Study 200622: A Randomized, Double-blind, Placebo-controlled Study to Investigate the Efficacy and Safety of Mepolizumab in the Treatment of Adolescent and Adult Subjects With Severe Hypereosinophilic Syndrome
Phase: PHASE3
Conditions: Hypereosinophilic Syndrome
Sponsor: GlaxoSmithKline

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GlaxoSmithKline group of companies
200622
1
TITLE PAGE
Division:  Worldwide Development
Information Type: Clinical Protocol
Title:
Study 200622: A randomized, double-blind, placebo-controlled 
study to investigate the efficacy and safety of mepolizumab in 
the treatment of adolescent and adult subjects with severe 
hypereosinophilic syndrome
Compound Number:
SB-240563
Development Phase
III
Effective Date:
29-APR-2016
Authors:
 
Copyright 2016 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD

PPD
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
Site Address
Primary 
Medical 
Monitor 
 
 
MD
Cell: 
Email: 
Cell: 
 
709 Swedeland 
Road, UW25-
3077B
King of Prussia, 
PA 19406
United States
Secondary 
Medical 
Monitor
 
MD
Office: 
Email: 
Cell
 
5 Moore Drive, 
PO Box 13398, 
RTP, NC 27709-
3398, United 
States
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 
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#: BB-IND 011295, EudraCT#: 2014-
001232-11
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 200622
I confirm agreement to conduct the study in compliance with the protocol.
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 Signature
Date

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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 200622........................................................8
2.
INTRODUCTION....................................................................................................13
2.1.
Study Rationale ..........................................................................................13
2.2.
Background ................................................................................................14
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................16
4.
STUDY DESIGN ....................................................................................................19
4.1.
Overall Design ............................................................................................19
4.2.
Treatment Arms and Duration.....................................................................19
4.3.
Type and Number of Subjects.....................................................................20
4.4.
Design Justification.....................................................................................21
4.5.
Dose Justification........................................................................................23
4.6.
Benefit:Risk Assessment ............................................................................24
4.6.1.
Risk Assessment .........................................................................25
4.6.2.
Benefit Assessment.....................................................................32
4.6.3.
Overall Benefit:Risk Conclusion...................................................32
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............32
5.1.
Inclusion Criteria.........................................................................................33
5.2.
Exclusion Criteria........................................................................................35
5.3.
Screening/Baseline/Run-in Failures............................................................37
5.4.
Withdrawal/Stopping Criteria.......................................................................38
5.4.1.
Liver Chemistry Stopping Criteria ................................................40
5.4.1.1.
Study Treatment Restart or Re-challenge...................40
5.4.2.
QTc Stopping Criteria ..................................................................41
5.5.
Subject and Study Completion....................................................................41
6.
STUDY TREATMENT ............................................................................................42
6.1.
Investigational Product and Other Study Treatment....................................42
6.2.
Treatment Assignment................................................................................43
6.3.
Treatment Blinding......................................................................................43
6.4.
Blood Eosinophil Blinding ...........................................................................44
6.5.
Packaging and Labeling..............................................................................47
6.6.
Preparation/Handling/Storage/Accountability..............................................47
6.7.
Compliance with Study Treatment Administration.......................................48
6.8.
Treatment of Study Treatment Overdose....................................................48
6.9.
Treatment after the End of the Study ..........................................................48
6.10.
Concomitant Medications and Non-Drug Therapies....................................48
6.10.1.
Permitted Medications and Non-Drug Therapies..........................48
6.10.2.
Prohibited Medications and Non-Drug Therapies.........................49
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................49
7.1.
Time and Events Table...............................................................................50
7.2.
Screening and Critical Baseline Assessments ............................................54
7.3.
Efficacy.......................................................................................................54
7.3.1.
HES flare .....................................................................................54

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7.3.2.
HES Core Assessments (Clinician Assessment)..........................56
7.3.3.
Spirometry ...................................................................................57
7.3.4.
Echocardiogram...........................................................................58
7.3.5.
Healthcare Resource Utilization (HCRU) .....................................58
7.4.
Safety .........................................................................................................58
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........59
7.4.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................59
7.4.1.2.
Method of Detecting AEs and SAEs ...........................60
7.4.1.3.
Follow-up of AEs and SAEs........................................60
7.4.1.4.
Cardiovascular and Death Events ..............................60
7.4.1.5.
Regulatory Reporting Requirements for SAEs............60
7.4.2.
Pregnancy ...................................................................................61
7.4.3.
Physical Exams ...........................................................................61
7.4.4.
Vital Signs....................................................................................61
7.4.5.
Electrocardiogram (ECG).............................................................61
7.4.6.
Clinical Safety Laboratory Assessments ......................................62
7.5.
Pharmacokinetics .......................................................................................64
7.5.1.
Blood Sample Collection..............................................................64
7.5.2.
Sample Analysis ..........................................................................64
7.6.
Pharmacodynamic Markers ........................................................................64
7.7.
Immunogenicity...........................................................................................64
7.8.
T-cell profile................................................................................................65
7.9.
F/P status ...................................................................................................65
7.10.
Biomarker Sub-study ..................................................................................65
7.11.
Genetics .....................................................................................................65
7.12.
Patient-Reported Outcomes (PROs)...........................................................66
7.12.1.
Brief Fatigue Inventory.................................................................66
7.12.2.
HES Daily Symptoms (HES-DS)..................................................66
7.12.3.
Clinician- and Subject-Rated Overall Response to 
Therapy Score (RTS)...................................................................66
7.12.4.
Subject-Rated Symptom Severity (SSR)......................................67
7.12.5.
Modified Memorial Symptom Assessment Scale-Short 
Form (MSAS-SF).........................................................................67
7.12.6.
Patient Reported Outcome Measurement Information 
System (PROMIS) Physical Function and Sleep..........................67
7.12.7.
SF-36 V2 .....................................................................................67
7.12.8.
Work Productivity and Activity Impairment Index – General 
Health (WPAI-GH) V2..................................................................68
7.12.9.
Steroid Perception Questionnaire ................................................68
8.
DATA MANAGEMENT ...........................................................................................68
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................69
9.1.
Hypotheses.................................................................................................69
9.2.
Sample Size Considerations.......................................................................69
9.2.1.
Sample Size Assumptions ...........................................................69
9.2.2.
Sample Size Sensitivity................................................................69
9.2.3.
Sample Size Re-estimation or Adjustment...................................70
9.3.
Data Analysis Considerations .....................................................................70
9.3.1.
Analysis Populations....................................................................70
9.3.2.
Treatment Comparisons ..............................................................71

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9.3.3.
Multiple Comparisons and Multiplicity ..........................................71
9.3.4.
Interim Analysis ...........................................................................72
9.4.
Key Elements of Analysis Plan ...................................................................72
9.4.1.
Efficacy Analyses.........................................................................72
9.4.2.
Safety Analyses...........................................................................74
9.4.3.
Pharmacokinetic Analyses...........................................................74
9.4.4.
Pharmacodynamic Analyses........................................................75
9.4.5.
Other Analyses ............................................................................75
10. STUDY GOVERNANCE CONSIDERATIONS........................................................75
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............75
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................75
10.3.
Quality Control (Study Monitoring) ..............................................................76
10.4.
Quality Assurance.......................................................................................77
10.5.
Study and Site Closure ...............................................................................77
10.6.
Records Retention......................................................................................77
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................78
10.8.
Independent Data Monitoring Committee....................................................78
11. REFERENCES.......................................................................................................79
12. APPENDICES........................................................................................................83
12.1.
Appendix 1: Abbreviations and Trademarks................................................83
12.2.
Appendix 2: Phase III-IV liver chemistry stopping and monitoring 
criteria, and required actions and follow-up assessments ...........................86
12.3.
Appendix 3: Genetic Research ...................................................................89
12.4.
Appendix 4: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................92
12.4.1.
Definition of Adverse Events........................................................92
12.4.2.
Definition of Serious Adverse Events...........................................93
12.4.3.
Definition of Cardiovascular Events .............................................94
12.4.4.
Recording of AEs and SAEs ........................................................95
12.4.5.
Evaluating AEs and SAEs............................................................95
12.4.6.
Reporting of SAEs to GSK...........................................................97
12.5.
Appendix 5: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in FRP and Collection of Pregnancy Information.......................98
12.5.1.
Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP) ..............98
12.5.2.
Collection of Pregnancy Information ............................................98
12.5.3.
References ..................................................................................99
12.6.
Appendix 6: Anaphylaxis Criteria ..............................................................101
12.7.
Appendix 7: Classification of Heart Failure................................................102
12.8.
Appendix 8: Country Specific Requirements.............................................103

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1.
PROTOCOL SYNOPSIS FOR STUDY 200622
Rationale
HES is a group of rare hematologic disorders without a known cause in which 
eosinophils are overproduced in the bone marrow for prolonged periods of time.  The 
sustained overproduction of eosinophils in the bone marrow results in high blood 
eosinophil levels (eosinophilia).  When activated eosinophils from the bloodstream 
infiltrate various tissues, they cause inflammatory tissue damage and dysfunction.  HES 
is only diagnosed when organ damage and/or dysfunction are present.  The current 
definition and diagnosis of HES in patients uses the following criteria: (1) blood 
eosinophilia of >1,500 eosinophils/µL on 2 examinations (at an interval ≥1month, except 
in case of life-threatening organ-damage when diagnosis can be made immediately) 
and/or tissue eosinophilia; (2) organ damage and/or dysfunction attributable to tissue 
eosinophilia; and (3) exclusion of other disorders or conditions as the major reason for 
organ damage [Valent, 2012].
Eosinophilia is central to the pathophysiology of HES and IL-5 is a key cytokine 
regulating the life-cycle of the eosinophil.  Neutralization of IL-5 with an anti-IL5 
monoclonal antibody, therefore offers a potential therapeutic option for HES.
Mepolizumab is a humanized monoclonal antibody (IgG1, kappa, mAb) which is specific 
for human IL-5.  Mepolizumab blocks binding of human IL-5 (hIL-5) to the alpha chain 
of the IL-5 receptor complex expressed on the eosinophil cell surface.  In conditions 
where eosinophilia is considered to play an important part in the pathology, including 
eosinophilic asthma, HES, and eosinophilic granulomatosis with polyangiitis (EGPA), a 
consistent reduction in blood eosinophil counts is observed in association with 
mepolizumab administration, with concomitant clinical improvement [Haldar, 2009; 
Kim, 2010; Moosig, 2011; Nair, 2009; Ortega, 2014; Pavord, 2012; Rothenberg, 2008; 
Stein, 2008].  The hypothesis that IL-5 is central to the pathology and clinical 
manifestations of HES is supported by clinical data from three completed clinical studies 
(MHE100185 [Rothenberg, 2008], MHE100901 [Roufosse, 2013], CRT112446 
[Stein, 2008]) and the ongoing compassionate use program (CUP) providing ‘proof-of-
concept’ evidence of efficacy of IL-5 blockade in the treatment of subjects with HES.  In 
addition, several published case studies have been reported demonstrating activity of 
mepolizumab in HES patients [Plötz, 2003; Braun-Falco, 2004; Garrett, 2004; 
Hargreaves, 2007; Mehr, 2009; Schwartz, 2010; Bleeker, 2012].
The purpose of this 32-week, randomized, double-blind, placebo-controlled study is to 
investigate the efficacy and safety of mepolizumab 300 mg SC every 4 weeks compared 
with placebo in adolescent and adult subjects with severe HES (demonstrated by a blood 
eosinophil count of 1000/L or higher during screening, and a history of two or more 
HES flares within the past year) receiving standard of care (SoC) therapy.  The primary 
objective of the study is to demonstrate maintenance of control of HES symptoms during 
the treatment period (i.e., avoidance of HES flare).

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Objective(s)/Endpoint(s)
Objectives
Endpoints
Primary

To demonstrate the efficacy of 
mepolizumab compared with 
placebo based on maintenance of 
control of HES symptoms during the 
treatment period.

Proportion of subjects who experience an HES 
flare during the 32-week study treatment 
period
Secondary

To demonstrate supportive 
evidence of the benefit of 
mepolizumab compared with 
placebo based on other measures 
of efficacy.

Time to first HES flare

Proportion of subjects who experience an HES 
flare during Week 20 through Week 32

Rate of HES flares

Change from baseline in fatigue severity based 
on Brief Fatigue Inventory (BFI) item 3 (worst 
level of fatigue during past 24 hours) at 
Week 32
Exploratory

To investigate mepolizumab 
compared with placebo with respect 
to additional measures of efficacy.

Proportion of subjects who receive blinded 
active OCS due to an elevated blood 
eosinophil level that meets the pre-defined 
threshold during the 32-week study treatment 
period

Lung function tests (FEV1, FVC, and ratio)

Echocardiogram

To investigate the efficacy of 
mepolizumab compared with 
placebo with respect to patient and 
clinician reported symptoms, health 
status, and disease impact.

Change from baseline in HES symptom 
severity based on HES Daily Symptoms 
(HES-DS) at Week 32

Change from baseline in the BFI total and 
domain scores at Week 32

Proportion of subjects with a favorable 
response as measured by clinician- and 
subject-rated overall response to therapy 
score (RTS) at Week 32

Change from baseline in Subject-rated 
symptom severity (SSR) at Week 32

Change from baseline in Modified Memorial 
Symptom Assessment Scale-Short Form 
(MSAS-SF) responses at Week 32

Change from baseline in physical function 

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Objectives
Endpoints
(Patient Reported Outcome Measurement 
Information System [PROMIS] physical 
function items) at Week 32

Change from baseline in sleep (PROMIS 
sleep items) at Week 32

To characterize the patient burden of 
HES.

SF-36 v2

Healthcare resource utilization (HCRU)

Work Productivity and Activity Impairment 
Index – General Health (WPAI-GH) v2

Steroid perception questionnaire

To investigate the pharmacokinetics 
(PK) of mepolizumab.

Plasma concentration of mepolizumab

To investigate the 
pharmacodynamics (PD) of 
mepolizumab.

IL-5 levels (serum free and total)

Blood eosinophil levels
Safety

To evaluate the safety of 
mepolizumab compared with 
placebo in subjects with HES 
receiving standard of care treatment 
over a 32-week study treatment 
period

Adverse events including local injection site 
reactions and systemic reactions (e.g., 
hypersensitivity)

Vital signs

12-lead ECG

Hematological and clinical laboratory tests

Immunogenicity (anti-drug antibody)
Overall Design

This is a 32-week treatment period, randomized, double-blind, placebo-controlled, 
parallel group, multicentre study of mepolizumab in adolescent and adult subjects 
with severe HES receiving SoC therapy (Figure 1 in Section 4.1).
Treatment Arms and Duration

The study is comprised of a screening period of up to approximately 4 weeks 
followed by a 32-week study treatment period and up to 8-week additional follow-up 
period (12 weeks after the last dose of study treatment).

Approximately 80 subjects who are able to maintain a stable regimen of HES therapy 
for the 4 weeks prior to Visit 2 will be randomized in a 1:1 ratio to receive either 
300 mg mepolizumab or placebo subcutaneously (SC) every 4 weeks while 

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continuing their HES therapy.  The sample size may be increased up to a maximum of 
120 subjects in total (see details below). The same regimen of HES therapy will be 
maintained throughout the 32-week study treatment period unless there is worsening 
of symptom(s) that requires an increase in therapy.  A reduction in dose for safety 
reasons, with return to the original dose if possible, is permitted in consultation with 
the GlaxoSmithKline (GSK) Medical Monitor.

The final dose of study treatment will be administered at Visit 10 (Week 28) with 
completion of the study treatment period achieved at the next 4-weekly visit. At 
Visit 11 (Week 32), subjects will complete the end-of-treatment assessment (4 weeks 
after the last dose).

Subjects who withdraw from study treatment prematurely should continue in the 
study per protocol (including HES flare-related assessments) until 32 weeks from 
randomization.

For subjects whose last dose of study treatment is on Visit 9 (Week 24) or Visit 10 
(Week 28) and who do not continue with open-label mepolizumab after completing 
Visit 11 assessment (32 weeks from randomization), there will be up to 8-week 
additional follow-up period, concluding with the 12 weeks post-last dose follow-up 
visit (Visit 12).

Subjects will be eligible to be considered to receive open-label mepolizumab 300 mg 
SC every 4 weeks after either:
i. Completion of the treatment period in the 200622 study
or
ii. If the subject was withdrawn from study treatment prematurely during the 200622 
study, but continued in the study per protocol (including HES flare-related 
assessments) until 32 weeks from randomization.

Subject management during the study will be according to routine medical care, i.e., 
subjects will be instructed to contact their investigator for evaluation or seek 
emergency care as necessary when they experience worsening of symptoms as per 
their usual practice.  The investigator will use the HES Core Assessments 
(Section 7.3.2) to assess for the presence of a HES flare (unscheduled ‘Flare’ visit in 
Section 7.1).

Investigators, participating subjects, and GSK study personnel will be blinded to 
absolute blood eosinophil counts, total white blood cell counts, and white blood count 
differentials (%) from randomization (Visit 2) to the end of the study.  Blood 
eosinophil-unblinded GSK personnel/delegates not involved with other aspects of 
study conduct will monitor the absolute blood eosinophil count results and trigger 
blinded OCS treatment to treat an eosinophilia when the blood eosinophil count 
reaches a pre-defined threshold (Section 6.4).

An Independent Data Monitoring Committee (IDMC) will be utilized in this study
(Section 10.8).

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Type and Number of Subjects

Subjects entering the study must have experienced at least two HES flares within the 
past 12 months and have a blood eosinophil count of 1000/L or higher during 
screening.  Historical HES flares for the study entry criteria are defined as 
documented HES-related worsening of clinical symptoms or blood eosinophil counts 
requiring an escalation in therapy.  In addition, at least one HES flare within the past 
12 months must not be related to a decrease in HES therapy during the 4 weeks prior 
to the flare.  For further details on the study entry criteria, see Section 5.

Approximately 80 subjects will be randomized in the initial recruitment phase. The 
proportion of subjects that have an HES flare will be monitored and the total number 
of subjects randomized may be increased if the blinded overall rate is predicted to be
<30%.  The sample size may be increased up to a maximum of 120 subjects in total.
Analysis
The primary efficacy endpoint is the proportion of subjects who experience an HES flare 
during the 32-week study treatment period.  The study is designed to continue to collect 
data on HES flares for subjects who prematurely discontinue from their randomized 
treatment.  All data on HES flares collected for these subjects will also be included in the 
primary analysis. For subjects who withdraw prematurely from the study and for whom 
collection of data on HES flares is not possible, it will be assumed for the primary 
endpoint that they are treatment failures, i.e., that they experience a flare following study 
withdrawal. 
This study is designed to test the superiority of mepolizumab versus placebo.
Significance tests will be performed at the two-sided 5% level (one sided 2.5%).
The primary efficacy endpoint will be compared between treatments using a Cochran-
Mantel-Haenszel test stratified by baseline OCS dose (0-≤20mg/day and >20mg/day 
prednisolone/prednisone or equivalent) and region.  The analysis will be supplemented 
with a logistic regression analysis adjusting for covariates of baseline OCS dose, region,
and treatment.  The model will be used to estimate the odds ratio for the treatment 
difference and associated p-value and 95% confidence limit.
When strong control of type I error is required for making inferences for the pre-defined 
secondary endpoints, multiplicity will be controlled using a hierarchical, closed testing 
procedure.  The hierarchy of endpoints will proceed from the primary endpoint to each of 
the secondary endpoints in the order they are listed above.

