Clinical trial NCT02555371
Conditions: Asthma
Keywords: Severe eosinophilic asthma mepolizumab asthma exacerbation
Sponsor: GlaxoSmithKline
Start date: 2016-01-07; Completion date: 2019-07-24
Enrollment: 306 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Primary objective of the study is to evaluate whether patients with severe eosinophilic asthma who have received long-term treatment with mepolizumab (at least 3 years) need to maintain treatment with mepolizumab to continue to receive benefit. Subjects who participated in the open-label studies MEA115666 or 201312 with at least 6 months of treatment with mepolizumab prior to Visit 1 and who have no more than 2 consecutive missed doses of mepolizumab treatment will be eligible to participate in this study. This study will be conducted in 4 parts in approximately 300 subjects. Part A will be Variable Open-Label Run-in (for subjects with less than 3 years of mepolizumab treatment). Once the required 3 year exposure is reached, subjects will enter Part B- Fixed Open-Label Run-In (4 weeks to 8 weeks). During Part A and B subjects will be administered Open-label mepolizumab (100 milligram \[mg\] Subcutaneous \[SC\]) every 4 weeks. Part C will be the randomized double-blinded part. Upon completion of Part B, eligible subjects will be randomized to mepolizumab (100 mg SC) every 4 weeks or placebo administered SC every 4 weeks for 52 weeks.

Subjects discontinuing investigational product (IP) due to a clinically significant asthma exacerbation will then enter optional Part D of the study. During Part D, subjects receive open-label mepolizumab in addition to their standard of care therapy for the remainder of the study, through Part D up to 52-weeks post-randomization. An Exit Visit will be conducted 52 weeks after randomization in order to assess subject's efficacy parameters, immunogenicity status, and to conduct additional safety assessments. Eligible subjects will participate in the study ranging from 56 to192 weeks, depending on the duration of Part A (0 to 132 weeks) and Part B (4 to 8 weeks).

Detailed description:

Arms: arm 1: There will be 4 parts during the study. Part A will be Variable Open-Label Run-in (maximum up to 132 weeks). Part B- Fixed Open-Label Run-In (4 Weeks to 8 weeks). Part C will be randomized double-blind treatment period (Up to 52 weeks) and in case of clinically significant asthma exacerbation, optional open label switch Part D (Up to 52 weeks post randomization). Subjects will receive mepolizumab (100 mg SC) every 4 weeks throughout study arm 2: There will be 4 parts during the study. Part A will be Variable Open-Label Run-in (maximum up to 132 weeks). Part B- Fixed Open-Label Run-In (4 Weeks to 8 weeks). Part C will be randomized double-blind treatment period (Up to 52 weeks) and in case of clinically significant asthma exacerbation, optional open label switch Part D (Up to 52 weeks post randomization). During Part A, B and D, subjects will receive open label mepolizumab (100 mg SC) every 4 weeks and during Part C, subjects will receive placebo SC every 4 weeks.
Interventions: intervention 1: Mepolizumab 100mg intervention 2: Placebo
Intervention descriptions: intervention 1: Mepolizumab is a fully humanised Immunoglobulin (IgG) antibody (IgG1, kappa) with human heavy and light chain frameworks. Mepolizumab will be provided as a lyophilised cake in sterile vials for individual use. intervention 2: The placebo will be 0.9% sodium chloride solution and will be provided by the study site.

Protocol documents:
Prot_000.pdf: 
2015N232375_03
CONFIDENTIAL
The GlaxoSmithKline group of companies
201810
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A multi-center, randomized, double-blind, placebo controlled, 
parallel group study to compare cessation versus continuation of 
long-term mepolizumab treatment in patients with severe 
eosinophilic asthma (201810)
Compound Number:
SB-240563
Development Phase:
IIIB
Effective Date:
07-JUL-2016
Protocol Amendment Number:  02
Author (s):
 
Copyright 2016 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited
PPD


2015N232375_03
CONFIDENTIAL
The GlaxoSmithKline group of companies
201810
2
Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2015N232375_00
2015-MAY-20
Original
2015N232375_01
2015-JUN-23
Republished
1.
Added birth control requirement for 4 months after last dose
2.
Corrected symptom score from ≥5 to 5
3.
Language allows for inflammatory biomarkers to be tested at GSK 
4.
eDiary arrow adjusted to span from Visit B2 to the Exit Visit or EW/IP DISC
5.
Estradiol, FSH, drug alcohol screens only conducted if clinically indicated
6.
Added further explanation of Part D switch during a visit
7.
Extended Part A to 2.5 years in text and Table 6
8.
In Section 7.9.2, added a statement that recreational drug us is not allowed during 
the study
9.
In Table 7, added a line for biomarker analysis
10.
Added clarifying language to the disallowance of treatment gaps during 201312 
and MEA115666
2015N232375_02
2015-NOV-06
Amendment No. 1
1.
Change of Secondary Medical Monitor
2.
Simplified definition of “continuous mepolizumab treatment”
3.
Clarified when a subject switches from Part C to Part D
4.
Removed the process of withdrawing a subject due to unblinding
5.
Several minor changes to the Time and Events table and corresponding text 
within the protocol to ensure subjects entering from MEA115666 and 201312 are 
consistently and correctly monitored
6.
Removed Urinalysis testing
7.
Updated contraception requirements
2015N232375_03
2016-JUL-07
Amendment No. 2
1.
Amended Section 5.6.1 Risk Assessment
2.
Corrected numbering of Exclusion Criteria
3.
Amended exclusion criterion No. 7 in Section 6.2: Exclusion Criteria
4.
Amended Randomization Exclusion criterion No. 7 in Section 6.3.2: 
Randomization Exclusion Criteria.
5.
Additional text added to Section 7.1 Investigational Product and Other Study 
Treatment 
6.
Amended Section 7.9.1 Permitted Medications and Non-Drug Therapies
7.
Multiple changes to Section 7.9.2 Prohibited Medications and Non-Drug 
Therapies
8.
Removed interactive response technology requirements from certain visits of the 
T&E tables
9.
Added Physical Examination at Visit C1 in Time and Events table 
10.
Added Physical Examination to C1 visit


2015N232375_03
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201810
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11.
Updated Subject/Clinician Rating of Global Impression of Disease Severity and 
Response to Therapy
12.
Clarified unblinding risk when performing local laboratory testing
13.
Updated biomarker collection text
14.
Removed “Xolair” from the Trademark Information section
.


PPD
PPD


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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
Fax 
Number
Site 
Address
Primary 
Medical 
Monitor 
 
 MD, 
MFPM
Not 
Applicable
Stockley 
Park 
West
1-3 
Ironbridge 
Road
Uxbridge, 
Middlesex
UB11 
1BT 
United
Kingdom
Secondary 
Medical 
Monitor
 
 MD, 
PMP 
Not 
Applicable
Stockley 
Park 
West
1-3 
Ironbridge 
Road
Uxbridge, 
Middlesex
UB11 
1BT 
United
Kingdom
SAE 
contact  
information 
Medical 
monitor as 
above
Sponsor Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate 
Company (or designee). If applicable, the details of the alternative Sponsor and contact 
PPD
PPD
PPD
PPD
PPD
PPD


2015N232375_03
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person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application.   
Regulatory Agency Identifying Number(s): IND No. 006971, EudraCT No: 2015-
002361-32


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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 201810
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 201810......................................................12
2.
INTRODUCTION....................................................................................................18
2.1.
Study Rationale ..........................................................................................18
2.2.
Brief Background ........................................................................................18
3.
OBJECTIVES.........................................................................................................19
3.1.
Primary Objective .......................................................................................19
3.2.
Secondary Objective...................................................................................19
4.
ENDPOINTS ..........................................................................................................19
5.
STUDY DESIGN ....................................................................................................21
5.1.
Overall Design ............................................................................................21
5.2.
Study Phases, Duration and Treatment Arms.............................................24
5.3.
Type and Number of Subjects.....................................................................25
5.4.
Design Justification.....................................................................................26
5.5.
Dose Justification........................................................................................27
5.6.
Benefit:Risk Assessment ............................................................................27
5.6.1.
Risk Assessment .........................................................................27
5.6.2.
Benefit Assessment.....................................................................34
5.6.3.
Overall Benefit:Risk Conclusion...................................................34
6.
SELECTION OF STUDY POPULATION, IP DISCONTINUATION AND 
WITHDRAWAL CRITERIA .....................................................................................34
6.1.
Inclusion Criteria.........................................................................................35
6.2.
Exclusion Criteria........................................................................................36
6.3.
Randomization Criteria ...............................................................................37
6.3.1.
Randomization Inclusion Criteria .................................................37
6.3.2.
Randomization Exclusion Criteria ................................................37
6.4.
Pre-screen/Screen/Run-in Failures.............................................................38
6.5.
Study Withdrawal Prior to Randomization: Withdrawal during Part A 
or Part B .....................................................................................................39
6.6.
Discontinuation of Investigational Product (IP) during Part C or Part 
D.................................................................................................................40
6.6.1.
IP Discontinuation Visit Assessments ..........................................42
6.6.2.
Reasons for Discontinuation of IP................................................42
6.7.
Study Withdrawal During Part C or Part D ..................................................42
6.7.1.
Study Withdrawal Criteria ............................................................42
6.7.2.
Study Withdrawal Assessments...................................................42
6.7.3.
Reasons for Withdrawal...............................................................42
6.7.4.
Lost to Follow Up.........................................................................42
6.8.
Subject and Study Completion....................................................................43
7.
STUDY TREATMENT ............................................................................................43
7.1.
Investigational Product and Other Study Treatment....................................43
7.2.
Treatment Assignment................................................................................44
7.3.
Blinding.......................................................................................................44


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7.4.
Packaging and Labeling..............................................................................45
7.5.
Preparation/Handling/Storage/Accountability..............................................45
7.6.
Compliance with Study Treatment Administration.......................................46
7.7.
Treatment of Study Treatment Overdose....................................................46
7.8.
Treatment after the End of the Study ..........................................................46
7.9.
Concomitant Medications and Non-Drug Therapies....................................47
7.9.1.
Permitted Medications and Non-Drug Therapies..........................47
7.9.2.
Prohibited Medications and Non-Drug Therapies.........................47
8.
STUDY ASSESSMENTS AND PROCEDURES .....................................................48
8.1.
Time and Events Tables .............................................................................49
8.2.
Screening and Critical Baseline Assessments ............................................57
8.2.1.
Critical procedures performed at Screening (Visit 1)....................57
8.2.2.
Critical procedures performed at entry to Part B (Visit B1)...........58
8.2.3.
Critical procedures performed at Randomization (Visit C1)..........58
8.3.
Efficacy.......................................................................................................59
8.3.1.
Efficacy Endpoints .......................................................................59
8.3.2.
Efficacy Assessments..................................................................59
8.3.2.1.
Asthma Exacerbations................................................59
8.3.2.1.1.
Guideline for Assessing Multiple 
Exacerbations.........................................60
8.3.2.2.
eDiary Reporting, Worsening of Asthma and 
Alerts: Part B, C and D ...............................................60
8.3.2.2.1.
eDiary Alerts Indicating Worsening 
of Asthma ...............................................60
8.3.2.2.2.
eDiary Daily Entry: Missed Days 
of Work or School...................................60
8.3.2.2.3.
eDiary Weekly Entry: Asthma 
Control Questionnaire-5 (ACQ-5)............61
8.3.2.2.4.
eDiary Compliance .................................61
8.3.2.3.
Paper Diary ................................................................61
8.3.2.4.
Spirometry..................................................................61
8.3.2.4.1.
Pre- and Post-
Albuterol/Salbutamol Spirometry ............62
8.3.2.5.
Paper-based Asthma Control Questionnaire-5 
(Part A only) ...............................................................62
8.3.2.6.
St. George’s Respiratory Questionnaire 
(SGRQ) ......................................................................62
8.3.2.7.
Subject/Clinician Rating of Global Impression 
of Disease Severity and Response to Therapy...........62
8.3.2.8.
Healthcare Resource Utilization..................................63
8.4.
Safety .........................................................................................................63
8.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........63
8.4.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................64
8.4.1.2.
Method of Detecting AEs and SAEs ...........................64
8.4.1.3.
Follow-up of AEs and SAEs........................................65
8.4.1.4.
Cardiovascular and Death Events ..............................65
8.4.1.4.1.
Cardiovascular Events............................65
8.4.1.4.2.
Death Events..........................................65
8.4.1.5.
Regulatory Reporting Requirements for SAEs............65
8.4.2.
Pregnancy ...................................................................................66


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8.4.3.
Physical Exams ...........................................................................66
8.4.4.
Vital Signs....................................................................................66
8.4.5.
Electrocardiogram (ECG).............................................................66
8.4.6.
Clinical Safety Laboratory Assessments ......................................67
8.4.6.1.
Immunogenicity ..........................................................69
8.5.
Biomarker(s)/Pharmacodynamic Markers ...................................................69
8.6.
Genetics .....................................................................................................69
9.
DATA MANAGEMENT ...........................................................................................69
10. STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................70
10.1.
Hypotheses.................................................................................................70
10.2.
Sample Size Considerations.......................................................................70
10.2.1.
Sample Size Assumptions ...........................................................70
10.2.2.
Sample Size Sensitivity................................................................70
10.2.3.
Sample Size Re-estimation or Adjustment...................................71
10.3.
Data Analysis Considerations .....................................................................71
10.3.1.
Analysis Populations....................................................................71
10.3.2.
Interim Analysis ...........................................................................72
10.4.
Key Elements of Analysis Plan ...................................................................72
10.4.1.
Primary Analyses.........................................................................72
10.4.2.
Secondary Analyses ....................................................................72
10.4.3.
Other Analyses ............................................................................73
10.4.3.1.
Efficacy Analyses .......................................................73
10.4.3.2.
Safety Analyses..........................................................73
10.4.3.2.1.
Extent of Exposure .................................73
10.4.3.2.2.
Adverse Events ......................................73
10.4.3.2.3.
Clinical Laboratory Evaluations...............73
10.4.3.2.4.
Other Safety Measures...........................73
10.4.3.2.5.
Immunogenicity ......................................73
10.4.3.3.
Pharmacogenetic Analyses ........................................74
11. STUDY GOVERNANCE CONSIDERATIONS........................................................74
11.1.
Posting of Information on Publicly Available Clinical Trial Registers............74
11.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................74
11.3.
Quality Control (Study Monitoring) ..............................................................75
11.4.
Quality Assurance.......................................................................................75
11.5.
Study and Site Closure ...............................................................................75
11.6.
Records Retention......................................................................................76
11.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................77
12. REFERENCES.......................................................................................................78
13. APPENDICES........................................................................................................81
13.1.
Appendix 1: Abbreviations and Trademarks................................................81
13.2.
Appendix 2: Liver Chemistry Stopping and Increased Monitoring 
Algorithm ....................................................................................................84
13.3.
Appendix 3: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................86


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13.4.
Appendix 4: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................90
13.4.1.
Definition of Adverse Events........................................................90
13.4.2.
Definition of Serious Adverse Events...........................................91
13.4.3.
Definition of Cardiovascular Events .............................................92
13.4.4.
Recording of AEs and SAEs ........................................................93
13.4.5.
Evaluating AEs and SAEs............................................................94
13.4.6.
Reporting of SAEs to GSK...........................................................95
13.5.
Appendix 5: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP) and 
Collection of Pregnancy Information ...........................................................96
13.5.1.
Collection of Pregnancy Information ............................................96
13.6.
Appendix 6: Cardiovascular Screening Questions ......................................98
13.7.
Appendix 7: Daily Asthma Symptom Score.................................................99
13.8.
Appendix 8: Anaphylaxis Criteria ..............................................................100
13.9.
Appendix 9: Country Specific Requirements.............................................101
13.10. Appendix 10: Protocol Amendment Changes............................................102
13.10.1. Amendment 01 (06-Nov-2015) from the Original Protocol 
(23-Jun-2015)............................................................................102
13.10.2. Amendment 2 (07-JUL-2016) from the Amendment 1 (06-
NOV-2015) ................................................................................136


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1.
PROTOCOL SYNOPSIS FOR STUDY 201810
Rationale
The efficacy of mepolizumab in severe asthma has been demonstrated over one year of 
continuous treatment in double-blinded studies. However, it is currently unknown 
whether chronic exposure is necessary for disease control. It was recently reported that 
discontinuation of mepolizumab after one year of treatment resulted in the increased 
presence of eosinophils and a corresponding increase in exacerbation frequency to pre-
study levels, suggesting that a treatment response was not sustained after treatment 
discontinuation. Beyond one year of treatment, there is no data available on the 
sustainability of a treatment response following the discontinuation of mepolizumab.
Asthma management guidelines recommend stepping down therapy once control is 
achieved in an effort to find the patient’s minimal effective treatment. Thus, it remains 
important to understand the duration of response to mepolizumab when treatment is 
withdrawn after longer-term exposure.
Objectives
Primary Objective
To evaluate whether patients with severe eosinophilic asthma who have received long-
term treatment with mepolizumab (at least 3 years) need to maintain treatment with 
mepolizumab to continue to receive benefit. 
Secondary Objective
To assess the safety and tolerability of mepolizumab continuation compared to placebo 
following long-term treatment with mepolizumab in patients with severe eosinophilic 
asthma.
Endpoints
Primary Endpoint

Time to first clinically significant exacerbation
Clinically significant exacerbations will be defined as worsening of asthma which 
requires use of systemic corticosteroids1 and/or hospitalisation and/or emergency 
department (ED) visits.
1For all subjects, i.v. or oral corticosteroid (e.g., prednisone) for at least 3 days 
or a single intramuscular (IM) corticosteroid dose is required. For subjects on 
maintenance systemic corticosteroids, at least double the existing maintenance 
dose for at least 3 days is required. 


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Secondary Endpoints

Ratio to baseline in blood eosinophil count at weeks 12, 24, 36 and 52

Time to a decrease in asthma control, defined as an increase from baseline in 
Asthma Control Questionnaire-5 (ACQ-5) score of ≥ 0.5 units

Time to first exacerbation requiring hospitalization or ED visit
Other Endpoints

Time to first exacerbation requiring hospitalization 

Mean change from baseline in clinic pre-bronchodilator FEV1 at weeks 12, 24, 
36, 52

Mean change from baseline in clinic post-bronchodilator FEV1 at weeks 12, 24, 
36, 52

Mean change from baseline in daily salbutamol/albuterol use

Mean change from baseline in daily asthma symptom scores 

Mean change from baseline in awakening at night due to asthma symptoms 
requiring rescue medication use

Mean change from baseline in morning (AM) Peak Expiratory Flow (PEF)

Time to worsening of asthma (subjects meeting at least 2 of the following 4 
criteria for worsening of asthma for at least 2 consecutive days)

AM PEF: Decrease in AM PEF 30% compared with baseline (last 7 
days of run-in Part B).

Rescue Medication Use: An increase of 50% in rescue medication 
compared with the average use for the previous week.

Night time awakenings requiring rescue medication: Awakening 
due to asthma symptoms requiring rescue medication

Symptoms: An asthma symptom score of 5

Mean change from baseline in ACQ-5 score 

Proportion of patients experiencing a decrease in asthma control, defined as an 
increase from baseline in ACQ-5 score of ≥0.5 or more units 

Proportion of subjects with a clinically meaningful worsening of health-related 
quality of life measurements (St. George’s Respiratory Questionnaire, SGRQ) at 
weeks 12, 24, 36 and 52 (defined as subjects who have a clinically relevant 
increase from baseline of ≥4 units in SGRQ score).

Mean change from baseline in SGRQ score at week 12, 24, 36 and 52

Subject/Clinician global impression of asthma severity rating at weeks 12, 24, 
36 and 52


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
Subject/Clinician  rating of response to therapy at weeks 12, 24, 36 and 52

Number of days in hospital due to asthma

Unscheduled healthcare contacts/resource utilisation

Days off of regular work/school
Safety Endpoints

Adverse Events and Serious Adverse Events

Clinical Laboratory parameters

12-lead ECG parameters

Vital Signs
Overall Design
This is a 52-week, 2-arm, randomized, double-blind, parallel-group, multi-center study 
evaluating mepolizumab 100 mg and placebo administered subcutaneously (SC) every 4 
weeks in subjects with severe eosinophilic asthma who have been treated with 
mepolizumab continuously in addition to standard of care therapy for at least 3 years. 
Subjects who participated in the open-label studies MEA115666 or 201312 and who have 
no treatment gaps of more than 12 weeks (84 days) between any two doses of 
mepolizumab in MEA115666 or 201312, will be eligible to participate in this study. 
It is intended that the Follow up/Exit Visit or Early Withdrawal (EW) Visit for studies 
MEA115666 and 201312 will serve as the Pre-Screening/Screening Visit (Visit 0/Visit 1) 
for this study.
Part A and B: Variable and Fixed Open-Label Run-In Periods
At Visit 1 (Screening), eligible subjects will have their exposure period for mepolizumab 
treatment assessed:

Subjects with less than 3 years of mepolizumab treatment will enter Part A of 
the study, a variable open-label run-in period on mepolizumab (100 mg SC every 
4 weeks) of 4 to 132 weeks, in order for subjects to reach 3 years of exposure to 
mepolizumab. 
o
Once the required 3 year exposure is reached, the subject will enter Part B 
of the study at Visit B1 and complete a fixed run-in period of 4 weeks (up 
to 8 weeks) during which open-label mepolizumab (100 mg SC every 4 
weeks) is administered, in order to collect baseline information.


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
Subjects with at least 3 years of mepolizumab treatment will directly enter 
Part B of the study. For these subjects, assessments for Visit 1 and Visit B1 
should be conducted on the same day. No assessments should be duplicated.
Part C: Double-Blind Treatment Period
Upon completion of the fixed run-in period Part B, eligible subjects will be randomized 
1:1 to the following double-blinded treatment arms at Visit C1:

mepolizumab (100 mg) administered SC every 4 weeks

placebo administered SC every 4 weeks 
Part D: Optional Switch to Open-Label Mepolizumab
Subjects who experience a clinically significant asthma exacerbation during the double-
blind treatment period Part C will require a prompt assessment by the investigator to 
determine if they should continue taking double-blind study treatment. 
Subjects deemed to be unsuitable to continue double-blind study treatment by the 
Investigator should discontinue double-blind investigational product (IP) and complete a 
Discontinuation of IP Visit approximately 4 weeks following their last dose of double-
blind IP.  
Subjects discontinuing IP due to a clinically significant asthma exacerbation are eligible 
to enter optional Part D of the study and receive open-label mepolizumab in addition to 
their standard of care therapy for the remainder of the study, through Part D, to Visit 
D13. Subjects switching to Part D should complete the Discontinuation of IP Visit and 
their first Part D visit on the same day, corresponding to the week post-randomization. 
No assessments should be duplicated.
Switch to Part D between visits: For example, if a subject completed Visit C7 at Week 24 
(and the subject received a dose of IP at Visit C7) and it is later determined that they 
should switch to Part D, the IP Discontinuation assessments and the first visit in Part D 
will be D8 at Week 28. 
Switch to Part D during a visit: If a subject is in the process of completing a Part C visit, 
as long as they have not yet received a dose of IP, they may be switched to Part D at that 
same visit (e.g., a subject that is part way through Visit C7 at Week 24 and whose last 
dose of IP was at Visit C6, Week 20 can be switched to Part D and complete the IP 
Discontinuation assessments and Visit D7 at that same visit, Week 24). 
An Exit Visit will be conducted 52 weeks after randomization (whether the subject is in 
Part C or Part D) in order to assess subject’s efficacy parameters, immunogenicity status, 
and to conduct additional safety assessments. 
Subjects who permanently discontinue study treatment in Part C or D of the study are 
NOT required to withdraw from the study. If a subject discontinues double blind study 
treatment during Part C and does not switch to Part D at their next visit (IP 


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Discontinuation Visit) after experiencing a clinically significant asthma exacerbation, the 
subject cannot enter Part D at a later visit.  
Treatment Arms and Duration
Eligible subjects will participate in the study ranging from 56 to192 weeks, depending on 
the duration of Part A (0 to 132 weeks) and Part B (4 to 8 weeks). A summary of study 
phases is described in Table 1.
Table 1
Study Phases, Duration and Study Treatments
Study 
Phase
Phase Title
Duration
Treatment arms
Part A
Variable 
Open-Label 
Run-in
0 to 132
weeks
Open-label mepolizumab (100 mg SC) 
every 4 weeks
Part B
Fixed Open-
Label Run-In
4 weeks (up 
to 8 weeks)
Open-label mepolizumab (100 mg SC) 
every 4 weeks
Part C
Double Blind 
Treatment 
Period
52 weeks
Subjects randomized 1:1 to double-blind 
study treatment:

mepolizumab (100 mg SC) every 4 
weeks

placebo administered SC every 4 
weeks 
Optional 
Part D
Open-Label 
Switch
Up to 52-
weeks post-
randomization
Open-label mepolizumab (100 mg SC) 
every 4 weeks
Type and Number of Subjects
Subjects with severe eosinophilic asthma who completed the Follow Up/Exit Visit or EW 
Visit from either open-label study MEA115666 or 201312 will be eligible to participate 
in this study.
Approximately 375 subjects from studies MEA115666 and 201312 are expected to be 
screened in order for approximately 300 subjects to be randomized 1:1 to double-blind 
study treatment (150 per arm). 


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Sample Size and Analysis
With a sample size of 300 randomized subjects (150 per arm), it is estimated that 
statistical significance will be declared if the proportion of subjects with a clinically 
significant exacerbation following withdrawal of mepolizumab is 52.5% compared to 
40% for those continuing to receive mepolizumab (hazard ratio = 0.686).
If the true hazard ratio is 0.55 (corresponding to a proportion with a clinically significant 
exacerbation following discontinuation of mepolizumab of 60.5%), then the study has a 
probability of 90% of observing a hazard ratio of < 0.686 and therefore the study has 
90% power for declaring statistical significance on this endpoint. 
Time to first clinically significant exacerbation will be compared between treatment 
groups using a Cox’s proportional hazards model allowing for covariates of region, 
exacerbations in the year prior to randomization and use of baseline maintenance oral 
corticosteroids (OCS vs no OCS).


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2.
INTRODUCTION
Eosinophilic inflammation of the airways specifically plays a central role in the 
pathogenesis of asthma [Cohn, 2004].  Eosinophils are not normally present in healthy 
lungs, and are thought to play a major role in maintaining airway inflammation [Walsh; 
2010; Wadsworth, 2011].  Studies in the severe asthma population have shown that more 
than half of these patients have persistent eosinophilic (>3% eosinophils) airway 
inflammation despite corticosteroid therapy [Wenzel, 2005; ENFUMOSA, 2003].
Of the inflammatory mediators postulated to contribute to the regulation of eosinophil 
trafficking and degranulation, interleukin-5 (IL-5) has been identified as the main 
cytokine to selectively regulate eosinophil function [Sumitas, 2011]. IL-5 specifically 
promotes the differentiation of eosinophils in the bone marrow and stimulates the release 
of eosinophils from the bone marrow into peripheral circulation [Sanderson, 1992; 
Collins, 1995]. Binding of IL-5 to eosinophil-expressing IL-5 receptors results in 
enhanced adhesion of eosinophils to endothelial cells and increased eosinophil survival 
and activation [Lopez, 1988].
Mepolizumab is a humanized anti-interleukin 5 (anti-IL5) antibody (IgG Kappa) that 
binds to and inactivates IL-5. Mepolizumab is currently under clinical development for 
the treatment of severe asthma.
2.1.
Study Rationale
The efficacy of mepolizumab in severe asthma has been demonstrated over one year of 
continuous treatment in double-blinded studies. However, it is currently unknown 
whether chronic exposure is necessary for disease control. It was recently reported that 
discontinuation of mepolizumab after one year of treatment resulted in the increased 
presence of eosinophils and a corresponding increase in exacerbation frequency to pre-
study levels, suggesting that a treatment response was not sustained after treatment 
discontinuation [Haldar, 2014].  Beyond one year of treatment, there is no data available 
on the sustainability of a treatment response following the discontinuation of 
mepolizumab.
Asthma management guidelines recommend stepping down therapy once control is 
achieved in an effort to find the patient’s minimal effective treatment [GINA, 2015].
Thus, it remains important to understand the duration of response to mepolizumab when 
treatment is withdrawn after longer-term exposure.
2.2.
Brief Background
Mepolizumab binds with high affinity to human IL-5 and blocks its binding to and the 
activation of the IL-5 receptor (CD125).
The randomized, multi-centre, placebo-controlled exacerbation studies (MEA112997, 
MEA115588) and Oral Corticosteroid (OCS) Reduction Study (MEA115575) have 
demonstrated the efficacy of mepolizumab and support the use of mepolizumab 100 mg 


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SC every 4 weeks as an add-on therapy for the treatment of severe eosinophilic asthma.
Compared with placebo, mepolizumab has been shown to: 

Reduce the rate of clinically significant exacerbations by approximately 50%.  These 
results were replicated in studies MEA112997 and MEA115588.

Reduce the rate of exacerbations requiring hospitalisations and/or Emergency 
Department (ED) visits, with mean reductions ranging from 32% to 61%.

Produce statistically significant and/or clinically relevant improvements in lung 
function based on forced expiratory volume in one second (FEV1), asthma control 
based on Asthma Control Questionnaire (ACQ-5), quality of life based on St. 
George’s Respiratory Questionnaire (SGRQ) and clinician and subject-rated overall 
response to therapy in the target population.  

Produce consistent reductions in blood eosinophil levels detected at Week 4 which 
were sustained for the duration of treatment.
Additional details of the pharmacology, efficacy and safety can be found in the 
Investigator Brochure (IB).
3.
OBJECTIVES
3.1.
Primary Objective
To evaluate whether patients with severe eosinophilic asthma who have received long-
term treatment with mepolizumab (at least 3 years) need to maintain treatment with 
mepolizumab to continue to receive benefit. 
3.2.
Secondary Objective
To assess the safety and tolerability of mepolizumab continuation compared to placebo 
following long-term treatment with mepolizumab in patients with severe eosinophilic 
asthma.
4.
ENDPOINTS
Primary Endpoint

Time to first clinically significant exacerbation
Clinically significant exacerbations will be defined as worsening of asthma which 
requires use of systemic corticosteroids1 and/or hospitalisation and/or ED visits.
1For all subjects, i.v. or oral corticosteroid (e.g., prednisone) for at least 3 days 
or a single intramuscular (IM) corticosteroid dose is required. For subjects on 
maintenance systemic corticosteroids, at least double the existing maintenance 
dose for at least 3 days is required. 


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Secondary Endpoints

Ratio to baseline in blood eosinophil count at weeks 12, 24, 36 and 52

Time to a decrease in asthma control, defined as an increase from baseline in 
Asthma Control Questionnaire-5 (ACQ-5) score of ≥ 0.5 units

Time to first exacerbation requiring hospitalization or ED visit
Other Endpoints

Time to first exacerbation requiring hospitalization 

Mean change from baseline in clinic pre-bronchodilator FEV1 at weeks 12, 24, 
36, 52

Mean change from baseline in clinic post-bronchodilator FEV1 at weeks 12, 24, 
36, 52

Mean change from baseline in daily salbutamol/albuterol use

Mean change from baseline in daily asthma symptom scores 

Mean change from baseline in awakening at night due to asthma symptoms 
requiring rescue medication use

Mean change from baseline in morning (AM) Peak Expiratory Flow (PEF)

Time to worsening of asthma (subjects meeting at least 2 of the following 4 
criteria for worsening of asthma for at least 2 consecutive days)

AM PEF: Decrease in AM PEF 30% compared with baseline (last 7 
days of run-in Part B)

Rescue Medication Use: An increase of 50% in rescue medication 
compared with the average use for the previous week

Night time awakenings requiring rescue medication: Awakening 
due to asthma symptoms requiring rescue medication

Symptoms: An asthma symptom score of 5

Mean change from baseline in ACQ-5 score 

Proportion of patients experiencing a decrease in asthma control, defined as an 
increase from baseline in ACQ-5 score of ≥ 0.5 units 

Proportion of subjects with a clinically meaningful worsening of health-related 
quality of life measurements (SGRQ) at weeks 12, 24, 36 and 52 (defined as 
subjects who have a clinically relevant increase from baseline of ≥4 units in 
SGRQ score).

Mean change from baseline in SGRQ score at week 12, 24, 36 and 52

Subject/Clinician global impression of asthma severity rating at weeks 12, 24, 
36 and 52


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
Subject/Clinician  rating of response to therapy at weeks 12, 24, 36 and 52

Number of days in hospital due to asthma

Unscheduled healthcare contacts/resource utilisation

Days off of regular work/school
Safety Endpoints

Adverse Events and Serious Adverse Events

Clinical Laboratory parameters

12-lead ECG parameters

Vital Signs
5.
STUDY DESIGN
5.1.
Overall Design
This is a 52-week, 2-arm, randomized, double-blind, parallel-group, multi-center study 
evaluating mepolizumab 100 mg and placebo administered SC every 4 weeks in subjects 
with severe eosinophilic asthma who have been treated with mepolizumab continuously 
in addition to standard of care therapy for at least 3 years.
Definition of Continuous Mepolizumab Treatment 
Continuous treatment with mepolizumab is defined as no more than 2 consecutive missed 
doses, i.e. no treatment gaps of more than 12 weeks (84 days) between any two doses. 
When deriving the period of continuous mepolizumab exposure, treatment from the 
following studies may be considered: MEA115666, MEA115588, MEA115575, 
MEA115661 and 201312. The earliest date of initiating mepolizumab treatment may be 
considered when deriving this total exposure, however if a gap of >84 days between any 
two doses of mepolizumab is experienced, this exposure period can no longer be 
considered ‘continuous’. If such an instance occurs the subject's period of continuous 
mepolizumab treatment will be derived from the first dose of mepolizumab following this 
gap in mepolizumab treatment. 
However, if a subject has experienced a gap of >12 weeks (84 days) between any two 
doses of mepolizumab within studies MEA115666 or 201312 this will exclude the 
subject from entry into 201810.
It is intended that the Follow Up/Exit Visit or Early Withdrawal (EW) for studies 
MEA115666 and 201312 will serve as the Pre-Screening/Screening Visit (Visit 0/Visit 1) 
for this study. For subjects who are unable to complete the Follow Up/Exit Visit or EW 
from their preceding study and Visit 1 for this study on the same day, a Pre-Screening 


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Visit (Visit 0) is included in order to obtain the signed informed consent, review 
concomitant medications, and perform an exacerbation review. In this case, Visit 1 must 
then be completed within 12 weeks (no more than 84 days) of the last dose in 
MEA115666/201312 to ensure continuous treatment with mepolizumab is maintained per 
inclusion criteria (Section 6.1). It is expected that in most cases, the Pre-Screening Visit 
and Screening Visit will be conducted on the same day. 
A study schematic is shown in Figure 1. Assessments at each visit are summarised in the 
Time and Events Tables (Table 5, Table 6, Table 7 and Table 8).
Figure 1
Study Schematic
Subjects will remain on standard of care asthma therapy (controller therapy) throughout 
the study. Standard of care will consist of inhaled corticosteroids (ICS) and another 
controller, e.g. Long-Acting Beta2-Agonists (LABA), with or without maintenance oral 
corticosteroids (OCS). Standard of care therapy may have been adjusted during the 
MEA115666 and 201312 studies and may be adjusted during the variable open-label run-
in period (Part A) at the discretion of the investigator. During the fixed open-label run-in 
period (Part B) and the double-blind treatment period (Part C), subjects should maintain 
the stable dose and regimen of controller therapy established in Part A or studies 
MEA115666 and 201312. 
Any change in controller regimen or dose in Part B and Part C (except for OCS use for 
the treatment of exacerbations) should be discussed with the medical monitor. 
Albuterol/salbutamol will be provided to subjects for use on an as needed basis for relief 
of asthma symptoms from Visit 1 throughout the study.  
Part A and B: Variable and Fixed Open-Label Run-In Periods
At Visit 1 (Screening), eligible subjects will have their exposure period for mepolizumab 
treatment assessed:


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
Subjects with less than 3 years of mepolizumab treatment will enter Part A of 
the study, a variable open-label run-in period on mepolizumab (100 mg SC every 
4 weeks) of 4 to 132 weeks, in order for subjects to reach 3 years of exposure to 
mepolizumab. 
o
Once the required 3 year exposure is reached, the subject will enter Part B 
of the study at Visit B1 and complete a fixed run-in period of 4 weeks (up 
to 8 weeks) during which open-label mepolizumab (100 mg SC every 4 
weeks) is administered, in order to collect baseline information.

Subjects with at least 3 years of mepolizumab treatment will directly enter 
Part B of the study. For these subjects, assessments for Visit 1 and Visit B1 
should be conducted on the same day. No assessments should be duplicated.
Part C: Double-Blind Treatment Period
Upon completion of the fixed run-in period Part B, eligible subjects will be randomized 
1:1 to the following double-blind treatment arms at Visit C1:

mepolizumab (100 mg) administered SC every 4 weeks

placebo administered SC every 4 weeks 
All subjects will be given a paper diary starting at Visit 1 through the Exit Visit or EW to
record any medical problems experienced during the study, and any medication taken for 
those medical problems. Any unscheduled healthcare resource utilization (e.g.; physician 
visits, emergency department visits) due to asthma will also be recorded. 
Subjects will complete a daily electronic diary (eDiary) during the fixed run-in Part B,
double-blind treatment period Part C and open-label Part D. Subjects will be asked to 
provide the following information daily:

AM Peak flow before rescue medication usage (L/min)

Rescue medication use

Nocturnal awakening due to asthma symptoms requiring rescue medication use

Asthma symptoms

Missed days of work/school due to asthma
Subjects will also be asked to provide the following information via eDiary weekly:

Asthma Control Questionnaire-5 (ACQ-5)
Part D: Optional Switch to Open-Label Mepolizumab
Subjects who experience a clinically significant asthma exacerbation during the double-
blind treatment period Part C will require a prompt assessment by the investigator to 
determine if they should continue taking double-blind study treatment. 


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Subjects deemed to be unsuitable to continue double-blind study treatment by the 
investigator should discontinue double-blind investigational product (IP) and complete a 
Discontinuation of IP Visit approximately 4 weeks following their last dose of double-
blind IP.  
Subjects discontinuing IP due to a clinically significant asthma exacerbation are eligible 
to enter optional Part D of the study and receive open-label mepolizumab in addition to 
their standard of care therapy for the remainder of the study, through Part D, to Visit 
D13. Subjects switching to Part D should complete the Discontinuation of IP Visit and 
their first Part D visit on the same day, corresponding to the week post-randomization. 
No assessments should be duplicated.
Switch to Part D between visits: For example, if a subject completed Visit C7 at Week 24 
(and the subject received a dose of IP at Visit C7) and it is later determined that they 
should switch to Part D, the IP Discontinuation assessments and the first visit in Part D 
will be D8 at Week 28. 
Switch to Part D during a visit: If a subject is in the process of completing a Part C visit, 
as long as they have not yet received a dose of IP, they may be switched to Part D at that 
same visit (e.g., a subject that is part way through Visit C7 at Week 24 and whose last 
dose of IP was at Visit C6, Week 20 can be switched to Part D and complete the IP 
Discontinuation assessments and Visit D7 at that same visit, Week 24).
Haematology samples will be collected for each of the subject’s first 3 visits of Part D, 
and then according to designated Visits in Table 8.
An Exit Visit will be conducted 52 weeks after randomization (whether the subject is in 
Part C or Part D) in order to assess subject’s efficacy parameters, immunogenicity status, 
and to conduct additional safety assessments. 
Subjects who permanently discontinue study treatment in Part C or D of the study are 
NOT required to withdraw from the study. If a subject discontinues double blind study 
treatment during Part C and does not switch to Part D at their next visit (IP 
Discontinuation Visit) after experiencing a clinically significant asthma exacerbation, the 
subject cannot enter Part D at a later visit.  
5.2.
Study Phases, Duration and Treatment Arms
Eligible subjects will participate in the study ranging from 56 to192 weeks, depending on 
the duration of Part A (0 to 132 weeks) and Part B (4 to 8 weeks). A summary of study 
phases is described in Table 2.


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Table 2
Study Phases, Duration and Study Treatments
Study 
Phase
Phase Title
Duration
Treatment arms
Part A
Variable 
Open-Label 
Run-In
0 to 132 weeks
Open-label mepolizumab (100 mg SC) 
every 4 weeks
Part B
Fixed Open-
Label Run-In
4 weeks (up to 
8 weeks)
Open-label mepolizumab (100 mg SC) 
every 4 weeks
Part C
Double Blind 
Treatment 
Period
52 weeks
Subjects randomized 1:1 to double-blind
study treatment:

mepolizumab (100 mg SC) every 4 
weeks

placebo administered SC every 4 
weeks 
Optional 
Part D
Open-Label 
Switch
Up to 52-
weeks post-
randomization.
Open-label mepolizumab (100 mg SC) 
every 4 weeks
5.3.
Type and Number of Subjects
Subjects with severe eosinophilic asthma who completed the Follow Up/Exit Visit or EW 
Visit from either open-label study MEA115666 or 201312 will be eligible to participate 
in this study.
It is estimated that approximately 375 subjects with severe eosinophilic asthma from 
studies MEA115666 and 201312 are expected to be screened in order to randomize 
approximately 300 subjects 1:1 to double-blind study treatment (150 per arm). It is 
anticipated that approximately 120 subjects will experience a clinically significant 
exacerbation and meet the criteria for the Switch to Open-Label Mepolizumab treatment 
within Part D. The sample size calculations assume 20% of subjects will withdraw prior 
to the end of the double-blind treatment phase before experiencing an exacerbation. It is 
anticipated that approximately 120 subjects will complete the double-blind treatment 
period within Part C, Visit 13.


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5.4.
Design Justification
This study is designed to evaluate treatment response following withdrawal of 
mepolizumab after at least 3 years of treatment in patients with severe eosinophilic 
asthma comparing mepolizumab continuation with placebo over one year. All subjects 
should continue standard of care therapy throughout the study, and both mepolizumab 
and placebo arms will be dosed in addition to standard of care. Subjects who have 
participated in studies MEA115666 and 201312 are eligible to enroll, as they have been 
determined to be appropriate candidates for treatment with mepolizumab and will have a 
substantial duration of mepolizumab treatment. This will minimize the duration of study 
participation compared to enrolment of mepolizumab naive subjects.
A placebo controlled, double-blinded study is a well established means to compare the 
effect of treatment in two treatment arms. There are currently no alternative approved 
therapies for severe eosinophilic asthma and, therefore, the comparator arm will be 
placebo in addition to standard of care treatment. Standard of care will consist of ICS and 
another controller, e.g. LABA, with or without maintenance OCS. This is consistent with 
current standard of care treatment used in a severe asthma population [ATS, 2000;
Chung, 2014].
A primary endpoint of time to first clinically significant exacerbation was selected as a 
robust measure to evaluate the return of disease activity following the discontinuation of 
mepolizumab treatment after long term use. Additional measures of exacerbation severity 
are also included. As this study is designed to evaluate withdrawal of treatment after long 
term use, it is anticipated that the rate of discontinuation from Part C may be high and 
therefore limit the ability to assess exacerbation rate. An optional switch to open- label 
mepolizumab is included in the study design (Part D) to collect additional safety data and 
to prevent loss to follow-up. A study duration of 52 weeks is considered adequate for the
evaluation of exacerbations [EMA, 2013].
Part A is designed to ensure that all subjects have a duration of mepolizumab treatment of 
at least 3 years prior to randomization. The purpose of Part B is to collect baseline eDiary 
and safety information.
Eosinophil levels are an important proxy of IL-5 activity, the biological target of 
mepolizumab. Increasing levels of eosinophils after mepolizumab withdrawal after 1 year 
or treatment have previously shown to be correlated to increasing exacerbation frequency 
[Haldar, 2014]. Thus, it is important to measure eosinophils as a biomarker of 
mepolizumab activity in patients who are withdrawn from mepolizumab treatment after 
long-term treatment. To ensure the integrity of the blind, eosinophil levels will be blinded 
to both the Investigator/site staff and the study team during Part C and Part D.
The Asthma Control Questionnaire (ACQ-5) will be used to assist the investigator in 
assessing the subject’s asthma status. The ACQ has been validated in several separate 
studies and the minimal clinically important difference value of ±0.5 has been established 
to demonstrate a significant clinical change in asthma status [Juniper, 2005].


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5.5.
Dose Justification
The dose selection is based on previous experience from a Phase 3 program, including 
two Phase 3 placebo-controlled studies (MEA115588 and MEA115575) that 
demonstrated the safety and efficacy of mepolizumab at a dose of 100 mg SC.
Additionally, this is the same dose that subjects received in precursor studies 
MEA115666 and 201312. See the IB for additional information.
5.6.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
mepolizumab can be found in the IB/IB supplement.  The following section (Table 3) 
outlines the risk assessment and mitigation strategy for this protocol:
5.6.1.
Risk Assessment

Across the mepolizumab development program, chronic dosing of mepolizumab up 
to 750 mg intravenous (IV) every 4 weeks has been associated with an adverse event 
(AE) profile similar to placebo (both dosed in addition to standard of care therapy),
in the patient populations studied, including mild to moderate asthma and severe
refractory asthma.  

The majority of reports of systemic non-allergic and allergic (i.e., hypersensitivity) 
reactions have been non-serious and resolved without sequelae following minimal 
supportive care. There have been rare reports of serious reactions.

Anti-drug antibodies (ADA) have been observed infrequently and have not been 
associated with negative clinical outcomes; there has been no evidence of untoward 
or persistent neutralizing antibodies (NaB) at any dose.

Infection rates have been similar across treatment groups. The data to date do not 
support an association between treatment with mepolizumab and an increased risk of 
clinically serious opportunistic or parasitic infections.

Reports of malignancies have been similar between treatment groups in placebo-
controlled trials.  The known biology of IL-5 and eosinophils suggest that blocking 
the binding of IL-5 to its receptor with mepolizumab would not likely induce an 
immuno-suppressive effect that would impair host surveillance against malignancy.  

There is a risk of exacerbation in subjects randomized to placebo (in addition to their 
standard of care therapy). An increased exacerbation frequency was reported in 
subjects withdrawn from mepolizumab after one year of treatment [Haldar, 2014]. 
However, it is undetermined if certain patients will continue to receive treatment 
benefit after withdrawal of mepolizumab following long-term treatment.


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Table 3
Risk Assessment and Mitigation Strategy
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) mepolizumab
Risk of Systemic Allergic and Non-allergic 
Reactions, including Anaphylaxis
Biopharmaceutical products administered 
subcutaneously may elicit systemic (e.g. 
hypersensitivity) and local site reactions.
Reactions reported to date across the 
mepolizumab program are summarized in the 
IB; see ‘Special Warnings and Special 
Precautions for Use’ section located in Section 6
titled ‘Summary of Data and Guidance for the 
Investigator’.
Daily monitoring of serious adverse events 
(SAEs) by medical monitor; regular systematic 
review of adverse event (AE)/SAE data from 
ongoing studies by a GSK safety review team. 
Specific case report form (CRF) pages utilized 
for targeted collection of reactions data.
Use of Joint NIAID/FAAN 2nd Symposium 
on Anaphylaxis to collect data on reports of 
anaphylaxis (see Appendix 8).
Safety monitoring of subjects is required during 
SC administration, in accordance with standard 
of care at the site.
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.
Immunogenicity data reported to date across the 
mepolizumab development program are 
summarized in the IB; See ‘Clinical 
Blood samples are collected in clinical studies 
for detection of both ADA and NaB.
Monitoring of subjects for immunogenic-related 
events will be done by the treating physician as 
per standard of care.
Immunogenicity profile will be updated in the 
Mepolizumab IB as appropriate.


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Immunogenicity’ and a summary of 
immunogenicity findings in the ‘Other 
Potentially Clinically Relevant Information for 
the Investigator’ section titled ‘Summary of 
Data and Guidance for the Investigator’.
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 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 
Subjects with uncontrolled, severe or clinically 
significant cardiovascular disease are excluded 
from study participation.
Daily monitoring of SAEs by medical monitor; 
regular systematic review of AE/SAE data from 
ongoing studies by a GSK safety review team.
CV monitoring for study includes:

ECG monitoring during the trial

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
Summary of Data/Rationale for Risk
Mitigation Strategy
System SOC).
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. 
An integrated safety analysis of all placebo-
controlled multiple dose asthma trials showed 
similar reports of infections, including serious 
and opportunistic, across treatment groups 
including placebo. 
Infections reported to date across the 
mepolizumab development program are 
summarized in the IB; see ‘Special Precautions 
and Warnings’ (for exclusion of subjects with 
underlying parasitic infections) and 
‘Undesirable Effects’ (for very common 
infections of nasopharyngitis, upper respiratory 
tract infection (URTI), rhinitis and bronchitis 
reported in other patient populations) sections
Daily monitoring of SAEs by 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 protocol


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
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. 
An integrated safety analysis of all placebo-
controlled multiple dose asthma trials showed 
similar reports of malignancies across treatment 
groups including placebo.
Malignancies reported to date across the 
mepolizumab development program are 
summarized in the IB.
Daily monitoring of SAEs by 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 protocol
Placebo
Inclusion of placebo arm
Mepolizumab has been shown to be an effective 
treatment for the reduction of exacerbations for 
patients with severe eosinophilic asthma. 
There is currently no pre-clinical or clinical 
evidence to suggest long-term continuation 
Both mepolizumab and placebo double-blind 
study treatments will be dosed in addition to 
standard of care therapy including corticosteroid 
treatment (ICS or OCS) and a long-acting 
bronchodilator. 


