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
Phase: PHASE2
Conditions: Asthma
Sponsor: GlaxoSmithKline

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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.
 
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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. 
 
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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.
 
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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.
 
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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 
 
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“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.  
 
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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
 
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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
 
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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
 
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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
 
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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
 
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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 
 
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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
 
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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
 
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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)
 
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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).
 
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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.
 
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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.
 
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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 
 
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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 
 
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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.
 
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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
 
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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
 
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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 
 
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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 
 
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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 
 
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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).
 
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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. 
 
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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 
 
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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: 
 
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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.
 
 
 
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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.
 
 
 
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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).
 
 
 
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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.
 
 
 
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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.
 
 
 
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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.
 
 
 
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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.
 
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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.
 
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[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.
 
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[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.
 
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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). 
 
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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.
 
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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)
 
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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. 
 
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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.
 
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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. 
 
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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).
 
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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
 
 
 
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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.
 
 
 
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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
 
 
 
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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.
 
 
 
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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] 
 
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(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:
 
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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.   
 
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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.
 
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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).
 
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
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
 
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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. 
 
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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 
 
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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.
 
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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 
 
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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.
 
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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. 
 
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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.
 
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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.
 
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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 
 
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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.
 
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11.
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Jurgensen HC, Ortega GH, Aceves SS. Treatment of Pediatric Eosinophilic Esophagitis 
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Bel EH, Wenzel SE, Thompson PJ, Prazma CM,  Keene ON, Yancey SW, Ortega HG, 
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Mepolizumab in Eosinophilic Asthma.  N Engl J Med 2014; 371:1189-1197 September 
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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 
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Fitzpatrick AM, Higgins M., Holguin F, et al. The molecular phenotype of severe asthma 
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Flood-Page P, Swenson C, Faiferman I, et al. International Mepolizumab Study Group. A 
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Gevaert P, Lang-Loidolt D, Lackner A, et al. Nasal IL5 levels determine the response to 
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Giubergia V, Fridman N, González Pena H. Healthcare Program for Children with Severe 
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GSK Document Number 2014N223495_00. Mepolizumab Paediatric Severe Asthma 
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Adolescent Dose Extrapolation. CPMS Clinical Pharmacology Modelling Report 
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(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 
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cross-sectional validation of the Childhood Asthma Control Test. J Allergy Clin Immunol 
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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 
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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 
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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, 
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Xu Z, Davis HM, Zhou H.  Rational development and utilization of antibody-based 
therapeutic proteins in pediatrics. Pharmacology & Therapeutics (2013) 137:225-247.
 
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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
 
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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
 
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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
 
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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
 
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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 
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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.
 
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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 
 
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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 
 
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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
 
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
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.
 
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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.
 
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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.
 
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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
 
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12.5.
Appendix 5: Sample ACQ-7 Questionnaire
 
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12.6.
Appendix 6: Sample ACQ-IA Questionnaire
 
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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 
 
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the fetus if transferred to a female partner via semen. Therefore, the use of condoms or 
other methods of contraception in the male study subject is not required.
 
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12.8.
Appendix 8: Country Specific Requirements
No country-specific requirements exist.
 
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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
 
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12.10.
Appendix 10:  Childhood Asthma Control Test (C-ACT)
 
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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 
 
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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
 
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
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).
 
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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 
 
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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 
 
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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.
 
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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.
 
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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: 
 
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PPD
PPD
PPD
PPD
PPD
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PPD
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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 
 
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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.
 
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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. 
 
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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).
 
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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 
 
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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.
 
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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.
 
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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.
 
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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.
 
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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)
 
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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
 
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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.
 
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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
 
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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)
 
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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 
 
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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.  
 
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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
 
 
 
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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.
 
 
 
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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. 
 
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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.  
 
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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 
 
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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.
 
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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.
 
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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 
 
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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.
 
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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.
 
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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).
 
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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).
 
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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.
 
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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.
 
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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
 
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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.  
 
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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
 
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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.
 
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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.
 
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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
 
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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
 
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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.  .
 
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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
 
 
 
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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
 
 
 
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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
 
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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.
 
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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
 
 
 
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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.
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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
 
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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. 
 
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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.
 
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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].
 
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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
 
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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 
 
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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.
 
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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
 
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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**.
 
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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 
 
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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 
 
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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.
 
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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 
 
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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.
 
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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
 
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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 
 
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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
 
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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
 
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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
 
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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.
 
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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.
 
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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).
 
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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
 
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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
 
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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
 
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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
 
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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.
 
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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.
 
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