Conditions: Hypereosinophilic Syndrome
Keywords: Safety Mepolizumab Hypereosinophilic syndrome HES flare Efficacy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 108
Healthy volunteers: no

Brief summary:
Mepolizumab is a humanized monoclonal antibody. In conditions where eosinophilia is considered to play an important part in the pathology, including eosinophilic asthma, HES, and eosinophilic granulomatosis with polyangiitis, a consistent reduction in blood eosinophil counts is observed in association with mepolizumab administration, with concomitant clinical improvement. 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 standard of care (SoC) therapy. This study will demonstrate the efficacy of mepolizumab compared with placebo based on maintenance of control of HES symptoms during the treatment period. The study will comprise of a screening period of up to approximately 4 weeks followed by a 32-Week study treatment period (subjects will be randomized 1:1 to placebo or mepolizumab) and up to 8-week additional follow-up period (12 weeks after the last dose of study treatment).

Detailed description:

Arms:
arm 1: Enrolled subjects will receive either mepolizumab 300 mg or placebo subcutaneous (SC) every 4 weeks while continuing their HES therapy. arm 2: Enrolled subjects will receive either mepolizumab 300 mg or placebo SC every 4 weeks while continuing their HES therapy.

Interventions: intervention 1: Mepolizumab 300 mg intervention 2: Placebo matching mepolizumab intervention 3: Active OCS capsules (5 mg prednisolone or prednisone) intervention 4: Placebo matching OCS capsules
Intervention descriptions: intervention 1: Mepolizumab is available as lyophilized powder for injection reconstituted with Sterile Water for Injection, just prior to use. intervention 2: Placebo is available as 0.9% sodium chloride solution intervention 3: All subjects will be provided with 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 with an increase in blood eosinophils above the pre-specified threshold will be instructed to start blinded OCS treatment from one of the bottles provided (active treatment) unless the subject's HES therapy has already been increased due to a symptom flare within the past 2 weeks. intervention 4: All subjects will be provided with 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.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 OCS treatment in a blinded manner, unless the subject's HES therapy has already been increased due to a symptom flare within the past 2 weeks.

Protocol document:
Prot_000.pdf: 
2013N171550_00
CONFIDENTIAL
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.
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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
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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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5
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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8
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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10
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.


2013N171550_00
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13
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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Klion AD. Hypereosinophilic Syndrome: Current Approach to Diagnosis and Treatment. 
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treatment in patients with severe eosinophilic asthma.  N Engl J Med. 2014; 371: 1198-
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Rothenberg ME, Klion AD, Roufosse FE et al. Treatment of patients with 
hypereosinophilic syndrome with mepolizumab. N Engl J Med. 2008; 358: 1215-28.
Roufosse F, de Lavareille A, Schandene L, et al. Mepolizumab as a corticosteroid-
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Roufosse FE, Goldman M, Cogan E.  Hypereosinophilic syndromes.  Orphanet Journal 
of Rare Diseases. 2007; 2: 37.
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Schwartz LB, Sheikh J, Singh A. Current Strategies in the management of 
hypereosinophilic syndrome, including mepolizumab. Curr Med Res Opinion. 2010; 26: 
1933-46.
Simon H, Plotz SG, Dummer R et al. Abnormal clones of T cells producing interleukin-5 
in idiopathic eosinophilia. N Eng J Med. 1999; 341: 1112-20.
Stein ML, Collins MH, Villaneuva JM, et al. Anti-IL-5 (mepolizumab) therapy for 
eosinophilic esophagitis. J Allergy Clin Immunol. 2006; 118: 1312-9.
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Valent P, Klion AD, Horny H-P, et al. Contemporary consensus proposal on criteria and 
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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.

SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
200622
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for Study 200622: A 
randomised, 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
Effective Date 
:
18-JUN-2019
Description:

The purpose of this RAP is to describe the planned efficacy and safety analyses and 
output to be included in the Clinical Study Report for Protocol 200622.

This RAP defines the content of the headline results and SAC deliverables.
RAP Author(s):
Author
Date
Project Statistician
07-JUN-2019
Clinical Pharmacology, Modelling and Simulation
Copyright 2019 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD
PPD


CONFIDENTIAL
The GlaxoSmithKline group of companies
200622
2
RAP Team Review Confirmations
(Method: E-mail):
Approver
Date
Clinical Pharmacology, Modelling and Simulation
11-JUN-2019
Lead Programmer
13-JUN-2019
07-JUN-2019
Project Physician Lead
12-JUN-2019
Safety Evaluation and Risk Management
Patient Centred Outcomes
07-JUN-2019
Clinical Statistics and Clinical Programming Line Approvals
(Method: Pharma TMF eSignature):
Approver
Date
18-JUN-2019
Senior Statistics Director
17-JUN-2019
Director Programming
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................8
1.1.
RAP Amendments ........................................................................................8
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................9
2.1.
Study Objective(s) and Endpoint(s)...............................................................9
2.2.
Study Design ..............................................................................................11
2.3.
Statistical Hypotheses / Statistical Analyses ...............................................13
2.4.
Changes to the Protocol Defined Statistical Analysis Plan..........................13
3.
PLANNED ANALYSES ..........................................................................................15
3.1.
Interim Analyses .........................................................................................15
3.2.
Final Analyses ............................................................................................15
4.
ANALYSIS POPULATIONS ...................................................................................16
4.1.
Protocol Deviations.....................................................................................17
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................18
5.1.
Study Treatment & Sub-group Display Descriptors.....................................18
5.2.
Baseline Definitions ....................................................................................18
5.3.
Multicentre Studies .....................................................................................18
5.4.
Examination of Covariates, Other Strata and Subgroups............................19
5.4.1.
Covariates and Other Strata ........................................................19
5.4.1.1.
Derivation of Baseline Oral Prednisone 
Equivalent Daily Dose ................................................19
5.4.2.
Examination of Subgroups...........................................................21
5.5.
Multiple Comparisons and Multiplicity .........................................................22
5.6.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................22
6.
STUDY POPULATION ANALYSES .......................................................................23
6.1.
Overview of Planned Study Population Analyses........................................23
7.
EFFICACY ANALYSES..........................................................................................24
7.1.
Primary Efficacy Analyses ..........................................................................24
7.1.1.
Endpoint / Variables.....................................................................24
7.1.2.
Summary Measure ......................................................................24
7.1.3.
Strategy for Intercurrent (Post-Randomization) Events ................24
7.1.3.1.
Primary Estimand .......................................................24
7.1.3.2.
Supplementary Estimand............................................25
7.1.4.
Statistical Analyses / Methods .....................................................25
7.1.4.1.
Statistical Methodology Specification..........................26
7.1.5.
Exploratory Modelling of Primary Endpoint ..................................27
7.2.
Secondary Efficacy Analysis – Time to First HES Flare ..............................28
7.2.1.
Endpoint / Variables.....................................................................28
7.2.2.
Summary Measure ......................................................................28
7.2.3.
Strategy for Intercurrent (Post-Randomization) Events ................28
7.2.4.
Statistical Analyses / Methods .....................................................28
7.2.4.1.
Statistical Methodology Specification..........................28


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7.3.
Secondary Efficacy Analysis – Proportion of Subject Who 
Experience a HES Flare During Week 20 Through Week 32 ......................30
7.3.1.
Endpoint / Variables.....................................................................30
7.3.2.
Summary Measure ......................................................................30
7.3.3.
Strategy for Intercurrent (Post-Randomization) Events ................30
7.3.4.
Statistical Analyses / Methods .....................................................30
7.3.4.1.
Statistical Methodology Specification..........................31
7.4.
Secondary Efficacy Analysis – Rate of HES Flares.....................................32
7.4.1.
Endpoint / Variables.....................................................................32
7.4.2.
Summary Measure ......................................................................32
7.4.3.
Strategy for Intercurrent (Post-Randomization) Events ................32
7.4.4.
Statistical Analyses / Methods .....................................................32
7.4.4.1.
Statistical Methodology Specification..........................33
7.5.
Secondary Efficacy Analysis – Change from Baseline in Fatigue 
Severity BFI Item 3 (Worst Level of Fatigue in Past 24 Hours) at 
Week 32 .....................................................................................................34
7.5.1.
Endpoint / Variables.....................................................................34
7.5.2.
Summary Measure ......................................................................34
7.5.3.
Strategy for Intercurrent (Post-Randomization) Events ................34
7.5.4.
Statistical Analyses / Methods .....................................................34
7.6.
Exploratory Efficacy Analyses.....................................................................36
7.6.1.
Proportion of Subjects Who Have an Elevated Blood 
Eosinophil Level That Meets the Pre-Defined Threshold 
During the 32-Week Study Treatment Period...............................36
7.6.1.1.
Endpoint / Variables ...................................................36
7.6.1.2.
Strategy for Intercurrent (Post-Randomization) 
Events ........................................................................36
7.6.1.3.
Statistical Analyses / Methods ....................................36
7.6.2.
FEV1, FVC and FEV1/FVC ratio ...................................................37
7.6.2.1.
Endpoint / Variables ...................................................37
7.6.2.2.
Strategy for Intercurrent (Post-Randomization) 
Events ........................................................................37
7.6.2.3.
Statistical Analyses / Methods ....................................37
7.6.3.
Echocardiogram...........................................................................38
7.6.4.
Change From Baseline in HES Symptom Severity Based 
on HES Daily Symptoms (HES-DS) at Week 32 ..........................38
7.6.4.1.
Endpoint / Variables ...................................................38
7.6.4.2.
Strategy for Intercurrent (Post-Randomization) 
Events ........................................................................38
7.6.4.3.
Statistical Analyses / Methods ....................................39
7.6.5.
Change from Baseline in BFI Total Score at Week 32 .................39
7.6.5.1.
Endpoint / Variables ...................................................39
7.6.5.2.
Strategy for Intercurrent (Post-Randomization) 
Events ........................................................................40
7.6.5.3.
Statistical Analyses / Methods ....................................40
7.6.6.
Clinician- and Subject-Rated Overall Response to 
Therapy Score (RTS) at Week 32................................................41
7.6.6.1.
Endpoint / Variables ...................................................41
7.6.6.2.
Strategy for Intercurrent (Post-Randomization) 
Events ........................................................................41
7.6.6.3.
Statistical Analyses / Methods ....................................41


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7.6.7.
Change from Baseline in Subject-Rated Symptom 
Severity (SSR) at Week 32 ..........................................................42
7.6.7.1.
Endpoint / Variables ...................................................42
7.6.7.2.
Strategy for Intercurrent (Post-Randomization) 
Events ........................................................................42
7.6.7.3.
Statistical Analyses / Methods ....................................42
7.6.8.
Change from Baseline in Modified Memorial Symptom 
Assessment Scale-Short Form (MSAS-SF) responses at 
Week 32 ......................................................................................43
7.6.8.1.
Endpoint / Variables ...................................................43
7.6.8.2.
Strategy for Intercurrent (Post-Randomization) 
Events ........................................................................44
7.6.8.3.
Statistical Analyses / Methods ....................................44
7.6.9.
Change from Baseline in Physical Function and Sleep 
(Patient Reported Outcome Measurement Information 
System [PROMIS]) at Week 32....................................................45
7.6.9.1.
Endpoint / Variables ...................................................45
7.6.9.2.
Strategy for Intercurrent (Post-Randomization) 
Events ........................................................................45
7.6.9.3.
Statistical Analyses / Methods ....................................45
8.
HEALTH OUTCOMES ANALYSIS .........................................................................47
8.1.
SF-36 v2.....................................................................................................47
8.2.
Healthcare Resource Utilization (HCRU) ....................................................47
8.2.1.
Work Productivity and Activity Impairment ...................................47
9.
POPULATION PHARMACOKINETIC ANALYSES .................................................48
9.1.
Population of Interest..................................................................................48
9.2.
Strategy for Intercurrent (Post-Randomization) Events ...............................48
9.3.
Population Pharmacokinetic Methodology ..................................................48
9.3.1.
Base Model..................................................................................49
9.3.2.
Investigation of Covariates...........................................................49
9.3.3.
Covariate Model Selection Procedures........................................50
9.3.4.
Model Evaluation .........................................................................51
10. PHARMACODYNAMIC ANALYSES.......................................................................52
10.1.
Blood Eosinophils .......................................................................................52
10.1.1.
Population of Interest...................................................................52
10.1.2.
Endpoint / Variables.....................................................................52
10.1.3.
Summary Measure ......................................................................52
10.1.4.
Strategy for Intercurrent (Post-Randomization) Events ................52
10.1.5.
Statistical Analyses / Methods .....................................................52
10.1.5.1.
Statistical Methodology Specification..........................52
10.2.
Serum Total IL-5.........................................................................................53
10.2.1.
Population of Interest...................................................................53
10.2.2.
Endpoint / Variables.....................................................................53
10.2.3.
Summary Measure ......................................................................53
10.2.4.
Strategy for Intercurrent (Post-Randomization) Events ................53
10.2.5.
Statistical Analyses / Methods .....................................................53
10.2.5.1.
Statistical Methodology Specification..........................54
11. SAFETY ANALYSES .............................................................................................55


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11.1.
Adverse Events Analyses ...........................................................................55
11.1.1.
Adverse Events of Special Interest ..............................................55
11.2.
Clinical Laboratory Analyses.......................................................................55
11.3.
Other Safety Analyses ................................................................................56
12. IMMUNOGENICITY ANALYSES............................................................................57
12.1.
Overview of Immunogenicity Analyses........................................................57
13. PHARMACOKINETIC / PHARMACODYNAMIC ANALYSES .................................58
13.1.
Population of Interest..................................................................................58
13.2.
Strategy for Intercurrent (Post-Randomization) Events ...............................58
13.3.
Population Pharmacokinetic/Pharmacodynamic Methodology ....................58
13.3.1.
Base Model..................................................................................59
13.3.2.
Investigation of Covariates...........................................................59
14. EXPLORATORY EXPOSURE-EFFICACY RESPONSE ANALYSIS ......................61
14.1.
Population of Interest..................................................................................61
14.2.
Endpoints....................................................................................................61
14.3.
Methodology...............................................................................................61
15. REFERENCES.......................................................................................................62
16. APPENDICES........................................................................................................63
16.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................63
16.1.1.
Exclusions from Per Protocol Population .....................................63
16.2.
Appendix 2: Schedule of Activities ..............................................................64
16.2.1.
Protocol Defined Schedule of Events...........................................64
16.3.
Appendix 3: Assessment Windows .............................................................69
16.3.1.
Definition of Weekly Assessment Windows..................................69
16.4.
Appendix 4: Study Phases..........................................................................71
16.4.1.
Treatment Phases for HES Flare .................................................71
16.4.2.
Treatment Phases for BFI and HES-DS.......................................71
16.4.3.
Treatment Phases for Other Efficacy Assessments .....................71
16.4.4.
Treatment Phases for Adverse Events.........................................71
16.4.5.
Study Phases for Concomitant Medication...................................72
16.5.
Appendix 5: Data Display Standards & Handling Conventions....................73
16.5.1.
Reporting Process .......................................................................73
16.5.2.
Reporting Standards....................................................................73
16.5.3.
Reporting Standards for Pharmacokinetic Data ...........................74
16.6.
Appendix 6: Derived and Transformed Data ...............................................76
16.6.1.
General........................................................................................76
16.6.2.
Change from Baseline Definitions................................................76
16.6.3.
Study Population..........................................................................77
16.6.4.
Efficacy........................................................................................78
16.6.5.
Safety ..........................................................................................80
16.7.
Appendix 7: Reporting Standards for Missing Data.....................................81
16.7.1.
Premature Withdrawals................................................................81
16.7.2.
Handling of Missing Data.............................................................81
16.7.2.1.
Handling of Missing and Partial Dates ........................81
16.8.
Appendix 8: Values of Potential Clinical Importance ...................................83
16.8.1.
Laboratory Values........................................................................83


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16.8.2.
Urinalysis.....................................................................................83
16.9.
Appendix 9: Abbreviations & Trade Marks ..................................................84
16.9.1.
Abbreviations...............................................................................84
16.9.2.
Trademarks .................................................................................85
16.10. Appendix 10: List of Data Displays..............................................................86
16.10.1. Data Display Numbering..............................................................86
16.10.2. Mock Example Shell Referencing ................................................86
16.10.3. Deliverables.................................................................................86
16.10.4. Study Population Tables..............................................................87
16.10.5. Efficacy Tables ............................................................................90
16.10.6. Efficacy Figures ...........................................................................99
16.10.7. Health Outcomes Tables ...........................................................107
16.10.8. Safety Tables.............................................................................108
16.10.9. Safety Figures ...........................................................................115
16.10.10.Pharmacokinetic Tables.............................................................116
16.10.11.Pharmacokinetic Figures ...........................................................117
16.10.12.Pharmacodynamic Tables .........................................................118
16.10.13.Pharmacodynamic Figures ........................................................119
16.10.14.Pharmacokinetic / Pharmacodynamic Tables ............................120
16.10.15.Pharmacokinetic / Pharmacodynamic Figures ...........................121
16.10.16.ICH Listings ...............................................................................122
16.11. Appendix 11: Example Mock Shells for Data Displays ..............................128


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1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol 200622:
Protocol Revision Chronology:
2013N171550_00
29-APR-2016
Original
1.1.
RAP Amendments
Revision chronology: 
RAP Section
Amendment Details
Reporting and Analysis Plan_200622_Final_V1 [12-FEB-2019]
Reporting and Analysis Plan_200622_Amendment_Final_V1 [18-JUN-2019]
Section 5.2

Update to the definition of baseline ECG to include ECG findings
Section 5.4.1.1

Update to the OCS conversion table to include fluticasone
Section 6.1

Additional details for the summary of steroid perception 
questionnaire
Section 7.1.4.1

Specify an additional sensitivity analysis of the primary estimand 
excluding subjects from a single site in Mexico.
Section 7.4.4.1

Update to the sensitivity analysis for missing data for the rate of 
HES flares endpoint
Section 7.5.4

Clarification of the implementation of the Wilcoxon rank sum test
Section 7.6.8

Update to the derivation of MSAS-SF endpoints to include detail of 
conversion of categorical responses to numeric scores.
Section 14

New section for exploratory exposure-efficacy response analysis
Section 16.4

Define treatment phases for HES flare and other efficacy 
assessments
Section 16.6

Define derivation of total observed time, time on treatment, time off 
treatment, missing time (days)

Clarification of QTcB calculation
Section 16.8

Additional PCI range for Creatine Phosphokinase
Section 16.10

Updates to relevant display titles in line with changes above

Minor changes to titles of summary tables for AESIs


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2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

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 a HES flare 
during the 32-week study treatment period
Secondary Objectives
Secondary Endpoints

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 a 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 Objectives
Exploratory Endpoints

To investigate mepolizumab 
compared with placebo with 
respect to additional measures of 
efficacy.

Proportion of subjects who have an elevated blood 
eosinophil level that meets the pre-defined threshold 
during the 32-week study treatment period1

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 score at Week 
322

Clinician- and subject-rated overall response to 
therapy score (RTS) at Week 323

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.

Total IL-54

Blood eosinophil levels
Safety Objectives
Safety Endpoints

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)
1Protocol endpoint was the proportion of subjects who receive blinded active oral corticosteroid (OCS) due to an 
elevated blood eosinophil level that meets the pre-defined threshold (2 x baseline value or baseline value + 2500 
cells/L) during the 32-week study treatment period. See Section 2.4 for rationale for change.
2Protocol endpoint was change from baseline in the BFI total and domain scores at Week 32. See Section 2.4 for 
rationale for change.
3Protocol endpoint was the proportion of subjects with a favourable response as measured by clinician- and subject-
rated overall response to therapy score (RTS) at Week 32. See Section 2.4 for rationale for change.
4Serum free and total IL-5 were planned in the protocol. See Section 2.4 for rationale for change.


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2.2.
Study Design
Overview of Study Design and Key Features
Design 
Features

32-week treatment period, randomised, double-blind, placebo-controlled, 
parallel group, multicentre study of mepolizumab in adolescent and adult 
subjects with severe HES receiving SoC therapy.

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.

Subjects who withdraw from study treatment prematurely should continue in 
the study per protocol (including HES flare-related assessments) until 32 
weeks from randomization.

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 (2 x baseline value or 
baseline value + 2500 cells/L). Provided the subject’s HES therapy has 
not been increased due to a symptom flare, the subject will take the blinded 
active OCS for 2 weeks. A subject who does not reach the pre-defined 
blood eosinophilia threshold with a similar blood draw date will be selected 
to initiate blinded placebo OCS treatment, to maintain study blood 
eosinophil blinding. Approximately 2 weeks after the scheduled clinic visit, 
the blood eosinophil count will be assessed again for the subjects who 


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Overview of Study Design and Key Features
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 until the next scheduled clinic visit if the blood eosinophil 
count is at or above the threshold unless the subject’s HES therapy 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.

An open-label study is also planned (study 205203) for subjects who 
complete study 200622.
Main subject 
entry criteria

Subjects 12 years with HES

At least 2 HES flares within the past 12 months; 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.

Blood eosinophil count 1000 cells/L during screening. Investigators 
were permitted to use local laboratory results to meet this inclusion criteria.
Dosing

300 mg mepolizumab or placebo SC every 4 weeks (8 administrations) 
while continuing their HES therapy.

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.
Treatment 
Assignment

Subjects will be randomised in a 1:1 ratio to receive either mepolizumab or 
placebo in addition to SoC therapy.

An initial sample size of N=80 subjects will be randomised. The proportion 
of subjects that have a HES flare will be monitored, blinded to treatment, 
and the total number of subjects randomised may be increased up to a 
maximum of 120 subjects if the blinded overall flare rate is predicted to be 
<30%. The blinded overall proportion of subjects who have a 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 7.1.1. 
In order to maintain the blood eosinophil blinding, HES flares meeting flare 
end point definition ‘b)’ in Section 7.1.1 will not be included in the 
calculation of the blinded overall proportion.

Treatments will be assigned randomly via an interactive response system 
(IRS).

Randomization schedule will be generated using GSK validated 
randomisation software RandAll NG.

Randomization stratified by region.
Time and 
events

See Appendix 2: Schedule of Activities.
Interim 

An external Independent Data Monitoring Committee (IDMC) will 


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Overview of Study Design and Key Features
Analysis
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 centre (SDAC). There 
are no circumstances under which IDMC review of the data would lead to a 
recommendation to stop for efficacy. Therefore, no adjustment to the final 
alpha level for efficacy will be made based on the safety stopping 
guidelines.
2.3.
Statistical Hypotheses / Statistical Analyses
The primary efficacy endpoint is the proportion of subjects who experience a 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 a HES flare during the 32-week study 
treatment period.

Alternative hypothesis: the proportion of subjects who experience a 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%).
2.4.
Changes to the Protocol Defined Statistical Analysis Plan

The following changes to the exploratory endpoints were made in this RAP:
Protocol Endpoint
RAP Endpoint
Rationale for Change
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
Proportion of 
subjects who 
have an elevated 
blood eosinophil 
level that meets 
the pre-defined 
threshold during 
the 32-week study 
treatment period
RAP endpoint considered to be more clinically 
meaningful as it includes all subjects with blood 
eosinophil counts meeting the pre-defined threshold 
during the 32-week study treatment period rather than 
including only the subset of these subjects who receive 
blinded active OCS. Subjects did not receive blinded 
active OCS if their physician had already increased 
their HES therapy based on symptoms.
Change from 
baseline in the BFI 
total and domain 
scores at Week 32
Change from 
baseline in the 
BFI total score at 
Week 32.
The BFI is a single construct and therefore domain 
scores are not applicable. 
Proportion of 
subjects with a 
favourable response 
as measured by 
clinician- and subject-
Clinician- and 
subject-rated 
overall response 
to therapy score 
(RTS) at Week 32
Improvement/worsening is measured on a 7-point scale 
from significant worsening to significant improvement. 
The endpoint will be summarised and analysed as a 7-
point ordinal endpoint to avoid loss of information and 
increase the sensitivity of the analysis.


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Protocol Endpoint
RAP Endpoint
Rationale for Change
rated overall 
response to therapy 
score (RTS) at Week 
32
Serum free and total 
IL-5
Total IL-5
Free IL-5 levels are generally very low in serum (<BLQ) 
and are expected to decrease post dosing because 
most of the free IL-5 becomes complexed with 
mepolizumab. Hence only total IL-5 will be measured.

Since some participants were randomised early in error prior to the first dose of 
mepolizumab, the following changes to the secondary endpoint derivations in the 
protocol are planned:
-
Time to first HES flare will be calculated from the date of first dose of study 
treatment and the onset date of the HES flare, rather than the date of 
randomisation and the onset date of the HES flare.
-
The rate of HES flares will be calculated using the date of the first dose of study 
treatment and the Week 32 visit/study withdrawal date, rather than the 
randomisation date and the Week 32 visit/study withdrawal date.
-
For the calculation of the change from baseline in BFI item 3, the mean of the 7 
daily assessments of BFI item 3 up to but not including the date of first dose of 
study treatment will be used as the baseline assessment. Since BFI item 3 is 
measured daily after 6pm, the date of dosing will not be included in the 
calculation of the baseline BFI.


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3.
PLANNED ANALYSES
3.1.
Interim Analyses
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 centre (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 emergency unblinding procedures described in Section 6.3 of the protocol, 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.
3.2.
Final Analyses
The final planned primary analyses will be performed after the completion of the 
following sequential steps:
1.
All subjects have completed the study as defined in the protocol.
2.
All required database cleaning activities have been completed and final database 
release (DBR) and database freeze (DBF) has been declared by Data Management.
3.
A review has taken place by the unblinded global study manager to identify any 
subjects with a discrepancy between randomised treatment and actual treatment 
received. This information will be included in the SDTM dataset at DBF. Actual 
treatment arm will be derived within the ADaM datasets based on the treatment 
received for more than 50% of treatment administrations. If a subject received an 
equal number of both treatments then the actual treatment arm will reflect the 
treatment to which they were randomised.
4.
All criteria for unblinding the randomisation codes have been met, and treatment 
allocations have been unblinded via the RandAll NG system, as described in 
SOP_54840.


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4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
Screened 

All participants who were screened for eligibility i.e. 
for whom record exists in the database.

Study Population
(Pre-screen and 
screen failures)
Enrolled

All participants who were successfully screened and 
entered the study.

Note: screening failures (who never passed 
screening even if rescreened) and participants who 
were successfully screened but did not complete any 
visit 2 assessments are excluded.

Study Population
(EudraCT 
required 
displays)
Intent-To-Treat 
(ITT)

All randomised subjects

This population will be based on the treatment to 
which the subject was randomised.

Any subject who receives a treatment 
randomisation number will be considered to 
have been randomised.

Study Population

Efficacy

Listing of 
Planned and 
Actual 
Treatments
Per-Protocol 
(PP)

Comprise 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 will be made prior to breaking the 
blind.

Protocol deviations that would exclude subjects 
from the PP population are defined in Appendix 
1: Protocol Deviation Management and 
Definitions for Per Protocol Population.

Supplementary 
analysis of 
primary endpoint
Safety

All subjects who are randomised and who 
receive at least one dose of study treatment. 
Randomised subjects will be assumed to have 
received study treatment unless definitive 
evidence to the contrary exists.

This population will be based on the treatment 
the subject actually received.

Subjects will be analysed according to treatment 
received for more than 50% of their treatment 
administrations. If a subject received an equal 
number of both treatments then they will be 
assigned to the treatment to which they were 
randomised.

Study Population

Safety
Pharmacokinetic

All subjects in the ITT population who received 

PK


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Population
Definition / Criteria
Analyses Evaluated
at least one dose of study treatment and for 
whom at least one PK sample was obtained, 
analysed and was measurable.
Pharmacodynamic

All subjects in the ITT population who received 
at least one dose of study treatment and who 
also had a baseline PD measurement and at 
least one post-treatment PD measurement.

PD
Refer to Appendix 10: List of Data Displays which details the population used for each display.
4.1.
Protocol Deviations

Protocol deviations will be tracked by the study team throughout the conduct of the 
study in accordance with the Protocol Deviation Management Plan (PDMP).

Data will be reviewed prior to Source Data Lock (SDL) to ensure all important 
deviations and deviations which lead to exclusion from the Per Protocol analysis
population are agreed prior to unblinding. Important deviations will be categorised in 
the SDTM data set. Deviations leading to exclusion from the Per Protocol population 
will be categorised in the ADaM data set.

Important protocol deviations (including deviations related to study 
inclusion/exclusion criteria, conduct of the trial, patient management or patient 
assessment) will be summarised and listed.

A separate summary and listing of all inclusion/exclusion criteria deviations will also 
be provided. This summary will be based on data as recorded on the 
inclusion/exclusion page of the eCRF.

Important protocol deviations which result in exclusion from the Per Protocol 
population will be summarised and listed (see Appendix 1: Protocol Deviation 
Management and Definitions for Per Protocol Population).


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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
RandAll NG 
Data Displays for Reporting 
Code
Description
Description
Order [1]
A
Mepolizumab 300mg SC
Mepolizumab 300mg SC
2
P
Placebo
Placebo
1
NOTES:
1.
Order represents treatments being presented in Tables, Figures and Listings (TFLs), as appropriate.
5.2.
Baseline Definitions

Baseline will be defined for all subjects in the ITT population.

For the BFI item 3 which is collected daily from the screening visit (Visit 1) the mean 
of the 7 daily assessments of BFI item 3 up to but not including the date of first dose 
of study treatment will be used as the baseline assessment.

For blood eosinophils, baseline will be defined as the latest central laboratory result 
prior to the first dose of study treatment. Investigators were permitted to use local 
laboratory results to meet inclusion criteria, however local laboratory results will not 
be used in the derivation of the baseline blood eosinophil value.

For all other endpoints the baseline values for each assessment will be the latest 
available assessment (including unscheduled visits) prior to first dose of study 
treatment. For ECG, if multiple assessments are recorded on the same day, the mean 
of the multiple assessments will be assigned as the baseline value, and the latest ECG 
interpretation prior to the first dose of study medication will be used as the baseline 
ECG finding.
5.3.
Multicentre Studies

In this multicentre global study, enrolment will be presented by investigative site and 
country.

The randomisation for this study is stratified by region, defined below, with 
consideration for standard of care medical practice.

USA

Argentina, Mexico and Brazil

Rest of World

The same definition of region will be used for covariate adjustment in the statistical 
analysis.

If there are insufficient subjects in each region for the planned statistical analysis, 
further combining of regions will be considered.


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5.4.
Examination of Covariates, Other Strata and Subgroups
5.4.1.
Covariates and Other Strata

Region and baseline OCS dose, expressed as prednisone equivalent dose, will be 
covariates in all statistical analysis. These covariates will be included as stratification 
variables for the Cochran-Mantel-Haenszel test and Wilcoxon Rank Sum test
according to the table below. For parametric analysis models, region will be included 
as a fixed categorical effect and baseline OCS dose will be included as a fixed 
continuous effect.
Category
Covariates and / or Subgroups
Region
See Section 5.3.

USA

Argentina, Mexico and Brazil

Rest of World
Baseline oral prednisone equivalent 
dose1
See Section 5.4.1.1

0-20mg prednisone or equivalent

>20mg prednisone or equivalent
1For parametric analysis models, baseline OCS dose will be included as a fixed continuous effect.

If the percentage of subjects is small within a region, then the region categories may 
be refined prior to unblinding the trial.