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
of treatment benefit after withdrawal of 
mepolizumab [Haldar, 2014], however, this 
has not been prospectively evaluated in 
subjects after long-term treatment with 
mepolizumab.
Subjects will be provided with rescue 
albuterol/salbutamol throughout the study. 
Subject’s condition will be assessed at clinic 
visits every 4 weeks.
Subjects’ symptoms and rescue medication 
usage will be tracked daily via eDiary. Subjects
with increasing respiratory symptoms indicative 
of worsening of asthma will automatically be 
notified through the symptom diary to contact 
their investigator for further evaluation.
Investigators will also receive alerts, and review 
eDiary data weekly.
Additionally, to minimize the impact of 
significant worsening due to withdrawal of 
therapy over 52 weeks, subjects may optionally 
switch to open-label mepolizumab (Part D) per 
investigator discretion after experiencing one 
clinically significant asthma exacerbation. 
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 
[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 
Daily monitoring of SAEs by 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 protocol


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
‘rebound’ from completed clinical trials of 
subjects with asthma, atopic dermatitis and 
eosinophilic esophagitis. Furthermore, the data 
do not support an exaggerated return of 
symptoms after cessation of treatment.
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) 


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5.6.2.
Benefit Assessment
Data from earlier studies [Haldar, 2009; Nair, 2009; Pavord, 2012] attest to the clinical 
utility of mepolizumab in the treatment of severe eosinophilic asthma, as do the data from 
recently completed Phase III studies MEA115575 and MEA115588 [Bel, 2014; Ortega, 
2014]. 
In this study, benefit considerations for a subject may include:

Continuation to receive active drug during study conduct that may have clinical 
benefit, even for subjects randomized to placebo who may undergo switch to open-
label mepolizumab after experiencing one clinically significant asthma exacerbation

Contributing to the process of developing new therapies in an area of unmet need, and 
providing insight into the need for continuous therapy in order to receive clinical 
benefit

Medical evaluations/assessments associated with study procedures
5.6.3.
Overall Benefit:Risk Conclusion
Current data from mepolizumab preclinical and clinical development indicate the ability 
of mepolizumab to inhibit IL-5 leading to consistent reduction in blood eosinophils, with 
demonstration of clinical benefit in the treatment of conditions associated with 
eosinophilic inflammation, such as asthma. Data from the Phase III asthma programme 
with mepolizumab demonstrates, compared to placebo, a reduction in asthma 
exacerbations, improvements in asthma control and quality of life (as measured by the 
ACQ and SGRQ, respectively), improvements in lung function and a reduction in steroid 
use in those subjects on chronic OCS treatment. To date, the safety profile of 
mepolizumab compared to placebo has been favorable and AEs reported commonly are 
non-serious and manageable with minimal supportive care.  Furthermore, evaluation of 
the post-treatment adverse event data from the severe asthma clinical program does not 
support an exaggerated return of symptoms after cessation of treatment.
Considering the measures taken to minimize risk to a subject participating in this study,
the potential risks identified are justified by the anticipated benefits that may be afforded 
to a subject with severe asthma. Therefore, the Sponsor considers that investigation of the 
effect of cessation versus continuation of long-term mepolizumab treatment in patients 
with severe eosinophilic asthma is justified in study 201810 with a positive benefit/risk 
ratio.
6.
SELECTION OF STUDY POPULATION, IP 
DISCONTINUATION 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/IB supplement(s).


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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.
6.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if ALL of the following criteria 
apply:
1. Informed Consent: Prior to commencing any study related activities, subjects 
must be able and willing to provide written informed consent, and an assent for 
subjects under 18 years of age, at Visit 0 (or Visit 1 if these Visits are conducted 
on the same day).
2. Continuous Mepolizumab Treatment during MEA115666 or 201312: 
Participation through the Follow Up/Exit Visit or Early Withdrawal Visit and 
documented evidence of treatment with mepolizumab with no treatment gaps of 
more than 12 weeks (84 days) between any two doses within MEA115666 or 
201312.  (A treatment gap of more than 12 weeks [84 days] cannot occur between 
the end of MEA115666 or 201312 and Visit 1).
3. Current Anti-Asthma Therapy: Asthma is currently being treated with a 
controller medication and the subject has been on a controller medication for the 
past 12 weeks. Subjects will be expected to continue controller therapy for the 
duration of the study.
4. Male or Eligible Female Subjects:
A female is eligible to enter and participate in the study if she is of:
Non-child bearing potential (i.e., physiologically incapable of becoming 
pregnant, including any female who is post-menopausal or surgically sterile). 
Surgically sterile females are defined as those with a documented hysterectomy 
and/or bilateral oophorectomy or tubal ligation. Post-menopausal females are 
defined as being amenorrhoeic for greater than 1 year with an appropriate clinical 
profile, e.g., age appropriate, > 45 years, in the absence of hormone replacement 
therapy.
OR
Child bearing potential, has a negative pregnancy test at screening, and agrees to 
acceptable contraceptive methods approved in their local country, when used 
consistently and correctly (i.e., in accordance with the approved product label and 
the instructions of the physician) for the duration of the study and for 4 months 
after the last study drug administration (see Appendix 5).
A urine pregnancy test is required of all females of child-bearing potential at
each scheduled study visit prior to the injection of study treatment, and at the Exit 
Visit, EW or Discontinuation of IP Visit.


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5. French subjects: In France, a subject will be eligible for inclusion in this study 
only if either affiliated to or a beneficiary of a social security category.
6.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if ANY of the following criteria 
apply:
1.
MEA115666 or 201312 IP Discontinuation: Subjects withdrawn from IP or 
withdrawn from study participation from either MEA115666 or 201312 for safety 
reasons
2.
Health Status: Clinically significant deterioration in health status at the completion 
of participation or EW from either the MEA115666 or 201312 trials which in the 
opinion of the investigator would make the subject unsuitable for participation in this 
study.
3.
Pregnancy: Subjects who are pregnant or breastfeeding. Subjects should not be 
enrolled if they plan to become pregnant during the time of study participation.
4.
Cardiovascular: Subjects who have severe or clinically significant cardiovascular 
disease uncontrolled with standard treatment. Including but not limited to:

known ejection fraction of <30% OR

severe heart failure meeting New York Heart Association Class IV 
classification OR

hospitalised in the 12 months prior to Visit 1 for severe heart failure meeting 
New York Heart Association Class III OR

angina diagnosed less than 3 months prior to Visit 1 or at Visit 1
5.
12-Lead ECG: ECG which has a clinically significant abnormality observed at the 
Screening Visit as determined by the investigator. Subjects with the following 
abnormalities are excluded from study participation: 

QTcF > 450 msec, or 

QTcF >480 msec for subjects with Bundle Branch Block.
6.
Malignancy: A current malignancy or previous history of cancer in remission for 
less than 12 months prior to screening (Subjects that had localized carcinoma of the 
skin which was resected for cure will not be excluded). [Note for South Korea: 
Korean subjects with a diagnosis of malignancy within 5 years are excluded].
7.
Other Monoclonal Antibodies: Subjects who have received any monoclonal 
antibody within 5 half-lives of Visit 1. 
8.
Adherence: Subjects who have known evidence of lack of adherence within studies 
MEA115666 or 201312 (less than 80%) to controller medications, scheduled study 
visits and/or ability to follow physician’s recommendations.
9.
Smoking status: Current smokers


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10. Inability to read: In the opinion of the Investigator, any subject who is unable to 
read and/or would not be able to complete a questionnaire.
6.3.
Randomization Criteria
6.3.1.
Randomization Inclusion Criteria
Subjects are eligible for randomization if ALL of the following are met:
1.
Continuous Mepolizumab Treatment: Documented evidence of at least 3 years 
(156 weeks) of treatment with mepolizumab with no treatment gaps of more than 
12 weeks (84 days) between any two doses while treated with mepolizumab. See 
Section 5.1 for the definition of continuous mepolizumab treatment.
2.
eDiary Compliance: Compliance with completion of the eDiary defined as:
Symptom Scores: Completion of symptom scores on 4 or more days out of the 
last 7 days immediately preceding Visit C1.
Rescue Medication Use: Completion of information relating to rescue 
medication use on 4 or more days out of the last 7 days immediately preceding 
Visit C1.
PEF Measurements: Completion of PEF measurements on 4 or more days out 
of the last 7 days immediately preceding Visit C1.
Night time awakenings requiring rescue medication: Completion of night
time awakenings on 4 or more days out of the last 7 days immediately preceding 
Visit C1.
Subjects who fail this criterion in the run-in Part B may extend their run-in Part B by 4 
weeks, and be re-educated on the importance of completion of eDiary daily entries.
3.
Maintenance Asthma Therapy: No changes in the dose or regimen of baseline ICS 
and/or additional controller medication (except for OCS for the treatment of an 
exacerbation) during the fixed run-in period (Part B).
6.3.2.
Randomization Exclusion Criteria
Subjects should not be randomized if ANY of the following are met:
1.
Health Status: Clinically significant deterioration in health status during Part A or 
Part B which in the opinion of the investigator would make the subject unsuitable for 
participation in this study.
2.
12-Lead ECG as assessed at Visit B1: ECG which has a clinically significant 
abnormality as assessed at Visit B1, as determined by the investigator. Subjects with 
the following abnormalities are excluded from further study participation: 

QTcF > 450 msec, or 


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
QTcF >480 msec for subjects with Bundle Branch Block.
3.
Liver function as assessed at Visit B1: 
Alanine transaminase (ALT) >2x upper limit of normal (ULN); and 
Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%)
Current active liver or biliary disease (with the exception of Gilbert’s syndrome or 
asymptomatic gallstones or otherwise stable chronic liver disease per investigator 
assessment).
NOTES: 

Stable chronic liver disease should generally be defined by the absence of 
ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or 
gastric varices, or persistent jaundice, or cirrhosis.

Chronic stable hepatitis B and C (e.g., presence of hepatitis B surface antigen 
(HBsAg) or positive hepatitis C antibody test result at screening or within 3 
months prior to first dose of study treatment) are acceptable if subject otherwise 
meets entry criteria
4.
Pregnancy: Positive pregnancy test
5.
Immunogenicity: Positive neutralizing antibody status based on the last result
obtained.
6.
Smoking status: Current smokers
7.
Current Asthma Exacerbation: Subjects with an asthma exacerbation (or asthma 
worsening) that has not resolved completely within 7 days of Visit C1. Subjects who 
experience an exacerbation (or asthma worsening) in the fixed run-in Part B which is 
not resolved within 7 days of Visit C1 may extend their run-in Part B by 4 weeks.
6.4.
Pre-screen/Screen/Run-in Failures
Pre-screen/screen failures/run-in failures are defined as subjects who consent to 
participate in the clinical trial but are never subsequently randomized. In order to ensure 
transparent reporting of screen failure subjects, meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements, and respond to queries from 
Regulatory authorities, a minimal set of screen failure information is required including, 
but not limited to Demography, Screen Failure details, Eligibility Criteria and Serious 
Adverse Events (see Section 8.4.1.5).
For the purposes of this study pre-screen/screen failures/run-in failures will be defined as 
follows:

Subjects will be assigned a study number at the time of signing the informed 
consent (Pre-screen Visit). Subjects who do not progress to the Screening Visit 
will be deemed a pre-screen failure.


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
Those subjects that complete at least one additional Visit 1 (Screening) procedure 
but do not enter the run-in period will be designated as screen failures.

Those subjects that enter Part A or Part B, but are not randomized, will be 
designated as run-in failures.
Subjects who fail to meet inclusion and exclusion criteria at Visit 1 will be considered 
screen failures and cannot be re-screened.
6.5.
Study Withdrawal Prior to Randomization: Withdrawal 
during Part A or Part B
Subjects have the right to discontinue study participation before the end of the study. A 
subject may also be asked to discontinue study participation at the investigator’s 
discretion or because the subject met the protocol defined stopping criteria detailed 
below.
Subjects in Parts A or B of the study MUST discontinue study participation if any of the 
following stopping criteria are met: 
1.
Liver Chemistry: Meets any of the protocol-defined liver chemistry stopping 
criteria (see Appendix 2).
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/GuidanceComplianceRegulatoryInformati
on/Guidances/UCM174090.pdf
If the liver chemistry stopping criteria are met by any subject participating in this 
study, treatment restart or re-challenge is not permitted.
2.
Pregnancy: Positive pregnancy test 
3.
Laboratory abnormality: Evidence of clinically significant abnormality in the 
haematological or biochemical screen, which in the opinion of the investigator 
would make the subject unsuitable for participation in this study.
4.
Hepatitis Status: Positive Hepatitis B Surface Antigen (HBsAg) screen
conducted at Visit 1.
5.
ECG: Discontinuation is required if any of the following ECG criteria are met 
during the study:

QTcF>500 msec or uncorrected QT>600 msec

Change from Visit 1 baseline: QTcF> 60msec


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For patients with underlying bundle branch block, follow the discontinuation 
criteria listed below:
Visit 1 Baseline QTc with 
Bundle Branch Block
Discontinuation QTc with 
Bundle Branch Block
< 450 msec
> 500 msec
450 – 480 msec
≥ 530 msec [Note: QTc(F)>500 
msec for Korean subjects]
Details on performing ECG assessments can be found in Section 8.4.5.
Subjects who discontinue open-label mepolizumab/withdraw from study participation 
during Part A or Part B should return to the clinic for an Early Withdrawal (EW) visit 
(Section 6.6.1) and to return any study materials approximately 4 weeks following their 
last dose of open-label mepolizumab. No additional follow-up is needed.
Subjects withdrawing from study participation in Part A or Part B, prior to randomization 
will be classified as run-in failures, as appropriate (Section 6.4). 
6.6.
Discontinuation of Investigational Product (IP) during Part C 
or Part D
Subjects in study Part C or D who have permanently discontinued double-blind or 
open-label IP are NOT required to withdraw from the study. Subjects have the right 
to permanently discontinue IP before the end of the study. A subject may also be asked to 
discontinue IP at the investigator’s discretion or because the subject met the protocol 
defined IP discontinuation criteria detailed below. Subjects who discontinue IP, but 
remain in the study will be treated per local standard of care, according to the judgment 
of the investigator.
Subjects in Parts C or D of the study MUST discontinue IP permanently if either 1, 2 or 3 
of the following stopping criteria are met: 
1.
Liver Chemistry: Meets any of the protocol-defined liver chemistry stopping 
criteria (see Appendix 2).
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/GuidanceComplianceRegulatoryInformati
on/Guidances/UCM174090.pdf
If the liver chemistry stopping criteria are met by any subject participating in this 
study, treatment restart or re-challenge is not permitted.
2.
Pregnancy: Positive pregnancy test 


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3.
ECG: Discontinuation is required if any of the following ECG criteria are met 
during the study:

QTcF>500 msec or uncorrected QT>600 msec

Change from Visit B1 baseline: QTcF> 60msec
For patients with underlying bundle branch block, follow the discontinuation 
criteria listed below:
Visit B1 Baseline QTc with 
Bundle Branch Block
Discontinuation QTc with 
Bundle Branch Block
< 450 msec
> 500 msec
450 – 480 msec
≥ 530 msec [Note: QTc(F)>500 
msec for Korean subjects]
Details on performing ECG assessments can be found in Section 8.4.5.
Subjects in Part C who meet IP discontinuation criteria 1, 2 or 3 will not be eligible to 
switch to open-label Part D.
Subjects who have permanently discontinued IP and have not withdrawn consent may 
continue in the study. Subjects wishing to remain in the study will complete an IP 
Discontinuation Visit (approximately 4 weeks after the last dose and may be at the same 
time as a scheduled visit) and continue to attend the clinic visits at the protocol 
designated time intervals and complete eDiary daily and weekly entries for important 
efficacy and safety assessments. However, if this is not possible then the investigator will 
encourage the subject to participate in as much of the study as they are willing (or able) 
to. Guidance is provided in the study reference manual (SRM) and can be used by the 
investigator to discuss and agree the appropriate level of ongoing study participation with 
subjects, after they have discontinued IP. 
If the subject is unable to visit the clinic to complete any study assessments which require
physical presence of the subject, visits will occur by telephone contact to review the 
following:

Exacerbations

Adverse Event (AE)/Serious Adverse Events (SAEs)

Concomitant medications
Subjects discontinuing IP, but remaining in the study should continue to record on their 
paper diary any medical problems experienced during the study, and any medication 
taken for those medical problems. 


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6.6.1.
IP Discontinuation Visit Assessments
The Investigator must make every effort to have the subject return to the clinic 
approximately 4 weeks after the subject permanently discontinues IP in order to complete 
the IP Discontinuation Visit. Evaluations and procedures as outlined in the Time and 
Events Tables (Table 5, Table 6, Table 7 and Table 8) should be completed and recorded 
in the eCRF as required.
6.6.2.
Reasons for Discontinuation of IP
The primary reason for permanent discontinuation of IP will be recorded in the eCRF on 
the IP discontinuation form. Specific regard should be given to distinguishing permanent 
discontinuation of IP due to an adverse event from other reasons for permanent 
discontinuation of IP.  
6.7.
Study Withdrawal During Part C or Part D
6.7.1.
Study Withdrawal Criteria
For this study there are no pre-determined protocol specific study withdrawal criteria (see
Protocol Defined IP Discontinuation Criteria, Section 6.6).
6.7.2.
Study Withdrawal Assessments
If a subject is withdrawn from the study for any reason, including but not limited to the 
Protocol Defined IP Discontinuation Criteria (Section 6.6), the Investigator must make 
every effort to have the subject to return to the clinic for an EW Visit approximately 4 
weeks following the last dose to perform EW Visit assessments and to return all study-
related materials. Assessments are described in the Time and Events Tables (Table 5, 
Table 6, Table 7 and Table 8). 
Subjects who have previously discontinued IP and have already completed their IP
Discontinuation Visit (approximately 4 weeks following the last dose) but then decide at 
a later date that they no longer wish to participate in the study, will be asked to return to 
the clinic to complete an EW Visit (approximately 4±1 weeks) to complete any EW 
assessments, as agreed by the subject and investigator, and to return any remaining study 
materials. No additional safety follow-up visit is required.
6.7.3.
Reasons for Withdrawal
The primary reason for study withdrawal will be recorded in the eCRF. Specific regard 
should be given to distinguishing withdrawal due to an adverse event from other reasons 
for withdrawal.  
6.7.4.
Lost to Follow Up
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:


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
The site must attempt to contact the subject and re-schedule the missed visit as 
soon as possible. 

The site must counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or should 
continue in the study. 

In cases where the subject is deemed ‘lost to follow up’, the investigator or 
designee must make every effort to regain contact with the subject (where 
possible, 3 telephone calls and if necessary a certified letter to the subject’s last 
known mailing address or local equivalent methods). These contact attempts 
should be documented in the subject’s medical record. 

Should the subject continue to be unreachable, only then will he/she be considered 
to have withdrawn from the study with a primary reason of “Lost to Follow-up”. 
6.8.
Subject and Study Completion
A subject will be considered to have completed study treatment if he/she receives study 
treatment at Visit C13 or D13 (Week 48). A subject will be considered to have completed 
the study if they continue to participate in the study until the Exit Visit assessments have 
been completed (regardless of whether the subject completed the study treatment 
schedule).
The end of the study is defined as the subject’s last visit.
7.
STUDY TREATMENT
7.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design. Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments.
Mepolizumab (SB-240563) is a fully humanised IgG 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, as described in the SRM.  
The placebo in this study will be 0.9% sodium chloride solution and will be provided by 
the study site. 
Trade label albuterol/salbutamol metered dose inhalers (MDIs) will be provided as rescue 
medication throughout the study. Albuterol/salbutamol will be sourced by GSK for 
centers in the United States of America. For all other centers it will be sourced locally 
where possible. Subjects will be dispensed an MDI at the time of Visit 1 to be used to 
primarily treat asthma symptoms on an as needed basis. The MDI should be replaced as 
needed, and collected at the Exit Visit or EW visit.


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Safety monitoring of subjects is required during SC administration in accordance with 
standard of care at the site. Such monitoring will include general safety monitoring 
including monitoring for systemic (i.e., allergic/IgE-mediated and non-allergic) and local 
injection site reactions. In the event of an acute severe reaction (e.g., anaphylaxis) 
following administration of study treatment, there are personnel/staff onsite at the 
treatment facility who are appropriately trained in basic life support to manage the 
subject 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.
7.2.
Treatment Assignment
At the Randomization Visit (Visit C1) those subjects who meet the randomization 
eligibility criteria will be randomized in a 1:1 ratio to receive one of the following study 
treatments every 4 weeks in addition to their standard of care asthma treatment:

Mepolizumab 100mg SC into the upper arm or thigh

Placebo 0.9% sodium chloride SC into the upper arm or thigh
Subjects eligible to enter the study will be assigned to treatment randomly via an 
interactive response technology (IRT) system. 
The randomization schedule will be generated using the GSK validated randomization 
software RandAll NG. The study will be randomized separately for each country.  
Subjects will be assigned to study treatment in accordance with the randomization 
schedule. Once a randomization number has been assigned to a subject, it cannot be 
reassigned to any other subject in the study.
7.3.
Blinding
Study treatment will be prepared by a designated unblinded member of the study site 
staff (i.e. a qualified person who is independent of the protocol-defined study 
assessments) and will be administered by a designated blinded member of the site staff.  
Once prepared, mepolizumab and placebo will be identical in appearance. The blinding 
of all those involved in the evaluation of the study treatment (e.g. physician/nurse as well 
as the subject) shall be maintained at all times, therefore, procedures must be in-place at 
the study site to ensure that this blinding is maintained. Additionally, the site staff and 
central study team will be blinded to each subject’s eosinophil count (including blood 
count differential) and IL-5 values within Part C and D.
With regards to the emergency unblinding of the study treatment assigned to a specific 
subject, the following will apply:

The investigator or treating physician may unblind a subject’s treatment assignment 
only in the case of an emergency OR in the event of a serious medical condition 
when knowledge of the study treatment is essential for the appropriate clinical 
management or welfare of the subject as judged by the investigator. 


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
Investigators have direct access to the subject’s individual study treatment. 

It is preferred (but not required) that the investigator first contacts the Medical 
Monitor or appropriate GSK study personnel to discuss options before unblinding 
the subject’s treatment assignment. 

If GSK personnel are not contacted before the unblinding, the investigator must 
notify GSK as soon as possible after unblinding, but without revealing the treatment 
assignment of the unblinded subject, unless that information is important for the 
safety of subjects currently in the study. 

If the treatment code assigned to a subject in Part C is unblinded to the subject,
Investigator and/or the treating physician/blinded member of site staff, please consult 
the Study Reference Manual and GSK for guidance. Remediation will be assessed on 
a case by case basis to minimise the impact of any possible bias.

The date and reason for the unblinding must be fully documented in the eCRF

GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any subject with an SAE. If the SAE requires that an 
expedited regulatory report be sent to one or more regulatory agencies, a copy of the 
report, identifying the subject’s treatment assignment, may be sent to investigators in 
accordance with local regulations and/or GSK policy.
7.4.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
7.5.
Preparation/Handling/Storage/Accountability
Only subjects enrolled in the study may receive study treatment and only authorized site 
staff may supply or administer study treatment.
A description of the methods and materials required for the preparation of placebo or 
reconstitution of mepolizumab will be detailed in the unblinded staff manual which is 
available in the SRM.
A qualified unblinded site staff member assigned to the study will be required to prepare 
the appropriate study treatment according to the study subject’s treatment assignment 
(see Section 7.2 for further details on treatment assignment):

Mepolizumab: 1 mL of reconstituted mepolizumab (equivalent to 100 mg of 
mepolizumab) will be drawn into a 1 mL polypropylene syringe. 

Placebo: 1 mL of 0.9% sodium chloride solution will be drawn into a 1mL
polypropylene syringe.
A blinded staff member will administer the study treatment into the subject’s upper arm 
or thigh via SC injection. 


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
Under normal conditions of handling and administration, study treatment 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. In the case of 
unintentional occupational exposure notify the monitor, Medical Monitor and/or GSK 
study contact.

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.

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’s unblinded site staff. 

In accordance with local regulatory requirements, the investigator’s designated 
unblinded site staff, or head of the medical institution (where applicable) must 
document the amount of investigational product dispensed and the investigator or 
designated blinded site staff will document the amount administered to study subjects. 
The designated unblinded site staff will document the amount returned by blinded 
staff, and the amount received from and returned to GSK, when applicable.  Product
dispensing/accountability logs will be maintained by a designated unblinded member 
of the site staff throughout the study.
Further guidance and information for final disposition of unused study treatment are 
provided in the SRM. 
7.6.
Compliance with Study Treatment Administration
Mepolizumab and placebo will be administered via SC injection to subjects at the study 
site.  Administration will be documented in the source documents and reported in the 
eCRF.
7.7.
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 judgment in treating the symptoms 
of a suspected overdose.
7.8.
Treatment after the End of the Study
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition, whether or not GSK is providing specific 
post-study treatment.
There are no plans to routinely provide mepolizumab following study completion, as 
mepolizumab is expected to be commercially available in the countries participating in 
this study.


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7.9.
Concomitant Medications and Non-Drug Therapies
Details of asthma-related medications taken from 12 weeks prior to the first dose of study 
medication (Visit 1), until the Exit Visit or EW, will be collected and recorded in the 
eCRF (except rescue medication, which is only recorded in the eDiary).
Details of non-asthma-related medications taken from the first dose of study medication 
(Visit 1) until the Exit Visit or EW, will be collected and recorded in the eCRF. 
The minimum requirement for recording of concomitant medication is that the drug name 
and the start and stop dates of administration are recorded in the eCRF.  
7.9.1.
Permitted Medications and Non-Drug Therapies
Standard of care will consist of ICS and another controller, e.g. LABA, with or without 
maintenance OCS.
During the fixed open-label period (Part B) and the double-blind treatment period (Part 
C), subjects should maintain the stable dose and regimen of controller therapy established 
in Part A or in studies MEA115666 and 201312. Any change in controller regimen or 
dose in Part B and Part C (except for OCS use for the treatment of exacerbations) should 
be discussed with the medical monitor. 
Additional asthma medications such as theophyllines or anti-leukotrienes will be 
permitted provided that they have been taken regularly (per label) in the 12 weeks prior 
to randomization (Visit C1).  If uncertain whether a medication is permitted please
confirm with the medical monitor.
Albuterol/salbutamol is permitted throughout the study, except in the 6 hour period prior 
to spirometry conducted at clinic visits. Study provided Albuterol/salbutamol should 
NOT be recorded in the eCRF, but will be captured in the eDiary.
LABAs or ICS/LABA fixed dose combinations should be withheld for 12 hours prior 
to spirometry, if possible.
Continuous Positive Airway Pressure (CPAP) for the treatment of obstructive sleep apnea 
is permitted, if initiated prior to the Screening Visit (Visit 1). This treatment must be 
captured in the eCRF.
7.9.2.
Prohibited Medications and Non-Drug Therapies
The following medications are not permitted during the 201810 study:


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Table 4
Medications not permitted during the study
Medications
Investigational drugs (other than mepolizumab)
Other monoclonal antibodies
Experimental anti-inflammatory drugs
Any medication with a significant immunosupressive effect. (some examples listed below)

Methotrexate, troleandomycin, cyclosporin, azathioprine 

Oral gold

Chemotherapy

Regular systemic (oral or parenteral) corticosteroids for the treatment of conditions other 
than asthma

Long acting depot, intramuscular injections of corticosteroids if used to treat a condition 
other than asthma
Additionally, Bronchial Thermoplasty and Radiotherapy are excluded for 12 months 
prior to Visit 1 and throughout the study.  
Neither CPAP nor oxygen therapy may be initiated on or after Visit 1.
Recreational drug use is not allowed during the study.
If uncertain whether a medication is permitted please contact the medical monitor prior to 
administration to confirm if the medication is prohibited.
8.
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, Section 8.1.


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8.1.
Time and Events Tables
Table 5
Time and Events Table: Screening/Variable Open-Label Run-In Weeks 0 - 52 - Part A
PART A
Procedures
Pre-
Screen1
Exit/EW 
Visit 
MEA115666 
or 201312/
Screen1
Variable Open-Label Treatment  Part A2
(window is 1 week)
EW Visit5
Visit
0
1
A1
A2
A3
A4
A5
A6
A7
A8
A9
A10
A11
A12
A13
Week of Variable Run-In
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Written Informed Consent
X
Demography
X
Medical History 
X
Assess cardiac risk factors
X
Smoking status
X
Inclusion/Exclusion Criteria
X
Safety Assessments3
Concomitant Medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examination
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments3
Haematology
X
X
X
X
Chemistry (incl. LFT)
X
X
X
X
Pregnancy Test4
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
Immunogenicity
X
X
X
HbsAg and hepatitis C 
antibody 
X
Efficacy Assessments3
Exacerbation review 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Asthma Control 
Questionnaire-5
X
X
X
X
X
X


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PART A
Procedures
Pre-
Screen1
Exit/EW 
Visit 
MEA115666 
or 201312/
Screen1
Variable Open-Label Treatment  Part A2
(window is 1 week)
EW Visit5
Visit
0
1
A1
A2
A3
A4
A5
A6
A7
A8
A9
A10
A11
A12
A13
Week of Variable Run-In
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Spirometry
X
X
X
X
Worksheets/Diary/IP/ eCRF
Administer open-label 
mepolizumab
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense 
albuterol/salbutamol
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect albuterol/salbutamol
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense paper diary
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect/review paper diary
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Contact IRT
X
X
Complete eCRF
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
1.
The Pre-Screen Visit and Screening Visit may occur on the same day.
2.
Visits should be conducted every 4 weeks until the subject has reached 3 years of mepolizumab exposure. 
3.
Please see the SRM for details on which screening procedures to perform for subjects entering from 201312 and MEA115666.  ALL procedures should be completed prior to 
dosing with open-label mepolizumab.
4.
Urine pregnancy tests (U) should be conducted for women of child bearing potential. 
5.
EW = Early Withdrawal. Should be conducted 4 ± 1 weeks from the subject’s last dose


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Table 6
Time and Events Table: Screening/Variable Open-Label Run-In Weeks 56 - 132- Part A
PART A
Procedures
Variable Open-Label Treatment  Part A1
(window is 1 week)
EW
Visit3
Visit
A14/A27
A15/A28
A16/A29
A17/A30
A18/A31
A19/A32
A20/A33
A21
A22
A23
A24
A25
A26
Week of Variable Run-In
56/108
60/112
64/116
68/120
72/124
76/128
80/132
84
88
92
96
100
104
Safety Assessments
Concomitant Medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examination
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments
Haematology
X
X
X
Chemistry (incl. LFT)
X
X
X
Pregnancy Test2
U
U
U
U
U
U
U
U
U
U
U
U
U
X
Immunogenicity
X
X
Efficacy Assessments
Exacerbation review 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Asthma Control Questionnaire-5
X
X
X
X
X
Spirometry
X
X
X
Worksheets/Diary/IP/eCRF
Administer open-label mepolizumab
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense albuterol/salbutamol
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect albuterol/salbutamol
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense paper diary
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect/review paper diary
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Contact IRT
X
Complete eCRF
X
X
X
X
X
X
X
X
X
X
X
X
X
X
1.
Visits should be conducted every 4 weeks until the subject has reached 3 years of mepolizumab exposure. 
2.
Urine pregnancy tests (U) should be conducted for women of child bearing potential. 
3.
EW = Early Withdrawal. Should be conducted 4 ± 1 weeks from the subject’s last dose


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Table 7
Time and Events Table: Fixed Run-In & Double-Blind Treatment Period – Parts B and C
PARTS 
B&C
Procedures
Fixed
Run-in
Part B
EW from 
Part B7
Randomization
Double-Blind Treatment Part C 
(window is 1 week)
IPDISC/EW 
Visit 7
Visit
B1
B21
Part B EW
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
C11
C12
C13
Exit 
Visit
Week of Study 
-4 
± 1
-4 ± 
11
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Smoking status
X
Randomization Criteria
X
Safety Assessments2
Concomitant 
Medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examination
X
X
X
X
X
Vital Signs 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG 
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory 
Assessments2
Haematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry (incl. LFT)
X
X
X
X
X
X
Biomarkers
X
X
X
X
X
X
X
X
X
Pregnancy Test 3
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
Immunogenicity
X
X 
X
Efficacy 
Assessments2
Subject/Clinician 
Global Impression 
Rating
X
X
X
X
X
X
Subject/Clinician 
Rating of Response to 
Therapy
X
X
X
X
X


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PARTS 
B&C
Procedures
Fixed
Run-in
Part B
EW from 
Part B7
Randomization
Double-Blind Treatment Part C 
(window is 1 week)
IPDISC/EW 
Visit 7
Visit
B1
B21
Part B EW
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
C11
C12
C13
Exit 
Visit
Week of Study 
-4 
± 1
-4 ± 
11
0
4
8
12
16
20
24
28
32
36
40
44
48
52
SGRQ
X
X
X
X
X
X
Exacerbation review 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 
Spirometry (pre- and 
post-
albuterol/salbutamol)
X8
X
X
X
X
X
X
Healthcare resource 
utilization
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Review eDiary4
(symptoms, rescue 
use, nocturnal 
awakenings, PEF, 
ACQ-5, missed days of 
work/school)
Worksheets/Diary/IP/
eCRF2
Administer open-label 
mepolizumab4
X
X
Administer double 
blind study treatment
X5
X
X
X
X
X
X
X
X
X
X
X
X
Dispense 
albuterol/salbutamol
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect 
albuterol/salbutamol
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense paper diary
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense  eDiary
X
Collect eDiary
X
X
X6


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PARTS 
B&C
Procedures
Fixed
Run-in
Part B
EW from 
Part B7
Randomization
Double-Blind Treatment Part C 
(window is 1 week)
IPDISC/EW 
Visit 7
Visit
B1
B21
Part B EW
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
C11
C12
C13
Exit 
Visit
Week of Study 
-4 
± 1
-4 ± 
11
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Collect/review paper 
diary
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Contact IRT
X
X
X
X
Complete eCRF
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
1.
Visit B2 is only intended for subjects who experience an exacerbation in the run-in Part B which is not resolved within 7 days of Visit C1 or subjects who fail eDiary Compliance 
Criteria (Section 6.3). 
2.
All assessments to be completed prior to dosing.
3.
Urine pregnancy tests (U) should be conducted every 4 weeks for women of child bearing potential.
4.
Subjects eDiary entries should be reviewed by the site weekly during Part C
5.
An unblinding card will be dispensed after Randomization at Visit C1.
6.
The eDiary is only collected at an Early Withdrawal visit and not at IPDISC in Part C.
7.
IPDISC/EW visit should be conducted 4 ± 1 weeks from the subject’s last dose
8.
Only pre-bronchodilator spirometry required at this visit.


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Table 8
Time and Events Table: Optional Open-Label Switch to Mepolizumab – Part D
PART D
Procedures
OPTIONAL Open-Label Switch to mepolizumab Part D1
(window is 1 week)
IPDISC/EW 
Visit 8
Visit
D1
D2
D3
D4
D5
D6
D7
D8
D9
D10
D11
D12
D13
Exit 
Visit
Week of Study2
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Safety Assessments3
Concomitant Medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examination
X
X
Vital Signs 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments3
Haematology4
X
X
X
X
X
Chemistry (incl. LFT)
X
X
X
Pregnancy Test 5
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
Immunogenicity
X
X
Efficacy Assessments3
Exacerbation review 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 
Spirometry
X
X
X
X
X
Worksheets/Diary/IP/ eCRF3
Administer open-label 
mepolizumab
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense albuterol/salbutamol
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect albuterol/salbutamol
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense paper diary
X
X
X
X
X
X
X
X
X
X
X
X
X
Review eDiary6  
(symptoms, rescue use, 
nocturnal awakenings, PEF, 
ACQ-5, missed days of 
work/school)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect eDiary
X
X7


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PART D
Procedures
OPTIONAL Open-Label Switch to mepolizumab Part D1
(window is 1 week)
IPDISC/EW 
Visit 8
Visit
D1
D2
D3
D4
D5
D6
D7
D8
D9
D10
D11
D12
D13
Exit 
Visit
Week of Study2
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Collect/review paper diary
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Contact IRT
X
X
Complete eCRF
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
1.
The combined treatment period (Part C) and any switch to open-label mepolizumab (Part D) should not exceed a total duration of 52 weeks.
2.
Subjects may enter the Open-label Switch Part D at any point during Part C provided they meet switch criteria, starting with the week of study that the switch is made and 
continuing until week 52, discontinuation of IP or early withdrawal. 
3.
All assessments to be completed prior to dosing
4.
Haematology samples will be collected for each of the subject’s first 3 visits of Part D, and then according to designated Visits in Table 8
5.
Urine pregnancy tests (U) should be conducted every 4 weeks for women of child bearing potential.
6.
The eDiary should be reviewed at each visit. Weekly review is not required in Part D.
7.
The eDiary is only collected at an Early Withdrawal or Exit visit.
8.
IPDISC/EW visit should be conducted 4 ± 1 weeks from the subject’s last dose


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8.2.
Screening and Critical Baseline Assessments
Informed consent/assent will be obtained at the Pre-screen Visit or Screening Visit (if 
Pre-screen and Screening Visits are performed on the same day).
8.2.1.
Critical procedures performed at Screening (Visit 1)
If the MEA115666 or 201312 Exit Visit/EW and 201810 Screening Visit are conducted 
on different days (no more than 84 days apart), the Physical Exam, Immunogenicity 
assessment, and Spirometry do not need to be repeated at Screening. Other assessments 
should be conducted at the Screening Visit.  Please see the Study Reference Manual 
(SRM) for full details.

Review Inclusion/Exclusion criteria (see Section 6)

Demographic information including gender, ethnic origin, race, year of birth

Medical history including smoking status, history of sinusitis, nasal 
polyposis, aspirin allergy, courses of rescue corticosteroids 

Vital signs 

Physical exam

Resting 12 lead ECG  

Therapy history (review concomitant medications from the previous 12 
weeks prior to the first dose of study medication)

Cardiovascular medical history/risk factors (as detailed in the eCRF) will be 
assessed at screening. This assessment must include a review of the subject 
responses to the cardiovascular assessment questions (see Appendix 6) 

Exacerbation review 

Smoking status

Asthma Control Questionnaire (ACQ-5)

Spirometry 

Laboratory tests:

Chemistry (including liver function test [LFT])

Haematology with differential

Immunogenicity  

Hepatitis B Surface Antigen and hepatitis C antibody

Urine pregnancy test- for all females of child bearing potential (Follicle 
Stimulating Hormone [FSH] will be assessed to confirm child-bearing 
status, if clinically indicated)

AE/SAE assessment 


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8.2.2.
Critical procedures performed at entry to Part B (Visit B1)

Vital signs

Resting 12- lead ECG

Physical examination

Concomitant medication review

Exacerbation review

Laboratory tests:

Chemistry (including LFT)  

Haematology with differential

Urine pregnancy test- for all females of child bearing potential

AE/SAE assessment
8.2.3.
Critical procedures performed at Randomization (Visit C1)

History of previous intubations, asthma exacerbation history in previous year, 
asthma triggers

Review of randomization criteria (see Section 6.3)

Subject/Clinician global impression of asthma severity rating

St. George’s Respiratory Questionnaire (SGRQ)

Vital signs

Physical examination

Spirometry (pre- and post-albuterol/salbutamol)

Review/Collect eDiary data 

Exacerbation review

Smoking status

Concomitant medication assessment

Laboratory tests:

Clinical Chemistry (including LFT)

Haematology with differential

Biomarker sample

Urine pregnancy test for all females of childbearing potential

AE/SAE assessment


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8.3.
Efficacy
8.3.1.
Efficacy Endpoints
Efficacy endpoints are listed in Section 4.
8.3.2.
Efficacy Assessments
The timings of all efficacy assessments are documented in the Time and Events 
Schedules (Table 5, Table 6, Table 7 and Table 8).
8.3.2.1.
Asthma Exacerbations
Clinically significant exacerbations of asthma are defined by:
Worsening of asthma which requires use of systemic corticosteroids1and/or 
hospitalisation and/or ED visits.
1For all subjects, i.v. or oral steroid (e.g., prednisone) for at least 3 days or a single IM
corticosteroid dose is required. For subjects on maintenance systemic corticosteroids, at 
least double the existing maintenance dose for at least 3 days is required. 
Clinically significant exacerbations recorded in the eCRF by the Investigator or designee 
will be verified using eDiary data to confirm that the exacerbation was associated with 
changes in:

AM peak flow (L/min)

rescue medication use

nocturnal awakening due to asthma symptoms requiring rescue medication 
use

symptoms 
In the case that an event described as a clinically significant exacerbation is not 
associated with deterioration in at least one of these objective eDiary parameters, the 
investigator will be asked to provide an explanation to support the decision for defining 
the event as an exacerbation.  In those circumstances where the event cannot be 
supported by any objective assessment, the case will not be included as a protocol 
defined clinically significant exacerbation, but will be included as an investigator defined 
exacerbation.  This verification process will be overseen by GSK clinical staff to ensure 
consistency. Additional details on the process for determination of clinically significant 
exacerbations can be found in the Reporting and Analysis Plan (RAP).
Details of each asthma exacerbation, including medications used to treat exacerbations 
should be recorded in the eCRF.
Asthma exacerbations should not be recorded as an Adverse Event unless they meet the 
definition of a Serious Adverse Event.


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The time period for collection of exacerbation information in the eCRF will be from the 
time that the ICF is signed until the Exit Visit or EW.
8.3.2.1.1.
Guideline for Assessing Multiple Exacerbations
Exacerbations which are separated by less than 7 days will be treated as a continuation of 
the same exacerbation.
8.3.2.2.
eDiary Reporting, Worsening of Asthma and Alerts: Part B, C and D
Subjects should be instructed to bring their eDiary to each Clinic Visit in Part B, Part C 
and Part D.
The subject will be asked to record the following parameters daily in the eDiary from 
Visit B1 until the completion of Part C or Part D:

Morning peak flow (best of three), before rescue medication usage (L/min). 

Asthma symptom score over the previous 24-hours using a 6-point scale (Appendix 
7)

Occasions of rescue medication usage over the previous 24-hours

Frequency of awakening due to asthma symptoms requiring rescue medication use
8.3.2.2.1.
eDiary Alerts Indicating Worsening of Asthma
For safety the following alerts, indicative of worsening asthma, will be programmed into 
the eDiary with instructions to contact the investigator if any of the alert criteria are met. 
NOTE: An alert in itself will not qualify as a clinically significant exacerbation:

Decrease in morning PEF 30% on at least two of three consecutive days, compared 
with baseline (last 7 days of run-in Part B)

A symptom score of 5 for at least two of three consecutive days

An increase of 50% in occasions of rescue medication on at least two of three 
consecutive days, compared with the average use for the previous week.

Awakening due to asthma symptoms requiring rescue medication use for at least two 
of three consecutive nights.
Sites should review subject data weekly during Part C through a study specific web 
portal, and contact subjects for follow-up as appropriate. Additionally, eDiary data will 
be reviewed at each clinic visit in Parts C and D by the site staff throughout the treatment 
period to confirm an association between any exacerbation event and eDiary data.
8.3.2.2.2.
eDiary Daily Entry: Missed Days of Work or School
Subjects who work for pay or go to school on a regular basis will record in the eDiary  
any full and part days of missed work or school due to asthma. 


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8.3.2.2.3.
eDiary Weekly Entry: Asthma Control Questionnaire-5 (ACQ-5)
Subjects in Part B, Part C and Part D should complete the ACQ-5 on their eDiary once 
weekly.
The ACQ-5 is a five-item questionnaire, which has been developed as a measure of 
subject’ asthma control that can be quickly and easily completed [Juniper, 2005].  The 
questions are designed to be self-completed by the subject.  The five questions enquire 
about the frequency and/or severity of symptoms over the previous week (nocturnal 
awakening on waking in the morning, activity limitation, and shortness of breath, 
wheeze).  The response options for all these questions consist of a zero (no 
impairment/limitation) to six (total impairment/ limitation) scale.
8.3.2.2.4.
eDiary Compliance
Subjects should be compliant in completing their daily eDiary entries between each pair 
of on-treatment visits.  Subjects should be ≥80% compliant with completion of their 
eDiary. Subjects who are non-compliant (<80%) should be re-educated on the 
requirement for daily diary entry compliance, and this re-education should be 
documented in the subjects source notes.
8.3.2.3.
Paper Diary
Subjects will be issued a paper worksheet to record adverse events, changes in 
concomitant medications and any visits to the hospital and/or emergency department 
during the study. Subjects will be asked to bring their worksheet to every study visit as it 
will be used to assist subject recall in discussions with the investigator, for site staff to 
then enter as appropriate in the eCRF.
8.3.2.4.
Spirometry
Spirometry will be performed to assess FEV1 and FVC using the sites own equipment as 
detailed in the Time and Events Tables (Table 5, Table 6, Table 7 and Table 8). 
The spirometer should meet American Thoracic Society standards and produce a print out 
of all data generated, which should be stored in the subjects source notes. The spirometer 
should be calibrated per manufacturer’s instructions and a calibration log maintained.
At least 3 acceptable and ideally, 2 repeatable spirometry manoeuvres (from a maximum 
of 8 attempts) should be achieved on each occasion that spirometry assessments are 
performed, in accordance with the American Thoracic Society/European Respiratory 
Society (ATS/ERS) standards [Miller, 2005]. At each visit, spirometry assessments 
should be performed at the same time of day (2 hours) as the baseline assessment for 
that part of the study (i.e., the same time of day as Visit 1 for Part A, Visit B1 for Part B, 
Visit C1 for Part C). Subjects should withhold rescue albuterol/salbutamol for 6 hours 
and LABAs or ICS/LABA fixed dose combinations for 12 hours prior to spirometry, if 
possible.


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Details on performing the spirometry assessments, as well as specific instructions on 
performing the spirometry manoeuvres, are documented in the SRM.
8.3.2.4.1.
Pre- and Post-Albuterol/Salbutamol Spirometry
At all spirometry assessments conducted within Part B and Part C, both pre- and post-
albuterol/salbutamol spirometry will be obtained.  
Bronchodilator responsiveness testing will be completed as follows:

Following pre-albuterol/salbutamol spirometry, the subject will self-administer 4 
puffs of albuterol/salbutamol via MDI.  Spirometry efforts should be obtained 
approximately 10 to 30 minutes after albuterol/salbutamol administration.
8.3.2.5.
Paper-based Asthma Control Questionnaire-5 (Part A only)
Subjects in Part A of the study will complete the ACQ-5 at specified clinic visits (Table 5
and Table 6) on paper, and their responses will be entered by site staff into the eCRF. 
Note: In parts B, C and D the ACQ-5 will be completed by subjects using their eDiary 
(Section 8.3.2.2.3).
8.3.2.6.
St. George’s Respiratory Questionnaire (SGRQ)
The St. George’s Respiratory Questionnaire is a well established instrument, comprising 
50 questions designed to measure Quality of Life in patients with diseases of airway 
obstruction, measuring symptoms, impact, and activity. The questions are designed to be 
self-completed by the subject, taking on average 20 minutes [Jones, 1992] with a recall 
over the past 4 weeks. It has been used successfully in studies of chronic obstructive 
pulmonary disease (COPD) and asthma subjects and has been translated and validated for 
use in most major languages.  Research has demonstrated that it is sensitive to change,
and interpretation of the results has been enhanced by determination of the score change 
necessary to achieve a clinically meaningful improvement in quality of life [Jones, 2002].  
Additional instructions for the completion of SGRQ are provided in the SRM.
8.3.2.7.
Subject/Clinician Rating of Global Impression of Disease Severity and 
Response to Therapy
The Global Impressions of Disease Severity and Response to Therapy should be the first 
procedure completed by the subject and clinician (Primary or Sub Investigators) at the 
specified study visit. To avoid biasing responses, the subjects should not be told the 
results of diagnostic tests prior to completing the questionnaires and these questionnaires 
should be completed before any procedures are performed on the subject to avoid 
influencing the subject’s and Investigator’s response.
Additional instructions will be found in the SRM.


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Global Impression of Disease Severity: The investigator (or designee) and subject will 
complete a Global Impression of Disease Severity question at Randomisation and visits 
described in Table 7. This single global question will ask subjects and clinicians to rate 
the subject’s asthma severity on a four-point scale (mild, moderate, severe, very severe).
Response to Therapy: The investigator (or designee) and subject will also be asked to 
rate the subject’s response to therapy at specified visits (Table 7). This is an overall 
evaluation of response to treatment, as compared to Visit C1. This will be conducted 
separately by the investigator (or designee) and the subject using a seven-point rating 
scale as follows: 
1 = significantly improved 
2 = moderately improved 
3 = mildly improved 
4 = no change 
5 = mildly worse
6 = moderately worse
7 = significantly worse 
8.3.2.8.
Healthcare Resource Utilization
All unscheduled asthma-related visits to a physician’s office, visits to urgent care, visits 
to the emergency department, and hospitalizations associated with the subject’s asthma 
will be recorded in the eCRF.
At Visits C2 through the Part C Exit Visit or EW, the resource utilization worksheet used 
by the patient to record all health care contacts experienced since the last visit will be 
presented to the investigator (or designated coordinator).  The investigator (or designated 
coordinator) should ask the subject if any of the health care contacts that are recorded on 
the worksheet were due to asthma.  The investigator can refer to his/her records to verify 
or supplement information given by the subject, if necessary. 
If any unscheduled healthcare contact is due to an asthma exacerbation, then the Asthma
Exacerbation section of the eCRF must be completed.
Details regarding completion of the Healthcare Utilization worksheet are located in the 
SRM.
8.4.
Safety
Planned time points for all safety assessments are listed in the Time and Events Tables
(Section 8.1).  
See Section 4 for details of the safety endpoints to be assessed in the study.
8.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 4.


