (OCS).  The ICS dose should represent medium or 
high dose in children aged 6-11 years of age [GINA, 2015].
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
155
Amended Text:
4. A well-documented requirement for regular treatment with inhaled corticosteroid 
(>200 μg/day fluticasone propionate (DPI) or equivalent daily) in the 12 months prior 
to Visit 1 with or without maintenance oral corticosteroids (OCS).  The ICS dose 
should represent medium or high dose in children aged 6-11 years of age [GINA, 
2015].
Protocol Amendment 05
Section 1:  Protocol Synopsis, Rationale:
Original Text:
Following the main study (Part A), subjects will be evaluated for eligibility to continue 
into the optional long-term extension phase (Part B) of this study.  For those subjects 
determined to be eligible and for whom appropriate informed consent/assent has been 
obtained there will be the option of continuing to receive treatment with mepolizumab 
during a Long-Term Safety / Pharmacodynamic Phase (Part B) which will include 
Treatment and Follow-up phases.  Part B will provide data to assess the long-term safety 
and tolerability of mepolizumab in this paediatric population and will also provide data to 
assess the durability of the pharmacodynamic response to mepolizumab.
Amended Test:
Following the main study (Part A), subjects will be evaluated for eligibility to continue 
into the optional long-term extension phase (Part B) of this study.  For those subjects 
determined to be eligible and for whom appropriate informed consent/assent has been 
obtained there will be the option of continuing to receive treatment with mepolizumab 
during a Long-Term Safety / Pharmacodynamic Phase (Part B) which will include 
Treatment and Follow-up phases (Part B Follow-up is not required for subjects 
transitioning to the long term access program at the end of Part B).  Part B will provide 
data to assess the long-term safety and tolerability of mepolizumab in this paediatric 
population and will also provide data to assess the durability of the pharmacodynamic 
response to mepolizumab.
Section 1:  Protocol Synopsis, Objective(s)/Endpoint(s), Long Term Safety/Long Term 
Pharmacodynamic Phase (Part B):
Original Test:
Objectives
Endpoints
Primary

To assess the long-term (52 weeks) 
safety and tolerability of mepolizumab 
when administered subcutaneously to 
subjects aged 6 to 11* years old with 
severe eosinophilic asthma  

Incidence of Adverse Events

Frequency of positive anti-
mepolizumab binding antibodies and 
neutralizing antibodies

Incidence of clinically significant 
changes in vital sign measurements
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
156
Objectives
Endpoints

Incidence of clinically significant  
changes in clinical laboratory 
parameters
Secondary

To characterize the long-term (52 
weeks) durability of 
pharmacodynamics of mepolizumab 
administered subcutaneously to  
subjects aged 6 to 11* years old with 
severe eosinophilic asthma

Change from Week 20 (Visit 9) in 
absolute blood eosinophil count at 
weeks 32, 44, 56, 68, 72 and 80.

Exploratory

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 
11* years old with severe eosinophilic 
asthma

To characterize the long-term (52 
weeks) asthma control following 
subcutaneous administration of 
mepolizumab to subjects aged 6 to 11* 
years old with severe eosinophilic 
asthma 

Incidence of asthma exacerbations

Change from Week 20 (Visit 9) in 
ACQ-7 and C-ACT at weeks 32, 44, 
56, 68, 72 and 80.
*Subjects who reach their 12th birthday during Part A may participate in Part B
Amended Text:
Objectives
Endpoints
Primary

To assess the long-term (52 weeks) 
safety and tolerability of mepolizumab 
when administered subcutaneously to 
subjects aged 6 to 11* years old with 
severe eosinophilic asthma  

Incidence of Adverse Events

Frequency of positive anti-
mepolizumab binding antibodies and 
neutralizing antibodies

Incidence of clinically significant 
changes in vital sign measurements

Incidence of clinically significant  
changes in clinical laboratory 
parameters
Secondary

To characterize the long-term (52 
weeks) durability of 

Change from Week 0 (Visit 2) in 
absolute blood eosinophil count at 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
157
Objectives
Endpoints
pharmacodynamics of mepolizumab 
administered subcutaneously to  
subjects aged 6 to 11* years old with 
severe eosinophilic asthma
weeks 32, 44, 56, 68, 72 and 80**.

Exploratory

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 
11* years old with severe eosinophilic 
asthma

To characterize the long-term (52 
weeks) asthma control following 
subcutaneous administration of 
mepolizumab to subjects aged 6 to 11* 
years old with severe eosinophilic 
asthma 

Incidence of asthma exacerbations

Change from Week 0 (Visit 2) in ACQ-
7 and C-ACT at weeks 32, 44, 56, 68, 
72 and 80**.
*Subjects who reach their 12th birthday during Part A may participate in Part B
**Week 80 is not applicable to subjects transitioning to the long-term access program
Section 1:  Protocol Synopsis, Objective(s)/Endpoint(s), Overall Design, Long Term 
Safety/Long Term Pharmacodynamic Phase (Part B):
Original Text:
This is a long-term safety / pharmacodynamic phase in which extended treatment for a 
further 52 weeks will be offered on an optional basis to those subjects eligible for 
continued treatment.  Subjects will receive either 40 or 100mg depending on subject 
bodyweight, administered SC every 4 weeks to subjects with severe eosinophilic asthma 
aged 6-11 years.  At the end of the 52 weeks extended treatment in Part B, subjects will 
have an Exit Visit 4 weeks after last dose and a Follow-Up visit 12 weeks after last dose.
Amended Text:
This is a long-term safety / pharmacodynamic phase in which extended treatment for a 
further 52 weeks will be offered on an optional basis to those subjects eligible for 
continued treatment.  Subjects will receive either 40 or 100mg depending on subject 
bodyweight, administered SC every 4 weeks to subjects with severe eosinophilic asthma 
aged 6-11 years.  At the end of the 52 weeks extended treatment in Part B, subjects will 
have an Exit Visit 4 weeks after last dose.  Subjects not transitioning to the long-term 
access program will also have a Follow-Up visit 12 weeks after last dose.
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
158
Section 1:  Protocol Synopsis, Objective(s)/Endpoint(s), Treatment Arms and Duration, 
Long Term Safety/Long Term Pharmacodynamic Phase (Part B), Part B Follow-up:  
Original Text:
Part B Follow-up:  Following completion of Visit 22, subjects will enter into the 
Follow-up phase which will consist of one additional follow-up visit at week 80 (Visit 
23).
Amended Text:
Part B Follow-up:  Following completion of Visit 22, subjects not transitioning to the 
long term access program will enter into the Follow-up phase which will consist of one 
additional follow-up visit at week 80 (Visit 23).
Section 3, Objective(s) and Endpoint(s), Long Term Safety/Long term Pharmacodynamic 
Phase (Part B):  
Original Text:
Objectives
Endpoints
Primary

To assess the long-term (52 weeks) 
safety and tolerability of mepolizumab 
when administered subcutaneously to 
subjects aged 6 to 11* years old with 
severe eosinophilic asthma  

Incidence of Adverse Events

Frequency of positive anti-
mepolizumab binding antibodies and 
neutralizing antibodies

Incidence of clinically significant 
changes in vital sign measurements

Incidence of clinically significant  
changes in clinical laboratory 
parameters
Secondary

To characterize the long-term (52 
weeks) durability of 
pharmacodynamics of mepolizumab 
administered subcutaneously to  
subjects aged 6 to 11* years old with 
severe eosinophilic asthma

Change from Week 20 (Visit 9) in 
absolute blood eosinophil count at 
weeks 32, 44, 56, 68, 72 and 80.

Exploratory

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 

Incidence of asthma exacerbations
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
159
Objectives
Endpoints
11* years old with severe eosinophilic 
asthma

To characterize the long-term (52 
weeks) asthma control following 
subcutaneous administration of 
mepolizumab to subjects aged 6 to 11* 
years old with severe eosinophilic 
asthma 

Change from Week 20 (Visit 9) in 
ACQ-7 and C-ACT at weeks 32, 44, 
56, 68, 72 and 80.
*Subjects who reach their 12th birthday during Part A may continue into Part B
Amended Text:
Objectives
Endpoints
Primary

To assess the long-term (52 weeks) 
safety and tolerability of mepolizumab 
when administered subcutaneously to 
subjects aged 6 to 11* years old with 
severe eosinophilic asthma  

Incidence of Adverse Events

Frequency of positive anti-
mepolizumab binding antibodies and 
neutralizing antibodies

Incidence of clinically significant 
changes in vital sign measurements

Incidence of clinically significant  
changes in clinical laboratory 
parameters
Secondary

To characterize the long-term (52 
weeks) durability of 
pharmacodynamics of mepolizumab 
administered subcutaneously to  
subjects aged 6 to 11* 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 80**.

Exploratory

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 
11* years old with severe eosinophilic 
asthma

To characterize the long-term (52 
weeks) asthma control following 
subcutaneous administration of 

Incidence of asthma exacerbations

Change from Week 0 (Visit 2) in ACQ-
7 and C-ACT at weeks 32, 44, 56, 68, 
72 and 80**.
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
160
Objectives
Endpoints
mepolizumab to subjects aged 6 to 11* 
years old with severe eosinophilic 
asthma 
*Subjects who reach their 12th birthday during Part A may continue into Part B
** Week 80 is not applicable to subjects transitioning to the long-term access program
Section 4, Study Design:
Original Text:
This study will consist of two phases: Part A will consist of Pre-
Screening/Screening/Run-in, Treatment, and Follow-up.  Part B will consist of Long-
Term Treatment and Follow-up.
Amended Text:
This study will consist of two phases: Part A will consist of Pre-
Screening/Screening/Run-in, Treatment, and Follow-up.  Part B will consist of Long-
Term Treatment and Follow-up. The Part B follow-up phase is not required for subjects 
transitioning to the long term access program.
Section 4, Study Design, Long Term Safety/Pharmacodynamic Phase (Part B), Follow-
up:
Original Text:
Follow-up:  Following completion of Visit 22, subjects will enter into the Follow-up 
phase which will consist of one additional follow-up visit at week 80 (Visit 23).
Study visits in Part B will have a window of 5 days.  The total duration of Part B is
approximately 60 weeks.  A subject will be regarded as having completed Part B if they 
complete all phases of Part B (Long-Term Treatment and Follow-up).
Amended Text:
Follow-up:  Following completion of Visit 22, subjects not transitioning to the long term 
access program will enter into the Follow-up phase which will consist of one additional 
follow-up visit at week 80 (Visit 23).
Study visits in Part B will have a window of 5 days.  The total duration of Part B is
approximately 60 weeks (52 weeks for subjects transitioning to the long-term access 
program).  A subject not transitioning to the long-term access program will be regarded 
as having completed Part B if they complete all phases of Part B (Long-Term Treatment 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
161
and Follow-up). A subject transitioning to the long-term access program will be regarded
as having completed Part B if they complete the Treatment Phase of Part B.
Section 4.1, Overall Design, Long Term Safety/Pharmacodynamic Phase (Part B):
Original Text:
This is a long-term safety / pharmacodynamic phase in which extended treatment for a 
further 52 weeks will be offered on an optional basis to those subjects eligible for 
continued treatment.  Subjects will receive either 40 or 100mg depending on subject 
bodyweight, administered SC every 4 weeks to subjects with severe eosinophilic asthma 
aged 6-11 years.  At the end of the 52 weeks extended treatment in Part B, subjects will 
have an Exit Visit 4 weeks after last dose and a Follow-Up visit 12 weeks after last dose.
Amended Text:
This is a long-term safety / pharmacodynamic phase in which extended treatment for a 
further 52 weeks will be offered on an optional basis to those subjects eligible for 
continued treatment.  Subjects will receive either 40 or 100mg depending on subject 
bodyweight, administered SC every 4 weeks to subjects with severe eosinophilic asthma 
aged 6-11 years.  At the end of the 52 weeks extended treatment in Part B, subjects will 
have an Exit Visit 4 weeks after last dose.  Subjects not transitioning to the long term 
access program will have a Follow-Up visit 12 weeks after last dose.
Section 4.2, Treatment Arms and Duration, Long Term Safety/Pharmacodynamic Phase 
(Part B):  
Original Text:
Following completion of Part A subjects will be evaluated for eligibility to continue into 
Part B of this study.  For those subjects determined to be eligible and for whom 
appropriate informed consent/assent has been obtained there will be a Long-Term Safety 
/ Pharmacodynamic Phase (Part B).  The total duration of Part B is approximately 60
Amended text:
Following completion of Part A subjects will be evaluated for eligibility to continue into 
Part B of this study.  For those subjects determined to be eligible and for whom 
appropriate informed consent/assent has been obtained there will be a Long-Term Safety 
/ Pharmacodynamic Phase (Part B). The total duration of Part B is approximately 60 
weeks (52 weeks for subjects transitioning to the long-term access program).
Section 4.4, Design Justification:
Original Text:
A treatment phase duration of 12 weeks is considered sufficient to support the primary 
PK and PD endpoint of the study. A dose ranging PK/PD study (MEA114092) of 
mepolizumab administered intravenously (75 mg) or subcutaneously (12.5, 125 and 250 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
162
mg) with a similar duration was conducted in adult asthmatic subjects with elevated 
blood eosinophil levels. Concordance in the blood eosinophil reduction at 75 mg IV 
between this study and the 12-month duration phase 2/3 study (Pavord, 2012) confirms 
suitability of the 12 weeks duration treatment for the chosen endpoint. Furthermore, 
comparable blood eosinophil count reduction was observed at 75 mg IV and 100 mg SC 
in a phase 3 study (MEA115588) with consistent blood eosinophil reduction observed 
from 12 weeks onwards. These data support conducting a study of 12 weeks duration  
and will allow comparison with adult/adolescent data to support the extrapolation of the 
safety and efficacy data observed in adults/adolescents in the severe asthma phase 3 
program to the 6-11 pediatric population. Subjects will be followed-up for a total of 12 
weeks after the last dose, which is consistent with the follow-up duration in adult studies. 
Amended Text:
A treatment phase duration of 12 weeks is considered sufficient to support the primary 
PK and PD endpoint of the study. A dose ranging PK/PD study (MEA114092) of 
mepolizumab administered intravenously (75 mg) or subcutaneously (12.5, 125 and 250 
mg) with a similar duration was conducted in adult asthmatic subjects with elevated 
blood eosinophil levels. Concordance in the blood eosinophil reduction at 75 mg IV
between this study and the 12-month duration phase 2/3 study (Pavord, 2012) confirms 
suitability of the 12 weeks duration treatment for the chosen endpoint. Furthermore, 
comparable blood eosinophil count reduction was observed at 75 mg IV and 100 mg SC 
in a phase 3 study (MEA115588) with consistent blood eosinophil reduction observed 
from 12 weeks onwards. These data support conducting a study of 12 weeks duration  
and will allow comparison with adult/adolescent data to support the extrapolation of the 
safety and efficacy data observed in adults/adolescents in the severe asthma phase 3 
program to the 6-11 pediatric population. Subjects will be followed-up for a total of 12 
weeks after the last dose in Part A, which is consistent with the follow-up duration in 
adult studies. 
Section 5.6, Subject and Study Completion:
Original text:
A completed subject is one who has completed all phases of the study including the 
follow-up visit.
The end of the study is defined as the last subject’s last visit.
Amended Text:
In Part A, a completed subject is one who has completed all phases of the study including 
the Part A follow-up visit.  In Part B, for subjects not transitioning to the long-term 
access program, a completed subject is one who has completed all phases of Part B 
(including the Part B follow-up visit) and for subjects transitioning to the long term 
access program a completed subject is one who has completed the Treatment Phase of 
Part B.
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
163
Section 6.8, Treatment After the Completion of Part A and Part B:
Original Text:
At the end of Part B, subjects will return to usual care and will be prescribed appropriate 
alternative asthma therapy, as required.
Amended Text:
At the end of Part B, when feasible, subjects will transition to a long term access 
program.  At the end of the Treatment Phase of Part B, subjects that are not able to 
transition to the long term access program will return to usual care and will be prescribed 
appropriate alternative asthma therapy, as required.  
Section 7, Study Assessments and Procedures, Table 3:
Original Text:
Procedure
Pre-
Screen1
Screening
Treatment Period
Exit 
Visit3
Follow-up 
Early 
Withdrawal
Visit Number 
0
1
2
3
4
5
6
7
88
Week of Study 
(visit window   3 days, 
±1 day Visit 5))
Prior to or 
same day 
as Visit 1
(up to 14 
days prior 
to Visit 2)
0
4
8
9
12
16
20
Subject Screen
Informed consent
X
Inclusion and exclusion 
criteria
X
X
Demography
X
Medical history, including 
bronchodilator 
reversibility history4
X
Past and current medical 
conditions 
X
Asthma exacerbation 
history 
X
Safety Assessments
Concomitant medications
X
X
X
X
X
X
X
X
X
X
Hematology (including 
eosinophils)
X
X
X
X
X
X
X
X
X
Clinical Chemistry
X
X
X
X
X
X
12-lead ECG
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
Bodyweight
X
Brief physical 
examination
X
Adverse events
X
X
X
X
X
X
X
X
X
Cardiovascular events
X
X
X
X
X
X
X
X
X
Liver events
X
X
X
X
X
X
X
X
X
Laboratory 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
164
Procedure
Pre-
Screen1
Screening
Treatment Period
Exit 
Visit3
Follow-up 
Early 
Withdrawal
Visit Number 
0
1
2
3
4
5
6
7
88
Week of Study 
(visit window   3 days, 
±1 day Visit 5))
Prior to or 
same day 
as Visit 1
(up to 14 
days prior 
to Visit 2)
0
4
8
9
12
16
20
Assessments
Urinalysis
X
X
X
Pregnancy Test
U
U5
U5
U5
U
U
U
U
HBsAg and hepatitis C 
antibody
X6
Serum IgE (total and 
specific)
X5
PK blood sample
X5
X5
X
X
X
X
X
IL5 serum sample
X5
X
Blood sample for 
immunogenicity2,7
X5
X
X2
X
Outcomes 
Assessments
FEV1
X
X
X
X
X
X
X
X
ACQ-7
X
X
X
X
X
X
X
C-ACT
X
X
X
X
X
X
X
Assessment of 
exacerbation
X
X
X
X
X
X
X
X
X
X
Investigational Product
Mepolizumab SC dose 
administered
X
X
X
Study Administration
Email to GSK 
Operational Lead
X
X
X
X
X
X
X
X
X
X
Complete eCRF
X
X
X
X
X
X
X
X
X
X
1.
Pre-screen must be completed prior to or on the same day as Screen Visit. 
2.
For subjects who had a positive anti-mepolizumab antibody response at the 12 week post-last-dose follow-up 
assessment (Visit 8) (or last study visit at which immunogenicity was assessed if the Follow-up (Visit 8) 
immunogenicity sample is not available) an attempt will be made to obtain a serum sample for anti-mepolizumab 
antibodies at least 4 months after the last dose of study drug in Part A or upon completion of Part A, whichever is 
later.
3.
Exit visit should be performed as close as possible to the planned week 12 visit date.
4.
Therapy history to include a detailed review of prior biologics received for treatment of asthma, including prior 
investigational anti-IL5 or anti-IL13 preparations.
5.
During the treatment period, all lab samples and procedures should be obtained prior to study treatment 
administration.
6.
A positive Hepatitis B Surface Antigen and Hepatitis C antibody is exclusionary
7.
This immunogenicity sample must always be collected 12 weeks (7 days) post-last-dose of study treatment; 
therefore, for subjects who withdraw from study treatment early, this sample must be collected 12 weeks (7 
days) after their confirmed last dose of study treatment (i.e., prior to Visit 8). In the event that this sample 
collection date coincides with an Early Withdrawal Visit, only one immunogenicity sample should be collected.
8.
Visit 8 to be performed 12 weeks post last dose. For subjects continuing into the long-term extension phase Part 
B, Visit 9 should be conducted on the same day as Visit 8 once all of the visit 8 assessments have been 
completed.  Assessments performed at Visit 8 that are also listed for Visit 9 should not be duplicated if Visit 8 and 
Visit 9 are performed on the same day.
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
165
Amended Text:
Procedure
Pre-
Screen1
Screening
Treatment Period
Exit 
Visit3
Follow-up 
Early 
Withdrawal
Visit Number 
0
1
2
3
4
5
6
7
88
Week of Study 
(visit window   3 days, 
±1 day Visit 5))
Prior to or 
same day 
as Visit 1
(up to 14 
days prior 
to Visit 2)
0
4
8
9
12
16
20
Subject Screen
Informed consent
X
Inclusion and exclusion 
criteria
X
X
Demography
X
Medical history, including 
bronchodilator 
reversibility history4
X
Past and current medical 
conditions 
X
Asthma exacerbation 
history 
X
Safety Assessments
Concomitant medications
X
X
X
X
X
X
X
X
X
X
Hematology (including 
eosinophils)
X
X
X
X
X
X
X
X
X
Clinical Chemistry
X
X
X
X
X
X
12-lead ECG
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
Bodyweight
X
Brief physical 
examination
X
Adverse events
X
X
X
X
X
X
X
X
X
Cardiovascular events
X
X
X
X
X
X
X
X
X
Liver events
X
X
X
X
X
X
X
X
X
Laboratory 
Assessments
Urinalysis
X
X
X
Pregnancy Test
U
U5
U5
U5
U
U
U
U
HBsAg and hepatitis C 
antibody
X6
Serum IgE (total)
X5
PK blood sample
X5
X5
X
X
X
X
X
IL5 serum sample
X5
X
Blood sample for 
immunogenicity2,7
X5
X
X2
X
Outcomes 
Assessments
FEV1
X
X
X
X
X
X
X
X
ACQ-7
X
X
X
X
X
X
X
C-ACT
X
X
X
X
X
X
X
Assessment of 
X
X
X
X
X
X
X
X
X
X
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
166
Procedure
Pre-
Screen1
Screening
Treatment Period
Exit 
Visit3
Follow-up 
Early 
Withdrawal
Visit Number 
0
1
2
3
4
5
6
7
88
Week of Study 
(visit window   3 days, 
±1 day Visit 5))
Prior to or 
same day 
as Visit 1
(up to 14 
days prior 
to Visit 2)
0
4
8
9
12
16
20
exacerbation
Investigational Product
Mepolizumab SC dose 
administered
X
X
X
Study Administration
Email to GSK 
Operational Lead
X
X
X
X
X
X
X
X
X
X
Complete eCRF
X
X
X
X
X
X
X
X
X
X
1.
Pre-screen must be completed prior to or on the same day as Screen Visit. 
2.
For subjects who had a positive anti-mepolizumab antibody response at the 12 week post-last-dose follow-up 
assessment (Visit 8) (or last study visit at which immunogenicity was assessed if the Follow-up (Visit 8) 
immunogenicity sample is not available) an attempt will be made to obtain a serum sample for anti-mepolizumab 
antibodies at least 4 months after the last dose of study drug in Part A or upon completion of Part A, whichever is 
later.
3.
Exit visit should be performed as close as possible to the planned week 12 visit date.
4.
Therapy history to include a detailed review of prior biologics received for treatment of asthma, including prior 
investigational anti-IL5 or anti-IL13 preparations.
5.
During the treatment period, all lab samples and procedures should be obtained prior to study treatment 
administration.
6.
A positive Hepatitis B Surface Antigen and Hepatitis C antibody is exclusionary
7.
This immunogenicity sample must always be collected 12 weeks (7 days) post-last-dose of study treatment; 
therefore, for subjects who withdraw from study treatment early, this sample must be collected 12 weeks (7 
days) after their confirmed last dose of study treatment (i.e., prior to Visit 8). In the event that this sample 
collection date coincides with an Early Withdrawal Visit, only one immunogenicity sample should be collected.
8.
Visit 8 to be performed 12 weeks post last dose. For subjects continuing into the long-term extension phase Part 
B, Visit 9 should be conducted on the same day as Visit 8 once all of the visit 8 assessments have been 
completed.  Assessments performed at Visit 8 that are also listed for Visit 9 should not be duplicated if Visit 8 and 
Visit 9 are performed on the same day.
Section 7, Study Assessments and Procedures, Table 4:
Original Text:
Procedure
Eligibili
ty 
Check 
/ First 
Dose
Treatment Period
Exi
t 
Vis
it
Follo
w-up
Early 
Withdraw
al
Visit
9
1
0
1
1
1
2
1
3
1
4
1
5
1
6
1
7
1
8
1
9
2
0
2
1
22
23
Week of 
Study 
(visit window 
5 days)
20
2
4
2
8
3
2
3
6
4
0
4
4
4
8
5
2
5
6
6
0
6
4
6
8
72
80
Subject 
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
167
Procedure
Eligibili
ty 
Check 
/ First 
Dose
Treatment Period
Exi
t 
Vis
it
Follo
w-up
Early 
Withdraw
al
Visit
9
1
0
1
1
1
2
1
3
1
4
1
5
1
6
1
7
1
8
1
9
2
0
2
1
22
23
Week of 
Study 
(visit window 
5 days)
20
2
4
2
8
3
2
3
6
4
0
4
4
4
8
5
2
5
6
6
0
6
4
6
8
72
80
Screen
Informed 
consent
X1
Inclusion and 
exclusion 
criteria
X1
Safety 
Assessment
s
Concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology 
(including 
eosinophils) 2
X
X
X
X
X
X
X
X
Clinical 
Chemistry2
X
X
X
X
X
X
X
12-lead ECG
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Bodyweight
X
X
1
X
1
X
1
X
1
X
1
X
1
X
1
X
1
X
1
X
1
X
1
X
1
Adverse 
events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Cardiovascul
ar events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Liver events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory 
Assessment
s2
Urinalysis
X1
X
X
X
Pregnancy 
Test
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
Blood sample 
for 
immunogenici
ty2
X
X
X
X
Outcomes 
Assessment
s
FEV1
X1
X
X
X
X
X
X
X
ACQ-7
X1
X
X
X
X
X
X
X
C-ACT
X1
X
X
X
X
X
X
X
Assessment 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
168
Procedure
Eligibili
ty 
Check 
/ First 
Dose
Treatment Period
Exi
t 
Vis
it
Follo
w-up
Early 
Withdraw
al
Visit
9
1
0
1
1
1
2
1
3
1
4
1
5
1
6
1
7
1
8
1
9
2
0
2
1
22
23
Week of 
Study 
(visit window 
5 days)
20
2
4
2
8
3
2
3
6
4
0
4
4
4
8
5
2
5
6
6
0
6
4
6
8
72
80
of 
exacerbation
Investigation
al Product
Mepolizumab 
SC dose 
administered
X
X
X
X
X
X
X
X
X
X
X
X
X
Study 
Administrati
on
Email to GSK 
Operational 
Lead
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete 
eCRF
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
1.
Bodyweight will be measured at Visit 9 and at each visit until such time as the subject reaches 40kg in weight. 
Subjects with bodyweight ≥40Kg at Visit 9 will not be weighed again during Part B.
2.
All laboratory samples should be collected prior to the administration of study medication
Amended Text:
Procedure
Eligibi
lity 
Chec
k / 
First 
Dose
Treatment Period
E
xit 
Vi
sit
Follow-up3
Early 
Withdra
wal
Visit
9
1
0
1
1
1
2
1
3
1
4
1
5
1
6
1
7
1
8
1
9
2
0
2
1
22
23
Week of 
Study 
(visit 
window 5
days)
20
2
4
2
8
3
2
3
6
4
0
4
4
4
8
5
2
5
6
6
0
6
4
6
8
72
Subject 
Screen
Informed 
consent
X1
Inclusion 
and 
exclusion 
X1
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
169
Procedure
Eligibi
lity 
Chec
k / 
First 
Dose
Treatment Period
E
xit 
Vi
sit
Follow-up3
Early 
Withdra
wal
Visit
9
1
0
1
1
1
2
1
3
1
4
1
5
1
6
1
7
1
8
1
9
2
0
2
1
22
23
Week of 
Study 
(visit 
window 5
days)
20
2
4
2
8
3
2
3
6
4
0
4
4
4
8
5
2
5
6
6
0
6
4
6
8
72
criteria
Safety 
Assessme
nts
Concomitan
t 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology 
(including 
eosinophils)
2
X
X
X
X
X
X
X
X
Clinical 
Chemistry2
X
X
X
X
X
X
X
12-lead 
ECG
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Bodyweight
X
X
1
X
1
X
1
X
1
X
1
X
1
X
1
X
1
X
1
X
1
X
1
X
1
Adverse 
events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Cardiovasc
ular events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Liver events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory 
Assessme
nts2
Urinalysis
X1
X
X
X
Pregnancy 
Test
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
Blood 
sample for 
immunogeni
city2
X
X
X
X
Outcomes 
Assessme
nts
FEV1
X1
X
X
X
X
X
X
X
ACQ-7
X1
X
X
X
X
X
X
X
C-ACT
X1
X
X
X
X
X
X
X
Assessment 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
170
Procedure
Eligibi
lity 
Chec
k / 
First 
Dose
Treatment Period
E
xit 
Vi
sit
Follow-up3
Early 
Withdra
wal
Visit
9
1
0
1
1
1
2
1
3
1
4
1
5
1
6
1
7
1
8
1
9
2
0
2
1
22
23
Week of 
Study 
(visit 
window 5
days)
20
2
4
2
8
3
2
3
6
4
0
4
4
4
8
5
2
5
6
6
0
6
4
6
8
72
of 
exacerbatio
n
Investigati
onal 
Product
Mepolizuma
b SC dose 
administere
d
X
X
X
X
X
X
X
X
X
X
X
X
X
Study 
Administra
tion
Email to 
GSK 
Operational 
Lead
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete 
eCRF
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
1.
Bodyweight will be measured at Visit 9 and at each visit until such time as the subject reaches 40kg in weight. 
Subjects with bodyweight ≥40Kg at Visit 9 will not be weighed again during Part B.
2.
All laboratory samples should be collected prior to the administration of study medication
3.
The 12-week post-dose follow-up visit (Visit 23) is not required for subjects transitioning to the long-term access 
program.
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
171
Section 7.2.6, Clinical Safety Laboratory Assessments:
Original Text:
All blood samples which will be taken prior to each administration of study medication 
will be sent to a central laboratory for analysis (details provided in the SRM). Standard 
reference ranges will be used.
Amended Text:
All blood samples which will be taken prior to each administration of study medication 
will be sent to a central laboratory for analysis (details provided in the Q2 Solutions 
Investigator Manual). Standard reference ranges will be used.  
Section 7.3, Pharmacokinetics:
Original Text
Blood samples for analysis of mepolizumab plasma concentration will be obtained as per 
the Part A Time and Events table (Table 3).  Samples obtained at visit 3 and 4 must be 
drawn prior to mepolizumab dosing.  The date and exact time of collection for each 
sample will be documented in the eCRF.
Details for collection and processing of samples may be found in the SRM.
Amended text:
Blood samples for analysis of mepolizumab plasma concentration will be obtained as per 
the Part A Time and Events table (Table 3).  Samples obtained at visit 3 and 4 must be 
drawn prior to mepolizumab dosing.  The date and exact time of collection for each 
sample will be documented in the eCRF.
Details for collection and processing of samples may be found in the Q2 Solutions 
Investigator Manual.
Section 7.5, Immunogenicity:
Original Text:
In Part B, immunogenicity samples will be collected prior to dosing at Visit 15 (week 
44), Visit 21 (week 68) and at Follow-up Visit 23 (week 80) and Early Withdrawal.
Details for sample collection and processing may be found in the SRM.
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
172
Amended Text:
In Part B, immunogenicity samples will be collected prior to dosing at Visit 15 (week 
44), Visit 21 (week 68) and, when applicable, at Follow-up Visit 23 (week 80) and Early 
Withdrawal.
Details for sample collection and processing may be found in the Q2 Solutions 
Investigator Manual.
Section 9.2, Sample Size Considerations:
Original Text:
With regards to the pre-planned secondary analysis, the trial simulations also showed that 
for the proposed sample size and sampling scheme, 80% of simulated trials yielded a 
bodyweight-adjusted clearance with 90% confidence limits falling within the bounds 0.8 
– 1.25 of the adult value (0.29 L/day). This precision is deemed sufficient for 
extrapolation purposes from adults to pediatric subjects aged 6 to 11 years supported by 
this study (GSK Document Number 2014N223495_00).
Amended Text:
With regards to the pre-planned secondary analysis, the trial simulations also showed that 
for the proposed sample size and sampling scheme, 80% of simulated trials yielded a 
bodyweight-adjusted apparent clearance with 90% confidence limits falling within the 
bounds 0.8 – 1.25 of the adult apparent clearance value (CL/F of 0.29 L/day). This 
precision is deemed sufficient for extrapolation purposes from adults to pediatric subjects 
aged 6 to 11 years supported by this study (GSK Document Number 2014N223495_00).
Section 9.4.2, Secondary Analyses:
Original Text:
The comparison of bodyweight-adjusted clearance between the 6-11 year olds and adults 
will be made by comparing the point estimate and 90% CI of bodyweight-adjusted 
clearance in this study with the historic value in adults of 0.29 L/day along with a 
proposed 80-125% interval around this estimate (i.e., 0.23-0.36 L/day).
Amended Text:
The comparison of bodyweight-adjusted clearance between the 6-11 year olds and adults 
will be made by comparing the point estimate and 90% CI of bodyweight-adjusted 
clearance in this study with the historic value in adults of 0.22 L/day (corresponding to an 
apparent clearance of 0.29 L/day assuming an absolute bioavailability of 75%) along with 
a proposed 80-125% interval around this estimate (i.e., 0.18-0.28 L/day).
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
173
Section 12.1, Appendix 1: Abbreviations and Trademarks:
Original text:
ACQ-7
Asthma Control Questionnaire-7
ADA
Anti-drug Antibody
AE
Adverse Event
ALT
Alanine aminotransferase (SGPT)
AST
Aspartate aminotransferase (SGOT)
AUC
Area under concentration-time curve
AUC(0-inf)
Area under concentration time curve to infinity
-HCG
Beta-Human Chorionic Gonadotropin
BUN
Blood urea nitrogen
C-ACT
Childhood Asthma Control Test 
CC
Cubic Centimeter
CI
Confidence Interval
CL
Systemic clearance of parent drug
Cmax
Maximum observed concentration 
CDC
Centers for Disease Control (US)
CO2
Carbon dioxide
CPK
Creatine phosphokinase
CPSR
Clinical Pharmacology Study Report
eCRF
Electronic Case Report Form
CS
Corticosteroids
CV
Cardiovascular
DCSI
Developmental Core Safety Information
DPI
Dry Powder Inhaler
ECG
Electrocardiogram
ED
Emergency Department
EGD
Esophagogastroduodenoscopy
EoE
Eosionophilic Esophagitis
FAAN
Food Allergy and Anaphylaxis Network
FEV1
Forced Expiratory Volume in 1 second
FVC
Forced Vital Capacity
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilence
GGT
Gamma glutamyltransferase
GINA
Global Initiative for Asthma
GSK
GlaxoSmithKline
HBsAg
Hepatitis B surface antigen
hCG
Human chorionic gonadotropin
HES
Hypereosinophilic syndrome
HR
Heart rate
IB
Investigator’s Brochure
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
174
ICH
International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for 
Human Use
ICS
Inhaled Corticosteroids
ID50/90
50% or 90% Inhibition of Maximum Effect
IEC
Independent Ethics Committee
IgG
Immunoglobulin
IL-5
Interleukin 5
IM
Intramuscular
Imax
Maximum Inhibition Model
IP
Investigational Product
IRB
Institutional Review Board
IUD
Intrauterine Device
IV
Intravenous
kg
Kilogram
LABA
Long acting inhaled β2 adrenoceptor agonist
LRTA
Leukotriene Receptor Antagonist
µg
Microgram
µL
Microliter
mAb
Monoclonal Antibody
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligrams
mL
Milliliter
MSDS
Material Safety Data Sheet
Nab
Neutralizing Antibody
NIAID
National Institute of Allergy and Infectious Diseases (US)
NIH
National Institute of Health (US)
OCS
Oral Corticosteroids
OLE
Open label extension
PD
Pharmacodynamic
PK
Pharmacokinetic
Pop-PK
Population Pharmacokinetics
QT
The QT interval is measured from the beginning of the QRS 
complex to the end of the T wave
QTc
QT duration corrected for heart rate
RAP
Reporting and Analysis Plan
SAE
Serious adverse event(s)
SAS
Statistical Analysis Software
SC
subcutaneous
SGOT
Serum glutamic-oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SOC
System Organ Class
SOP
Standard Operating Procedure
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
175
SRM
Study Reference Manual
SRT
Safety Review Team
SUSAR
Suspected, Unexpected, Serious Adverse drug Reaction
t½
Terminal phase half-life
Tmax
Time of occurrence of Cmax
TTS
Study Specific Technical Agreement Memo
µL
Microliter
ULN
Upper limit of normal
UK
United Kingdom
US
United States
Vc
Central Volume of Distribution
WBC
White blood cells
Vss
Steady State Volume of Distribution
Amended Text:
ACQ-7
Asthma Control Questionnaire-7
ADA
Anti-drug Antibody
AE
Adverse Event
ALT
Alanine aminotransferase (SGPT)
AST
Aspartate aminotransferase (SGOT)
AUC
Area under concentration-time curve
AUC(0-inf)
Area under concentration time curve to infinity
-HCG
Beta-Human Chorionic Gonadotropin
BUN
Blood urea nitrogen
C-ACT
Childhood Asthma Control Test 
CC
Cubic Centimeter
CI
Confidence Interval
CL
Systemic clearance of parent drug
CL/F
Apparent clearance after extravascular (e.g., subcutaneous) 
administration
Cmax
Maximum observed concentration 
CDC
Centers for Disease Control (US)
CO2
Carbon dioxide
CPK
Creatine phosphokinase
CPSR
Clinical Pharmacology Study Report
eCRF
Electronic Case Report Form
CS
Corticosteroids
CV
Cardiovascular
DCSI
Developmental Core Safety Information
DPI
Dry Powder Inhaler
ECG
Electrocardiogram
ED
Emergency Department
EGD
Esophagogastroduodenoscopy
EoE
Eosionophilic Esophagitis
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
176
FAAN
Food Allergy and Anaphylaxis Network
FEV1
Forced Expiratory Volume in 1 second
FVC
Forced Vital Capacity
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilence
GGT
Gamma glutamyltransferase
GINA
Global Initiative for Asthma
GSK
GlaxoSmithKline
HBsAg
Hepatitis B surface antigen
hCG
Human chorionic gonadotropin
HES
Hypereosinophilic syndrome
HR
Heart rate
IB
Investigator’s Brochure
ICH
International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for 
Human Use
ICS
Inhaled Corticosteroids
ID50/90
50% or 90% Inhibition of Maximum Effect
IEC
Independent Ethics Committee
IgG
Immunoglobulin
IL-5
Interleukin 5
IM
Intramuscular
Imax
Maximum Inhibition Model
IP
Investigational Product
IRB
Institutional Review Board
IUD
Intrauterine Device
IV
Intravenous
kg
Kilogram
LABA
Long acting inhaled β2 adrenoceptor agonist
LRTA
Leukotriene Receptor Antagonist
µg
Microgram
µL
Microliter
mAb
Monoclonal Antibody
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligrams
mL
Milliliter
MSDS
Material Safety Data Sheet
Nab
Neutralizing Antibody
NIAID
National Institute of Allergy and Infectious Diseases (US)
NIH
National Institute of Health (US)
OCS
Oral Corticosteroids
OLE
Open label extension
PD
Pharmacodynamic
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
177
PK
Pharmacokinetic
Pop-PK
Population Pharmacokinetics
QT
The QT interval is measured from the beginning of the QRS 
complex to the end of the T wave
QTc
QT duration corrected for heart rate
RAP
Reporting and Analysis Plan
SAE
Serious adverse event(s)
SAS
Statistical Analysis Software
SC
subcutaneous
SGOT
Serum glutamic-oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SOC
System Organ Class
SOP
Standard Operating Procedure
SRM
Study Reference Manual
SRT
Safety Review Team
SUSAR
Suspected, Unexpected, Serious Adverse drug Reaction
t½
Terminal phase half-life
Tmax
Time of occurrence of Cmax
TTS
Study Specific Technical Agreement Memo
µL
Microliter
ULN
Upper limit of normal
UK
United Kingdom
US
United States
Vc
Central Volume of Distribution
WBC
White blood cells
Vss
Steady State Volume of Distribution
Section 12.2, Appendix 2: Liver Safety Required Actions Follow-Up and Assessments, 
Footnote 5:
Original Text:
5.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.)  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment 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 SRM. 
Amended Text:
5.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.)  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment 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 Q2 Solutions Investigator Manual.
 