For analyses where a baseline value of the analysis variable is available this will also 
be included in the statistical analysis. These covariates will be included as 
stratification variables for the Cochran-Mantel-Haenszel test and Wilcoxon Rank 
Sum test, and as continuous fixed effects for all parametric analysis models.
5.4.1.1.
Derivation of Baseline Oral Prednisone Equivalent Daily Dose

For each subject, a baseline oral prednisone equivalent daily dose (mg) will be 
derived prior to unblinding the randomisation codes for the study. Baseline oral 
prednisone equivalent dose will be identified from the concomitant medications page 
according to the following criteria:
o
Start date < Date of first dose of study treatment
o
Either “ongoing” or end date Date of first dose of study treatment
o
Route = “PO”

Partial start and end dates will be handled as described in Section 16.7.2.1.

Corticosteroids will be identified from the list of coded concomitant medications for 
the study, by merging with the GSK respiratory medication class (RMC) reference 
data set by component code. This reference data is created by dictionary specialists 
who identify a list of component terms for corticosteroids, which then undergo 
clinical review to ensure the correct classification is assigned.

Subjects not receiving OCS therapy, i.e. subjects receiving cytotoxic and/or 
immunosuppressive HES therapy only at baseline, or subjects not receiving any HES


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therapy, will be assigned a prednisone equivalent daily dose of 0 mg and will be 
categorised in the 0-20mg prednisone or equivalent group.

The corticosteroid conversion factors in the table below will be used to scale each 
corticosteroid dose to a prednisone equivalent dose.
Medication Name 
Scaling Factor
Betamethasone 
8.33
Budesonide1
0
Cortisone 
0.2
Dexamethasone 
6.67
Deflazacort
0.83
Fluticasone1
0
Hydrocortisone 
0.25
Methylprednisone 
1.25
Meprednisone
1.25
Prednisone 
1
Prednisolone 
1
Prednisone acetate
1
Triamcinolone 
1.25
1Budesonide and fluticasone have negligible systemic exposure and will be classed as “Other HES therapy” rather than 
oral corticosteroid therapy.

Where the frequency of the recorded corticosteroid dose is not once daily, the 
following calculations will be used to determine the daily dose.
Medication Frequency 
Daily Dose Equivalent
BID
2 x dose
TID
3 x dose
QID
4 x dose
QOD
dose / 2
2XWK
(2 x dose) / 7
3XWK
(3 x dose) / 7
4XWK
(4 x dose) / 7
5XWK
(5 x dose) / 7


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5.4.2.
Examination of Subgroups

The subgroups in the table below are of interest in this study. A separate exploratory 
analysis of the primary endpoint within each subgroup will be carried out.

Subgroup categories may be further collapsed if there are a small number of subjects 
in a treatment arm within a subgroup leading to model convergence issues.

There is a biological rationale for potentially observing increased efficacy with 
increasing levels of baseline blood eosinophils.  The role of blood eosinophil counts 
at baseline on the effectiveness of mepolizumab with respect to the primary endpoint 
will be further assessed based on a statistical model including baseline (loge) blood 
eosinophil count as a continuous variable and an interaction with treatment term. 
Baseline blood eosinophil count is defined in Section 5.2. The analysis will also be 
adjusted for region and baseline OCS dose, as described in Section 5.4.1. Fractional 
polynomial models for the baseline blood eosinophil count may also be explored in 
order to find the best fitting model for the relationship.

Differential treatment effects are not expected for any of the other subgroups listed 
below and therefore any differences in efficacy for mepolizumab compared to 
placebo observed in categories of these subgroups will be viewed as exploratory.
Subgroup
Categories 
Age

12-<18 years

18-64 years

65 years
Sex

Male

Female
Race

Black or African American

White

Asian

Other
Region

USA

Argentina, Mexico and Brazil

Rest of World
Baseline OCS

0-20mg prednisone or equivalent

>20mg prednisone or equivalent
Baseline blood eosinophils

Quartiles, rounded to 1 decimal place (GI/L); equivalent to 
rounding to the nearest 100 cells/L


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5.5.
Multiple Comparisons and Multiplicity
When strong control of type I error is required for making inferences for the predefined 
secondary endpoints, multiplicity will be controlled using a hierarchical, closed testing 
procedure, according to the following hierarchy of endpoints:
1. Proportion of subjects who experience a HES flare during the 32-week study treatment 
period (primary endpoint)
2. Time to first HES flare
3. Proportion of subjects who experience a 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, statistical significance for an endpoint in 
the predefined hierarchy will be dependent on statistical significance for the previous 
endpoints in the hierarchy. 
P-values for secondary endpoints will be provided both unadjusted and adjusted for 
multiplicity using the hierarchy of endpoints above.
5.6.
Other Considerations for Data Analyses and Data Handling 
Conventions
Other considerations for data analyses and data handling conventions are outlined in the 
appendices:
Section
Component
16.3
Appendix 3: Assessment Windows
16.4
Appendix 4: Study Phases and Treatment Emergent Adverse Events
16.5
Appendix 5: Data Display Standards & Handling Conventions
16.6
Appendix 6: Derived and Transformed Data
16.7
Appendix 7: Reporting Standards for Missing Data
16.8
Appendix 8: Values of Potential Clinical Importance


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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
The study population analyses will be based on the ITT population, unless otherwise 
specified. If the ITT population and the safety populations differ, study population 
analyses will also be produced for the safety population.
Study population analyses including analyses of subject’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications,
exposure and treatment compliance (assessed by number of administrations of study 
treatment) will be based on GSK Core Data Standards. In addition, summaries of baseline 
HES therapy, most bothersome HES symptoms and steroid perception questionnaire will 
be produced; for the summary of the steroid perception questionnaire, only subjects 
completing the questionnaire who have a baseline oral steroid reported on their
concomitant medication form will be summarised.
Details of the planned displays are presented in Appendix 10: List of Data Displays.


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7.
EFFICACY ANALYSES
The target population for the primary estimand is as defined by the study 
inclusion/exclusion criteria and therefore the ITT population will be the primary 
population for all efficacy analyses.
7.1.
Primary Efficacy Analyses
7.1.1.
Endpoint / Variables
The primary endpoint is the proportion of subjects who experience a HES flare during the 
32-week study treatment period.
A HES flare is defined as either:
a) A 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 
- 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.
HES flares meeting definition a) will be captured on the ‘flare details’ page in the eCRF.
An increase in blood eosinophils above the pre-defined threshold level (2 x baseline 
value or baseline value + 2500 cells/L) without any other clinical manifestations during 
the study will lead to administration of blinded active OCS treatment (see Section 2.2). If 
a subject receives a second course of blinded active OCS during the 32-week treatment 
period, the subject will be considered to be experiencing a flare. The container list for the 
blinded OCS treatment (indicating which container numbers contained active OCS and 
which contained placebo OCS) will be used to define HES flares meeting endpoint 
definition b). 
7.1.2.
Summary Measure
The difference between mepolizumab and placebo in the proportion of subjects with HES 
flare during the 32-week study treatment period.
7.1.3.
Strategy for Intercurrent (Post-Randomization) Events
7.1.3.1.
Primary Estimand
The primary treatment effect to be estimated (estimand) will be the ‘treatment policy’ 
effect of initial randomised treatment.  A treatment policy strategy will be used for the 
intercurrent events of a) discontinuation of study medication and b) receipt of alternative
HES medications.


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The study is designed to continue to collect data on HES flares for subjects who 
prematurely discontinue from their randomised study treatment. All data on HES flares 
collected for these subjects will be included in the primary analysis. Subjects who 
withdraw from the study prior to Week 32 (Visit 11) and therefore have missing data on 
HES flares will be included in the primary analysis as treatment failures, i.e. for the
primary comparison, a subject will be classed as not experiencing a HES flare only if 
they have no flares reported and complete Week 32 (Visit 11).
Sensitivity analyses will be performed on the ITT population to examine the potential 
impact of the missing data:

Subjects withdrawing from the study prematurely prior to reporting a HES flare, 
with the primary reason for treatment withdrawal reported as AE or Lack of 
Efficacy, will be classed as experiencing a HES flare in the analysis. 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.

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.
7.1.3.2.
Supplementary Estimand
A supplementary estimand using the ‘while on treatment’ strategy will be assessed for the 
intercurrent event of discontinuation of study medication.
Subjects discontinuing from study treatment prematurely will be included as having a 
HES flare if a flare is recorded with an onset date equal or prior to 28 days after the last 
dose of study treatment, and not having a flare otherwise.
7.1.4.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK data standards and statistical principles.
A summary of the number and percentage of subjects with HES flares will be produced 
by treatment group. The total number of HES flares in each treatment group will also be 
presented. The summary will include all HES flares, as well as a separate breakdown of 
HES flares meeting definition a) and b) (see Section 7.1.1). A plot of the cumulative 
number of HES flares over time in each treatment group will be produced.


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7.1.4.1.
Statistical Methodology Specification
Primary Statistical Analyses
Endpoint

Proportion of subjects who experience a HES flare during the 32-week study treatment period.
Model Specification

Cochran-Mantel-Haenszel test stratified by baseline OCS dose (0-≤20mg/day and >20mg/day 
prednisone or equivalent) and region.

Supplemented by a logistic regression analysis adjusting for covariates of baseline OCS dose
(continuous scale), region, and treatment.
Model Checking & Diagnostics

To examine the fit of the logistic regression model, deviance residuals will be calculated and 
plotted.
Model Results Presentation

Number of subjects analysed in each treatment group.

Number of subjects with 1 HES flare or who withdraw from the study prior to Week 32 (Visit 
11).

Number of subjects with 1 HES flare.

Number of subjects with no HES flare who withdraw from the study prior to Week 32 (Visit 
11).

Number of subjects with no HES flare who complete Week 32 (Visit 11).

p-value from Cochran-Mantel-Haenszel test.

Odds ratio and 95% Confidence Interval (CI) from logistic regression model.

p-value from logistic regression model.
Subgroup Analyses

A logistic regression analysis will be fitted separately within each subgroup of interest defined 
in Section 5.4.2.

Odds ratios and 95% confidence intervals from the logistic regression model will be presented. 
Analysis will be descriptive only; no p-values will be presented for the subgroup analyses. If the 
number of subjects in each subgroup category are small, confidence intervals may also be 
omitted.
Sensitivity and Supportive Statistical Analyses

A supplementary estimand using the ‘while on treatment’ strategy for intercurrent events will be 
assessed.

The primary analysis will be repeated using the PP population.

Sensitivity analyses for the primary estimand to assess the impact of missing data will be 
performed using the ITT population as follows:

Subjects withdrawing from the study prematurely prior to reporting a HES flare, with the 
primary reason for treatment withdrawal reported as AE or Lack of Efficacy, will be classed 
as experiencing a 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 


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Primary Statistical Analyses
prior to study withdrawal, and as not having a flare if no flare is recorded prior to study 
withdrawal.

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.

The sensitivity of the results of the primary estimand to inclusion of subjects from site 
in Mexico will be investigated. An Investigation of this site was conducted by GSK following 
anomalies in pulmonary function test (PFT) data generated by this site for a GSK study with a 
different investigational product (Study 207597). The report concluded that “there was 
diminished confidence and trust in the integrity of the data generated at this site and this loss 
of trust extended to other aspects of study conduct at this site”. Therefore, a sensitivity analysis 
of the primary estimand excluding the two subjects from site 
will be performed.
7.1.5.
Exploratory Modelling of Primary Endpoint
The role of baseline blood eosinophil counts on the effectiveness of mepolizumab with 
respect to the proportion of subjects who experience a HES flare during the 32-week 
study treatment period will be investigated. A logistic regression model will be fitted, 
including baseline blood eosinophils fitted on the loge scale as a continuous covariate as 
well as a treatment-by-baseline blood eosinophils interaction term, in order to predict the 
odds ratio for mepolizumab vs placebo for each level of the baseline blood eosinophil 
count. The analysis will also be adjusted for region and baseline OCS dose, as described 
in Section 5.4.1. Fractional polynomial models may also be explored in order to find the 
best fitting model for the relationship.
PPD
PPD


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7.2.
Secondary Efficacy Analysis – Time to First HES Flare
7.2.1.
Endpoint / Variables
The time to first HES flare will be calculated from the date of first dose of study 
treatment and the onset date of the first HES flare as defined in Section 16.6.4. 
7.2.2.
Summary Measure
The difference between mepolizumab and placebo in the time to first HES flare.
7.2.3.
Strategy for Intercurrent (Post-Randomization) Events
The treatment effect to be estimated (estimand) will be the ‘treatment policy’ effect of 
initial randomised treatment.  A treatment policy strategy will be used for the intercurrent 
events of a) discontinuation of study medication and b) receipt of alternative HES 
medications. If a subject withdraws prematurely from the study prior to experiencing a 
HES flare, the event time will be censored at the time point at which the subject withdrew 
from the study. Sensitivity analyses will be performed to examine the potential impact of 
the missing data.
7.2.4.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK data standards and statistical principles.
Time to first HES flare will be graphically represented using a Kaplan-Meier plot of 
cumulative incidence rates over time for each treatment group.
7.2.4.1.
Statistical Methodology Specification
Endpoint

Time to first HES flare.
Model Specification

Log-rank test stratified by baseline OCS dose (0-≤20mg/day and >20mg/day prednisone or 
equivalent) and region. 

Supplemented by a Cox proportional hazards regression model allowing for covariates of
baseline OCS dose (continuous scale) and region. 
Model Checking & Diagnostics

To examine the fit of the Cox proportional hazards model, martingale and deviance residuals 
will be calculated and plotted.
Model Results Presentation

In each treatment group

Number of subject analysed.

Number of subjects with HES flare.


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
Number of subjects censored at study withdrawal.

Number of subjects censored at study completion.

Stratified Log-Rank test p-value for association between treatment and time to first HES flare.

Hazard ratio and 95% CI from Cox proportional hazards model.

Wald chi-square p-value from Cox proportional hazards model.
Subgroup Analyses

No subgroup analyses will be performed on this endpoint.
Sensitivity and Supportive Analyses

Sensitivity analyses to assess the impact of missing data will be performed using the ITT 
population as follows:

Subjects withdrawing from the study prematurely prior to reporting a HES flare will be 
included with a HES flare on the date of study withdrawal.

Subjects withdrawing from the study prematurely prior to reporting a HES flare, with 
primary reason for treatment withdrawal reported as Adverse Event or Lack of Efficacy will 
be included as a HES flare on the date of study withdrawal. For subjects withdrawing from 
the study prematurely prior to reporting a HES flare, with any other reason for 
discontinuation of study treatment, the event time will be censored at the date of study 
withdrawal.


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7.3.
Secondary Efficacy Analysis – Proportion of Subject Who 
Experience a HES Flare During Week 20 Through Week 32
7.3.1.
Endpoint / Variables
HES flare during Week 20 through Week 32 will be defined as a 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. 
7.3.2.
Summary Measure
The difference between mepolizumab and placebo in the proportion of subjects with HES 
flare during Week 20 through Week 32.
7.3.3.
Strategy for Intercurrent (Post-Randomization) Events
The treatment effect to be estimated (estimand) will be the ‘treatment policy’ effect of 
initial randomised treatment.  A treatment policy strategy will be used for the intercurrent 
events of a) discontinuation of study medication and b) receipt of alternative HES 
medications. Subjects who withdraw prematurely from the study prior to Week 32 (Visit 
11) and therefore have missing data on HES flares during Week 20 through Week 32 will 
be included in the analysis as treatment failures i.e., that they experience a flare during 
Week 20 through Week 32. Sensitivity analyses will be performed to examine the 
potential impact of the missing data.
7.3.4.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK data standards and statistical principles.
A summary of HES flares during Week 20 through Week 32 will be produced as for the 
primary endpoint (see Section 7.1.4).


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7.3.4.1.
Statistical Methodology Specification
Endpoint

Proportion of subjects who experience a HES flare during Week 20 through Week 32.
Model Specification

Cochran-Mantel-Haenszel test stratified by baseline OCS dose (0-≤20mg/day and >20mg/day 
prednisone or equivalent) and region.

Supplemented by a logistic regression analysis adjusting for covariates of baseline OCS dose 
(continuous scale), region, and treatment.
Model Checking & Diagnostics

To examine the fit of the logistic regression model, deviance residuals will be calculated and 
plotted.
Model Results Presentation

Number of subjects analysed in each treatment group.

Number of subjects with 1 HES flare during Week 20 through Week 32 in each treatment 
group.

Test statistic and p-value for association between treatment and flare from Cochran-Mantel-
Haenszel test.

Odds ratio and 95% CI from logistic regression model.

p-value from logistic regression model.
Subgroup Analyses

No subgroup analyses will be performed on this endpoint.
Sensitivity and Supportive Statistical Analyses

Sensitivity analyses to assess the impact of missing data will be performed using the ITT 
population as follows:

Subjects withdrawing from the study prematurely prior to reporting a HES flare during 
Week 20 through Week 32, with the primary reason for treatment withdrawal reported as 
AE or Lack of Efficacy, will be classed as experiencing a HES flare during Week 20 
through Week 32. Subjects withdrawing from the study prematurely with any other reason 
for treatment withdrawal will be included as having a flare if one is recorded during Week 
20 through Week 32 prior to study withdrawal, and as not having a flare if no flare during 
Week 20 through Week 32 is recorded prior to study withdrawal.

Subjects withdrawing from the study prematurely will be included as having a flare if one is 
recorded during Week 20 through Week 32 prior to study withdrawal, and as not having a 
flare if no flare during Week 20 through Week 32 is recorded prior to study withdrawal.


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7.4.
Secondary Efficacy Analysis – Rate of HES Flares
7.4.1.
Endpoint / Variables
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 the first dose of study treatment
and either the Week 32 visit date if available, or otherwise the study withdrawal date (see 
Section 16.6.4).
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 onset date of a HES flare must be at least 14 days apart from the resolution date of the 
preceding HES flare. 
For flares meeting endpoint definition b) described in Section 7.1.1, 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.).
See Section 16.6.4 for details of the definition of the onset and resolution date of HES 
flares and full details of the derivation of the rate of HES flares.
7.4.2.
Summary Measure
The difference between mepolizumab and placebo in the rate/year of HES flares.
7.4.3.
Strategy for Intercurrent (Post-Randomization) Events
The treatment effect to be estimated (estimand) will be the ‘treatment policy’ effect of 
initial randomised treatment.  A treatment policy strategy will be used for the intercurrent 
events of a) discontinuation of study medication and b) receipt of alternative HES 
medications. 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 will be performed to examine the potential impact 
of the missing data.
7.4.4.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK data standards and statistical principles.


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7.4.4.1.
Statistical Methodology Specification
Endpoint

Rate of HES flares.
Model Specification

Wilcoxon Rank Sum test stratified by baseline OCS dose (0-≤20mg/day and >20mg/day 
prednisone or equivalent) and region.

Supplemented by an analysis using a negative binomial generalised linear model with a log-
link function, including terms for baseline OCS dose (continuous scale), region and treatment, 
and including the log of the observed time as an offset variable. The model estimated mean 
flare rate per year will be weighted according to the observed proportion of the categorical 
covariates in the study data by inclusion of the OM (obsmargins) option in the LSMEANS 
statement of the GENMOD procedure. Missing data will be assumed to be missing at random 
(MAR) in this analysis.
Model Checking & Diagnostics

The fit of the negative binomial generalised linear model will be investigated by calculating and 
plotting standardised deviance residuals.
Model Results Presentation

In each treatment group:

Median rate/year.
o
Median rate/year for HES flares meeting definition a) (see Section 7.1.1).
o
Median rate/year for HES flares meeting definition b) (see Section 7.1.1).

Adjusted mean rate/year from negative binomial model.

p-value for difference between treatments in rate/year from Wilcoxon Rank Sum test.

Rate ratio and 95% CI from negative binomial model.

p-value from negative binomial model.
Subgroup Analyses

No subgroup analyses will be performed on this endpoint.
Sensitivity and Supportive Statistical Analyses

In order to assess the impact of missing data, a sensitivity analysis using a negative binomial 
generalized linear model will be performed using the ITT population. Missing data for subjects 
withdrawing from the study prematurely will be imputed for the period between withdrawal from 
the study and Week 32. For subjects in the mepolizumab treatment group, the missing time 
period will be imputed assuming that the subject’s expected flare rate is shifted to that of the 
placebo arm (Jump to Reference [J2R]) [Keene, 2014] . For subjects in the placebo group, 
missing data will be assumed MAR.


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7.5.
Secondary Efficacy Analysis – Change from Baseline in 
Fatigue Severity BFI Item 3 (Worst Level of Fatigue in Past 
24 Hours) at Week 32
7.5.1.
Endpoint / Variables
The BFI has 9 items. The subject rates their fatigue level right now, their usual fatigue 
level over the last 24 hours and their worst level of fatigue over the last 24 hours using an 
11-point rating scale anchored at 0 (no fatigue) and 10 (as bad as you can imagine). The 
subject also rates how, during the past 24 hours, fatigue has influenced each of the 
following on an 11-point rating scale anchored at 0 (does not interfere) and 10 
(completely interferes): general activity, mood, walking ability, normal work, relations 
with other people and enjoyment of life. The subject completes item 3 (worst level of 
fatigue during past 24 hours) of the BFI daily and the full BFI every 7 days at home on 
the eDiary.
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 but not including the date of first dose of 
study treatment as the baseline assessment. If any of the 7 daily assessments of BFI item 
3 are missing for either the Week 32 time point or the baseline time point, the mean of 
the available daily assessments over the 7-day period will be used to calculate the change 
from baseline.
7.5.2.
Summary Measure
The difference between mepolizumab and placebo in the change from baseline BFI item 
3 at Week 32.
7.5.3.
Strategy for Intercurrent (Post-Randomization) Events
The treatment effect to be estimated (estimand) will be the ‘treatment policy’ effect of 
initial randomised treatment.  A treatment policy strategy will be used for the intercurrent 
events of a) discontinuation of study medication and b) receipt of alternative HES 
medications. Subjects with missing change from baseline BFI item 3 at Week 32 will be 
included in the analysis with the largest (i.e. worst) value observed for any subject.
Sensitivity analyses to assess the impact of missing data will be performed.
7.5.4.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK data standards and statistical principles.
Summary statistics for BFI item 3 at each week of treatment will be presented, including 
change from baseline values. Assessment windows for each week are defined in Section 
16.3.1.


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The clinical relevance of changes in BFI item 3 at Week 32 will be assessed using a
cumulative distribution plot showing the percentage of subjects in each treatment group 
with a reduction in BFI item 3 greater than equal to each value in the observed range; this 
will allow assessment of the treatment difference against a range of clinically important 
differences.
Endpoint

Change from baseline in fatigue severity (BFI item 3) at Week 32.
Model Specification

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), baseline OCS dose (0-≤20mg/day and 
>20mg/day prednisone or equivalent) and region. This will be implemented using the FREQ 
procedure with the SCORES = MODRIDIT option.
Model Checking & Diagnostics

Not applicable.
Model Results Presentation

Number analysed in each treatment group.

Median change from baseline BFI item 3 at Week 32 in each treatment group.

p-value for difference between treatments from Wilcoxon Rank Sum test.
Subgroup Analyses

No subgroup analyses will be performed on this endpoint.
Sensitivity and Supportive Statistical Analyses

Repeated measures analysis including assessments at Week 4, 8, 12, 16, 20, 24, 28 and 32. 
In this analysis missing data will be assumed to be missing at random and will not be imputed 
with the largest i.e. worst value. A mixed effects model will be fitted with the following 
specification:

Time point, treatment and region included as fixed categorical effects.

Baseline BFI and baseline OCS dose included as continuous fixed covariates. 

Interaction terms for baseline-by-timepoint and treatment-by-time point interaction.

The Kenward and Roger method (DDFM = KR) for approximating the denominator 
degrees of freedom to correct for bias in the estimated variance-covariance matrix.

REPEATED statement with TYPE=UN to specify an unstructured covariance structure for 
the R matrix.

The OBSMARGIN option on the LSMEANS statement in order to compute the adjusted 
geometric means with weights proportional to the input data set.


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7.6.
Exploratory Efficacy Analyses
Details of the planned displays for the exploratory endpoints are provided in Appendix 
10: List of Data Displays and will be based on GSK data standards and statistical 
principles.
7.6.1.
Proportion of Subjects Who Have an Elevated Blood Eosinophil 
Level That Meets the Pre-Defined Threshold During the 32-Week 
Study Treatment Period.
7.6.1.1.
Endpoint / Variables
Subjects who have an elevated blood eosinophil level (2 x baseline value or baseline 
value + 2500 cells/L) during the 32-week study treatment period will be identified from 
the central laboratory haematology results. Samples taken from the date of first dose of 
study medication up until the date of Visit 11 (Week 32) will be considered in the 
derivation. Baseline will be defined as in Section 5.2.
7.6.1.2.
Strategy for Intercurrent (Post-Randomization) Events
The treatment effect to be estimated (estimand) will be the ‘treatment policy’ effect of 
initial randomised treatment.  A treatment policy strategy will be used for the intercurrent 
events of a) discontinuation of study medication and b) receipt of alternative HES 
medications. Subjects withdrawing from the study prematurely leading to missing blood 
assessments for blood eosinophil count will be included in the analysis as having an 
elevated blood eosinophil level that meets the pre-defined threshold.
7.6.1.3.
Statistical Analyses / Methods
Endpoint

Proportion of subjects who have an elevated blood eosinophil level during the 32-week study 
treatment period.
Model Specification

Cochran-Mantel-Haenszel test stratified by baseline OCS dose (0-≤20mg/day and >20mg/day 
prednisone or equivalent) and region.

A supplementary analysis using a logistic regression analysis adjusting for covariates of 
baseline OCS dose (continuous scale), region, and treatment will also be performed.
Model Results Presentation

Number of subjects analysed in each treatment group.

Number of subjects who have an elevated blood eosinophil level during the 32-week study 
treatment period.

Test statistic and p-value for association between treatment and endpoint from Cochran-
Mantel-Haenszel test.

Odds ratio and 95% CI from logistic regression model.

p-value from logistic regression model.


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Subgroup Analyses

No subgroup analyses will be performed on this endpoint.
Sensitivity and Supportive Statistical Analyses

No sensitivity/supportive analyses will be performed on this endpoint.
7.6.2.
FEV1, FVC and FEV1/FVC ratio
7.6.2.1.
Endpoint / Variables

Change from baseline FEV1 at each visit.

Change from baseline FVC at each visit.

FEV1/FVC at each visit.
7.6.2.2.
Strategy for Intercurrent (Post-Randomization) Events
The treatment effect to be estimated (estimand) will be the ‘treatment policy’ effect of 
initial randomised treatment.  A treatment policy strategy will be used for the intercurrent 
events of a) discontinuation of study medication and b) receipt of alternative HES 
medications. Subjects with missing data will be assumed to be missing at random in the 
analysis.
7.6.2.3.
Statistical Analyses / Methods
Summary statistics for FEV1, FVC and FEV1/FVC at each visit will presented by 
treatment, including change from baseline values. A separate summary and analysis 
excluding any data from timepoints where the subject did not withhold short-acting 
bronchodilators for 6 hours or long-acting bronchodilators for 12 hours will be produced.
No statistical analysis will be performed on FEV1/FVC.
Endpoint

Change from baseline in FEV1.

Change from baseline in FVC.
Model Specification

Repeated measures with missing data assumed to be missing at random. A mixed effects 
model will be fitted with the following specification: 

Visit, treatment and region included as fixed categorical effects.

Baseline FEV1 (or FVC as appropriate) and baseline OCS dose included as continuous 
fixed covariates. 

Interaction terms for baseline-by-visit and treatment-by-visit.

The Kenward and Roger method (DDFM = KR) for approximating the denominator 
degrees of freedom to correct for bias in the estimated variance-covariance matrix.

REPEATED statement with TYPE=UN to specify an unstructured covariance structure for 
the R matrix.


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
The OBSMARGIN option on the LSMEANS statement in order to compute the adjusted 
geometric means with weights proportional to the input data set.
Model Results Presentation

Number analysed in each treatment group.

LS Mean (SE) and LS Mean Change from baseline (SE) in each treatment group.

Mean difference, 95% CI and p-value for mepolizumab vs placebo.
Subgroup Analyses

No subgroup analyses will be performed on this endpoint.
Sensitivity and Supportive Statistical Analyses

The analysis will be repeated excluding any data from timepoints where the subject did not 
withhold short-acting bronchodilators for 6 hours or long-acting bronchodilators for 12 hours.
7.6.3.
Echocardiogram
Echocardiogram/MUGA scans at Screening and Week 32 will be summarised by 
treatment for the ITT population. No statistical analysis of this endpoint will be 
performed.
7.6.4.
Change From Baseline in HES Symptom Severity Based on HES 
Daily Symptoms (HES-DS) at Week 32
7.6.4.1.
Endpoint / Variables
For each of the 6 symptom domains (muscle/joint pain, chills or sweats, abdominal pain 
or bloating, breathing symptoms, nasal or sinus symptoms and skin symptoms), the 
change from baseline symptom score at Week 32 will be defined using the mean of the 7 
daily symptom scores up to and including the date of the Week 32 visit as the Week 32 
assessment, and the mean of the 7 daily symptom scores up to but not including the date 
of first dose of study treatment as the baseline assessment. For each symptom domain, if 
any of the 7 daily symptom scores are missing for either the Week 32 time point or the 
baseline time point, the mean of the available daily symptom scores for the relevant 
symptom domain over the 7-day period will be used to calculate the change from 
baseline.
The change from baseline most bothersome symptom score at Week 32 will be derived 
using the mean domain scores at Week 32 and baseline for the up to 3 symptom domains 
identified by the subject as most bothersome at Week 0 (Visit 2).
7.6.4.2.
Strategy for Intercurrent (Post-Randomization) Events
The treatment effect to be estimated (estimand) will be the ‘treatment policy’ effect of 
initial randomised treatment.  A treatment policy strategy will be used for the intercurrent 
events of a) discontinuation of study medication and b) receipt of alternative HES 
medications. Subjects with missing change from baseline symptom score or missing most 
bothersome symptom score at Week 32 will be included in the analysis with the largest 
(i.e. worst) value observed for any subject.


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7.6.4.3.
Statistical Analyses / Methods
Summary statistics for the most bothersome symptom score and the symptom score for
each symptom domain at each week of treatment will be presented, including change 
from baseline values. Assessment windows for each week are defined in Section 16.3.1.
Endpoint

Change from baseline in most bothersome HES symptom severity score (HES-DS) at 
Week 32.

Change from baseline in HES symptom severity score (HES-DS) for each symptom at Week 
32.
Model Specification

Wilcoxon Rank Sum test stratified by median baseline symptom severity (baseline symptom 
severity≤median and baseline symptom severity>median), baseline OCS dose (0-≤20mg/day 
and >20mg/day prednisone or equivalent) and region.
Model Results Presentation

Number analysed in each treatment group.

Median change from baseline at Week 32 in each treatment group.

p-value for difference between treatments from Wilcoxon Rank Sum test.
Subgroup Analyses

No subgroup analyses will be performed on this endpoint.
Sensitivity and Supportive Statistical Analyses

Repeated measures analysis including assessments at Week 4, 8, 12, 16, 20, 24, 28 and 32.
In this analysis missing data will be assumed to be missing at random and will not be imputed 
with the largest i.e. worst value. A mixed effects model will be fitted with the following 
specification: 

Time point, treatment and region included as fixed categorical effects.