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2.
INTRODUCTION
2.1.
Study Rationale
HES is a group of rare hematologic disorders without a known cause in which 
eosinophils are overproduced in the bone marrow for prolonged periods of time.  The 
sustained overproduction of eosinophils in the bone marrow results in high blood 
eosinophil levels (eosinophilia).  When activated eosinophils from the bloodstream 
infiltrate various tissues, they cause inflammatory tissue damage and dysfunction.  HES 
is only diagnosed when organ damage and/or dysfunction are present.  The current 
definition and diagnosis of HES in patients uses the following criteria: (1) blood 
eosinophilia of >1,500 eosinophils/µL on 2 examinations (at an interval ≥1month, except 
in case of life-threatening organ-damage when diagnosis can be made immediately) 
and/or tissue eosinophilia; (2) organ damage and/or dysfunction attributable to tissue 
eosinophilia; and (3) exclusion of other disorders or conditions as the major reason for 
organ damage [Valent, 2012].
Eosinophilia is central to the pathophysiology of HES and IL-5 is a key cytokine 
regulating the life-cycle of the eosinophil.  Neutralization of IL-5 with an anti-IL5 
monoclonal antibody, therefore offers a potential therapeutic option for HES.
Mepolizumab is a humanized monoclonal antibody (IgG1, kappa, mAb) which is specific 
for human IL-5.  Mepolizumab blocks binding of human IL-5 (hIL-5) to the alpha chain 
of the IL-5 receptor complex expressed on the eosinophil cell surface.  In conditions 
where eosinophilia is considered to play an important part in the pathology, including 
eosinophilic asthma, HES, and EGPA, a consistent reduction in blood eosinophil counts 
is observed in association with mepolizumab administration, with concomitant clinical 
improvement [Haldar, 2009; Kim, 2010; Moosig, 2011; Nair, 2009; Ortega, 2014; 
Pavord, 2012; Rothenberg, 2008; Stein, 2008].  The hypothesis that IL-5 is central to the 
pathology and clinical manifestations of HES is supported by clinical data from three 
completed clinical studies (MHE100185 [Rothenberg, 2008], MHE100901 [Roufosse, 
2013], CRT112446 [Stein, 2008]) and the ongoing Compassionate Use Protocol (CUP)
providing ‘proof-of-concept’ evidence of efficacy of IL-5 blockade in the treatment of 
subjects with HES.  In addition, several published case studies have been reported 
demonstrating activity of mepolizumab in HES patients [Plötz, 2003; Braun-Falco, 2004; 
Garrett, 2004; Hargreaves, 2007; Mehr, 2009; Schwartz, 2010; Bleeker, 2012].
The purpose of this 32-week, randomized, double-blind, placebo-controlled study is to 
investigate the efficacy and safety of mepolizumab 300 mg SC every 4 weeks compared 
with placebo in adolescent and adult subjects with severe HES (demonstrated by a blood 
eosinophil count of 1000/L or higher during screening, and a history of two or more 
HES flares within the past year) receiving SoC therapy.  The primary objective of the 
study is to demonstrate maintenance of control of HES symptoms during the treatment 
period (i.e., avoidance of HES flare).

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2.2.
Background
HES is a heterogeneous group of chronic inflammatory disorders characterized by 
persistent eosinophilia (elevated blood eosinophil counts) and diverse organ involvement, 
punctuated by flares of disease worsening.  Inadequate HES treatment can lead to 
profound end-organ damage and increased mortality.  Given the clinical heterogeneity of 
HES, clinicians use diverse classes of medications (such as high doses of OCSs), most of 
which are not approved to treat HES, have detrimental side effects, and may not result in 
complete remission of disease.
HES Classification
The ability to distinguish different HES variants is critical for optimal patient 
management because the clinical manifestations and response to treatment vary 
considerably depending on the etiology of eosinophilia [Klion, 2009].  The three most 
common types of HES are myeloproliferative (M-HES), lymphocytic (L-HES) and 
undefined [Wechsler, 2012].  M-HES is a clinically defined variant characterized by an 
extreme male predominance, pathologic evidence of eosinophil-related tissue damage and 
tissue fibrosis, elevated serum tryptase levels, and myeloproliferative features, including 
splenomegaly, anemia, thrombocytopenia, bone marrow hypercellularity with reticulin 
fibrosis, and increased numbers of atypical mast cells [Klion, 2009].  Identification of L-
HES rests upon recognition of distinct helper T cell subsets (Th1 and Th2) and clonal 
overgrowth of specific cytokine-producing cells, particularly production of interleukin-5 
(IL-5) by TH2 cell clones.  The most prevalent T cell clone associated with lymphocytic 
HES appears to be the CD3-CD4+ clone [Roufosse, 2007].
The identification of the FIP1L1-PDGFRα (F/P) fusion tyrosine kinase genetic 
translocation in the majority of patients with M-HES led to a dramatic improvement in 
prognosis for these patients due to response to imatinib (a tyrosine kinase inhibitor) 
treatment.  While the prevalence of M-HES has not been reported, the prevalence of the 
F/P mutation in the total HES patient population was found to be between 11% and 18% 
[Ogbogu, 2009; Helbig, 2010].  Therefore, for the majority of HES patients no definitive 
genetic basis underlying their disease has been identified.
Although patients with L-HES typically do not show the same high incidence of life-
threatening end-organ damage compared with M-HES, L-HES patients are at higher risk 
for developing peripheral T-cell lymphomas [Gleich, 2009].  Reported estimated 
incidence rates vary widely due to the small sample population from “rare”, to 5% up to 
14-25% [Valent, 2012; Simon, 1999; D’Souza, 2012]. In a study of F/P negative HES 
patients, 21% were diagnosed with L-HES [Roufosse, 2013].  In a retrospective study of 
21 French patients with CD3-CD4+ L-HES and negative for the F/P mutation, 
1 lymphoma occurred (5%) during the mean follow-up duration after HES diagnosis of 
6.95.1 years [Lefèvre, 2014].
Signs and Symptoms of HES
Although over the past three decades HES has become a chronic and less fatal disease, 
the morbidity associated with the disease or caused by the currently available therapy has 
a substantial negative impact on day-to-day functioning and quality of life.

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The signs and symptoms of HES vary widely depending on specific organ involvement. 
The most common reported clinical manifestations of HES are:

Constitutional: fever, night sweats, weakness, malaise, weight loss, myalgia;

Dermatologic: pruritus, dermatitis, angioedema;

Pulmonary: asthma, persistent non-productive cough, dyspnea;

Gastrointestinal: abdominal pain, vomiting, diarrhea;

Cardiac/thromboembolic: congestive heart failure, mitral regurgitation, 
intracardiac thrombus, myocardial ischemia, arrhythmias.
For example, one large retrospective study reported that out of 188 HES patients, 37% 
had dermatologic, 25% had pulmonary and 14% had gastrointestinal manifestations 
[Ogbogu, 2009].  Another retrospective study found similar end-organ manifestations as 
mentioned above and also reported that all of the 88 HES patients had constitutional 
manifestations [Helbig, 2010].  Additionally, echocardiographic and clinical 
cardiac/thromboembolic manifestations were reported in 49% of 49 HES patients 
[Ommen, 2000].  In another report, cardiac involvement was less prevalent at initial 
evaluation (5%, N=188), but becomes more prevalent (20%) over a period of up to 5 
years [Ogbogu, 2007].
Many patients have two or more organ systems affected [Ogbogu, 2009; Helbig, 2010].  
In the GSK CUP, where eligible patients include those with life-threatening disease and 
documented failure to standard HES therapies, 82% (N=199) had a history of more than 
two organ systems involved at presentation.  It is also noted that as the disease 
progresses, clinical manifestations may change.
Current Therapies and Unmet Medical Need
The goal of HES treatment is to reverse or delay progression of any further organ damage 
caused by activated eosinophils.  The current approach is based on reduction of blood 
eosinophilia, reduction of active inflammation, suppression of the immune response, and 
treatment of disease-specific and/or treatment-related complications.  SoC therapy for 
patients with HES includes glucocorticosteroids (for F/P negative or F/P positive with 
cardiac involvement at diagnosis) or imatinib (for F/P positive) as first-line therapy and 
cytotoxics (e.g., hydroxyurea, cyclophosphamide) or immunomodulators (interferon 
alpha [INF], cyclosporine, immunoglobulin) as second-line agents [Roufosse, 2010].  
Clinical responses to these therapies, however, are incomplete or inadequate in over 80% 
of HES patients (among those negative for F/P mutation).
The discovery of the F/P mutation in patients with myeloproliferative HES and its 
response to imatinib has improved survival and quality of life in this subpopulation 
[Klion, 2009; Wechsler, 2012].  For the majority of patients however, the only currently 
available treatment options are limited to chronic high doses of corticosteroids, IFNα, and 
cytotoxic agents such as hydroxyurea and cyclophosphamide.  The efficacy of these 
agents, even in combination, is not always adequate and side effects with long-term use 
are significant.  Additional agents with increased efficacy and decreased toxicity are 
therefore greatly needed.

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Although not approved for use in HES, corticosteroids are used in clinical practice as 
first-line treatment for most patients with HES due to lack of available options [Ogbogu, 
2009; Helbig, 2010].  The therapeutic strategy is to start with a moderate to high dose 
(≥40mg/day prednisone or equivalent) and taper very slowly while monitoring the blood 
eosinophil count closely.  Using this approach, most patients (85%, N=141) will respond 
initially to steroid therapy based on a decrease of eosinophil count to normal range and 
symptomatic improvement.  However, many HES patients (72%, N=179) will need to be 
maintained on low steroid doses (median 10mg/day) for long periods of up to 20 years 
since discontinuation of corticosteroids leads to eosinophilia and symptomatic recurrence 
in most patients [Klion, 2009; Ogbogu, 2009; Helbig, 2010].
The initial response to corticosteroid treatment is often positive, however long-term use is 
associated with significant and commonly reported side effects, including truncal obesity, 
moon facies, buffalo hump, increased blood pressure, weight gain, muscle atrophy, 
hyperglycemia, delayed wound healing, cataracts and glaucoma, peptic ulcers, and 
increased risk of infection [Poetker, 2010].  Therefore, with chronic use, the toxicities of 
steroid therapy become limiting, patient adherence diminishes, and additional or 
alternative corticosteroid-sparing therapies must be used [Roufosse, 2013].  The chronic 
use of corticosteroids is often discontinued (42%, N=179) or used in combination therapy 
(33%, N=179) due to toxicity or failure in the majority of HES patients [Ogbogu, 2009].
In the absence of targeted approved therapies for HES, several second line agents have 
been used based on empirical observational evidence of benefit.  Commonly used 
second-line therapies include chemotherapeutic agents such as hydroxyurea, IFNα, and 
other cytotoxics (e.g., cyclosporine, vincristine, methotrexate, busulfan).  These second-
line agents are effective (defined as a decrease of eosinophil count and symptomatic 
improvement) only in a small number of HES patients, are associated with significant 
toxicities, have a slow onset of therapeutic effect, and confer an increased risk of patients 
developing malignancy.  For example, the most commonly used second-line agent, 
hydroxyurea, is rarely useful as a single agent and its side effects and lack of efficacy 
result in discontinuation in the majority of patients (77%, N=64) [Ogbogu, 2009].
As described herein, due to the significant tolerability issues related to long-term use of 
corticosteroids and other chemotherapeutics, new alternative therapies with a positive 
risk:benefit profile are needed.
3.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Primary

To demonstrate the efficacy of 
mepolizumab compared with 
placebo based on maintenance of 
control of HES symptoms during the 
treatment period.

Proportion of subjects who experience an HES
flare during the 32-week study treatment 
period
Secondary

To demonstrate supportive 
evidence of the benefit of 

Time to first HES flare

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Objectives
Endpoints
mepolizumab compared with 
placebo based on other measures
of efficacy.

Proportion of subjects who experience an HES
flare during Week 20 through Week 32

Rate of HES flares

Change from baseline in fatigue severity based 
on Brief Fatigue Inventory (BFI) item 3 (worst 
level of fatigue during past 24 hours) at 
Week 32
Exploratory

To investigate mepolizumab 
compared with placebo with respect 
to additional measures of efficacy.

Proportion of subjects who receive blinded 
active OCS due to an elevated blood 
eosinophil level that meets the pre-defined 
threshold during the 32-week study treatment 
period

Lung function tests (FEV1, FVC, and ratio)

Echocardiogram

To investigate the efficacy of 
mepolizumab compared with 
placebo with respect to patient and 
clinician reported symptoms, health 
status, and disease impact.

Change from baseline in HES symptom 
severity based on HES Daily Symptoms 
(HES-DS) at Week 32

Change from baseline in the BFI total and 
domain scores at Week 32

Proportion of subjects with a favorable 
response as measured by clinician- and 
subject-rated overall response to therapy 
score (RTS) at Week 32

Change from baseline in Subject-rated 
symptom severity (SSR) at Week 32

Change from baseline in Modified Memorial 
Symptom Assessment Scale-Short Form 
(MSAS-SF) responses at Week 32

Change from baseline in physical function 
(Patient Reported Outcome Measurement 
Information System [PROMIS] physical 
function items) at Week 32

Change from baseline in sleep (PROMIS 
sleep items) at Week 32

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Objectives
Endpoints

To characterize the patient burden of 
HES.

SF-36 v2

Healthcare resource utilization (HCRU)

Work Productivity and Activity Impairment 
Index – General Health (WPAI-GH) v2

Steroid perception questionnaire

To investigate the pharmacokinetics 
(PK) of mepolizumab.

Plasma concentration of mepolizumab

To investigate the 
pharmacodynamics (PD) of 
mepolizumab.

IL-5 levels (serum free and total)

Blood eosinophil levels
Safety

To evaluate the safety of 
mepolizumab compared with 
placebo in subjects with HES 
receiving standard of care treatment 
over a 32-week study treatment 
period

Adverse events including local injection site 
reactions and systemic reactions (e.g., 
hypersensitivity)

Vital signs

12-lead ECG

Hematological and clinical laboratory tests

Immunogenicity (anti-drug antibody)

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4.
STUDY DESIGN
4.1.
Overall Design
Figure 1
Study schematic
This is a 32-week treatment period, randomized, double-blind, placebo-controlled, 
parallel group, multicentre study of mepolizumab in adolescent and adult subjects with 
severe HES receiving SoC therapy (Figure 1).
4.2.
Treatment Arms and Duration

The study is comprised of a screening period of up to approximately 4 weeks 
followed by a 32-week study treatment period and up to 8-week additional follow-up 
period (12 weeks after the last dose of study treatment).

Approximately 80 subjects who are able to maintain a stable regimen of HES therapy 
for the 4 weeks prior to Visit 2 will be randomized in a 1:1 ratio to receive either 
300 mg mepolizumab or placebo SC every 4 weeks while continuing their HES 
therapy.  The sample size may be increased up to a maximum of 120 subjects in total 
(Section 9.2.3).  The same regimen of HES therapy will be maintained throughout the 
32-week study treatment period unless there is worsening of symptom(s) that requires 
an increase in therapy.  A reduction in dose for safety reasons, with return to the 
original dosing regimen if possible, is permitted in consultation with the GSK 
Medical Monitor.

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
The final dose of study treatment will be administered at Visit 10 (Week 28) with 
completion of the study treatment period achieved at the next 4-weekly visit.  At 
Visit 11 (Week 32), subjects will complete the end-of-treatment assessment (4 weeks 
after the last dose).

Subjects who withdraw from study treatment prematurely should continue in the 
study per protocol (including HES flare-related assessments) until 32 weeks from 
randomization.

For subjects whose last dose of study treatment is on Visit 9 (Week 24) or Visit 10 
(Week 28) and who do not continue with open-label mepolizumab after completing 
Visit 11 assessment (32 weeks from randomization), there will be up to 8-week 
additional follow-up period, concluding with the 12 weeks post-last dose follow-up 
visit (Visit 12).

Subjects will be eligible to be considered to receive open-label mepolizumab 300 mg 
SC every 4 weeks after either:
i. Completion of the treatment period in the 200622 study
or
ii. If the subject was withdrawn from study treatment prematurely during the 200622 
study, but continued in the study per protocol (including HES flare-related 
assessments) until 32 weeks from randomization.

Subject management during the study will be according to routine medical care, i.e., 
subjects will be instructed to contact their investigator for evaluation or seek 
emergency care as necessary when they experience worsening of symptoms as per 
their usual practice.  The investigator will use the HES Core Assessments 
(Section 7.3.2) to assess for the presence of a HES flare (unscheduled ‘Flare’ visit in 
Section 7.1).

Investigators, participating subjects, and GSK study personnel will be blinded to 
absolute blood eosinophil counts, total white blood cell counts, and white blood count 
differentials (%) from randomization (Visit 2) until completing the 32-week period 
from randomization.  Blood eosinophil-unblinded GSK personnel/delegates not 
involved with other aspects of study conduct will monitor the absolute blood 
eosinophil count results and trigger blinded OCS treatment to treat an eosinophilia 
when the blood eosinophil count reaches a pre-defined threshold (Section 6.4).

An IDMC will be utilized in this study (Section 10.8).
4.3.
Type and Number of Subjects
Subjects entering the study must have experienced at least two HES flares within the 
past 12 months and have a blood eosinophil count of 1000/L or higher during screening.  
Historical HES flares for the study entry criteria are defined as documented HES-related 
worsening of clinical symptoms or blood eosinophil counts requiring an escalation in 
treatment.  In addition, at least one HES flare within the past 12 months must not be 

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related to a decrease in HES therapy during the 4 weeks prior to the flare.  For further 
details on the study entry criteria, see Section 5.
Approximately 80 subjects will be randomized in the initial recruitment phase. The 
proportion of subjects that have an HES flare will be monitored and the total number of 
subjects randomized may be increased if the blinded overall rate is predicted to be <30%.  
The sample size may be increased up to a maximum of 120 subjects in total.
4.4.
Design Justification
HES Therapy
This study is designed to evaluate the efficacy and safety of mepolizumab in adolescent 
and adult subjects with severe HES receiving SoC therapy.  Allowing use of background 
SoC therapy supports inclusion of a placebo group contributing to a favorable benefit:risk 
profile for participating subjects.  While permitting standard HES therapy during the 
study, an increase in the dose or addition of new therapy will not be allowed within 4 
weeks prior to randomization.  This requirement is to avoid randomizing subjects that are 
at risk of an imminent disease flare upon the start of study treatment.  If a subject has 
worsening of symptom(s) and requires an increase in therapy after randomization 
(Section 7.3.1), the subject will be considered to be experiencing an HES flare.
Study Population
To demonstrate the efficacy of mepolizumab compared with placebo in subjects 
receiving standard HES therapy, the study will enroll subjects with severe HES.  For 
identification of such a population, the study requires subjects to experience at least two 
HES flares within the past 12 months and have a blood eosinophil count of 1000/L or 
higher during screening.
Overall, the study population describes a group of subjects considered likely to benefit 
from addition of mepolizumab to existing therapy.  The study population will exclude 
patients with mild disease, since it is less likely that mepolizumab will show a clear 
benefit in this comparatively well-controlled population.  Subjects with uncontrolled 
organ-threatening or life-threatening disease will also be excluded from the study 
(Section 5.2).
Study Treatment Duration
The total study treatment duration is 32 weeks.  This length will provide adequate
treatment duration to support the registration of mepolizumab for the indication under 
investigation.  The duration of blinded study treatment is limited to 32 weeks to minimize 
the duration of time that investigators will be blinded from the blood eosinophil counts 
which are used in SoC to manage patients with HES.
Blood Eosinophil Blinding and Monitoring
The effect of mepolizumab on blood eosinophil counts is rapid, readily observable, and 
dramatic and may lead to inadvertent unblinding of the treatment assignment.  Therefore, 

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in this study, investigators, participating subjects, and GSK study personnel will be 
blinded to absolute blood eosinophil counts, total white blood cell counts, and white 
blood count differentials (%) from randomization (Visit 2) to the end of the study 
(Section 6.4).  Since initiating treatment based on an increase in eosinophil levels alone 
(without clinical symptoms) is part of SoC for HES patients, blood eosinophil-unblinded 
GSK personnel/delegates not involved with other aspects of study conduct will monitor 
the absolute eosinophil count results and trigger blinded OCS treatment to treat an 
eosinophilia flare.  This is to ensure that subjects will not be placed at undue risk during 
the study, while maintaining the treatment blind.
Definition of a Disease Flare for the Primary Endpoint
Clinical manifestations in HES patients vary widely depending on specific organ 
involvement.  This variability, combined with the lack of a validated biomarker, leads to 
persistent challenges in defining appropriate endpoints for disease characterization.  The 
pragmatic approach proposed for this Study 200622 is modeled after severe asthma study 
MEA112997 [Pavord, 2012] and EGPA study MEA115921 (ClinicalTrials.gov Identifier. 
NCT02020889).  In the severe asthma study, clinically significant asthma exacerbations
were defined as “validated episodes of acute asthma requiring treatment with oral 
corticosteroids, hospital admission, or a visit to an emergency department” 
[Pavord, 2012].  In the EGPA study, disease relapse is defined as worsening or 
persistence of active disease since the last visit characterized by active vasculitis, active 
asthma symptoms, or active nasal and/or sinus disease warranting an increase in OCS 
therapy, or an increased dose or addition of immunosuppressive therapy, or 
hospitalization related to EGPA worsening.  In this study, disease flare (HES flare) is 
defined as (1) an HES-related clinical manifestation based on a physician-documented 
change in clinical signs or symptoms resulting in the need for therapy adjustment 
(increase in OCS dose of at least 10mg/day or any increase in or addition of any 
cytotoxic/ immunosuppressive HES therapy) or (2) receipt of two or more courses of 
blinded active OCS during the study treatment period.  The primary objective of the 
study is to demonstrate maintenance of control of HES symptoms during the treatment 
period as evident by the absence of HES flares.
HES Core Assessments to Monitor Disease Activities and Identify HES Flares during the 
Study
The clinical presentation of HES covers a wide variety of end-organ manifestations.  In 
an effort to assess the clinical manifestations in the most commonly affected organ 
systems in patients with HES, the HES Core Assessments (Section 7.3.2) will be utilized 
by the investigators to characterize the disease at baseline and also to monitor the changes 
during the treatment period.  This core assessment is the product of collective input from 
a panel of experts in the field and will provide the consistent framework for the 
investigators to assess an HES flare.  The HES Core Assessments will be used to record 
the subject’s clinical manifestations, but ultimately investigators will use their clinical 
judgment to determine if a subject is experiencing an HES flare.