2017N314087_00


2014N216964_05
CONFIDENTIAL
200363
178
Section 12.3.6, Reporting of SAEs to GSK:
Original Text:

If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax it to the SAE coordinator
Amended Text:

If the electronic system is unavailable, the site will use the paper SAE data collection 
tool and fax it to the SAE coordinator within 24 hours.
 
2017N314087_00

SAP_001.pdf: 
2016N305235_00
CONFIDENTIAL
The GlaxoSmithKline group of companies
200363
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for study 200363: An open-label 
study to characterize the pharmacokinetics and 
pharmacodynamics of mepolizumab administered 
subcutaneously in children from 6 to 11 years of age with 
severe eosinophilic asthma
Compound Number 
:
Mepolizumab (SB-240563)
Effective Date 
:
09-DEC-2016
Description :

The purpose of this RAP is to describe the planned PK, PD and safety analyses and 
output to be included in the Clinical Study Report (CSR) for study 200363.

This RAP will be provided to the study team members to convey the content of the 
Part A and Part B Statistical Analysis Complete (SAC) deliverables.
Author’s Name and Functional Area: 
09-DEC-2016
Principal Statistician, Clinical Statistics
09-DEC-2016
Director, Clinical Pharmacology Modeling & Simulation  (CPMS)
Final Approval:
Approved via email by
Director, 
Clinical Statistics
09-DEC-2016
Copyright 2016 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
2017N314087_00
PPD
PPD
PPD


2016N305235_00
CONFIDENTIAL
200363
2
Agreed by Core RAP team (via e-mail): 
Project Physician Lead, 
Respiratory Therapeutic Unit
Medical Monitor, 
Respiratory Therapeutic Unit
Clinical Investigation Leader, 
Respiratory Therapeutic Unit
Director, 
Safety Evaluation & Risk Management
Senior Director, 
Clinical Pharmacology Modeling & Simulation
Manager, 
Clinical Programming
 
2017N314087_00
PPD


2016N305235_00
CONFIDENTIAL
200363
3
TABLE OF CONTENTS
PAGE
1.
REPORTING & ANALYSIS PLAN SYNPOSIS.........................................................6
2.
SUMMARY OF KEY PROTOCOL INFORMATION ................................................10
2.1.
Changes to the Protocol Defined Statistical Analysis Plan..........................10
2.2.
Study Objective(s) and Endpoint(s).............................................................10
2.2.1.
Pharmacokinetic/Pharmacodynamic Phase (Part A)....................10
2.2.2.
Long-Term Safety/Long-Term Pharmacodynamic Phase 
(Part B)........................................................................................12
2.3.
Study Design ..............................................................................................13
2.4.
Statistical Hypotheses.................................................................................14
3.
PLANNED ANALYSES ..........................................................................................14
3.1.
Part A Analysis ...........................................................................................14
3.2.
Part B Analysis ...........................................................................................15
4.
ANALYSIS POPULATIONS ...................................................................................15
4.1.
Protocol Deviations.....................................................................................16
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................17
6.
STUDY POPULATION ANALYSES .......................................................................17
6.1.
Overview of Planned Analyses ...................................................................17
7.
PRIMARY ANALYSES ...........................................................................................19
7.1.
Population PK Analysis (Part A)..................................................................20
7.1.1.
Overview of Planned Population PK Analysis ..............................20
7.2.
Analysis of Blood Eosinophil Count (Part A) ...............................................21
8.
SECONDARY ANALYSES.....................................................................................22
8.1.
Secondary and Exploratory Analyses .........................................................22
8.1.1.
Body-Weight-Adjusted Clearance ................................................23
8.1.2.
Asthma Control Questionnaire.....................................................24
8.1.3.
Childhood Asthma Control Test (C-ACT) .....................................24
8.1.4.
Analysis of Blood Eosinophil Count (Part B) ................................24
8.1.5.
Forced expiratory volume in 1 second (FEV1)..............................24
8.1.6.
Asthma Exacerbations.................................................................24
8.1.7.
Total Immunoglobulin-E (IgE) ......................................................25
8.1.8.
Total Interleukin-5 (IL-5)...............................................................25
8.2.
Safety Analyses..........................................................................................25
8.2.1.
Overview of Planned Adverse Event Analyses ............................25
8.2.1.1.
Adverse Events of Special Interest.............................26
8.2.1.2.
Cardiovascular Events................................................27
8.2.2.
Overview of Planned Clinical Laboratory Analyses ......................27
8.2.2.1.
Immunogenicity ..........................................................28
8.2.3.
Overview of Planned Other Safety Analyses................................29
9.
REFERENCES.......................................................................................................31
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
4
10. APPENDICES........................................................................................................32
10.1.
Appendix 1: Protocol Deviation Management .............................................32
10.2.
Appendix 2: Time & Events.........................................................................33
10.2.1.
Time & Events Table Pharmacokinetic/Pharmacodynamic 
Phase (Part A) .............................................................................33
10.2.2.
Time and Events Table Long-Term Safety / 
Pharmacodynamic Phase (Part B)...............................................35
10.3.
Appendix 3: Assessment Windows & Visit Slotting .....................................37
10.3.1.
Study Part (Part A and Part B).....................................................37
10.3.2.
Part A Data Cut Date...................................................................37
10.3.3.
Assessment Windows..................................................................37
10.3.4.
Early Withdrawal Visits ................................................................37
10.3.5.
Unscheduled Visits ......................................................................38
10.4.
Appendix 4: Treatment Phases...................................................................39
10.4.1.
Treatment Phases (Adverse Events) ...........................................39
10.4.2.
Treatment Phases (Exacerbations)..............................................40
10.4.3.
Treatment Phases (Concomitant Medications) ............................41
10.5.
Appendix 5: Data Display Standards & Handling Conventions....................42
10.5.1.
Study Treatment & Display Descriptors .......................................42
10.5.1.1.
Part A.........................................................................42
10.5.1.2.
Part B.........................................................................42
10.5.2.
Baseline Definition & Derivations .................................................43
10.5.2.1.
Definition of Baseline..................................................43
10.5.2.2.
Derivations of Change from Baseline Data.................43
10.5.3.
Reporting Process & Standards...................................................43
10.6.
Appendix 6: Derived and Transformed Data ...............................................46
10.6.1.
General........................................................................................46
10.6.2.
Study Population..........................................................................46
10.6.3.
Subject Disposition ......................................................................49
10.6.4.
Safety ..........................................................................................49
10.6.5.
Efficacy........................................................................................51
10.7.
Appendix 7: Premature Withdrawals & Handling of Missing Data ...............52
10.7.1.
Premature Withdrawals................................................................52
10.7.2.
Handling of Missing Data.............................................................52
10.7.2.1.
Handling of Missing and Partial Dates ........................53
10.8.
Appendix 8: Population Pharmacokinetic Analyses.....................................54
10.8.1.
Population-PK Analysis................................................................54
10.8.2.
Additional Analysis to Support Paediatric Extrapolation 
Strategy.......................................................................................55
10.8.2.1.
Population-PK analysis...............................................55
10.8.2.2.
Population-PK/PD analysis.........................................55
10.9.
Appendix 9: Abbreviations & Trade Marks ..................................................57
10.9.1.
Abbreviations...............................................................................57
10.9.2.
Trademarks .................................................................................58
10.10. Appendix 10: List of Data Displays..............................................................59
10.10.1. Data Display Numbering and Priority ...........................................59
10.10.1.1. Part A.........................................................................59
10.10.1.2. Part B.........................................................................59
10.10.2. Part A ..........................................................................................60
10.10.2.1. Study Population Tables.............................................60
10.10.2.2. Pharmacokinetic Tables .............................................63
10.10.2.3. Pharmacokinetic Figures ............................................65
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
5
10.10.2.4. Efficacy Tables...........................................................67
10.10.2.5. Efficacy Figures..........................................................70
10.10.2.6. Safety Tables .............................................................72
10.10.2.7. Safety Figures ............................................................79
10.10.2.8. ICH Listings................................................................80
10.10.2.9. Non-ICH Listings ........................................................85
10.10.3. Part B ..........................................................................................86
10.10.3.1. Study Population Tables.............................................86
10.10.3.2. Efficacy Tables...........................................................87
10.10.3.3. Efficacy Figures..........................................................89
10.10.3.4. Safety Tables .............................................................90
10.10.3.5. Safety Figures ............................................................97
10.10.3.6. ICH Listings................................................................98
10.11. Appendix 11: Example Mock Shells for Data Displays ..............................102
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
6
1.
REPORTING & ANALYSIS PLAN SYNPOSIS
Overview
Key Elements of the RAP
Purpose

The purpose of this reporting and analysis plan (RAP) is to describe the 
analyses to be included in the CSR for study 200363
Protocol

This RAP is based on protocol amendment 4 for study 200363 (GSK 
Document Number: 2014N216964_04) dated 05/MAY/2016 and the 
latest version of the electronic Case Report Form (eCRF) [eCRF
Version 4.0].