Baseline symptom severity and baseline OCS included as continuous fixed covariates. 

Interaction terms for baseline-by-timepoint and treatment-by-time point interaction.

The Kenward and Roger method (DDFM = KR) for approximating the denominator 
degrees of freedom to correct for bias in the estimated variance-covariance matrix.

REPEATED statement with TYPE=UN to specify an unstructured covariance structure for 
the R matrix.

The OBSMARGIN option on the LSMEANS statement in order to compute the adjusted 
geometric means with weights proportional to the input data set.
7.6.5.
Change from Baseline in BFI Total Score at Week 32
7.6.5.1.
Endpoint / Variables
The full BFI is completed every 7 days at home on the eDiary. The BFI total score will 
be calculated as the mean of the 9 item scores recorded for the weekly assessment, as 
long as at least 5 of the 9 item scores are complete. The change from baseline in BFI total 


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score at Week 32 will be calculated using the weekly assessment windows for Week 32 
and baseline defined in Section 16.3.1.
7.6.5.2.
Strategy for Intercurrent (Post-Randomization) Events
The treatment effect to be estimated (estimand) will be the ‘treatment policy’ effect of 
initial randomised treatment.  A treatment policy strategy will be used for the intercurrent 
events of a) discontinuation of study medication and b) receipt of alternative HES 
medications. Subjects with missing change from baseline symptom score at Week 32 will 
be included in the analysis with the largest (i.e. worst) value observed for any subject.
7.6.5.3.
Statistical Analyses / Methods
Summary statistics for BFI total score at each week of treatment will be presented, 
including change from baseline values. Assessment windows for each week are defined 
in Section 16.3.1.
Endpoint

Change from baseline in BFI total score at Week 32.
Model Specification

Wilcoxon Rank Sum test stratified by median baseline fatigue (baseline fatigue≤median and 
baseline fatigue>median), baseline OCS dose (0-≤20mg/day and >20mg/day prednisone or 
equivalent) and region.
Model Results Presentation

Number analysed in each treatment group.

Median change from baseline at Week 32 in each treatment group.

p-value for difference between treatments from Wilcoxon Rank Sum test.
Subgroup Analyses

No subgroup analyses will be performed on this endpoint.
Sensitivity and Supportive Statistical Analyses

For the change from baseline BFI total score, a repeated measures analysis including 
assessments at Week 4, 8, 12, 16, 20, 24, 28 and 32. In this analysis missing data will be 
assumed to be missing at random and will not be imputed with the largest i.e. worst value. A 
mixed effects model will be fitted with the following specification: 

Time point, treatment and region included as fixed categorical effects.

Baseline BFI total score and baseline OCS included as continuous fixed covariates. 

Interaction terms for baseline-by-timepoint and treatment-by-time point interaction.

The Kenward and Roger method (DDFM = KR) for approximating the denominator 
degrees of freedom to correct for bias in the estimated variance-covariance matrix.

REPEATED statement with TYPE=UN to specify an unstructured covariance structure for 
the R matrix.

The OBSMARGIN option on the LSMEANS statement in order to compute the adjusted 
geometric means with weights proportional to the input data set.


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7.6.6.
Clinician- and Subject-Rated Overall Response to Therapy Score 
(RTS) at Week 32
7.6.6.1.
Endpoint / Variables

Clinician-rated overall response to therapy (significantly improved [1], moderately 
improved [2], mildly improved [3], no change [4], mildly worse [5], moderately 
worse [6] and significantly worse [7]) at Week 32.

Subject-rated overall response to therapy (significantly improved [1], moderately 
improved [2], mildly improved [3], no change [4], mildly worse [5], moderately 
worse [6] and significantly worse [7]) at Week 32.
7.6.6.2.
Strategy for Intercurrent (Post-Randomization) Events
The treatment effect to be estimated (estimand) will be the ‘treatment policy’ effect of 
initial randomised treatment.  A treatment policy strategy will be used for the intercurrent 
events of a) discontinuation of study medication and b) receipt of alternative HES 
medications. Subjects with missing response at Week 32 will be included in the analysis 
with the largest (i.e. worst) value observed for any subject.
7.6.6.3.
Statistical Analyses / Methods
Summary statistics for clinician- and subject- rated overall response to therapy at each 
visit will be presented.
Endpoint

Clinician-rated overall response to therapy at Week 32.

Subject-rated overall response to therapy at Week 32
Model Specification

Wilcoxon Rank Sum test stratified by baseline OCS dose (0-≤20mg/day and >20mg/day 
prednisone or equivalent) and region.

Supplemented by an ordinal logistic regression (proportional odds) analysis adjusting for 
covariates of baseline OCS dose (continuous scale), region and treatment.
Model Results Presentation

Number analysed in each treatment group.

Median change from baseline at Week 32 in each treatment group.

p-value for difference between treatments from Wilcoxon Rank Sum test.

Odds ratio and 95% CI from ordinal logistic regression model.

p-value from ordinal logistic regression model.
Subgroup Analyses

No subgroup analyses will be performed on this endpoint.
Sensitivity and Supportive Statistical Analyses

Clinician- and subject-rated overall response to therapy will also be analysed at Week 4, 8, 12, 
16, 20, 24 and 28 in the same way as the Week 32 analysis.


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7.6.7.
Change from Baseline in Subject-Rated Symptom Severity (SSR) 
at Week 32
7.6.7.1.
Endpoint / Variables
At each visit, subjects are asked to rate their symptoms of HES now as none (0), mild (1), 
moderate (2), severe (3) or very severe (4). The change from baseline at Week 32 will be 
calculated from the Week 32 assessment and the Week 0 assessment and expressed in 
terms of number of categories of improvement or worsening of symptoms i.e. 4 point 
improvement (-4), 3 point improvement (-3), 2 point improvement (-2), 1 point 
improvement (-1), no change (0), 1 point worsening (1), 2 point worsening (2), 3 point 
worsening (3) or 4 point worsening (4).
7.6.7.2.
Strategy for Intercurrent (Post-Randomization) Events
The treatment effect to be estimated (estimand) will be the ‘treatment policy’ effect of 
initial randomised treatment.  A treatment policy strategy will be used for the intercurrent 
events of a) discontinuation of study medication and b) receipt of alternative HES 
medications. Subjects with missing SSR score at Week 32 will be included in the analysis 
with the largest (i.e. worst) value observed for any subject.
7.6.7.3.
Statistical Analyses / Methods
Summary statistics for the SSR score at each visit will be presented, as well as the change 
from baseline.
Endpoint

Change from baseline in subject-rated symptom severity (SSR) at Week 32.
Model Specification

Wilcoxon Rank Sum test stratified by baseline OCS dose (0-≤20mg/day and >20mg/day 
prednisone or equivalent) and region.

Supplemented by an ordinal logistic regression (proportional odds) analysis adjusting for 
covariates of baseline OCS dose (continuous scale), region and treatment.
Model Results Presentation

Number analysed in each treatment group.

Median change from baseline at Week 32 in each treatment group.

p-value for difference between treatments from Wilcoxon Rank Sum test.

Odds ratio and 95% CI from ordinal logistic regression model.

p-value from ordinal logistic regression model.
Subgroup Analyses

No subgroup analyses will be performed on this endpoint.
Sensitivity and Supportive Statistical Analyses

No sensitivity analyses will be performed.


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7.6.8.
Change from Baseline in Modified Memorial Symptom 
Assessment Scale-Short Form (MSAS-SF) responses at Week 32
7.6.8.1.
Endpoint / Variables
The MSAS-SF questionnaire records the distress or bother in the last week caused by 
each of 28 symptoms on 5-point scale (not at all, a little bit, somewhat, quite a bit, very 
much) as well as how often during the last week a further 4 symptoms occurred on a 4-
point scale (occurs rarely, occasionally, frequently, almost constantly). Conversion of 
each of the categorical responses to a numeric score will be performed as described in the 
table below.
Question Type
Categorical Response
Numeric 
Score
Distress or bother 
(28 symptoms) 
Symptom is absent
0
Symptom present but causes no distress or bother (i.e. level 
of distress or bother categorised as “not at all”)
0.8
Symptom present and causes a little bit of distress or bother
1.6
Symptom present and causes somewhat of distress or 
bother
2.4
Symptom present and causes quite a bit of distress or bother
3.2
Symptom present and causes very much distress or bother
4.0
How often 
(4 symptoms)
Symptom is absent
0
Symptom present and occurs rarely
1
Symptom present and occurs occasionally
2
Symptom present and occurs frequently
3
Symptom present and occurs almost constantly
4
Using the numeric conversion above, the following endpoints will be derived:

Total MSAS-SF score for each visit will be calculated as the mean of the 32 scores 
recorded for that visit. 

MSAS-SF global distress index (GDI) for each visit will be calculated as the mean of 
the scores for 10 symptoms (feeling sad, worrying, feeling irritable and feeling 
nervous, lack of energy, pain, lack of appetite, feeling drowsy, constipation, dry 
mouth).

MSAS-SF physical symptom subscale score for each visit will be calculated as the 
mean of the scores for 12 physical symptoms (lack of energy, pain, lack of appetite, 
feeling drowsy, constipation, dry mouth, nausea, vomiting, change in taste, weight 
loss, feeling bloated, and dizziness).


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
MSAS-SF psychological symptom subscale score for each visit will be calculated as 
the mean of the scores for 6 psychologic symptoms (worrying, feeling sad, feeling 
nervous, difficulty sleeping, feeling irritable, and difficulty concentrating).
For each score the change from baseline at Week 32 will be calculated from the 
assessment at Week 0 and Week 32.
7.6.8.2.
Strategy for Intercurrent (Post-Randomization) Events
The treatment effect to be estimated (estimand) will be the ‘treatment policy’ effect of 
initial randomised treatment.  A treatment policy strategy will be used for the intercurrent 
events of a) discontinuation of study medication and b) receipt of alternative HES 
medications. Subjects with missing change from baseline MSAS-SF score at Week 32 
will be included in the analysis with the largest (i.e. worst) value observed for any 
subject.
7.6.8.3.
Statistical Analyses / Methods
Summary statistics for MSAS-SF scores at each visit will be presented, including change 
from baseline values.
Endpoint

Change from baseline in Total Modified Memorial Symptom Assessment Scale-Short Form 
(MSAS-SF) score at Week 32.

Change from baseline in Modified Memorial Symptom Assessment Scale-Short Form (MSAS-
SF) global distress index at Week 32.

Change from baseline in Modified Memorial Symptom Assessment Scale-Short Form (MSAS-
SF) physical symptom subscale score at Week 32.

Change from baseline in Modified Memorial Symptom Assessment Scale-Short Form (MSAS-
SF) psychological symptom subscale score at Week 32.
Model Specification

Wilcoxon Rank Sum test stratified by median baseline score (baseline score≤median and 
baseline score>median), baseline OCS dose (0-≤20mg/day and >20mg/day prednisone or 
equivalent) and region.
Model Results Presentation

Number analysed in each treatment group.

Median change from baseline at Week 32 in each treatment group.

p-value for difference between treatments from Wilcoxon Rank Sum test.
Subgroup Analyses

No subgroup analyses will be performed on this endpoint.
Sensitivity and Supportive Statistical Analyses

A repeated measures analysis including assessments at Week 4, 8, 16, 24 and 32. In this 
analysis missing data will be assumed to be missing at random and will not be imputed with the 
largest i.e. worst value. A mixed effects model will be fitted with the following specification: 


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
Time point, treatment and region included as fixed categorical effects.

Baseline score and baseline OCS dose included as continuous fixed covariates. 

Interaction terms for baseline-by-timepoint and treatment-by-time point interaction.

The Kenward and Roger method (DDFM = KR) for approximating the denominator 
degrees of freedom to correct for bias in the estimated variance-covariance matrix.

REPEATED statement with TYPE=UN to specify an unstructured covariance structure for 
the R matrix.

The OBSMARGIN option on the LSMEANS statement in order to compute the adjusted 
geometric means with weights proportional to the input data set.
7.6.9.
Change from Baseline in Physical Function and Sleep (Patient 
Reported Outcome Measurement Information System [PROMIS]) 
at Week 32
7.6.9.1.
Endpoint / Variables

The PROMIS physical function score for each visit will be calculated as the mean of 
the scores for the 12 physical function items recorded for that visit, as long as at least 
6 of the 12 item scores are complete. The change from baseline at Week 32 will be 
calculated from the Week 32 assessment and the Week 0 assessment.

The PROMIS sleep score for each visit will be calculated as the mean of the scores 
for the 2 sleep items recorded for that visit; if either of the items has a missing score, 
the PROMIS sleep score will be assigned as missing for that visit. The change from 
baseline at Week 32 will be calculated from the Week 32 assessment and the Week 0 
assessment.
7.6.9.2.
Strategy for Intercurrent (Post-Randomization) Events
The treatment effect to be estimated (estimand) will be the ‘treatment policy’ effect of 
initial randomised treatment.  A treatment policy strategy will be used for the intercurrent 
events of a) discontinuation of study medication and b) receipt of alternative HES 
medications. Subjects with missing change from baseline PROMIS score at Week 32 will 
be included in the analysis with the largest (i.e. worst) value observed for any subject.
7.6.9.3.
Statistical Analyses / Methods
Summary statistics for PROMIS physical function and sleep score at each visit will be 
presented, including change from baseline values.
Endpoint

Change from baseline in PROMIS physical function score at Week 32.

Change from baseline in PROMIS sleep score at Week 32.
Model Specification

Wilcoxon Rank Sum test stratified by median baseline score (baseline score≤median and 
baseline score>median), baseline OCS dose (0-≤20mg/day and >20mg/day prednisone or 


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equivalent) and region.
Model Results Presentation

Number analysed in each treatment group.

Median change from baseline at Week 32 in each treatment group.

p-value for difference between treatments from Wilcoxon Rank Sum test.
Subgroup Analyses

No subgroup analyses will be performed on this endpoint.
Sensitivity and Supportive Statistical Analyses

A repeated measures analysis including assessments at Week 4, 8, 16, 24 and 32. In this 
analysis missing data will be assumed to be missing at random and will not be imputed with the 
largest i.e. worst value. A mixed effects model will be fitted with the following specification: 

Time point, treatment and region included as fixed categorical effects.

Baseline score and baseline OCS included as continuous fixed covariates. 

Interaction terms for baseline-by-timepoint and treatment-by-time point interaction.

The Kenward and Roger method (DDFM = KR) for approximating the denominator 
degrees of freedom to correct for bias in the estimated variance-covariance matrix.

REPEATED statement with TYPE=UN to specify an unstructured covariance structure for 
the R matrix.

The OBSMARGIN option on the LSMEANS statement in order to compute the adjusted 
geometric means with weights proportional to the input data set.


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8.
HEALTH OUTCOMES ANALYSIS
8.1.
SF-36 v2

Certified scoring of the SF-36 survey will be performed using OPTUMTM software.

The eight domain scores (bodily pain, general health, mental health, physical 
functioning, role emotional, role physical, social functioning and vitality) as well as 
the physical and mental component summary scores provided by the software will be
converted to SDTM and ADaM data sets by GSK Biostatistics.

Domain and component summary scores will be summarised by visit, including 
change from baseline. 

Summaries will be performed on the ITT population.

No statistical analysis of the SF-36 scores will be performed.
8.2.
Healthcare Resource Utilization (HCRU)

Healthcare resource utilisation associated with a HES flare will be summarised by 
treatment group.

Summaries will be performed on the ITT population.

For each resource type, the number of flares using resource, total amount of resource 
and mean (SD) resource per HES flare will be summarised.

No statistical analysis of this endpoint will be performed.
8.2.1.
Work Productivity and Activity Impairment
The following endpoints will be derived and summarised by treatment group and visit for 
the ITT population. Change from baseline will also be derived and summarised.
Endpoint
Derivation
Percentage work time missed due to health
Q2 / (Q2 + Q4)
Percentage impairment while working due to health
Q5 / 10
Percentage overall work impairment due to health
Q2 / (Q2 + Q4) + [(1- (Q2 / (Q2 + Q4))) x (Q5 / 10)]
Percentage activity impairment due to health
Q6 / 10
No statistical analysis of work productivity and activity impairment will be performed.


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9.
POPULATION PHARMACOKINETIC ANALYSES
Refer to Data Display Standards & Handling Conventions (Section 16.5.3 Reporting
Standards for Pharmacokinetic Data).
In support of the analysis described below, a specific dataset will be generated. 
Specifications for the generation of the dataset will be provided in a separate document.
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK Data Standards and statistical principles.
9.1.
Population of Interest
The population PK analysis will be performed on the PK population.
9.2.
Strategy for Intercurrent (Post-Randomization) Events
For subjects withdrawing prematurely from study treatment, all available data will be 
included in the analysis.
Based on mepolizumab PK knowledge, concentrations below the limit of quantification 
(BLQ) of the assay is considered unlikely at the 300 mg SC dose investigated, in view of 
the PK sampling scheme selected in the study. Thus, any such results will be treated as 
missing.
Outlier data will be assessed for plausibility; however, the aim is to use all available data 
whenever possible. Any decision to exclude data will be fully documented and specified 
in the clinical study report.
9.3.
Population Pharmacokinetic Methodology
Sparse blood sampling is implemented in this study for determination of mepolizumab 
plasma concentration and subsequent data analysis by population PK methods using the 
most recent population pharmacokinetics model (meta-analysis PK model of data across 
indications described in GlaxoSmithKline Document Number 2015N238436_00). Since 
mepolizumab PK following intravenous administration in HES subjects has already been 
evaluated within the population PK meta-analysis (using PK samples collected in 
previous Phase III study MHE100185), the main objectives of this population PK 
analysis are:

To evaluate mepolizumab pharmacokinetics in subjects with HES following the 
subcutaneous administration of a 300 mg dose every 4 weeks.

To investigate the impact of covariates of interest in the studied HES population 
(such as baseline characteristics, co-medication) on specific parameters (e.g. 
clearance) in order to identify potential sources of inter-individual variability in these 
parameters.

To obtain individual plasma concentration predictions for the timepoints at which PD 
is measured to allow the conduct of population PKPD analyses if deemed appropriate.


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Mepolizumab plasma concentration-time data (samples collected at Weeks 4, 16 and 32; 
at the early Withdrawal and the additional follow-up visits (if applicable)) will be 
analysed by population methods using nonlinear mixed-effects modelling. The analysis 
will be carried out using appropriate software (e.g., NONMEM or SAS).
9.3.1.
Base Model
In consideration of the sparse sampling (3 samples post-start of treatment over 32 weeks: 
Week 4, 16 and 32) and the wealth of mepolizumab PK knowledge, the most recent 
population PK model will be applied directly to the dataset without estimation (e.g. 
maxevals=0 in NONMEM) and predictions generated, against which the model will be 
validated prospectively using appropriate goodness of fit tests. For example, the 
Anderson-Darling and Cramér–von Mises tests are accepted methods of comparing 
Empirical Distribution Functions for model and data (i.e., PK concentrations) to evaluate 
whether independent observations (i.e., observed PK concentrations from the study) are 
adequately described by a model (i.e., most recent population PK model).
The following will be obtained:

A description of the key models tested during the model development will be 
provided and tabulated;

Population mepolizumab plasma PK parameter estimates with 95% CI from the final 
model will be tabulated. Goodness of fit plots for the final model will be presented;

Individual post-hoc PK parameter estimates (such as area under the plasma 
concentration-time curve over the dosing interval [AUC (0-)], CAV [AUC (0-)/]) 
will be summarised descriptively and listed;

Individual post-hoc predicted plasma concentrations will be summarised descriptively 
and listed;

Accumulation ratio estimate will be assessed at Week 16 and 32.
The most recent model consists of a two-compartment pharmacokinetic model with first-
order absorption and elimination. Bodyweight is incorporated into the model using 
allometry with fixed physiological allometric exponents of 0.75 and unity for clearance 
and volumes, respectively. Albumin and creatinine clearance are also included as 
covariates of mepolizumab clearance on physiological grounds, however their effects are 
small and not of clinical relevance. Details of the model can be found in report 
GlaxoSmithKline Document Number 2015N238436_00.
9.3.2.
Investigation of Covariates
The impact of the following prospectively selected covariates on mepolizumab exposure 
(e.g. clearance) will be evaluated using the procedures described in Section 9.3.3.
Category
Covariates
Demographics
Weight (included in the structural model), age, race, 
gender, country
Baseline clinical status
Creatinine clearance, albumin (both already included in the 


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Category
Covariates
current model), serum creatinine, alanine aminotransferase, 
aspartate aminotransferase, alkaline phosphatase, bilirubin, 
total protein
Baseline disease status
Flare history, blood eosinophils and baseline OCS dose
Concomitant medications
If data permits*, e.g. immunosuppressant therapies (e.g. 
methotrexate, azathioprine and mycophenolate mofetil), 
proton pump inhibitors, statins, pain relief (e.g.
paracetamol, NSAIDs), interferon alfa and antihypertensive 
drugs
Others
Presence/absence of anti-drug antibodies and previous 
biologics use (monoclonal antibodies).
*Attempt to investigate those classes of drug will be made providing data permits.
Covariate selection will be based on physiological plausibility, supported by graphical 
evaluation (PK parameters vs. covariates), and formally by automated linear model fitting 
using proc glmselect in SAS 9.2 (or higher). Individual PK parameters and covariates 
will be log-transformed and standardized before analysis. For forward and backward 
selections, significance levels of 0.1 and 0.05 will be applied respectively, in line with 
criteria used in previous analyses. Co-linearity between covariates will be carefully 
considered.
Identified covariates will then be subjected to traditional covariate analysis (with 
estimation step) and will follow the procedures described in Section 9.3.3. If deemed 
appropriate box plots of systemic clearance versus covariates of interest (e.g., 
immunogenicity status) will be provided.
9.3.3.
Covariate Model Selection Procedures
The covariate model building will follow a step-wise process consisting of a forward and 
backward selection procedure. The likelihood ratio test will be used to evaluate the 
significance of incorporating or removing covariates into the population model based on 
alpha levels set a priori. For forward and backward selections, a significance level of 
0.05 and 0.01 for first order conditional estimation with interaction (FOCE-I) will be 
used, respectively, in line with criteria used in previous analyses.

Step-wise forward addition procedure
Each covariate will be included individually in the ‘base model’ to identify covariates 
resulting in a decrease in the objective function value (OFV) of > 3.84, χ2 < 0.05 for 1 
degree of freedom (df) using FOCE-I. The retained covariates will then be added to the 
base model one by one, starting with the most significant ones until all covariates have 
been tested. Note, if a covariate exponent estimate is numerically small, the covariate will 
not be retained; irrespective of objective function. This will also be supported by 
examination of the goodness of fit. This will constitute the full model.


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
Backward elimination procedure
From the full model, the significance of each covariate will be tested individually by 
removing covariates one by one until all non-significant covariates have been excluded. 
A covariate will be retained if upon removal, the OFV increase by more than 6.64 points 
(χ2< 0.01 for 1 df) using FOCE-I. Note, a covariate may be retained in the model despite 
being found non-statistically significant, if there is a strong rationale for its inclusion. 
This will constitute the final model.
Note: centering of continuous covariates may be considered, as appropriate. The mean or 
median value of the subjects included in the analysis may be used for example.
The impact of the presence of anti-mepolizumab antibodies may not be formally tested as 
a covariate in the model, considering the low incidence observed in the mepolizumab 
programme to date. Instead a graphical approach will be used, if deemed appropriate.
9.3.4.
Model Evaluation
The uncertainty in the parameter estimates will be assessed (e.g. from the standard error 
estimates provided by NONMEM or from the 95% CI estimates provided by other 
appropriate analysis conducted using other software). Furthermore, the model 
performance will be investigated using a set of goodness of fit plots as well as Visual 
Predictive Check (VPC) method. Other evaluation methods may be used (e.g., 
bootstrapping) if deemed appropriate.


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10.
PHARMACODYNAMIC ANALYSES
10.1.
Blood Eosinophils
10.1.1.
Population of Interest
Blood eosinophil analyses will be based on the Pharmacodynamic population.
10.1.2.
Endpoint / Variables
Absolute and ratio to baseline blood eosinophil counts at each visit. For blood 
eosinophils, baseline will be defined as the latest blood eosinophil value measured by the 
central laboratory prior to the first dose of study treatment.
10.1.3.
Summary Measure
The difference between mepolizumab and placebo in the ratio to baseline of blood 
eosinophils.
10.1.4.
Strategy for Intercurrent (Post-Randomization) Events
For subjects withdrawing prematurely from study treatment, only the endpoint values up 
to and including 28 days after the last dose of study treatment will be included in the 
analysis (‘while on treatment’ estimand).
10.1.5.
Statistical Analyses / Methods

Blood eosinophil counts will be loge-transformed prior to analysis. Non-detectable 
blood eosinophil values of 0 GI/L, or results below the limit of quantification will be 
replaced by half of the lowest observed detectable (non-zero) value in the study data 
set, prior to log transformation.

Absolute and ratio to baseline blood eosinophil counts will be summarised by 
treatment group and visit. Only results from the central laboratory will be included in 
the summary, however all data will be listed.

Full details of data displays to be presented are given in Appendix 10: List of Data 
Displays.
10.1.5.1.
Statistical Methodology Specification
Endpoint

Ratio to baseline blood eosinophil count
Model Specification

A mixed effects repeated measures model will be fitted to the loge transformed blood 
eosinophil data with the following specification: 

Visit, treatment and region included as fixed categorical effects.


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
Baseline blood eosinophil count (loge scale) and baseline OCS dose included as 
continuous fixed covariates. 

Interaction terms for baseline (screening) blood eosinophil count-by-visit and treatment-by-
visit.

The Kenward and Roger method (DDFM = KR) for approximating the denominator 
degrees of freedom to correct for bias in the estimated variance-covariance matrix.

REPEATED statement with TYPE=UN to specify an unstructured covariance structure for 
the R matrix.

The OBSMARGIN option on the LSMEANS statement in order to compute the adjusted 
geometric means with weights proportional to the input data set.
Model Results Presentation

Number analysed in each treatment group.

LS Mean (SE) and LS Mean ratio to screening (SE) in each treatment group.

Mean treatment ratio, 95% CI and p-value for mepolizumab vs placebo.
Subgroup Analyses

No subgroup analyses will be performed on this endpoint.
Sensitivity and Supportive Statistical Analyses

The MMRM model specified above will also be fitted to the log transformed absolute blood 
eosinophil counts and adjusted mean absolute blood eosinophil counts and 95% CI from this 
model will be plotted.
10.2.
Serum Total IL-5
10.2.1.
Population of Interest
Total IL-5 analyses will be based on the Pharmacodynamic population.
10.2.2.
Endpoint / Variables
Absolute and ratio to baseline total IL-5 at Week 32
10.2.3.
Summary Measure
The difference between mepolizumab and placebo in the ratio to baseline of serum total 
IL-5 at Week 32.
10.2.4.
Strategy for Intercurrent (Post-Randomization) Events
For subjects withdrawing prematurely from study treatment, only the endpoint values up 
to and including 28 days after the last dose of study treatment will be included in the 
analysis (‘while on treatment’ estimand).
10.2.5.
Statistical Analyses / Methods

Total IL-5 values will be loge-transformed prior to analysis. Values below the limit of 
quantification will be replaced by half the limit of quantification, prior to log 


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transformation. Summary statistics will include the number and percentage of BLQ 
values.

Absolute and ratio to baseline total IL-5 values will be summarised by treatment 
group and visit (Baseline and Week 32).

Full details of data displays to be presented are given in Appendix 10: List of Data 
Displays.
10.2.5.1.
Statistical Methodology Specification
Endpoint

Ratio to baseline total IL-5 at Week 32
Model Specification

Wilcoxon Rank Sum test stratified by baseline OCS dose (0-≤20mg/day and >20mg/day 
prednisone or equivalent) and region.
Model Results Presentation

Number analysed in each treatment group.

Median change from baseline at Week 32 in each treatment group.

p-value for difference between treatments from Wilcoxon Rank Sum test.
Subgroup Analyses

No subgroup analyses will be performed on this endpoint.
Sensitivity and Supportive Statistical Analyses

No sensitivity analyses will be performed.


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11.
SAFETY ANALYSES
The safety analyses will be based on the Safety population, unless otherwise specified.
11.1.
Adverse Events Analyses
Adverse events analyses including the analysis of adverse events (AEs), Serious (SAEs)
and other significant AEs will be based on GSK Core Data Standards. Common AEs will 
be defined as AEs with frequency ≥3% (prior to rounding to nearest percent) in either 
treatment group.
The details of the planned displays are provided in Appendix 10: List of Data Displays.
11.1.1.
Adverse Events of Special Interest
Adverse events of special interest (AESIs) reported by the investigator as systemic 
reactions (further categorised by the investigator as either allergic [type I 
hypersensitivity] or other systemic reactions and assessed against Sampson criteria for 
anaphylaxis) are collected via targeted eCRF within the study. Local injection site 
reactions are also collected via targeted eCRF within the study.
AESIs of potential opportunistic infections, malignancies, serious cardiac, vascular and 
thromboembolic (CVT) events and serious ischemic events will be identified from a list 
of relevant preferred terms maintained within a project level reference dataset created 
based on the MedDRA dictionary available at the time of DBF for this study. Further 
details of how relevant preferred terms are identified are given in the Program Safety 
Analysis Plan (PSAP).
Separate summary tables showing the number and percent of subjects with each type of 
AESI, broken down by preferred term will be created.
For each type of AESI a profile summary table will be produced containing information 
including, but not limited to, the number of occurrences of the event, event 
characteristics, time to onset, intensity, outcome and action taken.
The relative risk of each AESI between mepolizumab and placebo with 95% confidence 
intervals will also be presented.
Separate listings of AESIs identified by the investigator as anaphylaxis, allergic (type I 
hypersensitivity), other systemic reactions and local injection site reactions will be 
produced, as well as listings of potential opportunistic infections, malignancies, serious 
CVT events and serious ischemic events.
11.2.
Clinical Laboratory Analyses
Laboratory evaluations including the analyses of Chemistry laboratory tests, 
Haematology laboratory tests and liver function tests will be based on GSK Core Data 
Standards. The details of the planned displays are provided in Appendix 10: List of Data 
Displays.


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A scatter plot of maximum ALT vs baseline ALT, and maximum ALT vs total bilirubin 
will be produced. In addition, if any liver stopping or liver monitoring events occur 
during the study, summaries of liver monitoring/stopping event reporting and 
hepatobiliary laboratory abnormalities will be produced.
11.3.
Other Safety Analyses
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified. The details of the 
planned displays are presented in Appendix 10: List of Data Displays.