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Adverse Events include systemic (i.e., allergic/IgE-mediated and non-allergic) and 
injection site reactions reported throughout all study treatment periods. If the investigator 
considers that there is a reasonable possibility that the Systemic reaction (e.g., 
Hypersensitivity) or Local injection site reaction event is related to investigational 
product, then additional information about the type of reaction and whether it meets 
anaphylaxis criteria will be collected in the eCRF.
NOTE: 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] (Appendix 8).  Information will be also collected from 
subjects to help with the assessment of potential localised injection site reactions.
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 
8.4.1.1.
Time period and Frequency for collecting AE and SAE information

AEs will be collected from the Screening visit (Visit 1), until the Exit Visit or EW
(see Section 8.4.1.3), at the timepoints specified in the Time and Events Tables
(Section 8.1).

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 CRF.

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 
concomitant medication will be recorded from the time a subject consents to 
participate in the study up to and including any Exit Visit or EW.

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Appendix 4.

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 4
8.4.1.2.
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 are you feeling?” 

“Have you had any (other) medical problems since your last visit/contact?” 


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
“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?”
8.4.1.3.
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 
(as related to the identified and potential risks described in Table 3) 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 6.7.4). Further information on 
follow-up procedures is given in Appendix 4.
8.4.1.4.
Cardiovascular and Death Events
8.4.1.4.1.
Cardiovascular Events
Cardiovascular-related AEs and SAEs that will require the investigator to complete event 
specific pages in the eCRF are listed in Section 13.4.3.
Cardiovascular events information should be recorded on the corresponding eCRF pages
within one week of when the AE/SAE(s) are first reported.  Please refer to Appendix 4
for timelines for reporting AE/SAEs.
8.4.1.4.2.
Death Events
In addition, all deaths will require completion of a specific death data collection page in 
the eCRF.  The death data collection page in the eCRF includes questions regarding 
cardiovascular (including sudden cardiac death) and non-cardiovascular death.
Death information should be recorded on the death eCRF page within one week of when 
the death is first reported.
Please refer to Appendix 4 for timelines for reporting SAEs.
8.4.1.5.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK of SAEs 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.


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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.
8.4.2.
Pregnancy

Details of all pregnancies in female subjects will be collected after the start of 
dosing (Visit 1) until the Exit Visit or EW
Based on the absence of an identified reproductive hazard from preclinical studies, 
absence of a genotoxic potential, and very low levels of mepolizumab that might be 
present in semen, there is no recognized risk for mepolizumab to affect human sperm 
or the fetus if transferred to a female partner via semen. Therefore, the use of 
condoms or other methods of contraception in the male study subject is not required.

If a pregnancy is reported then the investigator should inform GSK within 2 
weeks of learning of the pregnancy and should follow the procedures outlined in
Appendix 5.
8.4.3.
Physical Exams

A complete physical examination will include, at a minimum, assessment of the 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. Height and 
weight will also be measured and recorded in the eCRF. 

Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.4.4.
Vital Signs

As detailed in the Time and Events Schedules (Table 5, Table 6, Table 7 and Table 
8) vital signs will be measured in a semi-supine position after 5 minutes rest and will 
include systolic and diastolic blood pressure and heart rate.

Vital signs assessments will be taken before measurement of any clinic lung 
function tests or ECGs at the specified time point.
8.4.5.
Electrocardiogram (ECG)

Twelve-lead ECGs will be obtained at each time point specified in the Time and 
Events Schedules (Table 5, Table 6, Table 7 and Table 8).

ECG machines that automatically calculate the heart rate and measure PR, QRS, QT, 
and QTc intervals will be provided by GSK via a designated central laboratory.

The same QT correction formula must be used for each individual subject to 
determine eligibility for and discontinuation from the study.  This formula 
may not be changed or substituted once the subject has been enrolled.

For example, as a subject is eligible for the study based on QTcF, then QTcF 
must be used for discontinuation of this individual subject as well.

Once the QT correction formula has been chosen for a subject’s eligibility, 
the same formula must continue to be used for that subject for all QTc data 


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being collected for data analysis.  Safety ECGs and other non-protocol 
specified ECGs are an exception.  

The QTc should be based on the average QTc value of triplicate ECGs. For 
example, if an ECG demonstrates a prolonged QT interval, obtain two more 
ECGs over a brief period, and then use the averaged QTc values of the three 
ECGs to determine whether the patient should be discontinued from the 
study.

ECG measurements will be made after the subject has rested in the supine position 
for 5 minutes.  The ECG should be obtained after the vital signs assessments but 
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.

Paper ECG traces will be recorded at a standard paper speed of 25mm/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.

Paper ECG traces are required to be maintained at the site with other source 
documents.

Refer to Section 6.5 and Section 6.6 for QTc withdrawal and discontinuation of IP 
criteria.
8.4.6.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments (haematology and clinical chemistry) must 
be conducted in accordance with the Laboratory Manual, and Protocol Time and Events 
Schedule (Table 5, Table 6, Table 7 and Table 8). Laboratory requisition forms must be 
completed and samples must be clearly labelled with the subject number, protocol 
number, site/centre number, and visit date. Details for the preparation and shipment of 
samples will be provided by the laboratory and are detailed in the Laboratory Manual. 
Standard reference ranges for all safety parameters will be provided to the site by the 
laboratory responsible for the assessments.
All blood samples should be taken pre-dose, and will be sent to a central laboratory for 
analysis or for shipment to a GSK laboratory (details provided in the Laboratory 
Manual). 
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the eCRF. Please note that any non-
protocol specified local laboratory result has the potential to break the blind due to the 
eosinophils result being available.  Please see the Study Reference Manual for guidance.
Refer to the Laboratory Manual for appropriate processing and handling of samples to 
avoid duplicate and/or additional blood draws. 


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Haematology, clinical chemistry and additional parameters to be tested are listed in Table 
9.
Table 9
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Platelet Count
RBC Indices:
WBC count with Differential:
RBC Count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes
Hematocrit
Monocytes
Eosinophils
Basophils
Clinical 
Chemistry 1
BUN
Potassium
AST (SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
ALT (SGPT)
Total Protein
Glucose 
Calcium
Alkaline phosphatase
Albumin
Other 
Screening 
Tests

Hepatitis B (HBsAg)

Hepatitis C (Hep C antibody)2

FSH and estradiol (if clinically indicated, in women of non-child 
bearing potential only)

Alcohol and drug screen (if clinically indicated, to include at 
minimum: amphetamines, barbiturates, cocaine, opiates, 
cannabinoids and benzodiazepines)

Urine hCG Pregnancy test (for women of child bearing potential)3
NOTES :
1.
Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up 
Assessments after liver stopping or monitoring event are given in Appendix 2 and 
Appendix 3
2.
If Hepatitis C antibody positive result, a hepatitis C confirmatory test should be 
automatically performed to confirm the result. Test should be repeated as necessary 
if clinically indicated.
3.
Local urine testing will be standard for the protocol unless serum testing is required 
by local regulation or ethics committee.
All laboratory tests with values that are considered clinically significantly abnormal 
during participation in the study should be repeated until the values return to normal or 
baseline.  If such values do not return to normal within a period judged reasonable by the 
investigator, the etiology should be identified and the sponsor notified.


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To maintain the treatment blind, the site and the central study team will not be sent 
information on haematology differential or IL-5 value from any visits post-
randomization.
8.4.6.1.
Immunogenicity
Blood samples will be collected for the determination of anti-mepolizumab antibodies, 
prior to dosing, as detailed in the Time and Events Schedules (Table 5, Table 7 and Table 
8). 
Details for sample collection and processing may be found in the SRM.
8.5.
Biomarker(s)/Pharmacodynamic Markers
The following tests will be performed on the blood sample: 
Blood eosinophil counts will be recorded as part of the standard haematological
assessments performed at the visits specified in the Time and Events Schedules (Table 5, 
Table 6, Table 7 and Table 8). The site staff and central study team will be blinded to 
each subject’s eosinophil count (including blood count differential) from any visits post-
randomization.
Blood (serum) samples will be collected during this study and may be used for the 
purposes of measuring biomarkers to identify factors that may influence the development 
of asthma and/or medically related conditions, as well as the biological and clinical 
responses to mepolizumab. Blood samples for biomarker testing will be stored for up to 
15 years.  Those biomarker results, which have the potential to break the blind will be 
blinded to the site staff until the clinical study report is finalised.
Full details regarding sample collection, processing and shipping are provided in the 
central Laboratory Manual.
8.6.
Genetics
Data and genetic samples have previously been obtained from precursor studies:
MEA112997, MEA115588, and MEA115575. These samples may be used as part of a 
genetic analysis using data collected in this study, if relevant.  No additional genetic 
samples are required.
9.
DATA MANAGEMENT

For this study subject data will be entered into GSK defined CRFs, transmitted 
electronically to GSK or designee and combined with data provided from other 
sources in a validated data system.  

Management of clinical data will be performed in accordance with applicable 
GSK standards and data cleaning procedures to ensure the integrity of the data, 
e.g., removing errors and inconsistencies in the data.


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
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, 
date of birth or other personally identifiable information will not be collected or 
transmitted to GSK according to GSK policy.
10.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
10.1.
Hypotheses
The study is designed to test the superiority of continued mepolizumab 100 mg SC 
treatment vs. mepolizumab discontinuation (placebo). Significance tests will be 
performed at the two-sided 5% alpha level (one-sided 2.5%).
10.2.
Sample Size Considerations
Sample size is based on the primary efficacy endpoint of time to first clinically 
significant exacerbation.
10.2.1.
Sample Size Assumptions
With a sample size of 300 randomised subjects (150 per arm), it is estimated that 
statistical significance will be declared if the proportion of subjects with a clinically 
significant exacerbation following withdrawal of mepolizumab is 52.5% compared to 
40% for those continuing to receive mepolizumab (hazard ratio = 0.686).
If the true hazard ratio is 0.55 (corresponding to a proportion with an exacerbation 
following discontinuation of mepolizumab of 60.5%), then the study has a probability of 
90% of observing a hazard ratio of < 0.686 and therefore the study has 90% power for 
declaring statistical significance on this endpoint.
The estimated event rate for subjects randomized to mepolizumab is based on interim 
data from study MEA115666 which suggests 40% of subjects will experience an 
exacerbation within one year of randomization.   In study MEA115588, the observed 
hazard ratio for the combined treatment arms of mepolizumab 100mg SC and 75mg SC 
vs placebo was 0.5.  A lower event rate among those discontinuing mepolizumab is 
expected in this study than was observed for placebo in MEA115588 because of the 
continuing effects of previous treatment with mepolizumab.The sample size calculations 
assume 20% of subjects will withdraw prior to the end of the double-blind treatment 
phase before experiencing an exacerbation.
10.2.2.
Sample Size Sensitivity
If the true hazard ratio or proportion of events seen within the mepolizumab 
discontinuation (placebo) treatment group observed within this study differs from the 


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values assumed within Section 10.2.1, the power to detect a difference between the two 
treatment groups will be affected.
Table 10 illustrates the estimated power which would be obtained with different hazard 
ratios and proportion of events observed within the mepolizumab discontinuation 
(placebo) group, assuming a sample size of 150 randomised subjects per arm.
Table 10
Effect on power for varying hazard ratios and proportions of events 
observed within the mepolizumab discontinuation (placebo) 
treatment group
Proportion 
of events 
within the 
placebo 
group
Hazard ratio
0.40
0.45
0.50
0.55
0.60
0.65
0.70
50%
98.6%
96.0%
90.9%
82.6%
71.3%
58.0%
44.3%
55%
99.2%
97.5%
93.6%
86.4%
75.8%
62.5%
48.1%
60%
99.6%
98.5%
95.5%
89.5%
79.8%
66.7%
51.8%
65%
99.8%
99.1%
97.0%
92.1%
83.3%
70.6%
55.5%
10.2.3.
Sample Size Re-estimation or Adjustment
No sample size re-estimation is planned for this study.
10.3.
Data Analysis Considerations
10.3.1.
Analysis Populations
All Subjects Enrolled (ASE) Population
The ASE population will comprise all subjects enrolled and for whom a record exists on 
the study database. This population will be used for summarising reasons for screen and 
run-in failures and to report data collected within the variable open-label run-in (Part A) 
and fixed run-in (Part B).
Intent-to-Treat (ITT) Population
This population will consist of all randomized subjects who receive at least one dose of 
double-blind study medication, and will be the primary population for all analyses of 
efficacy and safety data. In cases where there is a discrepancy between the treatment to 
which a subject was randomized and the treatment they actually received a profile of the 
subjects’ data will be produced.


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Per Protocol (PP) Population
The PP population will consist of all subjects in the ITT population who have not been 
identified as full protocol deviators with respect to criteria that are considered to impact 
the primary efficacy analysis. The decision to exclude a subject from the PP Population 
or exclude part of their data from the PP Population analyses will be made prior to 
breaking the blind. The PP population will be used for a supplementary analysis of the 
primary endpoint.
10.3.2.
Interim Analysis
No interim analysis of data is planned for this study.
10.4.
Key Elements of Analysis Plan
Full details of all analysis methods to be used will be provided in the RAP which will be 
finalised prior to unblinding.
The study will be unblinded once the final subject has completed the Exit or EW Visit, all 
queries for data collected up to this time are resolved and the clinical study database is
frozen.
10.4.1.
Primary Analyses
Time to first clinically significant exacerbation will be compared between treatment 
groups using a Cox’s proportional hazards model allowing for covariates of region, 
exacerbations in the year prior to randomization and use of baseline maintenance oral 
corticosteroids (OCS vs no OCS). For geographical region, a grouping system for 
countries will be defined in the RAP.
Only Part C exacerbation data will be included in the primary analysis from the start of 
double-blind treatment until no greater than 4 weeks post-last-dose of double-blind 
treatment. The analysis will be performed on the Intent-to-Treat (ITT) population. A 
supporting analysis of the PP population will also be performed.
10.4.2.
Secondary Analyses
For subjects that complete Part C of the study, data will be included in the analysis of the 
secondary and other endpoints from the start of double-blind treatment until the Exit visit
date.  For those subjects that switch to open-label Part D, discontinue IP early or early 
withdraw from the study altogether, data will be included from the start of double-blind 
treatment until no greater than approximately 4 weeks post-last-dose of double-blind 
treatment.  Data collected following the switch to open-label treatment within Part D or 
IP discontinuation will also be omitted from the analysis of the these endpoints.
Ratio to baseline in blood eosinophil count will be analysed using mixed models repeated 
measures adjusting for the aforementioned covariates within the primary analysis and 
visit, plus interaction terms for visit by baseline and visit by treatment group.


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Time to a decrease in asthma control, defined as an increase from baseline in Asthma 
Control Questionnaire-5 (ACQ-5) score of ≥ 0.5 units, will be compared using a Cox’s 
proportional hazards model, as described for the primary endpoint.
Time to first exacerbation requiring hospitalization or ED visit will be compared using a 
Cox’s proportional hazards model, as described for the primary endpoint.
10.4.3.
Other Analyses
10.4.3.1.
Efficacy Analyses
See Section 4 for a list of all other efficacy endpoints. Full details of any analyses to be 
performed on these endpoints will be provided in the RAP.
10.4.3.2.
Safety Analyses
Summaries of data will report data according to the nominal visit for which it was 
recorded. Further details will be provided in the RAP.
10.4.3.2.1. Extent of Exposure
The number of subjects administered investigational product, the number of treatments 
administered and the number of days over which treatment was administered will be 
summarised.
10.4.3.2.2. Adverse Events
Adverse Events (AEs) will be coded using the standard Medical Dictionary for 
Regulatory Activities (MedDRA) and will be grouped by system organ class. AEs will be 
summarised by frequency and percentage of subjects, by system organ class and 
preferred term within each treatment group. Separate summaries will be presented for all 
AEs, drug-related AEs, serious AEs (SAEs), AE’s leading to permanent discontinuation 
of study treatment or withdrawal from study and for any AEs of special interest.
10.4.3.2.3. Clinical Laboratory Evaluations
Haematology (including blood eosinophils) and clinical chemistry data will be 
summarized at each scheduled assessment. The proportion of values outside of the 
normal reference range and those meeting the criteria for potential clinical significance 
will also be summarised. Further details will be provided in the RAP.
10.4.3.2.4. Other Safety Measures
Actual values and change from baseline for other scheduled safety assessments will be 
summarized at each visit per the Time and Events schedule (Table 5, Table 6, Table 7, 
Table 8). Further details will be provided in the RAP.
10.4.3.2.5. Immunogenicity
Immunogenicity data will be summarised using appropriate descriptive statistics.


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10.4.3.3.
Pharmacogenetic Analyses
Data and genetic samples have previously been obtained from precursor studies:
MEA112997, MEA115588, and MEA115575. These samples may be used as part of a 
genetic analysis using data collected in this study, if relevant.  No additional genetic 
samples are required.
11.
STUDY GOVERNANCE CONSIDERATIONS
11.1.
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.
11.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a site, GSK will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with International 
Conference on Harmonization (ICH) Good Clinical Practice (GCP) and applicable 
country-specific regulatory requirements.
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

Obtaining signed informed consent

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.

Signed informed consent must be obtained for each subject prior to participation 
in the study

The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research. 

Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.  


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
Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities.  In this situation, 
written approval of the clinical protocol should state that approval of optional 
assessments is being deferred and the study, with the exception of the optional 
assessments, can be initiated.
11.3.
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 eCRF 
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
11.4.
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.
11.5.
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.  


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
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.
11.6.
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 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.


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11.7.
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.
GSK will provide the investigator with the randomization codes for their site only after 
completion of the full statistical analysis.
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.
A manuscript will be progressed for publication in the scientific literature if the results 
provide important scientific or medical knowledge.


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12.
REFERENCES
Bel EH, Wenzel SE, Thompson PJ, Prazma CM, Keene ON, Yancey SW et al. Oral 
Glucocorticoid-Sparing Effect of Mepolizumab in Eosinophilic Asthma. N Engl J Med 
2014 September 8;371(13):1189-97.
Chung KF, Wenzel SE, Brozek JC et al. International ERS/ATS guidelines on definition, 
evaluation and treatment of severe asthma. Eur Respir J 2014; 43:343-373.
Cohn L, Elias JA, Chupp GL.  Asthma: mechanisms of disease persistence and 
progression.  Ann Rev Immunol 2004;22:789-815.
Collins PD, Marleau S, et al. Cooperation between interleukin-5 and the chemokine 
eotaxin to induce eosinophil accumulation in vivo. J Exp Med 1995;182(4):1169-74.
European Medicines Agency (EMA). Note for guidance on clinical investigation of 
medicinal products for treatment of asthma. 2013 Draft. CHMP/EWP/2922/01 Rev.1.
Gevaert P, Lang-Loidolt D, Lackner A, et al. Nasal IL-5 levels determine the response to 
anti-IL-5 treatment in patients with nasal polyps.  J Allergy Clin Immunol
2006;118:1133-41.
Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma 
(GINA) 2015. Available from: http://www.ginasthma.org/.
Haldar P, Brightling CE, Hargadon B et al. Mepolizumab and exacerbations of refractory 
eosinophilic asthma. N Engl J Med. 2009;360:973-984.
Haldar P, Brightling CE, Singapuri A, Hargadon B, Gupta S, Monteiro W et al.  
Outcomes after cessarion of mepolizumab therapy in severe eosinophilic asthma: A 12-
month follow-up analysis.  J Allergy Clin Immunol 2014;133:921-23.
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, Policar MS, editors. 
Contraceptive Technology. 20th edition.  Atlanta, Georgia: Ardent Media, Inc., 2011:50. 
Table 3-2.
ICH guideline M3(R2) on non-clinical safety studies for the conduct of human clinical 
trials and marketing authorisation for pharmaceuticals, 2009; EMA/CPMP/ICH/286/1995
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
Jones PW, Interpreting thresholds for a clinically significant change in health status in 
asthma and COPD. Eur Respir J. 2002;19:398-404.
Jones PW, Quirk FH, Baveystock CM, Littlejohns P. A self-complete measure for 
chronic airflow limitation - the St George's Respiratory Questionnaire. Am Rev Respir 
Dis 1992;145:1321-1327.


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Juniper EF, Svensson K, Mőrk AC, Ståhl E. Measurement properties and interpretation of 
three-shortened versions of the asthma control questionnaire. Resp Med 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;114:1449-55.
Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P, Gault E.  Quantification 
of Hepatitis Delta Virus RNA in Serum by Consensus Real-Time PCR Indicates 
Different Patterns of Virological Response to Interferon Therapy in Chronically Infected 
Patients.  J Clin Microbiol. 2005;43(5):2363–2369.
Lopez AF, Sanderson CJ, Gamble JR, et al.  Recombinant human interleukin-5 is a 
selective activator of human eosinophil function.  J Exp Med 1988;167:219-24.
Miller MR et al. (2005) Standardization of Lung Function Testing. Eur Resp J; 26:153-
161.
Nair P, Pizzichini MMM, Kjarsgaard M et al. Mepolizumab for prednisone-dependent 
asthma with sputum eosinophilia. N Engl J Med. 2009;360:985-993.
Ortega HG, Liu MC, Pavord ID, Brusselle GG, FitzGerald JM, Chetta A et al. 
Mepolizumab Treatment in Patients with Severe Eosinophilic Asthma. N Engl J Med 
2014 September 8;371(13):1198-207.
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.
Proceedings of the ATS workshop on refractory asthma: current understanding, 
recommendations, and unanswered questions. Am J Respir Crit Care Med
2000;162:2341-2351.
Sampson HA, Munoz-Furlong A, Campbell RL, et. al. Second symposium on the 
definition and management of anaphylaxis: summary report--Second National Institute of 
Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J 
Allergy Clin Immunol 2006;117:391-397.
Sanderson, CJ. Interleukin-5, eosinophils, and disease.  Blood 1992;79(12):3101-9.
Sumitas K, Radinger M and Bossios A.  Current update on eosinophilic lung diseases and 
anti-IL-5 treatment.  Recent Patents Anti-inf Drug Disc 2011;6:189-205.
The ENFUMOSA cross-sectional European multicentre study of the clinical phenotype 
of chronic severe asthma. European Network for Understanding Mechanisms of Severe 
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Wadsworth SJ, Sin DD, Dorscheid DR. Clinical update on the use of biomarkers of 
airway inflammation in the management of asthma. J Asthma Allergy. 2011;4: 77–86.
Walsh ER, Stokes K, August A. The Role of Eosinophils in Allergic Airway 
Inflammation. Discovery Medicine, 2010, 47:357-362.
Wenzel SE. Severe asthma in adults. Am J Respir Crit Care Med 2005;172:149-160.


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13.
APPENDICES
13.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
ACQ
Asthma Control Questionnaire
ADA
Anti-Drug Antibody
AE
Adverse Event
ALT
Alanine Transaminase
ASE
All Subjects Enrolled
AST
Aspartate Transaminase
ATS
American Thoracic Society
BP
Blood Pressure
COPD
Chronic Obstructive Pulmonary Disease
CPAP
Continuous Positive Airway Pressure
CPK
Serum Creatine Phosphokinase
CRP
C-Reactive Protein
CS
Corticosteroid
CV
Cardiovascular
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
ED
Emergency Department
eDiary
Electronic Diary
ERS
European Respiratory Society
EW
Early Withdrawal
FAAN
Food Allergy and Anaphylaxis Network
FDA
Food and Drug Administration
FEV1
Forced expiratory volume in 1 second
FRP
Females of Reproductive Potential
FSH
Follicle Stimulating Hormone
FVC
Forced Vital Capacity
GCP
Good clinical practice
GCSP
Global Clinical Safety and Pharmacovigilance
GINA
Global Initiative for Asthma
GSK
GlaxoSmithKline
HBsAg
Hepatitis B Surface Antigen
hCG
Human Chorionic Gonadotropin
HPLC
High Performance Liquid Chromatography
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization
ICS
Inhaled Corticosteroids
IEC
Independent Ethics Committee
Ig
Immunoglobulin


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IL
Interleukin
IM
Intramuscular
INR
International Normalized Ratio
IP
Investigational Product
IRB
Institutional Review Board
ITT
Intent to Treat
IV
Intravenous
IRT
Interactive Response Technology
kg
Kilogram
L/min
Liters per minute
LABA
Long-Acting Beta-2-Agonists
LFT
Liver Function Test
mAb
Monoclonal Antibody
MedDRA
Medicinal dictionary for regulatory activities
mcg (g)
Microgram
mcL (L)
Microliter
MDI
Metered Dose Inhaler
mg
Milligram
mL
Milliliter
N/A
Not Applicable
NaB
Neutralizing Antibodies
NIAID
National Institute of Allergy and Infectious Diseases
OCS
Oral Corticosteroids
PD
Pharmacodynamic
PEF
Peak Expiratory Flow
PK
Pharmacokinetic
PP
Per Protocol
QTc
QT interval corrected for heart rate
QTcB
QT interval corrected for heart rate by Bazett’s formula
QTcF
QT interval corrected for heart rate by Fridericia’s formula
RAP
Reporting and Analysis Plan
RNA
Ribonucleic acid
SAE
Serious Adverse Event
SC
Subcutaneous
SGRQ
St. George’s Respiratory Questionnaire
SOC
System Organ Class
SPD
Surfactant Protein D
SRM
Study Reference Manual
ULN
Upper Limit of Normal
URTI
Upper Respiratory Tract Infection


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Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
None


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13.2.
Appendix 2: Liver Chemistry Stopping and Increased 
Monitoring Algorithm
Phase III-IV Liver Chemistry Stopping and Increased Monitoring Algorithm
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 3.
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
≥8xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
No
Yes
Yes
Yes
No
No
No
See algorithm 
for continued 
therapy with 
increased liver 
chemistry 
monitoring
Yes
*INR value not applicable to subjects on anticoagulants 
ALT 
≥3xULN 
but 
<8xULN
Yes
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*


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Phase III-IV Liver Chemistry Increased Monitoring Algorithm with Continued 
Therapy for ALT 3xULN but <8xULN
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 3.
Continue Study Treatment   and   Monitor Liver Chemistry
Discontinue Study Treatment 
ALT≥5xULN 
but <8xULN
+ bili <2xULN +
no symptoms
No
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Yes
ALT ≥3xULN 
but <5xULN
+ bili <2xULN  +
no symptoms
Able to 
monitor  
weekly 
for  ≥2 
weeks
Persists for 
≥2 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
No
No
Able to 
monitor  
weekly 
for  ≥4 
weeks
Persists for 
≥4 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
Yes
ALT ≥5xULN 
ALT <5xULN 
Yes
Yes
*INR value not applicable to subjects on anticoagulants 
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*


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13.3.
Appendix 3: Liver Safety Required Actions and Follow up 
Assessments
Phase III-IV 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


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Phase III-IV liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria - Liver Stopping Event
ALT-absolute
ALT 8xULN
ALT Increase
ALT 5xULN but <8xULN  persists for 2 weeks
ALT 3xULN but <5xULN  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 5xULN but <8xULN and cannot be monitored weekly for 2 weeks
ALT 3xULN but <5xULN 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
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.

Restart/rechallenge is not  allowed, 
permanently discontinue study treatment and 
subject may continue in the study for any 
protocol specified follow up assessments

Viral hepatitis serology4

Only in those with underlying chronic 
hepatitis B at study entry (identified by 
positive hepatitis B surface antigen)
quantitative hepatitis B DNA and hepatitis 
delta antibody5.

Blood sample for pharmacokinetic (PK) 
analysis, obtained within 4 weeks after last
dose6

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


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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
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 High-
performance liquid chromatography 
(HPLC) assay (quantifies potential 
acetaminophen contribution to liver injury 
in subjects with definite or likely 
acetaminophen use in the preceding week 
[James, 2009]). NOTE: not required in 
China

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography)
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms.
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 international 
normalized ratio (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.
If hepatitis delta antibody assay cannot be performed,, it can be replaced with a PCR of hepatitis D RNA virus 
(where needed) [Le Gal, 2005].
6.
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.  


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Phase III-IV liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 5xULN and <8xULN and
bilirubin <2xULN without symptoms
believed to be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 2 weeks.
OR
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 treatment 

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 ALT decreases from ALT 5xULN and <8xULN 
to ≥3xULN but <5xULN, continue to monitor liver 
chemistries weekly. 

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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13.4.
Appendix 4: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
13.4.1.
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 or clinical chemistry),  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 
the disease/disorder being studied, unless more severe than expected for the subject’s 


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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.
13.4.2.
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.


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
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.
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.

See Appendix 2 for the required liver chemistry follow-up instructions
13.4.3.
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


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
Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
13.4.4.
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.

Subject-completed Value Evidence and Outcomes questionnaires and the collection 
of AE data are independent components of the study.

Responses to each question in the Value Evidence and Outcomes questionnaire will 
be treated in accordance with standard scoring and statistical procedures detailed by 
the scale’s developer.

The use of a single question from a multidimensional health survey to designate a 
cause-effect relationship to an AE is inappropriate.


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13.4.5.
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.
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.


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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 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.
13.4.6.
Reporting of SAEs to GSK
SAE 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 for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax it to the Medical Monitor.

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of 
the SAE.

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 Medical 
Monitor 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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13.5.
Appendix 5: Modified List of Highly Effective Methods for 
Avoiding Pregnancy in Females of Reproductive Potential 
(FRP) and Collection of Pregnancy Information
This list does not apply to FRP with same sex partners, when this is their preferred and 
usual lifestyle or for subjects who are and will continue to be abstinent from penile-
vaginal intercourse on a long term and persistent basis.
Subjects who are FRP must agree to acceptable contraceptive methods approved in their 
local country, when used consistently and correctly (i.e., in accordance with the approved 
product label and the instructions of the physician) for the duration of the study and for 4 
months after the last study drug administration.

Contraceptive subdermal implant 

Intrauterine device or intrauterine system 

Combined estrogen and progestogen oral contraceptive [Hatcher, 2011]

Injectable progestogen [Hatcher, 2011]

Contraceptive vaginal ring [Hatcher, 2011]

Percutaneous contraceptive patches [Hatcher, 2011]

Male partner sterilization with documentation of azoospermia prior to the female 
subject's entry into the study, and this male is the sole partner for that subject 
[Hatcher, 2011].  
This is an all inclusive list of those methods that meet the GSK definition of highly 
effective: having a failure rate of less than 1% per year when used consistently and, 
correctly and, when applicable, in accordance with the product label.  For non-product 
methods (e.g.  male sterility), the investigator determines what is consistent and correct 
use. The GSK definition is based on the definition provided by the ICH (ICH, M3 
[R2],2009)
The investigator is responsible for ensuring that subjects understand how to properly use 
these methods of contraception.
Based on the absence of an identified reproductive hazard from preclinical studies, 
absence of a genotoxic potential, and very low levels of mepolizumab that might be 
present in semen, there is no recognized risk for mepolizumab to affect human sperm or 
the fetus if transferred to a female partner via semen. Therefore, the use of condoms or 
other methods of contraception in the male study subject is not required.
13.5.1.
Collection of Pregnancy Information

Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study


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
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 4. 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 discontinue study medication or be withdrawn from the study (Section 6.5, 
Section 6.6 and Section 6.7).


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13.6.
Appendix 6: Cardiovascular Screening Questions
At screening each subject should be asked the following:
Unrelated to the symptoms you experience with your asthma:
1) Do you have any pain or discomfort (such as pressure) in your chest?

If yes, does this pain/discomfort/pressure go to other areas of your body 
such as neck, jaw, throat, or down your arms (including a numbness feeling 
in your arm) when it occurs?
2) When you walk at an ordinary pace on a level surface does this produce chest 
pain? If yes, respond to a and b:
a) Does this chest pain or discomfort occur when you are not doing any 
activities such as resting in bed or sitting in a chair?  
b) Has this chest pain/discomfort been more frequent or more intense or last 
longer or come on with less exertion lately?
3) When you walk uphill or hurry does this produce chest pain/discomfort?
4) Do you use or have you been previously prescribed nitroglycerine to relieve 
the discomfort?

If yes, have you needed to increase the number of pills or frequency of using 
the pills recently?
If the subject responds “yes” to any of the above questions a study physician should 
further assess for the presence of undiagnosed or unrecognized angina when 
evaluating Exclusion Criterion 4 (see Section 6.2)


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13.7.
Appendix 7: Daily Asthma Symptom Score
Each morning subjects will record an asthma symptom score using the following scale:

Daily Symptom Score:

0 = No symptoms during the previous 24-hours.

1 = Symptoms for one short period during the previous 24-hours.

2 = Symptoms for two or more short periods during the previous 24-hours.

3 = Symptoms for most of the previous 24-hours which did not affect my normal 
daily activities.

4 = Symptoms for most of the previous 24-hours which did affect my normal 
daily activities.

5 = Symptoms so severe that I could not go to work/school or perform normal 
daily activities.


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13.8.
Appendix 8: Anaphylaxis Criteria
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 blood pressure (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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13.9.
Appendix 9: Country Specific Requirements
No country-specific requirements exist.


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13.10.
Appendix 10: Protocol Amendment Changes
13.10.1.
Amendment 01 (06-Nov-2015) from the Original Protocol (23-Jun-
2015)
Scope: this applies to all sites
Protocol Changes specified in Amendment No. 01 are summarised below:
Change 1: Updated Medical Monitor/SAE Contact Information:
Original Text:
Role
Name
Day Time Phone Number 
and email address
After-hours 
Phone/Cell/
Pager Number
Fax 
Number
Site Address
Primary 
Medical 
Monitor 
 
 
 
MD, 
MFPM
Not Applicable
Stockley Park 
West
1-3 Ironbridge 
Road
Uxbridge, 
Middlesex,
UB11 1BT 
United
Kingdom
Secondary 
Medical 
Monitor
 
Not 
Applicable
5 Moore Drive
RTP, NC 
27709
SAE 
contact  
information 
Medical 
monitor 
as 
above
PPD
PPD
PP
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Revised Text:  
Role
Name
Day Time Phone Number and 
email address
After-hours 
Phone/Cell/
Pager 
Number
Fax 
Number
Site 
Address
Primary 
Medical 
Monitor 
 
 MD, 
MFPM
Not 
Applicable
 
 
Stockley 
Park 
West
1-3 
Ironbridge 
Road
Uxbridge, 
Middlesex
UB11 
1BT 
United
Kingdom
Secondary 
Medical 
Monitor
 
 MD, 
PMP 
Not 
Applicable
 
 
Stockley 
Park 
West
1-3 
Ironbridge 
Road
Uxbridge, 
Middlesex
UB11 
1BT 
United
Kingdom
SAE 
contact  
information 
Medical 
monitor as 
above
Change 2: Protocol Summary, Overall Design paragraph 1. Simplification of continuous 
treatment.
Original Text:
This is a 52-week, 2-arm, randomized, double-blind, parallel-group, multi-center study 
evaluating mepolizumab 100 mg and placebo administered subcutaneously (SC) every 4 
weeks in subjects with severe eosinophilic asthma who have been treated with 
mepolizumab continuously in addition to standard of care therapy for at least 3 years. 
Subjects who participated in the open-label studies MEA115666 or 201312 with at least 6 
months of treatment with mepolizumab prior to Visit 1 and who have no more than 2 
consecutive missed doses of mepolizumab treatment [no treatment gaps of more than 12 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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weeks (84 days) between any two doses while treated with mepolizumab in MEA115666 
or 201312] will be eligible to participate in this study. It is intended that the Follow 
up/Exit Visit or Early Withdrawal (EW) Visit for studies MEA115666 and 201312 will 
serve as the Pre-Screening/Screening Visit (Visit 0/Visit 1) for this study.
Revised Text:
This is a 52-week, 2-arm, randomized, double-blind, parallel-group, multi-center study 
evaluating mepolizumab 100 mg and placebo administered subcutaneously (SC) every 4 
weeks in subjects with severe eosinophilic asthma who have been treated with 
mepolizumab continuously in addition to standard of care therapy for at least 3 years. 
Subjects who participated in the open-label studies MEA115666 or 201312 and who have 
no treatment gaps of more than 12 weeks (84 days) between any two doses of 
mepolizumab in MEA115666 or 201312, will be eligible to participate in this study. 
It is intended that the Follow up/Exit Visit or Early Withdrawal (EW) Visit for studies 
MEA115666 and 201312 will serve as the Pre-Screening/Screening Visit (Visit 0/Visit 1) 
for this study.
Change 3: Study Design, Part D: Optional Switch to Open-Label Mepolizumab, last 
paragraph: clarification to process of subject moving from Part C to Part D.
Original Text:
Subjects who permanently discontinue study treatment in Part C or D of the study are 
NOT required to withdraw from the study. 
Revised Text:
Subjects who permanently discontinue study treatment in Part C or D of the study are 
NOT required to withdraw from the study. If a subject discontinues double blind study 
treatment during Part C and does not switch to Part D at their next visit (IP 
Discontinuation Visit) after experiencing a clinically significant asthma exacerbation, the 
subject cannot enter Part D at a later visit.  
Change 4: Simplification to definition of “continuous mepolizumab treatment”. Section 
5.1 Overall Design.
Original Text:
This is a 52-week, 2-arm, randomized, double-blind, parallel-group, multi-center study 
evaluating mepolizumab 100 mg and placebo administered SC every 4 weeks in subjects 
with severe eosinophilic asthma who have been treated with mepolizumab continuously 
in addition to standard of care therapy for at least 3 years. Subjects who participated in 
the open-label studies MEA115666 and 201312 with at least 6 months of continuous 
treatment with mepolizumab prior to Visit 1 will be eligible to participate in this study.
Continuous mepolizumab treatment: Continuous treatment with mepolizumab is defined 
as no more than 2 consecutive missed doses [no treatment gaps of more than 12 weeks 
(84 days) between any two doses]. To calculate the duration of continuous mepolizumab 


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treatment, the start date should be at least the start of treatment in studies MEA115666 
and 201312, and may include continuous mepolizumab treatment from the following 
prior studies: MEA115661, MEA115588, MEA115575.   
Revised Text:
This is a 52-week, 2-arm, randomized, double-blind, parallel-group, multi-center study 
evaluating mepolizumab 100 mg and placebo administered SC every 4 weeks in subjects 
with severe eosinophilic asthma who have been treated with mepolizumab continuously 
in addition to standard of care therapy for at least 3 years.
Definition of Continuous Mepolizumab Treatment 
Continuous treatment with mepolizumab is defined as no more than 2 consecutive missed 
doses, i.e. no treatment gaps of more than 12 weeks (84 days) between any two doses. 
When deriving the period of continuous mepolizumab exposure, treatment from the 
following studies may be considered: MEA115666, MEA115588, MEA115575, 
MEA115661 and 201312. The earliest date of initiating mepolizumab treatment may be 
considered when deriving this total exposure, however if a gap of > 84 days between any 
two doses of mepolizumab is experienced, this exposure period can no longer be 
considered ‘continuous’. If such an instance occurs the subject's period of continuous 
mepolizumab treatment will be derived from the first dose of mepolizumab following this 
gap in mepolizumab treatment. 
However, if a subject has experienced a gap of >12 weeks (84 days) between any two 
doses of mepolizumab within studies MEA115666 or 201312 this will exclude the 
subject from entry into 201810.
Change 5: To clarify that the controller medication from Part B and Part C should not be 
altered. Section 5.1 Overall Design
Original Text:
Any increase in controller therapy in Part B and Part C (except for OCS use for the 
treatment of exacerbations) should be discussed with the medical monitor.
Revised Text:
Any change in controller regimen or dose in Part B and Part C (except for OCS use for 
the treatment of exacerbations) should be discussed with the medical monitor. 
Change 6: To clarify the process of a subject switching from Part C to Part D. Section 
5.1 Overall Design: Part D: Optional Switch to Open-Label Mepolizumab.
Original Text:
Subjects who permanently discontinue study treatment in Part C or D of the study are 
NOT required to withdraw from the study. 


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Revised Text:
Subjects who permanently discontinue study treatment in Part C or D of the study are 
NOT required to withdraw from the study. If a subject discontinues double blind study 
treatment during Part C and does not switch to Part D at their next visit (IP 
Discontinuation Visit) after experiencing a clinically significant asthma exacerbation, the 
subject cannot enter Part D at a later visit.  
Change 7: Entry Criterion No. 2, Section 6.1 Inclusion Criteria updated to reflect 
simplification of continuous mepolizumab treatment.
Original Text:
2.
MEA115666 or 201312 Study Participation: Participation (through the Follow 
Up/Exit Visit or Early Withdrawal) in either study with documented evidence of 
at least 6 months of continous mepolizumab treatment prior to Visit 1. See 
Section 5.1 for the definition of continuous mepolizumab treatment.
Revised Text:
2.
Continuous Mepolizumab Treatment during MEA115666 or 201312:
Participation through the Follow Up/Exit Visit or Early Withdrawal Visit and 
documented evidence of treatment with mepolizumab with no treatment gaps of 
more than 12 weeks (84 days) between any two doses within MEA115666 or 
201312.  (A treatment gap of more than 12 weeks [84 days] cannot occur 
between the end of MEA115666 or 201312 and Visit 1).
Change 8: Added a reference to Section 5.1 in Section 6.3.1 Randomization Inclusion 
Criteria.
Original Text: 
1. Continuous Mepolizumab Treatment: Documented evidence of at least 3 years
(156 weeks) of treatment with mepolizumab with no treatment gaps of more than 
12 weeks (84 days) between any two doses while treated with mepolizumab. 
Revised Text:
1. Continuous Mepolizumab Treatment: Documented evidence of at least 3 years
(156 weeks) of treatment with mepolizumab with no treatment gaps of more than 
12 weeks (84 days) between any two doses while treated with mepolizumab. See 
Section 5.1 for the definition of continuous mepolizumab treatment.
Change 9: Removal of the Urinalysis test as it is not required within the mepolizumab 
programme in Section 6.5. Study Withdrawal Prior to Randomization: Withdrawal during 
Part A or Part B


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Original Text:
3. Laboratory abnormality: Evidence of clinically significant abnormality in the 
haematological, biochemical or urinalysis screen, which in the opinion of the 
investigator would make the subject unsuitable for participation in this study.
Revised Text:
3. Laboratory abnormality: Evidence of clinically significant abnormality in the 
haematological or biochemical  screen, which in the opinion of the investigator would 
make the subject unsuitable for participation in this study.
Change 10: Removal of a withdrawal criterion number 4 in Section 6.6 Discontinuation 
of Investigational Product (IP) during Part C or Part D
Removed Text:
4. Study treatment unblinded: Unblinding of the study treatment assigned to a subject 
in Part C.
Unblinded subjects may switch to open label Part D, per Investigators discrection.
Change 11: Updated section 7.3 Blinding.
Original Text:  

Subjects will be discontinued from study treatment if the treatment code is unblinded 
by the investigator or treating physician. Unblinded subjects may switch to open 
label Part D, per Investigators discrection (Section 6.6).
Revised Text:

If the treatment code assigned to a subject in Part C is unblinded to the subject,
Investigator and/or the treating physician/blinded member of site staff, please consult 
the Study Reference Manual and GSK for guidance. Remediation will be assessed on 
a case by case basis to minimise the impact of any possible bias.
Change 12: Section 7.9.1 Permitted Medications and Non-Drug Therapies updated to 
reflect Change 5.
Original Text:
During the fixed open-label period (Part B) and the double-blind treatment period (Part 
C), subjects should maintain the stable dose and regimen of controller therapy established 
in Part A or in studies MEA115666 and 201312. Any increase in controller therapy in 
Part B and Part C (except for OCS use for the treatment of exacerbations) should be 
discussed with the medical monitor. 


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Revised Text:
During the fixed open-label period (Part B) and the double-blind treatment period (Part 
C), subjects should maintain the stable dose and regimen of controller therapy established 
in Part A or in studies MEA115666 and 201312. Any change in controller regimen or 
dose in Part B and Part C (except for OCS use for the treatment of exacerbations) should 
be discussed with the medical monitor. 


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Change 13: The Time and Event table, Table 5, Table 6, Table 7 and Table 8 in Section 8.1 Time and Event Tables, corrected.
Original Section:
Section 8.1 Time and Events Tables
Table 5
Time and Events Table: Screening/Variable Open-Label Run-In Weeks 0 - 52 - Part A
PART A
Procedures
Pre-
Screen1
Exit/EW 
Visit 
MEA115666 
or 201312/
Screen1
Variable Open-Label Treatment  Part A2
(window is 1 week)
EW9
4 weeks
post last
injection
Visit
0
1
A1
A2
A3
A4
A5
A6
A7
A8
A9
A10
A11
A12
A13
Week of Variable Run-In
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Written Informed Consent
X
Demography
X
Medical History 
X
Assess cardiac risk factors
X
Smoking status
X
Inclusion/Exclusion Criteria
X
Safety Assessments
Concomitant Medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examination
X3
X
X
Vital Signs
X3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X4
X
X
X
Adverse Events
X5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments6
Haematology
X3
X
X
X
Chemistry (incl. LFT)
X3
X
X
X
Urinalysis
X3
X
X
X
Pregnancy Test7
U3
U
U
U
U
U
U
U
U
U
U
U
U
U
X
Immunogenicity
X3
X
X


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PART A
Procedures
Pre-
Screen1
Exit/EW 
Visit 
MEA115666 
or 201312/
Screen1
Variable Open-Label Treatment  Part A2
(window is 1 week)
EW9
4 weeks
post last
injection
Visit
0
1
A1
A2
A3
A4
A5
A6
A7
A8
A9
A10
A11
A12
A13
Week of Variable Run-In
0
4
8
12
16
20
24
28
32
36
40
44
48
52
HbsAg and hepatitis C 
antibody8
X
Efficacy Assessments
Exacerbation review 
X5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Asthma Control 
Questionnaire-5
X3
X
X
X
X
X
Spirometry
X3
X
X
X
Worksheets/Diary/IP/ eCRF
Administer open-label 
mepolizumab6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense 
albuterol/salbutamol
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect albuterol/salbutamol
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense paper diary
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect/review paper diary
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Contact IRT
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.
The Pre-Screen Visit and Screening Visit may occur on the same day.
2.
Visits should be conducted every 4 weeks until the subject has reached 3 years of mepolizumab exposure. 
3.
As assessed from the Follow Up/Exit Visit or EW from studies MEA115666 or 201312, if Screening for 201810 is conducted on the SAME day. If the MEA115666 or 201312 Exit Visit/EW and 201810 
Screening Visit are conducted on different days (no more than 84 days apart), the Physical Exam, Immunogenicity assessment, and Spirometry do not need to be repeated at Screening. Other 
assessments should be conducted at the Screening Visit.
4.
Screening ECG must be conducted with ECG equipment for study 201810.
5.
Any SAEs and exacerbations related to study participation should be recorded from the time of consent.
6.
All laboratory assessments to be completed prior to dosing
7.
Urine pregnancy tests (U) should be conducted every 4 weeks for women of child bearing potential during the variable open-label run-in period. Local urine testing will be standard for the protocol 
unless serum testing is required by local regulation or ethics committee.
8.
Hepatitis B Surface Antigen and Hepatitis C antibody ( if Hepatitis C antibody positive, a hepatitis C confirmatory test should be automatically performed to confirm the result. Test should be repeated 
as necessary if clinically indicated)
9.
EW = Early Withdrawal. Should be conducted 4 ± 1 weeks from the subjects last dose


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Table 6
Time and Events Table: Screening/Variable Open-Label Run-In Weeks 56 - 132- Part A
PART A
Procedures
Variable Open-Label Treatment  Part A1
(window is 1 week)
EW4 4 
weeks
post 
last 
injection
Visit
A14/A27
A15/A28
A16/A29
A17/A30
A18/A31
A19/A32
A20/A33
A21
A22
A23
A24
A25
A26
Week of Variable Run-In
56/108
60/112
64/116
68/120
72/124
76/128
80/132
84
88
92
96
100
104
Safety Assessments
Concomitant Medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examination
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments2
Haematology
X
X
X
Chemistry (incl. LFT)
X
X
X
Urinalysis
X
X
X
Pregnancy Test3
U
U
U
U
U
U
U
U
U
U
U
U
U
X
Immunogenicity
X
X
Efficacy Assessments
Exacerbation review 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Asthma Control Questionnaire-5
X
X
X
X
X
Spirometry
X
X
X
Worksheets/Diary/IP/eCRF
Administer open-label mepolizumab2
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense albuterol/salbutamol
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect albuterol/salbutamol
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense paper diary
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect/review paper diary
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Contact IRT
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


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1.
Visits should be conducted every 4 weeks until the subject has reached 3 years of mepolizumab exposure. 
2.
All laboratory assessments to be completed prior to dosing
3.
Urine pregnancy tests (U) should be conducted every 4 weeks for women of child bearing potential during the variable open-label run-in period. Local urine testing will be standard 
for the protocol unless serum testing is required by local regulation or ethics committee.
4.
EW=Early Withdrawal. Should be conducted 4 ± 1 weeks from the subjects last dose. 