The study protocol consists of two study parts with each study part to
be reported sequentially:
Pharmacokinetic/Pharmacodynamic Phase (Part A)
Long-Term Safety / Long-Term Pharmacodynamic Phase (Part B)
Primary 
Objectives
Part A:

To characterize the pharmacokinetics of mepolizumab administered 
subcutaneously to subjects aged 6 to 11 years old with severe 
eosinophilic asthma

To characterize the pharmacodynamics of mepolizumab administered 
subcutaneously to  subjects aged 6 to 11 years old with severe 
eosinophilic asthma
Part B:

To assess the long-term (52 weeks) safety and tolerability of 
mepolizumab when administered subcutaneously to subjects aged 6 to 
11 years old with severe eosinophilic asthma
Primary 
Endpoints
Part A:

Population-PK model  derived estimates of clearance, area under the 
plasma-concentration time curve (AUC(0-inf)), maximum plasma 
concentration (Cmax), and terminal phase elimination half-life (t1/2) 
of mepolizumab

Change from baseline in blood eosinophil count at week 12
Part B:

Incidence of Adverse Events

Frequency of positive anti-mepolizumab binding antibodies and 
neutralizing antibodies

Incidence of clinically significant changes in vital sign measurements

Incidence of clinically significant  changes in clinical laboratory 
parameters
Secondary 
Objectives
Part A:

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

To characterize asthma control following subcutaneous administration 
of mepolizumab to subjects aged 6 to 11 years old with severe 
eosinophilic asthma

To assess the safety and tolerability of mepolizumab when 
administered subcutaneously to subjects aged 6 to 11 years old with 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
7
Overview
Key Elements of the RAP
severe eosinophilic asthma
Part B:

To characterize the long-term (52 weeks) durability of 
pharmacodynamics of mepolizumab administered subcutaneously to  
subjects aged 6 to 11 years old with severe eosinophilic asthma
Secondary 
Endpoints
Part A:

Bodyweight-adjusted clearance estimates obtained by population PK 
methods.

Change from Baseline in ACQ-7 measured at week 12

Change from Baseline in ACQ-7 measured at week 4,8,16 and 20

Change from Baseline in C-ACT measured at week 12

Change from Baseline in C-ACT measured at week 4,8, 16 and 20

Incidence of Adverse Events (AEs)

Incidence of clinically significant  changes in clinical laboratory 
parameters

Frequency of positive anti-mepolizumab binding antibodies and 
neutralizing antibodies

Incidence of clinically significant changes in vital sign measurements
Part B:

Change from Baseline in absolute blood eosinophil count at weeks 32, 
44, 56, 68, 72 and 80.
Study 
Design
Part A:

This is a multi-centre, open-label study that will assess the 
pharmacokinetics and pharmacodynamics of three 4-weekly doses of 
mepolizumab, either 40 or 100mg SC depending on subject 
bodyweight, administered subcutaneously to subjects with severe 
eosinophilic asthma aged 6-11 years.

Approximately 40 male or female subjects with severe eosinophilic 
asthma, aged 6 to 11 years inclusive at screening (Visit 1), will be 
screened to achieve approximately 28 eligible subjects entering the 
treatment phase to allow availability of 20 evaluable subjects; with a 
minimum of six subjects enrolled in the < 40 kg bodyweight group. An 
evaluable subject is defined to be a subject who has received all three 
doses of mepolizumab and has had all PK and PD assessments 
completed through to Visit 6 (week 12).
Part B:

This is a long-term safety / pharmacodynamic phase in which extended 
treatment for a further 52 weeks will be offered on an optional basis to 
those subjects eligible for continued treatment. Subjects will receive 
either 40 or 100mg depending on subject bodyweight, administered SC 
every 4 weeks to subjects with severe eosinophilic asthma aged 6-11 
years. At the end of the 52 weeks extended treatment in Part B, 
subjects will have an Exit Visit 4 weeks after last dose and a Follow-
Up visit 12 weeks after last dose.

All subjects who completed Part A and meet the eligibility criteria for 
Part B will be allowed to participate in Part B.
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
8
Overview
Key Elements of the RAP
Planned 
Analyses
Part A:

A complete analysis of part A for an interim report in accordance with 
all Part A study objectives and endpoints will be performed after all 
subjects have completed Part A of the study. All outputs will be 
considered the final analyses for Part A.
Part B:

A complete analysis of part B for a final report in accordance with all 
Part B study objectives and endpoints will be performed after all 
subjects have completed Part B of the study.
Analysis 
Populations
Part A:

All Subjects Enrolled (ASE): All subjects for whom a record exists on 
the study database.

Safety Population: All subjects receiving at least one dose of 
mepolizumab beginning at Visit 2.

Pharmacokinetic (PK) Population: All subjects receiving at least one 
dose of mepolizumab beginning at Visit 2 and having at least one blood 
sample taken at Visit 3 or thereafter with measurable mepolizumab 
plasma concentration.  

Pharmacodynamic (Blood Eosinophils) (PDe) Population: All subjects 
receiving at least one dose of mepolizumab beginning at Visit 2 and 
having at least one Part A blood sample taken for blood eosinophil 
count.

Pharmacodynamic (Outcome Assessments) (PDo) Population: All 
subjects receiving at least one dose of mepolizumab beginning at Visit 
2 and having at least one Part A assessment of pharmacodynamic 
outcomes (ACQ-7, C-ACT, asthma exacerbation, FEV1, IgE or IL-5).

Pharmacokinetic / Pharmacodynamic (PKPD) : All subjects receiving at 
least one dose of mepolizumab beginning at Visit 2 and having at least 
one blood sample taken at Visit 3 or thereafter with measurable 
mepolizumab plasma concentration and who also have a baseline PDe
measurement and at least one post-treatment PDe measurement.
Part B:

Safety Population: All subjects receiving at least one dose of study 
medication beginning at Visit 9.

Pharmacodynamic (Blood Eosinophils) (PDe) Population:  All subjects 
receiving at least one dose of mepolizumab beginning at Visit 9 and 
having at least one Part B one blood sample taken for blood eosinophil 
count.  

Pharmacodynamic (Outcome Assessments) (PDo) Population: All 
subjects receiving at least one dose of mepolizumab beginning at Visit 9 
and having at least one Part B assessment of pharmacodynamic 
outcomes (ACQ-7, C-ACT, asthma exacerbation, or FEV1).
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
9
Overview
Key Elements of the RAP
Hypothesis

Formal hypothesis testing will not be performed for this study.  An 
estimation approach will be adopted to evaluate the objectives.
Primary 
Analyses
Part A:

PK samples will be analysed by population-PK methods based on the 
PK population. A number of pharmacokinetic parameters will be fixed 
from adult values in the model in support of the sparse sampling 
implemented in the study and the relatively small sample size. In 
particular meaningful estimation of absorption and distribution 
parameters is unlikely based on the sampling scheme. The population-
PK parameter estimates (AUC(0-inf), clearance, Cmax and t1/2) with 
95% confidence intervals from the final model will be tabulated. 

In addition, the individual PK parameter estimates (also called post-
hoc individual PK parameter estimates) (AUC(0-inf), clearance, Cmax 
and t1/2) will be summarised including 95% CIs.

The absolute blood eosinophil count and ratio of blood eosinophil 
count to baseline will be summarised using summary statistics 
including 95% CIs, for all post-dosing study visits.
Part B:

Safety data including adverse events, vital signs, clinical laboratory, 
electrocardiogram (ECG), and immunogenicity data will be 
summarised.
Secondary 
Analyses
Part A:

Bodyweight-adjusted clearance in this study from subjects aged 6 to 11 
years old will be compared with historical values from adults with 
severe eosinophilic asthma when mepolizumab is administered 
subcutaneously. For this purpose, the bodyweight-adjusted clearance 
obtained from the population PK model of data from this study will be 
presented in a separate table with 90% CI. This point estimate and 90% 
CI will be compared with the historic value in adults of 0.22 L/day 
(corresponding to an apparent clearance of 0.29 L/day assuming an 
absolute bioavailability of 75%), around which a proposed 80-125% 
interval was applied (i.e., 0.18-0.28 L/day).

Change from baseline in the overall ACQ-7 and C-ACT score will be 
summarised including 95% CIs. In addition the proportion of subjects 
meeting the minimally clinically significant change (reduction from 
baseline of ≥0.5 in the overall ACQ-7 score) will be presented.
Part B:

The absolute blood eosinophil count and ratio of blood eosinophil 
count to baseline will be summarised using summary statistics 
including 95% CIs, for all post-dosing study visits.
Safety

Safety data including adverse events, vital signs, clinical laboratory, 
electrocardiogram (ECG), and immunogenicity data will be 
summarised.
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
10
2.
SUMMARY OF KEY PROTOCOL INFORMATION
The study protocol consists of two study parts which are to be reported sequentially:

Pharmacokinetic/Pharmacodynamic Phase (Part A)

Long-Term Safety / Long-Term Pharmacodynamic Phase (Part B)
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
Any changes from the originally planned statistical analysis specified in the protocol 
amendment 4 (dated 05/MAY/2016) are outlined in Table 1.
Table 1
Changes to Protocol Defined Analysis Plan
Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes

Part B endpoint listed as 
‘Change from Week 20 (Visit 
9) in absolute blood 
eosinophil count at weeks 32, 
44, 56, 68, 72 and 80’

Part B endpoint listed as 
‘Change from Baseline 
in absolute blood eosinophil 
count at weeks 32, 44, 56, 68, 
72 and 80’

Patients will not have returned 
to their pre-mepolizumab 
treatment baseline at the start 
of part B [Week 20 (Visit 9)] 
and therefore individual patient 
comparisons back to Baseline 
(Week 0) are more of interest

Part B endpoint listed as 
‘Change from Week 20 (Visit 
9) in ACQ-7 and C-ACT at 
weeks 32, 44, 56, 68, 72 and 
80.’

Part B endpoint listed as 
‘Change from Baseline in ACQ-
7 and C-ACT at weeks 32, 44, 
56, 68, 72 and 80.’

Patients will not have returned 
to their pre-mepolizumab 
treatment baseline at the start 
of part B [Week 20 (Visit 9)] 
and therefore individual patient 
comparisons back to Baseline 
(Week 0) are more of interest
2.2.
Study Objective(s) and Endpoint(s)
2.2.1.
Pharmacokinetic/Pharmacodynamic Phase (Part A)
Objectives
Endpoints
Primary
To characterize the pharmacokinetics 
of mepolizumab administered 
subcutaneously to subjects aged 6 to 
11 years old with severe eosinophilic 
asthma
To characterize the 
pharmacodynamics 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 
(AUC(0-inf), maximum plasma 
concentration (Cmax), and terminal 
phase elimination half-life (t1/2) of 
mepolizumab

Change from baseline in blood 
eosinophil count at week 12
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
11
Objectives
Endpoints
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
To characterize asthma control 
following subcutaneous administration 
of mepolizumab to subjects aged 6 to 
11 years old with severe eosinophilic 
asthma 
To assess the safety and tolerability of 
mepolizumab when administered 
subcutaneously to subjects aged 6 to 
11 years old with severe eosinophilic 
asthma  

Bodyweight-adjusted clearance 
estimates obtained by population PK 
methods. 

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 week 4, 8, 16 and 20

Incidence of Adverse Events

Incidence of clinically significant  
changes in clinical laboratory 
parameters

Frequency of positive anti-
mepolizumab binding antibodies and 
neutralizing antibodies

Incidence of clinically significant 
changes in vital sign measurements
Exploratory 

To assess the number of asthma 
exacerbations that occur during the 
study following subcutaneous 
administration of mepolizumab to 
subjects aged 6 to 11 years old with 
severe eosinophilic asthma

To assess Forced expiratory volume 
in 1 second (FEV1) following 
subcutaneous 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-
week 12).

Number of asthma exacerbations that 
occur on- treatment and post-
treatment (week 0 – week 20)

Change from Baseline in FEV1  
measured at week 12
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
12
2.2.2.
Long-Term Safety/Long-Term Pharmacodynamic Phase (Part B)
Objectives
Endpoints
Primary 
To assess the long-term (52 weeks) 
safety and tolerability of 
mepolizumab when administered 
subcutaneously to subjects aged 6 to 
11 years old with severe eosinophilic 
asthma

Incidence of Adverse Events

Frequency of positive anti-
mepolizumab binding antibodies and 
neutralizing antibodies

Incidence of clinically significant 
changes in vital sign measurements

Incidence of clinically significant  
changes in clinical laboratory 
parameters
Secondary

To characterize the long-term (52 
weeks) durability of 
pharmacodynamics 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 weeks 32, 
44, 56, 68, 72 and 80.
Exploratory

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 11 years old with 
severe eosinophilic asthma

To characterize the long-term (52 
weeks) asthma control following 
subcutaneous administration of 
mepolizumab to subjects aged 6 to 11 
years old with severe eosinophilic 
asthma 

Incidence of asthma exacerbations

Change from Baseline in ACQ-7 and 
C-ACT at weeks 32, 44, 56, 68, 72 
and 80.
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
13
2.3.
Study Design
Overview of Study Design and Key Features
Part A:
Design
Features
Part A:

This is a multi-centre, open-label study that will assess the 
pharmacokinetics and pharmacodynamics of three 4-weekly doses of 
mepolizumab, either 40 or 100mg SC depending on subject 
bodyweight, administered subcutaneously to subjects with severe 
eosinophilic asthma aged 6-11 years.

Approximately 40 male or female subjects with severe eosinophilic 
asthma, aged 6 to 11 years inclusive at screening (Visit 1), will be 
screened to achieve approximately 28 eligible subjects entering the 
treatment phase to allow availability of 20 evaluable subjects; with a 
minimum of six subjects enrolled in the < 40 kg bodyweight group. An 
evaluable subject is defined to be a subject who has received all three 
doses of mepolizumab and has had all PK and PD assessments 
completed through to Visit 6 (week 12).
Part B:

This is a long-term safety / pharmacodynamic phase in which extended 
treatment for a further 52 weeks will be offered on an optional basis to 
those subjects eligible for continued treatment. Subjects will receive 
either 40 or 100mg depending on subject bodyweight, administered SC 
every 4 weeks to subjects with severe eosinophilic asthma aged 6-11 
years. At the end of the 52 weeks extended treatment in Part B, 
subjects will have an Exit Visit 4 weeks after last dose and a Follow-
Up visit 12 weeks after last dose.

All subjects who completed Part A and meet the eligibility criteria for 
Part B will be allowed to participate in Part B.

Countries participating in this study include: Japan, Poland, United 
States and United Kingdom. 
Dosing
Part A:

Mepolizumab will be administered as either 40mg (subjects <40kg at 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
14
Overview of Study Design and Key Features
Visit 2) or 100 mg SC (subjects ≥40kg at Visit 2) at week 0 (Visit 2), 
week 4 (Visit 3) and week 8 (Visit 4) which will provide therapeutic 
coverage through to week 12 (Visit 6). The mepolizumab dose received
throughout Part A will remain unchanged irrespective of bodyweight 
changes.
Part B:
Within Part B the subject’s dose will be adjusted to 100mg SC from the 
time the subject’s bodyweight reaches 40 kg. Subjects will receive 
either mepolizumab 40 or 100 mg SC, (depending on subject 
bodyweight measured at Visit 9; 40 mg for subjects <40 kg and 100 mg 
for subjects ≥ 40 kg). Subjects with bodyweight <40 kg at Visit 9 
should be weighed at each subsequent visit and have their dose adjusted 
to 100mg once their bodyweight reaches 40 kg.  Subjects weighing 
≥40kg at Visit 9 will receive the 100mg dose at all subsequent 
treatment visits and will not be weighed again.
Planned 
Analyses
Part A:

A complete analysis of part A for an interim report in accordance with 
all Part A study objectives and endpoints will be performed after all 
subjects have completed Part A of the study. All outputs will be 
considered the final analyses for Part A.
Part B:

A complete analysis of part B for a final report in accordance with all 
Part B study objectives and endpoints will be performed after all 
subjects have completed Part B of the study.
2.4.
Statistical Hypotheses
Formal hypothesis testing will not be performed for this study. An estimation approach 
will be adopted to evaluate the objectives.
3.
PLANNED ANALYSES
3.1.
Part A Analysis
A complete analysis of part A for an interim report in accordance with all Part A study 
objectives and endpoints will be performed after all subjects have completed Part A of 
the study and after the completion of the following sequential steps detailed below. 
All outputs will be considered the final analyses for Part A 
1.
All subjects have completed Part A (upon completion of all study procedures or 
premature discontinuation of the study) as defined in the protocol for study 200363.
2.
All required database cleaning activities have been completed and database release 
and database freeze has been declared by Data Management.
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
15
3.2.
Part B Analysis
A complete analysis of part B for a final report in accordance with all Part B study 
objectives and endpoints after all subjects have completed Part B of the study. The 
database will be locked after all subjects have completed all Part B assessments and the 
required database cleaning activities have been completed. Once this has been achieved 
the database will be frozen. Statistical outputs generated following the interim report 
(Part A) will not be reproduced.
4.
ANALYSIS POPULATIONS
Table 2
Analysis Populations
Population
Definition / Criteria
Analyses Evaluated
Part A
All Subjects
Enrolled (ASE)

All subjects for whom a record 
exists on the study database.

Pre-screen failures

Screen failures

Run-in failures
Safety

All subjects receiving at least one 
dose of mepolizumab beginning 
at Visit 2.

Study Population

Safety

Immunogenicity
Pharmacokinetic 
(PK) 

All subjects receiving at least one 
dose of mepolizumab beginning 
at Visit 2 and having at least one 
blood sample taken at Visit 3 or 
thereafter with measurable 
mepolizumab plasma 
concentration.

Pharmacokinetic
Pharmacodynamic
(Blood 
Eosinophils) (PDe)

All subjects receiving at least one 
dose of mepolizumab beginning 
at Visit 2 and having at least one 
Part A blood sample evaluable 
for blood eosinophil count.

Blood eosinophil count
Pharmacodynamic 
(Outcome 
Assessments) 
(PDo)

All subjects receiving at least one 
dose of mepolizumab beginning 
at Visit 2 and having at least one 
Part A assessment of 
pharmacodynamic outcomes 
(ACQ-7, C-ACT, asthma 
exacerbation, FEV1, IgE or IL-5).

ACQ-7

C-ACT

Asthma exacerbations 

FEV1

Immunoglobulin E (IgE)

IL-5
Pharmacokinetic / 
Pharmacodynamic
(PKPD)

All subjects receiving at least one 
dose of mepolizumab beginning 
at Visit 2 and having at least one 
blood sample taken at Visit 3 or 
thereafter with measurable 
mepolizumab plasma 
concentration and who also have 

PKPD
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
16
Population
Definition / Criteria
Analyses Evaluated
a baseline PDe measurement and 
at least one post-treatment PDe
measurement.
Part B
Safety

All subjects receiving at least one 
dose of study medication 
beginning at Visit 9.

Study Population

Safety

Immunogenicity
Pharmacodynamic 
(Blood 
Eosinophils) (PDe)

All subjects receiving at least one 
dose of mepolizumab beginning 
at Visit 9 and having at least one 
Part B blood sample taken for 
blood eosinophil count.  

Blood eosinophil count
Pharmacodynamic 
(Outcome 
Assessments) 
(PDo)

All subjects receiving at least one 
dose of mepolizumab beginning 
at Visit 9 and having at least one 
Part B assessment of 
pharmacodynamic outcomes 
(ACQ-7, C-ACT, asthma 
exacerbation, or FEV1).

ACQ-7

C-ACT

Asthma exacerbations 

FEV1
NOTES : 

Please refer to Appendix 10: List of Data Displays which details the population to be used for each of the displays 
being generated.
4.1.
Protocol Deviations

Protocol deviations will be tracked by the study team throughout the conduct of the 
study in accordance with the Protocol Deviation Management Plan (PDMP).

Data will be reviewed by the study team prior to DBR to ensure all important 
deviations are captured and categorised in the protocol deviations dataset.

This dataset will be the basis for the summaries and listings of protocol 
deviations.

Important protocol deviations (including deviations related to study 
inclusion/exclusion criteria, conduct of the trial, patient management or patient 
assessment) will be listed and summarised.

A separate summary and listing of all inclusion/exclusion criteria deviations will also 
be provided.  This summary will be based on the data as recorded on the 
inclusion/exclusion page of the eCRF.

The study endpoints will be reported using the populations detailed in Section 4 of 
this document regardless of whether the subjects deviate from the protocol. If there 
are subjects with protocol deviations that may potentially impact either the PK or the 
PD endpoints, exploratory sensitivity analyses may be considered (See Section 7).
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
17
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
Table 3 provides an overview of appendices within the RAP for outlining general 
considerations for data analyses and data handling conventions. 
Table 3
Overview of Appendices
Section
Component
10.1
Appendix 1: Protocol Deviation Management
10.2
Appendix 2: Time & Events
10.3
Appendix 3: Assessment Windows & Visit Slotting
10.4
Appendix 4: Treatment Phases
10.5
Appendix 5: Data Display Standards & Handling Conventions
10.6
Appendix 6: Derived and Transformed Data
10.7
Appendix 7: Premature Withdrawals & Handling of Missing Data
10.8
Appendix 8: Population Pharmacokinetic Analyses
Other RAP Appendices
10.9
Appendix 9: Abbreviations & Trade Marks
10.10
Appendix 10: List of Data Displays
10.11
Appendix 11: Example Mock Shells for Data Displays
6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Analyses
Table 4 and Table 5 and provide an overview of the planned study population displays,
with full details of data displays being presented in Appendix 10: List of Data Displays.
The study population listings and summaries will be based on the Safety population 
unless otherwise specified in Appendix 10: List of Data Displays.
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
18
Table 4
Overview of Study Population Summaries (Part A)
Endpoint / Parameter
Data Displays Generated
Table
Figure
Listing
Subject Disposition
Analysis populations
Y[1]
Reasons for screen or run-in failures
Y
Y
Failed inclusion/exclusion criteria for screen or run-in 
failures
Y
Failed inclusion/exclusion criteria for Safety Population
Y
Y
Subjects by country and site
Y
Reason for premature study withdrawal
Y
Y
Demographic and Baseline Characteristics
Demographic characteristics
Y
Y
Age Ranges
Y
Race and racial combinations
Y
Y[3]
Race and racial combinations details
Y
Medical Conditions
Past medical conditions
Y
Current medical conditions
Y
Cardiovascular assessments (family history)
Y
Baseline Disease Characteristics
Asthma exacerbation history[2]
Y
Asthma history and baseline disease characteristics
Y
Lung function results (screening and baseline)
Y
Prior and concomitant medications
Asthma concomitant medications (taken before/during run-
in, during treatment, post-treatment) by Respiratory 
Medication Class [4]
Y
Non-asthma concomitant medications taken during 
treatment
Y
Relationship between ATC level 1, Ingredient and verbatim 
text
Y
Protocol deviations
Important protocol deviations
Y
Y
NOTES :

Y = Yes display generated.

[1] To include summary of subjects moving into study Part B

[2] Asthma exacerbation recorded in 12 months prior to Screening 

[3] Listing of race

[4] Multi-ingredient medications will be presented according to their combination Anatomical Therapeutic Chemical (ATC) 
classification rather than the classification of the ingredients.
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
19
Table 5
Overview of Study Population Summaries (Part B)
Endpoint / Parameter
Data Displays Generated
Table
Figure
Listing
Subject Disposition
Analysis Populations
Y
Reason for premature study withdrawal
Y
Y
Prior and concomitant medications
Asthma concomitant medications (during treatment, post-
treatment) by Respiratory Medication Class [1]
Y
Non-Asthma concomitant medications taken during 
treatment
Y
Relationship between ATC level 1, Ingredient and verbatim 
text
Y
Protocol deviations
Important Protocol Deviations
Y
Y
NOTES :

Y = Yes display generated.

[1] Multi-ingredient medications will be presented according to their combination Anatomical Therapeutic Chemical (ATC) 
classification rather than the classification of the ingredients.
7.
PRIMARY ANALYSES
This section contains the details of the planned primary Pharmacokinetic (PK) and 
Pharmacodynamic (PD) analyses using the study populations defined in Section 4. If 
there are protocol deviations that are thought to potentially impact the primary PK and/or 
PD endpoints, an exploratory sensitivity analysis may be considered.  Any sensitivity 
analyses performed will be documented in the clinical study report.  
All safety analyses are detailed within Section 8.2.
Full details of data displays are presented in Appendix 10: List of Data Displays.
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
20
Table 6
Overview of Planned Primary Analysis (Part A)
Endpoint / 
Parameter/ Display 
Type]
Untransformed
Log-transformed
Pop-PK model
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
PK
PK Plasma 
Concentrations 
(Observed and 
Predicted)
Y
Y[1]
Y[2]
Y
Individual PK 
Parameter Estimates 
(also called post-hoc 
individual PK 
parameter estimates)
Y
Y
Y
Population PK 
parameter estimates
Y
Goodness of fit 
test/plots
Y
Y
Endpoint / 
Parameter/Display 
Type]
Raw Data
Ratio of Post Dosing Visit to  Baseline
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
Blood Eosinophil Count
Blood Eosinophil 
Count (Part A)
Y
Y
Y
Y
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data/predicted 
data.