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12.
IMMUNOGENICITY ANALYSES
12.1.
Overview of Immunogenicity Analyses
For the immunogenicity assessment, two types of anti-drug antibody (ADA) assays will 
be performed, a binding anti-drug antibody assay and a neutralizing antibody assay.
For the binding assay, there will be a three tiered analysis: screening, confirmation and 
titration. The screening assay produces a result of positive or negative relative to a 
screening cut point. Positive samples continue with the confirmation assay, which also 
produces a result of positive or negative relative to a confirmation cut point. For positive 
confirmation samples, a titre value will also be obtained to quantify the degree of binding 
in a titration assay and the sample will be tested with the neutralizing assay, which also 
reports results as positive or negative.
The binding ADA results at each visit will be categorised as negative, transient positive 
(defined as a single confirmatory positive immunogenic response that does not occur at 
the final study assessment) or persistent positive (defined as a confirmatory positive 
immunogenic response for at least 2 consecutive assessments excluding the screening 
visit, or a single result at the final study assessment). In addition, the highest post-
baseline binding ADA confirmatory result obtained for a subject will be summarised. 
Subjects with both positive and negative results will be identified in the positive category. 
Summary statistics for the titre result by visit will also be presented.
A summary of adverse events by highest post-baseline binding ADA confirmatory result 
(as defined above) will be produced.
A summary of treatment emergent positive confirmatory binding ADA results in the 
subset of subjects who did not have a positive confirmatory binding ADA result prior to 
the dosing of study treatment will also be presented. 
Neutralizing antibody assay results will be summarised by visit. In addition, the highest 
post-baseline neutralising antibody assay result during the treatment period of the study 
will be summarised, with subjects with both positive and negative results identified in the 
positive category.
Immunogenicity data will be listed for subjects with at least one positive screening 
binding assay.


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13.
PHARMACOKINETIC / PHARMACODYNAMIC
ANALYSES
In support of the analysis described below, a specific dataset will be generated.
Specifications for the generation of the dataset will be provided in a separate document.
The details of the planned displays are presented in Appendix 10: List of Data Displays.
13.1.
Population of Interest
The population PKPD analysis will be performed on the PK and PD populations.
13.2.
Strategy for Intercurrent (Post-Randomization) Events
For subjects withdrawing prematurely from study treatment, all available data will be 
included in the analysis.
Zero values for the baseline blood eosinophil count as well as for blood eosinophil count 
will be replaced by half of the lowest observed detectable (non-zero) value in the study 
data set (consistent with approaches used in other analyses).
Outlier data will be assessed for plausibility, however the aim is to use all available data 
whenever possible. Any decision to exclude data will be fully documented and specified 
in the clinical study report.
13.3.
Population Pharmacokinetic/Pharmacodynamic 
Methodology
If deemed appropriate, a population pharmacokinetic/pharmacodynamic analysis will be 
conducted.
Blood eosinophil count were measured during the course of the study over the 32 weeks 
treatment period and will be analysed by population methods using the most recent 
population PKPD model (meta-analysis PKPD model of data across indications described 
in GlaxoSmithKline Document Number 2015N238436_00).
The objectives of the population PKPD analysis are:

To evaluate mepolizumab pharmacodynamics in subjects with HES following 
subcutaneous administration of a 300 mg dose every 4 weeks;

To investigate the impact of covariates of interest in the studied HES population 
(such as baseline characteristics, co-medication) on specific parameters (e.g. 
maximum blood eosinophil reduction) in order to identify potential sources of 
inter-individual variability in these parameters.
Mepolizumab blood eosinophil count-time data (samples collected at screening, Week 2, 
Week 4 and every 4 weeks for the remainder of the 32-week treatment period) will be 
analysed by population methods using nonlinear mixed-effects modelling. The analysis 
will be carried out using appropriate software (e.g., NONMEM or SAS).


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13.3.1.
Base Model
The most recent population PKPD model will be applied directly to the dataset without 
estimation (e.g. maxevals=0 in NONMEM) and predictions generated against which the 
model will be validated prospectively using appropriate goodness of fit tests as described 
in Section 9.3.1 (using the observed data from the study).
The following will be obtained:

A description of the key models tested during the model development will be 
provided and tabulated.

The population PD parameter estimates with 95% CI from the final model will be 
tabulated. Goodness of fit plots for the final model will be presented.
The most recent population PKPD model consists of an indirect response model 
parameterised in term of baseline blood eosinophil count (KRO), rate of elimination of 
eosinophils in the blood (Kout), concentration resulting in 50% of maximum drug effect 
(IC50) and maximum effect (Imax). Observed baseline blood eosinophil count is included 
as covariates of both predicted baseline and mepolizumab inhibitory response; and 
disease for predicted baseline blood eosinophil count. Details of the model can be found 
in GlaxoSmithKline Document Number 2015N238436_00 and GlaxoSmithKline 
Document Number 2015N255079_00 (extension of the former report).
13.3.2.
Investigation of Covariates
The impact of the following prospectively selected plausible covariates on relevant 
parameters (i.e., baseline blood eosinophil count and maximum effect) will be evaluated.
Category
Covariates
Demographics
Age, race, gender
Baseline disease status
Flare history, blood eosinophils (already included in the 
current model)
Others
Baseline OCS absolute dose, presence/absence of anti-drug 
antibodies*, immunosuppressant therapies* (e.g. 
methotrexate, azathioprine and mycophenolate mofetil), 
interferon alfa*
*Attempt to investigate those covariates will be made providing data permits.
Covariate selection will be based on physiological plausibility, supported by graphical 
evaluation (PD parameters vs. covariates), and formally by automated linear model fitting 
using proc glmselect in SAS 9.2 (or higher). Individual PD parameters and covariates 
will be log-transformed and standardized before analysis. For forward and backward 
selections, significance levels of 0.1 and 0.05 will be applied respectively, in line with 
criteria used in previous analyses. Co-linearity between covariates will be carefully 
considered.


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Identified covariates will then be subjected to traditional covariate analysis (with 
estimation step) and will follow the same procedures as described in Section 9.3.3 for the 
population PK model.
Model evaluation will be as described in Section 9.3.4 for the population PK model.


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14.
EXPLORATORY EXPOSURE-EFFICACY RESPONSE
ANALYSIS
If deemed appropriate an exposure response analysis for the proportion of subjects who 
experience a HES flare during the 32-week study treatment period will be conducted.
14.1.
Population of Interest
The exploratory exposure-efficacy response analysis will be performed on the ITT
population.
14.2.
Endpoints
Two separate measures of exposure will be considered for this analysis:
i)
Dose/bodyweight
ii) Cav = Dose/(Tau*CL/F),
where CL/F is the PK model-estimated apparent systemic clearance for each individual, 
and Tau the (fixed) inter-dosing interval (28 days).
The efficacy endpoint analysed will be the primary endpoint of the proportion of subjects 
who experience a HES flare during the 32-week study treatment period. Subjects who 
withdraw from the study prior to Week 32 (Visit 11) and therefore have missing data on 
HES flares will be included in this analysis as treatment failures, i.e. a subject will be 
classed as not experiencing a HES flare only if they have no flares reported and complete 
Week 32 (Visit 11).
14.3.
Methodology
A logistic regression model (linear, and if necessary, non-linear) will be fitted with 
exposure (dose/bodyweight or Cav) fitted on the loge scale as a continuous covariate. The 
analysis will also be adjusted for region, baseline blood eosinophil count and baseline 
OCS dose. The odds ratio for each level of mepolizumab exposure versus placebo will be 
presented. Fractional polynomial models may also be explored in order to find the best 
fitting model for any relationship.


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15.
REFERENCES
GlaxoSmithKline Document Number 2013N171550_00 Study ID 200622. A randomised, 
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. Report Date 29-APR-2016. 
GlaxoSmithKline Document Number 2015N238436_00 Study ID N/A. A population PK 
and PKPD meta-analysis of combined intravenous and subcutaneous mepolizumab data. 
Report Date 27-MAY-2015. 
GlaxoSmithKline Document Number 2015N255079_00 Study ID N/A. Supplementary 
outputs from a population PK and PKPD meta-analysis of combined intravenous and 
subcutaneous mepolizumab data. Report Date 04-OCT-2015. 
Keene ON, Roger JH, Hartley BF, Kenward MG. Missing data sensitivity analysis for 
recurrent event data using controlled imputation. Pharm Stat. 2014;13(4):258-264. 


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16.
APPENDICES
16.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population
Subjects with important protocol deviations considered to potentially have an effect on 
the primary efficacy analysis will be excluded from the Per Protocol (PP) population. The 
decision to exclude a subject from the PP population or exclude part of their data from 
the PP population will be made prior to breaking the blind.
16.1.1.
Exclusions from Per Protocol Population
A subject meeting any of the following criteria will be excluded from the Per Protocol 
population:
Number
Exclusion Description
01
Inclusion #3 – Insufficient evidence that subject has been diagnosed with HES for at least 6 
months at randomization (Visit 2).
02
Inclusion #4 – Subject did not have a history of two or more flares within the past 12 
months prior to screening (Visit 1), with at least one HES flare not related to a decrease in 
HES therapy during the 4 weeks prior to the flare.
03
Inclusion #5 – Subject did not have a blood eosinophil count 1000 cells/L collected 
during screening (within 4 weeks prior to randomization). Investigators were permitted to 
use local laboratory results to meet this inclusion criteria, therefore if the screening 
central laboratory blood eosinophil count is <1000 cells/L but a local laboratory blood 
eosinophil count 1000 cells/L is available during screening the subject will not be 
considered a protocol deviation or excluded from the Per Protocol population.
04
Inclusion #6 – Subject was not on a stable dose of HES therapy for the 4 weeks prior to 
randomization (Visit 2).
05
Incorrect study treatment administered at any point during the study i.e. subject received 
placebo instead of mepolizumab or vice versa.
06
Subject received a medication or herbal remedy which may alter the course of HES or 
interact with the study treatment with the exception of HES therapy to treat a HES flare.


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16.2.
Appendix 2: Schedule of Activities
16.2.1.
Protocol Defined Schedule of Events
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 
SSR3
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 scales3
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 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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65
Procedures 
Pre-
screen 
Screen 
Randomi-
zation 
Double-blinded treatment period 
Additional 
follow-up 
assessment) /Flare detail 
Clinician-RTS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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


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Procedures 
Pre-
screen 
Screen 
Randomi-
zation 
Double-blinded treatment period 
Additional 
follow-up 
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 
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 


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Procedures 
Pre-
screen 
Screen 
Randomi-
zation 
Double-blinded treatment period 
Additional 
follow-up 
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 (Protocol Table 4) should be obtained pre-dose. 
9. Refer to protocol 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 randomised. 
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 protocol 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 a 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 protocol 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 (protocol 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 (protocol 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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16.3.
Appendix 3: Assessment Windows
16.3.1.
Definition of Weekly Assessment Windows
Daily assessments of BFI item 3 and HES daily symptoms as well as weekly assessments 
of the full BFI will be assigned a single weekly analysis time point according to the table 
below.
Analysis 
Timepoint
Analysis Window
Beginning 
Timepoint
Ending Timepoint
Special Rules for Handling
Overlapping Timepoints
Week 32
Week 32 (Visit 11) 
visit date – 6 days
Week 32 (Visit 11) visit date
Week 31
Week 32 (Visit 11) 
visit date – 13 days
Week 32 (Visit 11) visit date 
– 7 days
If assessment falls into Week 
31/Week 30/Week 29 and Week 
28, assign assessment as Week 
28.
If assessment date is less than 
Week 28 (Visit 10) visit date, 
assign a relevant timepoint less 
than Week 28.
Week 30
Week 32 (Visit 11) 
visit date – 20 days 
Week 32 (Visit 11) visit date 
– 14 days
Week 29
Week 32 (Visit 11) 
visit date – 27 days
Week 32 (Visit 11) visit date 
– 21 days
Week 28
Week 28 (Visit 10) 
visit date – 6 days
Week 28 (Visit 10) visit date
Week 27
Week 28 (Visit 10) 
visit date – 13 days
Week 28 (Visit 10) visit date 
– 7 days
If assessment falls into Week 
27/Week 26/Week 25 and Week 
24, assign assessment as Week 
24.
If assessment date is less than 
Week 24 (Visit 9) visit date, assign 
a relevant timepoint less than 
Week 24.
Week 26
Week 28 (Visit 10) 
visit date – 20 days 
Week 28 (Visit 10) visit date 
– 14 days
Week 25
Week 28 (Visit 10) 
visit date – 27 days
Week 28 (Visit 10) visit date 
– 21 days
Week 24
Week 24 (Visit 9) visit 
date – 6 days
Week 24 (Visit 9) visit date
Week 23
Week 24 (Visit 9) visit 
date – 13 days
Week 24 (Visit 9) visit date –
7 days
If assessment falls into Week 
23/Week 22/Week 21 and Week 
20, assign assessment as Week 
20.
If assessment date is less than 
Week 20 (Visit 8) visit date, assign 
a relevant timepoint less than 
Week 20.
Week 22
Week 24 (Visit 9) visit 
date – 20 days 
Week 24 (Visit 9) visit date –
14 days
Week 21
Week 24 (Visit 9) visit 
date – 27 days
Week 24 (Visit 9) visit date –
21 days
Week 20
Week 20 (Visit 8) visit 
date – 6 days
Week 20 (Visit 8) visit date
Week 19
Week 20 (Visit 8) visit 
date – 13 days
Week 20 (Visit 8) visit date –
7 days
If assessment falls into Week 
19/Week 18/Week 17 and Week 
16, assign assessment as Week 
16.
If assessment date is less than 
Week 16 (Visit 7) visit date, assign 
a relevant timepoint less than 
Week 18
Week 20 (Visit 8) visit 
date – 20 days 
Week 20 (Visit 8) visit date –
14 days
Week 17
Week 20 (Visit 8) visit 
date – 27 days
Week 20 (Visit 8) visit date –
21 days


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Analysis 
Timepoint
Analysis Window
Beginning 
Timepoint
Ending Timepoint
Special Rules for Handling
Overlapping Timepoints
Week 16.
Week 16
Week 16 (Visit 7) visit 
date – 6 days
Week 16 (Visit 7) visit date
Week 15
Week 16 (Visit 7) visit 
date – 13 days
Week 16 (Visit 7) visit date –
7 days
If assessment falls into Week 
15/Week 14/Week 13 and Week 
12, assign assessment as Week 
12.
If assessment date is less than 
Week 12 (Visit 6) visit date, assign 
a relevant timepoint less than 
Week 12.
Week 14
Week 16 (Visit 7) visit 
date – 20 days 
Week 16 (Visit 7) visit date –
14 days
Week 13
Week 16 (Visit 7) visit 
date – 27 days
Week 16 (Visit 7) visit date –
21 days
Week 12
Week 12 (Visit 6) visit 
date – 6 days
Week 12 (Visit 6) visit date
Week 11
Week 12 (Visit 6) visit 
date – 13 days
Week 12 (Visit 6) visit date –
7 days
If assessment falls into Week 
11/Week 10/Week 9 and Week 8, 
assign assessment as Week 8.
If assessment date is less than 
Week 8 (Visit 5) visit date, assign 
a relevant timepoint less than 
Week 8.
Week 10
Week 12 (Visit 6) visit 
date – 20 days 
Week 12 (Visit 6) visit date –
14 days
Week 9
Week 12 (Visit 6) visit 
date – 27 days
Week 12 (Visit 6) visit date –
21 days
Week 8
Week 8 (Visit 5) visit 
date – 6 days
Week 8 (Visit 5) visit date
Week 7
Week 8 (Visit 5) visit 
date – 13 days
Week 8 (Visit 5) visit date – 7 
days
If assessment falls into Week 
7/Week 6/Week 5 and Week 4, 
assign assessment as Week 4.
If assessment date is less than 
Week 4 (Visit 4) visit date, assign 
a relevant timepoint less than 
Week 4.
Week 6
Week 8 (Visit 5) visit 
date – 20 days 
Week 8 (Visit 5) visit date –
14 days
Week 5
Week 8 (Visit 5) visit 
date – 27 days
Week 8 (Visit 5) visit date –
21 days
Week 4
Week 4 (Visit 4) visit 
date – 6 days
Week 4 (Visit 4) visit date
Week 3
Week 4 (Visit 4) visit 
date – 13 days
Week 4 (Visit 4) visit date – 7 
days
If assessment falls into Week 
3/Week 2/Week 1 and Baseline 
(Week 0) or Screening, assign 
assessment as Baseline (Week 0)
or Screening.
Week 2
Week 4 (Visit 4) visit 
date – 20 days 
Week 4 (Visit 4) visit date –
14 days
Week 1
Week 4 (Visit 4) visit 
date – 27 days
Week 4 (Visit 4) visit date –
21 days
Baseline 
(Week 0)
Date of first dose of 
study treatment – 7
days
Date of first dose of study 
treatment - 1
Screening
N/A
Date of first dose of study 
treatment – 8 days


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71
16.4.
Appendix 4: Study Phases
Assessments and events will be classified according to the time of occurrence relative to 
the first dose of study treatment.
16.4.1.
Treatment Phases for HES Flare
Study Phase
Definition
Pre-Treatment 
Flare onset date < Date of first dose of study treatment 
On-Treatment
Date of first dose of study treatment Flare onset date Date of last dose of study 
treatment + 28 days
Off-Treatment
Date of last dose of study treatment + 28 days < Flare onset date Date of Week 32 
visit /Study withdrawal date
Post-Treatment
Flare onset date > Date of Week 32 visit
16.4.2.
Treatment Phases for BFI and HES-DS
Since the electronic diary is completed daily in the evening, BFI and HES-DS 
assessments will be classified as follows:
Study Phase
Definition
Pre-Treatment 
Assessment date < Date of first dose of study treatment 
On-Treatment
Date of first dose of study treatment Assessment date Date of last dose of study 
treatment + 28 days
Off-Treatment
Date of last dose of study treatment + 28 days < Assessment date Date of Week 32 
visit /Study withdrawal date
Post-Treatment
Assessment date > Date of Week 32 visit
16.4.3.
Treatment Phases for Other Efficacy Assessments 
Study Phase
Definition
Pre-Treatment 
Assessment date Date of first dose of study treatment 
On-Treatment
Date of first dose of study treatment < Assessment date Date of last dose of study 
treatment + 28 days
Off-Treatment
Date of last dose of study treatment + 28 days < Assessment date Date of Week 32 
visit /Study withdrawal date
Post-Treatment
Assessment date > Date of Week 32 visit
16.4.4.
Treatment Phases for Adverse Events
Study Phase
Definition
Pre-Treatment 
AE onset date/time < Date/time of first dose of study treatment
On-Treatment
Date/time of first dose of study treatment AE onset date/time Date of last dose of 
study treatment + 28 days
Post-Treatment
AE onset date > Date of last dose of study treatment + 28 days
NOTES: 

Please refer to Section 16.7.2.1 for handling of missing and partial dates for adverse events.


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16.4.5.
Study Phases for Concomitant Medication
Study Phase
Definition
Prior
If medication end date is not missing and is before the date of first dose of 
study treatment
Concomitant
Any medication that is not a prior
NOTES: 

Please refer to Section 16.7.2.1 for handling of missing and partial dates for concomitant medications.


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16.5.
Appendix 5: Data Display Standards & Handling 
Conventions
16.5.1.
Reporting Process
Software

The currently supported version of SAS software (SAS 9.4 or later) will be used.
Reporting Area
HARP Server
: uk1salx00175
HARP Area
: sb240563/mid200622
Analysis Datasets 

Analysis datasets will be created according to CDISC standards.

For creation of ADaM datasets (ADCM/ADAE), the same version of dictionary datasets will be 
implemented for conversion from SI to SDTM.
Generation of RTF Files

RTF files will be generated for the final reporting effort.
16.5.2.
Reporting Standards
General

All data displays (Tables, Figures & Listings) will use the term “Subject” rather than 
“Participant” which reflects CDISC and GSK Data Display Standards terminology.

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: 
https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx):

4.03 to 4.23: General Principles

5.01 to 5.08: Principles Related to Data Listings

6.01 to 6.11: Principles Related to Summary Tables

7.01 to 7.13: Principles Related to Graphics 

Do not include subject level listings in the main body of the GSK Clinical Study Report. All 
subject level listings should be located in the modular appendices as ICH or non-ICH listings
Formats

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DPs) will be adopted for 
reporting of data based on the raw data collected but may be adjusted to a clinically 
interpretable number of DPs.

For FEV1 and FVC, the mean and median (L) will be reported to 3 decimal places (i.e. to the 
nearest mL), SD to 4 decimal places, minimum and maximum to 2 decimal places.
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses:

Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled 
visit days on the analyses and interpretation of the results will be assessed as appropriate.


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
Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to 
IDSL Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject’s listings. 

Visits outside the protocol defined time-windows (i.e. recorded as protocol deviations) will be 
included in listings, summaries and statistical analyses.
Unscheduled Visits

HES flare data collected at unscheduled visits will be included in the derivation of all flare 
related endpoints for summary and analysis.

For summaries by visit, data recorded at an unscheduled visit will be re-assigned in the ADaM 
data sets to the closest nominal visit at which collection of data was scheduled, unless 
information already exists at that visit. Unscheduled data re-assigned to a scheduled visit will 
be included in analyses, summary tables and figures by scheduled visit. Unscheduled data that 
is not re-assigned to a scheduled visit will not be included in analyses, summary tables or 
figures by scheduled visit. Unscheduled data that is not re-assigned to a scheduled visit will be 
considered in the derivation of baseline and highest/worst case post baseline result for relevant 
summary tables.

Data recorded at unscheduled visits will be included in the assessment of maximum or worst 
case post-baseline for relevant endpoints.

All unscheduled visits will be included in listings.
Early Withdrawal Visits

Data recorded at the early withdrawal visit will be re-assigned in the ADaM data sets to the 
next scheduled visit, unless information already exists at that visit. Early withdrawal data re-
assigned to a scheduled visit will be included in analyses, summary tables and figures by 
scheduled visit. Early withdrawal visit data that is not re-assigned to a scheduled visit will not 
be included in analyses, summary tables or figures by scheduled visit.

Data recorded at early withdrawal visits will be included in the assessment of maximum or 
worst case post-baseline for relevant endpoints.

Data from all early withdrawal visits will be included in listings.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.
16.5.3.
Reporting Standards for Pharmacokinetic Data
Pharmacokinetic Concentration Data
Descriptive 
Summary 
Statistics, 
Graphical Displays 
and Listings
Refer to IDSL PK Display Standards.
Refer to IDSL Statistical Principle 6.06.1.
Note: BLQ concentration values will be imputed as per GUI_51487 for 
descriptive summary statistics only. 
NONMEM/Pop PK 
Pop-PK file (CSV and SAS format) for the POP-PK and POP-PKPD 


CONFIDENTIAL
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File
analyses performed by the Clinical Pharmacology Modelling and Simulation 
function will be created according to the POP-PKPD Dataset Specification 
document.
Pharmacokinetic Parameter Data
Descriptive 
Summary 
Statistics, 
Graphical Displays 
and Listings
Refer to IDSL PK Display Standards.
Refer to IDSL Statistical Principle 6.06.1.


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16.6.
Appendix 6: Derived and Transformed Data
16.6.1.
General
Multiple Measurements at One Analysis Time Point

If there are two results identified at a single visit the latter of the two measurements will be 
flagged and used in any derivation of summary statistics. All values will be presented on 
listings.

Subjects having both High and Low values for Normal Ranges at any post-baseline visits for 
safety parameters will be counted in both the High and Low categories of “Any visit post-
baseline” row of related summary tables. This will also be applicable to relevant Potential 
Clinical Importance summary tables.
Study Day

Calculated as the number of days from the date of the first dose of study treatment:

Ref Date = Missing              → Study Day = Missing 

Ref Date < First Dose Date → Study Day = Ref Date – First Dose Date

Ref Data ≥ First Dose Date → Study Day = Ref Date – (First Dose Date) + 1    
Total observed time, time on treatment, time off treatment, missing time

For subjects completing the Week 32 visit

Total observed time (days) = Week 32 visit date – Date of first dose + 1 day

Time on treatment (days) = Minimum(Week 32 visit date, Date of last dose + 28 days) –
Date of first dose + 1 day

Time off treatment (days) = Week 32 visit date – Minimum(Week 32 visit date, Date of last 
dose + 28 days)

Missing time (days) = 0

For subjects not completing the Week 32 visit

Total observed time (days) = Study withdrawal date – Date of first dose + 1 day

Time on treatment (days) = Minimum(Study withdrawal date, Date of last dose + 28 days) -
Date of first dose + 1 day

Time off treatment (days) = Study withdrawal date – Minimum(Study withdrawal date, Date 
of last dose + 28 days)

Missing time (days) = Predicted Week 32 visit date – Study withdrawal date, where 
predicted Week 32 visit date = Date of first dose + 224 days.

16.6.2.
Change from Baseline Definitions
Definition
Reporting Details
Change from Baseline
= Post-Dose Visit Value – Baseline
% Change from Baseline
= 100 x [(Post-Dose Visit Value – Baseline) / Baseline]
Ratio to Baseline
= Visit Value / Baseline


CONFIDENTIAL
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NOTES :

Unless otherwise specified, the baseline definitions specified in Section 5.2 will be used for derivations for 
endpoints / parameters.

Unless otherwise stated, if baseline data is missing no derivation will be performed and result will be set to 
missing.
16.6.3.
Study Population
Age

GSK standard IDSL algorithms will be used for calculating age where birth day and month will 
be imputed ‘

Birth date will be presented in listings as ‘YYYY’.

Age will be calculated relative to the date of the screening visit (Visit 1).
Body Mass Index (BMI)
Calculated as Weight (kg) / [Height (m)2]
Baseline HES Therapy

Baseline oral corticosteroid use and baseline oral prednisone equivalent daily dose will be 
derived as detailed in Section 5.4.1.1.

Cytotoxic therapy/immunosuppressive therapy and other HES therapy will be identified by 
clinical review of the concomitant medications page according to the following criteria:
o
Medication type = “Hypereosinophilic syndrome” 
o
Start date < Date of first dose of study treatment
o
Either “ongoing” or End date Date of first dose of study treatment

Oral budesonide has negligible systemic exposure and will be counted as “Other HES therapy” 
rather than oral corticosteroid therapy.
Duration of HES

Duration of HES in years will be calculated from the date of the screening visit (Visit 1) and the 
date of HES diagnosis as follows:
Duration (years) = (Date of visit 1 – date of HES diagnosis)/365.25

If the date of HES diagnosis is a partial date, a '01' will be used for a missing day and 'Jan' will 
be used for a missing month.
Exposure (therapeutic coverage)

The number of days of exposure (therapeutic coverage) to study drug will be calculated based 
on the formula:  
Duration of exposure in days = Date of last dose of study treatment – date of first dose of study 
treatment + 29.

Exposure in months will be calculated using the formula:  
Exposure (months) = (Exposure in days / 365.25) * 12

Total subject years exposure will be calculated using the formula:  
Total subject-years exposure = (Sum across subjects of exposure in days)/365.25
PPD


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16.6.4.
Efficacy
HES Flare
Definition of HES Flare

A HES flare is defined as either
a) A 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 
- 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 maintenance OCS dose is the dose received during the 4 weeks prior to randomisation i.e. 
baseline OCS therapy, which should be maintained for the duration of the treatment period. If a 
subject has their OCS dose reduced during the treatment period, the maintenance dose will be 
redefined as the new dose they have received for at least 4 weeks. If the OCS dose is 
increased during the treatment period, the maintenance OCS dose will not be redefined and 
will remain as therapy taken during the 4 weeks prior to randomisation.

Flares meeting endpoint definition a) will be captured on the ‘flare details’ form in the eCRF.

An increase in blood eosinophils above the pre-defined threshold level (2 x baseline value or 
baseline value + 2500 cells/L) without any other clinical manifestations during the study will 
lead to administration of blinded active OCS treatment (see Section 2.2). If a subject receives a 
second course of blinded active OCS during the 32-week treatment period, the subject will be 
considered to be experiencing a flare. The container list for the blinded OCS treatment 
(indicating which container numbers contained active OCS and which contained placebo OCS) 
will be used to define HES flares meeting endpoint definition b). This container list will be 
incorporated into the final SDTM data sets at the end of the study, at the same time as the 
randomised treatment information.
HES flare onset and resolution dates

The onset and resolution dates of HES flares meeting endpoint definition a) will be recorded on 
the ‘Flare details’ form in the eCRF.

The start date of HES flares meeting endpoint definition b) is defined as the date of the blood 
draw at which the second course of blinded active OCS was triggered via schedule blood 
sampling for eosinophil monitoring. The resolution date for a flare meeting endpoint definition 
b) is the date of the first blood draw at which blood eosinophil count is below the threshold to 
trigger blinded active OCS (see protocol Section 6.4 for full details of blood eosinophil 
monitoring).
HES flare during Week 20 through Week 32

Defined as a HES flare starting or ongoing on or after the date of the Week 20 visit (Visit 8) up 
to and including the date of the Week 32 visit (Visit 11).
Time to First HES Flare

Calculated for each subject as 
(Onset date of first HES flare – Date of first dose of study treatment) + 1


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HES Flare
Rate of HES Flares

For subjects completing the study, the rate of HES flares will be calculated as
365.25 × 
    
   32 (   11) −      $ % + 1

For subjects withdrawing prematurely from the study, the rate of HES flares will be calculated 
as
365.25 × 
    
  ' ( ℎ( −      $ % + 1
The number of HES flares is the number of unique starting dates for HES flares. To be considered 
as a separate episode of HES flare, the start date of a HES flare must be at least 14 days apart 
from the resolution date of the preceding HES flare.

For flares meeting endpoint definition b), 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.).
Subjects who have an elevated blood eosinophil level (2 x baseline value or baseline value + 
2500 cells/L) during the 32-week study treatment period

Subjects with elevated blood eosinophils either 2 x baseline value or baseline value + 2500 
cells/L during the 32-week study treatment period will be identified from the central laboratory 
haematology results. Samples taken from the date of first dose of study medication up until the 
date of Visit 11 (Week 32) will be considered in the derivation. Baseline will be defined as in 
Section 5.2.
Worst Level of Fatigue in Past 24 Hours (BFI Item 3)

A BFI item 3 score for baseline and each week of treatment will be derived by taking the mean 
of up to 7 available daily assessments in each week of treatment. 

Assessment windows defining each week will be based on the date recorded for each BFI 
assessment and are defined in Section 16.3.1.
HES Symptom Severity Based on HES Daily Symptoms (HES-DS)

For each of the 6 symptom domains (muscle/joint pain, chills or sweats, abdominal pain or 
bloating, breathing symptoms, nasal or sinus symptoms and skin symptoms, a symptom score 
for baseline and each week of treatment will be derived by taking the mean of up to 7 available 
daily assessments in each weekly assessment window. 

Assessment windows defining each week will be based on the date recorded for each HES-DS 
assessment and are defined in Section 16.3.1.

A symptom score for most bothersome symptoms will be derived by taking the mean of the 
symptom scores for the up to 3 symptom domains identified by the subject as most 
bothersome at visit 2 (Week 0).


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BFI Total Score

The BFI total score (range 0 – 10) will be calculated as the mean of the 9 domain scores 
(range 0 – 10) recorded for the weekly assessment. If less than 4 domain scores are complete, 
the BFI total score will be set to missing.
16.6.5.
Safety
Adverse Events
Drug Related AEs
AEs with relationship marked ‘YES’ or relationship missing.
AEs Leading to Permanent Discontinuation from Study Treatment or Withdrawal from the Study 
AEs with action marked “Study treatment withdrawn” or withdrawn from study status marked 
“YES”, or a response to either of these questions is missing.
AEs on Day of Dosing
AEs with an onset date equal to a study treatment dosing date and an onset time on or after the 
study treatment dosing time.
AE Time Since First Dose

If AE onset time is missing, calculate in days as follows:-
o
If AE start date < Date of first dose of study treatment then 
Time since first dose = AE start date - Date of first dose of study treatment 
o
If AE start date ≥ Date of first dose of study treatment then 
Time since first dose = AE start date – Date of first dose of study treatment +1
o
Missing if AE start date or date of first dose of study treatment is missing.