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4.5.
Dose Justification
A dose of mepolizumab 300 mg administered SC every 4 weeks has been selected for 
investigation in this study.  The dose selected is lower than the 750mg IV administered 
every 4 weeks previously investigated in a HES study (MHE100185). The dose selection
was guided by information observed during the uncontrolled phase of an open-label 
extension HES study MHE100901 during which dosing interval was tailored (4 to 12 
weeks) according to individual patient disease and response, including blood eosinophil 
count assessment [Roufosse, 2013].
In support of the dose selection, a dose-response meta-analysis for blood eosinophil 
reduction (a proxy marker of pharmacology), including data from sixteen studies and 
various eosinophilic conditions, albeit dominated by asthma, was carried out 
[GlaxoSmithKline Document Number 2015N238375_00].  Results highlighted 
differences between severe asthma and HES populations and confirmed the effects of 
OCS on blood eosinophil suppression in both diseases. Dose response models confirmed 
that baseline blood eosinophil count is an important determinant of overall response, with 
both location and maximum achievable drug inhibition being baseline-dependent.
Inversion of the dose response showed that to achieve clinically meaningful target 
absolute blood eosinophil counts in patients with HES, doses higher than the therapeutic 
severe asthma dose of 100 mg SC are required. Although HES experts recognise that 
there is no universal blood eosinophil level or degree of suppression cut-off at which 
clinical benefit would be expected in all HES patients, considering that the current 
therapeutic option aims to maintain blood eosinophils as low as possible, it is not 
unreasonable to target a level within a normal range, i.e., <500 cells/µL and ideally 
between 200-300 cells/µL in the majority of HES patients. Acknowledging the 
limitations of extrapolation outside the range of data included in the dose-response model 
(to adjust for the effects of concomitant OCS treatment), it is predicted that patients with 
a Baseline blood eosinophil count between 1000 (minimal level required at Baseline in 
the proposed study) and 8000 cells/µL would achieve a blood eosinophil count between 
100-500 cells/µL following a SC dose of mepolizumab 300 mg every 4 weeks [Figure 17 
of GlaxoSmithKline Document Number 2015N238375_00]. Further analysis shows 
however that there will be limited additional benefit beyond this dose.
This dose should also be able to prevent bursts of blood eosinophils, which are triggered 
by external factors not very well understood and/or following OCS reduction as part of 
SoC in clinical practice, and subsequently prevent flare.
The selection of the 4-week dosing interval is supported by mepolizumab half-life of 
approximately three weeks, the dose response meta-analysis, also based on a dosing 
interval of every four weeks, and the consistent maintenance of pharmacological effect 
over this 4-week dosing interval at doses of mepolizumab 75 mg IV/100 mg SC and 
higher (MEA112997) [Pavord, 2012].
Mepolizumab has been studied in patients with HES at doses three-fold higher than 
proposed in this study for durations of up to 11 years.  During this time no apparent 
safety signal has been detected and no clinically meaningful trends in hematology or 
clinical chemistry have been noted.  Data from mepolizumab treatment over a 10-fold 

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range (75 to 750 mg IV every 4 weeks) in patients with severe asthma also have not 
shown any apparent increase in adverse events or laboratory abnormalities and hence an 
absence of response and dose-response to increasing doses of mepolizumab. Of note a 
300 mg SC mepolizumab dose is currently under investigation in an ongoing randomized, 
placebo-controlled study in patients with EGPA (MEA115921), a disease which shares 
many similarities with HES with regards to blood eosinophil levels at the time of 
diagnosis and also multi-organ involvement. Therefore, in addition to this placebo-
controlled study assessing 300 mg SC dose of mepolizumab for the treatment duration of 
32 weeks, Study MEA115921 will provide one-year safety data at 300 mg SC that may 
also be concomitantly administered with immunosuppressive therapies.
Taken together, the above information suggests a mepolizumab dose of 300 mg SC 
(delivered 3x100mg SC injections) every four weeks could provide clinical benefit in the 
HES patient population targeted in the HES Study 200622, and has therefore been 
selected for investigation for a treatment duration of 32 weeks.
4.6.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with SB-
240563 can be found in the Investigator’s Brochure (IB).  The following section outlines 
the risk assessment and mitigation strategy for this protocol:

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4.6.1.
Risk Assessment
Potential Risk of Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
Investigative Medicinal Product (IMP): Mepolizumab
Pre-Clinical and Clinical Findings
Risk of Systemic Reactions 
(e.g., hypersensitivity) and 
Local Injection Site Reactions 

In the placebo-controlled severe asthma studies both acute 
and delayed systemic reactions including hypersensitivity 
have been reported following administration of mepolizumab 
with incidence rates similar between mepolizumab and 
placebo-treated subjects (6% in the mepolizumab [all doses 
combined] group and 3% in the mepolizumab [100 mg 
SC/75 mg IV] combined group as compared with 5% in the 
placebo group). The most common symptoms reported with 
any systemic reaction included headache, rash, pruritus, 
fatigue, and dizziness.

In the placebo-controlled severe asthma studies an increase 
in the incidence of local injection site reactions has been 
observed with SC administration of mepolizumab compared 
with placebo (8% vs. 3%). There have been no reports of 
severe reactions. Pain, erythema, swelling, itching, and 
burning sensation were the most common symptoms 
reported.

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 AEs (SAEs) by GSK Medical 
Monitor; regular systematic review of AE/SAE data from 
ongoing studies by a GSK safety review team. 

Specific case report form (CRF) pages utilized for targeted 
collection of systemic and local reactions data.

Utilization of anaphylaxis diagnostic criteria as outlined by 
the 2006Joint National Institute of Allergy and Infectious 
Disease/Food Allergy and Anaphylaxis Network 
(NIAID/FAAN) 2nd Symposium on Anaphylaxis to collect 
data on reports of anaphylaxis (see Section 12.6).

Subjects are monitored in clinic for 1 hour for the 1st three 
administrations following dosing, then follow monitoring 
policies for the center.

An IDMC will be utilized during study.
Potential Risk of 
Immunogenicity

Biopharmaceutical products may elicit anti-drug antibody 
(ADA) and neutralizing antibodies (NAB), which have the 
potential to modulate pharmacokinetics (PK), 
To characterize the potential risk of immunogenicity:

Blood samples are collected in clinical studies for detection 

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Potential Risk of Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
pharmacodynamics (PD) or produce adverse reactions.  
However, humanized and fully human antibodies are less 
immunogenic than mouse or chimeric monoclonal 
antibodies.

In the placebo controlled severe asthma studies low 
incidence (6% 100 mg SC and 2% all IV doses) and low titer 
of ADA and neutralizing antibodies have been reported. To 
date there have been no apparent association with adverse 
events, loss of disease control and/or markedly altered PK 
or PD profiles associated with anti-mepolizumab antibodies 
in any subjects.

Immunogenicity data reported to date across the 
mepolizumab development program are summarized in the 
IB; see Section 5.4. ‘Clinical Immunogenicity’ and a 
summary of immunogenicity findings in the ‘Other Potentially 
Clinically Relevant Information for the Investigator’ section 
located in Section 6 titled ‘Summary of Data and Guidance 
for the Investigator’.
of both ADA and NAB.

PK/PD assessments will be conducted.

For subjects who develop anti-mepolizumab antibodies 
systematic review of AE/SAE data at the end of the study 
(after unblinding) will be conducted.
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 electrocardiogram 
(ECG) data in humans.

Daily monitoring of SAEs by GSK Medical Monitor; regular 
systematic review of AE/SAE data from ongoing studies by 
a GSK safety review team.

CV monitoring for study includes:
o
Enhanced baseline collection of CV risk factors & 
functional status;
o
Baseline evaluation of clinical symptoms of 
ischemic heart disease, if clinically indicated;
o
Use of GSK standard CRFs to collect additional

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Potential Risk of Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy

In study MHE100185 HES subjects received mepolizumab 
750 mg IV every 4 weeks for up to 36 weeks, cardiac events 
were reported by 7% of subjects in both mepolizumab and 
placebo arm s.  There was 1 death, due to cardiac arrest in 
the mepolizumab group not considered related to 
mepolizumab treatment.  This subject had severe HES with 
multiple cardiovascular complications and concurrent renal 
failure.  Other cardiac disorder AE occurred is palpitation (2 
subjects in the mepolizumab group and 1 subject in the 
placebo group).  The following events reported in the 
placebo arm only:  cardiovascular disorder, arterial 
dilatation, ventricular dysfunction and ventricular 
hypertrophy.

In study MHE100901 (open-label extension [OLE] study to 
MHE100185 above), subjects received mepolizumab 
750 mg IV for up to 67 months, 1 fatal and 2 non-fatal SAEs 
reported due to cardiac failure, none considered related to 
mepolizumab.

In study MHE104317 (compassionate use) 7% of patients 
reported SAEs of cardiac disorders. 3 SAEs reported, 1 
secondary to CHF, 1 due to cardiac arrest, & 1 due to MI, all 
were considered unrelated to mepolizumab.
Severe Asthma:

In Study MEA112997, a numeric imbalance in the number of 
serious cardiac events was observed for mepolizumab 
(7 subjects: 2/153 on 75 mg IV [3 events: myocardial 
ischemia, acute myocardial infarction, coronary artery 
thrombosis], 1/152 on 250 mg IV [1 event: coronary artery 
insufficiency] and 4/156 on 750 mg IV [4 events: myocardial 
data on selected CV events (i.e., myocardial 
infarction, hospitalization for unstable angina and 
congestive heart failure, arterial thrombosis, 
pulmonary embolism and deep vein thrombosis).

An IDMC will be utilized during study.

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Potential Risk of Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
ischemia, atrial fibrillation, myocardial infarction and 
supraventricular tachycardia]) compared with placebo (1 of 
155 subjects reported atrial flutter). This imbalance was not 
replicated in subsequent Phase III placebo-controlled 
studies, MEA115588 and MEA115575, and it was not 
observed previously in other controlled asthma trials or in 
other populations studied such as HES. 

In the OLE studies, cardiovascular events were similar in 
frequency and type with those reported from the placebo-
controlled severe asthma (PCSA) studies.

Cardiovascular events in the severe asthma program are 
summarized under AESI section of the IB.
Potential risk of alterations in 
immune response, potentially 
leading to increase in 
infections

This is a theoretical concern with biologics; however, critical 
review of preclinical toxicity data and pharmacological 
properties of mepolizumab suggests that the risk for 
potential immunotoxicity 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.

Across all PCSA, the frequency of subjects with infections 

Eosinophils may be involved in the immunological response 
to some helminth infections.  Subjects with recent parasitic
(helminth) infections will be excluded from the study or 
required to be adequately treated for helminth infections
before initiation of study treatment.  If a subject becomes
infected whilst receiving study treatment and does not 
respond to anti-helminth treatment, temporary 
discontinuation of study treatment should be considered in 
consultation with GSK Medical Monitor.

Daily monitoring of SAE by GSK Medical Monitor; regular 
systematic review of AE/SAE data from ongoing studies by 
a GSK safety review team 

An IDMC will be utilized during study.

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Potential Risk of Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
was similar between placebo (239/412 or 58%), 
mepolizumab 100 mg SC (136/263 or 52%) and 
mepolizumab 75 mg IV (209/344 or 61%).

In the OLE studies, rates of infections, including all 
infections, serious and opportunistic infections, were similar 
to those from the PCSA studies.

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’ HES subsection (for very common 
infections of nasopharyngitis, upper respiratory tract 
infection (URTI), rhinitis and bronchitis reported in other 
patient populations) sections located in Section 6 titled 
‘Summary of Data and Guidance for the Investigator’.
Potential risk of alterations in 
immune response potentially 
leading to increase in 
malignancies

Non-clinical and clinical experience to date does not support 
a role for mepolizumab in the development of malignancies.  
No evidence of defective tumor surveillance in IL-5 or 
eosinophil-deficient mice. Mepolizumab is not believed to 
possess an inherent carcinogenic potential or increase the 
susceptibility to tumor formation secondary to significant 
immunosuppres-sion, and there is no evidence to date that 
mepolizumab has produced immunosuppression in animals.

Reports of malignancies in the overall mepolizumab program 
(including asthma, HES, other eosinophil-driven diseases & 
healthy subjects) were similar across treatment groups and 
are those types common in the general population with a 
frequency rate of <1% at all individual doses and all doses of 

Subjects with a history of lymphoma or current lymphoma
will be excluded from the study.

Exclusion of subjects with current malignancy or previous 
history of cancer in remission for less than 12 months prior 
to randomization (Visit 2).  Subjects that had localized 
carcinoma (i.e., basal or squamous cell) of the skin which 
was resected for cure will not be excluded. 

Daily monitoring of SAEs by GSK Medical Monitor; regular 
systematic review of AE/SAE data from this study by a GSK 
safety review team

An IDMC will be utilized during study.

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Potential Risk of Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
mepolizumab combined.
A review of a well established cohort of patients with 
hyperoesinophilia including those with HES at the Mayo 
clinic showed that 5.1% developed hematologic malignancy 
over 13-year period; the median time the malignancy 
developed was 10 months after the onset of 
hypereosinophilia.  T-cell derived malignancies were most 
commonly diagnosed [Jin, 2015].

Malignancies, including lymphoma, reported to date across 
the mepolizumab program (severe asthma and HES) are 
summarized in the IB; see also  ‘Special Warnings and 
Special Precautions for Use’ section located in IB Section 6 
titled ‘Summary of Data and Guidance for the Investigator’.
Potential risk for exaggerated 
response of symptoms upon 
cessation of treatment

No apparent rebound eosinophilia observed in monkeys 
treated with mepolizumab.

Across the PCSA program, post-treatment AEs of asthma 
did not appear to occur at a significantly greater incidence 
following cessation of treatment with mepolizumab 
compared with placebo.

Daily monitoring of SAEs by GSK Medical Monitor; regular 
systematic review of AE/SAE data from ongoing studies by 
a GSK safety review team

An IDMC will be utilized during study.
Study Procedures 
Blinding eosinophil counts

This study is a double-blind study which will be used to 
support approval of the use of mepolizumab in the treatment 
of HES.  Unblinding eosinophil counts would compromise 
the integrity of the study.

An IDMC will be utilized during study.

Blood eosinophil-unblinded GSK personnel/delegates not 
involved with other aspects of study conduct will monitor the 
absolute eosinophil count results and trigger blinded OCS 
treatment to treat an eosinophilia flare (Section 6.4).

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Potential Risk of Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
Investigators, participating subjects, and GSK study 
personnel will be blinded to absolute blood eosinophil 
counts, total white blood cell count, and white blood count 
differentials (%) from randomization to the end of the 
study.

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4.6.2.
Benefit Assessment
Study 200622 is a 32-week treatment period, randomized, double-blind, placebo-
controlled trial to investigate the efficacy and safety of mepolizumab in the treatment of 
HES in adolescent and adult subjects receiving SoC therapy.
Data from three completed studies support the clinical utility/proof-of-concept of 
mepolizumab in the treatment of HES having demonstrated the use of mepolizumab to 
allow for a safe reduction of corticosteroid dose while maintaining clinical stability 
(MHE100185 [Rothenberg, 2008] and CRT112446 [Stein, 2008]) and safety 
(MHE100901 [Roufosse, 2013]) in subjects with HES.  In addition, the interim review of 
the mepolizumab HES compassionate use program (MHE104317 as well as named 
patient supply [MHE112562 and 112000]) with over 200 patients (data cut-off date of 23 
September 2013) demonstrated that mepolizumab is well tolerated and provides long-
term clinical benefit to some patients with HES [GlaxoSmithKline Document Number 
ZM2006/00080/04; Duncan, 2015].  Furthermore, mepolizumab has also demonstrated 
clinical benefit in other conditions where eosinophilia is considered to play an important 
part in the pathology, e.g., severe asthma [Haldar, 2009; Nair, 2009; Pavord, 2012], 
EGPA [Kim, 2010] and EoE [Stein, 2006].
In addition, subjects will attend monthly visits and therefore may benefit from the 
additional disease monitoring and interaction with health care professionals.
Data obtained from Study 200622 will provide a robust clinical evaluation of the efficacy 
and safety of mepolizumab in the treatment of HES.  It is planned to use the study results 
and supporting data as the basis for global regulatory submissions for mepolizumab for 
the treatment of HES.
4.6.3.
Overall Benefit:Risk Conclusion
Data from mepolizumab preclinical and clinical development support the ability of 
mepolizumab to inhibit IL-5, and consequently treat conditions associated with 
eosinophilia, such as HES.  To date, the safety profile of mepolizumab has been 
favorable.  Furthermore, there are no safety concerns with mepolizumab to date that 
would preclude investigation in HES. The Sponsor therefore maintains that investigation 
of the efficacy, safety and tolerability of mepolizumab is justified in Study 200622.
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product (IP) or other study 
treatment that may impact subject eligibility is provided in the IB [GlaxoSmithKline 
Document Number CM2003/00010/10].
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is 
essential.