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Table 7
Time and Events Table: Fixed Run-In & Double-Blind Treatment Period – Parts B and C
PARTS B&C
Procedures
Fixed
Run-in
Part B
Randomization
Double-Blind Treatment Part C 
(window is 1 week)
IPDISC/EW2
4 weeks
post last
injection
Visit
B1
B21
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
C11
C12
C13
Exit 
Visit
Week of Study 
-4 ± 
1
-4 ± 11
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Smoking status
X
Randomization Criteria
X
Safety Assessments
Concomitant Medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examination
X
X
X
Vital Signs 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG 
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory 
Assessments3
Haematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry (incl. LFT)
X
X
X
X
X
Biomarkers
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
Pregnancy Test 4
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
Immunogenicity
X 
X
Efficacy Assessments
Subject/Clinician Global 
Impression Rating
X
X
X
X
X
X
Subject/Clinician Rating of 
Response to Therapy
X
X
X
X
X
SGRQ
X
X
X
X
X
X
Exacerbation review 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 


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PARTS B&C
Procedures
Fixed
Run-in
Part B
Randomization
Double-Blind Treatment Part C 
(window is 1 week)
IPDISC/EW2
4 weeks
post last
injection
Visit
B1
B21
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
C11
C12
C13
Exit 
Visit
Week of Study 
-4 ± 
1
-4 ± 11
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Spirometry (pre- and post-
albuterol/salbutamol)
X
X
X
X
X
X
Healthcare resource 
utilization
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Review eDiary5 (symptoms, 
rescue use, nocturnal 
awakenings, PEF, ACQ-5, 
missed days of 
work/school)
Worksheets/Diary/IP/
eCRF
Administer open-label 
mepolizumab4
X
X
Administer double blind 
study treatment3
X6
X
X
X
X
X
X
X
X
X
X
X
X
Dispense 
albuterol/salbutamol
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect 
albuterol/salbutamol
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense paper diary
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense  eDiary
X
Collect eDiary
X
X7
Collect/review paper diary
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Contact IRT
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete eCRF
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
1.
Visit B2 is only intended for subjects who experience an exacerbation in the run-in Part B which is not resolved within 7 days of Visit C1 or subjects who fail eDiary Compliance 
Criteria (Section 6.3). These subjects may extend their run-in Part B by 4 weeks and complete Visit B2. All other eligible subjects should proceed directly to Visit C1 following Visit 
B1. B2 will be scheduled 4 ± 1 week after B1, and 4 ± 1 week prior to C1.


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2.
IPDISC = Discontinuation of IP Visit (only applies to subjects in Part C). EW = Early Withdrawal. Either visit should be conducted 4 ± 1 weeks from the subjects last dose.
3.
All laboratory assessments to be completed prior to dosing.
4.
Urine pregnancy tests (U) should be conducted every 4 weeks for women of child bearing potential during the variable open-label run-in period. Local urine testing will be standard 
for the protocol unless serum testing is required by local regulation or ethics committee.
5.
Subjects eDiary entries should be reviewed by the site weekly
6.
An unblinding card will be dispensed after Randomization at Visit C1.
7.
The eDiary is only collected at an Early Withdrawal visit.


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Table 8
Time and Events Table: Optional Open-Label Switch to Mepolizumab – Part D
PART D
Procedures
OPTIONAL Open-Label Switch to mepolizumab Part D1
(window is 1 week)
IPDISC/EW
4 weeks
post last
injection3
Visit
D1
D2
D3
D4
D5
D6
D7
D8
D9
D10
D11
D12
D13
Exit 
Visit
Week of Study2
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Safety Assessments
Concomitant Medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examination
X
X
Vital Signs 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments4
Haematology5
X
X
X
X
X
Chemistry (incl. LFT)
X
X
X
Urinalysis
X
X
X
Pregnancy Test 6
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
Immunogenicity
X
X
Efficacy Assessments
Exacerbation review 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 
Spirometry
X
X
X
X
X
Worksheets/Diary/IP/ eCRF
Administer open-label 
mepolizumab4
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense albuterol/salbutamol
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect albuterol/salbutamol
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense paper diary
X
X
X
X
X
X
X
X
X
X
X
X
X
Review eDiary  
(symptoms, rescue use, 
nocturnal awakenings, PEF, 
ACQ-5, missed days of 
work/school)7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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PART D
Procedures
OPTIONAL Open-Label Switch to mepolizumab Part D1
(window is 1 week)
IPDISC/EW
4 weeks
post last
injection3
Visit
D1
D2
D3
D4
D5
D6
D7
D8
D9
D10
D11
D12
D13
Exit 
Visit
Week of Study2
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Collect eDiary
X
X8
Collect/review paper diary
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Contact IRT
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
1.
The combined treatment period (Part C) and any switch to open-label mepolizumab (Part D) should not exceed a total duration of 52 weeks.
2.
Subjects may enter the Open-label Switch Part D at any point during Part C provided they meet switch criteria, starting with the week of study that the switch is made and 
continuing until week 52, discontinuation of IP or early withdrawal. 
3.
IPDISC = Discontinuation of IP Visit. EW = Early Withdrawal. Either visit should be conducted 4 ± 1 weeks from the subjects last dose.
4.
All laboratory assessments to be completed prior to dosing
5.
Haematology samples will be collected for each of the subject’s first 3 visits of Part D, and then according to designated Visits in Table 8
6.
Urine pregnancy tests (U) should be conducted every 4 weeks for women of child bearing potential during the variable open-label run-in period. Local urine testing will be standard 
for the protocol unless serum testing is required by local regulation or ethics committee.
7.
The eDiary should be reviewed at each visit. Weekly review is not required in Part D.
8.
The eDiary is only collected at an Early Withdrawal visit.


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Revised Section:
Section 8.1 Time and Events Tables
Table 5
Time and Events Table: Screening/Variable Open-Label Run-In Weeks 0 - 52 - Part A
PART A
Procedures
Pre-
Screen1
Exit/EW 
Visit 
MEA115666 
or 201312/
Screen1
Variable Open-Label Treatment  Part A2
(window is 1 week)
EW Visit5
Visit
0
1
A1
A2
A3
A4
A5
A6
A7
A8
A9
A10
A11
A12
A13
Week of Variable Run-In
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Written Informed Consent
X
Demography
X
Medical History 
X
Assess cardiac risk factors
X
Smoking status
X
Inclusion/Exclusion Criteria
X
Safety Assessments3
Concomitant Medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examination
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments3
Haematology
X
X
X
X
Chemistry (incl. LFT)
X
X
X
X
Pregnancy Test4
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
Immunogenicity
X
X
X
HbsAg and hepatitis C 
antibody 
X
Efficacy Assessments3
Exacerbation review 
X5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


2015N232375_03
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119
PART A
Procedures
Pre-
Screen1
Exit/EW 
Visit 
MEA115666 
or 201312/
Screen1
Variable Open-Label Treatment  Part A2
(window is 1 week)
EW Visit5
Visit
0
1
A1
A2
A3
A4
A5
A6
A7
A8
A9
A10
A11
A12
A13
Week of Variable Run-In
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Asthma Control 
Questionnaire-5
X
X
X
X
X
X
Spirometry
X
X
X
X
Worksheets/Diary/IP/ eCRF
Administer open-label 
mepolizumab
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense 
albuterol/salbutamol
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect albuterol/salbutamol
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense paper diary
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect/review paper diary
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Contact IRT
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.
The Pre-Screen Visit and Screening Visit may occur on the same day.
2.
Visits should be conducted every 4 weeks until the subject has reached 3 years of mepolizumab exposure. 
3.
Please see the SRM for details on which screening procedures to perform for subjects entering from 201312 and MEA115666.  ALL procedures should be completed prior to 
dosing with open-label mepolizumab.
4.
Urine pregnancy tests (U) should be conducted for women of child bearing potential. 
5.
EW = Early Withdrawal. Should be conducted 4 ± 1 weeks from the subject’s last dose


2015N232375_03
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120
Table 6
Time and Events Table: Screening/Variable Open-Label Run-In Weeks 56 - 132- Part A
PART A
Procedures
Variable Open-Label Treatment  Part A1
(window is 1 week)
EW
Visit3
Visit
A14/A27
A15/A28
A16/A29
A17/A30
A18/A31
A19/A32
A20/A33
A21
A22
A23
A24
A25
A26
Week of Variable Run-In
56/108
60/112
64/116
68/120
72/124
76/128
80/132
84
88
92
96
100
104
Safety Assessments
Concomitant Medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examination
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments
Haematology
X
X
X
Chemistry (incl. LFT)
X
X
X
Pregnancy Test2
U
U
U
U
U
U
U
U
U
U
U
U
U
X
Immunogenicity
X
X
Efficacy Assessments
Exacerbation review 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Asthma Control Questionnaire-5
X
X
X
X
X
Spirometry
X
X
X
Worksheets/Diary/IP/eCRF
Administer open-label mepolizumab
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense albuterol/salbutamol
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect albuterol/salbutamol
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense paper diary
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect/review paper diary
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Contact IRT
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
1.
Visits should be conducted every 4 weeks until the subject has reached 3 years of mepolizumab exposure. 
2.
Urine pregnancy tests (U) should be conducted for women of child bearing potential. 
3.
EW = Early Withdrawal. Should be conducted 4 ± 1 weeks from the subject’s last dose


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Table 7
Time and Events Table: Fixed Run-In & Double-Blind Treatment Period – Parts B and C
PARTS 
B&C
Procedures
Fixed
Run-in
Part B
EW from 
Part B7
Randomization
Double-Blind Treatment Part C 
(window is 1 week)
IPDISC/EW 
Visit 7
Visit
B1
B21
Part B EW
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
C11
C12
C13
Exit 
Visit
Week of Study 
-4 
± 1
-4 ± 
11
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Smoking status
X
Randomization Criteria
X
Safety Assessments2
Concomitant 
Medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examination
X
X
X
X
Vital Signs 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG 
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory 
Assessments2
Haematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry (incl. LFT)
X
X
X
X
X
X
Biomarkers
X
X
X
X
X
X
X
X
X
Pregnancy Test 3
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
Immunogenicity
X
X 
X
Efficacy 
Assessments2
Subject/Clinician 
Global Impression 
Rating
X
X
X
X
X
X
Subject/Clinician 
Rating of Response to 
Therapy
X
X
X
X
X


2015N232375_03
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122
PARTS 
B&C
Procedures
Fixed
Run-in
Part B
EW from 
Part B7
Randomization
Double-Blind Treatment Part C 
(window is 1 week)
IPDISC/EW 
Visit 7
Visit
B1
B21
Part B EW
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
C11
C12
C13
Exit 
Visit
Week of Study 
-4 
± 1
-4 ± 
11
0
4
8
12
16
20
24
28
32
36
40
44
48
52
SGRQ
X
X
X
X
X
X
Exacerbation review 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 
Spirometry (pre- and 
post-
albuterol/salbutamol)
X8
X
X
X
X
X
X
Healthcare resource 
utilization
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Review eDiary4
(symptoms, rescue 
use, nocturnal 
awakenings, PEF, 
ACQ-5, missed days of 
work/school)
Worksheets/Diary/IP/
eCRF2
Administer open-label 
mepolizumab4
X
X
Administer double 
blind study treatment
X5
X
X
X
X
X
X
X
X
X
X
X
X
Dispense 
albuterol/salbutamol
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect 
albuterol/salbutamol
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense paper diary
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense  eDiary
X
Collect eDiary
X
X
X6


2015N232375_03
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123
PARTS 
B&C
Procedures
Fixed
Run-in
Part B
EW from 
Part B7
Randomization
Double-Blind Treatment Part C 
(window is 1 week)
IPDISC/EW 
Visit 7
Visit
B1
B21
Part B EW
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
C11
C12
C13
Exit 
Visit
Week of Study 
-4 
± 1
-4 ± 
11
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Collect/review paper 
diary
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Contact IRT
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete eCRF
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
1.
Visit B2 is only intended for subjects who experience an exacerbation in the run-in Part B which is not resolved within 7 days of Visit C1 or subjects who fail eDiary Compliance 
Criteria (Section 6.3). 
2.
All assessments to be completed prior to dosing.
3.
Urine pregnancy tests (U) should be conducted every 4 weeks for women of child bearing potential.
4.
Subjects eDiary entries should be reviewed by the site weekly during Part C
5.
An unblinding card will be dispensed after Randomization at Visit C1.
6.
The eDiary is only collected at an Early Withdrawal visit and not at IPDISC in Part C.
7.
IPDISC/EW visit should be conducted 4 ± 1 weeks from the subject’s last dose
8.
Only pre-bronchodilator spirometry required at this visit.


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Table 8
Time and Events Table: Optional Open-Label Switch to Mepolizumab – Part D
PART D
Procedures
OPTIONAL Open-Label Switch to mepolizumab Part D1
(window is 1 week)
IPDISC/EW 
Visit 8
Visit
D1
D2
D3
D4
D5
D6
D7
D8
D9
D10
D11
D12
D13
Exit 
Visit
Week of Study2
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Safety Assessments3
Concomitant Medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examination
X
X
Vital Signs 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments3
Haematology4
X
X
X
X
X
Chemistry (incl. LFT)
X
X
X
Pregnancy Test 5
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
Immunogenicity
X
X
Efficacy Assessments3
Exacerbation review 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 
Spirometry
X
X
X
X
X
Worksheets/Diary/IP/ eCRF3
Administer open-label 
mepolizumab
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense albuterol/salbutamol
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect albuterol/salbutamol
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense paper diary
X
X
X
X
X
X
X
X
X
X
X
X
X
Review eDiary6  
(symptoms, rescue use, 
nocturnal awakenings, PEF, 
ACQ-5, missed days of 
work/school)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect eDiary
X
X7


2015N232375_03
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125
PART D
Procedures
OPTIONAL Open-Label Switch to mepolizumab Part D1
(window is 1 week)
IPDISC/EW 
Visit 8
Visit
D1
D2
D3
D4
D5
D6
D7
D8
D9
D10
D11
D12
D13
Exit 
Visit
Week of Study2
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Collect/review paper diary
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Contact IRT
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
1.
The combined treatment period (Part C) and any switch to open-label mepolizumab (Part D) should not exceed a total duration of 52 weeks.
2.
Subjects may enter the Open-label Switch Part D at any point during Part C provided they meet switch criteria, starting with the week of study that the switch is made and 
continuing until week 52, discontinuation of IP or early withdrawal. 
3.
All assessments to be completed prior to dosing
4.
Haematology samples will be collected for each of the subject’s first 3 visits of Part D, and then according to designated Visits in Table 8
5.
Urine pregnancy tests (U) should be conducted every 4 weeks for women of child bearing potential.
6.
The eDiary should be reviewed at each visit. Weekly review is not required in Part D.
7.
The eDiary is only collected at an Early Withdrawal or Exit visit.
8.
IPDISC/EW visit should be conducted 4 ± 1 weeks from the subject’s last dose


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Change 14: Section 8.2 Screening and Critical Baseline Assessments updated to reflect 
changes made throughout protocol and specifically in the Tine and Event Tables.
Original Text:
8.2.
Screening and Critical Baseline Assessments
Informed consent/assent will be obtained at the Pre-screen Visit or Screening Visit (if 
Pre-screen and Screening Visits are performed on the same day).
8.2.1. Critical procedures performed at Screening (Visit 1)
If the MEA115666 or 201312 Exit Visit/EW and 201810 Screening Visit are conducted 
on different days (no more than 84 days apart), the Physical Exam, Immunogenicity 
assessment, and Spirometry do not need to be repeated at Screening. Other assessments 
should be conducted at the Screening Visit.

Review Inclusion/Exclusion criteria (see Section 6)

Demographic information including gender, ethnic origin, race, year of birth

Medical history including smoking status, history of sinusitis, nasal 
polyposis, aspirin allergy, duration of asthma, courses of rescue 
corticosteroids, history of previous intubations, asthma exacerbation history 
in previous year, asthma triggers

Vital signs 

Physical exam  (conducted at the Exit/EW Visit from study MEA115666 or 
201312) 

Resting 12 lead ECG  (using 201810 equipment)

Therapy history (review concomitant medications from the previous 12 
weeks prior to the first dose of study medication)

Cardiovascular medical history/risk factors (as detailed in the eCRF) will be 
assessed at screening. This assessment must include a review of the subject 
responses to the cardiovascular assessment questions (see Appendix 6) 

Exacerbation review 

Smoking status

Asthma Control Questionnaire (ACQ-5)

Spirometry (conducted at the Exit/EW Visit from study MEA115666 or 
201312)

Laboratory tests:

Chemistry (including liver function test [LFT])

Haematology with differential

Urinalysis


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
Immunogenicity  (conducted at the Exit/EW Visit from study 
MEA115666 or 201312) 

Hepatitis B Surface Antigen and hepatitis C antibody

Urine pregnancy test- for all females of child bearing potential (Follicle 
Stimulating Hormone [FSH] will be assessed to confirm child-bearing 
status, if clinically indicated)

AE/SAE assessment 
8.2.2. Critical procedures performed at entry to Part B (Visit B1)

Vital signs

Resting 12- lead ECG

Physical examination

Concomitant medication review

Exacerbation review

Laboratory tests:

Chemistry (including LFT)  

Haematology with differential

Urinalysis

Urine pregnancy test- for all females of child bearing potential

AE/SAE assessment
8.2.3. Critical procedures performed at Randomization (Visit C1)

Review of randomization criteria (see Section 6.3)

Subject/Clinician global impression of asthma severity rating

Subject/Clinician rating of response to therapy 

St. George’s Respiratory Questionnaire (SGRQ)

Vital signs

Spirometry (pre- and post-albuterol/salbutamol)

Review/Collect eDiary data 

Exacerbation review

Smoking status

Concomitant medication assessment 

Laboratory tests:

Clinical Chemistry (including LFT)

Haematology with differential


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
Biomarker sample

Urinalysis

Urine pregnancy test for all females of childbearing potential

AE/SAE assessment
Revised Text:
8.2.
Screening and Critical Baseline Assessments
Informed consent/assent will be obtained at the Pre-screen Visit or Screening Visit (if 
Pre-screen and Screening Visits are performed on the same day).
8.2.1. Critical procedures performed at Screening (Visit 1)
If the MEA115666 or 201312 Exit Visit/EW and 201810 Screening Visit are conducted 
on different days (no more than 84 days apart), the Physical Exam, Immunogenicity 
assessment, and Spirometry do not need to be repeated at Screening. Other assessments 
should be conducted at the Screening Visit.  Please see the Study Reference Manual 
(SRM) for full details.

Review Inclusion/Exclusion criteria (see Section 6)

Demographic information including gender, ethnic origin, race, year of birth

Medical history including smoking status, history of sinusitis, nasal 
polyposis, aspirin allergy,  courses of rescue corticosteroids, 

Vital signs 

Physical exam  

Resting 12 lead ECG  

Therapy history (review concomitant medications from the previous 12 
weeks prior to the first dose of study medication)

Cardiovascular medical history/risk factors (as detailed in the eCRF) will be 
assessed at screening. This assessment must include a review of the subject 
responses to the cardiovascular assessment questions (see Appendix 6) 

Exacerbation review 

Smoking status

Asthma Control Questionnaire (ACQ-5)

Spirometry 

Laboratory tests:

Chemistry (including liver function test [LFT])

Haematology with differential

Immunogenicity  

Hepatitis B Surface Antigen and hepatitis C antibody


2015N232375_02
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129

Urine pregnancy test- for all females of child bearing potential (Follicle 
Stimulating Hormone [FSH] will be assessed to confirm child-bearing 
status, if clinically indicated)

AE/SAE assessment 
8.2.2. Critical procedures performed at entry to Part B (Visit B1)

Vital signs

Resting 12- lead ECG

Physical examination

Concomitant medication review

Exacerbation review

Laboratory tests:

Chemistry (including LFT)  

Haematology with differential

Urine pregnancy test- for all females of child bearing potential

AE/SAE assessment
8.2.3. Critical procedures performed at Randomization (Visit C1)

History of previous intubations, asthma exacerbation history in previous year, 
asthma triggers

Review of randomization criteria (see Section 6.3)

Subject/Clinician global impression of asthma severity rating

St. George’s Respiratory Questionnaire (SGRQ)

Vital signs

Spirometry (pre- and post-albuterol/salbutamol)

Review/Collect eDiary data 

Exacerbation review

Smoking status

Concomitant medication assessment 

Laboratory tests:

Clinical Chemistry (including LFT)

Haematology with differential

Biomarker sample

Urine pregnancy test for all females of childbearing potential

AE/SAE assessment


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Change 14: Removal of text in Section 8.4.5 Electrocardiogram (ECG)
Original Text:
8.4.5. Electrocardiogram (ECG)

Twelve-lead ECGs will be obtained at each time point specified in the Time and 
Events Schedules (Table 5, Table 6, Table 7 and Table 8), using the equipment 
provided for Study 201810. 
Revised Text:
8.4.5. Electrocardiogram (ECG)

Twelve-lead ECGs will be obtained at each time point specified in the Time and 
Events Schedules (Table 5, Table 6, Table 7 and Table 8).
Change 15: Removal of Urinalysis from Section 8.4.6 Clinical Safety Laboratory 
Assessments and updating Table 9 to reflect updated footnotes in Time and Event tables.
Original Text: 
All protocol required laboratory assessments (haematology, clinical chemistry and 
urinalysis) must be conducted in accordance with the Laboratory Manual, and Protocol 
Time and Events Schedule (Table 5, Table 6, Table 7 and Table 8)..
Revised Text:
All protocol required laboratory assessments (haematology and clinical chemistry) must 
be conducted in accordance with the Laboratory Manual, and Protocol Time and Events 
Schedule (Table 5, Table 6, Table 7 and Table 8).
Original Text:
Haematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed in Table 9.
Table 9
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Platelet Count
RBC Indices:
WBC count with Differential:
RBC Count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes
Hematocrit
Monocytes
Eosinophils
Basophils
Clinical 
Chemistry 1
BUN
Potassium
AST (SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
ALT (SGPT)
Total Protein
Glucose 
Calcium
Alkaline phosphatase
Albumin
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood and ketones by dipstick

Microscopic examination (if blood or protein is abnormal)


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Laboratory 
Assessments
Parameters
Other 
Screening 
Tests

Hepatitis B (HBsAg)

Hepatitis C (Hep C antibody)

FSH and estradiol (if clinically indicated, in women of non-child 
bearing potential only)

Alcohol and drug screen (if clinically indicated, to include at 
minimum: amphetamines, barbiturates, cocaine, opiates, 
cannabinoids and benzodiazepines)

Urine hCG Pregnancy test (for women of child bearing potential) 2
NOTES :
1.
Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up 
Assessments after liver stopping or monitoring event are given in Appendix 2 and 
Appendix 3
2.
Local urine testing will be standard for the protocol unless serum testing is required 
by local regulation or ethics committee.
Revised Text:
Haematology, clinical chemistry and additional parameters to be tested are listed in Table 
9.
Table 9
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Platelet Count
RBC Indices:
WBC count with Differential:
RBC Count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes
Hematocrit
Monocytes
Eosinophils
Basophils
Clinical 
Chemistry 1
BUN
Potassium
AST (SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
ALT (SGPT)
Total Protein
Glucose 
Calcium
Alkaline phosphatase
Albumin
Other 
Screening 
Tests

Hepatitis B (HBsAg)

Hepatitis C (Hep C antibody)2

FSH and estradiol (if clinically indicated, in women of non-child 
bearing potential only)

Alcohol and drug screen (if clinically indicated, to include at 
minimum: amphetamines, barbiturates, cocaine, opiates, 


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Laboratory 
Assessments
Parameters
cannabinoids and benzodiazepines)

Urine hCG Pregnancy test (for women of child bearing potential) 3
NOTES :
1.
Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up 
Assessments after liver stopping or monitoring event are given in Appendix 2 and 
Appendix 3
2.
If Hepatitis C antibody positive result, a hepatitis C confirmatory test should be 
automatically performed to confirm the result. Test should be repeated as necessary 
if clinically indicated.
3.
Local urine testing will be standard for the protocol unless serum testing is required 
by local regulation or ethics committee.
Change 15: Removal of urinalysis from Section 13.4.1 Definition of an AE.
Original Text:

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.
Revised Text:

Any abnormal laboratory test results (hematology or clinical chemistry) 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.
Change 16: Updated Appendix 13.5 Modified List of Highly Effective Methods for 
Avoiding Pregnancy in Females of Reproductive Potential (FRP) and Collection of 
Pregnancy Information
Original Text:
Section 13.5: Appendix 5: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP) and Collection of Pregnancy 
Information
This list does not apply to FRP with same sex partners, when this is their preferred and 
usual lifestyle or for subjects who are and will continue to be abstinent from penile-
vaginal intercourse on a long term and persistent basis.
Subjects who are FRP must agree to acceptable contraceptive methods approved in their 
local country, when used consistently and correctly (i.e., in accordance with the approved 


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product label and the instructions of the physician) for the duration of the study and for 4 
months after the last study drug administration.

Contraceptive subdermal implant 

Intrauterine device or intrauterine system 

Oral Contraceptive, either combined or progestogen alone [Hatcher, 2007a] 

Injectable progestogen [Hatcher, 2007a]

Contraceptive vaginal ring [Hatcher, 2007a]

Percutaneous contraceptive patches [Hatcher, 2007a]

Male partner sterilization with documentation of azoospermia prior to the female 
subject's entry into the study, and this male is the sole partner for that subject 
[Hatcher, 2007a].  

Male condom plus partner use of one of the contraceptive options below:
o
Contraceptive subdermal implant 
o
Intrauterine device or intrauterine system 
o
Oral Contraceptive, either combined or progestogen alone [Hatcher, 
2007a] Injectable progestogen [Hatcher, 2007a]
o
Contraceptive vaginal ring [Hatcher, 2007a]
o
Percutaneous contraceptive patches [Hatcher, 2007a]
This is an all inclusive list of those methods that meet the GSK definition of highly 
effective: having a failure rate of less than 1% per year when used consistently and, 
correctly and, when applicable, in accordance with the product label.  For non-product 
methods (e.g.  male sterility), the investigator determines what is consistent and correct 
use. The GSK definition is based on the definition provided by the ICH (ICH guideline 
M3(R2) on non-clinical safety studies for the conduct of human clinical trials and 
marketing authorisation for pharmaceuticals, 2009; EMA/CPMP/ICH/286/1995). 
The investigator is responsible for ensuring that subjects understand how to properly use 
these methods of contraception.
Based on the absence of an identified reproductive hazard from preclinical studies, 
absence of a genotoxic potential, and very low levels of mepolizumab that might be 
present in semen, there is no recognized risk for mepolizumab to affect human sperm or 
the fetus if transferred to a female partner via semen. Therefore, the use of condoms or 
other methods of contraception in the male study subject is not required.
Revised Text:
This list does not apply to FRP with same sex partners, when this is their preferred and 
usual lifestyle or for subjects who are and will continue to be abstinent from penile-
vaginal intercourse on a long term and persistent basis.


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Subjects who are FRP must agree to acceptable contraceptive methods approved in their 
local country, when used consistently and correctly (i.e., in accordance with the approved 
product label and the instructions of the physician) for the duration of the study and for 4 
months after the last study drug administration.

Contraceptive subdermal implant 

Intrauterine device or intrauterine system 

Combined estrogen and progestogen oral contraceptive [Hatcher, 2011]

Injectable progestogen [Hatcher, 2011]

Contraceptive vaginal ring [Hatcher, 2011]

Percutaneous contraceptive patches [Hatcher, 2011]

Male partner sterilization with documentation of azoospermia prior to the female 
subject's entry into the study, and this male is the sole partner for that subject 
[Hatcher, 2011].  
This is an all inclusive list of those methods that meet the GSK definition of highly 
effective: having a failure rate of less than 1% per year when used consistently and, 
correctly and, when applicable, in accordance with the product label.  For non-product 
methods (e.g.  male sterility), the investigator determines what is consistent and correct 
use. The GSK definition is based on the definition provided by the ICH (ICH, M3 [R2]
The investigator is responsible for ensuring that subjects understand how to properly use 
these methods of contraception.
Based on the absence of an identified reproductive hazard from preclinical studies, 
absence of a genotoxic potential, and very low levels of mepolizumab that might be 
present in semen, there is no recognized risk for mepolizumab to affect human sperm or 
the fetus if transferred to a female partner via semen. Therefore, the use of condoms or 
other methods of contraception in the male study subject is not required.
Change 17: Changed Reference related to change 16 in Section 12 References
Original Text:
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, editors. 
Contraceptive Technology. 19th edition. New York: Ardent Media, 2007(a): 24. Table 3-
2.
Revised Text:
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, Policar MS, editors. 
Contraceptive Technology. 20th edition.  Atlanta, Georgia: Ardent Media, Inc., 2011:50. 
Table 3-2.
Change 18: Changed entry criterion No. 5 in Section 6.3.2 Randomisation Exclusion 
Criteria to allow the result to be communicated to Site Staff if positive.
Original Text: 


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5.  Immunogenicity: Positive neutralizing antibody status based on the last sample
obtained.
Revised Text:
5.  Immunogenicity: Positive neutralizing antibody status based on the last result
obtained.


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13.10.2.
Amendment 2 (07-JUL-2016) from the Amendment 1 (06-NOV-
2015)
Scope: this applies to all sites
Protocol Changes specified in Amendment No. 02 are summarised below:
Change 1: To amend Section 5.6.1 Risk Assessment.
Original text: 

The majority of reports of systemic non-allergic and allergic (i.e., hypersensitivity) 
reactions have been non-serious and resolved without sequelae following minimal 
supportive care. There have been rare reports of serious reactions. To date, there 
have been no reports of severe life-threatening anaphylaxis.
Revised text:

The majority of reports of systemic non-allergic and allergic (i.e., hypersensitivity) 
reactions have been non-serious and resolved without sequelae following minimal 
supportive care. There have been rare reports of serious reactions. 
Change 2: To correct the numbering of Section 6.2: Exclusion Criteria, which started at 
No. 2. All consequent exclusion criteria also change.
Original Text:
2.
MEA115666 or 201312 IP Discontinuation: Subjects withdrawn from IP or 
withdrawn from study participation from either MEA115666 or 201312 for safety 
reasons
Revised text:
1.
MEA115666 or 201312 IP Discontinuation: Subjects withdrawn from IP or 
withdrawn from study participation from either MEA115666 or 201312 for safety 
reasons
Change 3: To amend Exclusion criterion No. 7 in Section 6.2: Exclusion Criteria.
Original text:
8.
Other Monoclonal Antibodies: Subjects who have received any monoclonal 
antibody (other than Xolair) to treat inflammatory disease within 5 half-lives of Visit 
1. 
Revised text:
7.
Other Monoclonal Antibodies: Subjects who have received any monoclonal 
antibody within 5 half-lives of Visit 1. 


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Change 4: To amend Randomization Exclusion criterion No. 7 in Section 6.3.2: 
Randomization Exclusion Criteria.
Original text:
7.
Current Asthma Exacerbation: Subjects with an asthma exacerbation that has not 
resolved completely within 7 days of Visit C1. Subjects who experience an 
exacerbation in the fixed run-in Part B which is not resolved within 7 days of Visit 
C1 may extend their run-in Part B by 4 weeks.
Revised text:
7.
Current Asthma Exacerbation: Subjects with an asthma exacerbation (or asthma 
worsening) that has not resolved completely within 7 days of Visit C1. Subjects who 
experience an exacerbation (or asthma worsening) in the fixed run-in Part B which is 
not resolved within 7 days of Visit C1 may extend their run-in Part B by 4 weeks.
Change 5: Added text to Section 7.1 Investigational Product and Other Study 
Treatments.
Original Text: 

Safety monitoring of subjects is required during SC administration in accordance with 
standard of care at the site.
Revised text:

Safety monitoring of subjects is required during SC administration in accordance with 
standard of care at the site. Such monitoring will include general safety monitoring 
including monitoring for systemic (i.e., allergic/IgE-mediated and non-allergic) and 
local injection site reactions. In the event of an acute severe reaction (e.g., 
anaphylaxis) following administration of study treatment, there are personnel/staff 
onsite at the treatment facility who are appropriately trained in basic life support to 
manage the subject 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.
Change 6: To amend Section 7.9.1 Permitted Medications and Non-Drug Therapies.
Original text:
Additional asthma medications such as theophyllines, anti-leukotrienes or Xolair
(omalizumab) will be permitted provided that they have been taken regularly (per label)
in the 12 weeks prior to randomization (Visit C1).
Revised text: 
Additional asthma medications such as theophyllines or anti-leukotrienes will be 
permitted provided that they have been taken regularly (per label) in the 12 weeks prior 
to randomization (Visit C1).  If uncertain whether a medication is permitted please 
confirm with the medical monitor.


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Change 7: Multiple changes to Section 7.9.2 Prohibited Medications and Non-Drug 
Therapies.
Original text:
The following medications are not allowed prior to screening (Visit 1) according to the 
following schedule, or during the study:
Table 11
Medications not allowed prior to the Screening Visit 1 and throughout 
the study
Medication
Washout Time
Prior to Screening Visit 1
Investigational drugs
1 month or 5 half-lives whichever is 
longer
Other monoclonal antibodies (other than Xolair)
5 half-lives
Experimental anti-inflammatory drugs (non biologicals)
3 months
Immunosuppressive medications such as those listed below (not all inclusive)

Corticosteroids intramuscular, long-acting depot if 
used to treat a condition other than asthma
3 months

Methotrexate, troleandomycin, cyclosporin, 
azathioprine 
1 month

Oral gold
3 months

Chemotherapy used for conditions other than 
asthma
12 months

Regular systemic (oral or parenteral) corticosteroids 
for the treatment of conditions other than asthma
3 months
Additionally, Bronchial Thermoplasty and Radiotherapy are excluded for 12 months 
prior to Visit 1 and throughout the study.  Neither CPAP nor oxygen therapy may be 
initiated on or after Visit 1.
Recreational drug use is not allowed during the study.
Revised text:
The following medications are not permitted during the 201810 study:


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Table 12
Medications not permitted during the study
Medications
Investigational drugs (other than mepolizumab)
Other monoclonal antibodies
Experimental anti-inflammatory drugs
Any medication with a significant immunosupressive effect. (some examples listed below)

Methotrexate, troleandomycin, cyclosporin, azathioprine 

Oral gold

Chemotherapy

Regular systemic (oral or parenteral) corticosteroids for the treatment of conditions other 
than asthma

Long acting depot, intramuscular injections of corticosteroids if used to treat a condition 
other than asthma
Additionally, Bronchial Thermoplasty and Radiotherapy are excluded for 12 months 
prior to Visit 1 and throughout the study.  
Neither CPAP nor oxygen therapy may be initiated on or after Visit 1.
Recreational drug use is not allowed during the study.
If uncertain whether a medication is permitted please contact the medical monitor prior to 
administration to confirm if the medication is prohibited.
Change 8: Within Table5, 6, 7 and 8, in Section 8.1, removal of the per visit task of 
registering each visit via the IRT system.  In the interest of reducing replication, only 
Table 5 is shown below.


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Original table: 
Table 5          Time and Events Table: Screening/Variable Open-Label Run-In Weeks 0 - 52 - Part A
PART A
Procedures
Pre-
Screen1
Exit/EW 
Visit 
MEA115666 
or 201312/
Screen1
Variable Open-Label Treatment  Part A2
(window is 1 week)
EW Visit5
Visit
0
1
A1
A2
A3
A4
A5
A6
A7
A8
A9
A10
A11
A12
A13
Week of Variable Run-In
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Written Informed Consent
X
Demography
X
Medical History 
X
Assess cardiac risk factors
X
Smoking status
X
Inclusion/Exclusion Criteria
X
Safety Assessments3
Concomitant Medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examination
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments3
Haematology
X
X
X
X
Chemistry (incl. LFT)
X
X
X
X
Pregnancy Test4
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
Immunogenicity
X
X
X
HbsAg and hepatitis C 
antibody 
X
Efficacy Assessments3
Exacerbation review 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Asthma Control 
Questionnaire-5
X
X
X
X
X
X
Spirometry
X
X
X
X
Worksheets/Diary/IP/ eCRF


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PART A
Procedures
Pre-
Screen1
Exit/EW 
Visit 
MEA115666 
or 201312/
Screen1
Variable Open-Label Treatment  Part A2
(window is 1 week)
EW Visit5
Visit
0
1
A1
A2
A3
A4
A5
A6
A7
A8
A9
A10
A11
A12
A13
Week of Variable Run-In
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Administer open-label 
mepolizumab
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense 
albuterol/salbutamol
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect albuterol/salbutamol
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense paper diary
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect/review paper diary
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Contact IRT
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
Revised Table:
Table 13
Time and Events Table: Screening/Variable Open-Label Run-In Weeks 0 - 52 - Part A
PART A
Procedures
Pre-
Screen1
Exit/EW 
Visit 
MEA115666 
or 201312/
Screen1
Variable Open-Label Treatment  Part A2
(window is 1 week)
EW Visit5
Visit
0
1
A1
A2
A3
A4
A5
A6
A7
A8
A9
A10
A11
A12
A13
Week of Variable Run-In
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Written Informed Consent
X
Demography
X
Medical History 
X
Assess cardiac risk factors
X
Smoking status
X
Inclusion/Exclusion Criteria
X
Safety Assessments3


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PART A
Procedures
Pre-
Screen1
Exit/EW 
Visit 
MEA115666 
or 201312/
Screen1
Variable Open-Label Treatment  Part A2
(window is 1 week)
EW Visit5
Visit
0
1
A1
A2
A3
A4
A5
A6
A7
A8
A9
A10
A11
A12
A13
Week of Variable Run-In
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Concomitant Medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examination
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments3
Haematology
X
X
X
X
Chemistry (incl. LFT)
X
X
X
X
Pregnancy Test4
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
Immunogenicity
X
X
X
HbsAg and hepatitis C 
antibody 
X
Efficacy Assessments3
Exacerbation review 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Asthma Control 
Questionnaire-5
X
X
X
X
X
X
Spirometry
X
X
X
X
Worksheets/Diary/IP/ eCRF
Administer open-label 
mepolizumab
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense 
albuterol/salbutamol
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect albuterol/salbutamol
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense paper diary
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect/review paper diary
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Contact IRT
X
X
Complete eCRF
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Change 9:  Adding Physical Examination to Table 7.
Original Table:
Table 7 Time and Events Table: Fixed Run-In & Double-Blind Treatment Period – Parts B and C
PARTS 
B&C
Procedures
Fixed
Run-in
Part B
EW from 
Part B7
Randomization
Double-Blind Treatment Part C 
(window is 1 week)
IPDISC/EW 
Visit 7
Visit
B1
B21
Part B EW
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
C11
C12
C13
Exit 
Visit
Week of Study 
-4 
± 1
-4 ± 
11
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Smoking status
X
Randomization Criteria
X
Safety Assessments2
Concomitant 
Medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examination
X
X
X
X
Vital Signs 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG 
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Revised Table:
Table 7 Time and Events Table: Fixed Run-In & Double-Blind Treatment Period – Parts B and C
PARTS 
B&C
Procedures
Fixed
Run-in
Part B
EW from 
Part B7
Randomization
Double-Blind Treatment Part C 
(window is 1 week)
IPDISC/EW 
Visit 7
Visit
B1
B21
Part B EW
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
C11
C12
C13
Exit 
Visit
Week of Study 
-4 
± 1
-4 ± 
11
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Smoking status
X
Randomization Criteria
X
Safety Assessments2
Concomitant 
Medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examination
X
X
X
X
X
Vital Signs 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG 
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


2015N232375_03
CONFIDENTIAL
201810
145
Change 10: Adding Physical Examination to Section 8.2.3 
Original text:
8.2.3 Critical procedures performed at Randomization (Visit C1)

History of previous intubations, asthma exacerbation history in previous year, 
asthma triggers

Review of randomization criteria (see Section 6.3)

Subject/Clinician global impression of asthma severity rating

St. George’s Respiratory Questionnaire (SGRQ)

Vital signs

Spirometry (pre- and post-albuterol/salbutamol)

Review/Collect eDiary data 

Exacerbation review

Smoking status

Concomitant medication assessment Laboratory tests:

Clinical Chemistry (including LFT)

Haematology with differential

Biomarker sample

Urine pregnancy test for all females of childbearing potential

AE/SAE assessment
Revised text:
8.2.3 Critical procedures performed at Randomization (Visit C1)

History of previous intubations, asthma exacerbation history in previous year, 
asthma triggers

Review of randomization criteria (see Section 6.3)

Subject/Clinician global impression of asthma severity rating

St. George’s Respiratory Questionnaire (SGRQ)

Vital signs

Physical examination

Spirometry (pre- and post-albuterol/salbutamol)

Review/Collect eDiary data 

Exacerbation review


2015N232375_03
CONFIDENTIAL
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146

Smoking status

Concomitant medication assessment

Laboratory tests:

Clinical Chemistry (including LFT)

Haematology with differential

Biomarker sample

Urine pregnancy test for all females of childbearing potential

AE/SAE assessment
Change 11: To clarify how to administer and who should administer the 
Subject/Clinician Rating of Global Impression of Disease Severity and Response to 
Therapy
Original text:
8.3.2.7 Subject/Clinician Rating of Global Impression of Disease Severity and 
Response to Therapy
The Global Impressions of Disease Severity and Response to Therapy should be the first 
procedure completed by the subject at the specified study visit. To avoid biasing 
responses, the subjects should not be told the results of diagnostic tests prior to 
completing the questionnaire and should be completed before any procedures are 
performed on the subject to avoid influencing the subject’s response.
Revised Text:
8.3.2.7 Subject/Clinician Rating of Global Impression of Disease Severity and 
Response to Therapy
The Global Impressions of Disease Severity and Response to Therapy should be the first 
procedure completed by the subject and clinician (Primary or Sub Investigators) at the 
specified study visit. To avoid biasing responses, the subjects should not be told the 
results of diagnostic tests prior to completing the questionnaires and these questionnaires 
should be completed before any procedures are performed on the subject to avoid 
influencing the subject’s and Investigator’s response.
Change 12: Clarifying the risks to blind break when performing local laboratory testing 
in Section 8.4.6 Clinical Safety Laboratory Assessments
Original text:
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the eCRF.


2015N232375_03
CONFIDENTIAL
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147
Revised text:
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the eCRF. Please note that any non-
protocol specified local laboratory result has the potential to break the blind due to the 
eosinophils result being available.  Please see the Study Reference Manual for guidance.
Change 13: To amend Section 8.5 Biomarker(s)/Pharmacodynamic Markers to align it 
with recent standard text.
Original text:
Additionally, a broad spectrum of inflammatory biomarkers of interest in the blood will
also be considered for examination (e.g., interleukin (IL)-4, IL-5 (total and free), IL13, 
and periostin, IL9, IL25, IL33, YKL-40, osteopontin, C-reactive protein [CRP], 
surfactant protein D [SPD], etc.). All blood will be analyzed by a central laboratory or by 
GSK. The site staff and central study team will be blinded to each subject’s IL-5 values 
from any visits post-randomization. Full details regarding sample collection, processing 
and shipping are provided in the central Laboratory Manual.
Revised text: 
Blood (serum) samples will be collected during this study and may be used for the 
purposes of measuring biomarkers to identify factors that may influence the development 
of asthma and/or medically related conditions, as well as the biological and clinical 
responses to mepolizumab. Blood samples for biomarker testing will be stored for up to 
15 years.  Those biomarker results, which have the potential to break the blind will be 
blinded to the site staff until the clinical study report is finalised.
Full details regarding sample collection, processing and shipping are provided in the 
central Laboratory Manual.  
Change 14: Xolair removed from the Trademark Information section.
Original text:
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
Xolair


2015N232375_03
CONFIDENTIAL
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Revised text:
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
None

SAP_001.pdf: 
CONFIDENTIAL
201810
The GlaxoSmithKline group of companies
2019N395455_00
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for Study 201810, A multi-
center, randomized, double-blind, placebo controlled, parallel 
group study to compare cessation versus continuation of 
long-term mepolizumab treatment in patients with severe 
eosinophilic asthma
Compound Number 
:
SB-240563
Effective Date 
:
20-MAR-2019
Description:

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 201810.

The critical components RAP was completed on the 2nd December 2015. This 
document represents the final RAP which will be provided to the study team 
members to convey the content of the Statistical Analysis Complete (SAC) 
deliverable.
Author(s)
Author
Date
Lead
13-MAR-2019
Principal Statistician (Respiratory, Clinical Statistics)
Copyright 2019 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD


CONFIDENTIAL
201810
The GlaxoSmithKline group of companies
2019N395455_00
2
RAP Team Review Confirmations
(Method: E-mail)
Reviewer
Date
18-MAR-2019
Programming Manager (Respiratory, Clinical Programming)
19-MAR-2019
Project Physician Lead (Development, Medicine Delivery Unit)
17-MAR-2019
Safety Evaluation and Risk Management Director (Global Medical)
Clinical Statistics and Clinical Programming Line Approvals
(Method: Pharma TMF eSignature)
Approver
Date
20-MAR-2019
Senior Statistics Director (Respiratory, Clinical Statistics)
20-MAR-2019
Director (Respiratory, Clinical Programming)
PPD
PPD
PPD
PPD
PPD


CONFIDENTIAL
201810
2019N395455_00
3
TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................6
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................6
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................6
2.2.
Study Objective(s) ........................................................................................6
2.2.1.
Primary Objective ..........................................................................6
2.2.2.
Secondary Objective......................................................................6
2.3.
Study Endpoint(s) .........................................................................................7
2.3.1.
Primary Endpoint ...........................................................................7
2.3.2.
Secondary Endpoints.....................................................................7
2.3.3.
Other Endpoints.............................................................................7
2.3.4.
Safety Endpoints............................................................................8
2.4.
Study Design ................................................................................................9
2.5.
Statistical Hypotheses.................................................................................10
3.
PLANNED ANALYSES ..........................................................................................10
3.1.
Interim Analyses .........................................................................................10
3.2.
Final Analyses ............................................................................................10
4.
ANALYSIS POPULATIONS ...................................................................................11
4.1.
Protocol Deviations.....................................................................................12
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................13
5.1.
Study Treatment Display Descriptors..........................................................13
5.2.
Baseline Definitions and Derivations...........................................................14
5.2.1.
Baseline Definitions .....................................................................14
5.2.1.1.
Parts A/B Baseline Definition......................................14
5.2.1.2.
Part C Baseline Definition...........................................14
5.2.1.3.
Part D Baseline Definition...........................................15
5.2.2.
Derivations and Handling of Missing Baseline Data.....................15
5.2.3.
Screening Assessments (Copying from MEA115666 or 
201312) .......................................................................................16
5.3.
Multicentre Studies .....................................................................................17
5.4.
Examination of Covariates and Subgroups .................................................17
5.4.1.
Handling of Covariates.................................................................17
5.4.2.
Examination of Subgroups...........................................................18
5.4.3.
Exploratory Multivariable Modelling..............................................19
5.5.
Multiple Comparisons and Multiplicity .........................................................19
5.6.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................20
6.
STUDY POPULATION ANALYSES .......................................................................21
6.1.
Overview of Planned Study Population Analyses........................................21
6.2.
Subject Disposition .....................................................................................21
6.3.
Demographics ............................................................................................21
6.4.
Medical Conditions .....................................................................................22
6.5.
Cardiovascular Assessments at Screening.................................................22


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201810
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4
6.6.
Smoking Status...........................................................................................22
6.7.
Baseline Disease Characteristics................................................................22
6.8.
Concomitant Medications............................................................................22
6.9.
Protocol Deviations.....................................................................................23
6.10.
Continuous Exposure to Mepolizumab Prior to Randomization (Visit 
C1)..............................................................................................................23
6.11.
Extent of Exposure .....................................................................................23
7.
EFFICACY ANALYSES..........................................................................................24
7.1.
Primary Efficacy Analyses ..........................................................................24
7.1.1.
Endpoint / Variables.....................................................................24
7.1.2.
Summary Measure ......................................................................24
7.1.3.
Population of Interest...................................................................24
7.1.4.
Strategy for Intercurrent (Post-Randomization) Events ................25
7.1.5.
Statistical Analyses / Methods .....................................................25
7.1.5.1.
Statistical Methodology Specification..........................25
7.1.5.2.
Exacerbation Verification Process ..............................26
7.2.
Secondary Efficacy Analyses......................................................................27
7.2.1.
Population of Interest...................................................................27
7.2.2.
Statistical Analyses / Methods .....................................................27
7.2.2.1.
Statistical Methodology Specification..........................27
7.3.
Exploratory Efficacy Analyses.....................................................................29
7.3.1.
Population of Interest...................................................................29
7.3.2.
Statistical Analyses / Methods .....................................................29
7.3.2.1.
Statistical Methodology Specification..........................29
7.3.3.
Change from Baseline in eDiary Parameters ...............................33
7.3.4.
Unscheduled Healthcare Contacts/Resource Utilization ..............33
8.
SAFETY ANALYSES .............................................................................................34
8.1.
Adverse Events Analyses ...........................................................................34
8.1.1.
Adverse Events of Special Interest Analyses...............................34
8.1.2.
Cardiovascular Events and Deaths (All Causes)..........................35
8.2.
Clinical Laboratory Analyses.......................................................................35
8.3.
Other Safety Analyses ................................................................................35
8.3.1.
Immunogenicity............................................................................35
9.
BIOMARKER ANALYSES......................................................................................36
10. REFERENCES.......................................................................................................37
11. APPENDICES........................................................................................................39
11.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................39
11.1.1.
Exclusions from Per Protocol Population .....................................39
11.2.
Appendix 2: Schedule of Activities ..............................................................40
11.2.1.
Protocol Defined Schedule of Events...........................................40
11.3.
Appendix 3: Assessment Windows and Visit Slotting..................................48
11.3.1.
Analysis Visit Labels ....................................................................48
11.3.2.
Visit Based Assessments.............................................................48
11.3.3.
Early Withdrawal / Treatment (IP) Discontinuation Visits..............49
11.3.4.
Unscheduled Visits ......................................................................50
11.3.5.
Definitions of Assessment Windows for Analyses........................51


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201810
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5
11.4.
Appendix 4: Study Periods and Treatment Phases.....................................55
11.4.1.
Study Periods ..............................................................................55
11.4.2.
Treatment Phases (Exacerbations and Healthcare 
Resource Use).............................................................................56
11.4.3.
Treatment Phases (Visit Based Efficacy and Safety Data)...........57
11.4.4.
Treatment Phases (Adverse Events and Cardiovascular 
Events) ........................................................................................58
11.4.4.1.
Adverse Event Data Derivations.................................59
11.4.5.
Treatment Phases (Concomitant Medications) ............................60
11.5.
Appendix 5: Data Display Standards & Handling Conventions....................62
11.5.1.
Reporting Process .......................................................................62
11.5.2.
Reporting Standards....................................................................62
11.6.
Appendix 6: Derived and Transformed Data ...............................................64
11.6.1.
General........................................................................................64
11.6.2.
Study Population..........................................................................65
11.6.3.
Efficacy........................................................................................67
11.6.4.
Safety ..........................................................................................71
11.7.
Appendix 7: Reporting Standards for Missing Data.....................................73
11.7.1.
Premature Withdrawals................................................................73
11.7.2.
Handling of Missing Data.............................................................73
11.7.2.1.
Handling of Missing and Partial Dates ........................74
11.8.
Appendix 8: Values of Potential Clinical Importance ...................................75
11.8.1.
Laboratory Values........................................................................75
11.9.
Appendix 9: Guidelines for Exacerbation Verification Process ....................76
11.10. Appendix 10: Abbreviations & Trademarks .................................................79
11.10.1. Abbreviations...............................................................................79
11.10.2. Trademarks .................................................................................80
11.11. Appendix 11: List of Data Displays..............................................................81
11.11.1. Data Display Numbering..............................................................81
11.11.2. Mock Example Shell Referencing ................................................81
11.11.3. Deliverables.................................................................................81
11.11.4. Study Parts A/B ...........................................................................82
11.11.4.1. Study Population Tables (Parts A/B) ..........................82
11.11.4.2. Safety Tables (Parts A/B) ...........................................84
11.11.5. Part C ..........................................................................................89
11.11.5.1. Study Population Tables (Part C) ...............................89
11.11.5.2. Study Population Figures (Part C) ..............................91
11.11.5.3. Efficacy Tables (Part C)..............................................92
11.11.5.4. Efficacy Figures (Part C).............................................96
11.11.5.5. Safety Tables (Part C)................................................98
11.11.5.6. Safety Figures (Part C).............................................103
11.11.6. Part D ........................................................................................104
11.11.6.1. Study Population Tables (Part D) .............................104
11.11.6.2. Efficacy Tables (Part D)............................................105
11.11.6.3. Efficacy Figures (Part D)...........................................105
11.11.6.4. Safety Tables (Part D)..............................................106
11.11.7. ICH Listings ...............................................................................111
11.12. Appendix 12: Example Mock Shells for Data Displays ..............................116


CONFIDENTIAL
201810
2019N395455_00
6
1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the planned analyses 
and output to be included in the Clinical Study Report for Protocol 201810:
Revision Chronology of Protocol:
GSK Document 
Number
Date
Version
2015N232375_00
20-May-2015
Original
2015N232375_01
23-Jun-2015
Republished Original Protocol
2015N232375_02
06-Nov-2015
Amendment No. 1
2015N232375_03
07-Jul-2016
Amendment No. 2
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
This RAP is based on the protocol amendment 02 (Dated: 07-Jul-2016) of study 201810
(GSK Document No: 2015N232375_03) and eCRF Version 1.0.
There were no changes or deviations to the originally planned statistical analysis 
specified in protocol amendment 02 (Dated: 07-Jul-2016).
2.2.
Study Objective(s)
2.2.1.
Primary Objective

To evaluate whether patients with severe eosinophilic asthma who have received 
long-term treatment with mepolizumab (at least 3 years) need to maintain 
treatment with mepolizumab to continue to receive benefit. 
2.2.2.
Secondary Objective

To assess the safety and tolerability of mepolizumab continuation compared to 
placebo following long-term treatment with mepolizumab in patients with severe 
eosinophilic asthma.