If AE onset time is present, calculate in days, hours, minutes as 
Time since first dose = AE start date/time – Date/time of first dose of study 
treatment 
AE Duration (Days)

If AE onset time is missing, calculate in days as
AE end date – AE start date + 1

If AE onset time is present, calculate in days, hours and minutes as
AE end date/time – AE start date/time

Missing if AE start date or end date is missing.
AEs of Special Interest

See Section 11.1.1.
ECG

QTc(B) (msec) will be derived from QT (uncorrected in msec) and RR interval (msec) as


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16.7.
Appendix 7: Reporting Standards for Missing Data
16.7.1.
Premature Withdrawals
Element
Reporting Detail
General

A subject will be considered to have completed study treatment if they receive 
study treatment at week 28 (Visit 10).

For the purpose of the primary endpoint, a subject will be considered to have 
completed the study if they continue to participate in the study until Week 32 
(Visit 11). If a subject’s last dose of study treatment is on Week 24 (Visit 9) or 
Week 28 (Visit 10) and the subject does not continue into the open-label 
extension study 205203 after completing Visit 11 assessments (32 weeks from 
randomization), then the protocol requires an up to 8-week additional follow-up 
period, concluding with the 12-weeks post last dose follow-up visit (Visit 12).
Subjects who continue to participate in the study until Week 32 (Visit 11) but 
withdraw from the study prior to the final follow-up visit (Visit 12) will be 
documented separately in the study disposition table.

Subjects who discontinue study treatment or withdraw early will not be replaced 
in the study.
Pre-Screen 
and 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.

Screen failures are defined as subjects who consent to participate in the 
clinical trial but are never subsequently randomised.
16.7.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank 
fields on the collection instrument. These data will be indicated by the use of a 
“blank” in subject listing displays, unless all data for a specific visit are missing 
in which case the data is excluded from the listing. 

BLQ is not missing data and must be displayed as such and included in all 
listings and summaries. For blood eosinophil and IL-5 data, see Section 10.1.5
and Section 10.2.5 respectively. For PK data, refer to Section 16.5.3.
Outliers

Any subjects excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
16.7.2.1.
Handling of Missing and Partial Dates
Element
Reporting Detail
General

Partial dates will be displayed as captured in subject listing displays.
HES Flare 
and Adverse 
Events

Any partial dates for HES flare and adverse events will be raised to data 
management. If the full date cannot be ascertained, the following assumptions 
will be made:


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Element
Reporting Detail
o
If the partial date is a start date, a '01' will be used for the day and 'Jan' will 
be used for the month. 
o
However, if this imputation results in a date prior to the first dose of study 
treatment and the event could possibly have occurred during treatment from 
the partial information, then the date of the first dose of study treatment will 
be assumed to be the start date.
o
The event will then be considered to start on-treatment (worst case).
o
If the partial date is a stop date, a '28/29/30/31' will be used for the day 
(dependent on the month and year) and 'Dec' will be used for the month.

Completely missing start or end dates will remain missing, with no imputation 
applied. Consequently, time to onset and duration of such events will be 
missing.

The recorded partial date will be displayed in listings.
Concomitant 
Medications

Partial dates for any concomitant medications recorded in the CRF will be 
imputed using the following convention:
o
If the partial date is a start date, a '01' will be used for the day and 'Jan' will 
be used for the month
o
If the partial date is a stop date, a '28/29/30/31' will be used for the day 
(dependent on the month and year) and 'Dec' will be used for the month.

The recorded partial date will be displayed in listings.


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16.8.
Appendix 8: Values of Potential Clinical Importance
16.8.1.
Laboratory Values
Haematology
Laboratory Parameter
Units
Age 
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Hematocrit 
Ratio of 1
12+
0.201 
0.599 
Haemoglobin 
G/L
12+
71
199
Platelet Count 
GI/L
1+
31 
1499 
White Blood Cell Count (WBC)
GI/L
12+
1.1
Clinical Chemistry
Laboratory Parameter
Units
Age
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
ALT
U/L
3-12
>143 (and Total 
Bilirubin >43)
U/L
13+
>239 (and Total 
Bilirubin >43)
Calcium
mmol/L
3+
1.50
3.24
Glucose
mmol/L
1+
2.2
27.8
Phosphorus, Inorg
mmol/L
3+
0.32
Potassium
mmol/L
3+
2.8
6.5
Sodium
mmol/L
0+
120
160
Creatine Phosphokinase
IU/L
12+
>5 x ULN
Possible Hy’s Law Cases
Laboratory Parameter
Units
Category
Clinical Concern Range
ALT, Bilirubin
ALT ≥ 3xULN and Bilirubin ≥ 2xULN 
(>35% direct) 
ALT, INR
ALT ≥ 3xULN and INR > 1.5 
NOTES:

ULN = Upper Limit of Normal.
16.8.2.
Urinalysis
As per GSK IDSL display standards, a subject is considered to have urinalysis results of 
PCI if there is an increase in Protein or an increase in Occult Blood results during the 
study, or if microscopy is performed.


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16.9.
Appendix 9: Abbreviations & Trade Marks
16.9.1.
Abbreviations
Abbreviation
Description
ADaM
Analysis Data Model
AE
Adverse Event
A&R
Analysis and Reporting 
BFI
Brief Fatigue Index
BLQ
Below limit of quantification
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
CPMS
Clinical Pharmacology Modelling & Simulation
CS
Clinical Statistics
CSR
Clinical Study Report
DBF
Database Freeze
DBR
Database Release
DOB
Date of Birth
DP
Decimal Places
eCRF
Electronic Case Record Form
FEV1
Forced Expiratory Volume in one second
FVC
Forced Vital Capacity
GSK
GlaxoSmithKline
HCRU
Healthcare Resource Utilisation
HES-DS
HES Daily Symptoms
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee 
IDSL
Integrated Data Standards Library
ITT
Intent-To-Treat
J2R
Jump to Reference
MAR
Missing at Random
MMRM
Mixed Model Repeated Measures
MSAS-SF
Modified Memorial Symptom Assessment Scale – Short Form
MUGA
Multigated Aquisition
OCS
Oral Corticosteroid
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
PK
Pharmacokinetic
PP
Per Protocol
Pop-PK
Population PK
Pop-PKPD
Population PKPD
PROMIS
Patient Reported Outcome Measurement Information System
QC
Quality Control
QTcF
Frederica’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate


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Abbreviation
Description
RAP
Reporting & Analysis Plan
RMC
Respiratory Medication Class
SAC
Statistical Analysis Complete
SAE
Serious Adverse Event
SDTM
Study Data Tabulation Model
SoC
Standard of Care
SSR
Subject-Rated Symptom Severity
TFL
Tables, Figures & Listings 
16.9.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
NONE
NONMEM
SAS


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16.10.
Appendix 10: List of Data Displays
16.10.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.n
1.1 to 1.n
Efficacy
2.1 to 2.n
2.1 to 2.n
Health Outcome Tables
3.1 to 3.n
3.1 to 3.n
Safety
4.1 to 4.n
4.1 to 4.n
Pharmacokinetic
5.1 to 5.n
5.1 to 5.n
Pharmacodynamic and / or Biomarker
6.1 to 6.n
6.1 to 6.n
Pharmacokinetic / Pharmacodynamic
7.1 to 7.n
7.1 to 7.n
Section
Listings
ICH Listings
1 to x
16.10.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Appendix 11: Example Mock Shells for Data Displays.
Section
Figure
Table
Listing
Study Population
POP_Fn
POP_Tn
POP_Ln
Efficacy
EFF_Fn
EFF_Tn
EFF_Ln
Safety
SAFE_Fn
SAFE_Tn
SAFE_Ln
Pharmacokinetic
PK_Fn
PK_Tn
PK_Ln
Population Pharmacokinetic (PopPK)
POPPK_Fn
POPPK_Tn
POPPK_Ln
Pharmacodynamic and / or Biomarker
PD_Fn
PD_Tn
PD_Ln
Pharmacokinetic / Pharmacodynamic
PKPD_Fn
PKPD_Tn
PK/PD_Ln
NOTES: 

Non-Standard displays are indicated in the ‘IDSL /  Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’
16.10.3.
Deliverables
Deliverable
Description
Headline 
Headline results
SAC
Final Statistical Analysis Complete


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16.10.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
Subject Disposition
1.1.
ITT
ES1 
Summary of Subject Disposition
Include Completed, Withdrawn and 
subsets of completed/withdrawn as 
follows:-
Completed, Completed Week 32 and 
entered 205203, Completed Week 32
and Follow-up
Withdrawn, Withdrawn prior to Week 
32, Completed Week 32 and withdrawn
prior to Follow up
SAC
1.2.
ITT
SD1
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment
SAC
1.3.
ITT
POP_T1
Summary of Subject Accountability During 32-Week Treatment 
Period
SAC
1.4.
Screened
ES6
Summary of Screening Status and Reasons for Screen Failure
As a subset of “Enrolled” subjects, also 
include the number of subjects for 
whom inclusion criteria #5 is based on 
local rather than central laboratory 
result. Use text “Inclusion criteria #5 
based on local laboratory result [1]”, 
and add footnote: “[1] The number of 
subjects for whom the screening central 
laboratory blood eosinophil count is 
<1000 cells/uL but a local laboratory 
blood eosinophil count 1000 cells/uL 
was used to meet study inclusion 
criteria.”
SAC


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Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
1.5.
Enrolled
NS1
Summary of Number of Subjects by Country and Site ID
SAC
Protocol Deviation
1.6.
ITT
DV1
Summary of Important Protocol Deviations
SAC
Population Analysed
1.7.
Screened
SP1
Summary of Study Populations 
Headline
1.8.
ITT
SP2
Summary of Exclusions from the Per Protocol Population
SAC 
Demographic and Baseline Characteristics
1.9.
ITT
DM1
Summary of Demographic Characteristics
SAC
1.10.
Enrolled
DM11
Summary of Age Ranges
SAC 
1.11.
ITT
DM5
Summary of Race and Racial Combinations
SAC
1.12.
ITT
POP_T8
Summary of Duration of HES
SAC
Prior and Concomitant Medications/Conditions
1.13.
ITT
POP_T2
Summary of Baseline HES Therapy
SAC
1.14.
ITT
POP_T3
Summary of Baseline Prednisone Equivalent Daily Dose
Headline
1.15.
ITT
CM1
Summary of Concomitant Medications
SAC
1.16.
ITT
MH4
Summary of Current Medical Conditions
SAC
1.17.
ITT
MH4
Summary of Past Medical Conditions
SAC
Exposure and Treatment Compliance
1.18.
ITT
POP_T4
Summary of Exposure (Therapeutic Coverage) to Study 
Treatment
SAC


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Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
1.19.
ITT
POP_T5
Summary of Number of Treatments Administered
SAC
Most Bothersome HES Symptoms
1.20.
ITT
POP_T6
Summary of Most Bothersome HES Related Symptoms
SAC
Steroid Perception Questionnaire
1.21.
ITT
POP_T7
Summary of Steroid Perception Questionnaire
SAC


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16.10.5.
Efficacy Tables
Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
HES Flare
2.1.
ITT
EFF_T1
Overview of HES Flares
SAC
2.2.
ITT
EFF_T2
Summary of Frequency of All HES Flares
SAC 
2.3.
ITT
EFF_T3
Primary Analysis of Proportion of Subjects Who Experience a 
HES Flare During the 32-Week Treatment Period (Treatment 
Policy Estimand)
Headline
2.4.
ITT
EFF_T3a
Supportive Analysis of Proportion of Subjects Who Experience a 
HES Flare During the 32-Week Treatment Period (While on 
Treatment Estimand)
Headline
2.5.
PP
EFF_T3
Supportive Analysis of Proportion of Subjects Who Experience a 
HES Flare During the 32-Week Treatment Period (Treatment 
Policy Estimand, PP Population)
Headline
2.6.
ITT
EFF_T3b
Sensitivity Analysis of Proportion of Subjects Who Experience a 
HES Flare During the 32-Week Treatment Period (Treatment 
Policy Estimand, Alternative Missing Data Imputation Strategy 
#1)
Headline
2.7.
ITT
EFF_T3c
Sensitivity Analysis of Proportion of Subjects Who Experience a 
HES Flare During the 32-Week Treatment Period (Treatment 
Policy Estimand, Alternative Missing Data Imputation Strategy 
#2)
Headline
2.8.
ITT
EFF_T3
Sensitivity Analysis of Proportion of Subjects Who Experience a 
HES Flare During the 32-Week Treatment Period (Treatment 
Policy Estimand, Excluding Subjects From Site 
SAC
PPD


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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
2.9.
ITT
EFF_T3
Analysis of Proportion of Subjects Who Experience a HES Flare 
During the 32-Week Treatment Period by Age (Treatment Policy 
Estimand)
Descriptive summary only; do not 
present p-values.
SAC
2.10.
ITT
EFF_T3
Analysis of Proportion of Subjects Who Experience a HES Flare 
During the 32-Week Treatment Period by Sex (Treatment Policy 
Estimand)
Descriptive summary only; do not 
present p-values.
SAC
2.11.
ITT
EFF_T3
Analysis of Proportion of Subjects Who Experience a HES Flare 
During the 32-Week Treatment Period by Race (Treatment 
Policy Estimand)
Descriptive summary only; do not 
present p-values.
SAC
2.12.
ITT
EFF_T3
Analysis of Proportion of Subjects Who Experience a HES Flare 
During the 32-Week Treatment Period by Region (Treatment 
Policy Estimand)
Descriptive summary only; do not 
present p-values.
SAC
2.13.
ITT
EFF_T3
Analysis of Proportion of Subjects Who Experience a HES Flare 
During the 32-Week Treatment Period by Baseline OCS 
(Treatment Policy Estimand)
Descriptive summary only; do not 
present p-values.
SAC
2.14.
ITT
EFF_T3
Analysis of Proportion of Subjects Who Experience a HES Flare 
During the 32-Week Treatment Period by Baseline Blood 
Eosinophils (Treatment Policy Estimand)
Descriptive summary only; do not 
present p-values.
SAC
2.15.
ITT
EFF_T4
Analysis of Time to First HES Flare (Treatment Policy Estimand)
Add footnote: “Note: Subjects 
withdrawing from the study prematurely 
are censored at the date of study 
withdrawal.”
Headline
2.16.
ITT
EFF_T4a
Sensitivity Analysis of Time to First HES Flare (Treatment Policy 
Estimand, Alternative Missing Data Imputation Strategy #1)
Add footnote: “Note: Subjects 
withdrawing from the study prematurely 
prior to reporting a HES flare are 
included with a HES flare on the date of 
study withdrawal.”
SAC


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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
2.17.
ITT
EFF_T4b
Sensitivity Analysis of Time to First HES Flare (Treatment Policy 
Estimand, Alternative Missing Data Imputation Strategy #2)
Add footnote: “Note: Subjects 
withdrawing from the study prematurely 
prior to reporting a HES flare, with 
primary reason for treatment withdrawal 
reported as Adverse Event or Lack of 
Efficacy are included with a HES flare 
on the date of study withdrawal. For 
subjects withdrawing from the study 
prematurely prior to reporting a HES 
flare, with any other reason for 
discontinuation of study treatment, the 
event time will be censored at the date 
of study withdrawal.”
SAC
2.18.
ITT
EFF_T3
Analysis of Proportion of Subjects Who Experience a HES Flare 
During Week 20 Through Week 32 (Treatment Policy Estimand)
SAC
2.19.
ITT
EFF_T3
Sensitivity Analysis of Proportion of Subjects Who Experience a 
HES Flare During Week 20 Through Week 32 (Treatment Policy 
Estimand, Alternative Missing Data Imputation Strategy #1)  
SAC
2.20.
ITT
EFF_T3
Sensitivity Analysis of Proportion of Subjects Who Experience a 
HES Flare During Week 20 Through Week 32 (Treatment Policy 
Estimand, Alternative Missing Data Imputation Strategy #2)  
SAC
2.21.
ITT
EFF_T5
Analysis of Rate of HES Flares (Treatment Policy Estimand)
Add footnote: “Note: For subjects 
withdrawing prematurely from the study 
during the 32-week treatment period, all 
data up to the time of study withdrawal 
is used to calculate the rate of HES 
flares.”
Headline
2.22.
ITT
EFF_T5a
Sensitivity Analysis of Rate of HES Flares (Treatment Policy 
Estimand, Jump to Reference Negative Binomial Model)
SAC


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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
Daily Fatigue Severity - Worst Level of Fatigue in Past 24 Hours (BFI Item 3)
2.23.
ITT
EFF_T6
Summary of Mean Daily Fatigue Severity - Worst Level of 
Fatigue in Past 24 Hours (BFI Item 3) (Treatment Policy 
Estimand)
Present Baseline (week 0) up Week 32.
SAC
2.24.
ITT
EFF_T7
Analysis of Change from Baseline in Mean Daily Fatigue 
Severity - Worst Level of Fatigue in Past 24 Hours (BFI Item 3) –
at Week 32 (Treatment Policy Estimand)
SAC
2.25.
ITT
EFF_T8
Analysis of Change from Baseline in Mean Daily Fatigue 
Severity - Worst Level of Fatigue in Past 24 Hours (BFI Item 3) 
(Treatment Policy Estimand, Mixed Model Repeated Measures)
SAC
2.26.
ITT
EFF_T9
Summary of P-values for Primary and Secondary Endpoints 
(Treatment Policy Estimand)
SAC
Elevated Blood Eosinophil Level
2.27.
ITT
EFF_T10
Analysis of Proportion of Subjects Who Have an Elevated Blood 
Eosinophil Count (2 x Baseline Value or Baseline Value + 2500 
cells/L) During the 32-Week Treatment Period (Treatment 
Policy Estimand)
SAC
FEV1, FVC, FEV1/FVC Ratio
2.28.
ITT
EFF_T6
Summary of FEV1, FVC and FEV1/FVC
Add a by-line for parameter.
Column header “Visit” rather than 
“Analysis Time Point”.
SAC
2.29.
ITT
EFF_T8
Analysis of Change from Baseline in FEV1 (Treatment Policy 
Estimand, Mixed Model Repeated Measures)
SAC
2.30.
ITT
EFF_T8
Analysis of Change from Baseline in FVC (Treatment Policy 
Estimand, Mixed Model Repeated Measures)
SAC


CONFIDENTIAL
200622
94
Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
2.31.
ITT
EFF_T6
Summary of FEV1, FVC and FEV1/FVC - Excluding Data where 
SABA/LABA was Taken Within 6/12 Hours Respectively
Add a by-line for parameter.
Column header “Visit” rather than 
“Analysis Time Point”.
SAC
2.32.
ITT
EFF_T8
Analysis of Change from Baseline in FEV1 - Excluding Data 
where SABA/LABA was Taken Within 6/12 Hours Respectively 
(Treatment Policy Estimand, Mixed Model Repeated Measures)
SAC
2.33.
ITT
EFF_T8
Analysis of Change from Baseline in FVC - Excluding Data 
where SABA/LABA was Taken Within 6/12 Hours Respectively 
(Treatment Policy Estimand, Mixed Model Repeated Measures)
SAC
ECHO/MUGA
2.34.
ITT
EFF_T16
Summary of ECHO/MUGA
SAC


CONFIDENTIAL
200622
95
Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
HES Symptom Severity (HES-DS)
2.35.
ITT
EFF_T6a
Summary of Most Bothersome HES Symptom Severity Score 
(HES-DS)
Includes number (%) of subjects with 
no reported symptoms.
SAC
2.36.
ITT
EFF_T7
Analysis of Change from Baseline in Most Bothersome HES 
Symptom Severity Score (HES-DS) at Week 32 (Treatment 
Policy Estimand)
Scale 0 = None to 10 = As bad as you 
can imagine.
SAC
2.37.
ITT
EFF_T8
Analysis of Change from Baseline in Most Bothersome HES 
Symptom Severity Score (HES-DS) (Treatment Policy Estimand, 
Mixed Model Repeated Measures)
Scale 0 = None to 10 = As bad as you 
can imagine.
SAC
2.38.
ITT
EFF_T6a
Summary of HES Symptom Severity Score (HES-DS) by 
Symptom
Includes number (%) of subjects with 
no reported symptoms.
Use T_EFF6a with Endpoint = 
Symptom Severity Score and by line for 
symptom domain.
Add footnote “Note: 1. The mean of the 
available assessments on the 7 days 
up to and including the date of each 
study visit is used as the value for that 
visit. For time points between visits i.e 
week 1, 2, 3, 5, 6, 7, 9, 10, 11, 13, 14, 
15, 17, 18, 19, 21, 22, 23, 25, 26, 27, 
29, 30, 31, the number of available 
assessments depends on the elapsed 
time between visits. 2. Scale 0 = None 
to 10 = As bad as you can imagine.”
SAC
2.39.
ITT
EFF_T7
Analysis of Change from Baseline HES Symptom Severity Score 
(HES-DS) by Symptom at Week 32 (Treatment Policy Estimand)
Use T_EFF7 with by line for symptom 
domain.
Scale 0 = None to 10 = As bad as you 
can imagine
SAC


CONFIDENTIAL
200622
96
Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
2.40.
ITT
EFF_T8
Analysis of Change from Baseline in HES Symptom Severity 
Score (HES-DS) by Symptom (Treatment Policy Estimand, 
Mixed Model Repeated Measures)
Use T_EFF8 with by line for symptom 
domain.
Scale 0 = None to 10 = As bad as you 
can imagine.
SAC
Weekly Fatigue Severity – BFI Total Scores
2.41.
ITT
EFF_T6
Summary of Total BFI Score
Present Baseline (week 0) up Week 32.
Scale: 0 = No fatigue/Does not interfere 
to 10 = As bad as you can 
imagine/Completely interferes.
SAC
2.42.
ITT
EFF_T7
Analysis of Change from Baseline in Total BFI Score at Week 32 
(Treatment Policy Estimand)
Scale: 0 = No fatigue/Does not interfere 
to 10 = As bad as you can 
imagine/Completely interferes.
SAC
2.43.
ITT
EFF_T8
Analysis of Change from Baseline in Total BFI Score (Treatment 
Policy Estimand, Mixed Model Repeated Measures)
Scale: 0 = No fatigue/Does not interfere 
to 10 = As bad as you can 
imagine/Completely interferes.
SAC
Clinical- and Subject- Rated Overall Response to Therapy
2.44.
ITT
EFF_T11
Summary of Clinician-Rated Overall Response to Therapy
SAC
2.45.
ITT
EFF_T12
Analysis of Clinician-Rated Overall Response to Therapy 
(Treatment Policy Estimand)
SAC
2.46.
ITT
EFF_T11
Summary of Subject-Rated Overall Response to Therapy
SAC
2.47.
ITT
EFF_T12
Analysis of Subject-Rated Overall Response to Therapy 
(Treatment Policy Estimand)
SAC
Subject-Rated Symptom Severity (SSR) 
2.48.
ITT
EFF_T13
Summary of Subject-Rated Symptom Severity
SAC
2.49.
ITT
EFF_T12
Analysis of Subject-Rated Symptom Severity at Week 32 
(Treatment Policy Estimand)
SAC


CONFIDENTIAL
200622
97
Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
Modified Memorial Symptom Assessment Scale-Short Form (MSAS-SF)
2.50.
ITT
EFF_T6
Summary of MSAS-SF Total and Subscale Scores
Include by line: Total MSAS-SF Score, 
MSAS-SF Global Distress Index, 
MSAS-SF Physical Subscale Score, 
MSAS-SF Psychological Subscale 
Score.
Present Baseline (week 0) up Week 32.
Column header “Visit” rather than 
“Analysis Time Point”.
Add footnote: “Scale 0 = Not at all 
distressed or bothered/No symptoms to 
4 = Very much distressed or 
bothered/Almost constant symptoms.”
SAC
2.51.
ITT
EFF_T7
Analysis of Change from Baseline in MSAS-SF Total and 
Subscale Scores at Week 32 (Treatment Policy Estimand)
Include by line: Total MSAS-SF Score, 
MSAS-SF Global Distress Index, 
MSAS-SF Physical Subscale Score, 
MSAS-SF Psychological Subscale 
Score.
Scale 0 = Not at all distressed or 
bothered/No symptoms to 4 = Very 
much distressed or bothered/Almost 
constant symptoms.
SAC
2.52.
ITT
EFF_T8
Analysis of Change from Baseline in MSAS-SF Total and 
Subscale Scores (Treatment Policy Estimand, Mixed Model 
Repeated Measures)
Include by line: Total MSAS-SF Score, 
MSAS-SF Global Distress Index, 
MSAS-SF Physical Subscale Score, 
MSAS-SF Psychological Subscale 
Score.
Scale 0 = Not at all distressed or 
bothered/No symptoms to 4 = Very 
much distressed or bothered/Almost 
constant symptoms.
SAC


CONFIDENTIAL
200622
98
Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
PROMIS Physical Function and Sleep
2.53.
ITT
EFF_T6
Summary of PROMIS Physical Function Score
Present Baseline (week 0) up Week 32.
Column header “Visit” rather than 
“Analysis Time Point”.
Add footnote: “Scale 1 = Cannot 
do/unable to do to 5 = Not at all/Without 
any difficulty.”
SAC
2.54.
ITT
EFF_T7
Analysis of Change from Baseline in PROMIS Physical Function 
Score at Week 32 (Treatment Policy Estimand)
Scale 1 = Cannot do/unable to do to 5 = 
Not at all/Without any difficulty.
SAC
2.55.
ITT
EFF_T8
Analysis of Change from Baseline in PROMIS Physical Function 
Score (Treatment Policy Estimand, Mixed Model Repeated 
Measures)
Scale 1 = Cannot do/unable to do to 5 = 
Not at all/Without any difficulty.
SAC
2.56.
ITT
EFF_T6
Summary of PROMIS Sleep Score
Present Baseline (week 0) up Week 32.
Column header “Visit” rather than 
“Analysis Time Point”.
Add footnote: “Scale 1 = Not at all 
difficulty in falling asleep /Never trouble 
staying asleep to 5 = Very much 
difficulty in falling asleep /Always 
trouble staying asleep.”
SAC
2.57.
ITT
EFF_T7
Analysis of Change from Baseline in PROMIS Sleep Score at 
Week 32 (Treatment Policy Estimand)
Scale 1 = Not at all difficulty in falling 
asleep /Never trouble staying asleep to 
5 = Very much difficulty in falling asleep 
/Always trouble staying asleep.
SAC
2.58.
ITT
EFF_T8
Analysis of Change from Baseline in PROMIS Sleep Score
(Treatment Policy Estimand, Mixed Model Repeated Measures)
Scale 1 = Not at all difficulty in falling 
asleep /Never trouble staying asleep to 
5 = Very much difficulty in falling asleep 
/Always trouble staying asleep.
SAC


CONFIDENTIAL
200622
99
16.10.6.
Efficacy Figures
Efficacy: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
HES Flare
2.1.
ITT
EFF_F1
Cumulative Number of HES Flares
Headline
2.2.
ITT
EFF_F2
Analysis of Proportion of Subjects with HES Flare During the 32-
Week Treatment Period
Present odds ratios and 95% CI from 5
analyses of the primary endpoint on 
one figure: Primary estimand, While on 
treatment estimand, Per protocol
population, Alternative missing data 
imputation strategy #1, Alternative 
missing data imputation strategy #2.
Headline
2.3.
ITT
EFF_F3
Kaplan-Meier Cumulative Incidence Curve for Time to First HES 
Flare
SAC
2.4.
ITT
EFF_F2
Analysis of Time to First HES Flare (Treatment Policy Estimand)
Present relative risk and 95% CI from 3 
analyses corresponding to 3 missing 
data imputation strategies: Primary 
estimand, Alternative missing data 
imputation strategy #1, Alternative 
missing data imputation strategy #2
SAC
2.5.
ITT
-
Exploratory Modelling of Proportion of Subjects with HES Flare 
During the 32-Week Treatment Period vs Baseline Blood
Eosinophils
SAC
2.6.
ITT
EFF_F2
Analysis of Proportion of Subjects with HES Flare During Week 
20 Through Week 32 (Treatment Policy Estimand)
Present odds ratio and 95% CI from 3 
analyses corresponding to 3 missing 
data imputation strategies: Primary 
estimand, Alternative missing data 
imputation strategy #1, Alternative 
missing data imputation strategy #2
SAC


CONFIDENTIAL
200622
100
Efficacy: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
2.7.
ITT
EFF_F2
Analysis of Rate of HES Flare (Treatment Policy Estimand)
Present rate ratio and 95% CI from two 
analyses: Primary estimand, Jump to 
reference
SAC
Worst Level of Fatigue in Past 24 Hours (BFI Item 3)
2.8.
ITT
EFF_F6
Cumulative Distribution Plot for the Change from Baseline in 
Mean Daily Fatigue Severity - Worst Level of Fatigue in Past 24 
Hours (BFI Item 3) – at Week 32
SAC
2.9.
ITT
EFF_F4
Change from Baseline in Fatigue Severity - Worst Level of 
Fatigue in Past 24 Hours (BFI Item 3) (Treatment Policy 
Estimand, Mixed Model Repeated Measures)
Present adjusted mean (95% CI) 
change from baseline by time (weeks) 
from repeated measures model – Week 
0, 4, 8, 12, 16, 20, 24, 28, 32.
Add footnote: “Note: Adjusted for 
baseline (week 0) BFI item 3 score and 
region”.
SAC
2.10.
ITT
EFF_F5
Change from Baseline in Fatigue Severity - Worst Level of 
Fatigue in Past 24 Hours (BFI Item 3) - Treatment Difference vs 
Placebo (Treatment Policy Estimand, Mixed Model Repeated 
Measures)
Present adjusted mean treatment 
difference (95% CI) change from 
baseline by time (weeks) from repeated 
measures model – Week 0, 4, 8, 12, 
16, 20, 24, 28, 32.
Add footnote: “Note: Adjusted for 
baseline (week 0) BFI item 3 score and 
region”.
SAC
FEV1 and FVC
2.11.
ITT
EFF_F4
Change from Baseline in FEV1 (Treatment Policy Estimand, 
Mixed Model Repeated Measures)
SAC
2.12.
ITT
EFF_F5
Change from Baseline in FEV1 - Treatment Difference vs 
Placebo (Treatment Policy Estimand, Mixed Model Repeated 
Measures)
SAC


CONFIDENTIAL
200622
101
Efficacy: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
2.13.
ITT
EFF_F4
Change from Baseline in FVC (Treatment Policy Estimand, 
Mixed Model Repeated Measures)
SAC
2.14.
ITT
EFF_F5
Change from Baseline in FVC - Treatment Difference vs 
Placebo (Treatment Policy Estimand, Mixed Model Repeated 
Measures)
SAC
HES Symptom Severity (HES-DS)
2.15.
ITT
EFF_F4
Change from Baseline in Most Bothersome HES Symptom 
Severity Score (HES-DS) (Treatment Policy Estimand, Mixed 
Model Repeated Measures)
Present adjusted mean (95% CI) 
change from baseline by time (weeks) 
from repeated measures model – Week 
0, 4, 8, 12, 16, 20, 24, 28, 32.
Add footnote: “Note: Adjusted for 
baseline (week 0) most bothersome 
symptom score and region”.
SAC
2.16.
ITT
EFF_F5
Change from Baseline in Most Bothersome HES Symptom 
Severity Score (HES-DS) - Treatment Difference vs Placebo 
(Treatment Policy Estimand, Mixed Model Repeated Measures)
Present adjusted mean treatment 
difference (95% CI) change from 
baseline by time (weeks) from repeated 
measures model – Week 0, 4, 8, 12, 
16, 20, 24, 28, 32.
Add footnote: “Note: Adjusted for 
baseline (week 0) most bothersome 
symptom score and region”.
SAC
2.17.
ITT
EFF_F4
Change from Baseline in HES Symptom Severity Score (HES-
DS) by Symptom (Treatment Policy Estimand, Mixed Model 
Repeated Measures)
One page per domain with byline.
Present adjusted mean (95% CI) 
change from baseline by time (weeks) 
from repeated measures model – Week 
0, 4, 8, 12, 16, 20, 24, 28, 32.
Add footnote: “Note: Adjusted for 
baseline (week 0) symptom score and 
region”.
SAC