Individual = Represents FL related to any displays of individual subject (observed raw data/predicted data).
[1]
Model Predicted Mepolizumab Individual Plasma Concentration Time Profiles with Individual Observed Plasma 
Concentrations and Plasma Concentration Population Prediction from Final Model by Treatment
[2]
Model Predicted Mepolizumab Individual Plasma Concentration Time Profiles with Individual Observed Plasma 
Concentrations and Plasma Concentration Population Prediction from Final Model by Subject
7.1.
Population PK Analysis (Part A)
7.1.1.
Overview of Planned Population PK Analysis
This study is conducted to support the extrapolation of the safety and efficacy data 
observed in adults in the Phase III Mepolizumab Programme to the paediatric population. 
To this purpose, one of the PK objectives of the study is to characterize the 
pharmacokinetics of mepolizumab administered subcutaneously to subjects aged 6 to 11 
years old with severe eosinophilic asthma. 
A sparse PK sampling scheme has been implemented in this study and the PK samples 
collected will be analysed by population PK methods, using appropriate software, and 
based on the PK population defined, unless otherwise specified. All subjects who are in 
the PK population, i.e. who have at least one measurable PK concentration recorded, will 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
21
be included in this analysis. In order to model the paediatric data collected, a number of 
pharmacokinetic parameters in the model will be fixed using adult values because of the 
sparse sampling implemented in this paediatric study and the relatively small sample size 
selected. In particular estimation of absorption and distribution parameters is unlikely to 
be meaningful based on the proposed sampling scheme. 
A description of the key models tested during the model development will be provided 
and tabulated. The population PK parameter estimates (AUC(0-inf), clearance, Cmax and 
t1/2)  with 95% CI from the final model will be tabulated (for mepolizumab overall 
(Mepolizumab SC)). Goodness of fit plots for the final model will be presented. 
Additionally, the individual PK parameter estimates (also called model-predicted 
post-hoc individual PK parameter estimates) for AUC(0-inf), clearance, Cmax and t1/2 as 
well as the individual observed and predicted plasma PK concentrations will be listed and 
summarised by mepolizumab dose and mepolizumab overall using descriptive statistics. 
The summary of the model-predicted post-hoc individual PK parameter estimates will 
include summary statistics for untransformed and loge-transformed data.  See details of 
the summary statistics in Section 10.5.3.
A summary of plasma concentration data will be produced only including summary 
statistics for untransformed data.  Observed and model predicted concentrations will be 
presented graphically by treatment and subject. Furthermore, a plot of model predicted 
(5th, 50th, and 95th Percentiles) mepolizumab plasma concentrations with individual 
observed plasma concentrations for the final PK model for model evaluation will be 
generated. 
In support of the described analysis, a specific dataset will be generated. Further details 
of the population PK analysis are provided in Appendix 8: Population Pharmacokinetic 
Analyses.
Any subjects and/or PK concentration excluded from this analysis will be flagged in the 
data listings and documented in the clinical study report.
7.2.
Analysis of Blood Eosinophil Count (Part A)
The blood eosinophil count (primary PD endpoint in this study) is recorded during the 
laboratory investigations under hematology data at the visits indicated in the Appendix 2: 
Time & Events. Week 12 is the primary timepoint of interest for blood eosinophil count 
and ratio of blood eosinophil count to baseline. 
The absolute blood eosinophil count, and ratio to baseline will be summarised using 
geometric mean and other descriptive statistics and listed for each mepolizumab dose and 
overall by visit for the PDe population. Additionally the geometric mean ratio to baseline 
in blood eosinophil count (including 95% CI) for each mepolizumab dose and overall by 
visit will be presented graphically. See details of the summary statistics in Section 10.5.3.
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
22
8.
SECONDARY ANALYSES
8.1.
Secondary and Exploratory Analyses
Table 7 provides an overview of the planned analysis of secondary and exploratory 
endpoints with further details of data displays being presented in Appendix 10: List of 
Data Displays.
All safety analyses are detailed within Section 8.2.
Table 7
Overview of Planned Secondary and Exploratory Analyses
Endpoint / 
Parameter/Display
Type]
Raw Data
Change from Baseline
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
Secondary Endpoints
Part A
Body-weight-adjusted 
clearance
Y
ACQ-7 score
Y
Y
Y
C-ACT score
Y
Y
Y
Part B
Blood Eosinophil 
Count
Y
Y
Y
Y[1]
Y[1]
Exploratory Endpoints
Part A
ACQ-7 responder/non-
responder category
Y
ACQ-5 score
Y
Y
Y
ACQ-5 responder/non-
responder category
Y
FEV1
Y
Y
Y
Overview of 
Exacerbations
Y
Exacerbations (on-
treatment) (Week 0 –
Week 12)
Y
Exacerbations (on-
and post-treatment)
(Week 0 – Week 20)
Y
Y
Time to first 
exacerbation (Week 0 
– Week 20)
Y[2]
Y[2]
Total IgE
Y
Y[1]
Total IL-5
Y
Y
Y[1]
Y[1]
PK Plasma 
Concentrations 
(Observed and 
Predicted)
Y[3]
Y[4]
PK model goodness of 
fit test/plots
Y
Y
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
23
Endpoint / 
Parameter/Display
Type]
Raw Data
Change from Baseline
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
PKPD Plasma 
Concentrations 
(Observed and 
Predicted)
Y[3]
Y[4]
PKPD model 
goodness of fit 
test/plots
Y
Y
Part B
ACQ-7 score
Y
Y
ACQ-7 responder/non-
responder category
Y
ACQ-5 score
Y
Y
ACQ-5 responder/non-
responder category
Y
C-ACT score
Y
Y
FEV1
Y
Y
Overview of 
Exacerbations
Y
Exacerbations (on-
treatment) (Week 20 –
Week 72)
Y
Y
Time to first 
exacerbation (Week 
20 –Week 72)
Y[2]
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data/predicted 
data.

Individual = Represents FL related to any displays of individual subject (observed raw data/predicted data).
[1]
To be presented as a Ratio to Baseline
[2]
Kaplan-Meier estimates
[3]
Model Predicted Mepolizumab Individual Plasma Concentration Time Profiles with Individual Observed Plasma 
Concentrations and Plasma Concentration Population Prediction from Final Model by Treatment
[4]
Model Predicted Mepolizumab Individual Plasma Concentration Time Profiles with Individual Observed Plasma 
Concentrations and Plasma Concentration Population Prediction from Final Model by Subject
8.1.1.
Body-Weight-Adjusted Clearance
The secondary PK objective of the study is to compare the bodyweight-adjusted 
clearance in this study from subjects aged 6 to 11 years old with historical values for 
adults with severe eosinophilic asthma when mepolizumab is administered 
subcutaneously. To this purpose, the point estimate for the bodyweight-adjusted 
clearance parameter derived as part of the primary objective (Section 7) will be presented 
in an additional table with a 90% CI. This point estimate and 90% CI for subjects aged 6 
to 11 years will be compared with the historic adult estimated body-weight adjusted 
clearance of 0.22 L/day (corresponding to an apparent clearance of 0.29 L/day assuming 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
24
an absolute bioavailability of 75%), around which a proposed 80-125% interval was 
applied i.e. 0.18-0.28 L/day. The historic adult value is based on previous estimates 
obtained in studies conducted in adult subjects with severe eosinophilic asthma (i.e. 0.22 
L/day as analysed in study MEA115588 [GSK Document Number: 2013N178278_02] 
adjusted for an estimated bioavailability of 75%). 
8.1.2.
Asthma Control Questionnaire
The ACQ-7 score (mean of 7 items) and change from baseline in ACQ-7 score will be 
summarised by visit, mepolizumab dose and mepolizumab overall for the PDo 
population. For an overview of the ACQ-7 questionnaire and scoring algorithm please 
refer to Section 10.6.5.
The ACQ-5 score (mean of 5 symptom items) and change from baseline in ACQ-5 score 
will be summarised by visit, mepolizumab dose and mepolizumab overall for the PDo 
population. For an overview of the ACQ-5 questionnaire and scoring algorithm please 
refer to Section 10.6.5.
8.1.3.
Childhood Asthma Control Test (C-ACT)
The C-ACT score (sum of 7 items) and change from baseline in C-ACT score will be 
summarised by visit, mepolizumab dose and mepolizumab overall for the PDo 
population. For an overview of the C-ACT questionnaire and scoring algorithm please 
refer to Section 10.6.5.
8.1.4.
Analysis of Blood Eosinophil Count (Part B)
The absolute blood eosinophil count and ratio of blood eosinophil count to baseline will 
be summarised using descriptive statistics and listed for each mepolizumab dose and 
overall by visit for the PDe population as presented within Part A (See Section 7.2).
The same baseline definition (latest value recorded prior to the first dose of mepolizumab 
in Part A) will be used in the analyses of both Part A and Part B data, as described within 
Section 10.5.2. 
8.1.5.
Forced expiratory volume in 1 second (FEV1)
FEV1 recorded at post-dose visits and change from baseline will be listed and 
summarised by mepolizumab dose group and mepolizumab overall for each visit.
8.1.6.
Asthma Exacerbations
All asthma exacerbation data will be listed. Number of asthma exacerbations that occur 
while on-treatment (week 0-week 12) and number of asthma exacerbations that occur on-
treatment and post-treatment (week 0 – week 20) will be summarised by mepolizumab 
dose group and mepolizumab overall. Additionally the number of asthma exacerbations 
that occur during Part B (Week 20 –Week 72) will be summarised by mepolizumab dose 
group and mepolizumab overall. Further summaries will be presented as listed in Table 7.
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
25
8.1.7.
Total Immunoglobulin-E (IgE)
Total IgE will be summarised by mepolizumab dose group and mepolizumab overall for 
each visit.
8.1.8.
Total Interleukin-5 (IL-5)
Total IL-5 will be summarised by mepolizumab dose group and mepolizumab overall for 
each visit.
8.2.
Safety Analyses
8.2.1.
Overview of Planned Adverse Event Analyses
Safety analyses will be based on the Safety population unless otherwise specified in 
Appendix 10: List of Data Displays. The safety displays to be created as part of the RAP 
include all the required and relevant displays identified as per the RAP Core Safety 
Reporting Template Version 1.0.
Table 8 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 10: List of Data Displays. The same displays will 
be produced for both study Part A and study Part B data.
Adverse events will be coded using the latest version of the Medical Dictionary for 
Regulatory Activities (MedDRA).
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
26
Table 8
Overview of Planned Adverse Event Analyses
Endpoint
Absolute
Summary
Individual
T
F
F
L
Exposure
Number of treatments administered and time on-treatment
Y
Y
Adverse Event
Overview of Adverse Events
Y
AEs by SOC and Maximum Intensity
Y
Y
On-Treatment AEsby Overall Frequency
Y
All Drug-Related AEs by SOC and Maximum Intensity
Y
Number of subjects & occurrences of common non-serious AEs[1] by 
SOC and PT
Y
Subject Numbers for Individual AEs
Y
Relationship between AE SOCs, PT & verbatim text
Y
AEs by Highest Antidrug Antibody Result At Any Time Post Baseline
Y
Serious and Other Significant AEs
Fatal Serious AEs
Y
Y
Non-Fatal Serious AEs
Y
Y
Reasons for Considering as a Serious Adverse Event
Y
Serious AEs by SOC
Y
Drug-Related Serious AEs by SOC and Maximum Intensity
Y
AEs leading to Permanent Discontinuation of Study Treatment or 
Withdrawal from Study by Overall Frequency
Y
Y
Number of Subjects and Occurrences of Serious, Drug-Related 
Serious, Fatal Serious, and Drug-Related Fatal Serious AEs
Y
AEs of Special Interest (On-Treatment) [2]
Systemic Reactions (Hypersensitivity and Non-Allergic)
Y
Y
Local Injection Site Reactions
Y
Y
AEs meeting Anaphylaxis Criteria
Y
Y
Serious Cardiac, Vascular and Thromboembolic (CVT) AEs
Y
Y
Serious Ischemic AEs
Y
Y
Malignancies
Y
Y
Opportunistic Infections
Y
Y
Cardiovascular Events
All Cardiovascular Events
Y
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated. PT = Preferred Term, SOC = System Organ Class

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
[1]
Common AEs will be defined as AEs with frequency ≥3% (prior to rounding to nearest percent) in overall mepolizumab 
treatment group.
[2] 
On-treatment Summary Profiles of each type of AE of Special Interest will also be presented.
8.2.1.1.
Adverse Events of Special Interest
Adverse events of special interest (AESIs) are adverse events associated with the 
identified and potential risks of mepolizumab.  AESIs of anaphylaxis reactions, systemic 
reactions, and local injection site reactions are collected via targeted eCRF within the 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
27
study.  Events captured on the eCRF as systemic reactions will be further categorized as 
allergic/hypersensitivity reactions or non-allergic reactions.  Events with preferred terms 
such as injection related reaction or administration related reaction will be considered 
non-allergic reactions.  All remaining events will be considered allergic/hypersensitivity 
reactions.
AESIs of opportunistic infections, malignancies, serious CVT events and serious 
ischemic events will be identified from a list of relevant preferred terms maintained 
within a project level reference dataset created based on the MedDRA dictionary 
available at the time of database freeze for this study, further details of how relevant 
preferred terms are identified are given in the Program Safety Analysis Plan (PSAP).
Separate summary tables showing the number and percent of subjects with each type of 
AESI, broken down by preferred term will be created.  Information will be reported as 
part of the standard AE tables for AESIs of infections, serious infections, neoplasms, 
cardiac disorders and serious cardiac disorders. 
For each type of AESI a profile summary table will be produced containing information 
which would include, but not be limited to, the number of occurrences of the event, event 
characteristics, time to onset, intensity, outcome and action taken.
A listing of any subjects with systemic events identified by the investigators as meeting 
the criteria for anaphylaxis as outlined by the 2006 Joint National Institute of Allergy and 
Infectious Disease/Food Allergy and Anaphylaxis Network Second Symposium on 
Anaphylaxis [Sampson, 2006] will be provided.
8.2.1.2.
Cardiovascular Events
Cardiovascular events will be captured on targeted CV event pages of the CRF 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

Revascularization
8.2.2.
Overview of Planned Clinical Laboratory Analyses
Safety analyses will be based on the Safety population unless otherwise specified in 
Appendix 10: List of Data Displays. The safety displays to be created as part of the RAP 
include all the required and relevant displays identified as per the RAP Core Safety 
Reporting Template Version 1.0.
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
28
Table 9 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 10: List of Data Displays.
Table 9
Overview of Planned Clinical Laboratory Analyses
Endpoint
Absolute
Change from 
Baseline
Summary
Individual
Summary
Individual
T
F
F
L
T
F
F
L
Immunogenicity
Immunogenicity (ADA and NAb results)
Y
Y
Treatment Emergent ADA results
Y
Clinical Chemistry
Change from Baseline in Clinical Chemistry by Visit
Y
Chemistry Results (Change from Baseline Relative to 
Normal Range)
Y
Y
Haematology
Change from Baseline in Haematology by Visit
Y
Haematology Results (Change from Baseline Relative to 
Normal Range)
Y
Y
Urinalysis
Urinalysis Data
Y
Hepatobiliary (Liver)
Liver Monitoring/Stopping Event Reporting
Y
Chemistry Results for  Subjects Meeting Liver 
Monitoring/Stopping Event Criteria
Y
Medical Conditions for Subjects with Liver Stopping 
Events
Y
Listing of Substance Use for Subjects with Liver Stopping 
Events
Y
Hepatobiliary Laboratory Abnormalities
Y
Y
Scatter Plot of Maximum vs. Baseline for ALT
Y
Scatter Plot of Maximum ALT vs. Maximum Total Bilirubin
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Summary = Represents TF related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
8.2.2.1.
Immunogenicity
Immunogenicity is a measure of the immune response to a therapeutic drug (e.g. a 
monoclonal antibody) resulting in generation of anti-drug antibodies. Clinical samples 
are tested in a sequence of binding anti-drug antibody (ADA) and neutralising antibody 
assays:
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
29
a) Screening assay. Each sample is tested for the presence of anti-drug antibodies 
(ADA assay) and initially declared positive or negative according to assay cut-off 
criteria. Negative samples are not tested further. Positive samples are then tested 
in the confirmation ADA assay. 
b) Confirmation assay. Each positive sample from the screening assay is either 
confirmed positive in this assay (ADA assay), or is declared negative and are not 
tested further. Positive ADA samples are then tested in the titer assay and 
neutralization (NAb) assay.
c) Titration assay. Each positive sample from the ADA confirmation assay is serially
diluted to provide a titre, corresponding to the highest dilution factor that still 
yields a positive test result.
d) Neutralising assay. Each positive sample from the ADA confirmation assay is 
tested with the neutralising antibody assay and found as either positive or negative 
in this assay (NAb assay).
The mepolizumab ADA (screening/confirmation/titration) assay version 2011N122789 is 
performed at a Alliance Pharma (method 120711M01.V02). The mepolizumab Nab assay
version 2011n129752 is being performed within GSK.

A table will be produced summarising the number and percentage of negative and 
confirmed positive subjects ADA samples by treatment group and visit in the Safety 
population. The table will also summarise the highest assay result obtained post-
baseline for each subject.

A similar table will also be produced summarising results for the neutralising 
antibody assay in the Safety Population, by treatment group and visit. 

An additional summary of treatment emergent positive confirmatory binding antibody 
assay and results in the subset of subjects who did not have a positive confirmatory 
binding antibody assay result prior to the first dose of study treatment will also be 
presented.  

All immunogenicity results (i.e. ADA screening and confirmatory assay results, titre 
values, neutralising antibody results and observed mepolizumab concentration) will 
be listed.
8.2.3.
Overview of Planned Other Safety Analyses
The safety analyses will be based on the Safety population unless otherwise specified in 
Appendix 10: List of Data Displays. The safety displays to be created as part of the RAP 
include all the required and relevant displays identified as per the RAP Core Safety 
Reporting Template Version 1.0.
Table 10 provides an overview of the planned analyses, with further details of data
displays being presented in Appendix 10: List of Data Displays.
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
30
Table 10
Overview of Planned Other Safety Analyses
Endpoint
Absolute
Change from 
Baseline
Summary
Individual
Summary
Individual
T
F
F
L
T
F
F
L
ECG
ECG Findings
Y
Y
Change from Baseline in ECG Values by Visit
Y
Actual and Change From Baseline QTc(F) Values by 
Category
Y
Y
Vital Signs
Change From Baseline in Vital Signs by Visit
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Summary = Represents TF related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
31
9.
REFERENCES
GlaxoSmithKline Document Number 2013N178278_02 Study ID MEA115588. A 
randomised, double-blind, double-dummy, placebo-controlled, parallel-group, multi-
centre study of the efficacy and safety of mepolizumab adjunctive therapy in subjects 
with severe uncontrolled refractory asthma. Report Date 31-MAR-2015. 
GlaxoSmithKline Document Number 2014N216964_04 Study ID 200363. An open-label 
study to characterize the pharmacokinetics and pharmacodynamics of mepolizumab 
administered subcutaneously in children from 6 to 11 years of age with severe 
eosinophilic asthma. Report Date 05-MAY-2016. 
GlaxoSmithKline Document Number n/a Study ID Across Studies. Program Safety 
Analysis Plan for Mepolizumab (SB240563). Report Date 29-Apr-2016. 
Juniper EF, Gruffydd-Jones K, Ward S, Svensson K. Validation, measurement properties 
and interpretation of the Asthma Control Questionnaire in children. Eur Respir J. 
2010;36:1410-1416. 
Juniper EF, O'Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of 
a questionnaire to measure asthma control. Eur Respir J. 1999;14:902–907. 
Juniper EF, Svensson K, Mork AC, Stahl E. Measurement properties and interpretation of 
three shortened versions of the asthma control questionnaire. Respiratory Medicine. 
2005;99:553–558. 
Liu AH, Gilsenan W, Stanford RH, Lincourt W, Ziemiecki R, Ortega H. Status of 
Asthma Control in Pediatric Primary Care: Results from the Pediatric Asthma Control 
Characteristics and Prevalence Survey Study (ACCESS). J Pediatr. 2010;157:276-81. 
Liu AH, Zeiger R, Sorkness C, Mahr T, Ostrom N, Burgess S, et al. Development and 
cross-sectional validation of the Childhood Asthma Control Test. J Allergy Clin 
Immunol. 2007;119:817-25. 
Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, Enright PL, Hankinson 
JL, Ip MS, Zheng J, Stocks J. Multi-ethnic reference values for spirometry for the 3-95-yr 
age range: the global lung function 2012 equations. Eur Respir J. 2012;40(6):1324-43. 
Sampson HA, Munoz-Furlong A, Campbell RL et al. Second Symposium on the 
definition and management of anaphylaxis: Summary Report.Second National Institute of 
Allergy and Infectious Disease / Food Allergy and Anaphylaxis Network Symposium. 
Journal of Allergy and Clinical Immunology. 2006;117:391-397. 
Winthrop KL, Novosad SA, Baddley JW, et al. Opportunistic infections and biologic 
therapies in immune-mediated inflammatory diseases - consensus recommendations for 
infection reporting during clinical trials and postmarketing surveillance. Ann Rheum Dis. 
2015;0:1–10. 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
32
10.
APPENDICES
Section
Appendix
RAP Section 5 : General Considerations for Data Analyses & Data Handling Conventions
Section 10.1
Appendix 1: Protocol Deviation Management
Section 10.2
Appendix 2: Time & Events
Section 10.3
Appendix 3: Assessment Windows & Visit Slotting
Section 10.4
Appendix 4: Treatment Phases
Section 10.5
Appendix 5: Data Display Standards & Handling Conventions
Section 10.6
Appendix 6: Derived and Transformed Data
Section 10.7
Appendix 7: Premature Withdrawals & Handling of Missing Data
Section 10.8
Appendix 8: Population Pharmacokinetic Analyses
Other RAP Appendices
Section 10.9
Appendix 9: Abbreviations & Trade Marks
Section 10.10
Appendix 10: List of Data Displays
Section 10.11
Appendix 11: Example Mock Shells for Data Displays
10.1.
Appendix 1: Protocol Deviation Management

As detailed in Section 4.1 protocol deviations will be tracked by the study team 
throughout the conduct of the study in accordance with the Protocol Deviation 
Management Plan (PDMP) and important protocol deviations (including deviations 
related to study inclusion/exclusion criteria, conduct of the trial, patient management 
or patient assessment) will be listed and summarised.

A Per Protocol Population will not be defined for this study.  However if there are 
subjects with protocol deviations that may potentially impact either the PK or the PD 
endpoints, exploratory sensitivity analyses may be considered (See Section 7). Any 
additional sensitivity analyses will be documented in the CSR.
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
33
10.2.
Appendix 2: Time & Events
10.2.1.
Time & Events Table Pharmacokinetic/Pharmacodynamic Phase (Part A)
Procedure
Pre-Screen1
Screening
Treatment Period
Exit 
Visit3
Follow-
up 
Early 
Withdrawal
Visit Number 
0
1
2
3
4
5
6
7
88
Week of Study 
(visit window   3 days, ±1 day Visit 5))
Prior to or same day as 
Visit 1
(up to 14 days prior to 
Visit 2)
0
4
8
9
12
16
20
Subject Screen
Informed consent
X
Inclusion and exclusion criteria
X
X
Demography
X
Medical history, including bronchodilator reversibility 
history4
X
Past and current medical conditions 
X
Asthma exacerbation history 
X
Safety Assessments
Concomitant medications
X
X
X
X
X
X
X
X
X
X
Hematology (including eosinophils)
X
X
X
X
X
X
X
X
X
Clinical Chemistry
X
X
X
X
X
X
12-lead ECG
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
Bodyweight
X
Brief physical examination
X
Adverse events
X
X
X
X
X
X
X
X
X
Cardiovascular events
X
X
X
X
X
X
X
X
X
Liver events
X
X
X
X
X
X
X
X
X
Laboratory Assessments
Urinalysis
X
X
X
Pregnancy Test
U
U5
U5
U5
U
U
U
U
HBsAg and hepatitis C antibody
X6
Serum IgE (total and specific)
X5
PK blood sample
X5
X5
X
X
X
X
X
 
 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
34
Procedure
Pre-Screen1
Screening
Treatment Period
Exit 
Visit3
Follow-
up 
Early 
Withdrawal
Visit Number 
0
1
2
3
4
5
6
7
88
Week of Study 
(visit window   3 days, ±1 day Visit 5))
Prior to or same day as 
Visit 1
(up to 14 days prior to 
Visit 2)
0
4
8
9
12
16
20
IL5 serum sample
X5
X
Blood sample for immunogenicity2,7
X5
X
X2
X
Outcomes Assessments
FEV1
X
X
X
X
X
X
X
X
ACQ-7
X
X
X
X
X
X
X
C-ACT
X
X
X
X
X
X
X
Assessment of exacerbation
X
X
X
X
X
X
X
X
X
X
Investigational Product
Mepolizumab SC dose administered
X
X
X
Study Administration
Email to GSK Operational Lead
X
X
X
X
X
X
X
X
X
X
Complete eCRF
X
X
X
X
X
X
X
X
X
X
1.
Pre-screen must be completed prior to or on the same day as Screen Visit. 
2.
For subjects who had a positive anti-mepolizumab antibody response at the 12 week post-last-dose follow-up assessment (Visit 8) (or last study visit at which immunogenicity was 
assessed if the Follow-up (Visit 8) immunogenicity sample is not available) an attempt will be made to obtain a serum sample for anti-mepolizumab antibodies at least 4 months 
after the last dose of study drug in Part A or upon completion of Part A, whichever is later.
3.
Exit visit should be performed as close as possible to the planned week 12 visit date.
4.
Therapy history to include a detailed review of prior biologics received for treatment of asthma, including prior investigational anti-IL5 or anti-IL13 preparations.
5.
During the treatment period, all lab samples and procedures should be obtained prior to study treatment administration.
6.
A positive Hepatitis B Surface Antigen and Hepatitis C antibody is exclusionary
7.
This immunogenicity sample must always be collected 12 weeks (7 days) post-last-dose of study treatment; therefore, for subjects who withdraw from study treatment early, this 
sample must be collected 12 weeks (7 days) after their confirmed last dose of study treatment (i.e., prior to Visit 8). In the event that this sample collection date coincides with an 
Early Withdrawal Visit, only one immunogenicity sample should be collected.
8.
Visit 8 to be performed 12 weeks post last dose. For subjects continuing into the long-term extension phase Part B, Visit 9 should be conducted on the same day as Visit 8 once 
all of the visit 8 assessments have been completed.  Assessments performed at Visit 8 that are also listed for Visit 9 should not be duplicated if Visit 8 and Visit 9 are performed on 
the same day.
 