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201810
2019N395455_00
7
2.3.
Study Endpoint(s)
2.3.1.
Primary Endpoint

Time to first clinically significant exacerbation
Clinically significant exacerbations will be defined as worsening of asthma which 
requires use of systemic corticosteroids1 and/or hospitalisation and/or ED visits.
1For all subjects, i.v. or oral corticosteroid (e.g., prednisone) for at least 3 days 
or a single intramuscular (IM) corticosteroid dose is required. For subjects on 
maintenance systemic corticosteroids, at least double the existing maintenance 
dose for at least 3 days is required. 
2.3.2.
Secondary Endpoints

Ratio to baseline in blood eosinophil count at weeks 12, 24, 36 and 52

Time to a decrease in asthma control, defined as an increase from baseline in 
Asthma Control Questionnaire-5 (ACQ-5) score of ≥ 0.5 units

Time to first exacerbation requiring hospitalization or ED visit
2.3.3.
Other Endpoints

Time to first exacerbation requiring hospitalization 

Mean change from baseline in clinic pre-bronchodilator FEV1 at weeks 12, 24, 
36, 52

Mean change from baseline in clinic post-bronchodilator FEV1 at weeks 12, 24, 
36, 52

Mean change from baseline in daily salbutamol/albuterol use (occasions/day)

Mean change from baseline in daily asthma symptom scores 

Mean change from baseline in awakening at night due to asthma symptoms 
requiring rescue medication use

Mean change from baseline in morning (AM) Peak Expiratory Flow (PEF)

Time to worsening of asthma (subjects meeting at least 2 of the following 4 
criteria for worsening of asthma for at least 2 consecutive days)

AM PEF: Decrease in AM PEF 30% compared with baseline

Rescue Medication Use: An increase of 50% in rescue medication 
compared with the average use for the previous week

Night time awakenings requiring rescue medication: Awakening 
due to asthma symptoms requiring rescue medication

Symptoms: An asthma symptom score of 5

Mean change from baseline in ACQ-5 score 


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
Proportion of patients experiencing a decrease in asthma control, defined as an 
increase from baseline in ACQ-5 score of ≥ 0.5 units 

Proportion of subjects with a clinically meaningful worsening of health-related 
quality of life measurements (SGRQ) at weeks 12, 24, 36 and 52 (defined as 
subjects who have a clinically relevant increase from baseline of ≥4 units in 
SGRQ score).

Mean change from baseline in SGRQ Total score at week 12, 24, 36 and 52

Subject/Clinician global impression of asthma severity rating at weeks 12, 24, 
36 and 52

Subject/Clinician rating of response to therapy at weeks 12, 24, 36 and 52

Number of days in hospital due to asthma

Unscheduled healthcare contacts/resource utilization

Days off of regular work/school
2.3.4.
Safety Endpoints

Adverse Events and Serious Adverse Events

Clinical Laboratory parameters

12-lead ECG parameters

Vital Signs


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2.4.
Study Design
Overview of Study Design and Key Features
Design 
Features

A 52-week, 2-arm, randomized, double-blind, placebo-controlled, parallel-group, 
multicenter study evaluating mepolizumab 100 mg and placebo administered 
subcutaneously (SC) every 4 weeks in subjects with severe eosinophilic asthma who 
have been treated with mepolizumab continuously in addition to standard of care 
therapy for at least 3 years.

Prior to randomization subjects are required to have reached a total of 3 years
continuous exposure to mepolizumab treatment. If a subject has over 3 years 
continuous exposure to mepolizumab treatment at Screening they will immediately 
enter Part B of the study. Subjects with less than 3 years at Screening will be dosed 
within Part A until they achieve 3 years of continuous exposure to mepolizumab.

Subjects who completed the Follow Up/Exit Visit or EW Visit from either open-label 
studies MEA115666 or 201312 and who have no treatment gaps of more than 12 
weeks (84 days) between any two doses of mepolizumab in MEA115666 or 201312, 
will be eligible to participate in this study.
Dosing
Study design contains multiple parts (as shown within the study schematic above):

Part A: Open-label mepolizumab (100 mg SC) every 4 weeks for 0-132 weeks to allow 
subjects to achieve 3 years of continuous exposure to mepolizumab

Part B: Open-label mepolizumab (100 mg SC) every 4 weeks for 4-8 weeks

Part C: Double-blind treatment SC every 4 weeks for up to 52 weeks
(subjects may switch to Part D following experiencing an asthma exacerbation)

Part D: Optional switch to open-label mepolizumab (100 mg SC) every 4 weeks for up 
to 52 weeks following experiencing an asthma exacerbation during Part C
(for the remainder of the treatment period until an Exit Visit 52 weeks after Visit C1)
Additionally, subjects within Parts C and D had the option to permanently discontinue their 
assigned treatment and remain within the study off-treatment until conclusion.
Time & 
Events

Refer to Appendix 2: Schedule of Activities
Treatment 
Assignment

Approximately 300 subjects from studies MEA115666 and 201312 will be randomized 
1:1 to double-blind study treatment (150 per arm) at visit C1. 

GSK RandAll NG will be used to generate randomization schedules.

A web based interactive system performed centralized randomization separately for 
each country using GSK RAMOS NG for treatment allocation.
Interim 
Analysis

No interim analysis of data is planned for this study.


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2.5.
Statistical Hypotheses
The study is designed to test the superiority of continued mepolizumab 100 mg SC 
treatment vs. mepolizumab discontinuation (placebo) within Part C of the study. 
Significance tests will be performed at the two-sided 5% alpha level (one-sided 2.5%).
3.
PLANNED ANALYSES
3.1.
Interim Analyses
No interim analysis of data is planned for this study.
3.2.
Final Analyses
All decisions regarding final analysis, specified in this RAP document, will be made prior 
to Database Freeze (unblinding) of the study data.
The reporting of the study will be divided into three distinct periods, with displays 
reflecting data collected within each period separately:

Period 1: Parts A/B – variable and fixed run-in periods combined, with subjects 
receiving open-label mepolizumab treatment

Period 2: Part C – double-blind treatment period, with subjects receiving 
mepolizumab or placebo

Period 3: Part D – optional treatment switch period, with subjects returning to 
open-label mepolizumab treatment
A complete analysis in accordance with all study objectives and endpoints across all 
periods (Parts A/B, Part C, Part D) will be performed following the completion of the last 
study visit.
The final planned analyses will be performed after the completion of the following 
sequential steps:
1.
All participants have exited the study as defined in the protocol
2.
All required database cleaning activities have been completed and final database 
release (DBR) and database freeze (DBF) has been declared by Data Management.
3.
All criteria for unblinding the randomization codes have been met. 
4.
Randomization codes have been distributed according to RandAll NG procedures.


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4.
ANALYSIS POPULATIONS
Distinct analysis populations have been defined to support the reporting of each period 
separately, as shown below:
Population
Definition / Criteria
Analyses Evaluated
All Subjects 
Enrolled (ASE)

Comprised of all subjects enrolled and for whom a 
record exists on the study database.

Screen failures

Listings across 
study parts
As Treated (AT) 
[Part A/B]

Comprised of all subjects with at least one dose of 
open-label mepolizumab within Part A/B

Data collected 
within the variable 
open-label run-in 
(Part A) and fixed 
run-in (Part B)
Intent-to-Treat 
(ITT) [Part C1]

Comprised of all randomized subjects who receive at 
least one dose of double-blind study medication within 
Part C. 

Data collected 
within the double-
blind period (Part 
C)
Per Protocol (PP)
[Part C1]

Comprised of all subjects in the ITT population who 
have not been identified as full protocol deviators with 
respect to criteria that are considered to potentially 
impact the primary efficacy analysis within Part C. 

The decision to exclude a subject from the PP 
Population or exclude part of their data from the PP 
Population analyses will be made prior to breaking the 
blind. 

Protocol deviations that would exclude subjects from the 
PP population are defined in Section 4.1 (Protocol 
Deviations) and Appendix 1: Protocol Deviation 
Management and Definitions for Per Protocol 
Population.

Supplementary 
analysis of the 
primary endpoint in 
a supporting 
population to 
evaluate efficacy 
within Part C.
As Treated (AT) 
[Part D1]

Comprised of all subjects with at least one dose of 
open-label mepolizumab within Part D

Data collected 
within the open-
label treatment 
switch period (Part 
D)
Refer to Appendix 11: List of Data Displays which details the population used for each display.
1 - All analyses of Part C and Part D data will be analysed according to the treatment each subject received for more 
than 50% of injections within Part C (see Section 5.1).


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4.1.
Protocol Deviations
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan [Version 2, Dated: 15-Nov-
2017].
o Data will be reviewed prior to unblinding and freezing the database to ensure all 
important deviations and deviations which may lead to exclusion from the Per 
Protocol analysis are captured and categorised on the protocol deviations dataset. 
o This dataset will be the basis for the summaries and listings of protocol 
deviations.
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarised and listed.
Important deviations which result in exclusion from the analysis population will also be 
summarised and listed (Appendix 1: Protocol Deviation Management and Definitions for 
Per Protocol Population).
A separate summary and listing of all inclusion/exclusion/randomization criteria 
deviations will also be provided. This summary will be based on data as recorded on the 
inclusion/exclusion/randomization pages of the eCRF.


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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS
5.1.
Study Treatment Display Descriptors
The study treatment each subject receives may differ within each reporting period:

Period 1: Parts A/B – variable and fixed run-in periods combined, with subjects 
receiving open-label mepolizumab treatment

Period 2: Part C – double-blind treatment period, with subjects receiving 
mepolizumab or placebo

Period 3: Part D – optional treatment switch period, with subjects returning to 
open-label mepolizumab treatment
The treatment group descriptions within outputs will depend on the period of the study:
Treatment Group Descriptions (Parts A/B)
RandAll NG[1]
Data Displays for Reporting 
Code
Description
Description
Order in TFL 
N/A
N/A
Mepolizumab 100mg SC
1
Treatment Group Descriptions (Part C)
RandAll NG
Data Displays for Reporting 
Code
Description
Description
Order in TFL 
1
Placebo
Placebo
1
2
Mepolizumab 100mg SC
Mepolizumab 100mg SC
2
Treatment Group Descriptions (Part D)
RandAll NG[1]
Data Displays for Reporting 
Code
Description
Description
Order in TFL 
N/A
N/A
Mepolizumab 100mg SC
(Prev. Placebo)
1
N/A
N/A
Mepolizumab 100mg SC
(Prev. Mepo)
2
NOTES:
1.
Parts A/B and Part D are open-label treatment periods where all subjects received mepolizumab 100mg SC and 
therefore treatment group descriptions/assignments are not required for RandAll NG
Within displays summarising Part C and Part D, data will be presented according to the 
treatment each subject received for more than 50% of injections within Part C.


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5.2.
Baseline Definitions and Derivations
5.2.1.
Baseline Definitions
5.2.1.1.
Parts A/B Baseline Definition

The Part A and B baseline will be defined for all subjects who are within the As 
Treated (AT) [Part A/B] population.

For all endpoints the Part A/B baseline values for each assessment will be the latest 
available assessment prior to first dose of open-label mepolizumab, including data 
from unscheduled visits. 

Measurements on the same date as the first administration of open-label mepolizumab 
will be considered within the baseline derivation if measurement time is not captured. 
Where the measurement time is captured this should be compared against the time of 
first receiving open-label mepolizumab.

In order to reduce the burden of repeated procedures at the transition from precursor 
studies (MEA115666/201312) to 201810, some assessments collected at the last 
clinic visit of the precursor studies (MEA115666/201312) will be utilized as the 
Screening Visit (Visit 1) assessment for this study (201810). The following data 
collected at the last clinic visit of the precursor studies will be utilized for reporting 
and considered within the above baseline derivation (see Section 5.2.3 for further 
details):
o
12-lead ECG
o
Laboratory assessments (Haematology and Clinical Chemistry)
o
Immunogenicity
5.2.1.2.
Part C Baseline Definition

The Part C baseline will be defined for all subjects who are within the ITT (Part C) 
population.

For endpoints collected outside of the eDiary and Asthma Control Questionnaire 
(ACQ-5) collected in the eDiary the Part C baseline values for each assessment will 
be the latest available assessment prior to first dose of double-blind treatment
(however no earlier than the first dose of open-label mepolizumab), including data 
from unscheduled visits. 

Measurements on the same date as the first administration of double-blind treatment 
will be considered within the baseline derivation if measurement time is not captured. 
Where the measurement time is captured this should be compared against the time of 
first receiving double-blind treatment.

For data collected via the eDiary device (i.e. morning peak flow, usage of rescue 
medication [i.e. salbutamol/albuterol], asthma symptom score and frequency of 
awakening due to asthma symptoms), the Part C baseline for analyses of averaged 4-
weekly data will be calculated as an average using values over 7 days (immediately 


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prior and including the first dose of double-blind treatment), see Section 11.3.5 for
further details. 

The current smoking status at Visit C1 will be derived from the responses obtained at 
Screening and Visit C1 (where changes in smoking status are collected, See Section 
11.6.2).
5.2.1.3.
Part D Baseline Definition

The Part D baseline will be defined for all subjects who are within the As Treated 
(AT) [Part D] population.

For all endpoints (collected outside of the eDiary) the Part D baseline values for each 
assessment will be the latest available assessment prior to first dose of open-label 
mepolizumab within Part D (however no earlier than the first administration of 
double-blind treatment), including data from unscheduled visits. 

Measurements on the same date as the first administration of open-label mepolizumab 
within Part D will be considered within the baseline derivation if measurement time is 
not captured. Where the measurement time is captured this should be compared 
against the time of first receiving open-label mepolizumab within Part D.
5.2.2.
Derivations and Handling of Missing Baseline Data

Changes from baseline will be defined within each appropriate period (Parts A/B, 
Part C, Part D), comparing back to the baseline (last available measurement prior to 
first dose of treatment within each period).
Definition
Reporting Details
Change from Baseline
= Visit Value – Baseline
Ratio to Baseline
= Visit Value / Baseline

Unless otherwise specified, the baseline definitions specified in Section 5.2.1 Baseline Definitions will be used for 
derivations of endpoints / parameters and indicated on summaries and listings.

Unless otherwise stated, if baseline data is missing no derivation will be performed and baseline will be set to 
missing.


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5.2.3.
Screening Assessments (Copying from MEA115666 or 201312)
Subjects will enter this study (201810) after completion of either study MEA115666 or 
201312. In order to reduce the burden of repeated procedures at the transition from 
precursor studies (MEA115666/201312) to 201810 some assessments (where available) 
will be copied forward by Biostatistics within the analysis datasets from each subject’s 
last clinic visit within the previous study (typically the subject’s Early Withdrawal Visit 
or Follow Up Visit) and will be utilized as the Screening Visit (Visit 1) assessment for 
this study (201810). 
Detailed scenarios for the forward copying of assessments are described below. Under 
Scenario 1 and Scenario 2, assessments in bold (where available) will be copied from 
each subject’s last clinic visit within MEA115666 or 201312. The remaining assessments 
will be performed at Screening (Visit 1) of the 201810 study and therefore no copying 
from studies MEA115666 or 201312 is required.
Scenario 1: 201810 Screening (Visit 1) date is equal to the subject’s last clinic visit date 
of study MEA115666 or 201312;
Precursor Study
MEA115666
201312
ECG
Copy forward
Copy forward
Laboratory 
(including Haematology, Chemistry 
and Liver Event test panels)
Copy forward
Copy forward
Immunogenicity
Copy forward
Copy forward
Scenario 2: 201810 Screening (Visit 1) date is after the subject’s last clinic visit date of 
study MEA115666 or 201312; 
Precursor Study
MEA115666
201312
ECG
Re-performed in 201810
Re-performed in 201810
Laboratory 
(including Haematology, Chemistry 
and Liver Event test panels)
Re-performed in 201810
Re-performed in 201810
Immunogenicity
Copy forward
Copy forward


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5.3.
Multicentre Studies

In this multicentre global study, subjects will be presented pooled across 
investigative sites and countries.

For the purposes of covariate adjustment in the statistical analysis centres will be 
grouped into regions. The following regions are defined with consideration for 
standard of care medical practice, number of subjects enrolled and regulatory 
considerations:
Region
Countries
European Union
France, Germany, Netherlands, Poland, Romania, Spain
US/Canada
Canada, United States
Japan/Korea
Japan, Republic of Korea
Rest of World
Argentina, Australia, Russia, Ukraine
5.4.
Examination of Covariates and Subgroups
5.4.1.
Handling of Covariates

The following is a list of covariates that will be used in all model-based statistical 
analyses. For analyses where a baseline value (of the analysis variable) is available 
this will also be included as a covariate in the analyses.
Covariate[1]
Subgroups
Region
Europe, Rest of World (See Section 5.3 for further details)
Exacerbations in the year prior to 
randomization [Visit C1] (to be 
included as an ordinal variable)
0, 1, ≥2
Use of baseline maintenance oral 
corticosteroids at randomization
[Visit C1]
Yes (Requires OCS use), No (Without OCS use)
[1] Additional covariates of clinical interest may also be considered

Categories may be combined if a subgroup contains an insufficient number of
subjects to allow meaningful inference to be drawn from the model.


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5.4.2.
Examination of Subgroups

Analyses will be performed to investigate the influence of the following Part C 
baseline variables on the effect of study treatment within the analysis of the primary 
endpoint: 
Subgroup[1]
Categories 
Age at Visit C1
12-17,18-64, ≥65 years
Sex
Male, Female
Weight at Visit C1
<75kg, ≥75kg
Region
Europe, Rest of World (See Section 5.3 for further details)
Exacerbations in year prior to 
randomization [Visit C1]
0, 1, ≥2
Use of baseline maintenance oral 
corticosteroids at randomization
[Visit C1]
Yes (Requires OCS use), No (Without OCS use)
Part C Baseline blood eosinophils: 
<0.05, 0.05-<0.15, ≥0.15 GI/L
Part C Baseline anti-drug antibody 
(ADA) status
Positive, Negative
[1] Additional subgroups of clinical interest may also be considered
See Section 7.1 for further details regarding the analysis of the primary endpoint.

Treatment differences in each subgroup will be estimated in separate analysis models
similar to those used in the main analysis of each endpoint, including only subjects
contained within the corresponding subgroup.

The estimated hazard ratio (mepolizumab/placebo) in each subgroup will be reported 
along with the corresponding 95% confidence interval (CI).

No formal hypothesis testing in sub-groups of the populations will be performed.

If the category cannot be refined further, then descriptive rather than statistical 
comparisons may be performed for the particular subgroup.

The following list of subgroups will be used in descriptive summaries of adverse 
event safety data:
Subgroup[1]
Categories 
Age at start of Study Part[2]
12-17,18-64, ≥65 years
Highest ADA Result Any Time On-
Treatment During Study Part[3]
Positive, Negative
[1] Additional subgroups of clinical interest may also be considered
[2] Age defined at the baseline/start of Parts A/B, Part C and Part D, respectively.
[3] Highest ADA Result Any Time On-Treatment During Parts A/B, Part C and Part D, respectively.


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5.4.3.
Exploratory Multivariable Modelling

The potential effect of Part C baseline covariates on treatment efficacy will be 
investigated using variable selection procedures (e.g. backwards elimination) to 
determine which Part C baseline parameters are most influential on the estimated 
treatment effect (mepolizumab/placebo).

The Part C baseline variables listed in Section 5.4.2 will be considered for inclusion 
in the multivariate modelling.

Within the multivariate modelling age at Visit C1, weight at Visit C1, exacerbations in 
the year prior to randomization [Visit C1] (as an ordinal variable) and Part C 
baseline blood eosinophils will each be treated as continuous.  When presenting 
tabulations, each variable will be categorised as shown in Section 5.4.2.
5.5.
Multiple Comparisons and Multiplicity
The primary comparison of interest is during Part C of the study in the comparison
between continued mepolizumab treatment and mepolizumab discontinuation (subjects 
receiving placebo treatment) when assessing the primary endpoint in the ITT population.
Analyses of secondary and other efficacy endpoints will not be subject to any multiplicity 
adjustment.


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5.6.
Other Considerations for Data Analyses and Data Handling 
Conventions
Other considerations for data analyses and data handling conventions are outlined in the 
appendices:
Section
Component
11.3
Appendix 3: Assessment Windows
11.4
Appendix 4: Study Periods and Treatment Phases
11.5
Appendix 5: Data Display Standards & Handling Conventions
11.6
Appendix 6: Derived and Transformed Data
11.7
Appendix 7: Reporting Standards for Missing Data
11.8
Appendix 8: Values of Potential Clinical Importance
11.9
Appendix 9: Guidelines for Exacerbation Verification Process


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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
The study population analyses will be based on the following analysis populations for 
each reporting period, unless otherwise specified:
Period
Population
Parts A/B
As Treated (AT) [Part A/B]
Part C
Intent-to-Treat (ITT) [Part C1]
Part D
As Treated (AT) [Part D1]
1 - All analyses of Part C and Part D data will be analysed according to the treatment each subject received for 
more than 50% of injections within Part C (see Section 5.1).
Study population analyses including analyses of subject’s disposition, demographic and 
baseline characteristics, concomitant medications, protocol deviations, and exposure will 
be presented based on GSK Core Data Standards separately for each period (Parts A/B, 
Part C and Part D).  Details of the planned displays are presented in Appendix 11: List of 
Data Displays.
6.2.
Subject Disposition
A summary of the number of subjects included in each period (Parts A/B, Part C and Part 
D) and population will be produced.
The proportion of screen failures, reason for screen failure, proportion of run-in failures 
and reason for run-in failure will be presented. Additionally, the proportion who failed 
each eligibility/randomization criteria and number of randomised subjects who did not 
receive double-blind treatment will be presented.
The proportion of subjects who withdrew from the study, reasons for withdrawal, 
proportion of subjects who discontinued study treatment and reasons for discontinuing
treatment will be presented. A Kaplan-Meier plot presenting the percentage of subjects 
withdrawing from investigational product over time in Part C will be produced.
An additional summary of subject attendance at each Part C and Part D clinic visit and a 
by visit summary of the number of subjects who switched to open-label mepolizumab 
treatment within Part D will be provided.
6.3.
Demographics
Demographic characteristics (age, sex, ethnicity, height, weight and body mass index) 
will be summarised and listed for subjects enrolled into Part C. The proportion of 
subjects in each race and racial combination category will also be presented.
The proportion of subjects at each site and within each country and region will be 
presented. 


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6.4.
Medical Conditions
Each subject’s past and current medical history will be collected at Visit 1 (Screening). 
The proportion of subjects who report medical conditions in each class will be presented, 
for past and current conditions separately.
6.5.
Cardiovascular Assessments at Screening
A summary of the cardiovascular assessments at Visit 1 (Screening) will be presented. 
The proportion of subjects who report a family history of medical conditions that may 
indicate predisposition towards cardiovascular conditions will be summarised.
6.6.
Smoking Status
At Visit C1 (randomization) the proportion of subjects who report each smoking status
(never smoked, current smoker, former smoker) will be presented after accounting for 
subject’s change in status from Screening (See Section 11.6.2).
6.7.
Baseline Disease Characteristics
Asthma history at Randomisation (Visit C1) including duration of asthma (derived from
age of onset), Asthma Disease Characteristics (ATS Criteria), prior intubations related to 
asthma and OCS use will be summarised. Exacerbations in the 12 months prior to 
Randomisation (Visit C1) and causes of exacerbations will also be summarised. See 
Section 11.6.2 for further details of derivations.
The following clinic lung function results at Randomisation (Visit C1), as derived in 
Section 11.6.3, will be summarised:

Pre- and post-bronchodilator FEV1 (mL)

Pre- and post-bronchodilator percent predicted FEV1 (%)

Pre- and post-bronchodilator Forced Vital Capacity (FVC) (mL)

Pre- and post-bronchodilator FEV1/FVC

Reversibility (in mL and in %)
6.8.
Concomitant Medications
The proportion of subjects reporting each concomitant medication will be presented
according to GSK Drug dictionary coding. Multi-ingredient medications will be 
presented according to their combination ATC classification rather than the 
classifications of the ingredients. Summaries will be split into asthma and non-asthma 
concomitant medications taken during double-blind treatment in Part C. Asthma 
medication outputs will not display ATC grouping.
Classification of a medication as during double-blind treatment in Part C will be made 
relative to the study treatment start and stop dates and the medication start and stop dates
(as described in Section 11.4.5).


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6.9.
Protocol Deviations
Important protocol deviations and deviations resulting in exclusion from the protocol Per-
Protocol population (see Section 11.1) will be summarised and listed for each period 
(Parts A/B, Part C and Part D). More details are in Appendix 11: List of Data Displays. 
6.10.
Continuous Exposure to Mepolizumab Prior to 
Randomization (Visit C1)
For each subject the period of continuous mepolizumab exposure prior to randomization 
(first dose of double-blind treatment at Visit C1) will be summarised considering 
mepolizumab treatment from the following precursor studies where the same individuals 
participated: MEA115666, MEA115588, MEA115575, MEA115661, 201312 in addition 
to any mepolizumab treatment administered within 201810 Parts A/B.
See Section 11.6.2 for the definition of continuous exposure to mepolizumab prior to 
randomization (Visit C1).
6.11.
Extent of Exposure
The exposure to study treatment (mepolizumab/placebo) will be reported separately from 
each period (Parts A/B, Part C and Part D). The number of treatments administered and 
the number of days on-treatment will be summarised and listed.
See Section 11.6.2 for the definition of the duration of exposure to study treatment.


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7.
EFFICACY ANALYSES
Efficacy data will be presented for Part C. In addition, a descriptive summary of blood 
eosinophils from Part D will be produced.  Presentations of results will conform to 
GSK’s Integrated Data Standards Library (IDSL) standards.
The efficacy analyses will be based on the following analysis populations for each study 
period, unless otherwise specified:
Period
Population
Part C
Intent-to-Treat (ITT) [Part C1]
Part D
As Treated (AT) [Part D1]
1 - All analyses of Part C and Part D data will be analysed according to the treatment each subject received for 
more than 50% of injections within Part C (see Section 5.1).
7.1.
Primary Efficacy Analyses
7.1.1.
Endpoint / Variables
The primary efficacy analyses endpoint is the time to first clinically significant 
exacerbation within Part C relative to the date of first dose of double-blind treatment [see 
Section 11.6.1, Part C study day].
Clinically significant exacerbations will be defined as worsening of asthma which 
requires use of systemic corticosteroids1 and/or hospitalisation and/or Emergency 
Department (ED) visits.
1For all subjects, i.v. or oral corticosteroid (e.g., prednisone) for at least 3 days or a 
single intramuscular (IM) corticosteroid dose is required. For subjects on maintenance 
systemic corticosteroids, at least double the existing maintenance dose for at least 3 days 
is required. 
Exacerbations will only be included within the primary efficacy analyses if supported by 
objective assessments of asthma deterioration, as reviewed by the Exacerbation 
Verification Process (see Section 7.1.5.2).
For consistency, exacerbations separated by less than 7 days will be treated as a 
continuation of the same exacerbation (see Section 11.6.3). Handling of missing or partial 
dates in reported exacerbations is detailed within Section 11.7.2.1.
7.1.2.
Summary Measure
The hazard ratio (Mepolizumab 100mg SC / Placebo) will be the summary measure used
for the treatment comparison.
7.1.3.
Population of Interest 
The population of interest is represented by the randomization inclusion/exclusion criteria 
of the study and therefore the primary efficacy analyses will be based on the Intent-to-
Treat (ITT) [Part C] population, unless otherwise specified.


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7.1.4.
Strategy for Intercurrent (Post-Randomization) Events
A hypothetical estimand strategy will be applied in the handling of the intercurrent event
of discontinuation of double-blind treatment. The treatment effect therefore refers to the 
outcome if all patients had continued to take double-blind treatment. 
Only the On-treatment (Part C) period will be used in the analysis and subjects will be 
analysed according to the treatment each subject received for more than 50% of 
injections within Part C (see Section 5.1).
All subjects will be considered to be at risk from their first dose of double-blind treatment 
at visit C1. Subjects who complete Part C will be considered to be at risk up to their 
Week 52 (Exit Visit/C14) visit date. Subjects who discontinued double-blind treatment 
prior to experiencing an exacerbation (event) will be censored at the time of treatment 
discontinuation [see On-treatment (Part C) definition within Section 11.4.2].
7.1.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 11: List of Data Displays and 
will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 7.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
7.1.5.1.
Statistical Methodology Specification
Endpoint / Variables

Time to first clinically significant exacerbation (ADaM Dataset: ADTTE)
Model Specification

The endpoint will be compared between treatment groups using a Cox proportional hazards model.
Fixed Categorical Covariates:
Treatment, Region, Baseline maintenance OCS use [Visit C1]
Fixed Continuous Covariates:
Exacerbations in the year prior to randomization [Visit C1] (as an 
ordinal variable)
See Section 5.4.1 for further details around model covariates.
Model Checking & Diagnostics

The TIES=EXACT option will be applied for the handling of ties in failure times.

In the event that this model fails to converge, the list of covariates may be adjusted and/or reduced.

Distributional assumptions underlying the model used for analysis will be examined by:
o
assessing if a sufficient number of events occurred within covariate categories.

The proportional hazards assumptions will be examined by:
o
obtaining plots of the Kaplan-Meier curves and of the log of the cumulative hazard function (log of 
the negative log of the estimated survivor function) against the log of the survival time

If there are any major important departures from the distributional or proportional hazard assumptions 
transformations of covariates may be considered or alternative models may be explored as supportive
analysis.
Model Results Presentation

Summaries and graphs will be produced presenting the probability of an event over time by treatment 
group using Kaplan-Meier estimates and the corresponding 95% confidence intervals.


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
The hazard ratio (Mepolizumab/Placebo) from the Cox proportional hazards model will be reported with 
the corresponding 95% CI and p-value.
Sensitivity and Supportive Analyses

A supportive analysis of the Per Protocol (PP) population will also be performed.
Subgroup Analyses

Subgroup analyses of the primary endpoint will be performed for the Intent-To-Treat (ITT) population 
and all subgroups listed within Section 5.4.2.
7.1.5.2.
Exacerbation Verification Process
In order to provide an objective assessment of the circumstances linked to the clinical 
decision that defines asthma exacerbations, in study Part C and Part D each exacerbation
recorded in the eCRF by the Investigator or designee will be verified using data from the 
eDiary to confirm that the exacerbation was associated with changes in peak flow, rescue 
medication use, nocturnal awakening due to asthma symptoms requiring rescue 
medication use or symptoms. In the case that an exacerbation is regarded as not 
associated with deterioration in at least one of these objective eDiary parameters, the 
investigator will be asked to provide an explanation to support the decision for defining 
the event as a clinically significant exacerbation. In those circumstances where the event 
cannot be supported by any objective assessment, the case will not be included as a 
clinically significant exacerbation but will be included as an investigator defined 
exacerbation. This verification process will be overseen by GSK clinical staff to ensure 
consistency. This is the same process as employed in previous Phase III mepolizumab 
severe asthma studies (MEA112997, MEA115588, MEA115575). This verification 
process is described in detail within Section 11.9.


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7.2.
Secondary Efficacy Analyses
7.2.1.
Population of Interest 
The population of interest is represented by the randomization inclusion/exclusion criteria 
of the study and therefore the secondary efficacy analyses will be based on the Intent-to-
Treat (ITT) [Part C] population, unless otherwise specified.
7.2.2.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 11: List of Data Displays and 
will be based on GSK data standards and statistical principles.
7.2.2.1.
Statistical Methodology Specification
Endpoint / Variables

Ratio to baseline in blood eosinophil count at weeks 12, 24, 36 and 52 (ADaM Dataset: ADLB)

See Section 5.2 for further details regarding baseline and change from baseline derivations.

See Section 11.6.3 for additional details regarding handling blood eosinophil data.
Summary Measure

Mean treatment difference at weeks 12, 24, 36 and 52 (Exit Visit/C14)
Strategy for Intercurrent (Post-Randomization) Events

A hypothetical estimand strategy will be applied in the handling of the intercurrent event of 
discontinuation of double-blind treatment. The treatment effect therefore refers to the outcome if all 
patients had continued to take double-blind treatment.

Only the On-treatment (Part C) period will be used in the analysis and subjects will be analysed 
according to the treatment received for more than 50% of injections within Part C (see Section 5.1). 

All subjects will be considered on-treatment from their first dose of double-blind treatment at visit C1. 
Subjects who complete Part C will be considered on-treatment up to their Week 52 (Exit Visit/C14) visit 
date. Subjects who discontinued double-blind treatment will be considered on-treatment until the time of 
treatment discontinuation.
o
Blood Eosinophils: see On-treatment (Part C) definition within Section 11.4.3
Model Specification

Endpoint will be analysed using a mixed model repeated measures (MMRM) model

A log transformation will be applied to blood eosinophil count data prior to analysis.

Terms fitted in the MMRM model will include:
Fixed Categorical Covariates:
Treatment, Region, Baseline maintenance OCS use [Visit C1], 
Visit, Visit * Treatment Interaction
Fixed Continuous Covariates:
Baseline, Exacerbations in the year prior to randomization [Visit 
C1] (as an ordinal variable), Visit * Baseline
Repeated:
Visit
See Section 5.4.1 for further details around model covariates.
Model Checking & Diagnostics

The Kenward and Roger method for approximating the denominator degrees of freedom and correcting 
for bias in the estimated variance-covariance of the fixed effects will be used (DDMF=KR).

An unstructured covariance structure for the R matrix will be used by specifying ‘TYPE=UN’ on the 
REPEATED line.

In the event that this model fails to converge, the list of covariates may be adjusted and/or reduced.

Distributional assumptions underlying the model used for analysis will be examined by obtaining a 
normal probability plot of the residuals and a plot of the residuals versus the fitted values (i.e. checking 


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the normality assumption and constant variance assumption of the model respectively) to gain 
confidence that the model assumptions are reasonable.

If there are important departures from the distributional assumptions, transformations of covariates may 
be considered or alternative models may be explored as supportive analysis.
Model Results Presentation

The estimated means for each treatment group will be calculated from the model using the observed
marginal distributions of the sample covariates (OM option in LSMEANS statement).

Adjusted absolute means and mean changes from baseline will be presented for each treatment by visit
with corresponding standard errors of means on the loge scale. The estimated treatment ratios 
(Mepolizumab/Placebo) will also be presented at each visit with the corresponding 95% confidence 
intervals and p-values. 

Plots of LS means ratio to baseline in blood eosinophil count and 95% confidence intervals from the 
model will be generated for each treatment by visit.
Endpoint / Variables

Time to a decrease in asthma control, defined as an increase from baseline in Asthma Control 
Questionnaire-5 (ACQ-5) score of ≥ 0.5 units (ADaM Dataset: ADTTE)

Time to first exacerbation requiring hospitalization or ED visit (ADaM Dataset: ADTTE)

Time to first event within Part C will be derived relative to the date of first dose of double-blind treatment 
[see Section 11.6.1, Part C study day]. 

See Section 5.2 for further details regarding baseline and change from baseline derivations.

See Section 11.6.3 for details of the ACQ-5 questionnaire and Section 11.3.5 regarding visit windowing.

For consistency, exacerbations separated by less than 7 days will be treated as a continuation of the 
same exacerbation (see Section 11.6.3).

See Section 11.7.2.1 for details on handling missing/partial dates.
Summary Measure

The hazard ratio (Mepolizumab 100mg SC / Placebo) will be the summary measure used for the 
treatment comparison.
Strategy for Intercurrent (Post-Randomization) Events

A hypothetical estimand strategy will be applied in the handling of the intercurrent event of 
discontinuation of double-blind treatment. The treatment effect therefore refers to the outcome if all 
patients had continued to take double-blind treatment.

Only the On-treatment (Part C) period will be used in the analysis and subjects will be analysed 
according to the treatment received for more than 50% of injections within Part C (see Section 5.1). 

All subjects will be considered to be at risk from their first dose of double-blind treatment at visit C1. 
Subjects who complete Part C will be considered to be at risk up to their Week 52 (Exit Visit/C14) visit 
date. Subjects who discontinued double-blind treatment prior to experiencing an event will be censored 
at the time of treatment discontinuation.
o
Questionnaires: see On-treatment (Part C) definition within Section 11.4.3
o
Exacerbations: see On-treatment (Part C) definition within Section 11.4.2
Model Specification

See Primary Efficacy Statistical Analysis, Section 7.1.5.1
Model Checking & Diagnostics

See Primary Efficacy Statistical Analysis, Section 7.1.5.1
Model Results Presentation

See Primary Efficacy Statistical Analysis, Section 7.1.5.1


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7.3.
Exploratory Efficacy Analyses
7.3.1.
Population of Interest 
The population of interest is represented by the randomization inclusion/exclusion criteria 
of the study and therefore the exploratory efficacy analyses will be based on the Intent-to-
Treat (ITT) [Part C] population, unless otherwise specified.
7.3.2.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 11: List of Data Displays and 
will be based on GSK data standards and statistical principles.
7.3.2.1.
Statistical Methodology Specification
Endpoint / Variables

Time to first exacerbation requiring hospitalization (ADaM Dataset: ADTTE)

Time to worsening of asthma (subjects meeting at least 2 of the following 4 criteria for worsening of 
asthma for at least 2 consecutive days) (ADaM Dataset: ADTTE):
o
AM PEF: Decrease in AM PEF 30% compared with Part C baseline
o
Rescue Medication Use: An increase of 50% in rescue medication compared with the average 
use for the previous week
o
Night time awakenings requiring rescue medication: Awakening due to asthma symptoms requiring 
rescue medication
o
Symptoms: An asthma symptom score of 5

Time to first event within Part C will be derived relative to the date of first dose of double-blind treatment 
[see Section 11.6.1, Part C study day]. 

For consistency, exacerbations separated by less than 7 days will be treated as a continuation of the 
same exacerbation (see Section 11.6.3).

See Section 5.2 for further details regarding baseline and change from baseline derivations.

See Section 11.6.3 for details regarding eDiary data and Section 11.3.5 regarding visit windowing.

In the analysis of Time to worsening of asthma only non-missing measurements indicative of asthma 
worsening (per above endpoint definition) will be considered as an event. Intermediate missing 
responses in a subject’s eDiary data will be assumed to be missing at random, and will not be 
considered to indicate a worsening of their asthma. 

See Section 11.7.2 for further details on handling missing/partial data.
Summary Measure

The hazard ratio (Mepolizumab 100mg SC / Placebo) will be the summary measure used for the 
treatment comparison.
Strategy for Intercurrent (Post-Randomization) Events

A hypothetical estimand strategy will be applied in the handling of the intercurrent event of 
discontinuation of double-blind treatment. The treatment effect therefore refers to the outcome if all 
patients had continued to take double-blind treatment.

Only the On-treatment (Part C) period will be used in the analysis and subjects will be analysed 
according to the treatment received for more than 50% of injections within Part C (see Section 5.1). 

All subjects will be considered to be at risk from their first dose of double-blind treatment at visit C1. 
Subjects who complete Part C will be considered to be at risk up to their Week 52 (Exit Visit/C14) visit 
date. Subjects who discontinued double-blind treatment prior to experiencing an event will be censored 
at the time of treatment discontinuation.
o
Exacerbations: see On-treatment (Part C) definition within Section 11.4.2
o
eDiary data: see On-treatment (Part C) definition within Section 11.4.3.


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Model Specification

See Primary Efficacy Statistical Analysis, Section 7.1.5.1
Model Checking & Diagnostics

See Primary Efficacy Statistical Analysis, Section 7.1.5.1
Model Results Presentation

See Primary Efficacy Statistical Analysis, Section 7.1.5.1
Endpoint / Variables

Mean change from baseline in clinic pre-bronchodilator FEV1 at weeks 12, 24, 36, 52

Mean change from baseline in clinic post-bronchodilator FEV1 at weeks 12, 24, 36, 52 
(ADaM Dataset: ADPFT)

Mean change from baseline in ACQ-5 score (ADaM Dataset: ADACQ5)

Mean change from baseline in SGRQ Total score at week 12, 24, 36 and 52

Mean change from baseline in SGRQ Symptom Domain score at week 12, 24, 36 and 52

Mean change from baseline in SGRQ Activity Domain score at week 12, 24, 36 and 52 

Mean change from baseline in SGRQ Impacts Domain score at week 12, 24, 36 and 52
(ADaM Dataset: ADSGRQ)

See Section 5.2 for further details regarding baseline and change from baseline derivations.

See Section 11.6.3 for additional details regarding spirometry, the ACQ-5 and SGRQ questionnaires.

See Section 11.3.5 regarding visit windowing of the ACQ-5 questionnaire.
Summary Measure

Spirometry and SGRQ: Mean treatment difference at weeks 12, 24, 36 and 52 (Exit Visit/C14)

ACQ-5: Mean treatment difference at weeks 12, 24, 36 and 52
Strategy for Intercurrent (Post-Randomization) Events

A hypothetical estimand strategy will be applied in the handling of the intercurrent event of 
discontinuation of double-blind treatment. The treatment effect therefore refers to the outcome if all 
patients had continued to take double-blind treatment.

Only the On-treatment (Part C) period will be used in the analysis and subjects will be analysed 
according to the treatment received for more than 50% of injections within Part C (see Section 5.1). 

All subjects will be considered on-treatment from their first dose of double-blind treatment at visit C1. 
Subjects who complete Part C will be considered on-treatment up to their Week 52 (Exit Visit/C14) visit 
date. Subjects who discontinued double-blind treatment will be considered on-treatment until the time of 
treatment discontinuation.
o
Spirometry and Questionnaires: see On-treatment (Part C) definition within Section 11.4.3
Model Specification

See Secondary Efficacy Statistical Analysis, Section 7.2.2.1.
Model Checking & Diagnostics

See Secondary Efficacy Statistical Analysis, Section 7.2.2.1.
Model Results Presentation

The estimated means for each treatment group will be calculated from the model using the observed
marginal distributions of the sample covariates (OM option in LSMEANS statement).

Adjusted absolute means and mean changes from baseline will be presented for each treatment by visit
with corresponding standard errors of means. The estimated treatment difference (Mepolizumab –
Placebo) will also be presented at each visit with the corresponding 95% confidence intervals and p-
values. 

Plots of LS means change from baseline and 95% confidence intervals from the model will be 
generated for each treatment by visit.


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Endpoint / Variables

Proportion of patients experiencing a decrease in asthma control, defined as an increase from baseline 
in ACQ-5 score of ≥ 0.5 units (ADaM Dataset: ADACQ5)

Proportion of subjects with a clinically meaningful worsening of health-related quality of life 
measurements (SGRQ) at weeks 12, 24, 36 and 52 (defined as subjects who have a clinically relevant 
increase from baseline of ≥4 units in SGRQ total score) (ADaM Dataset: ADSGRQ)

See Section 5.2 for further details regarding baseline and change from baseline derivations.

See Section 11.6.3 for additional details regarding the ACQ-5 and SGRQ questionnaires.

See Section 11.3.5 regarding visit windowing of the ACQ-5 questionnaire.
Summary Measure

ACQ-5: Odds Ratio (Mepolizumab 100mg SC / Placebo) at weeks 12, 24, 36 and 52

SGRQ: Odds Ratio (Mepolizumab 100mg SC / Placebo) at weeks 12, 24, 36 and 52 (Exit Visit/C14)
Strategy for Intercurrent (Post-Randomization) Events

A composite estimand strategy will be applied in the handling of the intercurrent event of 
discontinuation of double-blind treatment. 

Subjects will be categorized during the On-treatment (Part C) period according to their questionnaire 
(ACQ-5 / SGRQ) response. Following treatment discontinuation (end of On-treatment [Part C] phase) 
subjects will be shown as missing and on analysis included in the least favorable category of increase 
from baseline of ≥ 0.5 units or ≥4 units for the ACQ-5 and SGRQ endpoints, respectively.

Subjects will be analysed according to the treatment received for more than 50% of injections within 
Part C (see Section 5.1). 

All subjects will be considered on-treatment from their first dose of double-blind treatment at visit C1. 
Subjects who complete Part C will be considered on-treatment up to their Week 52 (Exit Visit/C14) visit 
date. Subjects who discontinued double-blind treatment will be considered on-treatment until the time of 
treatment discontinuation.
o
Questionnaires: see On-treatment (Part C) definition within Section 11.4.3
Model Specification

Logistic regression will be used to compare the proportion of patients achieving a 0.5 units / 4 point or 
greater increase from baseline in ACQ-5 / SGRQ Total Score between treatment groups at each 
analysis visit (separate models will be used for each analysis visit).

Subjects with a missing response at a particular visit will be included in the least favorable category as 
having a 0.5 units / 4 point or greater increase from baseline in ACQ-5 / SGRQ Total Score in the 
logistic regression model for the analysis of that visit.

Terms fitted in each logistic regression model will include:
Fixed Categorical Covariates:
Treatment, Region, Baseline maintenance OCS use [Visit C1]
Fixed Continuous Covariates:
Baseline Score, Exacerbations in the year prior to randomization
[Visit C1] (as an ordinal variable)
See Section 5.4.1 for further details around model covariates.
Model Checking & Diagnostics

In the event that this model fails to converge, the list of covariates may be adjusted and/or reduced.

Distributional assumptions underlying the model used for analysis will be examined by:
o
assessing if a sufficient number of events occurred within covariate categories.

If there are any major important departures from the distributional assumptions transformations of 
covariates may be considered or alternative models may be explored as supportive analysis.
Model Results Presentation

The number and percentage of subjects achieving a 0.5 units / 4 point or greater increase in ACQ-5 / 
SGRQ Total Score compared to baseline will be presented by treatment group for each visit.

The estimated odds ratio (Mepolizumab/Placebo) at each visit for the treatment variable in the logistic 
regression model will be reported with the corresponding 95% CI and p-value.


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Endpoint / Variables

Subject/Clinician global impression of asthma severity rating at weeks 12, 24, 36 and 52
(ADaM Dataset: ADGLOBRT)

Subject/Clinician rating of response to therapy at weeks 12, 24, 36 and 52
(ADaM Dataset: ADEVRESP)

See Section 5.2 for further details regarding baseline derivations.