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5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
INFORMED CONSENT
1. Capable of giving signed informed consent/assent as described in Section 10.2 which 
includes compliance with the requirements and restrictions listed in the consent form 
and in this protocol.
AGE
2. 12 years of age or older, at the time of signing the informed consent/assent
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
3. Subjects who have been diagnosed with HES for at least 6 months at randomization 
(Visit 2). HES diagnosis is based on signs or symptoms of organ system involvement 
and/or dysfunction that can be directly related to:

blood eosinophilia of >1,500 eosinophils/µL on at least two occasions, and/or

tissue eosinophilia
documented prior to Visit 2 without a discernible secondary cause (e.g., drug 
hypersensitivity, parasitic helminth infection, human immunodeficiency virus [HIV]
infection, non-hematologic malignancy).
Tissue eosinophilia is defined as a history of one or more of the following:

The percentage of eosinophils exceeds 20% of all nucleated cells in bone 
marrow sections.

In the opinion of a pathologist, tissue infiltration by eosinophils is extensive 
(massive) when compared with the normal physiologic range, compared with 
other inflammatory cells, or both.

A specific stain directed against an established eosinophil granule protein (e.g., 
major basic protein) reveals extensive extracellular deposition of eosinophil-
derived proteins indicative of local eosinophil activation [Valent, 2012].
4.
A history of two or more HES flares within the past 12 months prior to screening 
(Visit 1).  Historical HES flares are defined as documented HES-related worsening 
of clinical symptoms or blood eosinophil counts requiring an escalation in therapy.  
At least one HES flare within the past 12 months must not be related to a decrease in 
HES therapy during the 4 weeks prior to the flare.
5.
Subjects must have blood eosinophil count ≥1000 cells/µL present in the sample 
collected during screening (within 4 weeks prior to randomization).
6.
Subjects must be on a stable dose of HES therapy for the 4 weeks prior to 
randomization (Visit 2).  HES therapy includes but is not limited to oral 

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corticosteroid (OCS), immunosuppressive, and cytotoxic therapy.
SEX
7.
Male or female
A female subject is eligible to participate if she is not pregnant (as confirmed by a 
negative urine human chorionic gonadotrophin [hCG] test), not lactating, and at least 
one of the following conditions applies:
a. Females of non-reproductive potential (FNRP) defined as:

Post-menopausal women (including all women over 60 years of age, see 
below), OR
Pre-menopausal females with one of the following procedures documented 
and no plans to utilize reproductive techniques (e.g., in vitro fertilization or 
donor embryo transfer:

Bilateral tubal ligation or salpingectomy

Hysteroscopic tubal occlusion procedure with follow-up confirmation 
of bilateral tubal occlusion 

Hysterectomy

Bilateral Oophorectomy (surgical menopause)

Post-Menopause

Females 60 years of age or older

Menopause is the phase associated with complete cessation of 
menstrual cycles and implies the loss of reproductive potential by 
ovarian failure. This typically occurs around 50 years of age, although 
it may occur earlier or later. A practical definition accepts menopause 
after 1 year without menses with an appropriate clinical profile, e.g., 
age appropriate, >45 years, in the absence of hormone replacement 
therapy (HRT) or medical suppression of the menstrual cycle (e.g., 
leuprolide treatment).

In questionable cases for women < 60 years of age, a blood sample 
with simultaneous follicle stimulating hormone and estradiol falling 
into the central laboratory’s postmenopausal reference range is 
confirmatory (these levels need to be adjusted for specific 
laboratories/assays) [Kronenberg, 2008; Strauss, 2004].

Females under 60 years of age, who are on HRT and wish to continue, 
and whose menopausal status is in doubt, are required to use a highly 
effective method to avoid pregnancy, as outlined in the protocol. 
Otherwise, they must discontinue HRT to allow confirmation of post-
menopausal status prior to study enrolment. For most forms of HRT, at 
least 2 to 4 weeks will elapse between the cessation of therapy and the 
blood draw; this interval depends on the type and dosage of HRT. 

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Following confirmation of their post-menopausal status, they can 
resume use of HRT during the study without use of a highly effective 
method to avoid pregnancy. If laboratory values for FSH and estradiol 
are drawn and the results do not confirm menopause on a potential 
subject that otherwise met the specifications for being post-menopausal 
defined above without question, the subject may still enrol in the study 
as a FNRP if approved by the GSK Medical Monitor and the safety 
physician.
b. Reproductive potential and agrees to follow one of the options listed in the 
Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of 
Reproductive Potential (FRP) (see Section 12.5) from 30 days prior to the first 
dose of study medication and until 4 months after the last dose of study treatment.
The investigator is responsible for ensuring that subjects understand how to properly 
use these methods of contraception.
5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL)
1. Life-threatening HES or life-threatening HES co-morbidities: Imminently life-
threatening HES disease severity such that the likelihood of death is high unless the 
course of the disease is interrupted within 12 weeks prior to randomization (Visit 2).  
2. Other concurrent medical conditions that may affect the subject’s safety:
Subjects who have known, pre-existing, clinically significant endocrine, 
autoimmune, metabolic, neurological, renal, gastrointestinal, hepatic, hematological, 
respiratory or any other system abnormalities that are not associated with HES and 
are uncontrolled with standard treatment.
3.
Eosinophilia of unknown clinical significance
4.
12-lead ECG finding:
QTc > 450 msec or QTc > 480 msec in subjects with bundle branch block
An abnormal ECG finding from the 12-lead ECG conducted at Visit 1 if considered 
to be clinically significant and would impact the subject’s participation during the 
study based on the evaluation of the Investigator.
NOTE: 12-lead ECG results at screening (Visit 1) with the over-read by the 
centralized independent cardiologist must be received prior to assessing eligibility at 
Visit 2 by the Investigator.
5.
Subjects with documented history of any clinically significant cardiac damage prior 
to screening (Visit 1) that, in the opinion of the investigator, would impact the 

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subject’s participation during the study.
6.
Liver abnormality/disease:

ALT >2.5xULN or ALT>5xULN if documented HES with liver manifestations

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).
NOTE: 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.
NOTE: 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.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
7.
Clinical diagnosis of eosinophilic granulomatosis with polyangiitis (EGPA)
8.
Malignancy:

Subjects with a history of or current lymphoma

Subjects with current malignancy or previous history of cancer in remission for 
less than 12 months prior to randomization (Visit 2).  Subjects that had localized 
carcinoma (i.e., basal or squamous cell) of the skin which was resected for cure 
will not be excluded.
9.
FIP1L1-PDGFRStatus: Subjects who test positive for the FIP1L1-PDGFRfusion 
tyrosine kinase gene translocation.
Blood sampling is required for all subjects at screening (Visit 1) for this test unless 
the documented result is available.
10. Infection:

Subjects with chronic or ongoing active infections requiring systemic treatment, 
as well as subjects who have experienced clinically significant infections due to 
viruses, bacteria, and fungi within 4 weeks prior to randomization (Visit 2).

Subjects with a pre-existing helminthes infestation within 6 months prior to 
randomization (Visit 2).
11. Subjects with a known immunodeficiency (e.g., HIV), other than that explained by 
the use of OCS or other therapy taken for HES.
12. Other laboratory abnormalities: Evidence of clinically significant abnormality in the 
hematological, biochemical or urinalysis screen from the sample collected 
at screening (Visit 1), that could put the subject’s safety at risk by participating in the 

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study, as judged by the investigator
CONCOMITANT MEDICATIONS
13. Subjects who have previously received mepolizumab in the 4 months prior to 
randomization (Visit 2).
14. Subjects receiving any of the following:

Intravenous or subcutaneous corticosteroids in the 4-week period prior to 
randomization (Visit 2).

Any other monoclonal antibodies within 30 days or 5 half-lives, whichever is 
longer, of randomization (Visit 2).
15. Other investigational product/clinical study:

Subjects who have received treatment with an investigational agent (biologic or 
non-biologic) within the past 30 days or 5 drug half-lives whichever is longer, 
prior to randomization (Visit 2).  The term “investigational” applies to any drug 
not approved for sale in the country in which it is being used or investigational 
formulations of marketed products

Subjects who are currently participating in any other interventional clinical 
study
CONTRAINDICATIONS 
16. Subjects who are not responsive to OCS based on clinical response or blood 
eosinophil counts
17. Subjects with any history of hypersensitivity to any monoclonal antibody (including 
mepolizumab) or any steroid or steroid-containing product.
RELEVANT HABITS
18. Subjects with a known or suspected history of alcohol or substance abuse at 
screening (Visit 1) which in the opinion of the investigator could interfere with the 
subject’s proper completion of the protocol requirement.
5.3.
Screening/Baseline/Run-in Failures
A subject will be assigned a subject number at the time when the informed consent form 
(ICF) is signed.
A subject who is assigned a subject number, but does not complete any Visit 1 
procedures will be considered a pre-screen failure.  A minimal set of pre-screen failure 
information including Demography and any SAEs will be collected.

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Screen 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 Demography, Screen Failure 
details, Eligibility Criteria, and SAE.
For both pre-screen and screen failures, HES diagnosis, HES flares and HES medications 
taken within the 12 months prior to Visit 1 will be collected.
Re-screening of subjects will be allowed only upon approval by the GSK Medical 
Monitor.
5.4.
Withdrawal/Stopping Criteria
A subject may withdraw from study treatment at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioural or 
administrative reasons.  If a subject withdraws from the study, he/she may request 
destruction of any samples taken, and the investigator must document this in the site 
study records.
Withdrawal from study treatment
Subjects who discontinue study treatment prematurely (for any reason) should, where 
possible, continue in the study per protocol (Refer to Section 7.1 – Visits 3-11 for 
subjects who prematurely discontinue study treatment) until 32 weeks after 
randomization, including the collection of biological samples for laboratory assessments 
approximately 4 weeks and 12 weeks after the last dose of study treatment as well as 
daily eDiary completion.  Subjects will be considered to receive open-label mepolizumab 
after 32 weeks lapse from randomization, completing ‘Visit 11 for subjects who 
prematurely discontinue study treatment’ (Section 4.1).  If a subject’s last dose of study 
treatment was on Visit 9 (Week 24) and the subject does not continue with open-label 
mepolizumab after completing Visit 11 assessments (32 weeks from randomization), 
there will be an additional 8-week follow-up period, concluding with the 12 weeks post-
last dose follow-up visit (Visit 12).
Reasons for premature discontinuation of study treatment must be captured in the CRF, 
e.g., AE, lack of efficacy, protocol deviation, pregnancy, investigator discretion, consent 
withdrawal, lost to follow-up, study termination.
If a subject experiences an organ-threatening or an life-threatening event, the investigator 
should discuss study treatment continuation with the GSK Medical Monitor.
Subjects will be withdrawn from study treatment for any of the following reasons:

Meet the liver chemistry stopping criteria (Section 5.4.1)

Meet QTc stopping criteria (Section 5.4.2)

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
Use prohibited medication (i.e., as noted in Exclusion Criteria # 13, 14, & 15,
and Section 6.10.2, Prohibited Medications and Non-Drug Therapies) that cannot 
be safely discontinued while maintaining the subject’s health.

Treatment code unblinded: Subjects must be discontinued from study treatment 
if the treatment code is unblinded by the Investigator or treating physician. The 
primary reason for withdrawal from study treatment (the event or condition which 
led to the unblinding) will be recorded in the CRF.

Pregnancy: Any female subject who becomes pregnant.
Following withdrawal from study treatment, investigators and participating subjects 
should, where possible, continue to be blinded to absolute blood eosinophil counts, total 
white blood cell counts, and white blood count differentials (%) until completing the 32-
week period from randomization.  The subject’s blood eosinophil count will be 
monitored and blinded OCS will be triggered according to the protocol during this time 
(Section 6.4).
Withdrawal from study
For this study there are no pre-determined protocol-specific study withdrawal criteria.  
Every effort should be made by the investigator to keep the subject in the study.  
However, subjects are free to withdraw consent to participate in the study at anytime.  
The investigator may also, at his or her discretion, withdraw a subject from further study 
participation.  Subjects who are withdrawn from the study will not be replaced.
Reasons for withdrawal from the study must be captured in the CRF, e.g., consent 
withdrawn, lost to follow-up, study terminated, etc.
In the event of early withdrawal (EW) from the study, every effort should be made to 
have the subject return to the clinic for an EW visit (including the collection of biological
samples for laboratory assessments approximately 4 weeks after the last dose of study 
treatment) as well as the last follow-up visit approximately 12 weeks after the last dose of 
study treatment, and return all study-related materials.
Following withdrawal from the study, investigators and participating subjects should, 
where possible, continue to be blinded to absolute blood eosinophil counts, total white 
blood cell counts, and white blood count differentials (%) for a period of 4 weeks after 
the last study treatment.
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

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.

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
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”.
5.4.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria (Section 12.2) 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
Figure 2
Phase III-IV Liver Stopping and Monitoring Event Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus 
Bilirubin≥2x
ULN (>35% 
direct) or plus
INR>1.5, if 
measured*
Possible  
Hy’s Law
ALT≥3xULN
Both
ALT
≥8xULN
And
≥ 2X 
baseline 
value
Both
ALT≥3xULN
And
≥1.5x baseline 
value
Plus
Symptoms of 
liver injury or 
hypersensitivity
No
Yes
Yes
Yes
No
No
No
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*
*INR value not applicable to subjects on anticoagulants 
ALT ≥3xULN 
And ≥ 1.5x 
baseline 
value 
BUT
ALT<8xULN 
And <2x 
baseline 
value
And able to 
monitor for 4 
weeks
Yes
Yes
No
ALT ≥3xULN 
And ≥ 1.5x 
baseline value 
BUT
ALT<8xULN 
And <2x 
baseline value
persists for 
4 weeks or 
other stopping 
criteria met
No
Yes
If subject to be monitored weekly must refer to Liver Safety Required Actions and Follow up   
Assessments section in the Appendix
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Section 12.2.
5.4.1.1.
Study Treatment Restart or Re-challenge
Study treatment restart or re-challenge after liver chemistry stopping criteria are met by 
any subject participating in this study is not allowed.

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5.4.2.
QTc Stopping Criteria
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, if a subject is eligible for the protocol based on QTcB, then QTcB 
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 being 
collected for data analysis.  Safety ECGs and other non-protocol specified ECGs 
are an exception.
The QTc should be based on single or averaged QTc values of triplicate 
electrocardiograms obtained over a brief (e.g., 5-10 minute) recording period.
A subject who meets either of the bulleted criteria below will be withdrawn from the 
study treatment:

QTc > 500 msec OR Uncorrected QT > 600 msec

Change from baseline of QTc > 60 msec]
These criteria 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 subject should be discontinued from the study.
For patients with underlying bundle branch block, follow the discontinuation criteria 
listed below:
Baseline QTc with Bundle Branch Block
Discontinuation QTc with Bundle 
Branch Block
< 450 msec
> 500 msec
450 – 480 msec
≥ 530 msec
5.5.
Subject and Study Completion
A subject is considered to have completed the study when finishing the end-of-treatment
visit (Visit 11) 32 weeks after randomization.  If a subject’s last dose of study treatment 
is on Visit 9 (Week 24) or Visit 10 (Week 28) and the subject does not continue with 
open-label mepolizumab after completing Visit 11 assessments (32 weeks from 
randomization), the subject is considered to have completed the study when finishing up 
to 8-week additional follow-up period, concluding with the 12 weeks post-last dose 
follow-up visit (Visit 12).
The end of the study is defined as the last subject’s last visit.

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6.
STUDY TREATMENT
6.1.
Investigational Product 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.
Study Treatment
Product name:
SB240563 (mepolizumab)
Formulation 
description:
Mepolizumab 100 mg vial for injection contains target quantities 
of 10.3 mg sodium phosphate dibasic heptahydrate, 0.96 mg 
polysorbate 80 and 230.4 mg xucrose per vial.
Dosage form:
Lyophilized powder for injection reconstituted with Sterile Water 
for Injection, just prior to use.
Unit dose 
strength(s)/Dosage 
level(s):
3 vials (100mg/vial) per administration
Route of Administration
3 SC injections per administration
Dosing instructions:
Subjects will be dosed with three 100 mg SC injections every 
4 weeks.
Injections should be administered into the abdomen, upper arm,
or thigh.
Physical description
Mepolizumab will be provided as a lyophilized cake in sterile 
vials for individual use.
If a subject becomes infected with helminths while receiving study treatment and does 
not respond to anti-helminth treatment, temporary discontinuation of study treatment 
should be considered in consultation with GSK Medical Monitor.
Mepolizumab
Mepolizumab is a humanized IgG antibody (IgG1, kappa) with human heavy and light 
chain frameworks.  Mepolizumab will be provided as a lyophilized cake in sterile vials 
for single use.  The vial will be reconstituted with Sterile Water for Injection just prior to 
use.  Further details of dose preparation and administration can be found in the IB 
[GlaxoSmithKline Document Number CM2003/00010/10] and the unblinded reference 
manual.
Mepolizumab will be provided by GSK as open-label product to the unblinded site staff. 
Unblinded site staff are required for this study.  Unblinded site staff will be responsible 
for receipt, storage, reconstitution, and labelling, and accountability of IP.
The placebo in this study will be 0.9% sodium chloride solution and will be provided by 
the study site.

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The contents of the label will be in accordance with all applicable regulatory 
requirements.
Blinded OCS
GSK will provide blinded OCS.  Each bottle will have a unique identifier number, and 
contain either 5 mg OCS (prednisolone or prednisone capsules) or matching placebo 
capsules.  Refer to Section 6.4 for dispensing.
6.2.
Treatment Assignment
Subjects will be assigned to study treatment in accordance with the randomization 
schedule generated by Clinical Statistics, prior to the start of the study, using validated 
internal software to receive either:
Mepolizumab:
or
Placebo (0.9% sodium chloride):
Three 100 mg SC injections
administered every 4 weeks 
(8 administrations)
Three SC injections administered every 
4 weeks (8 administrations)
Due to potential differences in standards of care between regions, the randomization will 
be stratified by region.
An unblinded site staff member will be assigned to the study to prepare the appropriate
medication according to the study subject’s treatment assignment.  Subjects eligible to 
enter the study will be assigned to treatment randomly through an interactive response 
technology (IRT).
Subjects will be monitored during SC administration and for 1 hour after the first three 
administrations and then follow monitoring policies for the center.  Such monitoring will 
include general safety monitoring including monitoring for both systemic reactions (e.g., 
hypersensitivity) and local 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.
6.3.
Treatment Blinding
Once prepared mepolizumab and placebo will be identical in appearance and will be 
administered by a blinded member of the site staff.  The blinding of those involved in the 
evaluation of the study, i.e., physician, nurse and subject will be maintained at all times.
This will be a double- blind study and the following will apply.

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
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.

Investigators have direct access to the subject’s individual study treatment.

It is preferred (but not required) that the investigator first contacts the GSK 
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. 

The date and reason for the unblinding must be fully documented in the CRF.
A subject will be withdrawn from study treatment if the subject’s treatment code is 
unblinded by the investigator or treating physician. The primary reason for 
discontinuation of study treatment (the event or condition which led to the unblinding) 
will be recorded in the CRF (Section 5.4).
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.
6.4.
Blood Eosinophil Blinding
Investigators, GSK personnel involved in the study, and subjects will be blinded to the 
results of absolute blood eosinophil counts, total white blood cell counts, and white blood 
count differentials (%).  Subjects that have an increase in blood eosinophils above the 
predetermined threshold will be instructed to take OCS capsules.  In order to maintain the 
blind, this treatment will be with blinded OCS capsules.
All subjects will be provided 2 bottles of blinded OCS capsules, one containing 5mg 
OCS capsules (active OCS treatment) and a second one containing matching placebo
capsules (placebo OCS treatment).  These will be dispensed to each subject at each 
scheduled clinic visit and as needed.  Subjects will also have blood drawn at each visit to 
assess the blood eosinophil count (Hematology assessment in Table 4).
A brief schematic of the trigger alert system is shown in Figure 3.