 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
35
10.2.2.
Time and Events Table Long-Term Safety / Pharmacodynamic Phase (Part B)
Procedure
Eligibility 
Check / First 
Dose
Treatment Period
Exit 
Visit
Follow-
up
Early 
Withdrawal
Visit
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Week of Study 
(visit window 5 days)
20
24
28
32
36
40
44
48
52
56
60
64
68
72
80
Subject Screen
Informed consent
X1
Inclusion and exclusion criteria
X1
Safety Assessments
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology (including eosinophils) 2
X
X
X
X
X
X
X
X
Clinical Chemistry2
X
X
X
X
X
X
X
12-lead ECG
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Bodyweight
X
X1
X1
X1
X1
X1
X1
X1
X1
X1
X1
X1
X1
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Cardiovascular events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Liver events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments2
Urinalysis
X1
X
X
X
Pregnancy Test
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
Blood sample for immunogenicity2
X
X
X
X
Outcomes Assessments
FEV1
X1
X
X
X
X
X
X
X
ACQ-7
X1
X
X
X
X
X
X
X
C-ACT
X1
X
X
X
X
X
X
X
Assessment of exacerbation
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
36
Procedure
Eligibility 
Check / First 
Dose
Treatment Period
Exit 
Visit
Follow-
up
Early 
Withdrawal
Visit
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Week of Study 
(visit window 5 days)
20
24
28
32
36
40
44
48
52
56
60
64
68
72
80
Investigational Product
Mepolizumab SC dose administered
X
X
X
X
X
X
X
X
X
X
X
X
X
Study Administration
Email to GSK Operational Lead
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete eCRF
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
1.
Bodyweight will be measured at Visit 9 and at each visit until such time as the subject reaches 40kg in weight. Subjects with bodyweight ≥40Kg at Visit 9 will not be weighed again 
during Part B.
2.
All laboratory samples should be collected prior to the administration of study medication
 
 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
37
10.3.
Appendix 3: Assessment Windows & Visit Slotting
10.3.1.
Study Part (Part A and Part B)
Data will be collected across two study parts (Part A and Part B) within a single study 
database. Data will be attributed to an individual study part according to the time of 
occurrence/assessment relative to specific visits.
Data points collected at scheduled clinic visits will be attributed to the correct study part 
utilising the collected visit label.
Spontaneous events (such as adverse events, exacerbations and unscheduled visits) will 
be attributed to an individual study part as follows:
Study Part
Definition
Part A
Visit 0 (Pre-screening) visit date ≤ Date & time ≤ Visit 8 (Week 20) visit date
Part B
Visit 9 (Week 20) visit date < Date & time ≤ Visit 23 (Week 80) visit date
Note: Visit 8 and Visit 9 will be performed on the same date
10.3.2.
Part A Data Cut Date
When reporting study Part A, a data cut date will be applied to all data collected within 
the Case Report Form (CRF) prior to SDTM conversion. This cut date subset the data to 
only those assessments/visits prior to the last subject completing the Visit 8 (Week 20) 
visit date (LSLV Part A). 
All external vendor data (e.g. Labs, ECGs, Immunogenicity) will not be possible to 
subset and therefore data will be present within the SDTM datasets past this data cut date.
When creating ADaM datasets all dates beyond this applied data cut date will be removed 
and will be documented clearly within the ADaM dataset metadata.
10.3.3.
Assessment Windows
Clinic visits are scheduled to take place as specified in Appendix 2: Time & Events. 
Measurements outside visit windows will not be excluded from analyses. For all clinic 
visits, nominal visit days and times will be used for reporting, such that if a subject 
recorded values that were outside of the ±7 day window for a visit they will still be 
reported under that visit.
10.3.4.
Early Withdrawal Visits
If a subject withdraws from the study at a scheduled visit (i.e. completes an Early 
Withdrawal Visit), where endpoint data were scheduled to be collected, the data will be 
summarised and analysed (as appropriate) together with data from subjects who did not 
withdraw from the study. If a subject withdraws from the study at a scheduled visit at 
which endpoint data were not scheduled to be collected, or if a subject withdraws 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
38
between scheduled visits, data will be slotted to the nearest adjacent visit where the 
endpoint data was scheduled to be collected (if data at that visit were not recorded) 
according to the Time and Events schedule (Appendix 2: Time & Events). 
For example, if a subject prematurely withdraws from the study and completed the Early 
Withdrawal Visit at Visit 5 (Week 9) and completes an Early Withdrawal Visit which 
includes an FEV1 assessment, the FEV1 data collected will need to be re-assigned to an 
adjacent visit where FEV1 data is scheduled for collection.  In this case the FEV1 data 
will be reassigned to Visit 4 (Week 8) (if data at that visit were not recorded) as this is the 
closest nominal visit at which collection of FEV1 data is scheduled.
10.3.5.
Unscheduled Visits
For unscheduled visits, similar logic will be applied. If a subject has an unscheduled 
assessment then this data would be slotted to the closest adjacent scheduled visit but only 
if information already exists at that visit. If an unscheduled visit occurred between two 
scheduled visits for which data has been reported, then the data from the unscheduled 
visit will remain in the unscheduled visit and will not be used in summary tables and 
analyses (except for endpoints using any post-baseline data) but will be presented in any 
relevant listings.
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
39
10.4.
Appendix 4: Treatment Phases
10.4.1.
Treatment Phases (Adverse Events)
Adverse events will be classified according to time of occurrence relative to the first and 
last dose of mepolizumab within specific study parts.
Treatment Phase
Definition
Pre-Treatment 
AE Onset Date & time < First Part A dose of mepolizumab
If mepolizumab treatment is never started then all AEs will be classified as pre-
treatment.
On-Treatment 
(Part A)
First Part A dose of mepolizumab ≤ AE Onset Date & time ≤ Last Part A dose of 
mepolizumab + 28 days
If an AE start date is missing or partial then the AE will be considered on-treatment 
unless there is evidence to the contrary (e.g. month/year of onset date is present and is 
earlier than the month/year of First Part A dose of mepolizumab).
Post-treatment 
(Part A)
For subjects entering Part B:
Last Part A dose of mepolizumab + 28 days < AE Onset Date & time < First dose of 
Part B mepolizumab
For subjects not entering Part B:
Last Part A dose of mepolizumab + 28 days < AE Onset Date & time ≤ Visit 8 (Week 
20) visit date
On-Treatment 
(Part B)
First dose of Part B mepolizumab ≤ AE Onset Date & time ≤ Last Part B dose of 
mepolizumab + 28 days
If an AE start date is missing or partial then the AE will be considered on-treatment 
unless there is evidence to the contrary (e.g. month/year of onset date is present and is 
earlier than the month/year of First Part B dose of mepolizumab).
Post-treatment 
(Part B)
AE Onset Date & time > Last Part B dose of mepolizumab + 28 days
Onset Time Since 
1st Dose (Days)*
If Treatment Start Date ˃  AE Onset Date = AE Onset Date - First Part A dose of 
mepolizumab
If Treatment Start Date ≤ AE Onset Date = AE Onset Date - First Part A dose of 
mepolizumab + 1
If Treatment Start Date or AE Onset Date is missing = missing.
Duration (Days) 
AE Resolution Date – AE Onset Date + 1
Drug-related
If relationship is marked ‘YES’ on Inform/eCRF OR value is missing.
* Note: will be derived as time since 1st dose of mepolizumab utilising the First Part A dose of mepolizumab 
for both study parts A and B
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
40
10.4.2.
Treatment Phases (Exacerbations)
Exacerbation data will be classified according to time of occurrence/assessment relative 
to the first and last dose of mepolizumab and the participation of subjects within to 
specific study parts (as dictated by attendance dates of specific visits).
Treatment Phase
Definition
Pre-Treatment 
Exacerbation Onset Date & time < First Part A dose of mepolizumab
If mepolizumab treatment is never started then all exacerbations will be classified as 
pre-treatment.
On-Treatment 
(Part A)
Subjects completing Part A:
First Part A dose of mepolizumab  ≤ Exacerbation Onset Date & time ≤ Visit 6 (Week 
12) visit date
Subjects discontinuing study treatment/withdrawing early from Part A:
First Part A dose of mepolizumab ≤ Exacerbation Onset Date & time ≤ Earliest of (1) 
Last Part A dose of mepolizumab + 28 days or (2) Early Withdrawal visit date
Post-treatment 
(Part A)
Subjects completing Part A and entering Part B:
Visit 6 (Week 12) visit date < Exacerbation Onset Date & time < First dose of Part B 
mepolizumab
Subjects completing Part A and not entering Part B:
Visit 6 (Week 12) visit date < Exacerbation Onset Date & time ≤ Visit 8 (Week 20) visit 
date
Subjects discontinuing study treatment/withdrawing early from Part A:
Earliest of (1) Last Part A dose of mepolizumab + 28 days or (2) Early Withdrawal visit 
date < Exacerbation Onset Date & time ≤Visit 8 (Week 20) visit date
On-Treatment 
(Part B)
Subjects completing Part B:
First Part B dose of mepolizumab ≤ Exacerbation Onset Date & time ≤ Visit 22 (Week 
72) visit date
Subjects discontinuing study treatment/withdrawing early from Part B:
First Part B dose of mepolizumab  ≤Exacerbation Onset Date & time ≤ Earliest of (1) 
Last Part B dose of mepolizumab + 28 days or (2) Early Withdrawal visit date
Post-treatment 
(Part B)
Subjects completing Part B:
Exacerbation Onset Date & time > Visit 22 (Week 72) visit date
Subjects discontinuing study treatment/withdrawing early from Part B:
Exacerbation Onset Date & time > Earliest of (1) Last Part B dose of mepolizumab + 28 
days or (2) Early Withdrawal visit date
Onset Time Since 
1st Dose (Days)*
If Treatment Start Date ˃   Exacerbation Onset Date  = Exacerbation Onset Date - First 
Part A dose of mepolizumab
If Treatment Start Date ≤ Exacerbation Onset Date = Exacerbation Onset Date - First 
Part A dose of mepolizumab + 1
If Treatment Start Date or AE Onset Date is missing = missing.
Duration (Days) 
Exacerbation Resolution Date – Exacerbation Onset Date + 1
* Note: will be derived as time since 1st dose of mepolizumab utilising the First Part A dose of mepolizumab 
for both study parts A and B
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
41
10.4.3.
Treatment Phases (Concomitant Medications)
Concomitant medications will be classified according to time of occurrence relative to the 
first and last dose of mepolizumab within specific study parts.
Treatment/Study 
Phase
Definition
Taken Before the 
Run-in
If Con-med Start Date < Date of Visit 1
Taken During the 
Run-in

If Con-med Start Date < Date of Visit 1 and Con-med Stop Date ≥Date of Visit 1,
or

If Date of Visit 1 ≤ Con-med Start Date < First Part A dose of mepolizumab
Taken During 
Treatment
(Part A)

If Con-med Start Date < First Part A dose of mepolizumab and Con-med Stop 
Date ≥First Part A dose of mepolizumab, or

If First Part A dose of mepolizumab≤ Con-med Start Date ≤ Last Part A dose of 
mepolizumab+ 28 days

If the con-med start or stop date is missing or partial then the con-med will be 
considered on-treatment unless there is evidence to the contrary (e.g. month/year 
of con-med stop date is present and is before the month/year of the first Part A 
dose of mepolizumab).
Started During 
Treatment
(Part A)
Subset of con-meds Taken During Treatment (Part A) for which:
First Part A dose of mepolizumab ≤ Con-med Start Date ≤ Last Part A dose of 
mepolizumab + 28 days
Taken Post 
Treatment
(Part A)

Con-med Stop Date > Last Part A dose of mepolizumab + 28 days
Taken During 
Treatment 
(Part B)

If Con-med Start Date < First Part B dose of mepolizumab and Con-med Stop 
Date ≥ First Part B dose of mepolizumab, 
or

If First Part B dose of mepolizumab≤ Con-med Start Date ≤ Last Part B dose of 
mepolizumab+ 28 days

If the con-med start or stop date is missing or partial then the con-med will be 
considered on-treatment unless there is evidence to the contrary (e.g. month/year 
of con-med stop date is present and is before the month/year of the first Part B 
dose of mepolizumab).
Started During 
Treatment 
(Part B)
Subset of con-meds Taken During Treatment (Part B) for which:
First Part B dose of mepolizumab ≤ Con-med Start Date ≤ Last Part B dose of 
mepolizumab + 28 days
Taken Post 
Treatment 
(Part B)

Con-med Stop Date > Last Part B dose of mepolizumab + 28 days
Time Since 1st
Dose (Days)*
If Treatment Start Date ˃   Con-med Start Date = Con-med Start Date - First Part A 
dose of mepolizumab
If Treatment Start Date ≤ Con-med Start Date = Con-med Start Date - First Part A dose 
of mepolizumab + 1
If Treatment Start Date or Con-med Start Date is missing = missing.
Duration (Days)
Con-med Stop Date –Con-med Start Date + 1
* Note: will be derived as time since 1st dose of mepolizumab utilising the First Part A dose of mepolizumab 
for both study parts A and B
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
42
A medication will be summarised in every treatment/study phase in which it was taken, 
so for example a medication that was started in the run-in and stopped during treatment 
will appear in both the during the run-in and during treatment tables
10.5.
Appendix 5: Data Display Standards & Handling 
Conventions
10.5.1.
Study Treatment & Display Descriptors
For all displays subjects will be presented in the treatment group received during the 
study.
10.5.1.1.
Part A
All displays will be presented by mepolizumab dose group within Part A (Mepolizumab 
40 mg and 100mg SC) and overall, when appropriate.
Treatment Group Descriptions
RandAll NG[1]
Data Displays for Reporting 
Code
Description
Description[3]
Order [2]
N/A
N/A
Mepolizumab 40 mg SC
1
Mepolizumab 100 mg SC
2
Mepolizumab SC
3
NOTES:
1.
This is not a randomised study and treatment group descriptions are not required for RandAll NG
2.
Order represents treatments being presented in TFL, as appropriate.
3.
‘Mepolizumab SC’ group includes all subjects who received at least one dose of mepolizumab regardless of dose.
10.5.1.2.
Part B
All displays will be presented by mepolizumab dose group within Part B and overall. 
Note: Subjects which are switched from 40mg to 100mg SC during Part B will be 
presented separately [Mepolizumab 40/100 mg SC].
Treatment Group Descriptions
RandAll NG[1]
Data Displays for Reporting 
Code
Description
Description[3]
Order [2]
N/A
N/A
Mepolizumab 40 mg SC
1
Mepolizumab 100 mg SC
2
Mepolizumab 40/100 mg SC
3
Mepolizumab SC
4
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
43
NOTES:
1.
This is not a randomised study and treatment group descriptions are not required for RandAll NG
2.
Order represents treatments being presented in TFL, as appropriate.
3.
‘Mepolizumab SC’ group includes all subjects who received at least one dose of mepolizumab regardless of dose.
10.5.2.
Baseline Definition & Derivations
10.5.2.1.
Definition of Baseline

The baseline value for each assessment will be the latest value recorded prior to the 
first dose of mepolizumab.

If an assessment was performed on the same day as the first dose of study treatment 
but it is known that the assessment was done after administration of treatment (i.e. 
because time of assessment is available and is after time of first dose) then this value 
will not be used as the baseline value.

The same baseline definition (latest value recorded prior to the first dose of 
mepolizumab in Part A) will be used in the analyses of both Part A and Part B data.
10.5.2.2.
Derivations of Change from Baseline Data
Definition
Reporting Details
Change from Baseline
= Post-Dose Visit Value – Baseline
Ratio to baseline 
= Post-Dose Visit Value / Baseline
Maximum Change from Baseline
= Highest Post-Dose Value - Baseline
NOTES :

Unless otherwise specified, the baseline definitions specified in Section 10.5.2.1 will be used for derivations for 
endpoints / parameters and indicated on summaries and listings.

The baseline definition will be footnoted on all change from baseline displays.
10.5.3.
Reporting Process & Standards
Reporting Process
Software
The currently supported versions of SAS software will be used to perform all data 
analyses, generate tables, figures and listings.
Reporting Area (Part A)
HARP Server
: UK1SAL00175
HARP Area
: /arenv/arprod/sb240563/mid200363/part_a
Quality Control 
(QC) Spread sheet
: /arenv/arwork/sb240563/mid200363/part_a/document
Reporting Area (Part B)
HARP Server
: UK1SAL00175
HARP Area
: /arenv/arprod/sb240563/mid200363/final
Quality Control 
(QC) Spread sheet
: /arenv/arwork/sb240563/mid200363/final/document
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
44
Reporting Process
Analysis Datasets 

Analysis datasets will be created according to CDISC standards (current versions of SDTM IG 
& ADaM IG).

For creation of ADaM datasets (ADCM/ADAE), the same version of dictionary datasets will be 
implemented for conversion from SI to SDTM.
Generation of RTF Files

RTF files will be generated only for summary tables
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated:
o
4.03 to 4.23: General Principles
o
5.01 to 5.08: Principles Related to Data Listings
o
6.01 to 6.11: Principles Related to Summary Tables
o
7.01 to 7.13: Principles Related to Graphics 
Formats

All data will be reported according to the actual treatment the subject received (see Section 
10.5.1).

The reported precision of data will follow the IDSL statistical principles but may be adjusted to
a clinically interpretable number of decimal places.
Planned and Actual Time

Reporting for tables and figures :

Nominal visits (planned time relative to dosing) will be used in summary figures and
summary tables. Actual time relative to dosing will be used in individual subject figures.

The impact of any major deviation from the planned assessment times and/or scheduled 
visit days on the analyses and interpretation of the results will be assessed as appropriate.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to 
IDSL Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject data listings

Scheduled visits outside the protocol defined time-windows (i.e. recorded as protocol
deviations) will be included in listings, summaries and statistical analyses. The impact of 
any major deviation from the planned assessment times and/or scheduled visit days on the 
summaries, figures, analyses will be assessed as appropriate. 
Unscheduled Visits

When possible unscheduled assessments will be slotted to the closest adjacent scheduled 
visit.  If an unscheduled visit occurs between two completed scheduled visits, the data from the 
unscheduled visit will not be used in summary tables which are based on by-visit assessments.  
The information from the unscheduled visit will be included in ‘any time post-baseline’ 
summaries and will also be presented in any relevant listings. See Section 10.3 for further 
details. 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
45
Reporting Standards
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N (number of subjects in the treatment group), n (number of subjects with
non-missing values), frequency, %
Reporting of Pharmacokinetic Concentration Data
Descriptive 
Summary Statistics
Refer to IDSL Statistical Principle 6.06.1
Refer to GUI_51487 for further details of handling NQ/BQL values
Reporting of Pharmacokinetic Parameters
Descriptive 
Summary Statistics
The following summary statistics will be presented for all parameters:
N, n, mean, median, SD, min and max
In addition the following summary statistics will be presented for all 
parameters with the exception of t1/2.
N, n, geometric mean, 95% CI of geometric mean, standard deviation (SD)
of logged data and [between] geometric coefficient of variation (CVb (%)) will 
be reported.
[1] CVb (%) = √(exp(SD2) – 1) * 100
(SD = SD of log transformed data)
Reporting of Blood Eosinophil Count
Descriptive 
Summary Statistics 
The following summary statistics will be presented for blood eosinophil 
count: 
N, n, geometric mean, 95% CI of geometric mean, SD (natural log scale), 
median, min and max
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
46
10.6.
Appendix 6: Derived and Transformed Data
10.6.1.
General
Multiple Measurements at One Time Point

There are no scheduled multiple measurements, however, if multiple measurements are 
recorded at a given time point the following process will be followed, unless a process for 
selection of the measurement for the visit is specified.

Mean of the measurements will be calculated and used in any derivation of summary statistics 
but if listed, all data will be presented.

If there are two values within a time window the value closest to the target day for that window 
will be used. If values are the same distance from the target then the mean will be taken.

Subjects having both High and Low values for Normal Ranges at any post-baseline visits for 
safety parameters will be counted in both the High and Low categories of “Any visit post-
baseline” row of related summary tables.
Study Day
Calculated as the number of days from first mepolizumab dose:

Ref Date = Missing
Study Day = Missing

Ref Date < First mepolizumab dose Study Day = Ref Date –First dose of mepolizumab

Ref Data ≥ First mepolizumab dose Study Day = Ref Date – (First dose of mepolizumab) + 1
10.6.2.
Study Population
Demographics
Age

Only year of birth was collected for subjects; actual birth data was not collected.

GSK standard IDSL algorithms will be used for calculating age where birth date of all subjects 
will be imputed as ‘30th June’.

Birth date will be presented in listings as ‘YYYY’.

Each subject’s derived age will be calculated as an integer value based on their imputed date of 
birth relative to the date of the subject’s screening visit (Visit 1)
[(30th June of the year of birth reported on eCRF – date of Screening)/365.25]

Derived age may not represent the actual age of a subject at entry to the study

All tables which include age will describe this as “derived age” and will include a footnote to 
indicate that a) actual age was not collected, b) age was derived using a value of 30th June for 
birth date and c) this may not represent the actual age of a subject at entry to the study.
Body Mass Index (BMI)

Calculated as Weight (kg) / [Height (m)2
Disease parameters
Percent Predicted FEV1

FEV1 % of predicted normal will be derived using the Global Lung Function Initiative 2012 look-
up tables [Quanjer, 2012]
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
47
Disease parameters
FEV1/FVC Ratio

Pre- and post-bronchodilator FEV1/FVC ratio will be calculated as the ratio of the FEV1 and FVC 
values.
Blood Eosinophils

Blood eosinophil count will be log transformed prior to analysis. Summary statistics will include
geometric mean and a measure of spread (SD or SE) on the natural log scale.

If a blood eosinophil count of zero is reported, it will be imputed with half of the lowest possible 
blood eosinophil count, where applicable, prior to log transforming the data (Note: this 
imputation has typically been 0.5 * 0.01 GI/L =  0.005 GI/L for previous mepolizumab studies). 
Categories defined based on databased information regarding blood eosinophil counts in 
the previous 12 months and observed blood eosinophil counts at the Screening visit.

Historical and Screening: Blood eosinophil count ≥300 cells/µl in previous 12 months and ≥150 
cells/µl at Screening

Historical Only: Blood eosinophil count ≥300 cells/µl in previous 12 months and <150 cells/µl at 
Screening

Screening Only: Blood eosinophil count <300 cells/µl or missing or unknown in previous 12 
months and ≥150 cells/µl at Screening
Baseline OCS daily dose

Only corticosteroids administered via oral, intravenous (IV) and intramuscular (IM) routes are to 
be considered when calculating a subject’s total daily prednisone/prednisolone asthma 
maintenance dose at baseline. All steroids administered via a sublingual route will also be 
considered as oral. 

The corticosteroid conversion factors shown below will be used, regardless of the route of 
administration, to scale each corticosteroid dose to a prednisone equivalent dose. These three 
routes of administration (oral, IV and IM) are to be considered equivalent as it has been noted 
that the bioavailability of methylprednisolone is considered to be roughly equivalent following 
administration as an oral, IV or IM steroid.
Standardised Medication Name
Scaling Factor
Betamethasone
8.33
Betamethasone Dipropionate
8.33
Betamethasone Sodium Phosphate
8.33
Cortisone
0.2
Cortisone Acetate
0.2
Cortivazol
17
Deflazacort 
0.833
Dexamethasone 
6.67
Dexamethasone Sodium Phosphate 
6.67
Fludrocortisone Acetate 
0
Hydrocortisone 
0.25
Hydrocortisone Sodium Succinate 
0.25
Hydrocortisone Sodium Phosphate 
0.25
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
48
Standardised Medication Name
Scaling Factor
Meprednisone
1
Methylprednisolone
1.25
Methylprednisolone Acetate
1.25
Methylprednisolone Sodium Succinate
1.25
Methylprednisone 
1.25
Methylprednisone Acetate 
1.25
Methylprednisolone Sodium Succinate 
1.25
Methylprednisone
1.25
Methylprednisone Acetate 
1.25
Prednisolone 
1
Prednisolone Acetate 
1
Prednisolone Hemisuccinate 
1
Prednisolone Sodium Succinate 
1
Prednisone 
1
Prednisone Acetate 
1
Triamcinolone 
1.25
Triamcinolone Acetonide 
1.25
Extent of Exposure (Days)

Within each study part (Part A/Part B) the number of days of total exposure to mepolizumab will 
be calculated based on the formula:  
Duration of Exposure = Last dose of mepolizumab – (First dose of mepolizumab) + 29

Within each study part (Part A/Part B) the number of days of exposure to specific mepolizumab 
doses will be calculated as follows: 
Subjects receiving mepolizumab 40mg SC only:
Duration of Exposure = Last dose of mepo 40mg – (First dose of mepo 40mg) + 29
Subjects receiving mepolizumab 100mg SC only:
Duration of Exposure = Last dose of mepo 100mg – (First dose of mepo 100mg) + 29
Subjects receiving mepolizumab 40mg SC and mepolizumab 100mg (Part B only):
Duration of 40mg Exposure = First dose of mepo 100mg – (First dose of mepo 40mg) + 1
Duration of 100mg Exposure = Last dose of mepo 100mg – (First dose of mepo 100mg) + 28

Subjects who never received a mepolizumab dose will be categorised as having zero days of 
exposure. 