See Section 11.6.3 for additional details regarding the Subject/Clinician global impression of asthma 
severity rating and the Subject/Clinician rating of response to therapy questionnaires.
Summary Measure

Subject/Clinician global impression of asthma severity rating: 
Odds Ratio (Mepolizumab 100mg SC / Placebo) at weeks 12, 24, 36 and 52 (Exit Visit/C14)

Subject/Clinician rating of response to therapy:
Odds Ratio (Mepolizumab 100mg SC / Placebo) at weeks 12, 24, 36 and 52 (Exit Visit/C14)
Strategy for Intercurrent (Post-Randomization) Events

A composite estimand strategy will be applied in the handling of the intercurrent event of 
discontinuation of double-blind treatment. 

Subjects will be categorized during the On-treatment (Part C) period according to their response. 
Following treatment discontinuation (end of On-treatment [Part C] phase) subjects will be shown as 
missing and on analysis included in the least favorable category of the respective outcome.

Subjects will be analysed according to the treatment received for more than 50% of injections within 
Part C (see Section 5.1). 

All subjects will be considered on-treatment from their first dose of double-blind treatment at visit C1. 
Subjects who complete Part C will be considered on-treatment up to their Week 52 (Exit Visit/C14) visit 
date. Subjects who discontinued double-blind treatment will be considered on-treatment until the time of 
treatment discontinuation.
o
Questionnaires: see On-treatment (Part C) definition within Section 11.4.3
Model Specification

Ordinal logistic regression (proportional odds model) will be used to compare the proportion of patients
in each response category between treatment groups at each analysis visit (separate models will be 
used for each analysis visit).

Subjects with a missing response at a particular visit will be included in the least favorable category of 
the respective outcome in the ordinal logistic regression model for the analysis of that visit.

Terms fitted in each ordinal logistic regression model will include:
Fixed Categorical Covariates:
Treatment, Baseline (Global impression of asthma severity 
rating only), Region, Baseline maintenance OCS use [Visit C1]
Fixed Continuous Covariates:
Exacerbations in the year prior to randomization [Visit C1] (as an 
ordinal variable)
See Section 5.4.1 for further details around model covariates.
Model Checking & Diagnostics

In the event that this model fails to converge, the list of covariates may be adjusted and/or reduced.

Distributional assumptions underlying the model used for analysis will be examined by:
o
assessing if a sufficient number of events occurred within covariate categories.

If there are any major important departures from the distributional assumptions transformations of 
covariates may be considered or alternative models may be explored as supportive analysis.
Model Results Presentation

The number and percentage of subjects in each response category and with a missing response will be 
presented by treatment group for each visit.

The estimated odds ratio (Mepolizumab/Placebo) at each visit for the treatment variable in the ordinal 
logistic regression model will be reported with the corresponding 95% CI and p-value.


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7.3.3.
Change from Baseline in eDiary Parameters
Daily eDiary data for the following parameters will be aggregated whilst on-treatment
over 4-weekly periods (see Section 11.3.5) within study Part C, respectively:

Occasions/day of rescue medication (salbutamol/albuterol) usage over the previous 
24-hours

Asthma symptom score over the previous 24-hours (using a 6-point scale)

Frequency of awakening due to asthma symptoms requiring rescue medication use

Morning peak expiratory flow [PEF] (L/min), before rescue medication usage 
The mean daily data whilst on-treatment, excluding days with missing data, will be 
calculated for each 4-weekly period (Weeks 0-4, 4-8, …, 48-52) within study Part C, 
respectively. Data for each 4-week period and change from baseline for each 4-week 
period will be summarised by treatment group.
7.3.4.
Unscheduled Healthcare Contacts/Resource Utilization
Number of days in hospital due to asthma, unscheduled healthcare resource use and 
number of days off work/school whilst on-treatment will be summarised separately for 
subjects who complete 12, 24, 36 and 52 weeks of Part C double-blind treatment.
Number of days in hospital due to asthma whilst on-treatment will be summarised by 
treatment group. See Section 11.6.3 for details regarding collection of days in hospital. 
Unscheduled healthcare resource use due to a clinically significant exacerbation whilst 
on-treatment will be summarised by treatment group. In addition, total unscheduled 
asthma related healthcare resource use whilst on-treatment (combining healthcare 
contacts due to a clinically significant exacerbation and not associated with an asthma 
exacerbation) will be summarised by treatment group. See Section 11.6.3 for details 
regarding collection of healthcare resource use.
Number of days off work/school whilst on-treatment will be summarised by treatment 
group.


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8.
SAFETY ANALYSES
Safety data will be presented separately from each period (Parts A/B, Part C and Part D) 
in tabular format and summarized descriptively according to GSK’s Integrated Data 
Standards Library (IDSL) standards.
The safety analyses will be based on the following analysis populations for each study 
period, unless otherwise specified:
Period
Population
Parts A/B
As Treated (AT) [Part A/B]
Part C
Intent-to-Treat (ITT) [Part C1]
Part D
As Treated (AT) [Part D1]
1 - All analyses of Part C and Part D data will be analysed according to the treatment each subject received for 
more than 50% of injections within Part C (see Section 5.1).
8.1.
Adverse Events Analyses
Adverse events analyses including the analysis of adverse events (AEs), Serious (SAEs) 
and other significant AEs will be based on GSK Core Data Standards. 
AEs occurring during the on-treatment phase will be summarised separately for each 
period (Parts A/B, Part C and Part D). Adverse events will be coded using the latest 
version of the Medical Dictionary for Regulatory Activities (MedDRA).
The number and percentage of subjects experiencing at least one AE will be summarised.
Exposure adjusted rates of AEs during Part C will also be presented to account for the 
length of subject exposure within the double-blind treatment period. For the definition of 
exposure adjusted AEs, see Section 11.6.4.
The details of the planned displays are provided in Appendix 11: List of Data Displays.
8.1.1.
Adverse Events of Special Interest Analyses
Adverse events of special interest (AESIs) for closer monitoring are listed in Section 
11.6.4.  
Separate summary tables showing the number and percent of subjects with each type of 
AESI, broken down by preferred term will be created.  Information will be reported as 
part of the standard AE tables for AESIs of infections, serious infections, neoplasms, 
cardiac disorders and serious cardiac disorders. 
For each type of AESI a profile summary table will be produced containing information 
which would include, but not be limited to, the number of occurrences of the event, event 
characteristics, time to onset, intensity, outcome and action taken.
A listing of any subjects with systemic events identified by the investigators as meeting 
the criteria for anaphylaxis as outlined by the 2006 Joint National Institute of Allergy and 
Infectious Disease/Food Allergy and Anaphylaxis Network Second Symposium on 
Anaphylaxis [Sampson, 2006] will be provided


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8.1.2.
Cardiovascular Events and Deaths (All Causes)
Cardiovascular events and deaths (all causes) will be captured on targeted event pages of 
the CRF for the following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization

Death (all causes)
8.2.
Clinical Laboratory Analyses
Laboratory evaluations including the analyses of Chemistry laboratory tests, 
Haematology laboratory tests, and liver function tests will be based on GSK Core Data 
Standards. The details of the planned displays are in Appendix 11: List of Data Displays.
8.3.
Other Safety Analyses
The analyses of non-laboratory safety test results including ECGs, vital signs and 
immunogenicity will be based on GSK Core Data Standards, unless otherwise specified. 
The details of the planned displays are presented in Appendix 11: List of Data Displays.
8.3.1.
Immunogenicity
Immunogenicity is a measure of the immune response to a therapeutic drug (e.g. a 
monoclonal antibody) resulting in generation of anti-drug antibodies (see Section 11.6.4). 
A table will be produced summarising the number and percentage of subjects with 
negative and confirmed positive on-treatment ADA samples by treatment group and visit. 
The table will also summarise the highest assay result obtained whilst on-treatment for 
each subject. A similar table will also be produced summarising results for the 
neutralising antibody assay by treatment group and visit. 
An additional summary of treatment emergent positive confirmatory binding antibody 
assay and results in the subset of subjects who did not have a positive confirmatory 
binding antibody assay result at the first dose of study treatment in each period (Parts 
A/B, Part C and Part D) will also be presented.  
All immunogenicity results (i.e. ADA screening and confirmatory assay results, titre 
values, neutralising antibody results) will be listed.
The details of the planned Immunogenicity displays are presented in Appendix 11: List of 
Data Displays.


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9.
BIOMARKER ANALYSES
Blood (serum) samples were collected during Part C of the study and may be used for the 
purposes of measuring biomarkers to identify factors that may influence the development 
of asthma and/or medically related conditions, as well as the biological and clinical 
responses to mepolizumab.
A separate plan will be produced detailing any additional analysis of collected biomarker 
data.


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10.
REFERENCES
GlaxoSmithKline Document Number 2011N122789_03 Study ID Across Studies. 
Electrochemiluminescent Immunoassay Method for the Detection of anti-SB240563 
(Mepolizumab) Antibodies in Human Serum (6th Generation Assay). Report Date 09-
Jun-2016. 
GlaxoSmithKline Document Number 2011N129752_03 Study ID Across Studies. 
Indirect Ligand-Binding Assay for the Detection of Neutralizing Antibody Against SB-
240563 in Human Serum. Report Date 07-Nov-2016. 
GlaxoSmithKline Document Number 2015N232375_00 Study ID 201810. A multi-
center, randomized, double-blind, placebo controlled, parallel group study to compare 
cessation versus continuation of long-term mepolizumab treatment in patients with severe 
eosinophilic asthma (201810). Report Date 20-May-2015. 
GlaxoSmithKline Document Number 2015N232375_01 Study ID 201810. A multi-
center, randomized, double-blind, placebo controlled, parallel group study to compare 
cessation versus continuation of long-term mepolizumab treatment in patients with severe 
eosinophilic asthma (201810). Report Date 23-Jun-2015. 
GlaxoSmithKline Document Number 2015N232375_02 Study ID 201810. A multi-
center, randomized, double-blind, placebo controlled, parallel group study to compare 
cessation versus continuation of long-term mepolizumab treatment in patients with severe 
eosinophilic asthma (201810). Report Date 06-Nov-2015. 
GlaxoSmithKline Document Number 2015N232375_03 Study ID 201810. A multi-
center, randomized, double-blind, placebo controlled, parallel group study to compare 
cessation versus continuation of long-term mepolizumab treatment in patients with severe 
eosinophilic asthma (201810). Report Date 07-Jul-2016. 
GlaxoSmithKline Document Number n/a Study ID Across Studies. Program Safety
Analysis Plan for Mepolizumab (SB240563). Report Date 31-Mar-2018. 
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. 
Quanjer P., Stanojevic S., Cole T., Baur X., Hall G., Culver B., Enright P., Hankinson J., 
Ip M., Zheng J., Stocks J., & ERS Global Lung Function Initiative. Multi-ethnic 
reference values for spirometry for the 3-95-yr age range: The global lung function 2012 
equations. European Respiratory Journal. 2012;40(6):1324-1343. 
Quanjer P., Stanojevic S., Cole T., Baur X., Hall G., Culver B., Enright P., Hankinson J., 
Ip M., Zheng J., Stocks J., & ERS Global Lung Function Initiative. Multi-ethnic 
reference values for spirometry for the 3-95-yr age range: The global lung function 2012 


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equations - Supplemental Material. European Respiratory Journal. 2012;40(6):1324-
1343. 
Sampson HA, Munoz-Furlong A, Campbell RL et al. Second Symposium on the 
definition and management of anaphylaxis: Summary Report.Second National Institute of 
Allergy and Infectious Disease / Food Allergy and Anaphylaxis Network Symposium. 
Journal of Allergy and Clinical Immunology. 2006;117:391-397. 
Winthrop KL, Novosad SA, Baddley JW, et al. Opportunistic infections and biologic 
therapies in immune-mediated inflammatory diseases - consensus recommendations for 
infection reporting during clinical trials and postmarketing surveillance. Ann Rheum Dis. 
2015;0:1–10. 


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11.
APPENDICES
11.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population
11.1.1.
Exclusions from Per Protocol Population
As detailed in Section 4.1 protocol deviations will be tracked by the study team 
throughout the conduct of the study in accordance with the Protocol Deviation 
Management Plan (PDMP) and important protocol deviations (including deviations 
related to study inclusion/exclusion/randomization criteria, conduct of the trial, patient 
management or patient assessment) will be listed and summarised.
Subjects with protocol deviations considered to potentially have an effect on efficacy will 
be removed from the Per Protocol (PP) population. Determination of the Per Protocol 
population will be performed whilst blinded to treatment, before the database is frozen. 
The reason for the exclusion of any subject will be documented.
A further review of the Per Protocol population will be performed following unblinding 
regarding protocol deviation criteria impacted by blinded study treatment (e.g. exclusion 
criteria number 5 below). Similarly the reason for the exclusion of any subject will be 
documented.
A subject meeting any of the following criteria will be excluded from the Per Protocol 
population:
Number
Exclusion Description
01
Randomization Inclusion Criterion #1 – Any subject without documented evidence of at least 
3 years (156 weeks) of treatment with mepolizumab, with no treatment gaps of greater than 
12 weeks (84 days) between any two doses at the time of randomization. See Section 
11.6.2 for further details regarding the definition of continuous mepolizumab treatment.
02
Randomization Inclusion Criterion #3 – Any subject with changes in the dose or regimen of 
ICS, and/or additional controller medication during the fixed run-in period (Part B).
N.B. This excludes the use of OCS for the treatment of an asthma exacerbation.
03
Any subject with changes in the dose or regimen of ICS, and/or additional controller 
medication during double-blind treatment (Part C).
N.B. This excludes the use of OCS for the treatment of an asthma exacerbation.
04
Breaking of the treatment blind at any point during Part C of the study.
05
Receiving the incorrect study treatment at any point during Part C of the study (not the 
treatment to which the subject was randomized) [1].
06
Use of any prohibited medication during Parts B or C of the study [2].
07
Randomization Exclusion Criterion #6 – Current smokers at Visit C1.
08
Randomization Exclusion Criterion #7 – Subjects with an asthma exacerbation that has not 
resolved completely within 7 days of Visit C1.

[1] This incorrect study treatment criteria will be re-assessed following unblinding, where an additional review of 
subject data will be performed. The reason for the exclusion of any subject will be documented.

[2] See Protocol Section 7.9.2 for the list of prohibited medications within this study.


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11.2.
Appendix 2: Schedule of Activities
11.2.1.
Protocol Defined Schedule of Events
Table 1
Time and Events Table: Screening/Variable Open-Label Run-In Weeks 0 - 52 - Part A
PART A
Procedures
Pre-
Screen1
Exit/EW 
Visit 
MEA115666 
or 201312/
Screen1
Variable Open-Label Treatment Part A2
(window is 1 week)
EW Visit5
Visit
0
1
A1
A2
A3
A4
A5
A6
A7
A8
A9
A10
A11
A12
A13
Week of Variable Run-In
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Written Informed Consent
X
Demography
X
Medical History 
X
Assess cardiac risk factors
X
Smoking status
X
Inclusion/Exclusion Criteria
X
Safety Assessments3
Concomitant Medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examination
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments3
Haematology
X
X
X
X
Chemistry (incl. LFT)
X
X
X
X
Pregnancy Test4
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
Immunogenicity
X
X
X
HbsAg and hepatitis C 
antibody 
X
Efficacy Assessments3
Exacerbation review 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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PART A
Procedures
Pre-
Screen1
Exit/EW 
Visit 
MEA115666 
or 201312/
Screen1
Variable Open-Label Treatment Part A2
(window is 1 week)
EW Visit5
Visit
0
1
A1
A2
A3
A4
A5
A6
A7
A8
A9
A10
A11
A12
A13
Week of Variable Run-In
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Asthma Control 
Questionnaire-5
X
X
X
X
X
X
Spirometry
X
X
X
X
Worksheets/Diary/IP/ eCRF
Administer open-label 
mepolizumab
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense 
albuterol/salbutamol
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect albuterol/salbutamol
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense paper diary
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect/review paper diary
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Contact IRT
X
X
Complete eCRF
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
1.
The Pre-Screen Visit and Screening Visit may occur on the same day.
2.
Visits should be conducted every 4 weeks until the subject has reached 3 years of mepolizumab exposure. 
3.
Please see the SRM for details on which screening procedures to perform for subjects entering from 201312 and MEA115666.  ALL procedures should be completed prior to 
dosing with open-label mepolizumab.
4.
Urine pregnancy tests (U) should be conducted for women of child bearing potential. 
5.
EW = Early Withdrawal. Should be conducted 4 ± 1 weeks from the subject’s last dose


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Table 2
Time and Events Table: Screening/Variable Open-Label Run-In Weeks 56 - 132- Part A
PART A
Procedures
Variable Open-Label Treatment Part A1
(window is 1 week)
EW
Visit3
Visit
A14/A27
A15/A28
A16/A29
A17/A30
A18/A31
A19/A32
A20/A33
A21
A22
A23
A24
A25
A26
Week of Variable Run-In
56/108
60/112
64/116
68/120
72/124
76/128
80/132
84
88
92
96
100
104
Safety Assessments
Concomitant Medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examination
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments
Haematology
X
X
X
Chemistry (incl. LFT)
X
X
X
Pregnancy Test2
U
U
U
U
U
U
U
U
U
U
U
U
U
X
Immunogenicity
X
X
Efficacy Assessments
Exacerbation review 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Asthma Control Questionnaire-5
X
X
X
X
X
Spirometry
X
X
X
Worksheets/Diary/IP/eCRF
Administer open-label mepolizumab
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense albuterol/salbutamol
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect albuterol/salbutamol
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense paper diary
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect/review paper diary
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Contact IRT
X
Complete eCRF
X
X
X
X
X
X
X
X
X
X
X
X
X
X
1.
Visits should be conducted every 4 weeks until the subject has reached 3 years of mepolizumab exposure. 
2.
Urine pregnancy tests (U) should be conducted for women of child bearing potential. 
3.
EW = Early Withdrawal. Should be conducted 4 ± 1 weeks from the subject’s last dose


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Table 3
Time and Events Table: Fixed Run-In & Double-Blind Treatment Period – Parts B and C
PARTS 
B&C
Procedures
Fixed
Run-in
Part B
EW from 
Part B7
Randomization
Double-Blind Treatment Part C 
(window is 1 week)
IPDISC/EW 
Visit 7
Visit
B1
B21
Part B EW
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
C11
C12
C13
Exit 
Visit
Week of Study 
-4 
± 1
-4 ± 
11
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Smoking status
X
Randomization Criteria
X
Safety Assessments2
Concomitant 
Medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examination
X
X
X
X
X
Vital Signs 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG 
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory 
Assessments2
Haematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry (incl. LFT)
X
X
X
X
X
X
Biomarkers
X
X
X
X
X
X
X
X
X
Pregnancy Test 3
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
Immunogenicity
X
X 
X
Efficacy 
Assessments2
Subject/Clinician Global 
Impression Rating
X
X
X
X
X
X
Subject/Clinician Rating 
of Response to 
Therapy
X
X
X
X
X
SGRQ
X
X
X
X
X
X


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PARTS 
B&C
Procedures
Fixed
Run-in
Part B
EW from 
Part B7
Randomization
Double-Blind Treatment Part C 
(window is 1 week)
IPDISC/EW 
Visit 7
Visit
B1
B21
Part B EW
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
C11
C12
C13
Exit 
Visit
Week of Study 
-4 
± 1
-4 ± 
11
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Exacerbation review 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 
Spirometry (pre- and 
post-
albuterol/salbutamol)
X8
X
X
X
X
X
X
Healthcare resource 
utilization
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Review eDiary4
(symptoms, rescue use, 
nocturnal awakenings, 
PEF, ACQ-5, missed 
days of work/school)
Worksheets/Diary/IP/
eCRF2
Administer open-label 
mepolizumab4
X
X
Administer double blind 
study treatment
X5
X
X
X
X
X
X
X
X
X
X
X
X
Dispense 
albuterol/salbutamol
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect 
albuterol/salbutamol
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense paper diary
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense eDiary
X
Collect eDiary
X
X
X6
Collect/review paper 
diary
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Contact IRT
X
X
X
X


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PARTS 
B&C
Procedures
Fixed
Run-in
Part B
EW from 
Part B7
Randomization
Double-Blind Treatment Part C 
(window is 1 week)
IPDISC/EW 
Visit 7
Visit
B1
B21
Part B EW
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
C11
C12
C13
Exit 
Visit
Week of Study 
-4 
± 1
-4 ± 
11
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Complete eCRF
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
1.
Visit B2 is only intended for subjects who experience an exacerbation in the run-in Part B which is not resolved within 7 days of Visit C1 or subjects who fail eDiary Compliance 
Criteria (Protocol Section 6.3). 
2.
All assessments to be completed prior to dosing.
3.
Urine pregnancy tests (U) should be conducted every 4 weeks for women of child bearing potential.
4.
Subjects eDiary entries should be reviewed by the site weekly during Part C
5.
An unblinding card will be dispensed after Randomization at Visit C1.
6.
The eDiary is only collected at an Early Withdrawal visit and not at IPDISC in Part C.
7.
IPDISC/EW visit should be conducted 4 ± 1 weeks from the subject’s last dose
8.
Only pre-bronchodilator spirometry required at this visit.


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Table 4
Time and Events Table: Optional Open-Label Switch to Mepolizumab – Part D
PART D
Procedures
OPTIONAL Open-Label Switch to mepolizumab Part D1
(window is 1 week)
IPDISC/EW 
Visit 8
Visit
D1
D2
D3
D4
D5
D6
D7
D8
D9
D10
D11
D12
D13
Exit 
Visit
Week of Study2
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Safety Assessments3
Concomitant Medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examination
X
X
Vital Signs 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments3
Haematology4
X
X
X
X
X
Chemistry (incl. LFT)
X
X
X
Pregnancy Test 5
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
Immunogenicity
X
X
Efficacy Assessments3
Exacerbation review 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 
Spirometry
X
X
X
X
X
Worksheets/Diary/IP/ eCRF3
Administer open-label 
mepolizumab
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense albuterol/salbutamol
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect albuterol/salbutamol
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense paper diary
X
X
X
X
X
X
X
X
X
X
X
X
X
Review eDiary6  
(symptoms, rescue use, 
nocturnal awakenings, PEF, 
ACQ-5, missed days of 
work/school)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect eDiary
X
X7


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PART D
Procedures
OPTIONAL Open-Label Switch to mepolizumab Part D1
(window is 1 week)
IPDISC/EW 
Visit 8
Visit
D1
D2
D3
D4
D5
D6
D7
D8
D9
D10
D11
D12
D13
Exit 
Visit
Week of Study2
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Collect/review paper diary
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Contact IRT
X
X
Complete eCRF
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
1.
The combined treatment period (Part C) and any switch to open-label mepolizumab (Part D) should not exceed a total duration of 52 weeks.
2.
Subjects may enter the Open-label Switch Part D at any point during Part C provided they meet switch criteria, starting with the week of study that the switch is made and 
continuing until week 52, discontinuation of IP or early withdrawal. 
3.
All assessments to be completed prior to dosing
4.
Haematology samples will be collected for each of the subject’s first 3 visits of Part D, and then according to designated Visits in Table 4
5.
Urine pregnancy tests (U) should be conducted every 4 weeks for women of child bearing potential.
6.
The eDiary should be reviewed at each visit. Weekly review is not required in Part D.
7.
The eDiary is only collected at an Early Withdrawal or Exit visit.
8.
IPDISC/EW visit should be conducted 4 ± 1 weeks from the subject’s last dose


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11.3.
Appendix 3: Assessment Windows and Visit Slotting
11.3.1.
Analysis Visit Labels
When summarising data within Parts A/B of the study nominal clinic visit will be 
presented (in weeks) relative to the date of first dose of open-label treatment (Parts A/B). For 
example: 
Screening = Week 0 
Visit A1 = Week 4
Visit A2 = Week 8
etc.
When summarising data within Part C of the study nominal clinic visit will be presented 
(in weeks) relative to the date of first dose of double-blind treatment (Part C). For example: 
Visit C1 = Week 0 
Visit C2 = Week 4
Visit C3 = Week 8
etc.
When summarising data within Part D of the study nominal clinic visit will be presented 
(in weeks) relative to the clinic visit where each subject received the first dose of open-
label treatment within Part D. For example, if a subject switched to open-label mepolizumab at 
Visit D4: 
Visit D4 = Week 0 
Visit D5 = Week 4
Visit D6 = Week 8
etc.
See Section 11.6.1 for the presentation of study days with each reporting period.
11.3.2.
Visit Based Assessments
In some circumstances certain Visit 1 (Screening) assessments will not be performed and 
assessments will be copied forward from each subject’s last clinic visit from the 
precursor studies MEA115666/201312. Refer to Section 5.2.3 for more details. 
All other visits are scheduled to take place as specified in Appendix 2: Schedule of 
Activities. No assessment windows are defined for visit based assessments, hence 
measurements outside visit windows will not be excluded from analyses. For all clinic 
visits, nominal visit days and times will be used for reporting, such that if a subject 
recorded values that were outside of the ±7 day window for a visit the subject will still be 
analysed under that visit.
See Section 11.3.3 and Section 11.3.4 for details regarding the slotting of data collected 
at an Early Withdrawal/Treatment Discontinuation Visit and unscheduled data to clinic 
visits for analysis.


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11.3.3.
Early Withdrawal / Treatment (IP) Discontinuation Visits
If a subject completes an Early Withdrawal or Treatment Discontinuation Visit at a visit
where endpoint data were not scheduled to be collected, the data will be summarised and 
analysed (as appropriate) together with other data recorded as scheduled at the nominal 
visits according to the Time and Events schedule (Appendix 2: Schedule of Activities).
Parts A/B
Subjects who discontinue open-label mepolizumab/withdraw from study participation 
during Part A/B were expected to return to the clinic for an Early Withdrawal (EW) visit 
and to return any study materials approximately 4 weeks following their last dose of 
open-label mepolizumab. No additional follow-up is needed.
If a subject completes a Parts A/B Early Withdrawal Visit at a scheduled visit at which 
endpoint data were not scheduled to be collected, data will be slotted to the nearest 
adjacent visit within Part A/B where the endpoint data was scheduled to be collected 
according to the Time and Events schedule (Appendix 2: Schedule of Activities) unless
data are already recorded at that visit.
Part C or Part D
Subjects who withdrew prematurely from treatment or from the study during Part C or 
Part D may have data recorded under either a nominal visit at which it was scheduled for 
collection, a nominal visit at which it was not scheduled for collection, or an early 
withdrawal/IP discontinuation visit.
Subjects switching from treatment within Part C to Part D following an asthma 
exacerbation are required to complete an IP discontinuation/switch visit with a full set of 
assessments at each subject’s first Part D visit, prior to first dose with open-label 
mepolizumab per Appendix 2: Schedule of Activities. Such IP discontinuation/switch 
visits will be handled as a Treatment Discontinuation Visit as discussed below and data 
will attempt to be slotted to the nearest adjacent visit within Part C where the endpoint 
data was scheduled to be collected according to the Time and Events schedule (Appendix 
2: Schedule of Activities) unless data are already recorded at that visit
If a subject was withdrawn from the study for any reason the Investigator must make 
every effort to have the subject to return to the clinic for an EW Visit approximately 4 
weeks following the last dose to perform EW Visit assessments and to return all study-
related materials. Assessments are described in Appendix 2: Schedule of Activities. 
Subjects in study Part C or Part D who have permanently discontinued double-blind or 
open-label IP were not required to withdraw from the study. Subjects who have 
permanently discontinued IP and have not withdrawn consent may have continued in the 
study off-treatment. 
Subjects wishing to remain in the study will have completed an IP Discontinuation Visit 
(approximately 4 weeks after the last dose at the same time as the next scheduled visit) 
and continued to attend the clinic visits at the protocol designated time intervals and 
completed eDiary daily and weekly entries for important efficacy and safety assessments. 


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If the subject was unable to visit the clinic to complete any study assessments which 
require physical presence of the subject, visits could have continued to occur by 
telephone contact to review exacerbations, adverse events and concomitant medications. 
Subjects who have previously discontinued IP and have already completed their IP
Discontinuation Visit (approximately 4 weeks following the last dose) but then decided at 
a later date that they no longer wish to participate in the study, will be asked to return to 
the clinic to complete an EW Visit approximately 4 weeks following the last clinic visit 
to complete any EW assessments and to return any remaining study materials. No
additional safety follow-up visit is required.
If a subject completes an Early Withdrawal or Treatment Discontinuation Visit in Part C 
or Part D at a scheduled visit at which endpoint data were not scheduled to be collected, 
data will be slotted to the nearest adjacent visit within the appropriate reporting period 
(Part C or Part D) where the endpoint data was scheduled to be collected according to the 
Time and Events schedule (Appendix 2: Schedule of Activities) unless data are already
recorded at that visit. 
11.3.4.
Unscheduled Visits
If a subject has an unscheduled assessment then this data will be slotted to the closest 
adjacent scheduled visit within the appropriate reporting period (Parts A/B, Part C or Part 
D) where the endpoint data was scheduled to be collected according to the Time and 
Events schedule (Appendix 2: Schedule of Activities) unless data are already recorded at 
that visit. If an unscheduled visit occurred between two scheduled visits for which data 
has been reported, then the data from the unscheduled visit will remain in the 
unscheduled visit and will not be included in any by visit summary tables; it will however 
be included in relevant summaries of any time on-treatment data and listings. 


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11.3.5.
Definitions of Assessment Windows for Analyses
The following assessments will be collected on a daily basis using an eDiary device: 
morning peak flow, usage of rescue medication (i.e. salbutamol/albutamol), asthma 
symptom score, frequency of awakening due to asthma symptoms requiring use of rescue 
medication and time missed from work/school. Part C data will be summarised in 4-
weekly periods relative to the first Part C dose, as shown in the below table.
Domain
Parameter
Analysis Window[1,2]
Analysis 
Timepoint
Beginning Timepoint
Ending Timepoint
eDiary Data
morning peak flow, 
usage of rescue 
medication (i.e. 
salbutamol/albuterol), 
asthma symptom 
score, frequency of 
awakening due to 
asthma symptoms
and time missed from 
work/school
6 days prior to day of first 
dose
Date of first dose
Baseline
Day after day of first dose
28 days after day of first 
dose
Week 0-4
29 days after day of first 
dose
56 days after day of first 
dose
Week 4-8
57 days after day of first 
dose
84 days after day of first 
dose
Week 8-12
85 days after day of first 
dose
112 days after day of first 
dose
Week 12-16
113 days after day of first 
dose
140 days after day of first 
dose
Week 16-20
141 days after day of first 
dose
168 days after day of first 
dose
Week 20-24
169 days after day of first 
dose
196 days after day of first 
dose
Week 24-28
197 days after day of first 
dose
224 days after day of first 
dose
Week 28-32
225 days after day of first 
dose
252 days after day of first 
dose
Week 32-36
253 days after day of first 
dose
280 days after day of first 
dose
Week 36-40
281 days after day of first 
dose
308 days after day of first 
dose
Week 40-44
309 days after day of first 
dose
336 days after day of first 
dose
Week 44-48
337 days after day of first 
dose
Week 52 visit date (or 364 
days after day of first dose, 
if earlier)
Week 48-52

[1] Only non-missing eDiary measurements will be summarised in 4-weekly windows, see Section 11.7.2 for 
further details.

[2] Day of first dose within this table referring to first dose of double-blind IP at visit C1.
For subjects analysis windowing to be restricted to 364 days following first dose of double-blind IP at visit C1.


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Within Part A ACQ-5 assessments will be performed at scheduled clinic visits (according 
to Appendix 2: Schedule of Activities) and captured within the subject’s eCRF. The 
ACQ-5 assessments within study Part B, Part C and Part D will be collected on a weekly
basis using an eDiary device. Part C data will be summarised weekly relative to the first 
Part C dose, as shown in the below table.
Domain
Parameter
Target [1]
Analysis Window[2]
Analysis 
Timepoint
Beginning 
Timepoint
Ending 
Timepoint
eDiary Data
ACQ-5
≥8 days prior to day of first dose
Run-in Period
(Not to be 
summarised)
Day 1
7 days prior to 
day of first dose
Date of first dose
Baseline
Day 8
Day after date of 
first dose
11 days after 
date of first dose
Week 1
Day 15
12 days after 
date of first dose
18 days after 
date of first dose
Week 2
Day 22
19 days after 
date of first dose
25 days after 
date of first dose
Week 3
Day 29
26 days after 
date of first dose
32 days after 
date of first dose
Week 4
Day 36
33 days after 
date of first dose
39 days after 
date of first dose
Week 5
Day 43
40 days after 
date of first dose
46 days after 
date of first dose
Week 6
Day 50
47 days after 
date of first dose
53 days after 
date of first dose
Week 7
Day 57
54 days after 
date of first dose
60 days after 
date of first dose
Week 8
Day 64
61 days after 
date of first dose
67 days after 
date of first dose
Week 9
Day 71
68 days after 
date of first dose
74 days after 
date of first dose
Week 10
Day 78
75 days after 
date of first dose
81 days after 
date of first dose
Week 11
Day 85
82 days after 
date of first dose
88 days after 
date of first dose
Week 12
Day 92
89 days after 
date of first dose
95 days after 
date of first dose
Week 13
Day 99
96 days after 
date of first dose
102 days after 
date of first dose
Week 14
Day 106
103 days after 
date of first dose
109 days after 
date of first dose
Week 15
Day 113
110 days after 
date of first dose
116 days after 
date of first dose
Week 16
Day 120
117 days after 
date of first dose
123 days after 
date of first dose
Week 17
Day 127
124 days after 
date of first dose
130 days after 
date of first dose
Week 18
Day 134
131 days after 
137 days after 
Week 19


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Domain
Parameter
Target [1]
Analysis Window[2]
Analysis 
Timepoint
Beginning 
Timepoint
Ending 
Timepoint
date of first dose
date of first dose
Day 141
138 days after 
date of first dose
144 days after 
date of first dose
Week 20
Day 148
145 days after 
date of first dose
151 days after 
date of first dose
Week 21
Day 155
152 days after 
date of first dose
158 days after 
date of first dose
Week 22
Day 162
159 days after 
date of first dose
165 days after 
date of first dose
Week 23
Day 169
166 days after 
date of first dose
172 days after 
date of first dose
Week 24
Day 176
173 days after 
date of first dose
179 days after 
date of first dose
Week 25
Day 183
180 days after 
date of first dose
186 days after 
date of first dose
Week 26
Day 190
187 days after 
date of first dose
193 days after 
date of first dose
Week 27
Day 197
194 days after 
date of first dose
200 days after 
date of first dose
Week 28
Day 204
201 days after 
date of first dose
207 days after 
date of first dose
Week 29
Day 211
208 days after 
date of first dose
214 days after 
date of first dose
Week 30
Day 218
215 days after 
date of first dose
221 days after 
date of first dose
Week 31
Day 225
222 days after 
date of first dose
228 days after 
date of first dose
Week 32
Day 232
229 days after 
date of first dose
235 days after 
date of first dose
Week 33
Day 239
236 days after 
date of first dose
242 days after 
date of first dose
Week 34
Day 246
243 days after 
date of first dose
249 days after 
date of first dose
Week 35
Day 253
250 days after 
date of first dose
256 days after 
date of first dose
Week 36
Day 260
257 days after 
date of first dose
263 days after 
date of first dose
Week 37
Day 267
264 days after 
date of first dose
270 days after 
date of first dose
Week 38
Day 274
271 days after 
date of first dose
277 days after 
date of first dose
Week 39
Day 281
278 days after 
date of first dose
284 days after 
date of first dose
Week 40
Day 288
285 days after 
date of first dose
291 days after 
date of first dose
Week 41
Day 295
292 days after 
date of first dose
298 days after 
date of first dose
Week 42
Day 302
299 days after 
305 days after 
Week 43


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Domain
Parameter
Target [1]
Analysis Window[2]
Analysis 
Timepoint
Beginning 
Timepoint
Ending 
Timepoint
date of first dose
date of first dose
Day 309
306 days after 
date of first dose
312 days after 
date of first dose
Week 44
Day 316
313 days after 
date of first dose
319 days after 
date of first dose
Week 45
Day 323
320 days after 
date of first dose
326 days after 
date of first dose
Week 46
Day 330
327 days after 
date of first dose
333 days after 
date of first dose
Week 47
Day 337
334 days after 
date of first dose
340 days after 
date of first dose
Week 48
Day 344
341 days after 
date of first dose
347 days after 
date of first dose
Week 49
Day 351
348 days after 
date of first dose
354 days after 
date of first dose
Week 50
Day 358
355 days after 
date of first dose
361 days after 
date of first dose
Week 51
Day 365
362 days after date of first dose
onwards
Week 52

[1] If multiple scores are available within analysis window see Section 11.6.1.

[2] Day of first dose within this table referring to first dose of double-blind IP at visit C1.
For subjects analysis windowing to be restricted to 364 days following first dose of double-blind IP at visit C1.


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11.4.
Appendix 4: Study Periods and Treatment Phases
11.4.1.
Study Periods
The reporting of the study will be divided into three distinct periods, with displays 
reflecting data collected within each period separately:

Period 1: Parts A/B – variable and fixed run-in periods combined, receiving open-
label mepolizumab treatment

Period 2: Part C – double-blind treatment period, receiving mepolizumab or 
placebo

Period 3: Part D – optional treatment switch period, returning to open-label 
mepolizumab treatment
Data will be collected across all periods within a single study database and will be 
attributed to an individual period according to the time of occurrence/assessment relative 
to the attendance of subjects at specific visits as follows:
Study 
Period
Period Start
Period End
Period 1: 
Parts A/B
Date of Pre-screening visit
Subjects who are randomized and receive double-
blind treatment:
Day prior to Period 2 (Part C) start
Subjects who are not randomized:
Date of study conclusion (screen/run-in failure)
Period 2: 
Parts C
Date of first dose within Part C (Visit 
C1)
Subjects completing study Part C:
Date of study conclusion
Subjects discontinuing study treatment/withdrawing 
early from within Part C:
Latest date of 1) Part C Early Withdrawal visit and 
2) study conclusion
Subjects who switch to study Part D:
Day prior to Period 3 (Part D) start
Period 3: 
Parts D
Date of first dose within Part D
Subjects completing study Part D:
Date of study conclusion
Subjects discontinuing study treatment/withdrawing 
early from within Part D:
Latest date of 1) Part D Early Withdrawal visit and 
2) study conclusion 


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11.4.2.
Treatment Phases (Exacerbations and Healthcare Resource Use)
Exacerbations and healthcare resource use will be classified into treatment phases 
according to the time of occurrence/assessment relative to the dates of the study treatment 
and/or the participation of subjects within specific study parts (as dictated by attendance 
at specific visits) as shown in the table below:
Treatment Phase
Definition
Pre-treatment 
Onset Date & time < First dose of open-label mepolizumab
On-treatment 
(Parts A/B)
Subjects who are randomized and receive double-blind treatment:
First dose of open-label mepolizumab ≤ Onset Date & time < First dose of double-blind 
treatment
Subjects who are not randomized:
First dose of open-label mepolizumab ≤ Onset Date & time ≤ Earliest of (1) Last dose 
of open-label mepolizumab + 28 days or (2) Early Withdrawal visit date [1]
Post-treatment 
(Parts A/B)
Subjects who are not randomized:
Onset Date & time > Earliest of (1) Last dose of open-label mepolizumab + 28 days or 
(2) Early Withdrawal visit date [1]
On-treatment 
(Part C)
Subjects completing study Part C:
First dose of double-blind treatment ≤ Onset Date & time ≤ C14 (Exit Visit) visit date
Subjects discontinuing study treatment/withdrawing early from within Part C:
First dose of double-blind treatment ≤ Onset Date & time ≤ Earliest of (1) Last dose of 
double-blind treatment + 28 days or (2) Early Withdrawal / IP Discontinuation visit date
Subjects who switch to study Part D:
First dose of double-blind treatment ≤ Onset Date & time < First dose of open-label 
mepolizumab within Part D
Post-treatment 
(Part C)
Subjects completing study Part C:
Onset Date & time > C14 (Exit Visit) visit date
Subjects discontinuing study treatment/withdrawing early from within Part C:
Onset Date & time > Earliest of (1) Last dose of double-blind treatment + 28 days or (2) 
Early Withdrawal / IP Discontinuation visit date
On-treatment 
(Part D)
Subjects completing study Part D:
First dose of open-label mepolizumab within Part D ≤ Onset Date & time ≤ D14 (Exit 
Visit) visit date
Subjects discontinuing study treatment/withdrawing early from within Part D:
First dose of open-label mepolizumab within Part D ≤ Onset Date & time ≤ Earliest of 
(1) Last dose of open-label mepolizumab within Part D + 28 days or (2) Early 
Withdrawal / IP Discontinuation visit date
Post-treatment 
(Part D)
Subjects completing study Part D:
Onset Date & time > D14 (Exit Visit) visit date
Subjects discontinuing study treatment/withdrawing early from within Part D:
Onset Date & time > Earliest of (1) Last dose of open-label mepolizumab within Part D 
+ 28 days or (2) Early Withdrawal / IP Discontinuation visit date
[1] Note subjects who are deemed not eligible for randomization at visit C1 will perform their Early Withdrawal visit and 
associated assessments at this visit.
Time of study treatment dosing and start/stop time of assessment should be considered, if collected.
Where the assessment occurs on the date of study treatment and time is not available, assessment assumed to have 
occurred following dosing.
Refer to Appendix 7: Reporting Standards for Missing Data for handling of missing and partial dates in exacerbations.


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11.4.3.
Treatment Phases (Visit Based Efficacy and Safety Data)
Visit based efficacy data, safety data and eDiary data will be classified into treatment 
phases according to the time of occurrence/assessment relative to the dates of the study 
treatment and/or the participation of subjects within specific study parts (as dictated by 
attendance at specific visits) as shown in the table below:
Treatment Phase
Definition
Pre-treatment 
Date & time ≤ First dose of open-label mepolizumab
On-treatment 
(Parts A/B)
Subjects who are randomized and receive double-blind treatment:
First dose of open-label mepolizumab < Date & time ≤ First dose of double-blind 
treatment
Subjects who are not randomized:
First dose of open-label mepolizumab < Date & time ≤ Earliest of (1) Last dose of open-
label mepolizumab + 28 days or (2) Early Withdrawal visit date [1]
Post-treatment 
(Parts A/B)
Subjects who are not randomized:
Date & time > Earliest of (1) Last dose of open-label mepolizumab + 28 days or (2) 
Early Withdrawal visit date [1]
On-treatment 
(Part C)
Subjects completing study Part C:
First dose of double-blind treatment < Date & time ≤ C14 (Exit Visit) visit date
Subjects discontinuing study treatment/withdrawing early from within Part C:
First dose of double-blind treatment < Date & time ≤ Earliest of (1) Last dose of double-
blind treatment + 28 days or (2) Early Withdrawal / IP Discontinuation visit date
Subjects who switch to study Part D:
First dose of double-blind treatment < Date & time ≤First dose of open-label 
mepolizumab within Part D
Post-treatment 
(Part C)
Subjects completing study Part C:
Date & time > C14 (Exit Visit) visit date
Subjects discontinuing study treatment/withdrawing early from within Part C:
Date & time > Earliest of (1) Last dose of double-blind treatment + 28 days or (2) Early 
Withdrawal / IP Discontinuation visit date
On-treatment 
(Part D)
Subjects completing study Part D:
First dose of open-label mepolizumab within Part D < Date & time ≤ D14 (Exit Visit) visit 
date
Subjects discontinuing study treatment/withdrawing early from within Part D:
First dose of open-label mepolizumab within Part D < Date & time ≤ Earliest of (1) Last 
dose of open-label mepolizumab within Part D + 28 days or (2) Early Withdrawal / IP 
Discontinuation visit date
Post-treatment 
(Part D)
Subjects completing study Part D:
Date & time > D14 (Exit Visit) visit date
Subjects discontinuing study treatment/withdrawing early from within Part D:
Date & time > Earliest of (1) Last dose of open-label mepolizumab within Part D + 28 
days or (2) Early Withdrawal / IP Discontinuation visit date
[1] Note subjects who are deemed not eligible for randomization at visit C1 will perform their Early Withdrawal visit and 
associated assessments at this visit.
Time of study treatment dosing and start/stop time of assessment should be considered, if collected.
Where the assessment occurs on the date of study treatment and time is not available, assessment assumed to have 
been performed prior to dosing.


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Data classified in this manner will include questionnaires, lung function, laboratory 
assessments, liver events, immunogenicity, ECGs, vital signs and diary data.
11.4.4.
Treatment Phases (Adverse Events and Cardiovascular Events)
Adverse events and cardiovascular events will be classified into treatment phases 
according to the time of occurrence relative to the dates of study treatment within specific 
study parts as shown in the table below:
Treatment Phase
Definition
Pre-treatment 
Onset Date & time < First dose of open-label mepolizumab
If mepolizumab treatment is never started, then all will be classified as pre-treatment.
On-treatment 
(Parts A/B)
Subjects who are randomized and receive double-blind treatment:
First dose of open-label mepolizumab ≤ Onset Date & time < First dose of double-blind 
treatment
Subjects who are not randomized:
First dose of open-label mepolizumab ≤ Onset Date & time ≤Last dose of open-label 
mepolizumab + 28 days
Post-treatment 
(Parts A/B)
Subjects who are not randomized:
Onset Date & time > Last dose of open-label mepolizumab + 28 days
On-treatment 
(Part C)
Subjects who switch to study Part D:
First dose of double-blind treatment ≤Onset Date & time < First dose of open-label 
mepolizumab within Part D
All other Part C Subjects:
First dose of double-blind treatment ≤Onset Date & time ≤ Last dose of double-blind 
treatment + 28 days
Post-treatment 
(Part C)
Subjects who do not switch to study Part D:
Onset Date & time > Last dose of double-blind treatment + 28 days
On-treatment 
(Part D)
First dose of open-label mepolizumab within Part D ≤Onset Date & time ≤ Last dose of 
open-label mepolizumab within Part D + 28 days
Post-treatment 
(Part D)
Onset Date & time > Last dose of open-label mepolizumab within Part D + 28 days
Time of study treatment dosing and start/stop time of event should be considered, if collected.
Where the event onset occurs on the date of study treatment and time is not available, event assumed to have occurred 
following dosing.
If an AE start date is missing or partial then the AE will be considered on-treatment unless there is evidence to the 
contrary (e.g. month/year of onset date is present and is earlier than the month/year of first dose of treatment).
Refer to Appendix 7: Reporting Standards for Missing Data for handling of missing and partial dates in adverse events
and cardiovascular events.


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11.4.4.1.
Adverse Event Data Derivations
Treatment State
Definition
Onset Time  
Since 1st Dose*
If Treatment Start Date ˃ AE Onset Date = AE Onset Date - Treatment Start Date
If Treatment Start Date ≤ AE Onset Date = AE Onset Date - Treatment Start Date +1
Missing otherwise.
Duration (Days) 
AE Resolution Date – AE Onset Date + 1
Drug-related
Adverse events are considered as drug-related if relationship is marked ‘YES’ on 
Inform/eCRF OR value is missing.
Severity
If adverse event severity is missing, severity is to be populated as ‘UNKNOWN’
* Note: will be derived as time since 1st dose of within the respective study period (Part A/B, Part C or Part 
D)
If less than 24 hours, will be derived in days, hours and minutes (where AE start datetime available). 
If greater than 24 hours or AE start datetime not available, will be derived in days


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11.4.5.
Treatment Phases (Concomitant Medications)
A medication will be summarised in every treatment/study phase in which it was taken, 
so for example a medication that was started in the run-in and stopped during treatment 
will appear in both the during the run-in and during treatment tables.
Concomitant medications will be classified into treatment phases according to start and 
stop dates for each medication relative to the dates of the study treatment within specific 
study parts as shown in the table below:
Treatment/Study 
Phase
Definition
Taken Before the 
Run-in 
If Con-med Start Date < First dose of open-label mepolizumab or (Con-med Start Date 
is missing)
Taken During the 
Run-in (Parts A/B)
Subjects who are randomized and receive double-blind treatment:

If (Con-med Start Date < First dose of open-label mepolizumab or Con-med Start 
Date is missing) and (Con-med Stop Date ≥ First dose of open-label 
mepolizumab, or Con-med Stop date is missing) or

If First dose of open-label mepolizumab ≤ Con-med Start Date < First dose of 
double-blind treatment
Subjects who are not randomized:

If (Con-med Start Date < First dose of open-label mepolizumab or Con-med Start 
Date is missing) and (Con-med Stop Date ≥ First dose of open-label 
mepolizumab, or Con-med Stop date is missing) or

If First dose of open-label mepolizumab ≤ Con-med Start Date ≤ Last dose of 
open-label mepolizumab + 28 days
Taken Post 
Treatment 
(Parts A/B)
Subjects who are not randomized:

Con-med Stop Date > Last dose of open-label treatment + 28 days, or

Con-med Stop Date is missing
Taken During 
Treatment 
(Part C)
Subjects who switch to study Part D:

If (Con-med Start Date < First dose of double-blind treatment or Con-med Start 
Date is missing) and (Con-med Stop Date ≥ First dose of double-blind treatment, 
or Con-med Stop date is missing) or

If First dose of double-blind treatment ≤ Con-med Start Date < First dose of open-
label mepolizumab within Part D
All other Part C Subjects:

If (Con-med Start Date < First dose of double-blind treatment or Con-med Start 
Date is missing) and (Con-med Stop Date ≥ First dose of double-blind treatment, 
or Con-med Stop date is missing) or

If First dose of double-blind treatment ≤ Con-med Start Date ≤ Last dose of 
double-blind treatment + 28 days
Taken Post 
Treatment 
(Part C)
Subjects who do not switch to study Part D:

Con-med Stop Date > Last dose of double-blind treatment + 28 days, or

Con-med Stop Date is missing
Taken During 
Treatment 
(Part D)

If (Con-med Start Date < First dose of open-label mepolizumab within Part D or 
Con-med Start Date is missing) and (Con-med Stop Date ≥ First dose of open-
label mepolizumab within Part D, or Con-med Stop date is missing) or

If First dose of open-label mepolizumab within Part D ≤ Con-med Start Date ≤ 


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Treatment/Study 
Phase
Definition
Last dose of open-label mepolizumab within Part D + 28 days
Taken Post
Treatment 
(Part D)

Con-med Stop Date > Last dose of open-label mepolizumab within Part D + 28 
days, or

Con-med Stop Date is missing
Taken at Visit C1 
(Randomization)

If (Con-med Start Date < First dose of double-blind treatment or Con-med Start 
Date is missing) and (Con-med Stop Date ≥ First dose of double-blind treatment, 
or Con-med Stop date is missing)
Time Since 1st
Dose (Days)*
If Treatment Start Date ˃ Con-med Start Date = Con-med Start Date - Treatment Start 
Date
If Treatment Start Date ≤ Con-med Start Date = Con-med Start Date - Treatment Start 
Date + 1
If Treatment Start Date or Con-med Start Date is missing = missing.
Duration (Days)
Con-med Stop Date –Con-med Start Date + 1
Refer to Appendix 7: Reporting Standards for Missing Data for handling of missing and partial dates in concomitant 
medications.
* Note: will be derived as time since 1st dose of within the respective study period (Part A/B, Part C or Part D)


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11.5.
Appendix 5: Data Display Standards & Handling 
Conventions
11.5.1.
Reporting Process
Software

The currently supported versions of SAS software will be used.
Reporting Area
HARP Server
: uk1salx00175
HARP Area
: sb240563/mid201810
Analysis Datasets 

Analysis datasets will be created according to CDISC standards (SDTM IG Version 3.1.3 & ADaM IG 
Version 1.0)

For creation of ADaM datasets (ADCM/ADAE), the same version of dictionary datasets (GSK 
Drug/MedDRA) will be implemented for conversion from SI to SDTM.
Generation of RTF Files

RTF files will be generated for the final reporting effort.
11.5.2.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx):

4.03 to 4.23: General Principles

5.01 to 5.08: Principles Related to Data Listings

6.01 to 6.11: Principles Related to Summary Tables

7.01 to 7.13: Principles Related to Graphics 

All subject level listings will be located in the modular appendices as ICH listings of the GSK Clinical 
Study Report.
Formats

Data within Part C will be reported according to the treatment each subject received for more than 50% 
of injections within Part C unless otherwise stated (see Section 5.1).