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Figure 3
Blood eosinophil blinding and blinded OCS trigger schematic
Blood eosinophil-unblinded GSK personnel/delegates not involved with other aspects of 
study conduct will review the results from the central laboratory for absolute blood 
eosinophil count.  If a pre-specified threshold blood eosinophil level (i.e., 2 x Baseline 
value [randomization] or Baseline value + 2500 cells/L) is reached (eosinophilia flare), 
blood eosinophil-unblinded GSK personnel/delegates will communicate with the 
investigator to initiate blinded OCS treatment from one of the bottles provided (active 
treatment) unless the subject’s HES therapy (OCS, cytotoxic agent, or 
immunosuppressive agent) has already been increased due to a symptom flare within the 
past 2 weeks.  The subject will take the blinded OCS from the assigned bottle for ~2 
weeks.  A subject who does not reach the pre-specified blood eosinophil threshold with a 
similar blood draw date will be selected to initiate a placebo treatment in a blinded 
manner, to maintain study blood eosinophil blinding.

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The dosing regimen for a course of blinded OCS is as shown in Table 1.
Table 1
A course of blinded OCS regimen
Days
Dose (mg/day)
Number of 5mg 
capsules/day
1-3
40
8
4-6
20
4
7-9
10
2
10-
Until notified regarding whether to discontinue or
start a new course of blinded OCS regimen
Otherwise, until the next scheduled clinic visit
5
1
Approximately 2 weeks after the scheduled clinic visit, the blood eosinophil count will be 
assessed again for the subject who started blinded OCS (both active and placebo).  The 
subject who has taken active blinded OCS will be instructed to continue with a new 
course of blinded OCS regimen from Day 1 (i.e., 40mg) until the next scheduled clinic 
visit if the blood eosinophil count is at or above the threshold unless the subject’s HES 
therapy (OCS, cytotoxic agent, or immunosuppressive agent) has been increased due to a 
symptom flare since the initiation of the current course of blinded OCS, and discontinue 
if the blood eosinophil count is below the threshold.  For subjects taking placebo-blinded 
OCS, continuation/discontinuation of blinded OCS will be determined depending on the 
continuation/discontinuation of their matched subject on active-blinded OCS as described 
in Figure 3.
A subject whose blood eosinophil count is at or above the threshold while receiving 
blinded placebo OCS will be re-evaluated when the subsequent test result from the 
scheduled clinical visit is available to determine whether blinded active OCS should be 
initiated.
A subject who starts blinded OCS based on the 2 weeks post-randomization (Visit 3) 
blood eosinophil count (both the active OCS and the matched placebo OCS subjects) will 
continue taking the blinded OCS until they return to the next scheduled clinic visit 
(Visit 4).
In the event that a subject has a blood eosinophil count that reaches the pre-defined 
threshold to trigger blinded active OCS for 2 consecutive monthly scheduled clinic visits,
blood eosinophil-unblinded GSK physician/delegates will inform the investigator so that 
the investigator can take further measures as necessary.

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Subjects who have to travel a great distance to the study site will be given an option to 
have a between-clinic visit blood draw locally and ship the sample to the central 
laboratory.
6.5.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
6.6.
Preparation/Handling/Storage/Accountability
A description of the methods and materials required for preparation of mepolizumab or 
placebo will be detailed in the unblinded reference manual.
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are 
reported and resolved before use of the study treatment.

Only subjects enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment.  All study 
treatments must be stored in a secure environmentally controlled and monitored 
(manual or automated) area in accordance with the labelled storage conditions 
with access limited to the investigator and authorized site staff. 

The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (i.e., receipt, reconciliation and final disposition records).  

Further guidance and information for final disposition of unused study treatment 
are provided in the Study Reference Manual (SRM).

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, GSK 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.
Mepolizumab must be stored in a secure area under the appropriate physical conditions 
for the product, which includes storage in a refrigerator or at a temperature of 2-8C and 
protected from light.  Maintenance of a temperature log (manual or automated) is 
required.  Access to study treatment will be limited to the investigator’s authorized 
unblinded site staff.  Maintenance of a temperature log (manual or automated) is 
required.  Study treatment must be dispensed or administered only to subjects enrolled in 
the study and in accordance with the protocol.

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6.7.
Compliance with Study Treatment Administration
Study treatment will be subcutaneously administered to subjects at the site.  
Administration will be documented in the source documents and reported in the CRF.
Compliance with blinded OCS will be based on pill counts at the time of dispense and 
collection of the bottles.  These will be documented in the source documents and reported 
in the CRF.
6.8.
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.
In the event that mepolizumab is administered more than as detailed in the protocol in 
terms of dose or frequency, the investigator should contact the GSK Medical Monitor 
immediately.
6.9.
Treatment after the End of the Study
Subjects who complete the protocol-specified assessments for the 32-week period from 
randomization (Section 4.3) will be evaluated, and if eligible, may be enrolled into an 
extension study to receive open-label mepolizumab.
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.
6.10.
Concomitant Medications and Non-Drug Therapies
6.10.1.
Permitted Medications and Non-Drug Therapies
Use of standard HES therapy including OCS, immunosuppressive or cytotoxic therapy 
(e.g., hydroxyurea, IFNα, cyclosporine, imatinib, methotrexate, azathioprine) will be 
permitted during the study.  As specified in Inclusion Criterion #6, subjects must be on a 
stable dose of HES therapy for the 4 weeks prior to randomization (Visit 2) [Section 5.1].  
The same regimen of HES therapy must be maintained throughout the 32-week study 
treatment period unless there is worsening of symptom(s) that requires an increase in 
therapy.  If a subject has worsening of symptom(s) and requires an increase in therapy 
after randomization, the subject will be considered to be experiencing a flare 
(Section 7.3.1).  Once the subject regains disease control, the investigator is encouraged, 
as medically appropriate, to adjust the dose of HES therapy back to the level prior to the 
disease worsening.
A reduction in standard HES therapy dose for safety reasons, with return to the original 
dosing regimen when possible, is permitted in consultation with the GSK Medical 
Monitor.

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Additional therapies required to treat non-HES related medical conditions during the 
study are permitted in consultation with the GSK Medical Monitor and must be 
prospectively captured in the CRF.
6.10.2.
Prohibited Medications and Non-Drug Therapies
Initiation of new medications or herbal remedies which may alter the course of HES or 
interact with the study treatment is prohibited within their specified timeframe and 
throughout the study (Visit 0 to Visit 11 inclusive) with the exception of HES therapy to 
treat an HES flare (Section 7.3.1).
In addition, the following medications will be prohibited:

Any investigational agents (biologic or non-biologic) within the 30 days or 5 drug 
half-lives whichever is longer, prior to screening (Visit 1), and until Visit 11.  The 
term “investigational” applies to any drug not approved for sale in the country in 
which it is being used or investigational formulations of marketed products.

Any other biologic agents (except for IFNα): within 30 days or 5 half-lives, 
whichever is longer, of screening (Visit 1), and until Visit 11.
In the event that the use of a prohibited medication is identified by the study site, the 
investigator must use clinical judgment in balancing protocol compliance (discontinuing 
the medication) and subject safety.  The investigator should assess whether the 
medication is required or likely to be required to maintain subject’s health in control.  
The investigator also should assess whether the medication can be stopped after subject’s 
health is re-established.
7.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct.
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Table (Section 7.1).
The following points must be noted:

Subject-completed assessments are done at the beginning of a visit in Section 7.1 in 
the order presented in the electronic device.

Blood draws are done after vital signs and prior to dosing of study treatment.

The timing and number of planned study assessments, including safety, PK, and PD
assessments may be altered during the course of the study based on newly available 
data to ensure appropriate monitoring.

The institutional Review Board (IRB)/Independent Ethics Committee (IEC) and 
investigators will be informed of any safety issues that require alteration of the safety 
monitoring scheme or amendment of the Informed Consent Form.

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7.1.
Time and Events Table
Table 2
Time and Events Table
Procedures
Pre-
screen
Screen Randomi-
zation
Double-blinded treatment period
Additional 
follow-up
Study visit
0
1
2
3
4
5
6
7
8
9
10
11
End-of-
treatment 
Flare19
3-11 for 
subjects 
who 
prematurely 
discontinue 
study 
treatment20
EW
12
Study week
Up to 
~4 
weeks
(wks)
0
2
(5
days)
4
1
wks
8
1
wks
12
1
wks
16
1
wks
20
1
wks
24
1
wks
28
1
wks
32
1 wks
~12 wks 
after last 
dose
1 wks
Informed consent1
X
Demography
X
Medical history
X
History of HES (diagnosis/flares) and treatment 
(past 12 months)
X
CV history/risk factors
X
Inclusion/exclusion
X
X
Parasite screening2
X
Efficacy and PRO assessments
Subject-RTS3
X
X
X
X
X
X
X
X
X
SSR2
X
X
X
X
X
X
X
X
X
X
Modified MSAS-SF3
X
X
X
X
X
X
X
X
PROMIS sleep and physical function scales2
X
X
X
X
X
X
SF-36 v23
X
X
X
X
X
X
X
X
X
X
X
WPAI-GH v23
X
X
X
X
X
X
X
X
X
X
X
Steroid perception questionnaire3
X
HES Core Assessments (clinician assessment) 
/Flare detail
X
X
X
X
X
X
X
X
X
X
X
X
Clinician-RTS
X
X
X
X
X
X
X
X
X

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Procedures
Pre-
screen
Screen Randomi-
zation
Double-blinded treatment period
Additional 
follow-up
Study visit
0
1
2
3
4
5
6
7
8
9
10
11
End-of-
treatment 
Flare19
3-11 for 
subjects 
who 
prematurely 
discontinue 
study 
treatment20
EW
12
Study week
Up to 
~4 
weeks
(wks)
0
2
(5
days)
4
1
wks
8
1
wks
12
1
wks
16
1
wks
20
1
wks
24
1
wks
28
1
wks
32
1 wks
~12 wks 
after last 
dose
1 wks
HCRU
X
X
X
X
X
X
X
X
X
X
Spirometry
X
X
X
X
X
X
Echocardiogram4
X
X
X
Safety assessments
Physical examination5
X
X
X
X
X
X
X
X
X
X
X
Height and weight6
X
X
X
X
X
Concomitant meds including maintenance OCS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs7
X
X
X
X
X
X
X
X
X
X
X
X
ECG
X
X
X
AEs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SAEs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory assessments8
Hematology9
X
X
X
X
X
X
X
X
X
X
X
X
X
X21
Chemistry10
X
X
X
X
X
X
X
X
X
X
X21
X21
Troponin
X
X
X
X
X
X
X
X
X
X
X21
X21
Pregnancy test11
X
X
X
X
X
X
X
X
X
X
X21
X21
Aldolase
X
X
X
X
X
X
X
X
X
X
Lipoproteins (fasting)12
X
Urinalysis13
X
X
X21
X21
Hep B & C serology14
X
F/P status15
X
T-cell profile
X
X
X21
X21
Total IgE
X

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Procedures
Pre-
screen
Screen Randomi-
zation
Double-blinded treatment period
Additional 
follow-up
Study visit
0
1
2
3
4
5
6
7
8
9
10
11
End-of-
treatment 
Flare19
3-11 for 
subjects 
who 
prematurely 
discontinue 
study 
treatment20
EW
12
Study week
Up to 
~4 
weeks
(wks)
0
2
(5
days)
4
1
wks
8
1
wks
12
1
wks
16
1
wks
20
1
wks
24
1
wks
28
1
wks
32
1 wks
~12 wks 
after last 
dose
1 wks
PK
X
X
X
X21
X21
X21
PD (IL-5)
X
X
X
Immunogenicity (Anti-drug antibody)
X
X
X
X21
X21
X21
Genetics16
X
Sample collection for biomarker sub-study17
X
X
X
X21
X21
Investigational product & other study treatment
Study treatment administration18
X
X
X
X
X
X
X
X
Dispense/collect blinded OCS
X
X
X
X
X
X
X
X
X
X
X
X
Interactive Response Technology (IRT)/electronic CRF (eCRF)/electronic Diary (eDiary)
Register visit on 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
Dispense (D) /collect (C) eDiary22
D
C
C for 
Visit 11
C
Review eDiary
X
X
X
X
X
X
X
X
X
X
X
X

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EW: Early withdrawal
1.
Pre-screen visit to obtain informed consent can occur on the same day as Visit 1, but informed consent must be obtained prior to starting Visit 1 procedures.
2.
Parasitic screening is only required in countries with high-risk or for subjects who have visited high-risk countries in the past 6 months.  Sites should use local laboratories.
3.
Subject-completed assessments are done at the beginning of a visit.
4.
Echocardiogram is performed to support CV assessment at screening and at the end of study treatment for all subjects.  Echocardiogram at Visit 1 is required unless there is a 
documented result within the previous 6 months from Visit 1.
5.
Findings during physical examination related to HES will be recorded in the HES Core Assessments/flare detail.
6.
Height to be measured at screening only.
7.
Vital sign measurements will include temperature, systolic and diastolic blood pressure and pulse rate.
8.
During the treatment period, all laboratory samples (Table 4) should be obtained pre-dose.
9.
Refer to Section 6.4 for additional blood draw between the scheduled clinical visits for subjects who will administer blinded OCS.
10. Clinical chemistry will include analytes and liver chemistry monitoring.
11. Negative urine pregnancy test result must be confirmed prior to dosing in women of reproductive potential.
12. Lipoprotein (fasting) included in clinical chemistry. Subject must be in a fasting state. If the subject has not fasted, he/she may return to the clinic to collect this sample.
13. Urine tests are done using dipstick.  If found abnormal, the urine sample will be sent to the central laboratory for further testing.
14. If test was performed within 3 months prior to randomization, testing at screening is not required.
15. F/P test is required if no documented results are available.
16. Informed consent for optional sub-studies (e.g., genetics research) must be obtained before collecting a sample.  Genetic sample collection is recommended at Visit 2, but may be 
drawn at any time after the subject is consented and randomized.
17. Sample collection for the optional biomarker sub-study should be done after obtaining a written consent.
18. The date and time of the administration of study treatment will be recorded in the CRF.  For safety monitoring requirement, refer to Section 6.2.
19. Assessments will be collected when possible depending on the clinical status during worsening of symptoms between scheduled clinic visits to evaluate for an HES flare.  
Spirometry for a respiratory flare, and troponin, echocardiogram, & ECG for a CV flare will be performed (Selective assessments depending on the type of flare are noted in the 
table with the gray shade).  Echocardiogram will be performed only if there is a change in HF classification (see Section 12.7) and/or the investigator determines that there is a 
need for assessment.  When attending the clinic visit at the time of a suspected HES flare is not possible, the investigator should make every effort to evaluate the subject via 
telephone and complete the HES Core Assessments (Section 7.3.2).
20. Subjects who prematurely discontinue study treatment will continue to attend 4-weekly scheduled clinic visit and complete these assessments.  Blood samples for hematology will 
be collected at these visits for blinded blood eosinophil monitoring (Section 6.4).  All other laboratory assessments are completed at 4 and 12 weeks after the last dose only as 
noted in footnote #21.
21. Approximately 4 weeks after the last dose of study treatment, every attempt should be made to collect urine and blood samples for laboratory assessments.  In addition, all
subjects will be brought in for an additional follow-up visit 12 weeks after the last dose, including the collection of a blood sample for measurement of anti-drug antibodies and PK,
unless the subject receives open-label mepolizumab according to the protocol criteria at that time.
22. Subjects will complete BFI and HES daily symptoms (HES-DS) in the eDiary on a daily basis.  Subjects must complete the eDiary for at least 7 days prior to randomization.  
Subjects who prematurely discontinue study treatment will continue daily eDiary completion and return the eDiary at Visit 11 for EW.

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7.2.
Screening and Critical Baseline Assessments
Cardiovascular medical history/risk factors (as detailed in the CRF) will be assessed at 
screening.
The following demographic parameters will be captured: year of birth, sex, race and 
ethnicity.
Medical/medication history will be assessed as related to the inclusion/exclusion criteria 
listed in Section 5.
Procedures conducted as part of the subject’s routine clinical management [e.g., blood
count] and obtained prior to signing of informed consent may be utilized for screening or 
baseline purposes provided the procedure meets the protocol-defined criteria and has 
been performed within the timeframe defined in the Time and Events Schedule.
PRO questionnaires should be completed by subjects before any other assessment at a 
clinic visit.
Evaluation of medical history relating to the subject’s HES at screening includes:

Date of diagnosis and/or approximate duration since diagnosis

Requirement for therapy (e.g., immunosuppressive or cytotoxic therapy) 
including OCS for the management of their HES during 12 months prior to 
screening (Visit 1)

Number and type(s) of HES flares (including organ systems affected and the type 
of interventions) experienced during the 12 months prior to screening (Visit 1).  
Refer to Section 5.1 for the definition of a historical HES flare (Inclusion 
Criterion #4).