The extent of exposure will also be summarised as the number of study treatments 
administered within each study part (Part A/Part B).
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
49
10.6.3.
Subject Disposition
Subject Disposition

It is an eligibility requirement that subjects must complete all study assessments up-to and 
including Visit 8 (and received all 3 doses of investigational product) in Part A before entering 
study Part B

Subjects who complete Part A will not have a disposition (study part completion/withdrawal) 
record created at the completion of Part A. Instead a derived disposition record will be required 
utilising the Part B status (RLSTUDY) flag. A disposition record will be available for Part B. 
10.6.4.
Safety
AEs of  Special Interest
Section 8.2.1.1 provides a full list of AEs of special interest for this compound.
AESIs of anaphylaxis reactions, systemic reactions, and local injection site reactions are collected 
via targeted eCRF.  Systemic reactions with preferred terms such as injection related reaction or 
administration related reaction will be considered non-allergic reactions; those with other preferred 
terms will be considered allergic/hypersensitivity reactions.
The AESIs of opportunistic infections, malignancies, serious CVT events and serious ischemic 
events will be identified from a list of relevant preferred terms maintained within a project level 
reference dataset; created based on the latest version of the MedDRA dictionary available at the 
time of database freeze for this study (See Program Safety Analysis Plan for additional details).
ECG Parameters
RR Interval
All ECG parameters required in this study will be databased, and therefore, further derivations will 
not be performed by Stats and Programming. The definitions of these parameters are given in this 
section.

If RR interval (msec) is not databased, then RR can be derived as :
[1] If QTcB is machine read & QTcF is not provided, then :
[2] If QTcF is machine read and QTcB is not provided, then: 

If ECGs are manually read, the RR value should be a collected value and will not be derived.
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
50
Corrected QT Intervals

When not databased, corrected QT intervals by Bazett’s (QTcB) and Fredericia’s (QTcF) 
formulas will be calculated, in msec, depending on the availability of other measurements.

If RR interval (msec) is provided then missing QTcB and/or QTcF will be derived as : 

Individual maximum QTc(F) and QTc(B) values will also be summarised by treatment group for 
each scheduled study visit to show the number of subjects with maximum values (msec) in the 
following categories:

<= 450

450 < to <= 480

480 < to <= 500

> 500 

Additionally, individual maximum changes from baseline in QTc(F) and QTc(B) values will be 
summarised by treatment group for each scheduled study visit to show the number of subjects 
with maximum changes (msec) in the following categories: 

< -60

≥ -60 to < -30

≥ -30 to < 0

≥  0 to < 30

≥  30 to < 60

≥ 60
Laboratory Parameters

If a laboratory value which is expected to have a numeric value for summary purposes, has a 
character value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than x in the 
comment field), the number of significant digits in the observed values will be used to determine 
how much to add or subtract in order to impute the corresponding numeric value. 
o
Example 1: 2 Significant Digits =  ‘< x ‘ becomes x – 0.01
o
Example 2: 1 Significant Digit   =  ‘> x’ becomes x + 0.1
o
Example 3: 0 Significant Digits = ‘< x’ becomes x – 1    

If a laboratory value is missing due to being below the limit of quantification (BLQ) then the
value will be imputed as half the lower limit of quantification for that measure (i.e. the lowest
observed value for that measure within the entire study database).
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
51
10.6.5.
Efficacy
Patient Reported Outcomes/Questionnaires
ACQ-7

The questionnaire includes 7 items; and requires a 1 week recall (for items on symptoms and 
rescue inhaler use).  The ACQ has a multidimensional construct assessing symptoms (5 items 
administered by clinic staff to the child) and rescue bronchodilator use (query to child or parent), 
and FEV1 % predicted (1 item) completed by clinic staff. 

Each question on the ACQ-7 is scored on a 7-point scale from 0 = no impairment to 6 =
maximum impairment. The questions are equally weighted and the ACQ-7 score will be the 
mean of the 7 questions, thus giving a score between 0 (totally controlled) and 6 (severely 
uncontrolled) [Juniper, 2010; Juniper, 1999; Juniper, 2005].

A subject will be deemed a responder if the subject has a ≥0.5 reduction in ACQ score from 
Baseline

If a subject does not complete 1 of the 7 questions at a visit, then the ACQ-7 score will be the
mean of the responses to the remaining 6 questions at that visit.

If a subject does not complete more than 1 of the 7 questions at a visit, then their ACQ-7 score
will be set to missing at that visit.

ACQ-7 Responder/Non-responder category will be missing if the overall ACQ-7 score is 
missing.
ACQ-5

The ACQ-5 questionnaire consists of the 5 symptoms questions (Q1-Q5) of the ACQ-7 
requiring a 1 week recall. 

Each question on the ACQ-5 is scored on a 7-point scale from 0 = no impairment to 6 =
maximum impairment. The questions are equally weighted and the ACQ-5 score will be the 
mean of the 5 questions, thus giving a score between 0 (totally controlled) and 6 (severely 
uncontrolled) [Juniper, 2010; Juniper, 1999; Juniper, 2005].

A subject will be deemed a responder if the subject has a ≥0.5 reduction in ACQ score from 
Baseline

If a subject does not complete 1 of the 5 questions at a visit, then the ACQ-5 score will be the
mean of the responses to the remaining 4 questions at that visit.

If a subject does not complete more than 1 of the 5 questions at a visit, then their ACQ-5 score
will be set to missing at that visit.

ACQ-5 Responder/Non-responder category will be missing if the overall ACQ-5 score is 
missing.
C-ACT

The C-ACT is a 7-question, 2-part questionnaire, with items one through 4 to be completed by 
the child (with assistance from a caregiver, as needed) and items 5 to 7 to be completed by the 
caregiver [Liu, 2010; Liu, 2007].

The scores for each of the questions will be summed to derive the total score for that subject at 
that visit. If the response to any question is missing then the C-ACT total score is also set to 
missing.
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
52
Exacerbations
An exacerbation of asthma as defined as:
Worsening of asthma which requires use of systemic corticosteroids1and/or hospitalisation and/or 
Emergency Department (ED) visits.

1For all subjects, i.v. or oral steroid (e.g., prednisone) for at least 3 days or a single IM CS dose 
is required. For subjects on maintenance systemic corticosteroids, at least double the existing 
maintenance dose for at least 3 days is required.
Exacerbations separated by less than 7 days will be treated as a continuation of the same 
exacerbation. Each individual exacerbation will be listed.
10.7.
Appendix 7: Premature Withdrawals & Handling of Missing 
Data
10.7.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion (i.e. completion of all study visits or withdraw 
prematurely from the study) was detailed in the study protocol. 

Withdrawn subjects will not be replaced in the study.

All available data from subjects who were withdrawn from the study will be listed 
and all available planned data will be included in data displays (e.g. summary 
tables) unless otherwise specified.
Pre-Screen, 
Screen and 
Run-in 
Failures
Pre-screen failures, screening failures and run-in failures will be defined as follows:

Subjects will be assigned a subject number at the time the informed consent is 
signed (Pre-screen Visit). Subjects who are assigned a subject number but do 
not have a Visit 1 (screening) procedure will be considered pre-screen failures.

Those subjects that complete at least one Visit 1 (Screening) procedure but do 
not enter the run-in period will be considered screen failures.

Those subjects that enter the run-in period but are not subsequently dosed will 
be considered run-in failures.
10.7.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided. These data will be 
indicated by the use of a “blank” in subject listing displays. Unless all data for a 
specific visit are missing in which case the data is excluded from the listing.
Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should not be displayed as missing.

PK concentrations reported as Not Quantified (NQ)/Below the Lower Limit of 
Quantification (BQL) will be handled as per standard GSK practice. Below the 
limit of quantification (BLQ) is not missing data and must be displayed as such 
and included in all listings and summaries
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
53
Element
Reporting Detail

If a blood eosinophil count of zero is reported, it will be imputed with half of the 
lowest possible blood eosinophil count, where applicable, prior to log 
transforming the data (Note: this imputation has typically been 0.5 * 0.01 GI/L =  
0.005 GI/L for previous mepolizumab studies). 

The ACQ-7 score will be considered as missing if <6 items of the questionnaire 
are completed at a visit. ACQ-7 Responder/Non-responder category will be 
missing if the overall ACQ-7 score is missing.

The ACQ-5 score will be considered as missing if <4 items of the questionnaire 
are completed at a visit. ACQ-5 Responder/Non-responder category will be 
missing if the overall ACQ-5 score is missing.

Missing values will not be imputed for any of the other endpoints.
Outliers

Any subjects excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
Sensitivity 
analysis

No sensitivity analyses are planned for this study. However as detailed in 
Section 7, exploratory sensitivity analyses may be considered if there are 
protocol deviations that may potentially affect the PK and/or PD endpoints. If any 
sensitivity analyses are performed the details will be documented in the clinical 
study report.
10.7.2.1.
Handling of Missing and Partial Dates
Element
Reporting Detail
General

The eCRF allows for the possibility of partial dates (i.e. only month and year) to
be recorded for event start and end dates; that is, the day of the month may be
missing.

Partial dates will be displayed as captured in subject listing displays.
Concomitant 
Medications

Partial dates for any concomitant medications recorded in the CRF will be
imputed using the following convention:
o
If the partial date is a start date, a ‘01’ will be used for the day and ‘Jan’ will 
be used for the month
o
If the partial date is a stop date, a ‘28/29/30/31’ will be used for the day 
(dependent on the month and year) and ‘Dec’ will be used for the month.

The recorded partial date will be displayed in listings.
AEs

Any partial dates for adverse events and exacerbations will be raised to data 
management. If the full date cannot be ascertained, the following assumptions 
will be made:
o
If the partial date is a start date, a ‘01’ will be used for the day and ‘Jan’ will 
be used for the month. 
o
However, if these results in a date prior to the first dose of mepolizumab and 
the event could possibly have occurred during treatment from the partial 
information, then the first dose of mepolizumab date will be assumed to be 
the start date. The AE will then be considered to start on-treatment (worst 
case) as per Appendix 4: Treatment Phases.
o
If the partial date is a stop date, a ‘28/29/30/31’ will be used for the day 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
54
Element
Reporting Detail
(dependent on the month and year) and ‘Dec’ will be used for the month.

The above conventions will also be applied when calculating the time to onset
and duration of the event containing missing or partial start and end dates.

The recorded partial date will be displayed in listings.

Start or end dates which are completely missing (i.e. no year specified) will 
remain missing, with no imputation applied. Consequently, time to onset and 
duration of such events will be missing.
10.8.
Appendix 8: Population Pharmacokinetic Analyses
10.8.1.
Population-PK Analysis
Sparse PK samples collected will be analysed by population PK methods, using 
appropriate software, and based on the PK population.
Based on mepolizumab PK knowledge, concentrations below the limit of quantification
(BLQ) of the assay is considered unlikely at the 100 mg and 40 mg SC dose investigated 
in view of the PK sampling scheme selected in the study. Thus any such results will be 
treated as missing in the population PK analysis.
Outlier data will be assessed for plausibility, however the aim is to use all available data
whenever possible. Any decision to exclude data will be fully documented and specified
in the clinical study report.
The established most recent adult population PK model parameterised in terms of macro-
constants (i.e. A, B, alpha, beta) will be used to conduct the analysis of the data from this 
study.
Ci (t) = Ai*exp(-Alpha*t) + Bi*exp(-Betai*t) – (Ai+Bi)*exp(-Ka*t), 
Where:
A denotes the coefficient of the distribution phase
B denotes the coefficient of the elimination phase
Alpha denotes the distribution phase rate constant
Beta denotes the terminal phase rate constant
pBWT denotes the power for the bodyweight covariate on a parameter
Kai absorption rate constant.
Bodyweight will be included as a structural covariate on parameters A, B, Alpha and 
Beta. In consideration of the sparse sampling used and the relatively small sample size in 
the study, a number of pharmacokinetic parameters will be fixed from adult values in the 
model as deemed necessary (e.g. absorption and inter-compartmental rate constant 
parameters, pBWT).
Individual AUC(0-inf), CL/F, Cmax and t1/2 will be derived as follow:
AUC(0-inf) = (A/alpha) + (B/beta) – (A+B)/Ka
CL/F = Dose/AUC(0-inf)
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
55
T1/2 = Ln(2)/beta
Cmax will be estimated using an approximation method as described below:
The approximate one compartment solution combining absorption and distribution phases 
takes the form:
Ci’(t) = B*(exp(-Beta*t) – exp(-Ka2*t))
With :
Ka2 = Ka + Alpha 
(from the bi-exponential model)
Hence 
Tmax = logn((Alpha+Ka)/Beta)/(Ka+Alpha-Beta)
Cmax(n doses) = ∑(j=1..n) B*(exp(-Beta*(Tmax+((j-1)*Tau))) – exp(-Ka2*(Tmax+((j-
1)*Tau))))
The parameter estimates from the final PK model, the derived parameters and diagnostic 
plots assessing the performance of the population PK model will be presented.
Simulation from the final PK model will be conducted and a plot of model predicted (5th, 
50th, and 95th Percentiles) mepolizumab plasma concentrations with individual observed 
plasma concentrations will be presented as a means to validate the final PK Model.
10.8.2.
Additional Analysis to Support Paediatric Extrapolation Strategy
10.8.2.1.
Population-PK analysis
In addition, to confirm that paediatric PK data from 6-11 years old subjects can be 
predicted from the adult PK model, the most recent population PK model will also be 
applied directly to the dataset without estimation (e.g. maxevals=0 in NONMEM) and 
predictions generated against which the model will be validated prospectively using 
appropriate goodness of fit tests. For example the Cramér–von Mises and Kolmogorov-
Smirnov tests are accepted methods of comparing Empirical Distribution Functions for 
model and data (i.e. PK concentrations) to evaluate whether independent observations 
(observed PK concentrations from the study) are adequately described by a model.
The current PK model consists of a two-compartment pharmacokinetic model with first-
order absorption and elimination. Bodyweight is incorporated into the model using 
allometry with fixed physiological allometric exponents of 0.75 and unity for clearance 
and volumes, respectively. Albumin and creatinine clearance are also included as 
covariates of mepolizumab clearance on physiological grounds, however their effects are 
small and not of clinical relevance.
10.8.2.2.
Population-PK/PD analysis
Likewise, to confirm that paediatric blood eosinophil count data from 6-11 years old 
subjects can be predicted from the adult PK/PD model, the most recent population PK/PD 
model will be applied directly to the dataset without estimation (e.g. maxevals=0 in 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
56
NONMEM) and predictions generated against which the model will be validated 
prospectively using appropriate goodness of fit tests as described above (using the 
observed data from the study).
The population PK/PD model consists of an indirect response model parameterised in 
term of baseline blood eosinophil count (KRO), rate of elimination of eosinophils in the 
blood (Kout), concentration resulting in 50% of maximum drug effect (IC50) and 
maximum effect (Imax). Observed baseline blood eosinophil count is included as 
covariates of both predicted baseline and mepolizumab inhibitory response; and disease 
for predicted baseline blood eosinophil count.
If a blood eosinophil count of zero is reported, it will be imputed with half of the lowest 
possible blood eosinophil count, where applicable, prior to log transforming the data 
(Note: this imputation has typically been 0.5 * 0.01 GI/L =  0.005 GI/L for previous 
mepolizumab studies). 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
57
10.9.
Appendix 9: Abbreviations & Trade Marks
10.9.1.
Abbreviations
Abbreviation
Description
ACQ-7
Asthma Control Questionnaire-7
ADA
Anti-drug Antibody
ADaM
Analysis Data Model
AE
Adverse Event
AESI
Adverse Event of Special Interest
ASE
All Subjects Enrolled
ATC
Anatomical Therapeutic Chemical
AUC
Area under concentration time curve
AUC(0-inf)
Area under concentration time curve to infinity
C-ACT
Childhood Asthma Control Test
BLQ
Below Limit of Quantification
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
Cmax
Maximum observed concentration
CPMS
Clinical Pharmacology Modelling & Simulation
CS
Clinical Statistics
CSR
Clinical Study Report
CVb / CVw
Coefficient of Variation (Between) / Coefficient of Variation (Within)
CVT
Cardiac, Vascular and Thromboembolic
DBF
Database Freeze
DBR
Database Release
DOB
Date of Birth
DP
Decimal Place
eCRF
Electronic Case Record Form
ECG
Electrocardiogram
FEV1
Forced expiratory volume in 1 second
FVC
Forced Vital Capacity
GSK
GlaxoSmithKline
GUI
Guidance
ICH
International Conference on Harmonisation
IDSL
Integrated Data Standards Library
IG
Implementation Guide
IgE
Immunoglobulin E
IL-5
Interleukin-5
IM
Intramuscular
IP
Investigational Product
ITT
Intent-To-Treat
IV
Intravenous
kg
Kilograms
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligrams
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
58
Abbreviation
Description
NAb
Neutralising Antibody
NQ
Non-quantifiable
PD
Pharmacodynamic
PDe
Pharmacodynamic (Blood Eosinophils) Population
PDo
Pharmacodynamic (Outcome Assessments) Population
PDMP
Protocol Deviation Management Plan
PK
Pharmacokinetic
Pop-PK
Population Pharmacokinetics
PT
Preferred Term
QC
Quality Control
QT
The QT interval is measured from the beginning of the QRS complex to 
the end of the T wave
QTcF
Frederica’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
RAP
Reporting & Analysis Plan
RTF
Rich Text Format
SAC
Statistical Analysis Complete
SAE
Serious adverse event(s)
SAS
Statistical Analysis Software
SC
Subcutaneous
SD
Standard Deviation
SDTM
Study Data Tabulation Model
SE
Standard Error
SOC
System Organ Class
t1/2
Terminal phase half-life
TFL
Tables, Figures & Listings 
Tmax
Time of occurrence of Cmax
µL
Microlitre
10.9.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
NONE
SAS
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
59
10.10.
Appendix 10: List of Data Displays
10.10.1.
Data Display Numbering and Priority
10.10.1.1. Part A
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.22
Not applicable
Pharmacokinetic Analysis 
2.1 to 2.11
2.1 to 2.15
Efficacy Analysis
2.12 to 2.24
2.16 to 2.23
Safety Analysis 
3.1 to 3.53
3.1 to 3.2
Section
Listings
ICH Listings
1 to 43
Other Listings
44 to 51
Delivery [Priority] [1]
Description
SAC1
Part A Statistical Analysis Complete 1
SAC2
Part A Statistical Analysis Complete 2 
(Further analyses supportive of mepolizumab paediatric extrapolation)
NOTES: 
1.
Indicates priority (i.e. order) in which displays will be generated for the respective reporting effort (Part A/Part B).
10.10.1.2. Part B
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.23 to 1.28
Not applicable
Efficacy Analysis 
2.25 to 2.34
2.24 to 2.25
Safety Analysis
3.54 to 3.106
3.3 to 3.4
Section
Listings
ICH Listings
52 to 89
Delivery [Priority] [1]
Description
SAC 
Part B Statistical Analysis Complete
NOTES: 
1.
Indicates priority (i.e. order) in which displays will be generated for the respective reporting effort (Part A/Part B).
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
60
10.10.2.
Part A
10.10.2.1. Study Population Tables
Study Population Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
Priority
Subject Disposition
1.1.
Safety
SA1
Summary of Subject Populations (Part A)
SAC1
1.2.
ASE 
ES6
Summary of Reasons for Screening or Run-In Failure (Part A)
Include separate pages for Pre-
screening, Screening and Run-in
SAC1
1.3.
ASE
IE2
Summary of Failed Inclusion/Exclusion Criteria for Screening or 
Run-in Failures (Part A)
SAC1
1.4.
Safety
IE2
Summary of Failed Inclusion/Exclusion Criteria for Subjects 
within the Safety Population (Part A)
SAC1
1.5.
Safety
NS1
Summary of Number of Subjects Dosed by Country and Site
(Part A)
SAC1
1.6.
Safety
ES1
Summary of Subject Disposition (Part A)
Should include subject disposition, 
reason for withdrawal.
See Section 10.6.3.
SAC1
Demography
1.7.
Safety
DM1
Summary of Demographic Characteristics (Part A)
SAC1
1.8.
ASE
DM11
Summary of Age Ranges (Part A)
EMA, keep row ≥2-11, ≥12-17 (if 
imputed age is above 12 yrs)
SAC1
1.9.
Safety
DM5 
Summary of Race and Racial Combinations (Part A)
SAC1
1.10.
Safety
DM6 
Summary of Race and Racial Combinations Details (Part A)
SAC1
Medical History 
1.11.
Safety
MH4
Summary of Past Medical Conditions (Part A)
SAC1
 
 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
61
Study Population Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
Priority
1.12.
Safety
MH4
Summary of Current Medical Conditions (Part A)
SAC1
1.13.
Safety
Summary of Cardiovascular Assessments – Family History (Part 
A)
See format of Study Population 
Table 1.14 (200862 ‘final’ reporting 
effort)
SAC1
Baseline Disease Characteristics
1.14.
Safety
SD1
Summary of Asthma Exacerbation History (Part A)
See format of Study Population 
Table 1.17 (200862 ‘final’ reporting 
effort)
SAC1
1.15.
Safety
Summary of Asthma History and Baseline Disease
Characteristics (Part A)
See format of Study Population 
Table 1.16 (200862 ‘final’ reporting 
effort)
To include OCS maintenance use
and the two eosinophil entry criteria 
in isolation and in combination
SAC1
1.16.
Safety
Summary of Screening and Baseline Lung Function Results
(Part A)
See format of Study Population 
Table 1.20 (200862 ‘final’ reporting 
effort)
SAC1
Prior and Concomitant Medications
1.17.
Safety
Summary of Asthma Concomitant Medication Taken Before the 
Run-In by Respiratory Medication Class (Part A)
See format of Study Population 
Table 1.21 (200862 ‘final’ reporting 
effort)
SAC1
1.18.
Safety
Summary of Asthma Concomitant Medication During the Run-In
by Respiratory Medication Class (Part A)
See format of Study Population 
Table 1.22 (200862 ‘final’ reporting 
effort)
SAC1
 
 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
62
Study Population Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
Priority
1.19.
Safety
Summary of Asthma Concomitant Medication Taken During 
Treatment by Respiratory Medication Class (Part A)
See format of Study Population 
Table 1.23 (200862 ‘final’ reporting 
effort)
SAC1
1.20.
Safety
Summary of Asthma Concomitant Medication Taken Post-
Treatment by Respiratory Medication Class (Part A)
See format of Study Population 
Table 1.25 (200862 ‘final’ reporting 
effort)
SAC1
1.21.
Safety
CM1
Summary of non-Asthma Concomitant Medication Taken During 
Treatment (Part A)
SAC1
Protocol Deviations
1.22.
Safety
DV1B
Summary of Important Protocol Deviations (Part A)
SAC1
 
 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
63
10.10.2.2. Pharmacokinetic Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
PK (Primary Endpoint)
2.1.
PK
DBRL1/DBRN1
Summary of Plasma Mepolizumab Pharmacokinetic 
Concentration-Time Data (observed and predicted)
Shell from Respiratory display 
standards
[Only the summary of untransformed 
data will be included]
Summary by mepolizumab dose group 
and mepolizumab overall.
SAC1
2.2.
PK
DBRL4/DBRN4
Summary Statistics of Individual Model Predicted and Plasma 
Mepolizumab Pharmacokinetic Parameters (non-transformed 
and log-transformed)
Include untransformed and log-
transformed summary statistics.  
Include 95% CIs for geometric mean.
Summary by mepolizumab dose group 
and mepolizumab overall
SAC1
2.3.
PK
Description and Evaluation of Key PK Models Tested
Provided by CPMS
SAC1
2.4.
PK
Population PK Parameter Estimates with 95% CI of Final PK 
Model
Provided by CPMS
Summary for mepolizumab overall
SAC1
2.5.
PK
Demographics Summary (only if different from study population)
Provided by CPMS
SAC1
2.6.
PK
Samples Summary
Provided by CPMS
SAC1
PK (Secondary Endpoint)
2.7.
PK
Population estimate and 90% CI of bodyweight-adjusted 
clearance in paediatric subjects together with historic value in 
adults around which a proposed 80-125% interval is applied.
Summarise mepolizumab overall
Provided by CPMS
SAC1
PK (Exploratory Analysis)
2.8.
PK
Goodness of Fit Test Results
Provided by CPMS
SAC2
 
