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)
Phase: PHASE3
Conditions: Asthma
Sponsor: GlaxoSmithKline

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
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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
CONFIDENTIAL
The GlaxoSmithKline group of companies
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 
Asthma.  Eur Respir J 2003;22:470-77.

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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

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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
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

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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
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

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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
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

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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
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

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
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

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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

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
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.

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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

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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