Documentation of any of the following complications of HES: gangrene, massive 
pulmonary hemorrhage or respiratory failure requiring ventilator support, 
congestive cardiac failure, renal failure requiring dialysis, cerebrovascular 
accident.
At randomization (Visit 2), the HES Core Assessments will be completed to establish the 
baseline characteristics of subjects’ HES.  Throughout the treatment period, the same set 
of the assessments will be utilized to monitor changes in their disease activity for major 
organ systems affected by HES.  Further information can be found in Section 7.3.2.
7.3.
Efficacy
7.3.1.
HES flare
An HES flare is defined as either
a) An HES-related clinical manifestation based on a physician-documented change 
in clinical signs or symptoms resulting in the need for either of the following:
- An increase in the maintenance OCS dose by at least 10mg/day for 5 days

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- An increase in or addition of any cytotoxic and/or immunosuppressive HES 
therapy
or
b) Receipt of two or more courses of blinded active OCS during the treatment 
period.
The start date for an HES flare meeting flare endpoint definition ‘a)’ will be defined as 
the date of therapy escalation confirmed by the investigator attributable to an HES-related 
clinical manifestation. The start date for an HES flare meeting flare endpoint definition 
‘b)’ will be defined as the date of the blood draw at which the second course of blinded 
active OCS was triggered via scheduled blood sampling for eosinophil monitoring.
When a subject experiences an HES flare as defined in ‘a)’ above, the investigator will 
monitor the change in disease control per routine medical care (e.g., follow-up call) and 
record the resolution of the flare including the end date.  Investigators are encouraged, as 
medically appropriate, to return the subject’s treatment regimen to the baseline 
(randomization) after the flare has resolved.
An increase in blood eosinophils only (without any other clinical manifestations) during 
the study may trigger an alert which will result in administration of additional blinded 
OCS (active treatment) [Section 6.4]. When a subject receives the second course of 
blinded active OCS during the 32-week treatment period, the subject will be considered
to be experiencing a flare.  Subsequently, the date of the first blood draw at which blood 
eosinophil count is below the threshold to trigger blinded active OCS will be the 
resolution date.  Each subsequent course of blinded active OCS beyond 14 days from the 
resolution date of the preceding flare will be considered as an additional flare (e.g., 
3 courses of blinded active OCS are considered as 2 flares, 4 courses of blinded active 
OCS are considered as 3 flares, etc.).
For subjects who reduce the dose of HES therapy after randomization for safety reasons 
(Section 4.1), the increase in HES therapy used to define an HES flare will be the change 
from the dose at randomization.
In the event of disease worsening for which the investigator suspects an HES flare 
between scheduled clinic visits, when possible, the subject will return to the clinic to have 
the unscheduled ‘Flare’ visit assessment completed as described in the Time and Events 
Table (Section 7.1).  When attending the clinic visit at the time of a suspected HES flare 
is not possible, the investigator should make every effort to evaluate the subject via 
telephone and complete the HES Core Assessments (Section 7.3.2).  If an escalation of 
therapy is initiated by a non-study physician, the investigator should confirm that the 
escalation in therapy is attributable to an HES-related clinical manifestation.
Investigators will be required to record details pertaining to the HES flare event in the 
CRF from randomization (Visit 2) until study completion at Week 32 or Early 
Withdrawal (EW).  This should include details regarding the clinical symptoms resulting 
in the flare with detail of the required intervention(s), e.g., OCS dose increase, or
addition or escalation of immunosuppressive or cytotoxic therapy.  In addition, all other 

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relevant clinical, laboratory or other diagnostic investigations required to confirm the 
flare must be captured in the CRF.
7.3.2.
HES Core Assessments (Clinician Assessment)
Clinical evaluation by the investigator will be guided by the HES Core Assessments 
(Table 3), consisting of clinical signs and symptoms that reflect the heterogeneous nature 
of HES observed in clinical practice.  During the study, the investigator will evaluate 
subjects at each clinic visit using the HES Core Assessments and determine whether 
worsening of signs/symptoms supports an increase in HES therapy.  In addition, to 
further characterize the basis for determination of flare and increase in therapy, the 
investigator will prepare a narrative for each HES flare.
The HES Core Assessments will characterize each subject’s clinical manifestations at 
baseline and monitor for changes throughout the study.  The investigator will be asked to 
rule out other possible etiologies for the change in clinical symptoms, such as an 
infection, prior to diagnosing an HES flare.  For the “others” category in Table 3, specific 
components of the physical exam will be used as part of the baseline core assessments 
and throughout the study to monitor for the presence or absence of changes in exam 
findings.  Findings of the HES Core assessments will be recorded in the electronic 
device.
Table 3
HES Core Assessments
Symptoms
Assessment
Constitutional
Fatigue
Pain (including but not limited to muscle, joint, general pain)
Angioedema (swelling under the skin)
Each symptom rated using a 0-3 
scale
Dermatologic
Rash
Itch
Hives
Others (specify)
Each symptom rated using a 0-3 
scale
Gastrointestinal
Average number of vomiting a day in the past week
Average number of diarrhea a day in the past week
Average number of stools a day in the past week
Abdominal pain
Difficulty in swallowing food
Each symptom rated using a 0-3 
scale

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Symptoms
Assessment
Respiratory
Breathing symptoms such as shortness of breath and 
wheezing
0-3 scale
Dyspnea (shortness of breath)
0-3 scale
Cough
0-3 scale
Sinus-related symptoms:
Nasal congestion
Sinus headache/facial pain/pressure
Postnasal drip (drainage down the back of the throat)
Purulent rhinorrhea (discoloured & thick nasal discharge)
Ear fullness
Each symptom rated using a 0-3 
scale
Cardiovascular
Heart failure classification for functional capacity
Classes I-IV
Heart failure classification for objective assessment
Classes: A-D
Neurologic
Sensory
Motor
Cognitive and Mental status change
Each symptom rated using a 0-3 
scale
Others
Vascular, venous, arterial, loss of pulse, splinter hemorrhage, 
renal failure, splenomegaly, other (specify)
Each identified symptom rated using 
a 0-3 scale
0-3 scale symptom score: 0 for not present or no impact, 1 for present but minimal impact, 2 for significant impact 
on daily activities, 3 for incapacitating
7.3.3.
Spirometry
Spirometry will be conducted at the visits specified in the Time and Events table (Table 
2).  Spirometry instrument and training will be provided by a vendor.
Prior to the randomization visit (Visit 2) and any visit where spirometry is assessed, 
subjects should withhold short-acting beta2-agonists (SABAs) for at least 6 hours and 
long-acting beta2-agonists (LABAs) for approximately 12 hours to minimize the effect of 
medications on spirometry.

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Due to diurnal variation associated with lung function, when possible, spirometry should 
be performed at the same time of day (1 hour) as at the randomization (Visit 2) 
assessment.
7.3.4.
Echocardiogram
Subjects who have a documented echocardiogram result within 6 months of Visit 1 will 
not require a screening echocardiogram.  When a CV flare is suspected during the study 
treatment period (based on a change in the HF class [see Section 12.7] and/or 
investigator’s judgment), an echocardiogram will be performed when possible.
7.3.5.
Healthcare Resource Utilization (HCRU)
All unscheduled HES-related healthcare utilization (Section 7.1) will be recorded in the 
CRF including telephone contacts, specialist nurse visits, visits to a physician’s office, 
home visits (day and night time), outpatient visits, visits to urgent care, visits to the 
emergency department, and hospitalizations associated with the subject’s worsening of 
symptoms.  Hospitalization data should be categorized by ward type (e.g., intensive care 
unit [ICU] and usual care).  Hospital length of stay in each type of ward will also be 
recorded.
The HCRU worksheet used by the subject to record all healthcare contacts experienced 
since the last visit will be presented to the investigator (or designee) at the clinic visits.  
Subjects will be asked to bring their worksheet to every study site 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. The investigator (or designee) should ask the subject if any of 
the healthcare contacts that are recorded on the worksheet were due to a worsening of 
HES symptom.  The investigator can refer to his/her records to verify or supplement 
information given by the subject, if necessary.
7.4.
Safety
Planned timepoints for all safety assessments are listed in the Time and Events Table 
(Section 7.1).  Additional timepoints for safety tests (such as vital signs, physical exams 
and laboratory safety tests) may be added during the course of the study based on newly 
available data to ensure appropriate safety monitoring.
Safety assessments include:

Adverse Events including systemic reactions (e.g., hypersensitivity) and local site 
injection-related reactions (AEs of special interest)
NOTE:  Systemic reactions can be allergic or non-allergic in nature and are typically 
mild to moderate in intensity, generally develop within several hours of the injection 
but also may have a delayed onset (i.e., days).  Anaphylaxis is the most severe form 
of hypersensitivity reactions.  Both AEs of special interest, local injection site 
reactions and systemic reactions, will have additional information (i.e., 
corresponding symptoms) collected via AE and SAE pages in the eCRF.  In addition, 
the information whether an event met the diagnostic criteria for anaphylaxis as 

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outlined by the Second Symposium on Anaphylaxis ([Sampson, 2006], see Section 
12.6), and in Section 12.6 will be collected on the AE and SAE CRF pages.

Hematological and clinical chemistry parameters

Vital signs (pulse rate and systolic and diastolic blood pressure)

Presence of anti-drug antibodies to mepolizumab
The following safety endpoints will be derived:

Change from baseline in systolic blood pressure

Change from baseline diastolic blood pressure

Change from baseline in pulse rate

12-lead ECG to derive the following endpoints:

Mean change from baseline in the QTcF (QT interval corrected by Fridericia's 
method)

Mean change from baseline in QTcB (QT interval corrected by Bazett's method)

Maximum change from baseline for QTcF and QTcB.
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Section 12.4.
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE.
7.4.1.1.
Time period and Frequency for collecting AE and SAE information

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK product 
will be recorded from the time a subject consents to participate in the study up to and 
including any follow-up contact.

AEs will be collected from the start of study treatment until the follow-up contact (see 
Section 7.4.1.3), at the timepoints specified in the Time and Events Table 
(Section 7.1).

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.

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Section 12.4.6.

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.

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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 
Section 12.4.5.
7.4.1.2.
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?” or “How does your child seem to feel?”

“Have you had any (other) medical problems since your last visit/contact?” or
“Has your child had any (other) medical problems or seem to act differently in 
any way since his/her last visit/contact?”

“Have you taken any new medicines, other than those provided in this study, 
since your last visit/contact?” or “Has your child needed to take any medicines, 
other than those provided in this study, since his/her last visit/contact?”
7.4.1.3.
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 defined in Section 7.4) will be followed until resolution, until the condition stabilizes, 
until the event is otherwise explained, or until the subject is lost to follow-up (as defined 
in Section 5.4). Further information on follow-up procedures is given in Section 12.4.3.
7.4.1.4.
Cardiovascular and Death Events
For any cardiovascular events detailed in Section 12.4.3 and all deaths, whether or not 
they are considered SAEs, specific CV and Death sections of the CRF will be required to 
be completed.  These sections include questions regarding cardiovascular (including 
sudden cardiac death) and non-cardiovascular death.
The CV CRFs are presented as queries in response to reporting of certain CV Medical 
Dictionary for Regulatory Activities (MedDRA) terms.  The CV information should be 
recorded in the specific cardiovascular section of the CRF within one week of receipt of a 
CV Event data query prompting its completion.
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
7.4.1.5.
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. 

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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, IRB/ IEC and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
7.4.2.
Pregnancy

Details of all pregnancies in female subjects that occur from the first dose of study 
treatment and until at least 4 months post-last dose of study treatment will be 
collected.

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 
Section 12.5.2.
7.4.3.
Physical Exams

A complete physical examination will include, at a minimum, assessment of the ENT, 
Cardiovascular, Respiratory, Gastrointestinal, Skin, and Neurological systems. 
Height (at screening only) and weight will also be measured and recorded (Section 
7.1).  Physical exam includes assessment of symptoms/signs noted as physician 
assessment in Section 7.3.2.  Findings during physical examination related to HES 
will be recorded in the HES Core Assessments/Flare details.

Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
7.4.4.
Vital Signs
Vital signs will be measured prior to blood draws in a sitting position after 5 minutes rest 
and will include temperature, systolic and diastolic blood pressure and pulse rate.
7.4.5.
Electrocardiogram (ECG)

Details of the cardiac monitoring procedures will be provided by the centralized 
cardiology service provider.

All sites will use standardized ECG equipment provided by a centralized external 
vendor.

Recordings will be made at timepoints outlined in Section 7.1.  Collection shortly 
after a meal or during sleep should be avoided since QT prolongation can occur at 
these times.  All ECG measurements will be made with the subject in a supine 

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position having rested in this position for approximately 5 minutes before each 
reading.

Paper ECG traces will be recorded at a standard paper speed of 25 mm/sec and gain 
of 10 mm/mV, with a lead II rhythm strip.  There will be electronic capture and 
storage of the data by a validated method, with subsequent transfer to the central 
laboratory for manual reading and calculation of the electrocardiographic parameters.  
Paper traces are required to be maintained at the site with other source documents.

The investigator, a designated sub-investigator, or other appropriately trained site 
personnel will be responsible for performing each 12-lead ECG.  The investigator 
must provide his/her dated signature on the original paper tracing, attesting to the 
authenticity of the ECG machine interpretation.

All ECGs will be electronically transmitted to an independent cardiologist (contracted 
by GSK) and evaluated. The independent cardiologist, blinded to treatment 
assignment, will be responsible for providing measurements of heart rate, QT 
intervals and an interpretation of all ECGs collected in this study. A hard copy of 
these results will be sent to the investigator. The investigator must provide his/her 
dated signature on the confirmed report, attesting to his/her review of the independent 
cardiologist’s assessment to support the decision regarding the continuation or 
discontinuation of study treatment based on the ECG results (Section 5.4.2).

A single 12-lead ECGs will be obtained at each timepoint during the study using an 
ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, 
and QTc intervals.  Refer to Section 5.4.2 for QTc stopping criteria and additional 
QTc readings that may be necessary.
7.4.6.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 4, must be conducted in 
accordance with the laboratory manual, and Protocol Time and Events Schedule
(Section 7.1). 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. Reference ranges for all safety 
parameters will be provided to the site by the laboratory responsible for the assessments.
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 CRF unless the central laboratory 
results are available in time to support medical intervention.  The investigator should 
make every effort to maintain the blinding to subject’s blood eosinophil level.
Refer to the laboratory manual for appropriate processing and handling of samples to 
avoid duplicate and/or additional blood draws.
All study-required laboratory assessments will be performed by a central laboratory.

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NOTE: Local laboratory results are only required in the event that the central laboratory 
results are not available in time for either a treatment and/or response evaluation to be 
performed.  If a local sample is required it is important that the sample for central 
analysis is obtained at the same time.  Additionally if the local laboratory results are used 
to make either a treatment or response evaluation, the results must be entered into the
CRF.
All blood samples should be taken after measuring vital signs and prior to 
administration of study treatment (for dosing visits).
Haematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed in Table 4.
Table 4
Clinical Laboratory Parameters
Routine Clinical Chemistry
Routine Hematology
Sodium
Hemoglobin
Potassium
Red cell count
Chloride
Platelet count
Calcium
Total white cell count#
Phosphorous inorganic
White cell differentials:
Glucose
  Neutrophil (absolute and differential [%]#)
Protein, total
  Lymphocytes (absolute and differential [%]#)
Albumin
  Monocyte count (absolute and differential [%]#)
CPK, total
  Eosinophil count (absolute# and differential [%]#)
Creatinine
  Basophil count (absolute and differential [%]#)
Urea nitrogen
Mean Corpuscular Volume (MCV)
Lactic dehydrogenase
Mean Corpuscular Hemoglobin (MCH)
Bilirubin, direct
Mean Corpuscular Hemoglobin Concentration 
(MCHC)
Bilirubin, indirect
Urinalysis
Bilirubin, total
Protein Qualitative
Aspartate amino transferase (AST)
Glucose
Alanine amino transferase (ALT)
Ketones
Gamma glutamyl transaminase (GGT)
Occult Blood
Alkaline phosphatase
Microscopic:  WBC and RBC
Lipoproteins
Other laboratory parameters
Cholesterol, total
F/P status
High density lipoprotein, Cholesterol, direct
CD3, CD4, CD8
Low density lipoprotein, calculation
Hepatitis B surface antigen (HBsAg)
Very low density lipoprotein, calculation
Hepatitis C antibody
Total IgE
Troponin
Aldolase
Urine pregnancy test

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NOTES :
1.
Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up 
Assessments after liver stopping or monitoring event are given in Section 5.4.1 and
Section 12.2.
2.
Local urine testing will be standard for the protocol unless serum testing is required by local 
regulation or ethics committee.
3.
Refer to Section 6.4 regarding the results that will not be sent to the investigators for blinding 
from the blood eosinophil counts [i.e., absolute blood eosinophil counts, total white blood cell 
counts and white blood count differentials (%)#].
7.5.
Pharmacokinetics
7.5.1.
Blood Sample Collection
Blood samples for determination of mepolizumab plasma concentration will be collected 
at the timepoints indicated in Section 7.1, Time and Events Table.  The actual date and 
time of each blood sample collection will be recorded.  The timing of PK samples may be 
altered and/or PK samples may be obtained at additional timepoints to ensure thorough 
PK monitoring.
Processing, storage and shipping procedures are provided in the laboratory manual.
7.5.2.
Sample Analysis
Plasma analysis will be performed under the control of PTS-DMPK/Scinovo, GSK.  
Concentrations of mepolizumab will be determined in plasma samples using the currently 
approved bioanalytical methodology.  Raw data will be archived at the bioanalytical site.
7.6.
Pharmacodynamic Markers

Blood eosinophil counts will be recorded as part of the standard hematology 
assessments performed at the visits specified in the Time and Events table (Section 
7.1).

Blood samples will be collected for measurement of serum free and total (free IL-5 
and mepolizumab-bound IL-5) IL-5 levels at the visits specified in the Time and 
Events table (Section 7.1).
7.7.
Immunogenicity
Blood samples will be collected prior to dosing at visits specified in the Time and Events 
Table (Section 7.1). Samples will be analysed for the presence of anti-mepolizumab 
antibodies.

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7.8.
T-cell profile
Patients with lymphoproliferative HES or those with an abnormal T-cell phenotype are at 
an increased risk of developing T-cell lymphoma as part of the natural history of the 
disease.  The risk benefit ratio in these patients should be considered prior to initiation 
and/or continuation of treatment with mepolizumab [GlaxoSmithKline Document 
Number CM2003/00010/10].
Subjects with a history of or current lymphoma, malignancy, or previous history of 
cancer in remission for less than 12 months prior to randomization will be excluded from 
the study.  In addition, T-cell profiling (including CD3, CD4, and CD8) will be 
performed during screening and at the end of study treatment.
7.9.
F/P status
The FIP1L1-PDGFRα (F/P) fusion tyrosine kinase gene is a consequence of an interstitial 
chromosomal deletion [Cools, 2003] and detected in a subset of patients with HES 
(Section 2.2).
A blood sample will be collected at Screening (Visit 1) to determine the F/P status for 
every subject unless the documented result is available.  Subjects who have the F/P 
fusion tyrosine kinase gene translocation (F/P positive) are excluded from this study (see 
Section 5).
7.10.
Biomarker Sub-study
With the subject’s consent, blood samples will be collected during this study and will be 
used for the biomarker sub-study.  In addition, the samples may be used for the purposes 
of measuring novel biomarkers to identify factors that may influence HES, and/or 
potentially medically related conditions (e.g., T-cell lymphoma), as well as the biological 
and clinical responses to study treatment.  If relevant, this approach will be extended to 
include the identification of biomarkers associated with adverse events.
Novel candidate biomarkers and subsequently discovered biomarkers of the biological 
response associated with HES conditions that are medically related to HES, and/or the 
action of study treatment may be identified by application.
All samples will be retained for a maximum of 15 years after the last subject completes 
the trial.
7.11.
Genetics
Information regarding genetic research is included in Section 12.3.