 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
64
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
PKPD (Exploratory Analysis)
2.9.
PKPD
Demographics Summary (only if different from study population)
Provided by CPMS
SAC2
2.10.
PKPD
Samples Summary
Provided by CPMS
SAC2
2.11.
PKPD
Goodness of Fit Test Results
Provided by CPMS
SAC2
 
 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
65
10.10.2.3. Pharmacokinetic Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
PK (Primary Endpoint)
2.1.
PK
Model Predicted Mepolizumab Individual Plasma Concentration 
Time Profiles with Individual Observed Plasma Concentrations 
and Plasma Concentration Population Prediction from Final PK 
Model (Linear and Semi Log Plots) by Treatment
Provided by CPMS
SAC1
2.2.
PK
Model Predicted Mepolizumab Individual Plasma Concentration 
Time Profiles with Individual Observed Plasma Concentrations 
and Plasma Concentration Population Prediction from Final PK 
Model (Semi Log Plots) by Subject
Provided by CPMS
SAC1
2.3.
PK
Model Goodness of Fit Plots
Provided by CPMS
SAC1
2.4.
PK
Observed Plasma Mepolizumab Concentration-Time Profiles by
Anti-drug Antibody Status
Provided by CPMS
SAC1
2.5.
PK
Plasma Mepolizumab Observed Concentration-Time Profiles
(Japanese versus non-Japanese Subjects)
Provided by CPMS
SAC1
2.6.
PK
PK Model Evaluation: Model Predicted (5th, 50th, and 95th 
Percentiles) Mepolizumab Plasma Concentrations with 
Individual Observed Plasma Concentrations For Final PK Model
Provided by CPMS
SAC1
PK (Exploratory Analysis)
2.7.
PK
Plasma Mepolizumab Observed/Predicted Concentration-Time 
Profiles (by Treatment)
Provided by CPMS
SAC2
2.8.
PK
Model Goodness of Fit Plots
Provided by CPMS
SAC2
2.9.
PK
Plasma Mepolizumab Observed/Predicted Concentration-Time 
Profiles (by Subject)
Provided by CPMS
SAC2
2.10.
PK
Visual Predictive Check
Provided by CPMS
SAC2
 
 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
66
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
PKPD (Exploratory Analysis)
2.11.
PKPD
Observed/Predicted Blood Eosinophil Count-Time Profiles (by 
Treatment)
Provided by CPMS
SAC2
2.12.
PKPD
Model Goodness of Fit Plots
Provided by CPMS
SAC2
2.13.
PKPD
Observed/Predicted Blood Eosinophil Count-Time Profiles (by 
Subject)
Provided by CPMS
SAC2
2.14.
PKPD
Visual Predictive Check
Provided by CPMS
SAC2
2.15.
PKPD
Blood Eosinophil Count-Time Profiles (Japanese versus non-
Japanese Subjects)
Provided by CPMS
SAC2
 
 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
67
10.10.2.4. Efficacy Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Blood Eosinophil Count (Primary Endpoint)
2.12.
PDe
Summary of Blood Eosinophil Count (Part A)
Log transformed with geometric 
mean, include ratio to baseline
See format of Efficacy Table 2.73 
(200862 ‘final’ reporting effort)
To also include 95% CIs by visit
SAC1
Asthma Control Questionnaire
2.13.
PDo
Summary of ACQ-7 Score (Part A)
See format of Efficacy Table 2.34 
(200862 ‘final’ reporting effort)
To also include 95% CIs by visit
SAC1
2.14.
PDo
Summary of 0.5 Point or More Reduction in ACQ-7 Score from 
Baseline (Part A)
See format of Efficacy Table 2.41 
(200862 ‘final’ reporting effort).
Note: Logistic regression to not be 
included and Odds Ratio to not be 
shown
SAC1
2.15.
PDo
Summary of ACQ-5 Score (Part A)
See format of Efficacy Table 2.34 
(200862 ‘final’ reporting effort)
To also include 95% CIs by visit
SAC1
2.16.
PDo
Summary of 0.5 Point or More Reduction in ACQ-5 Score from 
Baseline (Part A)
See format of Efficacy Table 2.41 
(200862 ‘final’ reporting effort).
Note: Logistic regression to not be 
included and Odds Ratio to not be 
shown
SAC1
 
 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
68
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Childhood Asthma Control Test (C-ACT)
2.17.
PDo
Summary of C-ACT Score (Part A)
See format of Efficacy Table 2.34 
(200862 ‘final’ reporting effort).
To also include 95% CIs by visit
SAC1
FEV1
2.18.
PDo
Summary of FEV1 (Part A)
See format of Efficacy Table 2.27 
(200862 ‘final’ reporting effort).
To also include 95% CIs by visit
SAC1
Asthma Exacerbations
2.19.
PDo
Overview of Asthma Exacerbations (Part A)
See format of Efficacy Table 2.61 
(200862 ‘final’ reporting effort).
SAC1
2.20.
PDo
Summary of Frequency of Exacerbations (Week 0 –Week 12)
(Part A)
See format of Efficacy Table 2.62 
(200862 ‘final’ reporting effort)
SAC1
2.21.
PDo
Summary of Frequency of Exacerbations (Week 0 –Week 20)
(Part A)
See format of Efficacy Table 2.62 
(200862 ‘final’ reporting effort)
SAC1
2.22.
PDo
Summary of Time to First Asthma Exacerbation (Part A)
See format of Efficacy Table 2.68 
(200862 ‘final’ reporting effort)
SAC1
IgE
2.23.
PDo
Summary of IgE (Part A)
Log transformed with geometric 
mean, include ratio to baseline 
See format of Efficacy Table 6.71 
(MEA115588 ‘final’ reporting effort)
SAC1
 
 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
69
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
IL-5
2.24.
PDo
Summary of IL-5 (Part A)
Log transformed with geometric 
mean, include ratio to baseline 
See format of Efficacy Table 6.71 
(MEA115588 ‘final’ reporting effort)
SAC1
 
 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
70
10.10.2.5. Efficacy Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Blood Eosinophil Count (Primary Endpoint)
2.16.
PDe
Figure of Absolute Blood Eosinophil Count (Mean Change from 
Baseline at Each Visit by Treatment Group) (Part A)
See format of Efficacy Figure 6.18 
(MEA115588 ‘final’ reporting effort)
SAC1
2.17.
PDe
Figure of Ratio of Blood Eosinophil Count to Baseline (Mean 
Change from Baseline at Each Visit by Treatment Group) (Part 
A)
See format of Efficacy Figure 6.18 
(MEA115588 ‘final’ reporting effort)
SAC1
Asthma Control Questionnaire
2.18.
PDo
Figure of Change from Baseline in Overall ACQ-7 score (Mean 
Change from Baseline at Each Visit by Treatment Group) (Part 
A)
See format of Efficacy Figure 2.11 
(200862 ‘final’ reporting effort)
SAC1
2.19.
PDo
Figure of Change from Baseline in Overall ACQ-5 score (Mean 
Change from Baseline at Each Visit by Treatment Group) (Part 
A)
See format of Efficacy Figure 2.11 
(200862 ‘final’ reporting effort)
SAC1
Childhood Asthma Control Test (C-ACT)
2.20.
PDo
Figure of Change from Baseline in Overall C-ACT score (Mean 
Change from Baseline at Each Visit by Treatment Group) (Part 
A)
See format of Efficacy Figure 2.11 
(200862 ‘final’ reporting effort)
SAC1
FEV1
2.21.
PDo
Figure of Change from Baseline in Pre-Bronchodilator FEV1
(mL) (Mean Change from Baseline at Each Visit by Treatment 
Group) (Part A)
See format of Efficacy Figure 2.09 
(200862 ‘final’ reporting effort)
SAC1
Exacerbations
2.22.
PDo
Kaplan-Meier Cumulative Incidence Curve for Time to First 
Exacerbation (Part A)
See format of Efficacy Figure 2.15 
(200862 ‘final’ reporting effort)
SAC1
 
 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
71
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
IL-5
2.23.
PDo
Figure of Ratio to Baseline in IL-5 Data (Mean Change from 
Baseline at Each Visit by Treatment Group) (Part A)
See format of Efficacy Figure 6.18 
(MEA115588 ‘final’ reporting effort)
SAC1
 
 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
72
10.10.2.6. Safety Tables
Safety Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Exposure
3.1.
Safety
Summary of Number of Treatments Administered and Time On-
Treatment (Part A)
See format of Study Population 
Table 1.28 (200862 ‘final’ reporting 
effort)
SAC1
AEs
3.2.
Safety
Overview of All Adverse Events (Part A)
See format of Safety Table 3.01 
(200862 ‘final’ reporting effort)
SAC1
3.3.
Safety
AE1
Summary of All On-Treatment Adverse Events by System Organ 
Class (Part A)
SAC1
3.4.
Safety
AE5
Summary of All On-Treatment Adverse Events by System Organ 
Class and Maximum Intensity (Part A)
Add a Total column across all severities
SAC1
3.5.
Safety
AE1
Summary of All Post-Treatment Adverse Events by System 
Organ Class (Part A)
SAC1
3.6.
Safety
AE5
Summary of All Post-Treatment Adverse Events by System 
Organ Class and Maximum Intensity (Part A)
Add a Total column across all severities
SAC1
3.7.
Safety
AE3
Summary of On-Treatment Adverse Events by Overall 
Frequency (Part A)
SAC1
3.8.
Safety
AE1
Summary of All On-Treatment Drug-Related Adverse Events by 
System Organ Class (Part A)
SAC1
3.9.
Safety
AE5
Summary of All On-Treatment Drug-Related Adverse Events by 
System Organ Class and Maximum Intensity (Part A)
Add a Total column across all severities
SAC1
3.10.
Safety
AE1
Summary of On-Treatment Adverse Events by Highest Anti Drug 
Antibody Result At Any Time Post Baseline (Part A)
Add in row with n in each ADA result 
category
SAC1
 
 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
73
Safety Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.11.
Safety
AE1
Summary of Post-Treatment Adverse Events by Highest Anti 
Drug Antibody Result At Any Time Post Baseline (Part A)
Add in row with n in each ADA result 
category
SAC1
3.12.
Safety
AE15
Summary of Number of Subjects and Occurrences of Common 
On-Treatment Non-Serious Adverse Events by System Organ 
Class (Part A)
≥3% (prior to rounding to nearest 
percent)
XML file to be produced using standard 
HARP macro
SAC1
Serious and Other Significant AEs
3.13.
Safety
AE1
Summary of Fatal Serious Adverse Events by System Organ 
Class (Part A)
SAC1
3.14.
Safety
AE1
Summary of Non-Fatal Serious On-Treatment Adverse Events
by System Organ Class (Part A)
SAC1
3.15.
Safety
AE1
Summary of Non-Fatal Serious Post-Treatment Adverse Events
by System Organ Class (Part A)
SAC1
3.16.
Safety
AE1
Summary of On-Treatment Serious Adverse Events by System 
Organ Class (Part A)
SAC1
3.17.
Safety
AE1
Summary of Post-Treatment Serious Adverse Events by System 
Organ Class (Part A)
SAC1
3.18.
Safety
AE1
Summary of Drug-Related Serious Adverse Events by System 
Organ Class (Part A)
SAC1
3.19.
Safety
AE1
Summary of Drug-Related Serious Adverse Events by System 
Organ Class and Maximum Severity (Part A)
Add a Total column across all severities
SAC1
3.20.
Safety
AE3
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study by 
Overall Frequency (Part A)
SAC1
 
 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
74
Safety Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.21.
Safety
AE16
Summary of Number of Subjects and Occurrences of Serious 
Adverse Events by System Organ Class and Preferred Term
(Part A)
SAC1
Adverse Events of Special Interest
3.22.
Safety
AE3
Summary of Systemic(non-allergic or allergic/hypersensitivity) 
Reactions (On-Treatment) (Part A)
Footnote 'Events defined by the 
investigator as being a Systemic 
Reaction’
SAC1
3.23.
Safety
Summary Profile of Systemic (non-allergic or 
allergic/hypersensitivity) Reactions (On-Treatment) (Part A)
See format of Safety Table 3.23 
(200862 ‘final’ reporting effort)
Footnote 'Events defined by the 
investigator as being a Systemic 
Reaction’
SAC1
3.24.
Safety
Summary Profile of Systemic Allergic Reactions (On-Treatment)
(Part A)
See format of Safety Table 3.24 
(200862 ‘final’ reporting effort)
Footnote 'Events defined by the 
investigator as being a Systemic 
Reaction’
SAC1
3.25.
Safety
Summary Profile of Systemic Non-Allergic Reactions (On-
Treatment) (Part A)
See format of Safety Table 3.25 
(200862 ‘final’ reporting effort)
Footnote 'Events defined by the 
investigator as being a Systemic 
Reaction’
SAC1
3.26.
Safety
AE3
Summary of Local Injection Site Reactions (On-Treatment) (Part 
A)
Footnote 'Events defined by the 
investigator as being a Local Injection 
Site Reaction’
SAC1
 
 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
75
Safety Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.27.
Safety
Summary of Local Injection Site Reactions by Relation to IP 
(On-Treatment) (Part A)
See format of Safety Table 3.28 
(200862 ‘final’ reporting effort)
Footnote 'Events defined by the 
investigator as being a Local Injection 
Site Reaction’
SAC1
3.28.
Safety
Summary Profile of Local Injection Site Reactions (On-
Treatment) (Part A)
See format of Safety Table 3.29 
(200862 ‘final’ reporting effort)
Footnote 'Events defined by the 
investigator as being a Local Injection 
Site Reaction’
SAC1
3.29.
Safety
AE1
Summary of AEs meeting Anaphylaxis Criteria (On-Treatment)
(Part A)
Present Anaphylactic Criterion 1,2 
and 3 rather than SOC as shown in 
AE1
Footnote 'Events identified by the 
investigator as meeting the criteria for 
anaphylaxis’
SAC1
3.30.
Safety
Summary Profile of AEs meeting Anaphylaxis Criteria (On-
Treatment) (Part A)
See format of Safety Table 3.31 
(200862 ‘final’ reporting effort)
Footnote 'Events identified by the 
investigator as meeting the criteria for 
anaphylaxis’
SAC1
3.31.
Safety
AE1
Summary of Serious Cardiac, Vascular and Thromboembolic 
Adverse Events (On-Treatment) (Part A)
Footnote ‘Serious events in the Cardiac 
Disorders and Vascular Disorders 
MedDRA System Organ Classes, 
thromboembolic events identified via 
SMQs and sub-SMQs’
SAC1
 
 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
76
Safety Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.32.
Safety
Summary Profile of Serious Cardiac, Vascular and 
Thromboembolic Adverse Events (On-Treatment) (Part A)
See format of Safety Table 3.33 
(200862 ‘final’ reporting effort)
Footnote ‘Serious events in the Cardiac 
Disorders and Vascular Disorders 
MedDRA System Organ Classes, 
thromboembolic events identified via 
SMQs and sub-SMQs’
SAC1
3.33.
Safety
AE3
Summary of Serious Ischemic AEs (On-Treatment) (Part A)
Footnote ‘Serious Ischemic events, a 
subset of serious cardiac, vascular and  
thromboembolic events,  identified via 
SMQs and sub-SMQs’
SAC1
3.34.
Safety
Summary Profile of Serious Ischemic AEs (On-Treatment) (Part 
A)
See format of Safety Table 3.35 
(200862 ‘final’ reporting effort)
Footnote ‘Serious Ischemic events, a 
subset of serious cardiac, vascular and  
thromboembolic events,  identified via 
SMQs and sub-SMQs’
SAC1
3.35.
Safety
AE3
Summary of Malignancies (On-Treatment) (Part A)
Footnote ‘Events identified from sub-
SMQs under the Malignancy SMQ’
SAC1
3.36.
Safety
Summary Profile of Malignancies (On-Treatment) (Part A)
See format of Safety Table 3.37 
(200862 ‘final’ reporting effort)
Footnote ‘Events identified from sub-
SMQs under the Malignancy SMQ’
SAC1
3.37.
Safety
AE3
Summary of Opportunistic Infections (On-Treatment) (Part A)
Footnote 'Events matching terms based 
on a published list considered as 
opportunistic infections in the setting of 
biologic therapy [Winthrop, 2015]’
SAC1
 
 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
77
Safety Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.38.
Safety
Summary Profile of Opportunistic Infections (On-Treatment)
(Part A)
See format of Safety Table 3.39 
(200862 ‘final’ reporting effort)
Footnote 'Events matching terms based 
on a published list considered as 
opportunistic infections in the setting of 
biologic therapy [Winthrop, 2015]’
SAC1
3.39.
Safety
Summary of Serious AEs and AEs of Special Interest (Part A)
See format of Safety Table 3.40 
(200862 ‘final’ reporting effort)
Do not include Relative Risk or % 
Risk Difference columns
SAC1
Cardiovascular Events
3.40.
Safety
Summary of All Cardiovascular Events Reported by the 
Investigator (Part A)
See format of Safety Table 3.11 
(200862 ‘final’ reporting effort)
SAC1
Immunogenicity
3.41.
Safety
Summary of ADA Assay Results (Part A)
See format of Safety Table 3.41 
(200862 ‘final’ reporting effort)
SAC1
3.42.
Safety
Summary of NAb Assay Results (Part A)
See format of Safety Table 3.42 
(200862 ‘final’ reporting effort)
SAC1
3.43.
Safety
Summary of Treatment Emergent ADA Assay Results (Part A)  
See format of Safety Table 3.41 
(200862 ‘final’ reporting effort)
SAC1
Laboratory Data
3.44.
Safety
LB1
Summary of Change From Baseline in Chemistry Data (Part A)  
Include Baseline values
SAC1
3.45.
Safety
LB3
Summary of Chemistry Results (Change from Baseline Relative 
to the Normal Range) (Part A)  
SAC1
3.46.
Safety
LB1
Summary of Change From Baseline in Haematology Data (Part 
A)  
Include Baseline values
SAC1
 
 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
78
Safety Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.47.
Safety
LB3
Summary of Haematology Results (Change from Baseline 
Relative to the Normal Range) (Part A)  
SAC1
Hepatobiliary (Liver)
3.48.
Safety
LIVER10
Summary of Subjects Meeting Emergent Hepatobiliary 
Laboratory Abnormality Criteria (Part A)
SAC1
Electrocardiogram (ECG)
3.49.
Safety
EG1
Summary of  ECG Findings (Part A)
SAC1
3.50.
Safety
EG2
Summary of Change from Baseline ECG Values by Visit (Part A)
Include Baseline values
SAC1
3.51.
Safety
Summary of Actual and Change From Baseline QTc(F) Values 
by Category (msec) (Part A)
See format of Safety Table 7.50 
(MEA115588 ‘final’ reporting effort)
See Section 10.6.4 for details
Note: For Any Time Post-Baseline, the 
highest post-baseline QTc value and 
the change from baseline for this 
highest post-baseline QTc value is  
categorised
SAC1
3.52.
Safety
Summary of Actual and Change From Baseline QTc(B) Values 
by Category (msec) (Part A)
See format of Safety Table 7.50 
(MEA115588 ‘final’ reporting effort)
See Section 10.6.4 for details
Note: For Any Time Post-Baseline, the 
highest post-baseline QTc value and 
the change from baseline for this 
highest post-baseline QTc value is  
categorised
SAC1
Vital Signs
3.53.
Safety
VS1
Summary of Change from Baseline in Vital Signs (Part A)
Include Baseline values
SAC1
 
 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
79
10.10.2.7. Safety Figures
Safety : Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Laboratory
3.1.
Safety
LIVER9
Scatter Plot of Maximum vs. Baseline for ALT (Part A)
SAC1
3.2.
Safety
LIVER9
Scatter Plot of Maximum ALT vs. Maximum Total Bilirubin (Part 
A)
SAC1
 
 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
80
10.10.2.8. ICH Listings
ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.
ASE
ES7
Listing of Reasons for Screening or Run-In Failure (Part A)
SAC1
2.
Safety
IE3
Listing of Subjects within Inclusion/Exclusion Criteria Deviations
(Part A)
SAC1
3.
Safety
ES2
Listing of Reasons for Premature Study Withdrawal (Part A)
SAC1
Demography
4.
Safety
DM2
Listing of Demographic Characteristics (Part A)
SAC1
5.
Safety
DM9
Listing of Race (Part A)
SAC1
Concomitant Medication
6.
Safety
CM6
Relationship Between ATC Level 1, Ingredient and Verbatim 
Text (Part A)
Include all asthma and non-asthma 
concomitant medications (including 
those given for exacerbation and 
rescue use) 
SAC1
Protocol Deviations
7.
Safety
DV2
Listing of Important Protocol Deviations (Part A)
SAC1
Blood Eosinophils
8.
PDe
Listing of Blood Eosinophil Data (10^9/L) (Part A)
See format of Efficacy Listing 18 
(200862 ‘final’ reporting effort)
SAC1
 
 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
81
ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Exacerbations
9.
PDo
Listing of Exacerbations (Part A)
See format of Efficacy Listing 17 
(200862 ‘final’ reporting effort)
Include Pre, on-treatment and Post-
treatment events within Part A (See 
Section 10.4.2)
SAC1
IL-5
10.
PDo
Listing of IL-5 Data (Part A)
See format of Efficacy Listing 18 
(200862 ‘final’ reporting effort)
SAC1
Exposure
11.
Safety
EX3
Listing of Study Treatment Data (Part A)
SAC1
Adverse Events
12.
Safety
AE8
Listing of All Adverse Events (Part A)
SAC1
13.
Safety
AE7
Listings of Subject Numbers for Individual Adverse Events (Part 
A)
SAC1
14.
Safety
AE2
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text (Part A)
SAC1
15.
Safety
AE8
Listing of all Fatal Adverse Events (Part A)
SAC1
16.
Safety
AE8
Listing of Non-Fatal Serious Adverse Events (Part A)
SAC1
17.
Safety
AE14
Listing of Reasons for Considering as a Serious Adverse Event
(Part A)
SAC1
18.
Safety
AE8
Listing of Adverse Events Leading to Permanent Discontinuation 
of Study Treatment or Withdrawal from Study by Overall 
Frequency (Part A)
SAC1
 
 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
82
ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
19.
Safety
Listing of Adverse Events Defined by the Investigator as a 
Systemic (non-allergic or allergic/hypersensitivity) Injection 
Reaction (Part A)
See format of Safety Listing 26 
(200862 ‘final’ reporting effort)
SAC1
20.
Safety
Listing of Adverse Events Defined by the Investigator as a Local 
Injection Site Reaction (Part A)
See format of Safety Listing 27 
(200862 ‘final’ reporting effort)
SAC1
21.
Safety
Listing of AEs meeting Anaphylaxis Criteria (Part A)
See format of Safety Listing 28 
(200862 ‘final’ reporting effort)
SAC1
22.
Safety
Listing of Serious Cardiac, Vascular and Thromboembolic (CVT) 
AEs (Part A)
See format of Safety Listing 29 
(200862 ‘final’ reporting effort)
SAC1
23.
Safety
Listing of Serious Ischemic AEs (Part A)
See format of Safety Listing 30 
(200862 ‘final’ reporting effort)
SAC1
24.
Safety
Listing of Malignancies (Part A)
See format of Safety Listing 31 
(200862 ‘final’ reporting effort)
SAC1
25.
Safety
Listing of Opportunistic Infections (Part A)
See format of Safety Listing 32 
(200862 ‘final’ reporting effort)
SAC1
Cardiovascular Events
26.
Safety
Listing of Investigator Reported Cardiovascular Events: 
Arrhythmias (Part A)
See format of Safety Listing 33 
(200862 ‘final’ reporting effort)
SAC1
27.
Safety
Listing of Investigator Reported Cardiovascular Events: 
Congestive Heart Failure (Part A)
See format of Safety Listing 34 
(200862 ‘final’ reporting effort)
SAC1
28.
Safety
Listing of Investigator Reported Cardiovascular Events: 
Cerebrovascular Events/Stroke (Part A)
See format of Safety Listing 35 
(200862 ‘final’ reporting effort)
SAC1
29.
Safety
Listing of Investigator Reported Cardiovascular Events: Deep 
venous Thrombosis/ Pulmonary Embolism (Part A)
See format of Safety Listing 36 
(200862 ‘final’ reporting effort)
SAC1
 