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for reporting of 
data based on the raw data collected, unless otherwise stated.

Numeric data will be reported at the precision collected on the eCRF.

The reported precision (decimal places) from non eCRF sources will follow the IDSL statistical 
principles but may be adjusted to a clinically interpretable number of DP’s.
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses:

Nominal visits (planned time relative to dosing) will be used in figures, summaries, statistical 
analyses and calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled visit days 
on the analyses and interpretation of the results will be assessed as appropriate.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1).


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
Unscheduled or unplanned readings will be presented within the subject’s listings. 

Scheduled visits outside the protocol defined time-windows (i.e. recorded as protocol deviations) 
will be included in listings, summaries and statistical analyses.
Unscheduled Visits

When possible, unscheduled assessments will be slotted to the closest adjacent scheduled visit where 
the endpoint data was scheduled to be collected and not already recorded at that visit.  If an 
unscheduled visit occurs between two completed scheduled visits, the data from the unscheduled visit 
will not be used in summary tables which are based on by-visit assessments.  The information from the 
unscheduled visit will be included in ‘any time on-treatment’ summaries and will also be presented in 
any relevant listings. See Section 11.3.4 for further details.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N (number of subjects in the treatment group), n (number of subjects with
non-missing values), frequency, %
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.


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11.6.
Appendix 6: Derived and Transformed Data
11.6.1.
General
Multiple Measurements at One Analysis Time Point

Multiple ECG measurements may be performed (e.g. in triplicate) at a single clinic visit. See Section 
11.6.4 for further details on handling these multiple measurements at a single visit.

If there are two values within a time window (as possible per Section 11.3.5) the value closest to the 
target day for that window will be used. If values are the same distance from the target, then the mean 
will be taken.

Participants having both High and Low values for Normal Ranges within summaries of any time on-
treatment for safety parameters will be counted in both the High and Low categories of “Any time on-
treatment” row of related summary tables. This will also be applicable to relevant Potential Clinical 
Importance summary tables.
Study Day

Study Day will be derived relative to the treatment start dates in each of the three reporting periods:
1)
Study day (Parts A/B) will be calculated as the number of days from date of first dose of open-label 
treatment (Parts A/B):
Ref Date = Missing
→
Study day (Parts A/B) = Missing 
Ref Date < Date of first dose of open-label treatment
→
Study day (Parts A/B) = Ref Date – Date of first dose of open-label treatment
Date of first open-label treatment ≤ Ref Data < Date of first double-blind treatment
→
Study day (Parts A/B) = Ref Date – (Date of first dose of open-label treatment) + 1
Subjects considered as screen failures (i.e. not receiving treatment within Parts A/B) will have 
study day (Parts A/B) populated as missing.
2)
Study day (Part C) will be calculated as the number of days from date of first dose of double-blind 
treatment (Part C):
Ref Date = Missing
→
Study Day (Part C) = Missing 
Subjects who switch to study Part D:
Date of first double-blind treatment ≤ Ref Data < Date of first open-label Part D treatment →
Study Day (Part C) = Ref Date – (Date of first dose of double-blind treatment) + 1
All other Part C Subjects:
Date of first double-blind treatment ≤ Ref Data 
→
Study Day (Part C) = Ref Date – (Date of first dose of double-blind treatment) + 1
3)
Study day (Part D) will be calculated as the number of days from date of first dose of open-label 
treatment within Part D:
Ref Date = Missing
→
Study day (Part D) = Missing 
Date of first open-label Part D treatment ≤ Ref Data
→
Study day (Part D) = Ref Date – (First open-label mepolizumab dose within Part D) + 1


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11.6.2.
Study Population
Demographics
Age

Only year of birth was collected for subjects; actual birth date was not collected.

Each subject’s full birth date is available and will be utilised from each subject’s first enrolled 
mepolizumab study: MEA112997, MEA115588 or MEA115575

Each subject’s age will be calculated as an integer value based on their imputed date of birth relative 
to the date of each subject’s screening visit.

For those subjects randomized to double-blind treatment each subject’s age will be also calculated 
based on their imputed date of birth relative to the date of the visit C1.
Body Mass Index (BMI)

Calculated as Weight (kg) / Height (m)2
Smoking Status

At Visit C1 an update in each subject’s smoking status since Screening (Visit 1) will be collected. 

Where no change in smoking status is reported, the respective subject’s smoking status information 
will be utilised within the analysis datasets at Visit C1 unchanged from Screening (Visit 1). 

Where a change in smoking status is observed such that the subject started smoking, the subject will 
be presented as a ‘Current Smoker’ at Visit C1. 

Where a change in smoking status is observed such that the subject stopped smoking, the subject 
will be presented as a ‘Former Smoker’ at Visit C1. 
Baseline Characteristics
Disease Duration

Prior to enrolment into study MEA115666, subjects previously enrolled into study MEA112997

Similarly, prior to enrolment into study 201312, subjects previously enrolled into studies MEA115575 
or MEA115588 followed by study MEA115661

Each subject reported disease duration relative to the age of onset at the screening visit of the pre-
cursor studies MEA112997 / MEA115588 / MEA115575.

Each subject’s duration of asthma at Visit C1 will be derived as the total of (1) the disease duration 
up to the screening visit of study MEA112997 / MEA115588 / MEA115575 and (2) the duration from 
the screening visit of study MEA112997 / MEA115588 / MEA115575 to Visit C1.
Baseline OCS daily dose [Visit C1]

Only corticosteroids administered via oral, intravenous (IV) and intramuscular (IM) routes are to be 
considered when calculating a subject’s total daily prednisone/prednisolone asthma maintenance 
dose at baseline (Visit C1). All steroids administered via a sublingual route will also be considered as 
oral. 

The corticosteroid conversion factors shown below will be used, regardless of the route of 
administration, to scale each corticosteroid dose to a prednisone equivalent dose. These three 
routes of administration (oral, IV and IM) are to be considered equivalent as it has been noted that 
the bioavailability of methylprednisolone is considered to be roughly equivalent following 
administration as an oral, IV or IM steroid.

If two corticosteroid records are seen to overlap on the day of first double-blind treatment, these 
overlapping records will be summed in order to obtain a total prednisone/prednisolone equivalent 
dose received.


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Standardised Medication Name
Scaling Factor
Betamethasone
8.33
Betamethasone Dipropionate
8.33
Betamethasone Sodium Phosphate
8.33
Cortisone
0.2
Cortisone Acetate
0.2
Cortivazol
17
Deflazacort 
0.833
Dexamethasone 
6.67
Dexamethasone Sodium Phosphate 
6.67
Fludrocortisone Acetate 
0
Hydrocortisone 
0.25
Hydrocortisone Sodium Succinate 
0.25
Hydrocortisone Sodium Phosphate 
0.25
Meprednisone
1
Methylprednisolone
1.25
Methylprednisolone Acetate
1.25
Methylprednisolone Sodium Succinate
1.25
Methylprednisone 
1.25
Methylprednisone Acetate 
1.25
Methylprednisolone Sodium Succinate 
1.25
Methylprednisone
1.25
Methylprednisone Acetate 
1.25
Prednisolone 
1
Prednisolone Acetate 
1
Prednisolone Hemisuccinate 
1
Prednisolone Sodium Succinate 
1
Prednisone 
1
Prednisone Acetate 
1
Triamcinolone 
1.25
Triamcinolone Acetonide 
1.25
Exposure
Continuous Mepolizumab Exposure Prior to Randomization (Visit C1)

For each subject the period of continuous mepolizumab exposure prior to randomization (first dose of 
double-blind treatment at Visit C1) will be summarised considering mepolizumab treatment from the 
following precursor studies where the same individuals participated: MEA115666, MEA115588, 
MEA115575, MEA115661, 201312 in addition any mepolizumab treatment administered within 201810 
Parts A/B. Study MEA112997 will not be considered in the assessment of continuous mepolizumab 
exposure prior to randomization since each subject experienced a prolonged gap in treatment of at 
least 12 months between studies MEA112997 and MEA115666.

Number of days of continuous mepolizumab exposure prior to randomization will be calculated based 
on the formula:  
Duration of Exposure in Days = Treatment Stop Date – (Treatment Start Date) + 29
Note: where the first double-blind treatment at Visit C1 < treatment stop date + 29, the duration of 


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exposure will be truncated at the first double-blind treatment at Visit C1.

The earliest date of initiating mepolizumab treatment will be considered when deriving each subject’s 
total prior exposure, however if a gap of >84 days between any two doses of mepolizumab is 
experienced (corresponding to more than 2 consecutive missed doses), this exposure period can no 
longer be considered ‘continuous’. If such an instance occurs the subject's period of continuous 
mepolizumab treatment will be derived from the first dose of mepolizumab following this gap in 
treatment. 

If a subject experiences a gap of >12 weeks (84 days) between any two doses of mepolizumab within 
studies MEA115666 or 201312 this will exclude the subject from entry into 201810 (Inclusion Criterion 
#2).
Extent of Exposure

Exposure data will be reported separately from each period (Parts A/B, Part C and Part D).

Number of days of exposure to study drug will be calculated based on the formula:  
Duration of Exposure in Days = Treatment Stop Date – (Treatment Start Date) + 29
Note: where subjects transition between periods (e.g. from Parts A/B to Part C, or equivalently from 
Part C to Part D) and the first treatment within the next period < treatment stop date + 29, the duration 
of exposure within the preceding period will be truncated at the first treatment within the subsequent 
period.

The extent of exposure will also be summarised as the number of study treatments administered.
11.6.3.
Efficacy
Exacerbations

Within each subject, exacerbations separated by less than 7 days will be treated as a continuation of 
the same exacerbation and programmatically collapsed into a single exacerbation. Exacerbations for 
which the collapsing has already been performed will be included in the summaries and analyses. 
Exacerbations will be displayed in listings as captured within the eCRF. Exacerbations which are 
programmatically collapsed into a single exacerbation will be highlighted.

The programmatically collapsed exacerbation records will be constructed as follows: 
o
Start date (ASTDT) is the start date of the first exacerbation in the series 
o
End date (AENDT) is the end date of the last exacerbation in the series 
o
Outcome (CEOUT) is the worst outcome in the series (worst to best is Fatal, Not 
Resolved, Resolved) 
o
Cause (EBCAUSE) is the cause associated with the first exacerbation in the series 
o
Clinical significance of exacerbation (ACAT) are set to ‘Clinically significant’ if any value 
for the respective variable in the series equals ‘Clinically significant’ (see Section 7.1.5.2)
o
Withdrawal due to exacerbation (EBWD), OCS taken for exacerbation (OCSEXB), 
corticosteroids taken for exacerbation (CTSEXB), hospitalization due to exacerbation 
(HSPEXB), emergency visit due to exacerbation (EREXB), and intubation for 
exacerbation (INTUBEXB) are set to ‘Y’ if any value for the respective variable in the 
series equals ‘Y’ 
o
Number of telephone calls (TPCNUM), home day visits (HMDYVSN), home night visits 
(HMNTVSN), home day+night visits (HMDYNTV), office visits (OFCVSN), urgent 
care/outpatient visits (UCOUTVSN), emergency room visits (ERVSN), days in intensive 
care (ICSDYNUM), days in general ward (GWDYNUM) and days hospitalized 
(HSPDYNUM) are the sum of all of the values in the series for each respective variable
Blood Eosinophils

Blood eosinophils will be log-transformed prior to analysis. Summary statistics will include geometric 
mean, and a measure of spread (SD or SE) on the natural log scale.


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
If a blood eosinophil count of zero is reported, it will be imputed with half of the lowest possible blood 
eosinophil count, where applicable, prior to log transforming the data (Note: this imputation will be 0.5 * 
0.01 109/L = 0.005 109/L as in previous mepolizumab studies).
Patient Reported Outcomes/Questionnaires
Asthma Control Questionnaire (ACQ)-5

The ACQ-5 questionnaire consists of 5 symptom related questions (Q1-Q5) and requires a 1 week 
recall. 

In Part A subjects self-complete the ACQ-5 at specified clinic visits (see Section 11.2) on paper with 
their responses transcribed into the eCRF. In Parts B, C or D subjects self-complete the ACQ-5 on their 
eDiary once weekly.

The five questions enquire about the frequency and/or severity of symptoms over the previous week 
(nocturnal awakening on waking in the morning, activity limitation, and shortness of breath, wheeze).  

Each question on the ACQ-5 is scored on a 7-point scale from 0 = no impairment to 6 = maximum 
impairment. The questions are equally weighted and the ACQ-5 score will be the mean of the 5 
questions, thus giving a score between 0 (totally controlled) and 6 (severely uncontrolled) [Juniper, 
1999; Juniper, 2005]. 

If a subject does not complete 1 of the 5 questions at a visit, then the ACQ-5 score will be the mean of 
the responses to the remaining 4 questions at that visit.

If a subject does not complete more than 1 of the 5 questions at a visit, then their ACQ-5 score will be 
set to missing at that visit.

A subject will be deemed to have experienced a decrease in asthma control (non-responder) if the 
subject has a ≥0.5 increase in ACQ-5 score from Baseline. ACQ-5 Responder/Non-responder category 
will be missing if the ACQ-5 score is missing.
St George’s Respiratory Questionnaire (SGRQ)

The SGRQ comprises 50 questions designed to measure Quality of Life in patients with diseases of 
airway obstruction, measuring symptoms, impact, and activity with a recall period of 4 weeks.

Scores are expressed as the percentage of overall impairment with 100 equal to the worst possible 
health and 0 the best.

Scoring of each domain of the SGRQ (Symptoms, Activity, Impacts) and the Total score are described 
in the St George’s Respiratory Questionnaire Manual (Version 2.3).

A subject will be deemed to have experienced a clinically meaningful worsening of health-related quality 
of life (non-responder) if the subject has a ≥4 increase in SGRQ score from Baseline. SGRQ 
Responder/Non-responder category will be missing if the Total SGRQ score is missing.
Global Impression of Disease Severity Rating

The investigator (or designee) and subject will complete a Global Impression of Disease Severity 
question at Randomization and visits described in Table 3. 

This single global question will ask subjects and clinicians to rate the subject’s asthma severity on a 
four-point scale (mild, moderate, severe, very severe) 
Rating of Response to Therapy

The investigator (or designee) and subject will be asked to rate the subject’s response to therapy at 
specified visits (Table 3). 

This is an overall evaluation of response to treatment, as compared to Visit C1. 

This questionnaire/assessment will be conducted separately by the investigator (or designee) and the 
subject using a seven-point rating scale as follows: 
1 = significantly improved 
2 = moderately improved 
3 = mildly improved 
4 = no change 


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5 = mildly worse
6 = moderately worse
7 = significantly worse 
Spirometry (Lung Function)

Spirometry will be performed to assess FEV1 and FVC using the sites own equipment at specified clinic 
visits (see Section 11.2) on paper with their responses transcribed into the eCRF. Subjects should 
withhold rescue albuterol/salbutamol for 6 hours and LABAs or ICS/LABA fixed dose combinations for 
12 hours prior to spirometry, if possible.

At all spirometry assessments conducted within Parts B and C, both pre- and post-bronchodilator 
spirometry will be obtained.  All spirometry assessments in Parts A and D will be pre-bronchodilator 
only.
Percent Predicted FEV1

FEV1 % of predicted normal will be derived using the Global Lung Function Initiative 2012 look-up 
tables which are based on the Quanjer equations [Quanjer, 2012] according to the Race/Ethnicity 
designations specified below:
Collected Race[1]
Quanjer Designation
African American/African Heritage 
African-American calculation will be applied
American Indian or Alaskan Native 
Other calculation will be applied
Asian-Central/South Asian Heritage 
South East Asian calculation will be applied
Asian-East Asian Heritage 
North East Asian calculation will be applied
Asian-Japanese Heritage 
Other calculation will be applied
Asian- South-east Heritage 
South East Asian calculation will be applied
Native Hawaiian or Other Pacific Islander 
Other calculation will be applied
White-Arabic/North African Heritage 
Caucasian calculation will be applied
White-White/Caucasian/European Heritage 
Caucasian calculation will be applied
NOTE: If multiple races are selected for a single subject then the “Other” calculation will be applied.
FEV1/FVC Ratio

Pre- and post-bronchodilator FEV1/FVC ratio will be calculated as the ratio of the FEV1 and FVC values
at a given clinic visit from the same spirometry assessment.
Reversibility

Bronchodilator responsiveness (reversibility) will be calculated as the absolute difference (mL) and 
percentage difference (%) in pre- and post-bronchodilator FEV1 values at a given clinic visit from the 
same spirometry assessment.
Electronic Diary (eDiary)

The subject will record the following parameters daily in the eDiary from Visit B1 until the completion of 
Part C or Part D:
o Morning peak flow (best of three), before rescue medication usage (L/min). 
o Asthma symptom score over the previous 24-hours using a 6-point scale 
o Occasions of rescue medication usage over the previous 24-hours
o Frequency of awakening due to asthma symptoms requiring rescue medication use

Subjects who work for pay or go to school on a regular basis will record in the eDiary any full and part 
days of missed work or school due to asthma.

Whilst in Part B, C or D subjects self-complete the ACQ-5 on their eDiary once weekly (see above for 
details of this questionnaire).


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Healthcare Resource Utilization

All unscheduled asthma-related visits to a physician’s office, visits to urgent care, visits to the 
emergency department, and hospitalizations associated with the subject’s asthma will be recorded in 
the eCRF. 

Healthcare resource use will be collected as unscheduled asthma-related healthcare resource use (1) 
associated with an asthma exacerbation, and (2) not associated with an asthma exacerbation. 
Additionally, healthcare resource use will be combined in order to summarise total unscheduled 
asthma-related healthcare resource use.

For consistency, exacerbations separated by less than 7 days will be treated as a continuation of the 
same exacerbation (see above for details of further details on collapsing exacerbations)

The number of days in hospital is collected separately for the number of days in (1) intensive care and
(2) in general ward
This information is additionally collected separately for (1) associated with an asthma exacerbation, and 
(2) not associated with an asthma exacerbation.
Therefore:
o Number of days in hospital = Number of days in intensive care + days in general ward
o Total days in hospital due to asthma = Number of days in hospital associated with an exacerbation 
+ Number of days in hospital not-associated with an exacerbation


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11.6.4.
Safety
Adverse Events
Adverse Events of Special Interest

Adverse events of special interest (AESIs) of systemic reactions (including systemic reactions meeting 
Sampson’s criteria for anaphylaxis) and local injection site reactions are collected via targeted eCRF 
pages within the study. Events captured on the eCRF as systemic reactions will be further categorized 
as allergic/hypersensitivity reactions or non-allergic reactions.  Systemic reactions with preferred terms 
such as injection related reaction or administration related reaction will be considered non-allergic 
reactions; those with other preferred terms will be considered allergic/hypersensitivity reactions.

The AESIs of opportunistic infections, malignancies, serious CVT events and serious ischemic events 
will be identified from a list of relevant preferred terms maintained within a project level reference 
dataset; created based on the latest version of the MedDRA dictionary available at the time of database 
freeze for this study. For further details of how relevant preferred terms are identified are detailed within 
the Program Safety Analysis Plan (PSAP).
Exposure Adjusted Adverse Events

The number of events per 1000 subject-years of exposure will be calculated as:
Laboratory Parameters
Haematology and Clinical Chemistry

If a laboratory value which is expected to have a numeric value for summary purposes, has a character 
value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than x in the comment field), the 
number of significant digits in the observed values will be used to determine how much to add or 
subtract in order to impute the corresponding numeric value. 
o
Example 1: 2 Significant Digits = ‘< x‘ becomes x – 0.01
o
Example 2: 1 Significant Digit   = ‘> x’ becomes x + 0.1
o
Example 3: 0 Significant Digits = ‘< x’ becomes x – 1    

Regarding blood eosinophil laboratory data see Section 11.6.3.

See Section 11.8 for further details regarding laboratory results of potential clinical concern.
ECG Parameters

Multiple ECG measurements may be performed (e.g. in triplicate) at a single clinic visit.

If multiple ECGs are performed at a single visit, ECG parameters (such as QTcB or QTcF) will be based 
on the average value of each measurement ECG.

If multiple ECGs are performed at a single visit, ECG interpretations will be based on the worst-case 
interpretation across the ECGs performed, considering the following to be of increasing severity:
o No Result, Unable to Evaluate, Normal, Abnormal, Abnormal – Possibly Significant 
RR Interval
All ECG parameters required in this study will be databased, and therefore, further derivations will not be 
performed by Stats and Programming. The definitions of these parameters are given in this section.

If RR interval (msec) is not databased, then RR can be derived as:
[1] If QTcB is machine read & QTcF is not provided, then:


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[2] If QTcF is machine read and QTcB is not provided, then: 

If ECGs are manually read, the RR value should be a collected value and will not be derived.
Corrected QT Intervals

When not databased, corrected QT intervals by Bazett’s (QTcB) and Fredericia’s (QTcF) formulas will 
be calculated, in msec, depending on the availability of other measurements.

If RR interval (msec) is provided then missing QTcB and/or QTcF will be derived as: 

Individual maximum QTc(F) and QTc(B) on-treatment values will also be summarised by treatment 
group for each scheduled study visit to show the number of subjects with maximum values (msec) in 
the following categories:

≤450

450 < to ≤480

480 < to ≤500

> 500 

Additionally, individual maximum changes from baseline in QTc(F) and QTc(B) values will be 
summarised by treatment group for each scheduled study visit to show the number of subjects with 
maximum changes (msec) in the following categories: 

< -60

≥ -60 to ≤60

>60
Immunogenicity

Clinical samples are tested in a sequence of binding anti-drug antibody (ADA) and neutralising antibody 
assays:
o
Screening assay. Each sample is tested for the presence of anti-drug antibodies (ADA assay) and 
initially declared positive or negative according to assay cut-off criteria. Negative samples are not 
tested further. Positive samples are then tested in the confirmation ADA assay. 
o
Confirmation assay. Each positive sample from the screening assay is either confirmed positive in 
this assay (ADA assay) or is declared negative and are not tested further. Positive ADA samples 
are then tested in the titer assay and neutralization (NAb) assay.
o
Titration assay. Each positive sample from the ADA confirmation assay is serially diluted to provide 
a titre, corresponding to the highest dilution factor that still yields a positive test result.
o
Neutralising assay. Each positive sample from the ADA confirmation assay is tested with the 
neutralising antibody assay and found as either positive or negative in this assay (NAb assay).

The mepolizumb ADA (screening/confirmation/titration) assay version 2011N122789_03 is performed at 
a Alliance Pharma (method 120711M01.V02). The mepolizumb Nab assay version 2011N129752_03 is 
being performed within GSK.


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11.7.
Appendix 7: Reporting Standards for Missing Data
11.7.1.
Premature Withdrawals
Element
Reporting Detail
General

A subject will be considered to have completed randomized study treatment if he/she 
receives study treatment at Visit C13 (Week 48). 

A subject will be considered to have completed study treatment if he/she receives study 
treatment at Visit C13 or D13 (Week 48). 

A subject will be considered to have completed the study if they continue to participate 
in the study until the Part C/Part D Exit Visit assessments have been completed 
(regardless of whether the subject completed the study treatment schedule).

Subjects who discontinue study treatment or withdraw early will not be replaced in the 
study.

The number of subjects who discontinue randomized study treatment or withdraw early 
will be summarised and listed.

All available data from participants who were withdrawn from the study will be listed 
and all available data up to and including the date of early withdrawal will be included in 
summary tables and figures, unless otherwise specified.

Withdrawal visits will be slotted to an analysis clinic visit as per Section 11.3.2 for 
summary tables/figures and data will be listed under the collected early withdrawal visit.
Pre-Screen 
Failures, 
Screen 
Failures and 
Run-in 
Failures
For the purposes of this study pre-screen failures, screen failures and run-in failures will be 
defined as follows:

Subjects will be assigned a study number at the time of signing the informed consent 
(Pre-screen Visit). Subjects who do not progress to the Screening Visit will be deemed 
a pre-screen failure.

Those subjects that complete at least one additional Visit 1 (Screening) procedure but 
do not enter the run-in period will be designated as screen failures.

Those subjects that enter Part A/Part B (run-in period), but are not randomized, will be 
designated as run-in failures.
11.7.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank fields on 
the collection instrument:
o
These data will be indicated by the use of a “blank” in subject listing displays. 
Unless all data for a specific visit are missing in which case the data is 
excluded from the listing. 
o
Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as reported.

Results which are found to be below the limit of quantification (BLQ) are not missing 
data and will be included in all displays. See Section 11.6 for the handling of this data.

If a blood eosinophil count of zero is reported, it will be imputed with half of the lowest 
possible blood eosinophil count, where applicable, prior to log transforming the data 
(Note: this imputation has typically been 0.5 * 0.01 109/L = 0.005 109/L for previous 
mepolizumab studies). 

The ACQ-5 score will be considered as missing if 2 or more items of the questionnaire 
are not completed at a visit. ACQ-5 Responder/Non-responder category will be missing 
if the ACQ-5 score is missing.


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Element
Reporting Detail

Scoring of each domain of the SGRQ (Symptoms, Activity, Impacts) and the Total score 
are described in the St George’s Respiratory Questionnaire Manual (Version 2.3), 
including possible missing scores following missed items. SGRQ Responder/Non-
responder category will be missing if the Total SGRQ score is missing.

Missing values will not be imputed for any of the other endpoints.

When handling eDiary parameters (see Section 11.6.3) missing responses in each 
patient’s daily diary will be assumed to be missing at random. As a result only non-
missing eDiary measurements will be summarised in 4-weekly windows (see Section 
11.3.5) and only non-missing eDiary measurements will be considered in the 
exploratory endpoint of Time to worsening of asthma which is defined according to the 
four measured eDiary parameters (see Section 7.3.2.1).
Outliers

Any participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
11.7.2.1.
Handling of Missing and Partial Dates
Element
Reporting Detail
General

The eCRF allows for the possibility of missing or partial dates (i.e., only month and 
year is captured) to be recorded for event start and end dates.

The recorded missing or partial date will be displayed in listings as captured.
Concomitant 
Medications

Partial dates for any concomitant medications recorded in the CRF will be imputed 
using the following convention: 
o
If the partial date is a start date, a '01' (first of the month) will be used for the day 
and 'Jan' will be used for the month. However, if this results in a date prior to the 
start of double-blind treatment and the event could possibly have occurred during 
double-blind treatment from the partial information, then the start date of double-
blind treatment date will be assumed to be the start date, as per Appendix 4:
Study Periods and Treatment Phases.
o
If the partial date is a stop date, a '28/29/30/31' (last day of the month) will be 
used for the day (dependent on the month and year) and 'Dec' will be used for 
the month. 
Adverse 
Events, 
Exacerbations 
and 
Healthcare 
Resource Use

Any partial dates for adverse events, cardiovascular events and exacerbations will be 
raised to data management. If the full date cannot be ascertained, the following 
assumptions will be made:
o
If the partial date is a start date, a '01' (first of the month) will be used for the day 
and 'Jan' will be used for the month. However, if this results in a date prior to the 
start of treatment and the event could possibly have occurred during treatment 
from the partial information, then the study treatment start date will be assumed 
to be the start date, as per Appendix 4: Study Periods and Treatment Phases.
o
If the partial date is a stop date, a '28/29/30/31' (last day of the month) will be 
used for the day (dependent on the month and year) and 'Dec' will be used for 
the month.

The above listed imputations will also be applied when calculating the time to onset 
and the duration of the event containing missing or partial start and end dates.

Completely missing start or end dates (i.e. no year specified) will remain missing, with 
no imputation applied. Consequently, time to onset and duration of such events will 
be missing.


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11.8.
Appendix 8: Values of Potential Clinical Importance
11.8.1.
Laboratory Values
Chemistry Values of Potential Clinical Concern
Laboratory 
Parameter
Age
Sex
Units
Clinical Concern 
Low Flag 
(< x)
Clinical Concern 
High Flag 
(> x)
Calcium
≥3
Both
mmol/L
1.50
3.24
Glucose
≥1
Both
mmol/L
2.2
27.8
Potassium
≥3
Both
mmol/L
2.8
6.5
Sodium
≥0
Both
mmol/L
120
160
ALT (SGPT)
3-12
Both
U/L
>143 U/L (and Total 
Bilirubin > 43 
µmol/L)
ALT (SGPT)
≥13
Both
U/L
>239 U/L (and Total 
Bilirubin > 43 
µmol/L)
Haematology Values of Potential Clinical Concern
Laboratory 
Parameter
Age
Sex
Units
Clinical Concern 
Low Flag 
(< x)
Clinical Concern 
High Flag 
(> x)
Hematocrit
≥12
Both
Ratio of 1
0.201
0.599
Haemoglobin
≥12
Both
g/L
71
199
Platelet Count
≥1
Both
x109/ L
31
1499
While Blood Cell 
Count (WBC) / 
Leukocytes
≥12
Both
x109/ L
1.1


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11.9.
Appendix 9: Guidelines for Exacerbation Verification 
Process
Purpose
The purpose of this appendix is to describe the methodology to be used to determine if 
exacerbations recorded by the investigators (or designees) in InForm are based on 
objective assessments of asthma deterioration.  These evaluations will be made in a 
blinded manner. All exacerbations recorded in InForm will be compared with data 
collected in the eDiary and if necessary other pages in InForm.  This process will 
determine whether the exacerbation forms part of the primary endpoint analysis 
(clinically significant exacerbations).
It is expected that all exacerbations reported as such meet the basic protocol definition:
Worsening of asthma which requires use of systemic corticosteroids1 and/or 
hospitalisation and/or Emergency Department (ED) visits.
1For all subjects, IV or oral steroid (e.g., prednisone) for at least 3 days or a single IM 
corticosteroid dose is required. For subjects on maintenance systemic corticosteroids, at 
least double the existing maintenance dose for at least 3 days is required.
Responsibilities
The in-stream review will be performed by the medical monitor (or delegate) on the 
study. This review will be performed at approximately 3 month intervals during the 
study, and will be performed on all resolved exacerbations reported up to that point. The 
review will be done on complete data.
Prior to the review performed by the medical monitor (or delegate), the data will have 
undergone a clinical review to ensure it meets basic protocol criteria for an exacerbation
(stated above).
Guidelines
The intention-to-treat principle will be used in identifying events to be evaluated.  As a 
result, all cases will be reviewed whether or not the subject received randomized 
treatment and whether or not he/she continued to receive the randomized treatment for 
the planned duration of the study. Evaluations will be performed blinded to study 
treatment assignments.


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Evaluation Process
Clinically Significant Asthma Exacerbations
In order to provide an objective assessment of the circumstances linked to the clinical 
decision that defines asthma exacerbations, the investigator must take into account 
changes on one or more of the following parameters recorded in the subject’s eDiary:
•
decrease in morning peak flow
•
increase in the use of rescue medication
•
increase in the frequency of nocturnal awakening due to asthma symptoms 
requiring rescue medication use
•
increase in overall asthma symptom score
This clinical verification process is designed to verify that the exacerbations recorded by 
the investigator are associated with objective evidence, such as the eDiary parameters 
described above.
The following steps will be followed for verification of asthma exacerbations:
1. Clinical Review will initially be performed by the CIL (Clinical Investigation Leader) 
to evaluate each exacerbation to determine whether the event meets the protocol 
definition (shown above).  Follow up will be done with the Investigator in the event 
that data needs to be queried. This initial clinical review will be performed for all 
study Parts (pre-screen, A, B, C and D).
2. For exacerbations that start within study Parts B, C or D the medical monitor (or 
delegate) will review each exacerbation in InForm and verify the exacerbation against 
eDiary data (extracted from the ERT Portal), to confirm the exacerbation was 
associated with one of the following:
a.
Decreases in peak flow: 
i. as flagged by an alert in the eDiary (Decrease in morning PEF ≥30% 
on at least two of three successive days, compared with baseline) or;
ii. any other decrease judged by the medical monitor (or delegate) to be 
clinically significant
b. Increase in rescue medication use: 
i. as flagged by an alert in the eDiary (An increase of ≥50% in rescue 
medication on at least two of three successive days, compared with the 
average use for the previous week) or;
ii. any other increase judged by the medical monitor (or delegate) to be 
clinically significant (e.g. ≥4 puffs in 2 or more consecutive days)
c.
Increase in nocturnal awakenings due to asthma symptoms requiring use of 
rescue medication 
i. as flagged by an alert in the eDiary (Awakening due to asthma 
symptoms requiring rescue medication use for at least two of three 
successive nights) or;
ii. any other increase judged by the medical monitor (or delegate) to be 
clinically significant


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d. Changes in Asthma Symptoms (increase in overall asthma symptom score):
i. as flagged by an alert in the eDiary (A symptom score of 5 for at least 
two of three successive days) or;
ii. any other change judged by the medical monitor (or delegate) to be 
clinically significant (e.g. ≥4 during 2 or more consecutive days when 
baseline is 0)
No eDiary is provided to the subject prior to visit B1; therefore this and latter process 
steps will not be performed on exacerbations which start within the pre-screen period 
or Part A of the study.
3. The medical monitor (or delegate) will review data in the eDiary 10 days prior to the 
event start date and 5 days post the event start date. In exceptional circumstances data 
from outside this window may be considered adequate evidence.
4. If sufficient evidence was available within the eDiary data the medical monitor (or 
delegate) will confirm that the exacerbation is “clinically significant” within the CRF 
and will tick the relevant check-box (i.e. peak flow; rescue med use; nocturnal 
awakenings; asthma symptoms) based on the objective evidence available.
5. For each exacerbation for which objective evidence is not available in the eDiary data 
the medical monitor (or delegate) will follow up with the investigator to determine if 
there is alternative objective data (not in the eDiary) to support it being a “clinically 
significant” exacerbation.
6. A final decision will be made by the medical monitor on whether exacerbations with 
no supporting eDiary data but possibly other objective data can be included as part of 
the primary endpoint analysis  of “clinically significant” exacerbations.
7. If an exacerbation with no eDiary data to support it is deemed as having another 
source of objective evidence, the medical monitor (or delegate) will confirm that the 
exacerbation is “clinically significant” within the CRF and will update the comments 
section of the InForm adjudication page to clearly specify what evidence is 
supporting the decision.
8. In the event that the investigator is unable to provide objective evidence to support 
the exacerbation, then the event will be confirmed as an “Investigator- defined” 
exacerbation within the CRF. Frequencies of “Investigator- defined” exacerbations 
will be summarised within the analysis of efficacy .  
Documentation of Discussions with Investigator
In the event that the medical monitor (or delegate) has a discussion with the investigator 
about an exacerbation that does not have eDiary data to support it, the contact 
(telephone/email) should be documented with the following:

Date of conversation

Details of Discussion

Decision

Action Item
This documentation will be filed and archived as part of the central study file.


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11.10.
Appendix 10: Abbreviations & Trademarks
11.10.1.
Abbreviations
Abbreviation
Description
ACQ
Asthma Control Questionnaire
ADA
Anti-drug Antibody
ADaM
Analysis Data Model
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine Transaminase
AM
Morning (ante meridiem)
ASE
All Subjects Enrolled
AT
As Treated
ATC
Anatomical Therapeutic Chemical
BLQ
Below Limit of Quantification
BMI
Body Mass Index
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
CIL
Clinical Investigation Leader
CS
Corticosteroid
CSR
Clinical Study Report
CTR
Clinical Trial Register
CVT
Cardiac, Vascular and Thromboembolic
DBF
Database Freeze
DBR
Database Release
DOB
Date of Birth
DP
Decimal Places
ECG
Electrocardiogram
eCRF
Electronic Case Record Form
ED
Emergency Department
eDiary
Electronic Diary
EW
Early Withdrawal
FDAAA
Food and Drug Administration Clinical Results Disclosure Requirements
FEV1
Forced expiratory volume in 1 second
FVC
Forced Vital Capacity
GSK
GlaxoSmithKline
HbsAg
Hepatitis B Surface Antigen
ICH
International Conference on Harmonization
ICS
Inhaled Corticosteroids
IDSL
Integrated Data Standards Library
IG
Implementation Guide
IM
Intramuscular
IP
Investigational Product
IPDISC
Investigational Product Discontinuation
IRT
Interactive Response Technology
ITT
Intent-To-Treat
IV
Intravenous
kg
Kilograms
LABA
Long-acting beta-agonist


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Abbreviation
Description
LFT
Liver Function Test
LLQ
Lower Limit of Quantification
MMRM
Mixed Model Repeated Measures
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
mL
Milliliters
Nab
Neutralising Antibody
OCS
Oral Corticosteroids
PCI
Potential Clinical Importance 
PDMP
Protocol Deviation Management Plan
PEF
Peak Expiratory Flow
PP
Per Protocol
PSAP
Program Safety Analysis Plan
PT
Preferred Term
QC
Quality Control
QTcF
Frederica’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
RAMOS NG
Randomization & Medication Ordering System Next Generation
RAP
Reporting & Analysis Plan
RTF
Rich Text Format
SAC
Statistical Analysis Complete
SAE
Serious Adverse Event
SAS
Statistical Analysis Software
SC
Subcutaneous
SD
Standard Deviation
SDTM
Study Data Tabulation Model
SE
Standard Error
SGRQ
St. George’s Respiratory Questionnaire
SMQ
Standard MedDRA Query
SOC
System Organ Class
SRM
Study Reference Manual
TFL
Tables, Figures & Listings 
TMF
Trial Master File
TST
Therapeutic Standards Team
WBC
White Blood Cell
11.10.2.
Trademarks
Trademarks of the GlaxoSmithKline Group 
of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
None
SAS


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11.11.
Appendix 11: List of Data Displays
11.11.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Parts A/B
Section
Tables
Figures
Study Population
1.1 to 1.12
N/A
Efficacy
N/A
N/A
Safety
3.1 to 3.52
N/A
Part C
Section
Tables
Figures
Study Population
1.13 to 1.34
1.1
Efficacy
2.1 to 2.49
2.1 to 2.17
Safety
3.53 to 3.107
3.1 to 3.2
Part D
Section
Tables
Figures
Study Population
1.35 to 1.40
N/A
Efficacy
2.50
2.18
Safety
3.108 to 3.158
N/A
Listings
Section
Listings
ICH Listings
1 to 46
11.11.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays will be provided on request. 
11.11.3.
Deliverables
Delivery[1]
Description
SAC
Final Statistical Analysis Complete
NOTES: 
1.
Indicates priority (i.e. order) in which displays will be generated for the reporting effort


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11.11.4.
Study Parts A/B
11.11.4.1. Study Population Tables (Parts A/B)
Study Population Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Population Analysed
1.1.
ASE
ES4
Summary of Participant Disposition within Each Study Period
ICH E3
Presenting the number of subjects in 
each reporting period (Parts A/B, C, D)
SAC
1.2.
ASE
SHELL
Summary of Study Populations (Parts A/B)
IDSL
Include All Subjects Enrolled and As 
Treated (Parts A/B) Populations
Also include number of subjects 
entering immediately into Part A/Part B
SAC
Subject Disposition
1.3.
ASE
ES6
Summary of Screening Status and Reasons for Screen Failure (Parts 
A/B)
Journal Requirements
SAC
1.4.
ASE
IE2
Summary of Failed Inclusion/Exclusion/Continuation Criteria for Screen 
Failures (Parts A/B)
SAC
1.5.
AT (Part A/B)
IE2
Summary of Failed Inclusion/Exclusion/Continuation Criteria for 
Subjects within the As Treated Population (Parts A/B)
SAC
1.6.
AT (Part A/B)
ES8
Summary of Subject Status and Reason for Study Withdrawal (Parts 
A/B)
ICH E3, FDAAA, EudraCT
SAC
Medical Conditions
1.7.
AT (Part A/B)
MH4
Summary of Past Medical Conditions (Parts A/B)
ICH E3
SAC
1.8.
AT (Part A/B)
MH4
Summary of Current Medical Conditions (Parts A/B)
ICH E3
SAC
1.9.
AT (Part A/B)
FH1
Summary of Cardiovascular Assessments – Family History (Parts A/B)
Note: Family history in women <65 
years or men < 55 years (first degree 
relatives only).  Half siblings considered 
first degree relatives
SAC
1.10.
AT (Part A/B)
FH1
Summary of Cardiovascular Assessments – Screening Questions 
(Parts A/B)
SAC


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Study Population Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Protocol Deviation
1.11.
AT (Part A/B)
DV1
Summary of Important Protocol Deviations (Parts A/B)
ICH E3
SAC
Exposure
1.12.
AT (Part A/B)
SHELL
Summary of Exposure to Study Treatment (Parts A/B)
ICH E3
See Study Population Table 1.1 
(204471 ‘FINAL_01’ reporting effort)
SAC


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11.11.4.2. Safety Tables (Parts A/B)
Safety: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events (AEs)
3.1.
AT (Part A/B)
SHELL
Overview of Adverse Events (Parts A/B)
SAC
3.2.
AT (Part A/B)
AE1
Summary of On-Treatment Adverse Events by System Organ Class 
and Preferred Term (Parts A/B)
ICH E3
SAC
3.3.
AT (Part A/B)
AE5
Summary of On-Treatment Adverse Events by Maximum Intensity by 
System Organ Class and Preferred Term (Parts A/B)
ICH E3
Add a Total column across all severities
SAC
3.4.
AT (Part A/B)
AE3
Summary of Common (≥3%) On-treatment Adverse Events by Overall 
Frequency (Parts A/B)
ICH E3
≥3% (prior to rounding to nearest 
percent)
SAC
3.5.
AT (Part A/B)
AE1
Summary of On-Treatment Drug-Related Adverse Events by System 
Organ Class and Preferred Term (Parts A/B)
ICH E3
SAC
3.6.
AT (Part A/B)
AE5
Summary of On-Treatment Drug-Related Adverse Events by System 
Organ Class and Preferred Term and Maximum Intensity (Parts A/B)
Add a Total column across all severities
SAC
3.7.
AT (Part A/B)
SHELL
Summary of On-Treatment Adverse Events by Age Group (12-17, 18-
64, ≥65 years) (Parts A/B)
SAC
3.8.
AT (Part A/B)
SHELL
Summary of On-Treatment Adverse Events by Highest Anti Drug 
Antibody Result At Any Time On-Treatment (Parts A/B)
SAC
3.9.
AT (Part A/B)
AE15
Summary of Common (≥3%) Non-serious On-Treatment Adverse 
Events by System Organ Class and Preferred Term (Number of 
Subjects and Occurrences) (Parts A/B)
FDAAA, EudraCT
≥3% (prior to rounding to nearest 
percent)
SAC
3.10.
AT (Part A/B)
AE1
Summary of On-Treatment Drug-Related Non-Serious Adverse Events 
by System Organ Class and Preferred Term (Parts A/B)
Table required for plain language 
summary
SAC
Serious and Other Significant Adverse Events
3.11.
AT (Part A/B)
AE1
Summary of Pre-Treatment Serious Adverse Events by System Organ 
Class and Preferred Term (Parts A/B)
SAC


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Safety: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.12.
AT (Part A/B)
AE1
Summary of On-Treatment Serious Adverse Events by System Organ 
Class and Preferred Term (Parts A/B)
SAC
3.13.
AT (Part A/B)
SHELL
Summary of On-Treatment Serious Adverse Events by Age Group (12-
17, 18-64, ≥65 years) (Parts A/B)
SAC
3.14.
AT (Part A/B)
AE1
Summary of On-Treatment Fatal Serious Adverse Events (Parts A/B)
SAC
3.15.
AT (Part A/B)
SHELL
Summary of On-Treatment Fatal Serious Adverse Events by Age 
Group (12-17, 18-64, ≥65 years) (Parts A/B)
SAC
3.16.
AT (Part A/B)
AE1
Summary of On-Treatment Non-Fatal Serious Adverse Events by 
System Organ Class and Preferred Term (Parts A/B)
SAC
3.17.
AT (Part A/B)
AE1
Summary of On-Treatment Drug-Related Serious Adverse Events by 
System Organ Class and Preferred Term (Parts A/B)
Table required for plain language 
summary
SAC
3.18.
AT (Part A/B)
AE1
Summary of On-Treatment Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study by 
System Organ Class and Preferred Term (Parts A/B)
IDSL
SAC
3.19.
AT (Part A/B)
AE16
Summary of On-Treatment Serious Adverse Events by System Organ 
Class and Preferred Term (Number of Subjects and Occurrences)
(Parts A/B)
FDAAA, EudraCT
SAC
Adverse Events of Special Interest
3.20.
AT (Part A/B)
SHELL
Summary of On-treatment Serious Adverse Events and Adverse 
Events of Special Interest (Parts A/B)
SAC
3.21.
AT (Part A/B)
AE1
Summary of On-Treatment Systemic Reactions Meeting Anaphylaxis 
Criteria (Parts A/B)
Present by Anaphylactic Criterion 1, 2 
and 3 rather than SOC as shown in 
AE1
Insert footnote: “Events displayed are a 
subset of reactions defined by the 
Investigator as being systemic”
SAC


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Safety: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.22.
AT (Part A/B)
SHELL
Summary Profile of On-Treatment Systemic Reactions Meeting 
Anaphylaxis Criteria (Parts A/B)
Insert footnote: “Events displayed are a 
subset of reactions defined by the 
Investigator as being systemic”
SAC
3.23.
AT (Part A/B)
AE1
Summary of On-Treatment Adverse Events Defined by the Investigator 
as Being Systemic (non-allergic or allergic/hypersensitivity) Reactions
(Parts A/B)
SAC
3.24.
AT (Part A/B)
SHELL
Summary Profile of On-Treatment Systemic (non-allergic or 
allergic/hypersensitivity) Reactions (Parts A/B)
SAC
3.25.
AT (Part A/B)
SHELL
Summary Profile of On-Treatment Systemic Allergic Reactions (Parts 
A/B)
SAC
3.26.
AT (Part A/B)
SHELL
Summary Profile of On-Treatment Systemic Non-Allergic Reactions
(Parts A/B)
SAC
3.27.
AT (Part A/B)
AE1
Summary of On-Treatment Adverse Events Defined by the Investigator 
as being Local Injection Site Reactions (Parts A/B)
SAC
3.28.
AT (Part A/B)
SHELL
Summary Profile of On-Treatment Local Injection Site Reactions (Parts 
A/B)
SAC
3.29.
AT (Part A/B)
AE1
Summary of On-Treatment Opportunistic Infections (Parts A/B)
SAC
3.30.
AT (Part A/B)
SHELL
Summary Profile of On-Treatment Opportunistic Infections (Parts A/B)
SAC
3.31.
AT (Part A/B)
AE1
Summary of On-Treatment Malignancies (Parts A/B)
SAC
3.32.
AT (Part A/B)
SHELL
Summary Profile of On-Treatment Malignancies (Parts A/B)
SAC
3.33.
AT (Part A/B)
AE1
Summary of On-Treatment Serious Cardiac, Vascular and 
Thromboembolic Adverse Events (Parts A/B)
SAC
3.34.
AT (Part A/B)
SHELL
Summary Profile of On-Treatment Serious Cardiac, Vascular and 
Thromboembolic Adverse Events (Parts A/B)
SAC
3.35.
AT (Part A/B)
AE1
Summary of On-Treatment Serious Ischemic Adverse Events (Parts 
A/B)
SAC