CONFIDENTIAL
200622
102
Efficacy: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
2.18.
ITT
EFF_F5
Change from Baseline in HES Symptom Severity Score (HES-
DS) by Symptom - Treatment Difference vs Placebo (Treatment 
Policy Estimand, Mixed Model Repeated Measures)
One page per domain with byline.
Present adjusted mean treatment 
difference (95% CI) change from 
baseline by time (weeks) from repeated 
measures model – Week 0, 4, 8, 12, 
16, 20, 24, 28, 32.
Add footnote: “Note: Adjusted for 
baseline (week 0) symptom score and 
region”.
SAC
Weekly Fatigue Severity – BFI Total Scores
2.19.
ITT
EFF_F4
Change from Baseline in Total BFI Score (Treatment Policy 
Estimand, Mixed Model Repeated Measures)
Present adjusted mean (95% CI) 
change from baseline by time (weeks) 
from repeated measures model – Week 
0, 4, 8, 12, 16, 20, 24, 28, 32.
Add footnote: “Note: Adjusted for 
baseline (week 0) total BFI score and 
region”.
SAC
2.20.
ITT
EFF_F5
Change from Baseline in Total BFI Score - Treatment Difference 
vs Placebo (Treatment Policy Estimand, Mixed Model Repeated 
Measures)
Present adjusted mean treatment 
difference (95% CI) change from 
baseline by time (weeks) from repeated 
measures model – Week 0, 4, 8, 12, 
16, 20, 24, 28, 32.
Add footnote: “Note: Adjusted for 
baseline (week 0) total BFI score and 
region”.
SAC
Modified Memorial Symptom Assessment Scale-Short Form (MSAS-SF)


CONFIDENTIAL
200622
103
Efficacy: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
2.21.
ITT
EFF_F4
Change from Baseline in MSAS-SF Total and Subscale Scores
(Treatment Policy Estimand, Mixed Model Repeated Measures)
One plot per page, 4 pages with by line: 
Total MSAS-SF Score, MSAS-SF 
Global Distress Index, MSAS-SF 
Physical Subscale Score, MSAS-SF 
Psychological Subscale Score.
Present adjusted mean (95% CI) 
change from baseline by time (weeks) 
from repeated measures model – Week 
0, 4, 8, 16, 24, 32.
Add footnote: “Note: Adjusted for 
baseline (week 0) score and region. 
Scale: 0 = Not at all distressed or 
bothered/No symptoms to 4 = Very 
much distressed or bothered/Almost 
constant symptoms.”
SAC


CONFIDENTIAL
200622
104
Efficacy: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
2.22.
ITT
EFF_F5
Change from Baseline in MSAS-SF Total and Subscale Scores -
Treatment Difference vs Placebo (Treatment Policy Estimand, 
Mixed Model Repeated Measures)
Either one plot per page, 4 pages with 
by line, or 4 lines on one plot, as data 
permit: Total MSAS-SF Score, MSAS-
SF Global Distress Index, MSAS-SF 
Physical Subscale Score, MSAS-SF 
Psychological Subscale Score.
Present adjusted mean treatment 
difference (95% CI) change from 
baseline by time (weeks) from repeated 
measures model – Week 0, 4, 8, 12, 
16, 20, 24, 28, 32.
Add footnote: “Note: Adjusted for 
baseline (week 0) score and region. 
Scale: 0 = Not at all distressed or 
bothered/No symptoms to 4 = Very 
much distressed or bothered/Almost 
constant symptoms.”
SAC


CONFIDENTIAL
200622
105
Efficacy: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
PROMIS Physical Function and Sleep
2.23.
ITT
EFF_F4
Change from Baseline in PROMIS Physical Function and Sleep 
Score (Treatment Policy Estimand, Mixed Model Repeated 
Measures)
One plot per page, 2 pages with by line: 
PROMIS Physical Function Score, 
PROMIS Sleep Score.
Present adjusted mean (95% CI) 
change from baseline by time (weeks) 
from repeated measures model – Week 
0, 4, 8, 16, 24, 32.
Add footnote: “Note: 1. Adjusted for 
baseline (week 0) score and region.
2. Sleep score scale 1 = Not at all 
difficulty in falling asleep /Never trouble 
staying asleep to 5 = Very much 
difficulty in falling asleep /Always 
trouble staying asleep.
3. Physical function scale 0 = Not at all 
distressed or bothered/No symptoms to 
4 = Very much distressed or 
bothered/Almost constant symptoms.”
SAC


CONFIDENTIAL
200622
106
Efficacy: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
2.24.
ITT
EFF_F5
Change from Baseline in PROMIS Physical Function and Sleep 
Score - Treatment Difference vs Placebo (Treatment Policy 
Estimand, Mixed Model Repeated Measures)
Either one plot per page, 2 pages with 
by line, or 2 lines on one plot, as data 
permit: PROMIS Physical Function 
Score, PROMIS Sleep Score.
Present adjusted mean treatment 
difference (95% CI) change from 
baseline by time (weeks) from repeated 
measures model – Week 0, 4, 8, 16, 
24, 32.
Add footnote: “Note: 1. Adjusted for 
baseline (week 0) score and region.
2. Sleep score scale 1 = Not at all 
difficulty in falling asleep /Never trouble 
staying asleep to 5 = Very much 
difficulty in falling asleep /Always 
trouble staying asleep.
3. Physical function scale 0 = Not at all 
distressed or bothered/No symptoms to 
4 = Very much distressed or 
bothered/Almost constant symptoms.”
SAC


CONFIDENTIAL
200622
107
16.10.7.
Health Outcomes Tables
Health Outcomes: Tables
No.
Population
IDSL /  Example 
Shell
Title
Programming Notes
Deliverable
SF-36
3.1.
ITT
EFF_T6
Summary of SF-36 Health Survey Domain Scores
Include change from baseline values. 
Include 95% CIs for the mean.
SAC
3.2.
ITT
EFF_T6
Summary of SF-36 Health Survey Component Summary Scores
Include change from baseline values
Include 95% CIs for the mean.
SAC
Healthcare Resource Utilisation
3.3.
ITT
EFF_T14
Summary of Healthcare Resource Utilisation Associated with 
HES Flare
SAC
Work Productivity and Activity Impairment Questionnaire
3.4.
ITT
EFF_T15
Summary of Work Productivity and Activity Impairment
SAC


CONFIDENTIAL
200622
108
16.10.8.
Safety Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
Adverse Event Overview
4.1.
Safety
SAFE_T1
Adverse Event Overview
SAC
Adverse Events 
4.2.
Safety
AE1
Summary of All On-Treatment Adverse Events by System Organ 
Class and Preferred Term
SAC
4.3.
Safety
AE1
Summary of All Post-Treatment Adverse Events by System 
Organ Class and Preferred Term
SAC
4.4.
Safety
AE3
Summary of Common (>=3% Incidence) On-Treatment Adverse 
Events by Overall Frequency
SAC
4.5.
Safety
AE15
Summary of Common (>=3% Incidence) On-Treatment Non-
Serious Adverse Events by System Organ Class and Preferred 
Term (Number of Subjects and Occurrences)
SAC
4.6.
Safety
AE5A
Summary of All On-Treatment Adverse Events by Maximum 
Intensity by System Organ Class and Preferred Term
SAC
4.7.
Safety
AE1
Summary of All Drug-Related Adverse Events by System Organ 
Class and Preferred Term
SAC
4.8.
Safety
AE5A
Summary of All Drug-Related Adverse Events by Maximum 
Intensity by System Organ Class and Preferred Term
SAC
4.9.
Safety
AE1
Summary of Non-Serious Drug-Related Adverse Events by 
System Organ Class and Preferred Term
SAC
4.10.
Safety
AE1
Summary of On-Treatment Adverse Events by Highest Post-
Baseline Binding Antibody Result
Add in row with n in each binding 
antibody result category.
SAC


CONFIDENTIAL
200622
109
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
4.11.
Safety
AE3
Summary of All Adverse Events Leading to Permanent 
Discontinuation from Study Treatment by Overall Frequency
SAC
4.12.
Safety
AE3
Summary of All Adverse Events Leading to Withdrawal from the 
Study by Overall Frequency
SAC
4.13.
Safety
AE1
Summary of Adverse Events Reported on the Day of Dosing by 
System Organ Class and Preferred Term
SAC
4.14.
Safety
AE7
Listing of Subject Numbers for Individual On-Treatment Adverse 
Events
SAC
4.15.
Safety
AE7
Listing of Subject Numbers for Individual Post-Treatment 
Adverse Events
SAC
4.16.
Safety
AE2
Listing of Relationship of Adverse Event, System Organ 
Classes, Preferred Terms and Verbatim Text
SAC
Serious Adverse Events 
4.17.
Safety
AE3
Summary of Fatal Serious Adverse Events by Overall Frequency
Headline
4.18.
Safety
AE3
Summary of Drug-Related Fatal Serious Adverse Events by 
Overall Frequency
SAC
4.19.
Safety
AE3
Summary of Non-Fatal Serious Adverse Events by Overall 
Frequency
SAC
4.20.
Safety
AE3
Summary of All Serious Adverse Events by Overall Frequency
Headline
4.21.
Safety
AE1
Summary of All On-Treatment Serious Adverse Events by 
System Organ Class and Preferred Term
SAC
4.22.
Safety
AE1
Summary of All Post-Treatment Serious Adverse Events by 
System Organ Class and Preferred Term
SAC


CONFIDENTIAL
200622
110
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
4.23.
Safety
AE1
Summary of All Pre-Treatment Serious Adverse Events by 
System Organ Class and Preferred Term
SAC
4.24.
Safety
AE16
Summary of All Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Subjects and Occurrences)
SAC
4.25.
Safety
AE1
Summary of All Drug-Related Serious Adverse Events by 
System Organ Class and Preferred Term
SAC
Adverse Events of Special Interest
4.26.
Safety
SAFE_T5
Summary of On-Treatment Serious AEs and AEs of Special 
Interest
Incidence, Relative Risk and Risk Difference – Mepolizumab 
300mg SC vs Placebo
SAC
4.27.
Safety
AE1
Summary of On-Treatment Adverse Events Reported by the 
Investigator as Systemic Reactions Meeting the Criteria for 
Anaphylaxis
SAC
4.28.
Safety
SAFE_T2
Summary Profile of On-Treatment Adverse Events Reported by 
the Investigator as Systemic Reactions Meeting the Criteria for 
Anaphylaxis
SAC
4.29.
Safety
AE1
Summary of On-Treatment Adverse Events Reported by the 
Investigator as Systemic Reactions - Allergic (Type I 
Hypersensitivity) and Other Systemic
SAC
4.30.
Safety
SAFE_T2
Summary Profile of On-Treatment Adverse Events Reported by 
the Investigator as Systemic Reactions - Allergic (Type I 
Hypersensitivity) and Other Systemic
SAC


CONFIDENTIAL
200622
111
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
4.31.
Safety
AE1
Summary of On-Treatment Adverse Events Reported by the 
Investigator as Systemic Reactions - Allergic (Type I 
Hypersensitivity)
SAC
4.32.
Safety
SAFE_T2
Summary Profile of On-Treatment Adverse Events Reported by 
the Investigator as Systemic Reactions - Allergic (Type I 
Hypersensitivity)
SAC
4.33.
Safety
AE1
Summary of On-Treatment Adverse Events Reported by the 
Investigator as Systemic Reactions – Other Systemic
SAC
4.34.
Safety
SAFE_T2
Summary Profile of On-Treatment Adverse Events Reported by 
the Investigator as Systemic Reactions - Other Systemic
SAC
4.35.
Safety
AE1
Summary of On-Treatment Adverse Events Reported by the 
Investigator as Local Injection Site Reactions
SAC
4.36.
Safety
SAFE_T2
Summary Profile of On-Treatment Adverse Events Reported by 
the Investigator as Local Injection Site Reactions
SAC
4.37.
Safety
AE1
Summary of On-Treatment Adverse Events Categorised as 
Serious Cardiac, Vascular and Thromboembolic Events
SAC
4.38.
Safety
SAFE_T2
Summary Profile of On-Treatment Adverse Events Categorised 
as Serious Cardiac, Vascular and Thromboembolic Events
SAC
4.39.
Safety
AE1
Summary of On-Treatment Adverse Events Categorised as 
Serious Ischemic Events
SAC
4.40.
Safety
SAFE_T2
Summary Profile of On-Treatment Adverse Events Categorised 
as Serious Ischemic Events
SAC
4.41.
Safety
AE1
Summary of On-Treatment Adverse Events Categorised as 
Malignancies
SAC


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112
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
4.42.
Safety
SAFE_T2
Summary Profile of On-Treatment Adverse Events Categorised 
as Malignancies
SAC
4.43.
Safety
AE1
Summary of On-Treatment Adverse Events Categorised as
Potential Opportunistic Infections
SAC
4.44.
Safety
SAFE_T2
Summary Profile of On-Treatment Adverse Events Categorised 
as Potential Opportunistic Infections
SAC
Laboratory – Haematology
4.45.
Safety
LB1
Summary of Haematology Changes from Baseline by Visit
Include baseline values
SAC
4.46.
Safety
LB3
Summary of Haematology Shifts from Baseline Relative to 
Normal Range by Visit
Include worst case post-baseline. If 
there are unscheduled assessments 
add footnote: “Note: Worst case post 
baseline Includes scheduled and 
unscheduled assessments.”
SAC
4.47.
Safety
LB3
Summary of Haematology Shifts from Baseline Relative to PCI 
Criteria by Visit
Include worst case post-baseline. If 
there are unscheduled assessments 
add footnote: “Note: Worst case post 
baseline Includes scheduled and 
unscheduled assessments.”
SAC
Laboratory – Clinical Chemistry
4.48.
Safety
LB1
Summary of Clinical Chemistry Changes from Baseline by Visit
Include baseline values
SAC
4.49.
Safety
LB3
Summary of Clinical Chemistry Shifts from Baseline Relative to 
Normal Range by Visit
Include worst case post-baseline. If 
there are unscheduled assessments 
add footnote: “Note: Worst case post 
baseline Includes scheduled and 
unscheduled assessments.”
SAC


CONFIDENTIAL
200622
113
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
4.50.
Safety
LB3
Summary of Clinical Chemistry Shifts from Baseline Relative to 
PCI Criteria by Visit
Include worst case post-baseline. If 
there are unscheduled assessments 
add footnote: “Note: Worst case post 
baseline Includes scheduled and 
unscheduled assessments.”
SAC
Laboratory – Urinalysis
4.51.
Safety
UR1
Summary of Worst Case Urinalysis Results Post-Baseline 
Relative to Baseline
SAC
Laboratory: Hepatobiliary (Liver)
4.52.
Safety
LIVER1
Summary of Liver Monitoring/Stopping Event Reporting
SAC
4.53.
Safety
LIVER10
Summary of Hepatobiliary Laboratory Abnormalities
SAC
ECG
4.54.
Safety
EG1
Summary of ECG Findings by Visit
Include worst case post-baseline. If 
there are unscheduled assessments 
add footnote: “Note: Worst case post 
baseline Includes scheduled and 
unscheduled assessments.”
SAC
4.55.
Safety
EG2
Summary of Change from Baseline in ECG Values by Visit
Include baseline values
SAC
4.56.
Safety
EG10
Summary of Maximum QTc Values Post-Baseline Relative to 
Baseline by Category
QTc(B) and QTc(F)
If there are unscheduled assessments 
add footnote: “Note: Includes scheduled 
and unscheduled assessments.”
SAC


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200622
114
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
4.57.
Safety
EG11
Summary of Maximum Increase in QTc Values Post-Baseline 
Relative to Baseline by Category
QTc(B) and QTc(F)
If there are unscheduled assessments 
add footnote: “Note: Includes scheduled 
and unscheduled assessments.”
SAC
Vital Signs
4.58.
Safety
VS1
Summary of Vital Signs by Visit
SAC
4.59.
Safety
VS1
Summary of Change from Baseline in Vital Signs by Visit
Include baseline values
SAC
Immunogenicity
4.60.
Safety
SAFE_T3
Summary of Binding Antibody by Visit
Include highest post baseline result. 
SAC
4.61.
Safety
SAFE_T3
Summary of Binding Antibody By Visit – Subjects Without 
Positive Result Prior to Dosing
Post-Week 0 visits only, plus highest 
post baseline result.
SAC
4.62.
Safety
SAFE_T4
Summary of Neutralising Antibody by Visit
Include highest post baseline result. 
SAC


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200622
115
16.10.9.
Safety Figures
Safety: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
Adverse Events
4.1.
Safety
AE10
Common (>=3% Incidence) On-Treatment Adverse Events and 
Relative Risk
SAC
4.2.
Safety
SAFE_F1
Relative Risk of On-Treatment Serious Adverse Events and AEs 
of Special Interest
Mepolizumab 300mg SC vs Placebo
SAC
Laboratory
4.3.
Safety
LIVER14
Scatter Plot of Maximum vs Baseline for ALT
If there are unscheduled assessments 
add footnote: “Note: Maximum Value 
includes scheduled and unscheduled 
assessments.”
SAC
4.4.
Safety
LIVER9
Scatter Plot of Maximum Total Bilirubin vs Maximum ALT
If there are unscheduled assessments 
add footnote: “Note: Maximum Value 
includes scheduled and unscheduled 
assessments.”
SAC


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200622
116
16.10.10. Pharmacokinetic Tables
Pharmacokinetic: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
5.1.
PK
PK01
Summary of Plasma Mepolizumab Concentration-Time Data
(Observed and Predicted)
SAC
5.2.
PK
PK06
Summary Statistics of Individual Model Predicted Plasma 
Mepolizumab Pharmacokinetic Parameters (Non-transformed 
and Log-transformed)
SAC
5.3.
PK
-
Description and Evaluation of Key PK Models Tested
Provided by CPMS
SAC
5.4.
PK
-
Population PK Parameter Estimates with 95% CI of Final PK 
Model
Provided by CPMS
SAC
5.5.
PK
-
Demographics Summary
Provided by CPMS
SAC
5.6.
PK
-
Samples Summary
Provided by CPMS
SAC
5.7.
PK
-
Accumulation Ratio Estimate at Week 16 and 32
Provided by CPMS
SAC


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200622
117
16.10.11. Pharmacokinetic Figures
Pharmacokinetic: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
5.1.
PK
-
Plasma Mepolizumab Concentration-Time Profiles (by 
Treatment)
Provided by CPMS
SAC
5.2.
PK
-
Model Goodness of Fit Plots
Provided by CPMS
SAC
5.3.
PK
-
Continuous Covariate Correlation Plot
Provided by CPMS
SAC
5.4.
PK
-
Categorical Covariate Correlation Plot
Provided by CPMS
SAC
5.5.
PK
-
Automated Covariate Selection
Provided by CPMS
SAC
5.6.
PK
-
Visual Predictive Check
Provided by CPMS
SAC
5.7.
PK
-
Observed Plasma Mepolizumab Concentration-Time Profiles by 
Anti-Drug Antibody Status
Provided by CPMS
SAC
5.8.
PK
-
Plasma Mepolizumab Observed/Predicted Concentration-Time 
Profiles (by Subject)
Provided by CPMS
SAC
5.9.
PK
-
Box Plot of Systemic Clearance versus Covariates of Interest
Provided by CPMS
SAC


CONFIDENTIAL
200622
118
16.10.12. Pharmacodynamic Tables
Pharmacodynamic: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
Blood Eosinophils
6.1.
PD
PD_T1
Summary of Blood Eosinophil Count
Include absolute blood eosinophils at 
Screening, Baseline and Week 2
through Week 32, and ratio to baseline
values for Week 2 through Week 32.
Number of decimal places as follows: 
geometric mean (2), SD logs (3), 
median (2), min (2), max (2).
SAC
6.2.
PD
PD_T2
Analysis of On-Treatment Ratio to Baseline Blood Eosinophils
(While on Treatment Estimand, Mixed Model Repeated 
Measures)
Include Week 2 through Week 32.
SAC
IL-5
6.3.
PD
PD_T1
Summary of Serum Total IL-5
Include absolute and ratio to baseline 
values.
Include summary statistics for the 
number and % of BLQ values.
SAC
6.4.
PD
PD_T3
Analysis of On-Treatment Ratio to Baseline Serum Total IL-5 at 
Week 32 (While on Treatment Estimand)
SAC


CONFIDENTIAL
200622
119
16.10.13. Pharmacodynamic Figures
Pharmacodynamic: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
Blood Eosinophils
6.1.
PD
EFF_F4
On-Treatment Absolute Blood Eosinophils (While on Treatment 
Estimand, Mixed Model Repeated Measures)
No reference line.
Include screening and baseline
unadjusted geometric mean values 
without 95% CI.
Week 2 onwards adjusted estimates 
from MMRM model with 95% CI.
SAC
6.2.
PD
EFF_F4
On-Treatment Ratio to Baseline Blood Eosinophils (While on 
Treatment Estimand, Mixed Model Repeated Measures)
Reference line at 1.
SAC
6.3.
PD
EFF_F5
On-Treatment Ratio to Baseline Blood Eosinophils – Treatment 
Difference vs Placebo (While on Treatment Estimand, Mixed 
Model Repeated Measures)
Reference line at 1.
SAC


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200622
120
16.10.14. Pharmacokinetic / Pharmacodynamic Tables
Pharmacokinetic / Pharmacodynamic: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
7.1.
PK and PD
-
Description and Evaluation of Key PKPD Models Tested
Provided by CPMS
SAC
7.2.
PK and PD
-
Population PD Parameter Estimates with 95% CI of Final PKPD 
Model
Provided by CPMS
SAC
7.3.
PK and PD
-
Demographics Summary
Provided by CPMS
SAC
7.4.
PK and PD
-
Samples Summary
Provided by CPMS
SAC
7.5.
ITT
-
Exploratory Exposure-Efficacy Response Modelling of 
Proportion of Subjects with HES Flare During the 32-Week 
Treatment Period vs Dose/Body weight
Post-SAC
7.6.
ITT
-
Exploratory Exposure-Efficacy Response Modelling of 
Proportion of Subjects with HES Flare During the 32-Week 
Treatment Period vs Cav
Post-SAC


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200622
121
16.10.15. Pharmacokinetic / Pharmacodynamic Figures
Pharmacokinetic / Pharmacodynamic: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
7.1.
PK and PD
-
Blood Eosinophil Count-Time Profiles
Provided by CPMS
SAC
7.2.
PK and PD
-
Model Goodness of Fit Plots
Provided by CPMS
SAC
7.3.
PK and PD
-
Continuous Covariate Correlation Plot
Provided by CPMS
SAC
7.4.
PK and PD
-
Categorical Covariate Correlation Plot
Provided by CPMS
SAC
7.5.
PK and PD
-
Automated Covariate Selection
Provided by CPMS
SAC
7.6.
PK and PD
-
Visual Predictive Check
Provided by CPMS
SAC
7.7.
PK and PD
-
Observed Blood Eosinophil Count -Time Profiles by Anti-Drug 
Antibody Status
Provided by CPMS
SAC
7.8.
PK and PD
-
Observed/Predicted Blood Eosinophil Count-Time Profiles (by 
Subject)
Provided by CPMS
SAC
7.9.
ITT
-
Exploratory Exposure-Efficacy Response Modelling of 
Proportion of Subjects with HES Flare During the 32-Week 
Treatment Period vs Dose/Body weight
Post-SAC
7.10.
ITT
-
Exploratory Exposure-Efficacy Response Modelling of 
Proportion of Subjects with HES Flare During the 32-Week 
Treatment Period vs Cav
Post-SAC


CONFIDENTIAL
200622
122
16.10.16. ICH Listings
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
Subject Disposition
1.
Screened
ES7
Listing of Reasons for Screen Failure
SAC
2.
ITT
ES2
Listing of Reasons for Study Withdrawal
SAC
3.
ITT
SD2
Listing of Reasons for Study Treatment Discontinuation
SAC
4.
ITT
BL1
Listing of Subjects for Whom the Treatment Blind was Broken
SAC
5.
ITT
TA1
Listing of Planned and Actual Treatments
SAC
Protocol Deviations
6.
ITT
DV2
Listing of Important Protocol Deviations 
SAC
7.
ITT
IE3
Listing of Subjects with Inclusion/Exclusion Criteria Deviations
SAC
Populations Analysed
8.
ITT
SP3
Listing of Subjects Excluded from Any Population
Include Per Protocol, Safety, PK, PD
SAC
Demographic and Baseline Characteristics
9.
ITT
DM2
Listing of Demographic Characteristics
SAC
10.
ITT
DM9
Listing of Race
SAC
11.
ITT
MH2
Listing of Medical Conditions
SAC
Prior and Concomitant Medications
12.
ITT
CP_CM3
Listing of Concomitant Medications
Flag baseline HES therapy on listing.
SAC
Exposure and Treatment Compliance
13.
ITT
EX3
Listing of Exposure Data
Exposure to Mepolizumab/Placebo 
only.
SAC


CONFIDENTIAL
200622
123
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
Burden of HES
14.
ITT
POP_L1
Listing of Most Bothersome HES Related Symptoms
SAC
15.
ITT
POP_L2
Listing of Steroid Perception Questionnaire
SAC
Efficacy
16.
ITT
EFF_L1
Listing of Investigator Reported HES Flare
SAC
17.
ITT
EFF_L2
Listing of Blinded OCS Therapy
SAC
18.
ITT
EFF_L3
Listing of Mean Daily Fatigue Severity – Worst Level of Fatigue 
in the Past 24 Hours (BFI Item 3) 
and Weekly Fatigue Severity (Total BFI Score)
SAC
19.
ITT
EFF_L4
Listing of FEV1, FVC and FEV1/FVC
SAC
20.
ITT
EFF_L5
Listing of Echocardiogram/MUGA
SAC
21.
ITT
EFF_L6
Listing of Symptom Severity (HES-DS)
SAC
22.
ITT
EFF_L7
Listing of Subject- and Clinician-Rated Overall Response to 
Therapy
SAC
23.
ITT
EFF_L8
Listing of Subject-Rated Symptom Severity
SAC
24.
ITT
EFF_L9
Listing of MSAS-SF Total and Subscale Scores
SAC
25.
ITT
EFF_L10
Listing of PROMIS Physical Function and Sleep Score
SAC
Healthcare Resource Utilisation
26.
ITT
EFF_L11
Listing of SF-36 Health Survey
SAC
27.
ITT
EFF_L12
Listing of Healthcare Resource Utilisation Associated with HES 
Flare
SAC
28.
ITT
EFF_L13
Listing of Work Productivity and Activity Impairment
SAC


CONFIDENTIAL
200622
124
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
Adverse Events
29.
Safety
AE8
Listing of All Adverse Events
Add phase: Pre-treatment, on-
treatment, post-treatment.
Include treatment in by-line.
SAC
Serious and Other Significant Adverse Events[1]
30.
Safety
AE8
Listing of Fatal Serious Adverse Events
Add phase: Pre-treatment, on-
treatment, post-treatment.
Include treatment in by-line.
SAC
31.
Safety
AE8
Listing of Non-Fatal Serious Adverse Events
Add phase: Pre-treatment, on-
treatment, post-treatment.
Include treatment in by-line.
SAC
32.
Safety
AE14
Listing of Reasons for Considering as a Serious Adverse Event
Add phase: Pre-treatment, on-
treatment, post-treatment.
Include treatment in by-line.
SAC
33.
Safety
AE8
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment
Add phase: Pre-treatment, on-
treatment, post-treatment.
Include treatment in by-line.
SAC
34.
Safety
AE8
Listing of Adverse Events Reported on the Day of Dosing
Add phase: Pre-treatment, on-
treatment, post-treatment.
Include treatment in by-line.
SAC
35.
Safety
AE8
Listing of Adverse Events Reported by the Investigator as 
Systemic Reactions Meeting the Criteria for Anaphylaxis
Add phase: Pre-treatment, on-
treatment, post-treatment.
Add injection reaction symptoms and 
number of doses prior to event.
Include treatment in by-line.
SAC


CONFIDENTIAL
200622
125
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
36.
Safety
AE8
Listing of Adverse Events Reported by the Investigator as 
Systemic Reactions - Allergic (Type I Hypersensitivity)
Add phase: Pre-treatment, on-
treatment, post-treatment.
Add injection reaction symptoms and 
number of doses prior to event.
Include treatment in by-line.
SAC
37.
Safety
AE8
Listing of Adverse Events Reported by the Investigator as 
Systemic Reactions – Other Systemic
Add phase: Pre-treatment, on-
treatment, post-treatment.
Add injection reaction symptoms and 
number of doses prior to event.
Include treatment in by-line.
SAC
38.
Safety
AE8
Listing of Adverse Events Reported by the Investigator as Local 
Injection Site Reactions
Add phase: Pre-treatment, on-
treatment, post-treatment.
Add injection reaction symptoms and 
number of doses prior to event.
Include treatment in by-line.
SAC
39.
Safety
AE8
Listing of Adverse Events Categorised as Serious Cardiac, 
Vascular and Thromboembolic Events
Add phase: Pre-treatment, on-
treatment, post-treatment.
Include treatment in by-line.
SAC
40.
Safety
AE8
Listing of Adverse Events Categorised as Serious Ischemic 
Events
Add phase: Pre-treatment, on-
treatment, post-treatment.
Include treatment in by-line.
SAC
41.
Safety
AE8
Listing of Adverse Events Categorised as Malignancies
Add phase: Pre-treatment, on-
treatment, post-treatment.
Include treatment in by-line.
SAC


CONFIDENTIAL
200622
126
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
42.
Safety
AE8
Listing of Adverse Events Categorised as Potential Opportunistic 
Infections
Add phase: Pre-treatment, on-
treatment, post-treatment.
Include treatment in by-line.
SAC
Hepatobiliary (Liver)
43.
Safety
MH2
Listing of Medical Conditions for Subjects with Liver Stopping 
Events
Programming note: Include all subjects 
meeting protocol defined liver stopping 
criteria even if liver pages were not 
completed by the site.
SAC
44.
Safety
SU2
Listing of Substance Use for Subjects with Liver Stopping 
Events
Programming note: Include all subjects 
meeting protocol defined liver stopping 
criteria even if liver pages were not 
completed by the site.
SAC
All Laboratory
45.
Safety
LB5
Listing of Haematology Data for Subjects with Any Value of 
Potential Clinical Importance
SAC 
46.
Safety
LB5
Listing of Clinical Chemistry Data for Subjects with Any Value of 
Potential Clinical Importance
SAC
47.
Safety
LB14
Listing of Laboratory Data with Character Results
SAC
48.
Safety
UR2A
Listing of Urinalysis Data for Subjects with Any Value of 
Potential Clinical Importance
SAC
ECG
49.
Safety
EG3
Listing of All ECG Values for Subjects Meeting Protocol Defined 
QTc Stopping Criteria
SAC
Immunogenicity
50.
Safety
SAFE_L1
Listing of Immunogenicity Data for Subjects with at Least One 
Positive Screening Binding Assay
SAC


CONFIDENTIAL
200622
127
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
Pharmacokinetic
51.
PK
-
Listing of Data and Subjects Excluded from Analysis
Provided by CPMS
SAC
52.
PK
-
Final PK Model Listings
Provided by CPMS
SAC
Pharmacodynamic
53.
Safety
PD_L1
Listing of Blood Eosinophils (unit)
SAC
54.
Safety
PD_L2
Listing of Serum Total IL-5 (unit)
SAC
Pharmacokinetic / Pharmacodynamic
55.
PK and PD
-
Listing of Data and Subjects Excluded from Analysis
Provided by CPMS
SAC
56.
PK and PD
-
Final PKPD Model Listings
Provided by CPMS
SAC
[1] For deaths and any cardiovascular events, subject profiles will be produced as per GSK IDSL standard template.