 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
83
ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
30.
Safety
Listing of Investigator Reported Cardiovascular Events: 
Myocardial Infarction/Unstable Angina (Part A)
See format of Safety Listing 37 
(200862 ‘final’ reporting effort)
SAC1
31.
Safety
Listing of Investigator Reported Cardiovascular Events: 
Peripheral Arterial Thrombosis Embolism (Part A)
See format of Safety Listing 38 
(200862 ‘final’ reporting effort)
SAC1
32.
Safety
Listing of Investigator Reported Cardiovascular Events: 
Pulmonary Hypertension (Part A)
See format of Safety Listing 39 
(200862 ‘final’ reporting effort)
SAC1
33.
Safety
Listing of Investigator Reported Cardiovascular Events: 
Revascularisation (Part A)
See format of Safety Listing 40 
(200862 ‘final’ reporting effort)
SAC1
34.
Safety
Listing of Investigator Reported Cardiovascular Events: 
Valvulopathy (Part A)
See format of Safety Listing 41 
(200862 ‘final’ reporting effort)
SAC1
35.
Safety
Listing of Investigator Reported Cardiovascular Events: All 
Cause Deaths (Part A)
See format of Safety Listing 42 
(200862 ‘final’ reporting effort)
SAC1
Immunogenicity
36.
Safety
Listing of Immunogenicity Results (Part A)
See format of Safety Listing 43 
(200862 ‘final’ reporting effort)
SAC1
Laboratory Data
37.
Safety
Listing of Urinalysis (Part A)
See format of Safety Listing 44 
(200862 ‘final’ reporting effort)
SAC1
Liver Event
38.
Safety
LIVER5
Listing of Liver Monitoring/Stopping Event Reporting (Part A)
SAC1
39.
Safety
LB5
Chemistry Results for  Subjects Meeting Liver 
Monitoring/Stopping Event Criteria (Part A)
Subset for subjects in above Liver 
Monitoring/Stopping Event listing
SAC1
40.
Safety
MH2
Listing of Medical Conditions for Subjects with Liver Stopping 
Events (Part A)
SAC1
 
 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
84
ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
41.
Safety
SU2
Listing of Substance Use for Subjects with Liver Stopping 
Events (Part A)
SAC1
42.
Safety
LIVER13
Listing of Subjects Meeting Hepatobiliary Laboratory Criteria 
Post-Baseline (Part A)
SAC1
Electrocardiogram (ECG)
43.
Safety
EG6
Listing of ECG Findings for Abnormal Interpretations (Part A)
See format of Safety Listing 7.32 
(MEA115588 ‘final’ reporting effort)
SAC1
 
 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
85
10.10.2.9. Non-ICH Listings
Non-ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
PK
44.
PK
Listing of Mepolizumab Plasma Pharmacokinetic Concentration 
Data (Observed and Predicted)
See format of Safety Listing 10.01 
(MEA115588 ‘final’ reporting effort)
SAC1
45.
PK
Listing of Individual Model-Predicted and Derived Plasma 
Mepolizumab Pharmacokinetic Parameters
See format of Safety Listing 10.02 
(MEA115588 ‘final’ reporting effort)
SAC1
46.
PK
Listing of Data and Subjects Excluded from PK Analysis
Provided by CPMS
SAC1
47.
PK
N/A
Final PK Model Listings (Primary Endpoint)
Provided by CPMS
SAC1
48.
PK
N/A
Output from the Validation of the Final PK Model
Provided by CPMS
SAC1
PK (Exploratory Analysis)
49.
PK
N/A
Final PK Model Listings (Exploratory Endpoint)
Provided by CPMS
SAC2
PKPD (Exploratory Analysis)
50.
PKPD
Listing of Data and Subjects Excluded from PKPD Analysis (only 
if different from PK analysis)
Provided by CPMS
SAC2
51.
PKPD
N/A
Final PKPD Model Listings (Exploratory Endpoint)
Provided by CPMS
SAC2
 
 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
86
10.10.3.
Part B
10.10.3.1. Study Population Tables
Study Population Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
Priority
Subject Disposition
1.23.
Safety
SA1
Summary of Subject Populations (Part B)
SAC
1.24.
Safety
ES1
Summary of Subject Disposition (Part B)
Should include subject disposition, 
reason for withdrawal.
SAC
Prior and Concomitant Medications
1.25.
Safety
Summary of Asthma Concomitant Medication Taken During 
Treatment by Respiratory Medication Class (Part B)
See format of Study Population 
Table 1.23 (200862 ‘final’ reporting 
effort)
SAC
1.26.
Safety
Summary of Asthma Concomitant Medication Taken Post-
Treatment by Respiratory Medication Class (Part B)
See format of Study Population 
Table 1.25 (200862 ‘final’ reporting 
effort)
SAC
1.27.
Safety
CM1
Summary of non-Asthma Concomitant Medication Taken During 
Treatment (Part B)
SAC
Protocol Deviations
1.28.
Safety
DV1B
Summary of Important Protocol Deviations (Part B)
SAC
 
 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
87
10.10.3.2. Efficacy Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Blood Eosinophil Count
2.25.
PDe
Summary of Blood Eosinophil Count (Part B)
Log transformed with geometric 
mean, include ratio to baseline 
See format of Efficacy Table 2.73 
(200862 ‘final’ reporting effort)
To also include 95% CIs by visit
SAC
Asthma Control Questionnaire
2.26.
PDo
Summary of ACQ-7 Score (Part B)
See format of Efficacy Table 2.34 
(200862 ‘final’ reporting effort)
To also include 95% CIs by visit
SAC
2.27.
PDo
Summary of 0.5 Point or More Reduction in ACQ-7 Score from 
Baseline (Part B)
See format of Efficacy Table 2.41 
(200862 ‘final’ reporting effort).
Note: Logistic regression to not be 
included and Odds Ratio to not be 
shown
SAC
2.28.
PDo
Summary of ACQ-5 Score (Part B)
See format of Efficacy Table 2.34 
(200862 ‘final’ reporting effort)
To also include 95% CIs by visit
SAC
2.29.
PDo
Summary of 0.5 Point or More Reduction in ACQ-5 Score from 
Baseline (Part B)
See format of Efficacy Table 2.41 
(200862 ‘final’ reporting effort).
Note: Logistic regression to not be 
included and Odds Ratio to not be 
shown
SAC
 
 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
88
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Childhood Asthma Control Test (C-ACT)
2.30.
PDo
Summary of C-ACT Score (Part B)
See format of Efficacy Table 2.34 
(200862 ‘final’ reporting effort)
To also include 95% CIs by visit
SAC
FEV1
2.31.
PDo
Summary of FEV1 (Part B)
See format of Efficacy Table 2.27 
(200862 ‘final’ reporting effort)
To also include 95% CIs by visit
SAC
Asthma Exacerbations
2.32.
PDo
Overview of Asthma Exacerbations (Part B)
See format of Efficacy Table 2.61 
(200862 ‘final’ reporting effort).
SAC
2.33.
PDo
Summary of Frequency of Exacerbations (Week 20 –Week 72)
(Part B)
See format of Efficacy Table 2.62 
(200862 ‘final’ reporting effort)
SAC
2.34.
PDo
Summary of Time to First Asthma Exacerbation (Part B)
See format of Efficacy Table 2.68 
(200862 ‘final’ reporting effort)
SAC
 
 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
89
10.10.3.3. Efficacy Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Blood Eosinophil Count
2.24.
PDe
Figure of Absolute Blood Eosinophil Count (Mean Change from 
Baseline at Each Visit by Treatment Group) (Part B)
See format of Efficacy Figure 6.18 
(MEA115588 ‘final’ reporting effort)
SAC
2.25.
PDe
Figure of Ratio of Blood Eosinophil Count to Baseline (Mean 
Change from Baseline at Each Visit by Treatment Group) (Part 
B)
See format of Efficacy Figure 6.18 
(MEA115588 ‘final’ reporting effort)
SAC
 
 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
90
10.10.3.4. Safety Tables
Safety Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Exposure
3.54.
Safety
Summary of Number of Treatments Administered and Time On-
Treatment (Part B)
See format of Study Population 
Table 1.28 (200862 ‘final’ reporting 
effort)
SAC
AEs
3.55.
Safety
Overview of All Adverse Events (Part B)
See format of Safety Table 3.01 
(200862 ‘final’ reporting effort)
SAC
3.56.
Safety
AE1
Summary of All On-Treatment Adverse Events by System Organ 
Class (Part B)
SAC
3.57.
Safety
AE5
Summary of All On-Treatment Adverse Events by System Organ 
Class and Maximum Intensity (Part B)
Add a Total column across all severities
SAC
3.58.
Safety
AE1
Summary of All Post-Treatment Adverse Events by System 
Organ Class (Part B) 
SAC
3.59.
Safety
AE5
Summary of All Post-Treatment Adverse Events by System 
Organ Class and Maximum Intensity (Part B)
Add a Total column across all severities
SAC
3.60.
Safety
AE3
Summary of On-Treatment Adverse Events by Overall 
Frequency (Part B)
SAC
3.61.
Safety
AE1
Summary of All On-Treatment Drug-Related Adverse Events by 
System Organ Class (Part B)
SAC
3.62.
Safety
AE5
Summary of All On-Treatment Drug-Related Adverse Events by 
System Organ Class and Maximum Intensity (Part B)
Add a Total column across all severities
SAC
3.63.
Safety
AE1
Summary of On-Treatment Adverse Events by Highest Anti Drug 
Antibody Result At Any Time Post Baseline (Part B)
Add in row with n in each ADA result 
category
SAC
 
 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
91
Safety Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.64.
Safety
AE1
Summary of Post-Treatment Adverse Events by Highest Anti 
Drug Antibody Result At Any Time Post Baseline (Part B)
Add in row with n in each ADA result 
category
SAC
3.65.
Safety
AE15
Summary of Number of Subjects and Occurrences of Common 
On-Treatment Non-Serious Adverse Events by System Organ 
Class (Part B)
≥3% (prior to rounding to nearest 
percent)
XML file to be produced using standard 
HARP macro
SAC
Serious and Other Significant AEs
3.66.
Safety
AE1
Summary of Fatal Serious Adverse Events by System Organ 
Class (Part B)
SAC
3.67.
Safety
AE1
Summary of Non-Fatal Serious On-Treatment Adverse Events
by System Organ Class (Part B)
SAC
3.68.
Safety
AE1
Summary of Non-Fatal Serious Post-Treatment Adverse Events
by System Organ Class (Part B)
SAC
3.69.
Safety
AE1
Summary of On-Treatment Serious Adverse Events by System 
Organ Class (Part B)
SAC
3.70.
Safety
AE1
Summary of Post-Treatment Serious Adverse Events by System 
Organ Class (Part B)
SAC
3.71.
Safety
AE1
Summary of Drug-Related Serious Adverse Events by System 
Organ Class (Part B)
SAC
3.72.
Safety
AE1
Summary of Drug-Related Serious Adverse Events by System 
Organ Class and Maximum Severity (Part B)
Add a Total column across all severities
SAC
3.73.
Safety
AE3
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study by 
Overall Frequency (Part B)
SAC
 
 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
92
Safety Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.74.
Safety
AE16
Summary of Number of Subjects and Occurrences of Serious 
Adverse Events by System Organ Class and Preferred Term
(Part B)
SAC
Adverse Events of Special Interest
3.75.
Safety
AE3
Summary of Systemic(non-allergic or allergic/hypersensitivity) 
Reactions (On-Treatment) (Part B)
Footnote 'Events defined by the 
investigator as being a Systemic 
Reaction’
SAC
3.76.
Safety
Summary Profile of Systemic (non-allergic or 
allergic/hypersensitivity) Reactions (On-Treatment) (Part B)
See format of Safety Table 3.23 
(200862 ‘final’ reporting effort)
Footnote 'Events defined by the 
investigator as being a Systemic 
Reaction’
SAC
3.77.
Safety
Summary Profile of Systemic Allergic Reactions (On-Treatment)
(Part B)
See format of Safety Table 3.24 
(200862 ‘final’ reporting effort)
Footnote 'Events defined by the 
investigator as being a Systemic 
Reaction’
SAC
3.78.
Safety
Summary Profile of Systemic Non-Allergic Reactions (On-
Treatment) (Part B)
See format of Safety Table 3.25 
(200862 ‘final’ reporting effort)
Footnote 'Events defined by the 
investigator as being a Systemic 
Reaction’
SAC
3.79.
Safety
AE3
Summary of Local Injection Site Reactions (On-Treatment) (Part 
B)
Footnote 'Events defined by the 
investigator as being a Local Injection 
Site Reaction’
SAC
 
 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
93
Safety Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.80.
Safety
Summary of Local Injection Site Reactions by Relation to IP 
(On-Treatment) (Part B) 
See format of Safety Table 3.28 
(200862 ‘final’ reporting effort)
Footnote 'Events defined by the 
investigator as being a Local Injection 
Site Reaction’
SAC
3.81.
Safety
Summary Profile of Local Injection Site Reactions (On-
Treatment) (Part B) 
See format of Safety Table 3.29 
(200862 ‘final’ reporting effort)
Footnote 'Events defined by the 
investigator as being a Local Injection 
Site Reaction’
SAC
3.82.
Safety
AE1
Summary of AEs meeting Anaphylaxis Criteria (On-Treatment) 
(Part B) 
Present Anaphylactic Criterion 1,2 
and 3 rather than SOC as shown in 
AE1
Footnote 'Events identified by the 
investigator as meeting the criteria for 
anaphylaxis’
SAC
3.83.
Safety
Summary Profile of AEs meeting Anaphylaxis Criteria (On-
Treatment) (Part B) 
See format of Safety Table 3.31 
(200862 ‘final’ reporting effort)
Footnote 'Events identified by the 
investigator as meeting the criteria for 
anaphylaxis’
SAC
3.84.
Safety
AE1
Summary of Serious Cardiac, Vascular and Thromboembolic 
Adverse Events (On-Treatment) (Part B) 
Footnote ‘Serious events in the Cardiac 
Disorders and Vascular Disorders 
MedDRA System Organ Classes, 
thromboembolic events identified via 
SMQs and sub-SMQs’
SAC
 
 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
94
Safety Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.85.
Safety
Summary Profile of Serious Cardiac, Vascular and 
Thromboembolic Adverse Events (On-Treatment) (Part B) 
See format of Safety Table 3.33 
(200862 ‘final’ reporting effort)
Footnote ‘Serious events in the Cardiac 
Disorders and Vascular Disorders 
MedDRA System Organ Classes, 
thromboembolic events identified via 
SMQs and sub-SMQs’
SAC
3.86.
Safety
AE3
Summary of Serious Ischemic AEs (On-Treatment) (Part B) 
Footnote ‘Serious Ischemic events, a 
subset of serious cardiac, vascular and  
thromboembolic events,  identified via 
SMQs and sub-SMQs’
SAC
3.87.
Safety
Summary Profile of Serious Ischemic AEs (On-Treatment) (Part 
B) 
See format of Safety Table 3.35 
(200862 ‘final’ reporting effort)
Footnote ‘Serious Ischemic events, a 
subset of serious cardiac, vascular and  
thromboembolic events,  identified via 
SMQs and sub-SMQs’
SAC
3.88.
Safety
AE3
Summary of Malignancies (On-Treatment) (Part B) 
Footnote ‘Events identified from sub-
SMQs under the Malignancy SMQ’
SAC
3.89.
Safety
Summary Profile of Malignancies (On-Treatment) (Part B) 
See format of Safety Table 3.37 
(200862 ‘final’ reporting effort)
Footnote ‘Events identified from sub-
SMQs under the Malignancy SMQ’
SAC
3.90.
Safety
AE3
Summary of Opportunistic Infections (On-Treatment) (Part B)
Footnote 'Events matching terms based 
on a published list considered as 
opportunistic infections in the setting of 
biologic therapy [Winthrop, 2015]’
SAC
 
 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
95
Safety Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.91.
Safety
Summary Profile of Opportunistic Infections (On-Treatment) 
(Part B) 
See format of Safety Table 3.39 
(200862 ‘final’ reporting effort)
Footnote 'Events matching terms based 
on a published list considered as 
opportunistic infections in the setting of 
biologic therapy [Winthrop, 2015]’
SAC
3.92.
Safety
Summary of Serious AEs and AEs of Special Interest (Part B)
See format of Safety Table 3.40 
(200862 ‘final’ reporting effort)
Do not include Relative Risk or % 
Risk Difference columns
SAC
Cardiovascular Events
3.93.
Safety
Summary of All Cardiovascular Events Reported by the 
Investigator (Part B)
See format of Safety Table 3.11 
(200862 ‘final’ reporting effort)
SAC
Immunogenicity
3.94.
Safety
Summary of ADA Assay Results (Part B) 
See format of Safety Table 3.41 
(200862 ‘final’ reporting effort)
SAC
3.95.
Safety
Summary of NAb Assay Results (Part B) 
See format of Safety Table 3.42 
(200862 ‘final’ reporting effort)
SAC
3.96.
Safety
Summary of Treatment Emergent ADA Assay Results (Part B) 
See format of Safety Table 3.41 
(200862 ‘final’ reporting effort)
SAC
Laboratory Data
3.97.
Safety
LB1
Summary of Change From Baseline in Chemistry Data (Part B)  
Include Baseline values
SAC
3.98.
Safety
LB3
Summary of Chemistry Results (Change from Baseline Relative 
to the Normal Range) (Part B)  
SAC
3.99.
Safety
LB1
Summary of Change From Baseline in Haematology Data (Part 
B)  
Include Baseline values
SAC
 
 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
96
Safety Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.100.
Safety
LB3
Summary of Haematology Results (Change from Baseline 
Relative to the Normal Range) (Part B)  
SAC
Hepatobiliary (Liver)
3.101.
Safety
LIVER10
Summary of Subjects Meeting Emergent Hepatobiliary 
Laboratory Abnormality Criteria (Part A)
SAC
Electrocardiogram (ECG)
3.102.
Safety
EG1
Summary of  ECG Findings (Part B)
SAC
3.103.
Safety
EG2
Summary of Change from Baseline ECG Values by Visit (Part B)
Include Baseline values
SAC
3.104.
Safety
Summary of Actual and Change From Baseline QTc(F) Values 
by Category (msec) (Part B)
See format of Safety Table 7.50 
(MEA115588 ‘final’ reporting effort)
See Section 10.6.4 for details
Note: For Any Time Post-Baseline, the 
highest post-baseline QTc value and 
the change from baseline for this 
highest post-baseline QTc value is  
categorised
SAC
3.105.
Safety
Summary of Actual and Change From Baseline QTc(B) Values 
by Category (msec) (Part B)
See format of Safety Table 7.50 
(MEA115588 ‘final’ reporting effort)
See Section 10.6.4 for details
Note: For Any Time Post-Baseline, the 
highest post-baseline QTc value and 
the change from baseline for this 
highest post-baseline QTc value is  
categorised
SAC
Vital Signs
3.106.
Safety
VS1
Summary of Change from Baseline in Vital Signs (Part B)
Include Baseline values
SAC
 
 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
97
10.10.3.5. Safety Figures
Safety : Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Laboratory
3.3.
Safety
LIVER9
Scatter Plot of Maximum vs. Baseline for ALT (Part B)
SAC
3.4.
Safety
LIVER9
Scatter Plot of Maximum ALT vs. Maximum Total Bilirubin (Part 
B)
SAC
 
 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
98
10.10.3.6. ICH Listings
ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
52.
Safety
ES2
Listing of Reasons for Premature Study Withdrawal (Part B)
SAC
Concomitant Medication
53.
Safety
CM6
Relationship Between ATC Level 1, Ingredient and Verbatim 
Text (Part B) 
Include all asthma and non-asthma 
concomitant medications (including 
those given for exacerbation and 
rescue use) 
SAC
Protocol Deviations
54.
Safety
DV2
Listing of Important Protocol Deviations (Part B)
SAC
Blood Eosinophils
55.
PDe
Listing of Blood Eosinophil Data (10^9/L) (Part B) 
See format of Efficacy Listing 18 
(200862 ‘final’ reporting effort)
SAC
Exacerbations
56.
PDo
Listing of Exacerbations (Part B) 
See format of Efficacy Listing 17 
(200862 ‘final’ reporting effort)
Include Pre, on-treatment and Post-
treatment events within Part A (See 
Section 10.4.2)
SAC
Exposure
57.
Safety
EX3
Listing of Study Treatment Data (Part B) 
SAC
Adverse Events
58.
Safety
AE8
Listing of All Adverse Events (Part B)
SAC
 
 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
99
ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
59.
Safety
AE7
Listings of Subject Numbers for Individual Adverse Events (Part 
B)
SAC
60.
Safety
AE2
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text (Part B)
SAC
61.
Safety
AE8
Listing of all Fatal Adverse Events (Part B)
SAC
62.
Safety
AE8
Listing of Non-Fatal Serious Adverse Events (Part B)
SAC
63.
Safety
AE14
Listing of Reasons for Considering as a Serious Adverse Event
(Part B)
SAC
64.
Safety
AE8
Listing of Adverse Events Leading to Permanent Discontinuation 
of Study Treatment or Withdrawal from Study by Overall 
Frequency (Part B)
SAC
65.
Safety
Listing of Adverse Events Defined by the Investigator as a 
Systemic (non-allergic or allergic/hypersensitivity) Injection 
Reaction (Part B)
See format of Safety Listing 26 
(200862 ‘final’ reporting effort)
SAC
66.
Safety
Listing of Adverse Events Defined by the Investigator as a Local 
Injection Site Reaction (Part B)
See format of Safety Listing 27 
(200862 ‘final’ reporting effort)
SAC
67.
Safety
Listing of AEs meeting Anaphylaxis Criteria (Part B)
See format of Safety Listing 28 
(200862 ‘final’ reporting effort)
SAC
68.
Safety
Listing of Serious Cardiac, Vascular and Thromboembolic (CVT) 
AEs (Part B)
See format of Safety Listing 29 
(200862 ‘final’ reporting effort)
SAC
69.
Safety
Listing of Serious Ischemic AEs (Part B)
See format of Safety Listing 30 
(200862 ‘final’ reporting effort)
SAC
70.
Safety
Listing of Malignancies (Part B)
See format of Safety Listing 31 
(200862 ‘final’ reporting effort)
SAC
 
 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
100
ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
71.
Safety
Listing of Opportunistic Infections (Part B)
See format of Safety Listing 32 
(200862 ‘final’ reporting effort)
SAC
Cardiovascular Events
72.
Safety
Listing of Investigator Reported Cardiovascular Events: 
Arrhythmias (Part B)
See format of Safety Listing 33 
(200862 ‘final’ reporting effort)
SAC
73.
Safety
Listing of Investigator Reported Cardiovascular Events: 
Congestive Heart Failure (Part B)
See format of Safety Listing 34 
(200862 ‘final’ reporting effort)
SAC
74.
Safety
Listing of Investigator Reported Cardiovascular Events: 
Cerebrovascular Events/Stroke (Part B)
See format of Safety Listing 35 
(200862 ‘final’ reporting effort)
SAC
75.
Safety
Listing of Investigator Reported Cardiovascular Events: Deep 
venous Thrombosis/ Pulmonary Embolism (Part B)
See format of Safety Listing 36 
(200862 ‘final’ reporting effort)
SAC
76.
Safety
Listing of Investigator Reported Cardiovascular Events: 
Myocardial Infarction/Unstable Angina (Part B)
See format of Safety Listing 37 
(200862 ‘final’ reporting effort)
SAC
77.
Safety
Listing of Investigator Reported Cardiovascular Events: 
Peripheral Arterial Thrombosis Embolism (Part B)
See format of Safety Listing 38 
(200862 ‘final’ reporting effort)
SAC
78.
Safety
Listing of Investigator Reported Cardiovascular Events: 
Pulmonary Hypertension (Part B)
See format of Safety Listing 39 
(200862 ‘final’ reporting effort)
SAC
79.
Safety
Listing of Investigator Reported Cardiovascular Events: 
Revascularisation (Part B)
See format of Safety Listing 40 
(200862 ‘final’ reporting effort)
SAC
80.
Safety
Listing of Investigator Reported Cardiovascular Events: 
Valvulopathy (Part B)
See format of Safety Listing 41 
(200862 ‘final’ reporting effort)
SAC
81.
Safety
Listing of Investigator Reported Cardiovascular Events: All 
Cause Deaths (Part B)
See format of Safety Listing 42 
(200862 ‘final’ reporting effort)
SAC
 
 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
101
ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Immunogenicity
82.
Safety
Listing of Immunogenicity Results (Part B)
See format of Safety Listing 43 
(200862 ‘final’ reporting effort)
SAC
Laboratory Data
83.
Safety
Listing of Urinalysis (Part B)
See format of Safety Listing 44 
(200862 ‘final’ reporting effort)
SAC
Liver Event
84.
Safety
LIVER5
Listing of Liver Monitoring/Stopping Event Reporting (Part B)
SAC
85.
Safety
LB5
Chemistry Results for  Subjects Meeting Liver 
Monitoring/Stopping Event Criteria (Part B)
Subset for subjects in above Liver 
Monitoring/Stopping Event listing
SAC
86.
Safety
MH2
Listing of Medical Conditions for Subjects with Liver Stopping 
Events (Part B)
SAC
87.
Safety
SU2
Listing of Substance Use for Subjects with Liver Stopping 
Events (Part B)
SAC
88.
Safety
LIVER13
Listing of Subjects Meeting Hepatobiliary Laboratory Criteria 
Post-Baseline (Part B) 
SAC
Electrocardiogram (ECG)
89.
Safety
EG6
Listing of ECG Findings for Abnormal Interpretations (Part B)
See format of Safety Listing 7.32 
(MEA115588 ‘final’ reporting effort)
SAC
 
 
 
2017N314087_00


2016N305235_00
CONFIDENTIAL
200363
102
10.11.
Appendix 11: Example Mock Shells for Data Displays
See Supplementary RAP material
 
 
 
2017N314087_00