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Safety: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.36.
AT (Part A/B)
SHELL
Summary Profile of On-Treatment Serious Ischemic Adverse Events
(Parts A/B)
SAC
Cardiovascular Events and Deaths (All Causes)
3.37.
AT (Part A/B)
SHELL
Summary of Cardiovascular Events and Deaths (All Causes) Reported 
by the Investigator (On-Treatment, Parts A/B)
SAC
Laboratory: Chemistry
3.38.
AT (Part A/B)
LB1
Summary of Chemistry Changes from Baseline (On-Treatment, Parts 
A/B)
ICH E3
Includes Baseline values.
SAC
3.39.
AT (Part A/B)
LB3
Summary of Chemistry Results (Changes from Baseline Relative to the 
Normal Range) (On-Treatment, Parts A/B)
ICH E3
SAC
3.40.
AT (Part A/B)
LB3
Summary of Chemistry Results (Changes from Baseline Relative to the 
Reference Range [Potential Clinical Importance]) (On-Treatment, Parts 
A/B)
ICH E3
SAC
Laboratory: Haematology
3.41.
AT (Part A/B)
LB1
Summary of Haematology Changes from Baseline (On-Treatment, 
Parts A/B)
ICH E3
Includes baseline values.
SAC
3.42.
AT (Part A/B)
LB3
Summary of Haematology Results (Changes from Baseline Relative to 
the Normal Range) (On-Treatment, Parts A/B)
ICH E3
SAC
3.43.
AT (Part A/B)
LB3
Summary of Haematology Results (Changes from Baseline Relative to 
the Reference Range [Potential Clinical Importance]) (On-Treatment, 
Parts A/B)
ICH E3
SAC
Laboratory: Hepatobiliary (Liver)
3.44.
AT (Part A/B)
LIVER10
Summary of Hepatobiliary Laboratory Abnormalities (On-Treatment, 
Parts A/B)
IDSL
SAC
ECG
3.45.
AT (Part A/B)
EG1
Summary of ECG Findings (On-Treatment, Parts A/B)
IDSL
SAC


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Safety: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.46.
AT (Part A/B)
EG2
Summary of Change from Baseline in ECG Values by Visit (On-
Treatment, Parts A/B)
IDSL
Includes Baseline values.
SAC
3.47.
AT (Part A/B)
SHELL
Summary of Actual and Change From Baseline QTc(F) Values by 
Category (msec) (On-Treatment, Parts A/B)
SAC
3.48.
AT (Part A/B)
SHELL
Summary of Actual and Change From Baseline QTc(B) Values by 
Category (msec) (On-Treatment, Parts A/B)
SAC
Vital Signs
3.49.
AT (Part A/B)
VS1
Summary of Change from Baseline in Vital Signs (On-Treatment, Parts 
A/B)
ICH E3
Includes Baseline values.
SAC
Immunogenicity
3.50.
AT (Part A/B)
SHELL
Summary of ADA Assay Results (On-Treatment, Parts A/B)
SAC
3.51.
AT (Part A/B)
SHELL
Summary of Treatment Emergent ADA Assay Results (On-Treatment, 
Parts A/B)
SAC
3.52.
AT (Part A/B)
SHELL
Summary of NAb Assay Results (On-Treatment, Parts A/B)
SAC


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11.11.5.
Part C
11.11.5.1. Study Population Tables (Part C)
Study Population Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Population Analysed
1.13.
ASE
SHELL
Summary of Study Populations (Part C)
IDSL
Include Randomized, Intent-to-Treat 
(Part C) and Per-Protocol Populations
SAC
Subject Disposition
1.14.
ASE
ES6
Summary of Run-in Status and Reasons for Run-in Failure (Part C)
Journal Requirements
SAC
1.15.
ASE
IE2
Summary of Failed Randomization Inclusion/Exclusion Criteria for Run-
in Failures (Part C)
SAC
1.16.
ITT (Part C)
IE2
Summary of Failed Randomization Inclusion/Exclusion Criteria for 
Subjects within the Intent-to-Treat Population (Part C)
SAC
1.17.
ITT (Part C)
ES8
Summary of Subject Status and Reason for Study Withdrawal (Part C)
ICH E3, FDAAA, EudraCT
SAC
1.18.
ITT (Part C)
SD1
Summary of Treatment Status and Reasons for Discontinuation of 
Study Treatment (Part C)
ICH E3
SAC
1.19.
ITT (Part C)
SHELL
Summary of Attendance at Each Clinic Visit (Part C)
SAC
1.20.
ITT (Part C)
SHELL
Summary of Visit Where Subject Switched To Open-Label 
Mepolizumab Treatment within Part D (Part C)
SAC
Demographics
1.21.
ITT (Part C)
DM1
Summary of Demographic Characteristics (Part C)
ICH E3, FDAAA, EudraCT
SAC
1.22.
ITT (Part C)
DM5
Summary of Race and Racial Combinations (Part C)
ICH E3, FDA, FDAAA, EudraCT
SAC
1.23.
ITT (Part C)
NS1
Summary of Number of Subjects by Region, Country and Site (Part C)
EudraCT/Clinical Operations
Add total for regions and a total for 
country
SAC
Smoking Status
1.24.
ITT (Part C)
SU1
Summary of History of Tobacco Use (Part C)
SAC


CONFIDENTIAL
201810
2019N395455_00
90
Study Population Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Baseline Disease Characteristics
1.25.
ITT (Part C)
SHELL
Summary of Asthma History and Baseline Disease Characteristics
(Part C)
Include disease duration, Asthma 
Disease Characteristics (ATS Criteria), 
prior intubations related to asthma and 
maintenance OCS use
SAC
1.26.
ITT (Part C)
SHELL
Summary of Previous Exacerbation History (Part C)
Include number or preview 
exacerbations and reasons/causes of 
exacerbation
SAC
1.27.
ITT (Part C)
SHELL
Summary of Baseline Lung Function Tests (Part C)
Include FEV1, %Predicted FEV, FVC, 
FEV/FVC and Reversibility
SAC
Concomitant Medications
1.28.
ITT (Part C)
CM1
Summary of Asthma Concomitant Medications Taken at Visit C1 by 
Respiratory Medication Class Group (Part C)
ICH E3
Footnote: Multi-component medications 
displayed under the respiratory 
medication class of each component
Programming note: Display RMC and 
ingredient as per previous Asthma 
studies
SAC
1.29.
ITT (Part C)
CM1
Summary of Asthma Concomitant Medications Taken During 
Treatment by Respiratory Medication Class Group (Part C)
ICH E3
Footnote: Multi-component medications 
displayed under the respiratory 
medication class of each component
Programming note: Display RMC and 
ingredient as per previous Asthma 
studies
SAC
1.30.
ITT (Part C)
CM1
Summary of Non-Asthma Medications Taken During Treatment (Part 
C)
ICH E3
Footnote: Medications may be 
displayed under more than one ATC 
classification
SAC
Protocol Deviation
1.31.
ITT (Part C)
DV1
Summary of Important Protocol Deviations (Part C)
ICH E3
SAC
1.32.
ITT (Part C)
SP2
Summary of Exclusions from the Per Protocol Population (Part C)
IDSL
SAC


CONFIDENTIAL
201810
2019N395455_00
91
Study Population Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Continuous Exposure to Mepolizumab Prior to Randomization
1.33.
ITT (Part C)
SHELL
Summary of Continuous Exposure to Mepolizumab (Therapeutic 
Coverage) Prior to Randomization at Visit C1 (Part C)
See Study Population Table 2.1 
(201312 ‘FINAL’ reporting effort)
Exposure
1.34.
ITT (Part C)
SHELL
Summary of Exposure to Study Treatment (Part C)
ICH E3
See Study Population Table 1.1 
(204471 ‘FINAL_01’ reporting effort)
SAC
11.11.5.2. Study Population Figures (Part C)
Study Population Figures
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.1.
ITT (Part C)
SHELL
Time to Subject Withdrawal From Investigation Product (Part C)
See Study Population Figure 1.1 
(204471 ‘FINAL_01’ reporting effort)
SAC


CONFIDENTIAL
201810
2019N395455_00
92
11.11.5.3. Efficacy Tables (Part C)
Efficacy: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Exacerbations
2.1.
ITT (Part C)
SHELL
Overview of All Exacerbations (Part C)
SAC
2.2.
ITT (Part C)
SHELL
Summary of Frequency of Clinically Significant Exacerbations (Part C)
SAC
2.3.
ITT (Part C)
SHELL
Analysis of Time to First Clinically Significant Exacerbation (Part C)
SAC
2.4.
PP (Part C)
SHELL
Analysis of Time to First Clinically Significant Exacerbation (Part C)
Per protocol supportive analysis
SAC
2.5.
ITT (Part C)
SHELL
Analysis of Time to First Clinically Significant Exacerbation by Age (12-
17, 18-64, ≥65 years) (Part C)
SAC
2.6.
ITT (Part C)
SHELL
Analysis of Time to First Clinically Significant Exacerbation by Sex
(Part C)
SAC
2.7.
ITT (Part C)
SHELL
Analysis of Time to First Clinically Significant Exacerbation by Weight 
(<75kg, ≥75kg) (Part C)
SAC
2.8.
ITT (Part C)
SHELL
Analysis of Time to First Clinically Significant Exacerbation by Region 
(Europe, Rest of World) (Part C)
SAC
2.9.
ITT (Part C)
SHELL
Analysis of Time to First Clinically Significant Exacerbation by 
Exacerbations in the Year Prior to Randomization (0, 1, ≥2) (Part C)
SAC
2.10.
ITT (Part C)
SHELL
Analysis of Time to First Clinically Significant Exacerbation by 
Maintenance OCS Use (Part C)
SAC
2.11.
ITT (Part C)
SHELL
Analysis of Time to First Clinically Significant Exacerbation by Baseline 
Blood Eosinophils (<0.50, ≥0.50-<0.10, ≥0.10-<0.15, ≥0.15 GI/L) (Part 
C)
SAC
2.12.
ITT (Part C)
SHELL
Analysis of Time to First Clinically Significant Exacerbation by Baseline 
Anti-Drug Antibody (ADA) Status (Part C)
SAC
2.13.
ITT (Part C)
SHELL
Summary of Frequency of Exacerbations Requiring Hospitalisation or 
Emergency Department visit (Part C)
SAC


CONFIDENTIAL
201810
2019N395455_00
93
Efficacy: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.14.
ITT (Part C)
SHELL
Analysis of Time to First Exacerbation Requiring Hospitalisation or 
Emergency Department visit (Part C)
SAC
2.15.
ITT (Part C)
SHELL
Summary of Frequency of Exacerbations Requiring Hospitalisation
(Part C)
SAC
2.16.
ITT (Part C)
SHELL
Analysis of Time to First Exacerbation Requiring Hospitalisation (Part 
C)
SAC
Blood Eosinophils
2.17.
ITT (Part C)
SHELL
Summary of Blood Eosinophils (109/L) (Part C)
SAC
2.18.
ITT (Part C)
SHELL
Analysis of Ratio to Baseline in Blood Eosinophils (109/L) (Part C)
SAC
Asthma Control Questionnaire (ACQ-5)
2.19.
ITT (Part C)
SHELL
Summary of Asthma Control Questionnaire (ACQ-5) Score (Part C)
SAC
2.20.
ITT (Part C)
SHELL
Analysis of Change from Baseline in Asthma Control Questionnaire 
(ACQ-5) Score (Part C)
SAC
2.21.
ITT (Part C)
SHELL
Analysis of Time to First 0.5 Point or More Increase in ACQ-5 Score 
from Baseline (Part C)
SAC
2.22.
ITT (Part C)
SHELL
Summary and Analysis of 0.5 Point or More Increase in ACQ-5 Score 
from Baseline (Part C)
SAC
St George’s Respiratory Questionnaire (SGRQ)
2.23.
ITT (Part C)
SHELL
Summary of St. George's Respiratory Questionnaire (SGRQ) Total 
Score (Part C)
SAC
2.24.
ITT (Part C)
SHELL
Analysis of Change From Baseline in St. George's Respiratory 
Questionnaire (SGRQ) Total Score (Part C)
SAC
2.25.
ITT (Part C)
SHELL
Summary of St. George's Respiratory Questionnaire (SGRQ) Symptom 
Domain Score (Part C)
SAC
2.26.
ITT (Part C)
SHELL
Analysis of Change From Baseline in St. George's Respiratory 
Questionnaire (SGRQ) Symptom Domain Score (Part C)
SAC


CONFIDENTIAL
201810
2019N395455_00
94
Efficacy: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.27.
ITT (Part C)
SHELL
Summary of St. George's Respiratory Questionnaire (SGRQ) Activity 
Domain Score (Part C)
SAC
2.28.
ITT (Part C)
SHELL
Analysis of Change From Baseline in St. George's Respiratory 
Questionnaire (SGRQ) Activity Domain Score (Part C)
SAC
2.29.
ITT (Part C)
SHELL
Summary of St. George's Respiratory Questionnaire (SGRQ) Impacts 
Domain Score (Part C)
SAC
2.30.
ITT (Part C)
SHELL
Analysis of Change From Baseline in St. George's Respiratory 
Questionnaire (SGRQ) Impacts Domain Score (Part C)
SAC
2.31.
ITT (Part C)
SHELL
Summary and Analysis of 4 Point or More Improvement in SGRQ Total 
Score From Baseline (Part C)
SAC
Spirometry
2.32.
ITT (Part C)
SHELL
Summary of Clinic Pre-Bronchodilator FEV1 (mL) (Part C)
SAC
2.33.
ITT (Part C)
SHELL
Analysis of Change From Baseline in Clinic Pre-Bronchodilator FEV1 
(mL) (Part C)
SAC
2.34.
ITT (Part C)
SHELL
Summary of Clinic Post-Bronchodilator FEV1 (mL) (Part C)
SAC
2.35.
ITT (Part C)
SHELL
Analysis of Change From Baseline in Clinic Post-Bronchodilator FEV1 
(mL) (Part C)
SAC
Global Impression of Asthma Severity Rating
2.36.
ITT (Part C)
SHELL
Summary and Analysis of Subject Global Impression of Asthma 
Severity Rating (Part C)
SAC
2.37.
ITT (Part C)
SHELL
Summary of Shift From Baseline in Subject Global Impression of 
Asthma Severity Rating (Part C)
SAC
2.38.
ITT (Part C)
SHELL
Summary and Analysis of Clinician Global Impression of Asthma 
Severity Rating (Part C)
SAC
2.39.
ITT (Part C)
SHELL
Summary of Shift From Baseline in Clinician Global Impression of 
Asthma Severity Rating (Part C)
SAC


CONFIDENTIAL
201810
2019N395455_00
95
Efficacy: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Rating of Response to Therapy
2.40.
ITT (Part C)
SHELL
Summary and Analysis of Subject Rated Overall Evaluation of 
Response to Therapy (Part C)
SAC
2.41.
ITT (Part C)
SHELL
Summary and Analysis of Clinician Rated Overall Evaluation of 
Response to Therapy (Part C)
SAC
eDiary Parameters
2.42.
ITT (Part C)
SHELL
Summary of Daily Salbutamol/Albuterol Use (occasions/day) by 4-
Week Period (Part C)
SAC
2.43.
ITT (Part C)
SHELL
Summary of Daily Asthma Symptom Scores by 4-Week Period (Part C)
SAC
2.44.
ITT (Part C)
SHELL
Summary of Awakening at Night Due to Asthma Symptoms Requiring 
Rescue Medication Use by 4-Week Period (Part C)
SAC
2.45.
ITT (Part C)
SHELL
Summary of Morning Peak Expiratory Flow (PEF) by 4-Week Period 
(L/min) (Part C)
SAC
2.46.
ITT (Part C)
SHELL
Analysis of Time to First Worsening of Asthma Defined by Daily eDiary 
Parameters (Part C)
Footnote: Subjects meeting at least 2 of 
the possible 4 criteria for worsening of 
asthma for at least 2 consecutive days
SAC
Number of Days in Hospital Due to Asthma
2.47.
ITT (Part C)
SHELL
Summary of Days in Hospital Due to Asthma Symptoms (Part C)
SAC
Unscheduled Healthcare Contacts/Resource Utilization
2.48.
ITT (Part C)
SHELL
Summary of Unscheduled Healthcare Resource Use (Part C)
Separate pages for:
1) use associated with an exacerbation
2) use not associated with an 
exacerbation, 3) total resource use
SAC
Number of Days off Work/School
2.49.
ITT (Part C)
SHELL
Summary of Days Off Work/School Due to Asthma Symptoms (Part C)
SAC


CONFIDENTIAL
201810
2019N395455_00
96
11.11.5.4. Efficacy Figures (Part C)
Efficacy: Figures
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Exacerbations
2.1.
ITT (Part C)
SHELL
Kaplan-Meier Cumulative Incidence Curve for Time to First Clinically 
Significant Exacerbation (Part C)
SAC
2.2.
ITT (Part C)
SHELL
Kaplan-Meier Cumulative Incidence Curve for Time to First 
Exacerbation Requiring Hospitalisation or Emergency Department visit
(Part C)
SAC
2.3.
ITT (Part C)
SHELL
Kaplan-Meier Cumulative Incidence Curve for Time to First 
Exacerbation Requiring Hospitalisation (Part C)
SAC
2.4.
ITT (Part C)
SHELL
Figure of Hazard Ratio (Mepolizumab/Placebo) from Analysis of Time 
to First Exacerbation (Part C)
SAC
Blood Eosinophils
2.5.
ITT (Part C)
SHELL
Figure of Analysis of Ratio to Baseline in Blood Eosinophils (Adjusted 
Mean at Each Visit by Treatment Group) (Part C)
SAC
2.6.
ITT (Part C)
SHELL
Figure of Analysis of Blood Eosinophils (Difference Between Treatment 
Groups in Ratio to Baseline at Each Visit) (Part C)
SAC
Asthma Control Questionnaire (ACQ-5)
2.7.
ITT (Part C)
SHELL
Figure of Analysis of Change from Baseline in ACQ-5 Score (Adjusted 
Mean at Each Visit by Treatment Group) (Part C)
SAC
2.8.
ITT (Part C)
SHELL
Figure of Analysis of ACQ-5 Score (Difference Between Treatment 
Groups in Mean Change from Baseline at Each Visit) (Part C)
SAC
2.9.
ITT (Part C)
SHELL
Kaplan-Meier Cumulative Incidence Curve for Time to First 0.5 Point or 
More Increase in ACQ-5 Score from Baseline (Part C)
SAC
St George’s Respiratory Questionnaire (SGRQ)
2.10.
ITT (Part C)
SHELL
Figure of Analysis of Change from Baseline in SGRQ Total Score 
(Adjusted Mean at Each Visit by Treatment Group) (Part C)
SAC


CONFIDENTIAL
201810
2019N395455_00
97
Efficacy: Figures
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
2.11.
ITT (Part C)
SHELL
Figure of Analysis of SGRQ Total Score (Difference Between 
Treatment Groups in Adjusted Mean Change from Baseline at Each 
Visit) (Part C)
SAC
2.12.
ITT (Part C)
SHELL
Figure of Analyses of SGRQ by Domain (Difference Between 
Treatment Groups in Adjusted Mean Change from Baseline at Each 
Visit) (Part C)
SAC
Spirometry
2.13.
ITT (Part C)
SHELL
Figure of Analysis of Change from Baseline in Pre-bronchodilator 
FEV1 (mL) (Adjusted Mean at Each Visit by Treatment Group) (Part C)
SAC
2.14.
ITT (Part C)
SHELL
Figure of Analysis of Pre-Bronchodilator FEV1 (mL) (Difference 
Between Treatment Groups in Adjusted Mean Change from Baseline 
at Each Visit) (Part C)
SAC
2.15.
ITT (Part C)
SHELL
Figure of Analysis of Change from Baseline in Post-bronchodilator 
FEV1 (mL) (Adjusted Mean at Each Visit by Treatment Group) (Part C)
SAC
2.16.
ITT (Part C)
SHELL
Figure of Analysis of Post -Bronchodilator FEV1 (mL) (Difference 
Between Treatment Groups in Adjusted Mean Change from Baseline 
at Each Visit) (Part C)
SAC
eDiary Parameters
2.17.
ITT (Part C)
SHELL
Kaplan-Meier Cumulative Incidence Curve for Time to First Worsening 
of Asthma Defined by Daily eDiary Parameters (Part C)
Footnote: Subjects meeting at least 2 of 
the possible 4 criteria for worsening of 
asthma for at least 2 consecutive days
SAC


CONFIDENTIAL
201810
2019N395455_00
98
11.11.5.5. Safety Tables (Part C)
Safety: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events (AEs)
3.53.
ITT (Part C)
SHELL
Overview of Adverse Events (Part C)
SAC
3.54.
ITT (Part C)
AE1
Summary of On-Treatment Adverse Events by System Organ Class 
and Preferred Term (Part C)
ICH E3
SAC
3.55.
ITT (Part C)
AE5
Summary of On-Treatment Adverse Events by Maximum Intensity by 
System Organ Class and Preferred Term (Part C)
ICH E3
Add a Total column across all severities
SAC
3.56.
ITT (Part C)
SHELL
Summary of Exposure Adjusted On-Treatment Adverse Events by 
System Organ Class and Preferred Term (Part C)
SAC
3.57.
ITT (Part C)
AE3
Summary of Common (≥3%) On-treatment Adverse Events by Overall 
Frequency (Part C)
ICH E3
≥3% (prior to rounding to nearest 
percent)
SAC
3.58.
ITT (Part C)
SHELL
Summary of Exposure Adjusted On-Treatment Common (≥3%) 
Adverse Events by System Organ Class and Preferred Term (Part C)
≥3% (prior to rounding to nearest 
percent)
SAC
3.59.
ITT (Part C)
AE1
Summary of On-Treatment Drug-Related Adverse Events by System 
Organ Class and Preferred Term (Part C)
ICH E3
SAC
3.60.
ITT (Part C)
AE5
Summary of On-Treatment Drug-Related Adverse Events by System 
Organ Class and Preferred Term and Maximum Intensity (Part C)
Add a Total column across all severities
SAC
3.61.
ITT (Part C)
SHELL
Summary of Exposure Adjusted On-Treatment Drug-Related Adverse 
Events by System Organ Class and Preferred Term (Part C)
SAC
3.62.
ITT (Part C)
SHELL
Summary of On-Treatment Adverse Events by Age Group (12-17, 18-
64, ≥65 years) (Part C)
SAC
3.63.
ITT (Part C)
SHELL
Summary of On-Treatment Adverse Events by Highest Anti Drug 
Antibody Result At Any Time On-Treatment (Part C)
SAC


CONFIDENTIAL
201810
2019N395455_00
99
Safety: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.64.
ITT (Part C)
AE15
Summary of Common (≥3%) Non-serious On-Treatment Adverse 
Events by System Organ Class and Preferred Term (Number of 
Subjects and Occurrences) (Part C)
FDAAA, EudraCT
≥3% (prior to rounding to nearest 
percent)
SAC
3.65.
ITT (Part C)
AE1
Summary of On-Treatment Drug-Related Non-Serious Adverse Events 
by System Organ Class and Preferred Term (Part C)
Table required for plain language 
summary
SAC
Serious and Other Significant Adverse Events
3.66.
ITT (Part C)
AE1
Summary of On-Treatment Serious Adverse Events by System Organ 
Class and Preferred Term (Part C)
SAC
3.67.
ITT (Part C)
SHELL
Summary of Exposure Adjusted On-Treatment Serious Adverse Events 
by System Organ Class and Preferred Term (Part C)
SAC
3.68.
ITT (Part C)
SHELL
Summary of On-Treatment Serious Adverse Events by Age Group (12-
17, 18-64, ≥65 years) (Part C)
SAC
3.69.
ITT (Part C)
AE1
Summary of On-Treatment Fatal Serious Adverse Events (Part C)
SAC
3.70.
ITT (Part C)
SHELL
Summary of On-Treatment Fatal Serious Adverse Events by Age 
Group (12-17, 18-64, ≥65 years) (Part C)
SAC
3.71.
ITT (Part C)
AE1
Summary of On-Treatment Non-Fatal Serious Adverse Events by 
System Organ Class and Preferred Term (Part C)
SAC
3.72.
ITT (Part C)
AE1
Summary of On-Treatment Drug-Related Serious Adverse Events by 
System Organ Class and Preferred Term (Part C)
Table required for plain language 
summary
SAC
3.73.
ITT (Part C)
AE1
Summary of On-Treatment Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study by 
System Organ Class and Preferred Term (Part C)
IDSL
SAC
3.74.
ITT (Part C)
AE16
Summary of On-Treatment Serious Adverse Events by System Organ 
Class and Preferred Term (Number of Subjects and Occurrences)
(Part C)
FDAAA, EudraCT
SAC


CONFIDENTIAL
201810
2019N395455_00
100
Safety: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events of Special Interest
3.75.
ITT (Part C)
SHELL
Summary of On-treatment Serious Adverse Events and Adverse 
Events of Special Interest (Incidence, Relative Risk and Risk 
Difference) (Part C)
SAC
3.76.
ITT (Part C)
AE1
Summary of On-Treatment Systemic Reactions Meeting Anaphylaxis 
Criteria (Part C)
Present by Anaphylactic Criterion 1, 2 
and 3 rather than SOC as shown in 
AE1
Insert footnote: “Events displayed are a 
subset of reactions defined by the 
Investigator as being systemic”
SAC
3.77.
ITT (Part C)
SHELL
Summary Profile of On-Treatment Systemic Reactions Meeting 
Anaphylaxis Criteria (Part C)
Insert footnote: “Events displayed are a 
subset of reactions defined by the 
Investigator as being systemic”
SAC
3.78.
ITT (Part C)
AE1
Summary of On-Treatment Adverse Events Defined by the Investigator 
as Being Systemic (non-allergic or allergic/hypersensitivity) Reactions
(Part C)
SAC
3.79.
ITT (Part C)
SHELL
Summary Profile of On-Treatment Systemic (non-allergic or 
allergic/hypersensitivity) Reactions (Part C)
SAC
3.80.
ITT (Part C)
SHELL
Summary Profile of On-Treatment Systemic Allergic Reactions (Part C)
SAC
3.81.
ITT (Part C)
SHELL
Summary Profile of On-Treatment Systemic Non-Allergic Reactions
(Part C)
SAC
3.82.
ITT (Part C)
AE1
Summary of On-Treatment Adverse Events Defined by the Investigator 
as being Local Injection Site Reactions (Part C)
SAC
3.83.
ITT (Part C)
SHELL
Summary Profile of On-Treatment Local Injection Site Reactions (Part 
C)
SAC
3.84.
ITT (Part C)
AE1
Summary of On-Treatment Opportunistic Infections (Part C)
SAC
3.85.
ITT (Part C)
SHELL
Summary Profile of On-Treatment Opportunistic Infections (Part C)
SAC
3.86.
ITT (Part C)
AE1
Summary of On-Treatment Malignancies (Part C)
SAC


CONFIDENTIAL
201810
2019N395455_00
101
Safety: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.87.
ITT (Part C)
SHELL
Summary Profile of On-Treatment Malignancies (Part C)
SAC
3.88.
ITT (Part C)
AE1
Summary of On-Treatment Serious Cardiac, Vascular and 
Thromboembolic Adverse Events (Part C)
SAC
3.89.
ITT (Part C)
SHELL
Summary Profile of On-Treatment Serious Cardiac, Vascular and 
Thromboembolic Adverse Events (Part C)
SAC
3.90.
ITT (Part C)
AE1
Summary of On-Treatment Serious Ischemic Adverse Events (Part C)
SAC
3.91.
ITT (Part C)
SHELL
Summary Profile of On-Treatment Serious Ischemic Adverse Events
(Part C)
SAC
Cardiovascular Events and Deaths (All Causes)
3.92.
ITT (Part C)
SHELL
Summary of Cardiovascular Events and Deaths (All Causes) Reported 
by the Investigator (On-Treatment, Part C)
SAC
Laboratory: Chemistry
3.93.
ITT (Part C)
LB1
Summary of Chemistry Changes from Baseline (On-Treatment, Part C)
ICH E3
Includes Baseline values.
SAC
3.94.
ITT (Part C)
LB3
Summary of Chemistry Results (Changes from Baseline Relative to the 
Normal Range) (On-Treatment, Part C)
ICH E3
SAC
3.95.
ITT (Part C)
LB3
Summary of Chemistry Results (Changes from Baseline Relative to the 
Reference Range [Potential Clinical Importance]) (On-Treatment, Part 
C)
ICH E3
SAC
Laboratory: Haematology
3.96.
ITT (Part C)
LB1
Summary of Haematology Changes from Baseline (On-Treatment, Part 
C)
ICH E3
Includes baseline values.
SAC
3.97.
ITT (Part C)
LB3
Summary of Haematology Results (Changes from Baseline Relative to 
the Normal Range) (On-Treatment, Part C)
ICH E3
SAC
3.98.
ITT (Part C)
LB3
Summary of Haematology Results (Changes from Baseline Relative to 
the Reference Range [Potential Clinical Importance]) (On-Treatment, 
Part C)
ICH E3
SAC


CONFIDENTIAL
201810
2019N395455_00
102
Safety: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Laboratory: Hepatobiliary (Liver)
3.99.
ITT (Part C)
LIVER10
Summary of Hepatobiliary Laboratory Abnormalities (On-Treatment, 
Part C)
IDSL
SAC
ECG
3.100.
ITT (Part C)
EG1
Summary of ECG Findings (On-Treatment, Part C)
IDSL
SAC
3.101.
ITT (Part C)
EG2
Summary of Change from Baseline in ECG Values by Visit (On-
Treatment, Part C)
IDSL
Includes Baseline values.
SAC
3.102.
ITT (Part C)
SHELL
Summary of Actual and Change From Baseline QTc(F) Values by 
Category (msec) (On-Treatment, Part C)
SAC
3.103.
ITT (Part C)
SHELL
Summary of Actual and Change From Baseline QTc(B) Values by 
Category (msec) (On-Treatment, Part C)
SAC
Vital Signs
3.104.
ITT (Part C)
VS1
Summary of Change from Baseline in Vital Signs (On-Treatment, Part 
C)
ICH E3
Includes Baseline values.
SAC
Immunogenicity
3.105.
ITT (Part C)
SHELL
Summary of ADA Assay Results (On-Treatment, Part C)
SAC
3.106.
ITT (Part C)
SHELL
Summary of Treatment Emergent ADA Assay Results (On-Treatment, 
Part C)
SAC
3.107.
ITT (Part C)
SHELL
Summary of NAb Assay Results (On-Treatment, Part C)
SAC


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11.11.5.6. Safety Figures (Part C)
Safety: Figures
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events
3.1.
ITT (Part C)
AE10
Plot of Common (≥3%) On-treatment Adverse Events and Relative 
Risk (Part C)
IDSL
≥3% (prior to rounding to nearest 
percent)
SAC
3.2.
ITT (Part C)
SHELL
Figure of On-treatment Serious Adverse Events and Adverse Events of 
Special Interest (Relative Risk, 100mg SC vs Placebo) (Part C)
SAC


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11.11.6.
Part D
11.11.6.1. Study Population Tables (Part D)
Study Population Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Population Analysed
1.35.
ASE
SHELL
Summary of Study Populations (Part D)
IDSL
Include As Treated (Part D) Population
SAC
Subject Disposition
1.36.
AT (Part D)
ES8
Summary of Subject Status and Reason for Study Withdrawal (Part D)
ICH E3, FDAAA, EudraCT
SAC
1.37.
AT (Part D)
SD1
Summary of Treatment Status and Reasons for Discontinuation of 
Study Treatment (Part D)
ICH E3
SAC
1.38.
ITT (Part D)
SHELL
Summary of Attendance at Each Clinic Visit (Part D)
SAC
Protocol Deviation
1.39.
AT (Part D)
DV1
Summary of Important Protocol Deviations (Part D)
ICH E3
SAC
Exposure
1.40.
AT (Part D)
SHELL
Summary of Exposure to Study Treatment (Part D)
ICH E3
See Study Population Table 1.1 
(204471 ‘FINAL_01’ reporting effort)
SAC


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11.11.6.2. Efficacy Tables (Part D)
Efficacy: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Blood Eosinophils
2.50.
AT (Part D)
SHELL
Summary of Blood Eosinophils (109/L) (Part D)
SAC
11.11.6.3. Efficacy Figures (Part D)
Efficacy: Figures
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Blood Eosinophils
2.18.
AT (Part D)
SHELL
Figure of Ratio to Baseline in Blood Eosinophils (Part D)
SAC


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11.11.6.4. Safety Tables (Part D)
Safety: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events (AEs)
3.108.
AT (Part D)
SHELL
Overview of Adverse Events (Part D)
SAC
3.109.
AT (Part D)
AE1
Summary of On-Treatment Adverse Events by System Organ Class 
and Preferred Term (Part D)
ICH E3
SAC
3.110.
AT (Part D)
AE5
Summary of On-Treatment Adverse Events by Maximum Intensity by 
System Organ Class and Preferred Term (Part D)
ICH E3
Add a Total column across all severities
SAC
3.111.
AT (Part D)
AE3
Summary of Common (≥3%) On-treatment Adverse Events by Overall 
Frequency (Part D)
ICH E3
≥3% (prior to rounding to nearest 
percent)
SAC
3.112.
AT (Part D)
AE1
Summary of On-Treatment Drug-Related Adverse Events by System 
Organ Class and Preferred Term (Part D)
ICH E3
SAC
3.113.
AT (Part D)
AE5
Summary of On-Treatment Drug-Related Adverse Events by System 
Organ Class and Preferred Term and Maximum Intensity (Part D)
Add a Total column across all severities
SAC
3.114.
AT (Part D)
SHELL
Summary of On-Treatment Adverse Events by Age Group (12-17, 18-
64, ≥65 years) (Part D)
SAC
3.115.
AT (Part D)
SHELL
Summary of On-Treatment Adverse Events by Highest Anti Drug 
Antibody Result At Any Time On-Treatment (Part D)
SAC
3.116.
AT (Part D)
AE15
Summary of Common (≥3%) Non-serious On-Treatment Adverse 
Events by System Organ Class and Preferred Term (Number of 
Subjects and Occurrences) (Part D)
FDAAA, EudraCT
≥3% (prior to rounding to nearest 
percent)
SAC
3.117.
AT (Part D)
AE1
Summary of On-Treatment Drug-Related Non-Serious Adverse Events 
by System Organ Class and Preferred Term (Part D)
Table required for plain language 
summary
SAC
Serious and Other Significant Adverse Events
3.118.
AT (Part D)
AE1
Summary of On-Treatment Serious Adverse Events by System Organ 
Class and Preferred Term (Part D)
SAC


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Safety: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.119.
AT (Part D)
SHELL
Summary of On-Treatment Serious Adverse Events by Age Group (12-
17, 18-64, ≥65 years) (Part D)
SAC
3.120.
AT (Part D)
AE1
Summary of On-Treatment Fatal Serious Adverse Events (Part D)
SAC
3.121.
AT (Part D)
SHELL
Summary of On-Treatment Fatal Serious Adverse Events by Age 
Group (12-17, 18-64, ≥65 years) (Part D)
SAC
3.122.
AT (Part D)
AE1
Summary of On-Treatment Non-Fatal Serious Adverse Events by 
System Organ Class and Preferred Term (Part D)
SAC
3.123.
AT (Part D)
AE1
Summary of On-Treatment Drug-Related Serious Adverse Events by 
System Organ Class and Preferred Term (Part D)
Table required for plain language 
summary
SAC
3.124.
AT (Part D)
AE1
Summary of On-Treatment Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study by 
System Organ Class and Preferred Term (Part D)
IDSL
SAC
3.125.
AT (Part D)
AE16
Summary of On-Treatment Serious Adverse Events by System Organ 
Class and Preferred Term (Number of Subjects and Occurrences)
(Part D)
FDAAA, EudraCT
SAC
Adverse Events of Special Interest
3.126.
AT (Part D)
SHELL
Summary of On-treatment Serious Adverse Events and Adverse 
Events of Special Interest (Part D)
SAC
3.127.
AT (Part D)
AE1
Summary of On-Treatment Systemic Reactions Meeting Anaphylaxis 
Criteria (Part D)
Present by Anaphylactic Criterion 1, 2 
and 3 rather than SOC as shown in 
AE1
Insert footnote: “Events displayed are a 
subset of reactions defined by the 
Investigator as being systemic”
SAC
3.128.
AT (Part D)
SHELL
Summary Profile of On-Treatment Systemic Reactions Meeting 
Anaphylaxis Criteria (Part D)
Insert footnote: “Events displayed are a 
subset of reactions defined by the 
Investigator as being systemic”
SAC


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Safety: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.129.
AT (Part D)
AE1
Summary of On-Treatment Adverse Events Defined by the Investigator 
as Being Systemic (non-allergic or allergic/hypersensitivity) Reactions
(Part D)
SAC
3.130.
AT (Part D)
SHELL
Summary Profile of On-Treatment Systemic (non-allergic or 
allergic/hypersensitivity) Reactions (Part D)
SAC
3.131.
AT (Part D)
SHELL
Summary Profile of On-Treatment Systemic Allergic Reactions (Part D)
SAC
3.132.
AT (Part D)
SHELL
Summary Profile of On-Treatment Systemic Non-Allergic Reactions
(Part D)
SAC
3.133.
AT (Part D)
AE1
Summary of On-Treatment Adverse Events Defined by the Investigator 
as being Local Injection Site Reactions (Part D)
SAC
3.134.
AT (Part D)
SHELL
Summary Profile of On-Treatment Local Injection Site Reactions (Part 
D)
SAC
3.135.
AT (Part D)
AE1
Summary of On-Treatment Opportunistic Infections (Part D)
SAC
3.136.
AT (Part D)
SHELL
Summary Profile of On-Treatment Opportunistic Infections (Part D)
SAC
3.137.
AT (Part D)
AE1
Summary of On-Treatment Malignancies (Part D)
SAC
3.138.
AT (Part D)
SHELL
Summary Profile of On-Treatment Malignancies (Part D)
SAC
3.139.
AT (Part D)
AE1
Summary of On-Treatment Serious Cardiac, Vascular and 
Thromboembolic Adverse Events (Part D)
SAC
3.140.
AT (Part D)
SHELL
Summary Profile of On-Treatment Serious Cardiac, Vascular and 
Thromboembolic Adverse Events (Part D)
SAC
3.141.
AT (Part D)
AE1
Summary of On-Treatment Serious Ischemic Adverse Events (Part D)
SAC
3.142.
AT (Part D)
SHELL
Summary Profile of On-Treatment Serious Ischemic Adverse Events
(Part D)
SAC
Cardiovascular Events and Deaths (All Causes)
3.143.
AT (Part D)
SHELL
Summary of Cardiovascular Events and Deaths (All Causes) Reported 
by the Investigator (On-Treatment, Part D)
SAC


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Safety: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Laboratory: Chemistry
3.144.
AT (Part D)
LB1
Summary of Chemistry Changes from Baseline (On-Treatment, Part D)
ICH E3
Includes Baseline values.
SAC
3.145.
AT (Part D)
LB3
Summary of Chemistry Results (Changes from Baseline Relative to the 
Normal Range) (On-Treatment, Part D)
ICH E3
SAC
3.146.
AT (Part D)
LB3
Summary of Chemistry Results (Changes from Baseline Relative to the 
Reference Range [Potential Clinical Importance]) (On-Treatment, Part 
D)
ICH E3
SAC
Laboratory: Haematology
3.147.
AT (Part D)
LB1
Summary of Haematology Changes from Baseline (On-Treatment, Part 
D)
ICH E3
Includes baseline values.
SAC
3.148.
AT (Part D)
LB3
Summary of Haematology Results (Changes from Baseline Relative to 
the Normal Range) (On-Treatment, Part D)
ICH E3
SAC
3.149.
AT (Part D)
LB3
Summary of Haematology Results (Changes from Baseline Relative to 
the Reference Range [Potential Clinical Importance]) (On-Treatment, 
Part D)
ICH E3
SAC
Laboratory: Hepatobiliary (Liver)
3.150.
AT (Part D)
LIVER10
Summary of Hepatobiliary Laboratory Abnormalities (On-Treatment, 
Part D)
IDSL
SAC
ECG
3.151.
AT (Part D)
EG1
Summary of ECG Findings (On-Treatment, Part D)
IDSL
SAC
3.152.
AT (Part D)
EG2
Summary of Change from Baseline in ECG Values by Visit (On-
Treatment, Part D)
IDSL
Includes Baseline values.
SAC
3.153.
AT (Part D)
SHELL
Summary of Actual and Change From Baseline QTc(F) Values by 
Category (msec) (On-Treatment, Part D)
SAC
3.154.
AT (Part D)
SHELL
Summary of Actual and Change From Baseline QTc(B) Values by 
Category (msec) (On-Treatment, Part D)
SAC


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Safety: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Vital Signs
3.155.
AT (Part D)
VS1
Summary of Change from Baseline in Vital Signs (On-Treatment, Part 
D)
ICH E3
Includes Baseline values.
SAC
Immunogenicity
3.156.
AT (Part D)
SHELL
Summary of ADA Assay Results (On-Treatment, Part D)
SAC
3.157.
AT (Part D)
SHELL
Summary of Treatment Emergent ADA Assay Results (On-Treatment, 
Part D)
SAC
3.158.
AT (Part D)
SHELL
Summary of NAb Assay Results (On-Treatment, Part D)
SAC


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11.11.7.
ICH Listings
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.
ASE
ES7
Listing of Reasons for Screen Failure (Parts A/B)
Journal Guidelines
SAC
2.
ASE
IE3
Listing of Failed Inclusion/Exclusion Criteria (Parts A/B)
ICH E3
SAC
3.
ASE
ES7
Listing of Reasons for Run-in Failure (Part C)
Journal Guidelines
SAC
4.
ASE
IE3
Listing of Failed Randomization Inclusion/Exclusion Criteria (Part C)
ICH E3
SAC
5.
ASE
SHELL
Listing of Randomised Subjects who Did Not Receive Double-Blind 
Treatment
ICH E3
SAC
6.
ASE
ES2
Listing of Reasons for Study Withdrawal (Parts A/B, Part C, Part D)
ICH E3
Including column of treatment and 
study part
SAC
7.
ASE
SD2
Listing of Reasons for Study Treatment Discontinuation (Part C, Part 
D)
ICH E3
Including column of treatment and 
study part
SAC
8.
ITT (Part C)
BL1
Listing of Participants for Whom the Treatment Blind was Broken (Part 
C)
ICH E3
SAC
9.
ITT (Part C)
TA1
Listing of Planned and Actual Treatments (Part C)
IDSL
SAC
Demographic and Baseline Characteristics
10.
ASE
DM2
Listing of Demographic Characteristics (Part C)
ICH E3
SAC
11.
ASE
DM9
Listing of Race (Part C)
ICH E3
SAC
Protocol Deviations
12.
ASE
DV2
Listing of Important Protocol Deviations (Parts A/B, Part C, Part D)
ICH E3
Listing also includes analysis 
population exclusions.
Including column of treatment and 
study part
SAC


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No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Exposure
13.
ASE
EX3
Listing of Exposure Data (Parts A/B, Part C, Part D)
ICH E3
Including column of treatment and 
study part
SAC
Efficacy
14.
ASE
SHELL
Listing of Exacerbations (Parts A/B, Part C, Part D)
Including column of treatment, study 
part and phase
SAC
Adverse Events
15.
ASE
SHELL
Listing of All Adverse Events (Parts A/B, Part C, Part D)
ICH E3
Including column of treatment, study 
part and phase
SAC
16.
ASE
AE7
Listing of Subject Numbers for Individual Adverse Events (Parts A/B, 
Part C, Part D)
ICH E3
Including column of treatment, study 
part and phase
SAC
17.
ASE
AE2
Listing of Relationship Between Adverse Event System Organ Classes, 
Preferred Terms, and Verbatim Text (Parts A/B, Part C, Part D)
IDSL
SAC
Serious and Other Significant Adverse Events
18.
ASE
AE8CP
Listing of Fatal Serious Adverse Events (Parts A/B, Part C, Part D)
ICH E3
Including column of treatment, study 
part and phase
SAC
19.
ASE
AE8CP
Listing of Non-Fatal Serious Adverse Events (Parts A/B, Part C, Part 
D)
ICH E3
Including column of treatment, study 
part and phase
SAC
20.
ASE
AE14
Listing of Reasons for Considering as a Serious Adverse Event (Parts 
A/B, Part C, Part D)
ICH E3
Including column of treatment, study 
part and phase
SAC
21.
ASE
SHELL
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment (Parts A/B, Part C, Part 
D)
ICH E3
Including column of treatment, study 
part and phase
SAC


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No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events of Special Interest
22.
ASE
SHELL
Listing of Systemic Reactions Meeting Anaphylaxis Criteria (Parts A/B, 
Part C, Part D)
Including column of treatment, study 
part and phase
Insert footnote: “Events displayed are a 
subset of reactions defined by the
Investigator as being systemic”
SAC
23.
ASE
SHELL
Listing of Adverse Events Defined by the Investigator as a Systemic 
(non-allergic or allergic/hypersensitivity) Reaction (Parts A/B, Part C, 
Part D)
Including column of treatment, study 
part and phase
Add a column stating whether AE is 
related to IP.
SAC
24.
ASE
SHELL
Listing of Adverse Events Defined by the Investigator as a Local 
Injection Site Reaction (Parts A/B, Part C, Part D)
Add a column stating whether AE is 
related to IP.
Including column of treatment, study 
part and phase
SAC
25.
ASE
SHELL
Listing of Opportunistic Infections (Parts A/B, Part C, Part D)
Including column of treatment, study 
part and phase
SAC
26.
ASE
SHELL
Listing of Malignancies (Parts A/B, Part C, Part D)
Including column of treatment, study 
part and phase
SAC
27.
ASE
SHELL
Listing of Serious Cardiac, Vascular and Thromboembolic (CVT) 
Adverse Events (Parts A/B, Part C, Part D)
Including column of treatment, study 
part and phase
SAC
28.
ASE
SHELL
Listing of Serious Ischemic Adverse Events (Parts A/B, Part C, Part D)
Including column of treatment, study 
part and phase
SAC
Cardiovascular Events
29.
ASE
SHELL
Listing of Investigator Reported Cardiovascular Events: Arrhythmias
(Parts A/B, Part C, Part D)
Including column of treatment, study 
part and phase
SAC
30.
ASE
SHELL
Listing of Investigator Reported Cardiovascular Events: Congestive 
Heart Failure (Parts A/B, Part C, Part D)
Including column of treatment, study 
part and phase
SAC
31.
ASE
SHELL
Listing of Investigator Reported Cardiovascular Events: 
Cerebrovascular Events/Stroke (Parts A/B, Part C, Part D)
Including column of treatment, study 
part and phase
SAC


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No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
32.
ASE
SHELL
Listing of Investigator Reported Cardiovascular Events: Deep venous 
Thrombosis/Pulmonary Embolism (Parts A/B, Part C, Part D)
Including column of treatment, study 
part and phase
SAC
33.
ASE
SHELL
Listing of Investigator Reported Cardiovascular Events: Myocardial 
Infarction/Unstable Angina (Parts A/B, Part C, Part D)
Including column of treatment, study 
part and phase
SAC
34.
ASE
SHELL
Listing of Investigator Reported Cardiovascular Events: Peripheral 
Arterial Thrombosis Embolism (Parts A/B, Part C, Part D)
Including column of treatment, study 
part and phase
SAC
35.
ASE
SHELL
Listing of Investigator Reported Cardiovascular Events: Pulmonary 
Hypertension (Parts A/B, Part C, Part D)
Including column of treatment, study 
part and phase
SAC
36.
ASE
SHELL
Listing of Investigator Reported Cardiovascular Events: 
Revascularisation (Parts A/B, Part C, Part D)
Including column of treatment, study 
part and phase
SAC
37.
ASE
SHELL
Listing of Investigator Reported Cardiovascular Events: Valvulopathy
(Parts A/B, Part C, Part D)
Including column of treatment, study 
part and phase
SAC
38.
ASE
SHELL
Listing of Investigator Reported Cardiovascular Events: All Cause 
Deaths (Parts A/B, Part C, Part D)
Including column of treatment, study 
part and phase
SAC
Hepatobiliary (Liver)
39.
ASE
LIVER5
Listing of Liver Monitoring/Stopping Event Reporting (Parts A/B, Part 
C, Part D)
Including column of treatment, study 
part and phase
SAC
40.
ASE
MH2
Listing of Medical Conditions for Participants with Liver Stopping 
Events (Parts A/B, Part C, Part D)
IDSL
SAC
41.
ASE
SU2
Listing of Substance Use for Participants with Liver Stopping Events 
(Parts A/B, Part C, Part D)
IDSL
SAC
42.
ASE
LIVER13
Listing of Subjects Meeting Hepatobiliary Laboratory Criteria Post-
Baseline (Parts A/B, Part C, Part D)
Including column of treatment, study 
part and phase
SAC
All Laboratory
43.
ASE
LB5
Listing of All Chemistry Data for Participants with Liver 
Monitoring/Stopping Events Reported (Parts A/B, Part C, Part D)
ICH E3
Including column of treatment, study 
part and phase
SAC


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No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
ECG
44.
ASE
EG5
Listing of All ECG Findings for Subjects with an Abnormal ECG 
Interpretation (Parts A/B, Part C, Part D)
IDSL
Including column of treatment, study 
part and phase
SAC
45.
ASE
EG3
Listing of All ECG Values for Subjects Meeting Protocol Defined QTc 
Stopping Criteria (Parts A/B, Part C, Part D)
Including column of treatment, study 
part and phase
SAC
Immunogenicity
46.
ASE
SHELL
Listing of Immunogenicity Results (Parts A/B, Part C, Part D)
IDSL
Including column of treatment, study 
part and phase
SAC


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11.12.
Appendix 12: Example Mock Shells for Data Displays
The data display shells are available on request.