CONFIDENTIAL
200622
128
16.11.
Appendix 11: Example Mock Shells for Data Displays
Available upon request


CONFIDENTIAL
The GlaxoSmithKline group of companies
200622
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for Study 200622: A 
randomised, 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
Effective Date 
:
12-FEB-2019
Description:

The purpose of this RAP is to describe the planned efficacy and safety analyses and 
output to be included in the Clinical Study Report for Protocol 200622.

This RAP defines the content of the headline results and SAC deliverables.
RAP Author(s):
Author
Date
Project Statistician
05-FEB-2019
Clinical Pharmacology, Modelling and Simulation
Copyright 2019 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD
PPD


CONFIDENTIAL
The GlaxoSmithKline group of companies
200622
2
RAP Team Review Confirmations
(Method: E-mail):
Approver
Date
Clinical Pharmacology, Modelling and Simulation
07-FEB-2019
Lead Programmer
06-FEB-2019
06-FEB-2019
Project Physician Lead
07-FEB-2019
Safety Evaluation and Risk Management
Patient Centred Outcomes
06-FEB-2019
Clinical Statistics and Clinical Programming Line Approvals
(Method: Pharma TMF eSignature):
Approver
Date
12-FEB-2019
Senior Statistics Director
11-FEB-2019
Director Programming
PPD
PPD
PPD
PPD
PPD
PPD
PPD


CONFIDENTIAL
200622
3
TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................8
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................8
2.1.
Study Objective(s) and Endpoint(s)...............................................................8
2.2.
Study Design ..............................................................................................10
2.3.
Statistical Hypotheses / Statistical Analyses ...............................................12
2.4.
Changes to the Protocol Defined Statistical Analysis Plan..........................12
3.
PLANNED ANALYSES ..........................................................................................14
3.1.
Interim Analyses .........................................................................................14
3.2.
Final Analyses ............................................................................................14
4.
ANALYSIS POPULATIONS ...................................................................................15
4.1.
Protocol Deviations.....................................................................................16
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................17
5.1.
Study Treatment & Sub-group Display Descriptors.....................................17
5.2.
Baseline Definitions ....................................................................................17
5.3.
Multicentre Studies .....................................................................................17
5.4.
Examination of Covariates, Other Strata and Subgroups............................18
5.4.1.
Covariates and Other Strata ........................................................18
5.4.1.1.
Derivation of Baseline Oral Prednisone 
Equivalent Daily Dose ................................................18
5.4.2.
Examination of Subgroups...........................................................20
5.5.
Multiple Comparisons and Multiplicity .........................................................21
5.6.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................21
6.
STUDY POPULATION ANALYSES .......................................................................22
6.1.
Overview of Planned Study Population Analyses........................................22
7.
EFFICACY ANALYSES..........................................................................................23
7.1.
Primary Efficacy Analyses ..........................................................................23
7.1.1.
Endpoint / Variables.....................................................................23
7.1.2.
Summary Measure ......................................................................23
7.1.3.
Strategy for Intercurrent (Post-Randomization) Events ................23
7.1.3.1.
Primary Estimand .......................................................23
7.1.3.2.
Supplementary Estimand............................................24
7.1.4.
Statistical Analyses / Methods .....................................................24
7.1.4.1.
Statistical Methodology Specification..........................25
7.1.5.
Exploratory Modelling of Primary Endpoint ..................................26
7.2.
Secondary Efficacy Analysis – Time to First HES Flare ..............................27
7.2.1.
Endpoint / Variables.....................................................................27
7.2.2.
Summary Measure ......................................................................27
7.2.3.
Strategy for Intercurrent (Post-Randomization) Events ................27
7.2.4.
Statistical Analyses / Methods .....................................................27
7.2.4.1.
Statistical Methodology Specification..........................27


CONFIDENTIAL
200622
4
7.3.
Secondary Efficacy Analysis – Proportion of Subject Who 
Experience an HES Flare During Week 20 Through Week 32 ....................29
7.3.1.
Endpoint / Variables.....................................................................29
7.3.2.
Summary Measure ......................................................................29
7.3.3.
Strategy for Intercurrent (Post-Randomization) Events ................29
7.3.4.
Statistical Analyses / Methods .....................................................29
7.3.4.1.
Statistical Methodology Specification..........................30
7.4.
Secondary Efficacy Analysis – Rate of HES Flares.....................................31
7.4.1.
Endpoint / Variables.....................................................................31
7.4.2.
Summary Measure ......................................................................31
7.4.3.
Strategy for Intercurrent (Post-Randomization) Events ................31
7.4.4.
Statistical Analyses / Methods .....................................................31
7.4.4.1.
Statistical Methodology Specification..........................31
7.5.
Secondary Efficacy Analysis – Change from Baseline in Fatigue 
Severity BFI Item 3 (Worst Level of Fatigue in Past 24 Hours) at 
Week 32 .....................................................................................................33
7.5.1.
Endpoint / Variables.....................................................................33
7.5.2.
Summary Measure ......................................................................33
7.5.3.
Strategy for Intercurrent (Post-Randomization) Events ................33
7.5.4.
Statistical Analyses / Methods .....................................................33
7.6.
Exploratory Efficacy Analyses.....................................................................35
7.6.1.
Proportion of Subjects Who Have an Elevated Blood 
Eosinophil Level That Meets the Pre-Defined Threshold 
During the 32-Week Study Treatment Period...............................35
7.6.1.1.
Endpoint / Variables ...................................................35
7.6.1.2.
Strategy for Intercurrent (Post-Randomization) 
Events ........................................................................35
7.6.1.3.
Statistical Analyses / Methods ....................................35
7.6.2.
FEV1, FVC and FEV1/FVC ratio ...................................................36
7.6.2.1.
Endpoint / Variables ...................................................36
7.6.2.2.
Strategy for Intercurrent (Post-Randomization) 
Events ........................................................................36
7.6.2.3.
Statistical Analyses / Methods ....................................36
7.6.3.
Echocardiogram...........................................................................37
7.6.4.
Change From Baseline in HES Symptom Severity Based 
on HES Daily Symptoms (HES-DS) at Week 32 ..........................37
7.6.4.1.
Endpoint / Variables ...................................................37
7.6.4.2.
Strategy for Intercurrent (Post-Randomization) 
Events ........................................................................37
7.6.4.3.
Statistical Analyses / Methods ....................................38
7.6.5.
Change from Baseline in BFI Total Score at Week 32 .................38
7.6.5.1.
Endpoint / Variables ...................................................38
7.6.5.2.
Strategy for Intercurrent (Post-Randomization) 
Events ........................................................................39
7.6.5.3.
Statistical Analyses / Methods ....................................39
7.6.6.
Clinician- and Subject-Rated Overall Response to 
Therapy Score (RTS) at Week 32................................................40
7.6.6.1.
Endpoint / Variables ...................................................40
7.6.6.2.
Strategy for Intercurrent (Post-Randomization) 
Events ........................................................................40
7.6.6.3.
Statistical Analyses / Methods ....................................40


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7.6.7.
Change from Baseline in Subject-Rated Symptom 
Severity (SSR) at Week 32 ..........................................................41
7.6.7.1.
Endpoint / Variables ...................................................41
7.6.7.2.
Strategy for Intercurrent (Post-Randomization) 
Events ........................................................................41
7.6.7.3.
Statistical Analyses / Methods ....................................41
7.6.8.
Change from Baseline in Modified Memorial Symptom 
Assessment Scale-Short Form (MSAS-SF) responses at 
Week 32 ......................................................................................42
7.6.8.1.
Endpoint / Variables ...................................................42
7.6.8.2.
Strategy for Intercurrent (Post-Randomization) 
Events ........................................................................42
7.6.8.3.
Statistical Analyses / Methods ....................................42
7.6.9.
Change from Baseline in Physical Function and Sleep 
(Patient Reported Outcome Measurement Information 
System [PROMIS]) at Week 32....................................................43
7.6.9.1.
Endpoint / Variables ...................................................43
7.6.9.2.
Strategy for Intercurrent (Post-Randomization) 
Events ........................................................................44
7.6.9.3.
Statistical Analyses / Methods ....................................44
8.
HEALTH OUTCOMES ANALYSIS .........................................................................45
8.1.
SF-36 v2.....................................................................................................45
8.2.
Healthcare Resource Utilization (HCRU) ....................................................45
8.2.1.
Work Productivity and Activity Impairment ...................................45
9.
POPULATION PHARMACOKINETIC ANALYSES .................................................46
9.1.
Population of Interest..................................................................................46
9.2.
Strategy for Intercurrent (Post-Randomization) Events ...............................46
9.3.
Population Pharmacokinetic Methodology ..................................................46
9.3.1.
Base Model..................................................................................47
9.3.2.
Investigation of Covariates...........................................................47
9.3.3.
Covariate Model Selection Procedures........................................48
9.3.4.
Model Evaluation .........................................................................49
10. PHARMACODYNAMIC ANALYSES.......................................................................50
10.1.
Blood Eosinophils .......................................................................................50
10.1.1.
Population of Interest...................................................................50
10.1.2.
Endpoint / Variables.....................................................................50
10.1.3.
Summary Measure ......................................................................50
10.1.4.
Strategy for Intercurrent (Post-Randomization) Events ................50
10.1.5.
Statistical Analyses / Methods .....................................................50
10.1.5.1.
Statistical Methodology Specification..........................50
10.2.
Serum Total IL-5.........................................................................................51
10.2.1.
Population of Interest...................................................................51
10.2.2.
Endpoint / Variables.....................................................................51
10.2.3.
Summary Measure ......................................................................51
10.2.4.
Strategy for Intercurrent (Post-Randomization) Events ................51
10.2.5.
Statistical Analyses / Methods .....................................................51
10.2.5.1.
Statistical Methodology Specification..........................52
11. SAFETY ANALYSES .............................................................................................53


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11.1.
Adverse Events Analyses ...........................................................................53
11.1.1.
Adverse Events of Special Interest ..............................................53
11.2.
Clinical Laboratory Analyses.......................................................................53
11.3.
Other Safety Analyses ................................................................................54
12. IMMUNOGENICITY ANALYSES............................................................................55
12.1.
Overview of Immunogenicity Analyses........................................................55
13. PHARMACOKINETIC / PHARMACODYNAMIC ANALYSES .................................56
13.1.
Population of Interest..................................................................................56
13.2.
Strategy for Intercurrent (Post-Randomization) Events ...............................56
13.3.
Population Pharmacokinetic/Pharmacodynamic Methodology ....................56
13.3.1.
Base Model..................................................................................57
13.3.2.
Investigation of Covariates...........................................................57
14. REFERENCES.......................................................................................................59
15. APPENDICES........................................................................................................60
15.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................60
15.1.1.
Exclusions from Per Protocol Population .....................................60
15.2.
Appendix 2: Schedule of Activities ..............................................................61
15.2.1.
Protocol Defined Schedule of Events...........................................62
15.3.
Appendix 3: Assessment Windows .............................................................66
15.3.1.
Definition of Weekly Assessment Windows..................................66
15.4.
Appendix 4: Study Phases..........................................................................68
15.4.1.
Treatment Phases for Adverse Events.........................................68
15.4.2.
Study Phases for Concomitant Medication...................................68
15.5.
Appendix 5: Data Display Standards & Handling Conventions....................69
15.5.1.
Reporting Process .......................................................................69
15.5.2.
Reporting Standards....................................................................69
15.5.3.
Reporting Standards for Pharmacokinetic Data ...........................70
15.6.
Appendix 6: Derived and Transformed Data ...............................................72
15.6.1.
General........................................................................................72
15.6.2.
Change from Baseline Definitions................................................72
15.6.3.
Study Population..........................................................................72
15.6.4.
Efficacy........................................................................................74
15.6.5.
Safety ..........................................................................................76
15.7.
Appendix 7: Reporting Standards for Missing Data.....................................77
15.7.1.
Premature Withdrawals................................................................77
15.7.2.
Handling of Missing Data.............................................................77
15.7.2.1.
Handling of Missing and Partial Dates ........................77
15.8.
Appendix 8: Values of Potential Clinical Importance ...................................79
15.8.1.
Laboratory Values........................................................................79
15.8.2.
Urinalysis.....................................................................................79
15.9.
Appendix 9: Abbreviations & Trade Marks ..................................................80
15.9.1.
Abbreviations...............................................................................80
15.9.2.
Trademarks .................................................................................81
15.10. Appendix 10: List of Data Displays..............................................................82
15.10.1. Data Display Numbering..............................................................82
15.10.2. Mock Example Shell Referencing ................................................82
15.10.3. Deliverables.................................................................................82


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15.10.4. Study Population Tables..............................................................83
15.10.5. Efficacy Tables ............................................................................86
15.10.6. Efficacy Figures ...........................................................................95
15.10.7. Health Outcomes Tables ...........................................................103
15.10.8. Safety Tables.............................................................................104
15.10.9. Safety Figures ...........................................................................111
15.10.10.Pharmacokinetic Tables.............................................................112
15.10.11.Pharmacokinetic Figures ...........................................................113
15.10.12.Pharmacodynamic Tables .........................................................114
15.10.13.Pharmacodynamic Figures ........................................................115
15.10.14.Pharmacokinetic / Pharmacodynamic Tables ............................115
15.10.15.Pharmacokinetic / Pharmacodynamic Figures ...........................116
15.10.16.ICH Listings ...............................................................................117
15.11. Appendix 11: Example Mock Shells for Data Displays ..............................123


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1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol 200622:
Protocol Revision Chronology:
2013N171550_00
29-APR-2016
Original
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

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 Objectives
Secondary Endpoints

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 Objectives
Exploratory Endpoints

To investigate mepolizumab 
compared with placebo with 
respect to additional measures of 
efficacy.

Proportion of subjects who have an elevated blood 
eosinophil level that meets the pre-defined threshold 
during the 32-week study treatment period1

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 score at Week 
322

Clinician- and subject-rated overall response to 
therapy score (RTS) at Week 323

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) 


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Objectives
Endpoints
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

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.

Total IL-54

Blood eosinophil levels
Safety Objectives
Safety Endpoints

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)
1Protocol endpoint was the proportion of subjects who receive blinded active oral corticosteroid (OCS) due to an 
elevated blood eosinophil level that meets the pre-defined threshold (2 x baseline value or baseline value + 2500 
cells/L) during the 32-week study treatment period. See Section 2.4 for rationale for change.
2Protocol endpoint was change from baseline in the BFI total and domain scores at Week 32. See Section 2.4 for 
rationale for change.
3Protocol endpoint was the proportion of subjects with a favourable response as measured by clinician- and subject-
rated overall response to therapy score (RTS) at Week 32. See Section 2.4 for rationale for change.
4Serum free and total IL-5 were planned in the protocol. See Section 2.4 for rationale for change.


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2.2.
Study Design
Overview of Study Design and Key Features
Design 
Features

32-week treatment period, randomised, double-blind, placebo-controlled, 
parallel group, multicentre study of mepolizumab in adolescent and adult 
subjects with severe HES receiving SoC therapy.

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.

Subjects who withdraw from study treatment prematurely should continue in 
the study per protocol (including HES flare-related assessments) until 32 
weeks from randomization.

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 (2 x baseline value or 
baseline value + 2500 cells/L). Provided the subject’s HES therapy has 
not been increased due to a symptom flare, the subject will take the blinded 
active OCS for 2 weeks. A subject who does not reach the pre-defined 
blood eosinophilia threshold with a similar blood draw date will be selected 
to initiate blinded placebo OCS treatment, to maintain study blood 
eosinophil blinding. Approximately 2 weeks after the scheduled clinic visit, 
the blood eosinophil count will be assessed again for the subjects who 


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Overview of Study Design and Key Features
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 until the next scheduled clinic visit if the blood eosinophil 
count is at or above the threshold unless the subject’s HES therapy 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.

An open-label study is also planned (study 205203) for subjects who 
complete study 200622.
Main subject 
entry criteria

Subjects 12 years with HES

At least 2 HES flares within the past 12 months; 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.

Blood eosinophil count 1000 cells/L during screening. Investigators 
were permitted to use local laboratory results to meet this inclusion criteria.
Dosing

300 mg mepolizumab or placebo SC every 4 weeks (8 administrations) 
while continuing their HES therapy.

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.
Treatment 
Assignment

Subjects will be randomised in a 1:1 ratio to receive either mepolizumab or 
placebo in addition to SoC therapy.

An initial sample size of N=80 subjects will be randomised. The proportion 
of subjects that have an HES flare will be monitored, blinded to treatment, 
and the total number of subjects randomised may be increased up to a 
maximum of 120 subjects if the blinded overall flare rate is predicted to be 
<30%. 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 7.1.1. 
In order to maintain the blood eosinophil blinding, HES flares meeting flare 
end point definition ‘b)’ in Section 7.1.1 will not be included in the 
calculation of the blinded overall proportion.

Treatments will be assigned randomly via an interactive response system 
(IRS).

Randomization schedule will be generated using GSK validated 
randomisation software RandAll NG.

Randomization stratified by region.
Time and 
events

See Appendix 2: Schedule of Activities.
Interim 

An external Independent Data Monitoring Committee (IDMC) will 


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Overview of Study Design and Key Features
Analysis
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 centre (SDAC). There 
are no circumstances under which IDMC review of the data would lead to a 
recommendation to stop for efficacy. Therefore, no adjustment to the final 
alpha level for efficacy will be made based on the safety stopping 
guidelines.
2.3.
Statistical Hypotheses / Statistical Analyses
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%).
2.4.
Changes to the Protocol Defined Statistical Analysis Plan

The following changes to the exploratory endpoints were made in this RAP:
Protocol Endpoint
RAP Endpoint
Rationale for Change
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
Proportion of 
subjects who 
have an elevated 
blood eosinophil 
level that meets 
the pre-defined 
threshold during 
the 32-week study 
treatment period
RAP endpoint considered to be more clinically 
meaningful as it includes all subjects with blood 
eosinophil counts meeting the pre-defined threshold 
during the 32-week study treatment period rather than 
including only the subset of these subjects who receive 
blinded active OCS. Subjects did not receive blinded 
active OCS if their physician had already increased 
their HES therapy based on symptoms.
Change from 
baseline in the BFI 
total and domain 
scores at Week 32
Change from 
baseline in the 
BFI total score at 
Week 32.
The BFI is a single construct and therefore domain 
scores are not applicable. 
Proportion of 
subjects with a 
favourable response 
as measured by 
clinician- and subject-
Clinician- and 
subject-rated 
overall response 
to therapy score 
(RTS) at Week 32
Improvement/worsening is measured on a 7-point scale 
from significant worsening to significant improvement. 
The endpoint will be summarised and analysed as a 7-
point ordinal endpoint to avoid loss of information and 
increase the sensitivity of the analysis.


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Protocol Endpoint
RAP Endpoint
Rationale for Change
rated overall 
response to therapy 
score (RTS) at Week 
32
Serum free and total 
IL-5
Total IL-5
Free IL-5 levels are generally very low in serum (<BLQ) 
and are expected to decrease post dosing because 
most of the free IL-5 becomes complexed with 
mepolizumab. Hence only total IL-5 will be measured.

Since some participants were randomised early in error prior to the first dose of 
mepolizumab, the following changes to the secondary endpoint derivations in the 
protocol are planned:
-
Time to first HES flare will be calculated from the date of first dose of study 
treatment and the onset date of the HES flare, rather than the date of 
randomisation and the onset date of the HES flare.
-
The rate of HES flares will be calculated using the date of the first dose of study 
treatment and the Week 32 visit/study withdrawal date, rather than the 
randomisation date and the Week 32 visit/study withdrawal date.
-
For the calculation of the change from baseline in BFI item 3, the mean of the 7
daily assessments of BFI item 3 up to but not including the date of first dose of 
study treatment will be used as the baseline assessment. Since BFI item 3 is 
measured daily after 6pm, the date of dosing will not be included in the 
calculation of the baseline BFI.


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3.
PLANNED ANALYSES
3.1.
Interim Analyses
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 centre (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 emergency unblinding procedures described in Section 6.3 of the protocol, 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.
3.2.
Final Analyses
The final planned primary analyses will be performed after the completion of the 
following sequential steps:
1.
All subjects have completed the study as defined in the protocol.
2.
All required database cleaning activities have been completed and final database 
release (DBR) and database freeze (DBF) has been declared by Data Management.
3.
A review has taken place by the unblinded global study manager to identify any 
subjects with a discrepancy between randomised treatment and actual treatment 
received. This information will be included in the SDTM dataset at DBF. Actual 
treatment arm will be derived within the ADaM datasets based on the treatment 
received for more than 50% of treatment administrations. If a subject received an 
equal number of both treatments then the actual treatment arm will reflect the 
treatment to which they were randomised.
4.
All criteria for unblinding the randomisation codes have been met, and treatment 
allocations have been unblinded via the RandAll NG system, as described in 
SOP_54840.


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4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
Screened 

All participants who were screened for eligibility i.e. 
for whom record exists in the database.

Study Population
(Pre-screen and 
screen failures)
Enrolled

All participants who were successfully screened and 
entered the study.

Note: screening failures (who never passed 
screening even if rescreened) and participants who 
were successfully screened but did not complete any 
visit 2 assessments are excluded.

Study Population
(EudraCT 
required 
displays)
Intent-To-Treat 
(ITT)

All randomised subjects

This population will be based on the treatment to 
which the subject was randomised.

Any subject who receives a treatment 
randomisation number will be considered to 
have been randomised.

Study Population

Efficacy

Listing of 
Planned and 
Actual 
Treatments
Per-Protocol 
(PP)

Comprise 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 will be made prior to breaking the 
blind.

Protocol deviations that would exclude subjects 
from the PP population are defined in Appendix 
1: Protocol Deviation Management and 
Definitions for Per Protocol Population.

Supplementary 
analysis of 
primary endpoint
Safety

All subjects who are randomised and who 
receive at least one dose of study treatment. 
Randomised subjects will be assumed to have 
received study treatment unless definitive 
evidence to the contrary exists.

This population will be based on the treatment 
the subject actually received.

Subjects will be analysed according to treatment 
received for more than 50% of their treatment 
administrations. If a subject received an equal 
number of both treatments then they will be 
assigned to the treatment to which they were 
randomised.

Study Population

Safety
Pharmacokinetic

All subjects in the ITT population who received 

PK


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Population
Definition / Criteria
Analyses Evaluated
at least one dose of study treatment and for 
whom at least one PK sample was obtained, 
analysed and was measurable.
Pharmacodynamic

All subjects in the ITT population who received 
at least one dose of study treatment and who 
also had a baseline PD measurement and at 
least one post-treatment PD measurement.

PD
Refer to Appendix 10: List of Data Displays which details the population used for each display.
4.1.
Protocol Deviations

Protocol deviations will be tracked by the study team throughout the conduct of the 
study in accordance with the Protocol Deviation Management Plan (PDMP).

Data will be reviewed prior to Source Data Lock (SDL) to ensure all important 
deviations and deviations which lead to exclusion from the Per Protocol analysis
population are agreed prior to unblinding. Important deviations will be categorised in 
the SDTM data set. Deviations leading to exclusion from the Per Protocol population 
will be categorised in the ADaM data set.

Important protocol deviations (including deviations related to study 
inclusion/exclusion criteria, conduct of the trial, patient management or patient 
assessment) will be summarised and listed.

A separate summary and listing of all inclusion/exclusion criteria deviations will also 
be provided. This summary will be based on data as recorded on the 
inclusion/exclusion page of the eCRF.

Important protocol deviations which result in exclusion from the Per Protocol 
population will be summarised and listed (see Appendix 1: Protocol Deviation 
Management and Definitions for Per Protocol Population).


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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
RandAll NG 
Data Displays for Reporting 
Code
Description
Description
Order [1]
A
Mepolizumab 300mg SC
Mepolizumab 300mg SC
2
P
Placebo
Placebo
1
NOTES:
1.
Order represents treatments being presented in Tables, Figures and Listings (TFLs), as appropriate.
5.2.
Baseline Definitions

Baseline will be defined for all subjects in the ITT population.

For the BFI item 3 which is collected daily from the screening visit (Visit 1) the mean 
of the 7 daily assessments of BFI item 3 up to but not including the date of first dose 
of study treatment will be used as the baseline assessment.

For blood eosinophils, baseline will be defined as the latest central laboratory result 
prior to the first dose of study treatment. Investigators were permitted to use local 
laboratory results to meet inclusion criteria, however local laboratory results will not 
be used in the derivation of the baseline blood eosinophil value.

For all other endpoints the baseline values for each assessment will be the latest 
available assessment (including unscheduled visits) prior to first dose of study 
treatment. For ECG, if multiple assessments are recorded on the same day, the mean 
of the multiple assessments will be assigned as the baseline value.
5.3.
Multicentre Studies

In this multicentre global study, enrolment will be presented by investigative site and 
country.

The randomisation for this study is stratified by region, defined below, with 
consideration for standard of care medical practice.

USA

Argentina, Mexico and Brazil

Rest of World

The same definition of region will be used for covariate adjustment in the statistical 
analysis.

If there are insufficient subjects in each region for the planned statistical analysis, 
further combining of regions will be considered.


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5.4.
Examination of Covariates, Other Strata and Subgroups
5.4.1.
Covariates and Other Strata

Region and baseline OCS dose, expressed as prednisone equivalent dose, will be 
covariates in all statistical analysis. These covariates will be included as stratification 
variables for the Cochran-Mantel-Haenszel test and Wilcoxon Rank Sum test
according to the table below. For parametric analysis models, region will be included 
as a fixed categorical effect and baseline OCS dose will be included as a fixed 
continuous effect.
Category
Covariates and / or Subgroups
Region
See Section 5.3.

USA

Argentina, Mexico and Brazil

Rest of World
Baseline oral prednisone equivalent 
dose1
See Section 5.4.1.1

0-20mg prednisone or equivalent

>20mg prednisone or equivalent
1For parametric analysis models, baseline OCS dose will be included as a fixed continuous effect.

If the percentage of subjects is small within a region, then the region categories may 
be refined prior to unblinding the trial.

For analyses where a baseline value of the analysis variable is available this will also 
be included in the statistical analysis. These covariates will be included as 
stratification variables for the Cochran-Mantel-Haenszel test and Wilcoxon Rank 
Sum test, and as continuous fixed effects for all parametric analysis models.
5.4.1.1.
Derivation of Baseline Oral Prednisone Equivalent Daily Dose

For each subject, a baseline oral prednisone equivalent daily dose (mg) will be 
derived prior to unblinding the randomisation codes for the study. Baseline oral 
prednisone equivalent dose will be identified from the concomitant medications page 
according to the following criteria:
o
Start date < Date of first dose of study treatment
o
Either “ongoing” or end date Date of first dose of study treatment
o
Route = “PO”

Partial start and end dates will be handled as described in Section 15.7.2.1.

Corticosteroids will be identified from the list of coded concomitant medications for 
the study, by merging with the GSK respiratory medication class (RMC) reference 
data set by component code. This reference data is created by dictionary specialists 
who identify a list of component terms for corticosteroids, which then undergo 
clinical review to ensure the correct classification is assigned.

Subjects not receiving OCS therapy, i.e. subjects receiving cytotoxic and/or 
immunosuppressive HES therapy only at baseline, or subjects not receiving any HES 


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therapy, will be assigned a prednisone equivalent daily dose of 0 mg and will be 
categorised in the 0-20mg prednisone or equivalent group.

The corticosteroid conversion factors in the table below will be used to scale each 
corticosteroid dose to a prednisone equivalent dose.
Medication Name 
Scaling Factor
Betamethasone 
8.33
Budesonide1
0
Cortisone 
0.2
Dexamethasone 
6.67
Deflazacort
0.83
Hydrocortisone 
0.25
Methylprednisone 
1.25
Meprednisone
1.25
Prednisone 
1
Prednisolone 
1
Prednisone acetate
1
Triamcinolone 
1.25
1Budesonide has negligible systemic exposure and will be classed as “Other HES therapy” rather than oral 
corticosteroid therapy.

Where the frequency of the recorded corticosteroid dose is not once daily, the 
following calculations will be used to determine the daily dose.
Medication Frequency 
Daily Dose Equivalent
BID
2 x dose
TID
3 x dose
QID
4 x dose
QOD
dose / 2
2XWK
(2 x dose) / 7
3XWK
(3 x dose) / 7
4XWK
(4 x dose) / 7
5XWK
(5 x dose) / 7


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5.4.2.
Examination of Subgroups

The subgroups in the table below are of interest in this study. A separate exploratory 
analysis of the primary endpoint within each subgroup will be carried out.

Subgroup categories may be further collapsed if there are a small number of subjects 
in a treatment arm within a subgroup leading to model convergence issues.

There is a biological rationale for potentially observing increased efficacy with 
increasing levels of baseline blood eosinophils.  The role of blood eosinophil counts 
at baseline on the effectiveness of mepolizumab with respect to the primary endpoint 
will be further assessed based on a statistical model including baseline (loge) blood 
eosinophil count as a continuous variable and an interaction with treatment term. 
Baseline blood eosinophil count is defined in Section 5.2. The analysis will also be 
adjusted for region and baseline OCS dose, as described in Section 5.4.1. Fractional 
polynomial models for the baseline blood eosinophil count may also be explored in 
order to find the best fitting model for the relationship.