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7.12.
Patient-Reported Outcomes (PROs)
Daily Electronic Diary
The electronic diary (eDiary) will be dispensed at the screening visit and will be 
completed at home by the subject on a daily basis.  Subjects should complete the eDiary 
at approximately the same time each day.  Subjects must complete the eDiary for at least 
7 days before randomization.
Completion of PRO Questionnaires
PRO questionnaires are to be administered at the beginning of the visits specified in 
Section 7.1 in the order presented in the electronic device.  To avoid biasing responses, 
the subjects should not be told the results of diagnostic tests prior to completing the 
questionnaires, and the questionnaires should be completed before any procedures are 
performed on the subject to avoid influencing the subject’s response.  Adequate time 
must be allowed to complete all items on the questionnaires, and if necessary, the subject 
must be encouraged to complete any missing items.
7.12.1.
Brief Fatigue Inventory
The Brief Fatigue Inventory (BFI) is a tool developed for the rapid assessment of fatigue 
severity for use in both clinical screening and clinical trials [Mendoza, 1999]. The BFI 
has 9 items.  The subject should rate their average and worst fatigue levels over the 
previous 24 hours using a numeric rating scale anchored with 0 (no fatigue/interference) 
and 10 (as bad as you can imagine/completely interferes) numeric rating scales.  The 
subject will complete one item of the BFI daily and the full BFI every 7 days at home on 
the eDiary.
7.12.2.
HES Daily Symptoms (HES-DS)
The HES Daily Symptoms (HES-DS) include 6 constitutional and organ system-specific 
symptoms commonly reported by patients with HES.  At the randomization study visit, 
the subject will identify up to three symptoms that are most bothersome to him/her.  Each 
of the 7 symptoms will be rated daily at home on the eDiary.  Each item has a 11-point 
numeric rating scale with 0 indicating that the symptom is not present and 10 indicating 
symptom is worst imaginable.  The symptoms will be rated each evening recalling the 
worst symptom experience over the previous 24 hours.
7.12.3.
Clinician- and Subject-Rated Overall Response to Therapy Score 
(RTS)
The clinician and the subject will rate the response to therapy (the investigator and the 
subject should complete the assessment independently) at the visits specified in the Time 
and Events schedule (Section 7.1).  The subject should complete the Subject-RTS as the 
first procedure at the study visit prior to study procedure or examinations by a clinician.  
Clinician-RTS will be completed at the end of their subject evaluation.  This is an overall 
evaluation of response to treatment using a 7-point rating scale. This rating scale uses the 
following definitions:

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
1 = significantly improved

2 = moderately improved

3 = mildly improved

4 = no change

5 = mildly worse

6 = moderately worse

7 = significantly worse.
7.12.4.
Subject-Rated Symptom Severity (SSR)
The subject will rate overall severity of symptoms at the visits specified in the Time and 
Events schedule (Section 7.1).  This is an overall evaluation of symptom severity using a 
5-point rating scale of none, mild, moderate, severe and very severe.
7.12.5.
Modified Memorial Symptom Assessment Scale-Short Form 
(MSAS-SF)
The Memorial Symptom Assessment Scale (MSAS) was developed to measure physical 
and psychological symptom prevalence, severity and distress across a range of cancers 
[Chang, 2000; Portenoy, 1994].  The MSAS provides a total, physical and psychological 
score of symptom burden based on ratings of symptom frequency and distress. A
modified version of the MSAS was developed based on the symptoms described in 
literature and confirmed in qualitative interviews with 26 patients with HES.  The MSAS 
has a recall period of the previous 7 days.
7.12.6.
Patient Reported Outcome Measurement Information System 
(PROMIS) Physical Function and Sleep
The Patient Reported Outcome Measurement Information System (PROMIS) is a 
psychometrically validated, dynamic system to measure PROs efficiently in study 
participants with a wide range of chronic diseases and demographic characteristics based 
on calibrated item banks (sets of well-defined and validated items), and includes concepts
such as pain, fatigue, physical function, depression, anxiety and social function.  These 
calibrated item banks can be used to derive short forms (typically requiring 4-10 items 
per concept), or computerized adaptive testing (typically requiring 3-7 items per concept 
for more precise measurement) [Reeve, 2007].
To support assessment of physical function and sleep, short-form assessments of these 
concepts have been developed.  The PROMIS physical function (14 items) and sleep 
scales (2 items) have a recall of 7 days and 5-point response scales, and will be 
completed at study visits as defined in Section 7.1.
7.12.7.
SF-36 V2
The SF-36 v2 is a health status survey with 36 questions [Maruish, 2011].  It yields an 8-
scale profile of functional health and well-being scores as well as psychometrically-based 

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physical and mental health summary measures and a preference-based health utility 
index.  It is a generic measure, as opposed to one that targets a specific age, disease, or 
treatment group.  Accordingly, the SF-36 v2 has proven useful in differentiating the 
health benefits produced by a wide range of different treatments.
The SF-36 v2 assesses eight health concepts: 1) limitations in physical activities because 
of health problems; 2) limitations in social activities because of physical or emotional 
problems; 3) limitations in usual role activities because of physical health problems; 4) 
bodily pain; 5) general mental health (psychological distress and well-being); 6) 
limitations in usual role activities because of emotional problems; 7) vitality (energy and 
fatigue); and 8) general health perceptions.  The survey was constructed for self-
administration by persons 14 years of age and older.
The SF-36 will be completed with a 4-week recall at a scheduled clinic visits as specified 
in Section 7.1, to support assessment of overall change in health-related quality of life 
(HRQoL).  The SF-36 will be completed with a 1-week recall at an unscheduled ‘Flare’
visit, to provide an assessment of the impact of flare on HRQoL.
7.12.8.
Work Productivity and Activity Impairment Index – General 
Health (WPAI-GH) V2
The WPAI-GH v2 is a self or interviewer administered tool comprised of 6 questions 
which address absenteeism, presenteeism (reduced effectiveness while working), overall 
work productivity loss (absenteeism plus presenteeism), and activity impairment.  This 
validated tool captures data from the past 7 days.  WPAI-GH outcomes are scored as 
impairment percentages, with a higher percentage indicating greater impairment and less 
productivity [Reilly, 1993].
7.12.9.
Steroid Perception Questionnaire
The use of maintenance oral corticosteroids can have many and diverse adverse effects.  
The steroid perception questionnaire was developed to better assess the subjects 
perception of the adverse effects associated with the use of daily OCS including physical 
and mood impacts.  In this study, HES therapy including a stable dose of OCS will be 
maintained throughout the 32-week study treatment period unless there is worsening of 
symptom(s) that requires an increase in therapy.  Therefore, the questionnaire will be 
implemented at Randomization (Visit 2) only to characterize burden of OCS in this 
population of patients with HES.
8.
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.

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9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1.
Hypotheses
The primary efficacy endpoint is the proportion of subjects who experience an HES flare 
during the 32-week study treatment period.  This study is designed to test the superiority 
of mepolizumab versus placebo.  The primary analysis will test the following hypothesis:

Null hypothesis: no difference between mepolizumab relative to placebo for the 
proportion of subjects who experience an HES flare during the 32-week study 
treatment period.

Alternative hypothesis: the proportion of subjects who experience an HES flare 
during the 32-week study treatment period is smaller for mepolizumab compared 
to placebo.
Significance tests will be performed at the two-sided 5% level (one sided 2.5%).
9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
This study is designed to test the superiority of mepolizumab versus placebo.
The primary efficacy endpoint is the proportion of subjects who experience an HES flare 
during the 32-week study treatment period.  The power calculation assumes that 60% of 
subjects on placebo will experience an HES flare during the 32-week study treatment 
period.  With a two-sided 5% level of significance and a sample size of 40 randomized 
subjects per arm, the null hypothesis will be rejected if the observed proportion of 
patients with an HES flare on placebo is 60% and on mepolizumab is 35% or less.  If the 
true population proportion of subjects who would experience an HES flare during the 32-
week study treatment period on placebo is 60% and on mepolizumab is 22%, the study 
has 90% power for demonstrating a statistically significant result for this assumed true 
population effect.
This endpoint is novel, and has not explicitly been used in clinical trials of HES.  There is 
therefore little previous data on which to base estimates of the number of subjects who 
will experience an HES flare during the 32-week study treatment period.
9.2.2.
Sample Size Sensitivity
If either the actual percentage of subjects on placebo who experience an HES flare during 
the 32-week study treatment period or the impact of mepolizumab is different from the 
values assumed in Section 9.2.1, the power to detect a change in the proportion of 
subjects who experience an HES flare during the 32-week study treatment period will be 
affected. Due to the uncertainty in the number of subjects who will experience an HES 
flare during the 32-week study treatment period, a blinded sample size re-estimation is 
planned (see Section 9.2.3).

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9.2.3.
Sample Size Re-estimation or Adjustment
While the estimate of 60% of placebo subjects and 22% of mepolizumab subjects having 
an HES flare during the 32-week study treatment period is felt by clinical experts to be 
reasonable for this population, the proportion of subjects who have an HES flare will be 
monitored, blinded to treatment, and if the blinded overall proportion is predicted to be 
<30% the sample size may be increased up to a maximum of 60 subjects per group (total 
120 subjects). The planned increase to sample size will depend on the observed blinded 
overall proportion of subjects as follows:
Blinded overall 
proportion1 (%)
N per group
≥30
40 (no increase)
27.5 – 30
45
25-<27.5
50
<25
60
1Proportion of subjects who have an HES flare during the 32-week study treatment period.
The decision to increase the sample size will be made when at least 30 subjects per arm 
have been randomised. The blinded overall proportion of subjects who have an HES 
flare will be calculated based on the HES flare data available in the CRF. This will 
include all HES flares meeting flare endpoint definition ‘a)’ in Section 7.3.1. The 
number of HES flares due to flare endpoint definition ‘b)’ is expected to be small, 
therefore in order to maintain the blood eosinophil blinding, HES flares due to subjects 
receiving two or more courses of blinded active OCS will not be included in the 
calculation of the blinded overall proportion.
9.3.
Data Analysis Considerations
All pre-specified analyses will be described in a full reporting analysis plan (RAP) which 
will be finalized prior to unblinding.
The study will be unblinded once the final subject has completed the Week 32 visit plus 
the safety follow-up visit (if applicable), all queries for data collected up to this time are 
resolved and the clinical study database is frozen.
9.3.1.
Analysis Populations
Intent-to-Treat Population:
The intent-to-treat (ITT) population will consist of all subjects who are randomized.  This 
will constitute the primary population for all analyses of efficacy measures.
Per Protocol Population:
The Per Protocol (PP) population will consist of all subjects in the ITT population not 
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 

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breaking the blind.  The PP population will be used for a supplementary analysis of the 
primary endpoint.
Safety Population:
The Safety Population will consist of all subjects who are randomized and who receive at 
least one dose of trial medication.  Randomized subjects will be assumed to have 
received study treatment unless definitive evidence to the contrary exists.  This will 
constitute the primary population for all analyses of safety measures.
PK Population:
The PK population is defined as all subjects in the ITT population who received at least 
one dose of study medication and for whom at least one PK sample was obtained, 
analyzed and was measurable.  This will be the primary population for assessing PK.
PD Population:
The PD population is defined as all subjects in the ITT population who received at least 
one dose of study treatment and who also have a baseline PD measurement and at least 
one post-treatment PD measurement. This will be the primary population for assessing 
PD.
9.3.2.
Treatment Comparisons
All treatment comparisons are between mepolizumab and placebo.
9.3.3.
Multiple Comparisons and Multiplicity
In order to provide strong control of type I error when making inferences for the pre-
defined secondary endpoints, multiplicity will be controlled using a hierarchical, closed 
testing procedure.
The hierarchy of endpoints is defined as follows:
1.
Proportion of subjects who experience an HES flare during the 32-week study 
treatment period (primary endpoint)
2.
Time to first HES flare
3.
Proportion of subjects who experience an HES flare during Week 20 through 
Week 32
4.
Rate of HES flares
5.
Change from baseline in fatigue severity based on BFI item 3 (worst level of fatigue 
during past 24 hours) at Week 32
When strong control of type I error is required, each endpoint in the hierarchy will be 
formally tested for confirmatory evidence of statistical significance only if all preceding 
tests are statistically significant.

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9.3.4.
Interim Analysis
As described in Section 10.8, an external Independent Data Monitoring Committee 
(IDMC) will periodically review unblinded safety data from the study, in accordance 
with the IDMC Charter.  The safety data analyses for the IDMC reviews will be 
performed by an independent statistical analysis data center (SDAC).  There are no 
circumstances under which IDMC review of the data would lead to a recommendation to 
stop for efficacy of mepolizumab. Other than the procedures described in Section 6.3, all 
personnel having direct responsibility for the conduct of the study will remain blinded to 
treatment groups for all data until the database is frozen.
9.4.
Key Elements of Analysis Plan
9.4.1.
Efficacy Analyses
The study is designed to continue to collect data on HES flares for subjects who 
prematurely discontinue from their randomized treatment.  All data on HES flares 
collected for these subjects will also be included in the primary analysis. For subjects 
who withdraw prematurely from study treatment and for whom collection of data on HES 
flares is not possible, it will be assumed for the primary endpoint that they are treatment 
failures, i.e., that they experience a flare following study withdrawal.  This strategy 
corresponds to a de facto estimand of treatment effect. Sensitivity analyses will be 
performed to examine the potential impact of the missing data.
Primary endpoint
The primary efficacy endpoint will be compared between treatments using a Cochran-
Mantel-Haenszel test stratified by baseline OCS dose (0-≤20mg/day and >20mg/day 
prednisolone/prednisone or equivalent) and region.
The analysis will be supplemented with a logistic regression analysis adjusting for 
covariates of baseline OCS dose, region, and treatment.  The model will be used to 
estimate the odds ratio for the treatment difference and associated p-value and 95% 
confidence limit.
Sensitivity analyses to assess the impact of missing data will be performed as follows:

Subjects withdrawing from the study prematurely prior to reporting an HES flare, 
with the primary reason for treatment withdrawal reported as AE or Lack of 
Efficacy, will be assumed to experience an HES flare. Subjects withdrawing from 
the study prematurely with any other reason for treatment withdrawal will be 
included as having a flare if one is recorded prior to study withdrawal, and as not 
having a flare if no flare is recorded prior to study withdrawal.

Observed data analysis. Subjects withdrawing from the study prematurely will be 
included as having a flare if one is recorded prior to study withdrawal, and as not 
having a flare if no flare is recorded prior to study withdrawal.

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Secondary endpoints
Time to first HES flare
The time to first HES flare will be calculated from the date of randomization and the start 
date of the HES flare (see Section 7.3.1). Time to first HES flare will be analyzed using 
a log-rank test stratified by baseline OCS dose and region.  This analysis will be 
supplemented by a Cox proportional hazards regression model allowing for covariates of 
baseline OCS dose and region.  The hazard ratio will be derived along with 95% 
confidence limits.  Cumulative event rates will be calculated using the Kaplan-Meier 
method.  Subjects who withdraw prematurely from randomized treatment will continue to 
be monitored for HES flares.  If a subject withdraws prematurely from the study and 
collection of data on flares is not possible, the event time will be censored at the time
point at which they withdrew from the study. Sensitivity analyses to assess the impact of 
missing data will be performed with full details provided in the Reporting and Analysis 
Plan (RAP).
Proportion of subjects who experience an HES flare during Week 20 through Week 32
An HES flare during Week 20 through Week 32 will be defined as an HES flare starting 
or ongoing on or after the date of the Week 20 visit up to and including the date of the 
Week 32 visit. Subjects withdrawing from the study prematurely, prior to reporting an 
HES flare during Week 20 through Week 32, will be assumed to experience a flare 
during Week 20 through Week 32.
The proportion of subjects who experience an HES flare during Week 20 through 
Week 32 will be analyzed in the same way as the primary endpoint, using a Cochran-
Mantel-Haenszel test stratified by baseline OCS dose and region. The analysis will be 
supplemented with a logistic regression analysis adjusting for covariates of baseline OCS 
dose, region and treatment.
Sensitivity analyses to assess the impact of missing data will be performed with full 
details provided in the RAP.
Rate of HES flares
The rate of HES flares will be calculated for each subject as the number of observed HES 
flares divided by the time (expressed in years) between randomisation and either the 
week 32 visit date if available, or otherwise the study withdrawal date. The number of 
observed HES flares will be calculated for each subject as the number of unique starting 
dates for HES flares. To be considered as a separate episode of HES flare, the start date 
of an HES flare must be at least 14 days apart from the resolution date of the preceding 
HES flare. See Section 7.3.1 for detailed definitions of flare start and resolution dates. 
For subjects withdrawing prematurely from the study during the 32 week treatment 
period, all data up to the time of study withdrawal will be used to calculate the rate of 
HES flares. Sensitivity analyses to assess the impact of missing data will be performed 
with full details provided in the RAP.

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The rate of HES flares will be compared between treatment groups using a stratified 
Wilcoxon Rank Sum test, stratified by baseline OCS dose and region.  This analysis will 
be supplemented by an analysis using a negative binomial generalised linear model with 
a log link-function. The model will include terms for treatment group, region, baseline 
OCS dose and observed time (as an offset variable). The estimated mean rates per year, 
treatment ratio and confidence limits will be presented.
Change from baseline in fatigue severity based on BFI item 3 (worst level of fatigue 
during past 24 hours) at Week 32
The change from baseline in fatigue severity (worst level of fatigue during past 24 hours) 
at week 32 will be calculated using the mean of the 7 daily assessments of BFI item 3 up 
to and including the date of the week 32 visit as the week 32 assessment, and the mean of 
the 7 daily assessments of BFI item 3 up to and including the date of randomisation as the 
baseline assessment. Subjects withdrawing prematurely from the study during the 32 
week treatment period will be assumed to have the largest (i.e., worst) value observed for 
any subject for the change from baseline BFI item 3 at week 32. Sensitivity analyses to 
assess the impact of missing data will be performed with full details provided in the RAP.
The change from baseline in fatigue severity at week 32 will be compared between 
treatment groups using a stratified Wilcoxon Rank Sum test, stratified by baseline fatigue 
severity (“severe” defined as BFI item 3 >=7, and “not severe” defined as BFI item 3<7) 
and region.
9.4.2.
Safety Analyses
AEs will be coded using the MedDRA coding dictionary and summarized by preferred 
term and treatment group. SAEs pre-treatment and AEs and SAEs on-treatment, during 
active treatment, and post-treatment will be summarized separately. Separate summaries 
will be provided for all AEs, IP-related AEs, SAEs, events of special interest (including 
systemic reactions and local injection site reactions) and for AEs leading to permanent 
discontinuation of IP or withdrawal from the study. All laboratory parameters for clinical 
chemistry and hematology will be summarized and tabulated.
Each ECG parameter at every assessed time point will be summarized using summary 
statistics.  Summary statistics of QT interval corrected for heart rate according to 
Fridericia’s formula (QTcF) and QT interval corrected for heart rate according to Bazett’s 
formula (QTcB) as well as change from baseline value will be presented by visit.
Summary statistics of pulse rate and systolic and diastolic blood pressure will be 
presented by visit.
Immunogenicity will be summarized using appropriate descriptive statistics.
9.4.3.
Pharmacokinetic Analyses
Blood samples will be collected to determine mepolizumab plasma concentrations 
(Section 7.5).  Sparse blood sampling is being implemented in this study.  The 
mepolizumab plasma concentrations from this study will be evaluated using the 
population PK model developed based on previous mepolizumab data collected during 

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mepolizumab clinical development.  The analysis will be conducted using an appropriate 
software and will allow the determination for example of the population and/or individual 
systemic exposure, apparent volume of distribution and apparent clearance as well as 
characterize the between- and within subject variability.  The effect of subjects’ 
characteristics such as, for example, body weight, age, gender, serum creatinine on 
mepolizumab systemic exposure will also be explored in order to explain the inter-subject 
variability in drug exposure.  Pharmacokinetic data will be presented in graphical and/or 
tabular form and will be summarized descriptively.
Further details of the analysis will be described in the RAP.
9.4.4.
Pharmacodynamic Analyses
Ratio to baseline in blood eosinophil count will be compared between treatments using a 
mixed model repeated measures analysis adjusting for the covariates of baseline blood 
eosinophil count, baseline OCS dose and region.  Values below the lower limit of 
quantification will be imputed as half the lower limit of quantification prior to analysis.  
Data will be log-transformed prior to analysis. Visit will be fitted as a categorical variable 
with the effect of treatment group and baseline eosinophil count varying at each visit (i.e.,
visit by baseline and visit by treatment group interactions will also be included in the 
model).
9.4.5.
Other Analyses
Full details of the analyses to be performed on all exploratory endpoints will be given in 
the RAP.
If genetic analysis is warranted, a separate research analysis plan will be drafted 
(Section 12.3).
If biomarker analysis is warranted, a separate research analysis plan will be drafted 
(Section 7.10).
10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a site, GSK will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.

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The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki.  This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable

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.  

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.
10.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK monitors will contact the site prior to the start of the study to review with the 
site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and GSK requirements.  

When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the CRF will 
serve as the source document.
GSK will monitor the study and site activity to verify that:

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.

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
The investigator and the head of the medical institution (where applicable) 
agrees to allow the monitor direct access to all relevant documents
10.4.
Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK 
may conduct a quality assurance assessment and/or audit of the site records, and the 
regulatory agencies may conduct a regulatory inspection at any time during or after 
completion of the study.

In the event of an assessment, audit or inspection, the investigator (and institution) 
must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all 
relevant documents and to allocate their time and the time of their staff to discuss the 
conduct of the study, any findings/relevant issues and to implement any corrective 
and/or preventative actions to address any findings/issues identified.
10.5.
Study and Site Closure

Upon completion or premature discontinuation of the study, the GSK monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and GSK Standard Operating 
Procedures.

GSK reserves the right to temporarily suspend or prematurely discontinue this study 
at any time for reasons including, but not limited to, safety or ethical issues or severe 
non-compliance. For multicenter studies, this can occur at one or more or at all sites.

If GSK determines such action is needed, GSK will discuss the reasons for taking 
such action with the investigator or the head of the medical institution (where 
applicable).  When feasible, GSK will provide advance notification to the 
investigator or the head of the medical institution, where applicable, of the 
impending action.

If the study is suspended or prematurely discontinued for safety reasons, GSK will
promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action.

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation.
10.6.
Records Retention

Following closure of the study, the investigator or the head of the medical institution 
(where applicable) must maintain all site study records (except for those required by 
local regulations to be maintained elsewhere), in a safe and secure location.

The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review in 

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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.
10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
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.
10.8.
Independent Data Monitoring Committee
An IDMC will be utilized in this study to ensure external objective medical and/or 
statistical review of safety data in order to protect the ethical and safety interests of 
subjects and to protect the scientific validity of the study.  The schedule of any planned 
interim analysis and the analysis plan for IDMC review is described in the charter.

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11.
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G, Maisonneuve H, Ghomari K, Ackerman F, Legrand F, Baruchel A, Launay D, Terriou 
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Hypereosinophilic Syndrome with Anti-Interleukin-5. J Pediatrics. 2009; 155: 289–91.
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with sputum eosinophilia. N Engl J Med. 2009; 360: 985-93.
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multicenter, retrospective analysis of clinical characteristics and response to therapy. J 
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Ogbogu PU, Rossing DR, Horne, MK. Cardiovascular manifestations of 
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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
ACQ
Asthma Control Questionnaire
ADA
Anti-drug antibody
AE
Adverse Event
ALT
Alanine transaminase
ANCA
anti-neutrophil cytoplasmic antibodies
AST
Aspartate transaminase
BP
Blood pressure
CONSORT
Consolidated Standards of Reporting Trials
CPK
Creatine phosphokinase
CRF
Case Report Form
C-RTS
Clinician-rated overall Response to Therapy score
CUP
Compassionate Use Program
CV
Cardiovascular
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic case report form
eDiary
Electronic diary
EGPA
Eosinophilic Granulomatosis with Polyangiitis
EoE
Eosinophilic Esophagitis
EW
Early Withdrawal
FAAN
Food Allergy and Anaphylaxis Network
FRP
Female of reproductive potential
FEV1
Forced Expiratory Volume in one second
FISH
Fluorescence in situ hybridization
F/P
Fip1-like1-Platelet Derived Growth Factor Receptor 
(FIP1L1-PDGFRa)
FSH
Follicle stimulating hormone
FVC
Forced Vital Capacity
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GI
Gastrointestinal
GSK
GlaxoSmithKline
HBsAg
Hepatitis B Surface Antigen
hCG
human chorionic gonadotrophin
HCRU
Healthcare resource utilization
HCV
Hepatitis C Virus
HES
Hypereosinophilic Syndrome
HF
Heart failure
HIV
Human Immunodeficiency Virus
HPLC
High performance liquid chromatography

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HRQoL
Health-related quality of life
HRT
Hormone replacement therapy
IB
Investigator’s Brochure
ICU
Intensive care unit
IDMC
Independent data monitoring committee
IEC
Independent Ethics Committee
Ig
Immunoglobulin
IL
Interleukin
INF
Interferon alpha
INR
International normalized ratio
IP
Investigational Product
IRB
Institutional review board
IRT
Interactive response technology
ITT
Intent-to-Treat
IV
Intravenous(ly)
LABA
Long-acting beta2-agonist
LDH
Lactate dehydrogenase
L-HES
Lymphocytic hypereosinophilic syndrome
mAb
Monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligrams
M-HES
Myeloproliferative hypereosinophilic syndrome
MSAS-SF
Memorial Symptom Assessment Scale-Short Form
MSDS
Material Safety Data Sheet
msec
millisecond
NAB
Neutralizing antibodies
NIAID
National Institute of Allergy and Infectious Disease
NYHA
New York Heart Association
OCS
Oral corticosteroid
OLE
Open-label extension
PCR
Polymerase chain reaction
PCSA
Placebo-controlled severe asthma
PD
Pharmacodynamics
PEF
Peak expiratory flow
PK
Pharmacokinetics
PMS
Post marketing surveillance
PP
Per protocol
PRO
Patient reported outcome
PROMIS
Patient Reported Outcome Measurement Information 
System
QTcB
QT interval corrected for heart rate according to Bazett’s 
formula
QTcF
QT interval corrected for heart rate according to Fridericia’s 
formula
RAP
Reporting and Analysis Plan
RBC
Red blood cell

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RNA
Ribonucleic acid
RTS
Response to Therapy Score
SABA
Short-acting beta2-agonist
SAE
Serious Adverse Event
SC
Subcutaneous(ly)
SDAC
Statistical analysis data center
SOC
System Organ Class
SoC
Standard of care
SRM
Study reference manual
SSR
Subject-Rated Symptom Severity
URTI
Upper respiratory tract infection
WBC
White blood cell
Wks
Weeks
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
None

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12.2.
Appendix 2: Phase III-IV liver chemistry stopping and 
monitoring criteria, and required actions and follow-up 
assessments
Phase III-IV liver chemistry stopping criteria
Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT absolute
Both ALT 8xULN and 2X baseline value
ALT Increase
Both ALT 3xULN and ≥ 1.5x baseline value  that 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
Both ALT 3xULN and ≥ 1.5x baseline value and cannot be monitored weekly 
for 4 weeks
Symptomatic3
Both ALT 3xULN and ≥ 1.5x baseline value 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 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 unless allowed per protocol and GSK 
Medical Governance approval is granted.
If restart/rechallenge not  allowed or not 
granted, permanently discontinue study treatment 
and may continue subject in the study for any 
protocol specified follow up assessments.
MONITORING:
For bilirubin or INR criteria:
Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform liver 
Viral hepatitis serology4
Obtain INR and recheck with each liver 
chemistry assessment until the transaminases 
values show downward trend.
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 1 week of the liver 
event6.
Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).
Fractionate bilirubin, if total bilirubin2xULN.
Obtain complete blood count with differential to 
assess eosinophilia.
Note: To ensure investigators remain blinded 
to eosinophil count, as for all other blood 
count tests after randomization, sites will only 
be sent absolute lymphocyte, monocyte, 
neutrophil, and basophil counts.  The 

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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.
complete blood count with differential 
(including eosinophil count will be available 
after the subject’s treatment has been 
unblinded.
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 formincluding 
acetaminophen, herbal remedies, other over the 
counter medications.
Record alcohol use on the liver event alcohol 
intake case report form.
For bilirubin or INR criteria:
Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney microsomal 
antibodies, and quantitative total 
immunoglobulin G (IgG or gamma globulins)
Serum acetaminophen adduct HPLC assay 
(quantifies potential acetaminophen contribution 
to liver injury in subjects with definite or likely 
acetaminophen use in the preceding week 
[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 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 3xULN and ≥ 1.5x baseline value but
ALT <8x ULN and < 2x baseline value 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, after 4 weeks of monitoring, ALT <3xULN and 
<1.5 X baseline value, and bilirubin <2xULN, 
monitor subjects twice monthly until liver 
chemistries normalize or return to within baseline
References
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.
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. 

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12.3.
Appendix 3: Genetic Research
Genetics – Background
Naturally occurring genetic variation may contribute to inter-individual variability in 
response to medicines, as well as an individual's risk of developing specific diseases. 
Genetic factors associated with disease characteristics may also be associated with 
response to therapy, and could help to explain some clinical study outcomes. For 
example, genetic variants associated with age-related macular degeneration (AMD) are 
reported to account for much of the risk for the condition [Gorin, 2012] with certain 
variants reported to influence treatment response [Chen, 2012]. Thus, knowledge of the 
genetic etiology of disease may better inform understanding of disease and the 
development of medicines. Additionally, genetic variability may impact the 
pharmacokinetics (absorption, distribution, metabolism, and elimination), or 
pharmacodynamics (relationship between concentration and pharmacologic effects or the 
time course of pharmacologic effects) of a specific medicine and/or clinical outcomes 
(efficacy and/or safety) observed in a clinical study.
Genetic Research Objectives and Analyses
The objectives of the genetic research are to investigate the relationship between genetic 
variants and:

Response to medicine, including mepolizumab or any concomitant medicines;

HES susceptibility, severity, and progression and related conditions.
Genetic data may be generated while the study is underway or following completion of 
the study.  Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses). Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above.  Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives.
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in a RAP prior to initiation of the 
analysis. Planned analyses and results of genetic investigations will be reported either as 
part of the clinical RAP and study report, or in a separate genetics RAP and report, as 
appropriate.
Study Population
Any subject who is enrolled in the study can participate in genetic research.  Any subject 
who has received an allogeneic bone marrow transplant must be excluded from the 
genetic research.
Study Assessments and Procedures
A key component of successful genetic research is the collection of samples during 
clinical studies. Collection of samples, even when no a priori hypothesis has been 

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identified, may enable future genetic analyses to be conducted to help understand 
variability in disease and medicine response.
A 6 ml blood sample will be taken for DNA extraction.  A blood sample is collected at 
the baseline visit, after the subject has been randomized and provided informed consent 
for genetic research. If a subject initially declines to participate in genetic research and 
then changes their mind, a sample should be obtained at the earliest opportunity. 
Instructions for collection and shipping of the genetic sample are described in the 
laboratory manual.  The DNA from the blood sample may undergo quality control 
analyses to confirm the integrity of the sample.  If there are concerns regarding the 
quality of the sample, then the sample may be destroyed.  The blood sample is taken on a 
single occasion unless a duplicate sample is required due to inability to utilize the original 
sample.
The genetic sample is labeled (or “coded”) with the same study specific number as used 
to label other samples and data in the study.  This number can be traced or linked back to 
the subject by the investigator or site staff. Coded samples do not carry personal 
identifiers (such as name or social security number).
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study or GSK may destroy the samples sooner.  GSK or those working 
with GSK (for example, other researchers) will only use samples collected from the study 
for the purposes stated in this protocol and in the informed consent form.  Samples may 
be used as part of the development of a companion diagnostic to support the GSK 
medicinal product.
Subjects can request their sample to be destroyed at any time.
Informed Consent
Subjects who do not wish to participate in the genetic research may still participate in the 
study.  Genetic informed consent must be obtained prior to any blood being taken.
Subject Withdrawal from Study
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample, if already 
collected:

Continue to participate in the genetic research in which case the genetic DNA 
sample is retained

Discontinue participation in the genetic research and destroy the genetic DNA 
sample.
If a subject withdraws consent for genetic research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in 
the site study records.

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Genotype data may be generated during the clinical study or after completion of the 
clinical study and may be analyzed during the clinical study or stored for future analysis.

If a subject withdraws consent for genetic research and genotype data has not 
been analyzed, it will not be analyzed or used for future research.

Genetic data that has been analyzed at the time of withdrawn consent will 
continue to be stored and used, as appropriate.
Screen and Baseline Failures
If a sample for genetic research has been collected and it is determined that the subject 
does not meet the entry criteria for participation in the study, then the investigator should 
instruct the subject that their genetic sample will be destroyed. No forms are required to 
complete this process as it will be completed as part of the consent and sample 
reconciliation process.  In this instance a sample destruction form will not be available to 
include in the site files.
Provision of Study Results and Confidentiality of Subject’s Genetic Data
GSK may summarize the genetic research results in the clinical study report, or 
separately and may publish the results in scientific journals.
GSK may share genetic research data with other scientists to further scientific 
understanding in alignment with the informed consent. GSK does not inform the subject, 
family members, insurers, or employers of individual genotyping results that are not 
known to be relevant to the subject’s medical care at the time of the study, unless 
required by law. This is due to the fact that the information generated from genetic 
studies is generally preliminary in nature, and therefore the significance and scientific 
validity of the results are undetermined.  Further, data generated in a research laboratory 
may not meet regulatory requirements for inclusion in clinical care.
References
Chen H, Yu KD, Xu GZ. Association between Variant Y402H in Age-Related Macular 
Degeneration (AMD) Susceptibility Gene CFH and Treatment Response of AMD: A 
Meta-Analysis. PloS ONE 2012; 7: e42464
Gorin MB. Genetic insights into age-related macular degeneration: Controversies 
addressing risk, causality, and therapeutics. Mol. Asp. Med. 2012; 33: 467-486.

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12.4.
Appendix 4: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.4.1.
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, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae).

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE.  However, the signs and symptoms and/or clinical 
sequelae resulting from lack of efficacy will be reported if they fulfil the definition 
of an AE or SAE.
Events NOT meeting definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
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.
12.4.2.
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.
Refer to Section 12.2 for the required liver chemistry follow-up instructions
12.4.3.
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
12.4.4.
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 PRO questionnaires and the collection of AE data are 
independent components of the study.

Responses to each question in the PRO 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.
12.4.5.
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 

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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.
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 

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or investigations, histopathological examinations or consultation with other health 
care professionals.

If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide GSK with a copy of any post-mortem findings, 
including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
12.4.6.
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 GSK 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 GSK 
Medical Monitor by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Medical Monitor/Sponsor Information page.

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12.5.
Appendix 5: Modified List of Highly Effective Methods for 
Avoiding Pregnancy in FRP and Collection of Pregnancy 
Information
12.5.1.
Modified List of Highly Effective Methods for Avoiding Pregnancy 
in Females of Reproductive Potential (FRP)
The list does not apply to FRP with same sex partners or for subjects who are and will 
continue to be abstinent from penile-vaginal intercourse on a long term and persistent 
basis, when this is their preferred and usual lifestyle.  Periodic abstinence (e.g. calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.
1.
Contraceptive subdermal implant
2.
Intrauterine device or intrauterine system
3.
Combined estrogen and progestogen oral contraceptive [Hatcher, 2011])
4.
Injectable progestogen [Hatcher, 2011]
5.
Contraceptive vaginal ring [Hatcher, 2011]
6.
Percutaneous contraceptive patches [Hatcher, 2011]
7.
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].  The documentation on male sterility can come from the site 
personnel’s: review of subject’s medical records, medical examination and/or semen 
analysis, or medical history interview provided by her or her partner.
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label.  The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
12.5.2.
Collection of Pregnancy Information

Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study

Information will be recorded on the appropriate form and submitted to GSK within 
2 weeks of learning of a subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on mother and infant, which will be 
forwarded to GSK.  Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date.

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.

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
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 Section 12.4.6. While the investigator is not obligated to actively 
seek this information in former study participants, he or she may learn of an SAE 
through spontaneous reporting.
Any female subject who becomes pregnant while participating will be withdrawn 
from study treatment.
12.5.3.
References
CHMP, 2005 - EMA - Guideline on Adjuvants in Vaccines for Human Use, 
(CHMP/VEG/134716/2004), January 2005.
Cole LA, Khanlian SA, Sutton JM, Davies S, Rayburn WF. Accuracy of home pregnancy 
tests at the time of missed menses. Am J Ob Gyn 2004(190):100-5.
EMA/CHMP/ICH/449035/2009: General principles to address virus and vector shedding. 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/
WC500002680.pdf Accessed 28 Nov 2014.
EMEA/CHMP/GTWP/125459/2006: Guideline on the Nonclinical Studies Required 
Before First Clinical Use of Gene Therapy Medicinal Products [2008]
FDA CBER Guidance for industry, “Considerations for Developmental Toxicity Studies 
for Preventive and Therapeutic Vaccines for Infectious Disease Indications. U.S. FDA; 
Feb. 2006. 
FDA Medical Devices Safety Alerts and Notices, “Blood human chorionic gonadotropin 
(hCG) assays: What laboratorians should know about false-positive results”, 
http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/TipsandArticlesonDeviceS
afety/ucm109390.htm, accessed 17 Nov 2014.
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.
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals For Human Use. ICH Harmonized Tripartite Guideline. Detection of 
Toxicity to Reproduction for Medicinal Products & Toxicity to Male Fertility. Parent 
Guideline dated 24 June 1993 (Addendum dated 9 November 2000 incorporated in 
November 2005. ICH S5 (R2)
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals For Human Use.  ICH Harmonized Tripartite Guideline. Nonclinical 
Evaluation for Anticancer Pharmaceuticals. ICH S9. 2009.

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International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals For Human Use. ICH Harmonized Tripartite Guideline. Nonclinical 
Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for
Pharmaceuticals. ICH M3 (R2). 2009.
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals For Human Use. ICH Harmonized Tripartite Guideline. Preclinical 
Safety Evaluation of Biotechnology-Derived Pharmaceuticals. ICH S6 and Addendum 
ICH S6 (R1). 2011.
Kronenberg HM, Melmed S, Polonsky KS, Larsen PR, editors. Williams Textbook of 
Endocrinology, 11th edition. Philadelphia: Saunders, 2008.
Strauss JF, Barbieri RL, editors. Yen and Jaffe’s Reproductive Endocrinology. 5th 
edition, Philadelphia, Elsevier/Saunders, 2004.
U.S. Dept of Health and Human Services, FDA, Center For Biologics Evaluation and 
Research: Guidance for Human Somatic Cell Therapy and Gene Therapy [1998]
WHO, 2013 - WHO - Guidelines on the Nonclinical Evaluation of Vaccine Adjuvants 
and Adjuvanted Vaccines, 2013
World Health Organization. WHO/CONRAD Technical Consultation on Nonoxynol-9.
World Health Organization; Department of Reproductive Health and Research; Geneva; 
9-10 October 2001. Summary Report. 2001. WHO/RHR/03.8.

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12.6.
Appendix 6: Anaphylaxis Criteria
Hypersensitivity reactions will be monitored using the diagnostic criteria for anaphylaxis 
as outlined by the Joint NIAID/FAAN Second Symposium on Anaphylaxis 
[Sampson, 2006].  The criteria do not make a distinction based on underlying mechanism. 
These criteria are summarized as follows:
1.
Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, swollen lips-
tongue-uvula), and at least one of the following:

Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced 
peak expiratory flow [PEF], hypoxemia)

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):

Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, 
swollen lips-tongue-uvula)

Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced 
PEF, hypoxemia)

Reduced BP or associated symptoms (e.g., hypotonia [collapse], syncope, 
incontinence)

Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting)
3.
Reduced BP after exposure to known allergen for that patient (minutes to several 
hours):

Infants and children: low systolic BP (age specific) or greater than 30% decrease 
in systolic BP

Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from 
that person’s baseline.

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12.7.
Appendix 7: Classification of Heart Failure
Physicians usually classify patients' heart failure according to the severity of their 
symptoms [American Heart Association, 2014].  The table below describes the most 
commonly used classification system, the NYHA Functional Classification.  It places 
patients in one of four categories based on how much they are limited during physical 
activity.
Class
Functional Capacity: How a patient with cardiac disease feels during physical 
activity
I
Patients with cardiac disease but resulting in no limitation of physical activity. 
Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea or 
anginal pain.
II
Patients with cardiac disease resulting in slight limitation of physical activity. They 
are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, 
dyspnea or anginal pain.
III
Patients with cardiac disease resulting in marked limitation of physical activity. They 
are comfortable at rest. Less than ordinary activity causes fatigue, palpitation, 
dyspnea or anginal pain.
IV
Patients with cardiac disease resulting in inability to carry on any physical activity 
without discomfort. Symptoms of heart failure or the anginal syndrome may be 
present even at rest.
Class
Objective assessment
A
No objective evidence of cardiovascular disease. No symptoms and no limitation in 
ordinary physical activity.
B
Objective evidence of minimal cardiovascular disease. Mild symptoms and slight 
limitation during ordinary activity. Comfortable at rest.
C
Objective evidence of moderately severe cardiovascular disease. Marked limitation 
in activity due to symptoms, even during less-than-ordinary activity. Comfortable 
only at rest.
D
Objective evidence of severe cardiovascular disease. Severe limitations. 
Experiences symptoms even while at rest.
For Example:

A patient with minimal or no symptoms but a large pressure gradient across the 
aortic valve or severe obstruction of the left main coronary artery is classified: 
Function Capacity I, Objective Assessment D.

A patient with severe anginal syndrome but angiographically normal coronary 
arteries is classified: Functional Capacity IV, Objective Assessment A.

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12.8.
Appendix 8: Country Specific Requirements
No country-specific requirements exist.