Differential treatment effects are not expected for any of the other subgroups listed 
below and therefore any differences in efficacy for mepolizumab compared to 
placebo observed in categories of these subgroups will be viewed as exploratory.
Subgroup
Categories 
Age

12-<18 years

18-64 years

65 years
Sex

Male

Female
Race

Black or African American

White

Asian

Other
Region

USA

Argentina, Mexico and Brazil

Rest of World
Baseline OCS

0-20mg prednisone or equivalent

>20mg prednisone or equivalent
Baseline blood eosinophils

Quartiles, rounded to 1 decimal place (GI/L); equivalent to 
rounding to the nearest 100 cells/L


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5.5.
Multiple Comparisons and Multiplicity
When strong control of type I error is required for making inferences for the predefined 
secondary endpoints, multiplicity will be controlled using a hierarchical, closed testing 
procedure, according to the following hierarchy of endpoints:
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, statistical significance for an endpoint in 
the predefined hierarchy will be dependent on statistical significance for the previous 
endpoints in the hierarchy. 
P-values for secondary endpoints will be provided both unadjusted and adjusted for 
multiplicity using the hierarchy of endpoints above.
5.6.
Other Considerations for Data Analyses and Data Handling 
Conventions
Other considerations for data analyses and data handling conventions are outlined in the 
appendices:
Section
Component
15.3
Appendix 3: Assessment Windows
15.4
Appendix 4: Study Phases and Treatment Emergent Adverse Events
15.5
Appendix 5: Data Display Standards & Handling Conventions
15.6
Appendix 6: Derived and Transformed Data
15.7
Appendix 7: Reporting Standards for Missing Data
15.8
Appendix 8: Values of Potential Clinical Importance


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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
The study population analyses will be based on the ITT population, unless otherwise 
specified. If the ITT population and the safety populations differ, study population 
analyses will also be produced for the safety population.
Study population analyses including analyses of subject’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications,
exposure and treatment compliance (assessed by number of administrations of study 
treatment) will be based on GSK Core Data Standards. In addition, summaries of baseline 
HES therapy, most bothersome HES symptoms and steroid perception questionnaire will 
be produced.
Details of the planned displays are presented in Appendix 10: List of Data Displays.


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7.
EFFICACY ANALYSES
The target population for the primary estimand is as defined by the study 
inclusion/exclusion criteria and therefore the ITT population will be the primary 
population for all efficacy analyses.
7.1.
Primary Efficacy Analyses
7.1.1.
Endpoint / Variables
The primary endpoint is the proportion of subjects who experience an HES flare during 
the 32-week study treatment period.
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 
- 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.
HES flares meeting definition a) will be captured on the ‘flare details’ page in the eCRF.
An increase in blood eosinophils above the pre-defined threshold level (2 x baseline 
value or baseline value + 2500 cells/L) without any other clinical manifestations during 
the study will lead to administration of blinded active OCS treatment (see Section 2.2). If 
a subject receives a second course of blinded active OCS during the 32-week treatment 
period, the subject will be considered to be experiencing a flare. The container list for the 
blinded OCS treatment (indicating which container numbers contained active OCS and 
which contained placebo OCS) will be used to define HES flares meeting endpoint 
definition b). 
7.1.2.
Summary Measure
The difference between mepolizumab and placebo in the proportion of subjects with HES 
flare during the 32-week study treatment period.
7.1.3.
Strategy for Intercurrent (Post-Randomization) Events
7.1.3.1.
Primary Estimand
The primary treatment effect to be estimated (estimand) will be the ‘treatment policy’ 
effect of initial randomised treatment.  A treatment policy strategy will be used for the 
intercurrent events of a) discontinuation of study medication and b) receipt of alternative
HES medications.


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The study is designed to continue to collect data on HES flares for subjects who 
prematurely discontinue from their randomised study treatment. All data on HES flares 
collected for these subjects will be included in the primary analysis. Subjects who 
withdraw from the study prior to Week 32 (Visit 11) and therefore have missing data on 
HES flares will be included in the primary analysis as treatment failures, i.e. for the
primary comparison, a subject will be classed as not experiencing an HES flare only if 
they have no flares reported and complete Week 32 (Visit 11).
Sensitivity analyses will be performed on the ITT population to examine the potential 
impact of the missing data:

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 classed as experiencing an HES flare in the analysis. 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.

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.
7.1.3.2.
Supplementary Estimand
A supplementary estimand using the ‘while on treatment’ strategy will be assessed for the 
intercurrent event of discontinuation of study medication.
Subjects discontinuing from study treatment prematurely will be included as having a 
HES flare if a flare is recorded with an onset date equal or prior to 28 days after the last 
dose of study treatment, and not having a flare otherwise.
7.1.4.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK data standards and statistical principles.
A summary of the number and percentage of subjects with HES flares will be produced 
by treatment group. The total number of HES flares in each treatment group will also be 
presented. The summary will include all HES flares, as well as a separate breakdown of 
HES flares meeting definition a) and b) (see Section 7.1.1). A plot of the cumulative 
number of HES flares over time in each treatment group will be produced.


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7.1.4.1.
Statistical Methodology Specification
Primary Statistical Analyses
Endpoint

Proportion of subjects who experience an HES flare during the 32-week study treatment 
period.
Model Specification

Cochran-Mantel-Haenszel test stratified by baseline OCS dose (0-≤20mg/day and >20mg/day 
prednisone or equivalent) and region.

Supplemented by a logistic regression analysis adjusting for covariates of baseline OCS dose
(continuous scale), region, and treatment.
Model Checking & Diagnostics

To examine the fit of the logistic regression model, deviance residuals will be calculated and 
plotted.
Model Results Presentation

Number of subjects analysed in each treatment group.

Number of subjects with 1 HES flare or who withdraw from the study prior to Week 32 (Visit 
11).

Number of subjects with 1 HES flare.

Number of subjects with no HES flare who withdraw from the study prior to Week 32 (Visit 
11).

Number of subjects with no HES flare who complete Week 32 (Visit 11).

p-value from Cochran-Mantel-Haenszel test.

Odds ratio and 95% Confidence Interval (CI) from logistic regression model.

p-value from logistic regression model.
Subgroup Analyses

A logistic regression analysis will be fitted separately within each subgroup of interest defined 
in Section 5.4.2.

Odds ratios and 95% confidence intervals from the logistic regression model will be presented. 
Analysis will be descriptive only; no p-values will be presented for the subgroup analyses. If the 
number of subjects in each subgroup category are small, confidence intervals may also be 
omitted.
Sensitivity and Supportive Statistical Analyses

A supplementary estimand using the ‘while on treatment’ strategy for intercurrent events will be 
assessed.

The primary analysis will be repeated using the PP population.

Sensitivity analyses for the primary estimand to assess the impact of missing data will be 
performed using the ITT population 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 classed 
as experiencing 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 


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Primary Statistical Analyses
prior to study withdrawal, and as not having a flare if no flare is recorded prior to study 
withdrawal.

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.
7.1.5.
Exploratory Modelling of Primary Endpoint
The role of baseline blood eosinophil counts on the effectiveness of mepolizumab with 
respect to the proportion of subjects who experience an HES flare during the 32-week 
study treatment period will be investigated. A logistic regression model will be fitted, 
including baseline blood eosinophils fitted on the loge scale as a continuous covariate as 
well as a treatment-by-baseline blood eosinophils interaction term, in order to predict the 
odds ratio for mepolizumab vs placebo for each level of the baseline blood eosinophil 
count. The analysis will also be adjusted for region and baseline OCS dose, as described 
in Section 5.4.1. Fractional polynomial models may also be explored in order to find the 
best fitting model for the relationship.


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7.2.
Secondary Efficacy Analysis – Time to First HES Flare
7.2.1.
Endpoint / Variables
The time to first HES flare will be calculated from the date of first dose of study 
treatment and the onset date of the first HES flare as defined in Section 15.6.4. 
7.2.2.
Summary Measure
The difference between mepolizumab and placebo in the time to first HES flare.
7.2.3.
Strategy for Intercurrent (Post-Randomization) Events
The treatment effect to be estimated (estimand) will be the ‘treatment policy’ effect of 
initial randomised treatment.  A treatment policy strategy will be used for the intercurrent 
events of a) discontinuation of study medication and b) receipt of alternative HES 
medications. If a subject withdraws prematurely from the study prior to experiencing an 
HES flare, the event time will be censored at the time point at which the subject withdrew 
from the study. Sensitivity analyses will be performed to examine the potential impact of 
the missing data.
7.2.4.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK data standards and statistical principles.
Time to first HES flare will be graphically represented using a Kaplan-Meier plot of 
cumulative incidence rates over time for each treatment group.
7.2.4.1.
Statistical Methodology Specification
Endpoint

Time to first HES flare.
Model Specification

Log-rank test stratified by baseline OCS dose (0-≤20mg/day and >20mg/day prednisone or 
equivalent) and region. 

Supplemented by a Cox proportional hazards regression model allowing for covariates of
baseline OCS dose (continuous scale) and region. 
Model Checking & Diagnostics

To examine the fit of the Cox proportional hazards model, martingale and deviance residuals 
will be calculated and plotted.
Model Results Presentation

In each treatment group

Number of subject analysed.

Number of subjects with HES flare.


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
Number of subjects censored at study withdrawal.

Number of subjects censored at study completion.

Stratified Log-Rank test p-value for association between treatment and time to first HES flare.

Hazard ratio and 95% CI from Cox proportional hazards model.

Wald chi-square p-value from Cox proportional hazards model.
Subgroup Analyses

No subgroup analyses will be performed on this endpoint.
Sensitivity and Supportive Analyses

Sensitivity analyses to assess the impact of missing data will be performed using the ITT 
population as follows:

Subjects withdrawing from the study prematurely prior to reporting an HES flare will be 
included with an HES flare on the date of study withdrawal.

Subjects withdrawing from the study prematurely prior to reporting an HES flare, with 
primary reason for treatment withdrawal reported as Adverse Event or Lack of Efficacy will 
be included as an HES flare on the date of study withdrawal. For subjects withdrawing 
from the study prematurely prior to reporting an HES flare, with any other reason for 
discontinuation of study treatment, the event time will be censored at the date of study 
withdrawal.


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7.3.
Secondary Efficacy Analysis – Proportion of Subject Who 
Experience an HES Flare During Week 20 Through Week 32
7.3.1.
Endpoint / Variables
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. 
7.3.2.
Summary Measure
The difference between mepolizumab and placebo in the proportion of subjects with HES 
flare during Week 20 through Week 32.
7.3.3.
Strategy for Intercurrent (Post-Randomization) Events
The treatment effect to be estimated (estimand) will be the ‘treatment policy’ effect of 
initial randomised treatment.  A treatment policy strategy will be used for the intercurrent 
events of a) discontinuation of study medication and b) receipt of alternative HES 
medications. Subjects who withdraw prematurely from the study prior to Week 32 (Visit 
11) and therefore have missing data on HES flares during Week 20 through Week 32 will 
be included in the analysis as treatment failures i.e., that they experience a flare during 
Week 20 through Week 32. Sensitivity analyses will be performed to examine the 
potential impact of the missing data.
7.3.4.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK data standards and statistical principles.
A summary of HES flares during Week 20 through Week 32 will be produced as for the 
primary endpoint (see Section 7.1.4).


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7.3.4.1.
Statistical Methodology Specification
Endpoint

Proportion of subjects who experience an HES flare during Week 20 through Week 32.
Model Specification

Cochran-Mantel-Haenszel test stratified by baseline OCS dose (0-≤20mg/day and >20mg/day 
prednisone or equivalent) and region.

Supplemented by a logistic regression analysis adjusting for covariates of baseline OCS dose 
(continuous scale), region, and treatment.
Model Checking & Diagnostics

To examine the fit of the logistic regression model, deviance residuals will be calculated and 
plotted.
Model Results Presentation

Number of subjects analysed in each treatment group.

Number of subjects with 1 HES flare during Week 20 through Week 32 in each treatment 
group.

Test statistic and p-value for association between treatment and flare from Cochran-Mantel-
Haenszel test.

Odds ratio and 95% CI from logistic regression model.

p-value from logistic regression model.
Subgroup Analyses

No subgroup analyses will be performed on this endpoint.
Sensitivity and Supportive Statistical Analyses

Sensitivity analyses to assess the impact of missing data will be performed using the ITT 
population as follows:

Subjects withdrawing from the study prematurely prior to reporting an HES flare during 
Week 20 through Week 32, with the primary reason for treatment withdrawal reported as 
AE or Lack of Efficacy, will be classed as experiencing an HES flare during Week 20 
through Week 32. Subjects withdrawing from the study prematurely with any other reason 
for treatment withdrawal will be included as having a flare if one is recorded during Week 
20 through Week 32 prior to study withdrawal, and as not having a flare if no flare during 
Week 20 through Week 32 is recorded prior to study withdrawal.

Subjects withdrawing from the study prematurely will be included as having a flare if one is 
recorded during Week 20 through Week 32 prior to study withdrawal, and as not having a 
flare if no flare during Week 20 through Week 32 is recorded prior to study withdrawal.


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7.4.
Secondary Efficacy Analysis – Rate of HES Flares
7.4.1.
Endpoint / Variables
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 the first dose of study treatment
and either the Week 32 visit date if available, or otherwise the study withdrawal date (see 
Section 15.6.4). 
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 onset date of an HES flare must be at least 14 days apart from the resolution date of 
the preceding HES flare. 
For flares meeting endpoint definition b) described in Section 7.1.1, 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.).
See Section 15.6.4 for details of the definition of the onset and resolution date of HES 
flares and full details of the derivation of the rate of HES flares.
7.4.2.
Summary Measure
The difference between mepolizumab and placebo in the rate/year of HES flares.
7.4.3.
Strategy for Intercurrent (Post-Randomization) Events
The treatment effect to be estimated (estimand) will be the ‘treatment policy’ effect of 
initial randomised treatment.  A treatment policy strategy will be used for the intercurrent 
events of a) discontinuation of study medication and b) receipt of alternative HES 
medications. 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 will be performed to examine the potential impact 
of the missing data.
7.4.4.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK data standards and statistical principles.
7.4.4.1.
Statistical Methodology Specification
Endpoint

Rate of HES flares.
Model Specification

Wilcoxon Rank Sum test stratified by baseline OCS dose (0-≤20mg/day and >20mg/day 


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prednisone or equivalent) and region.

Supplemented by an analysis using a negative binomial generalised linear model with a log-
link function, including terms for baseline OCS dose (continuous scale), region, treatment and 
observed time (as an offset variable). The model estimated mean flare rate per year will be 
weighted according to the observed proportion of the categorical covariates in the study data
by inclusion of the OM (obsmargins) option in the LSMEANS statement of the GENMOD 
procedure.
Model Checking & Diagnostics

The fit of the negative binomial generalised linear model will be investigated by calculating and 
plotting standardised deviance residuals.
Model Results Presentation

In each treatment group:

Median rate/year.
o
Median rate/year for HES flares meeting definition a) (see Section 7.1.1).
o
Median rate/year for HES flares meeting definition b) (see Section 7.1.1).

Adjusted mean rate/year from negative binomial model.

p-value for difference between treatments in rate/year from Wilcoxon Rank Sum test.

Rate ratio and 95% CI from negative binomial model.

p-value from negative binomial model.
Subgroup Analyses

No subgroup analyses will be performed on this endpoint.
Sensitivity and Supportive Statistical Analyses

Sensitivity analyses to assess the impact of missing data will be performed using the ITT 
population as follows:

Subjects withdrawing from the study prematurely will have the missing time period imputed 
with the placebo flare rate for the missing time period, regardless of the reason for 
treatment discontinuation.

Subjects withdrawing from the study prematurely with primary reason for treatment 
discontinuation reported as AE or Lack of Efficacy, will have the missing time period 
imputed with the placebo flare rate for the missing time period. Subjects withdrawing from 
the study prematurely with a primary reason for treatment discontinuation other than AE or 
Lack of Efficacy will have HES flare rate calculated using available data up to study 
withdrawal date only.


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7.5.
Secondary Efficacy Analysis – Change from Baseline in 
Fatigue Severity BFI Item 3 (Worst Level of Fatigue in Past 
24 Hours) at Week 32
7.5.1.
Endpoint / Variables
The BFI has 9 items. The subject rates their fatigue level right now, their usual fatigue 
level over the last 24 hours and their worst level of fatigue over the last 24 hours using an 
11-point rating scale anchored at 0 (no fatigue) and 10 (as bad as you can imagine). The 
subject also rates how, during the past 24 hours, fatigue has influenced each of the 
following on an 11-point rating scale anchored at 0 (does not interfere) and 10 
(completely interferes): general activity, mood, walking ability, normal work, relations 
with other people and enjoyment of life. The subject completes item 3 (worst level of 
fatigue during past 24 hours) of the BFI daily and the full BFI every 7 days at home on 
the eDiary.
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 but not including the date of first dose of 
study treatment as the baseline assessment. If any of the 7 daily assessments of BFI item 
3 are missing for either the Week 32 time point or the baseline time point, the mean of 
the available daily assessments over the 7-day period will be used to calculate the change 
from baseline.
7.5.2.
Summary Measure
The difference between mepolizumab and placebo in the change from baseline BFI item 
3 at Week 32.
7.5.3.
Strategy for Intercurrent (Post-Randomization) Events
The treatment effect to be estimated (estimand) will be the ‘treatment policy’ effect of 
initial randomised treatment.  A treatment policy strategy will be used for the intercurrent 
events of a) discontinuation of study medication and b) receipt of alternative HES 
medications. Subjects with missing change from baseline BFI item 3 at Week 32 will be 
included in the analysis with the largest (i.e. worst) value observed for any subject.
Sensitivity analyses to assess the impact of missing data will be performed.
7.5.4.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK data standards and statistical principles.
Summary statistics for BFI item 3 at each week of treatment will be presented, including 
change from baseline values. Assessment windows for each week are defined in Section 
15.3.1.


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The clinical relevance of changes in BFI item 3 at Week 32 will be assessed using a 
cumulative distribution plot showing the percentage of subjects in each treatment group 
with a reduction in BFI item 3 greater than equal to each value in the observed range; this 
will allow assessment of the treatment difference against a range of clinically important 
differences.
Endpoint

Change from baseline in fatigue severity (BFI item 3) at Week 32.
Model Specification

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), baseline OCS dose (0-≤20mg/day and 
>20mg/day prednisone or equivalent) and region.
Model Checking & Diagnostics

Not applicable.
Model Results Presentation

Number analysed in each treatment group.

Median change from baseline BFI item 3 at Week 32 in each treatment group.

p-value for difference between treatments from Wilcoxon Rank Sum test.
Subgroup Analyses

No subgroup analyses will be performed on this endpoint.
Sensitivity and Supportive Statistical Analyses

Repeated measures analysis including assessments at Week 4, 8, 12, 16, 20, 24, 28 and 32. 
In this analysis missing data will be assumed to be missing at random and will not be imputed 
with the largest i.e. worst value. A mixed effects model will be fitted with the following 
specification:

Time point, treatment and region included as fixed categorical effects.

Baseline BFI and baseline OCS dose included as continuous fixed covariates. 

Interaction terms for baseline-by-timepoint and treatment-by-time point interaction.

The Kenward and Roger method (DDFM = KR) for approximating the denominator 
degrees of freedom to correct for bias in the estimated variance-covariance matrix.

REPEATED statement with TYPE=UN to specify an unstructured covariance structure for 
the R matrix.

The OBSMARGIN option on the LSMEANS statement in order to compute the adjusted 
geometric means with weights proportional to the input data set.


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7.6.
Exploratory Efficacy Analyses
Details of the planned displays for the exploratory endpoints are provided in Appendix 
10: List of Data Displays and will be based on GSK data standards and statistical 
principles.
7.6.1.
Proportion of Subjects Who Have an Elevated Blood Eosinophil 
Level That Meets the Pre-Defined Threshold During the 32-Week 
Study Treatment Period.
7.6.1.1.
Endpoint / Variables
Subjects who have an elevated blood eosinophil level (2 x baseline value or baseline 
value + 2500 cells/L) during the 32-week study treatment period will be identified from 
the central laboratory haematology results. Samples taken from the date of first dose of 
study medication up until the date of Visit 11 (Week 32) will be considered in the 
derivation. Baseline will be defined as in Section 5.2.
7.6.1.2.
Strategy for Intercurrent (Post-Randomization) Events
The treatment effect to be estimated (estimand) will be the ‘treatment policy’ effect of 
initial randomised treatment.  A treatment policy strategy will be used for the intercurrent 
events of a) discontinuation of study medication and b) receipt of alternative HES 
medications. Subjects withdrawing from the study prematurely leading to missing blood 
assessments for blood eosinophil count will be included in the analysis as having an 
elevated blood eosinophil level that meets the pre-defined threshold.
7.6.1.3.
Statistical Analyses / Methods
Endpoint

Proportion of subjects who have an elevated blood eosinophil level during the 32-week study 
treatment period.
Model Specification

Cochran-Mantel-Haenszel test stratified by baseline OCS dose (0-≤20mg/day and >20mg/day 
prednisone or equivalent) and region.

A supplementary analysis using a logistic regression analysis adjusting for covariates of 
baseline OCS dose (continuous scale), region, and treatment will also be performed.
Model Results Presentation

Number of subjects analysed in each treatment group.

Number of subjects who have an elevated blood eosinophil level during the 32-week study 
treatment period.

Test statistic and p-value for association between treatment and endpoint from Cochran-
Mantel-Haenszel test.

Odds ratio and 95% CI from logistic regression model.

p-value from logistic regression model.


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Subgroup Analyses

No subgroup analyses will be performed on this endpoint.
Sensitivity and Supportive Statistical Analyses

No sensitivity/supportive analyses will be performed on this endpoint.
7.6.2.
FEV1, FVC and FEV1/FVC ratio
7.6.2.1.
Endpoint / Variables

Change from baseline FEV1 at each visit.

Change from baseline FVC at each visit.

FEV1/FVC at each visit.
7.6.2.2.
Strategy for Intercurrent (Post-Randomization) Events
The treatment effect to be estimated (estimand) will be the ‘treatment policy’ effect of 
initial randomised treatment.  A treatment policy strategy will be used for the intercurrent 
events of a) discontinuation of study medication and b) receipt of alternative HES 
medications. Subjects with missing data will be assumed to be missing at random in the 
analysis.
7.6.2.3.
Statistical Analyses / Methods
Summary statistics for FEV1, FVC and FEV1/FVC at each visit will presented by 
treatment, including change from baseline values. A separate summary and analysis 
excluding any data from timepoints where the subject did not withhold short-acting 
bronchodilators for 6 hours or long-acting bronchodilators for 12 hours will be produced.
No statistical analysis will be performed on FEV1/FVC.
Endpoint

Change from baseline in FEV1.

Change from baseline in FVC.
Model Specification

Repeated measures with missing data assumed to be missing at random. A mixed effects 
model will be fitted with the following specification: 

Visit, treatment and region included as fixed categorical effects.

Baseline FEV1 (or FVC as appropriate) and baseline OCS dose included as continuous 
fixed covariates. 

Interaction terms for baseline-by-visit and treatment-by-visit.

The Kenward and Roger method (DDFM = KR) for approximating the denominator 
degrees of freedom to correct for bias in the estimated variance-covariance matrix.

REPEATED statement with TYPE=UN to specify an unstructured covariance structure for 
the R matrix.


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
The OBSMARGIN option on the LSMEANS statement in order to compute the adjusted 
geometric means with weights proportional to the input data set.
Model Results Presentation

Number analysed in each treatment group.

LS Mean (SE) and LS Mean Change from baseline (SE) in each treatment group.

Mean difference, 95% CI and p-value for mepolizumab vs placebo.
Subgroup Analyses

No subgroup analyses will be performed on this endpoint.
Sensitivity and Supportive Statistical Analyses

The analysis will be repeated excluding any data from timepoints where the subject did not 
withhold short-acting bronchodilators for 6 hours or long-acting bronchodilators for 12 hours.
7.6.3.
Echocardiogram
Echocardiogram/MUGA scans at Screening and Week 32 will be summarised by 
treatment for the ITT population. No statistical analysis of this endpoint will be 
performed.
7.6.4.
Change From Baseline in HES Symptom Severity Based on HES 
Daily Symptoms (HES-DS) at Week 32
7.6.4.1.
Endpoint / Variables
For each of the 6 symptom domains (muscle/joint pain, chills or sweats, abdominal pain 
or bloating, breathing symptoms, nasal or sinus symptoms and skin symptoms), the 
change from baseline symptom score at Week 32 will be defined using the mean of the 7 
daily symptom scores up to and including the date of the Week 32 visit as the Week 32 
assessment, and the mean of the 7 daily symptom scores up to but not including the date 
of first dose of study treatment as the baseline assessment. For each symptom domain, if 
any of the 7 daily symptom scores are missing for either the Week 32 time point or the 
baseline time point, the mean of the available daily symptom scores for the relevant 
symptom domain over the 7-day period will be used to calculate the change from 
baseline.
The change from baseline most bothersome symptom score at Week 32 will be derived 
using the mean domain scores at Week 32 and baseline for the up to 3 symptom domains 
identified by the subject as most bothersome at Week 0 (Visit 2).
7.6.4.2.
Strategy for Intercurrent (Post-Randomization) Events
The treatment effect to be estimated (estimand) will be the ‘treatment policy’ effect of 
initial randomised treatment.  A treatment policy strategy will be used for the intercurrent 
events of a) discontinuation of study medication and b) receipt of alternative HES 
medications. Subjects with missing change from baseline symptom score or missing most 
bothersome symptom score at Week 32 will be included in the analysis with the largest 
(i.e. worst) value observed for any subject.


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7.6.4.3.
Statistical Analyses / Methods
Summary statistics for the most bothersome symptom score and the symptom score for
each symptom domain at each week of treatment will be presented, including change 
from baseline values. Assessment windows for each week are defined in Section 15.3.1.
Endpoint

Change from baseline in most bothersome HES symptom severity score (HES-DS) at 
Week 32.

Change from baseline in HES symptom severity score (HES-DS) for each symptom at Week 
32.
Model Specification

Wilcoxon Rank Sum test stratified by median baseline symptom severity (baseline symptom 
severity≤median and baseline symptom severity>median), baseline OCS dose (0-≤20mg/day 
and >20mg/day prednisone or equivalent) and region.
Model Results Presentation

Number analysed in each treatment group.

Median change from baseline at Week 32 in each treatment group.

p-value for difference between treatments from Wilcoxon Rank Sum test.
Subgroup Analyses

No subgroup analyses will be performed on this endpoint.
Sensitivity and Supportive Statistical Analyses

Repeated measures analysis including assessments at Week 4, 8, 12, 16, 20, 24, 28 and 32.
In this analysis missing data will be assumed to be missing at random and will not be imputed 
with the largest i.e. worst value. A mixed effects model will be fitted with the following 
specification: 

Time point, treatment and region included as fixed categorical effects.

Baseline symptom severity and baseline OCS included as continuous fixed covariates. 

Interaction terms for baseline-by-timepoint and treatment-by-time point interaction.

The Kenward and Roger method (DDFM = KR) for approximating the denominator 
degrees of freedom to correct for bias in the estimated variance-covariance matrix.

REPEATED statement with TYPE=UN to specify an unstructured covariance structure for 
the R matrix.

The OBSMARGIN option on the LSMEANS statement in order to compute the adjusted 
geometric means with weights proportional to the input data set.
7.6.5.
Change from Baseline in BFI Total Score at Week 32
7.6.5.1.
Endpoint / Variables
The full BFI is completed every 7 days at home on the eDiary. The BFI total score will 
be calculated as the mean of the 9 item scores recorded for the weekly assessment, as 
long as at least 5 of the 9 item scores are complete. The change from baseline in BFI total 


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score at Week 32 will be calculated using the weekly assessment windows for Week 32 
and baseline defined in Section 15.3.1.
7.6.5.2.
Strategy for Intercurrent (Post-Randomization) Events
The treatment effect to be estimated (estimand) will be the ‘treatment policy’ effect of 
initial randomised treatment.  A treatment policy strategy will be used for the intercurrent 
events of a) discontinuation of study medication and b) receipt of alternative HES 
medications. Subjects with missing change from baseline symptom score at Week 32 will 
be included in the analysis with the largest (i.e. worst) value observed for any subject.
7.6.5.3.
Statistical Analyses / Methods
Summary statistics for BFI total score at each week of treatment will be presented, 
including change from baseline values. Assessment windows for each week are defined 
in Section 15.3.1.
Endpoint

Change from baseline in BFI total score at Week 32.
Model Specification

Wilcoxon Rank Sum test stratified by median baseline fatigue (baseline fatigue≤median and 
baseline fatigue>median), baseline OCS dose (0-≤20mg/day and >20mg/day prednisone or 
equivalent) and region.
Model Results Presentation

Number analysed in each treatment group.

Median change from baseline at Week 32 in each treatment group.

p-value for difference between treatments from Wilcoxon Rank Sum test.
Subgroup Analyses

No subgroup analyses will be performed on this endpoint.
Sensitivity and Supportive Statistical Analyses

For the change from baseline BFI total score, a repeated measures analysis including 
assessments at Week 4, 8, 12, 16, 20, 24, 28 and 32. In this analysis missing data will be 
assumed to be missing at random and will not be imputed with the largest i.e. worst value. A 
mixed effects model will be fitted with the following specification: 

Time point, treatment and region included as fixed categorical effects.

Baseline BFI total score and baseline OCS included as continuous fixed covariates. 

Interaction terms for baseline-by-timepoint and treatment-by-time point interaction.

The Kenward and Roger method (DDFM = KR) for approximating the denominator 
degrees of freedom to correct for bias in the estimated variance-covariance matrix.

REPEATED statement with TYPE=UN to specify an unstructured covariance structure for 
the R matrix.

The OBSMARGIN option on the LSMEANS statement in order to compute the adjusted 
geometric means with weights proportional to the input data set.


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7.6.6.
Clinician- and Subject-Rated Overall Response to Therapy Score 
(RTS) at Week 32
7.6.6.1.
Endpoint / Variables

Clinician-rated overall response to therapy (significantly improved [1], moderately 
improved [2], mildly improved [3], no change [4], mildly worse [5], moderately 
worse [6] and significantly worse [7]) at Week 32.

Subject-rated overall response to therapy (significantly improved [1], moderately 
improved [2], mildly improved [3], no change [4], mildly worse [5], moderately 
worse [6] and significantly worse [7]) at Week 32.
7.6.6.2.
Strategy for Intercurrent (Post-Randomization) Events
The treatment effect to be estimated (estimand) will be the ‘treatment policy’ effect of 
initial randomised treatment.  A treatment policy strategy will be used for the intercurrent 
events of a) discontinuation of study medication and b) receipt of alternative HES 
medications. Subjects with missing response at Week 32 will be included in the analysis 
with the largest (i.e. worst) value observed for any subject.
7.6.6.3.
Statistical Analyses / Methods
Summary statistics for clinician- and subject- rated overall response to therapy at each 
visit will be presented.
Endpoint

Clinician-rated overall response to therapy at Week 32.

Subject-rated overall response to therapy at Week 32
Model Specification

Wilcoxon Rank Sum test stratified by baseline OCS dose (0-≤20mg/day and >20mg/day 
prednisone or equivalent) and region.

Supplemented by an ordinal logistic regression (proportional odds) analysis adjusting for 
covariates of baseline OCS dose (continuous scale), region and treatment.
Model Results Presentation

Number analysed in each treatment group.

Median change from baseline at Week 32 in each treatment group.

p-value for difference between treatments from Wilcoxon Rank Sum test.

Odds ratio and 95% CI from ordinal logistic regression model.

p-value from ordinal logistic regression model.
Subgroup Analyses

No subgroup analyses will be performed on this endpoint.
Sensitivity and Supportive Statistical Analyses

Clinician- and subject-rated overall response to therapy will also be analysed at Week 4, 8, 12, 
16, 20, 24 and 28 in the same way as the Week 32 analysis.


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7.6.7.
Change from Baseline in Subject-Rated Symptom Severity (SSR) 
at Week 32
7.6.7.1.
Endpoint / Variables
At each visit, subjects are asked to rate their symptoms of HES now as none (0), mild (1), 
moderate (2), severe (3) or very severe (4). The change from baseline at Week 32 will be 
calculated from the Week 32 assessment and the Week 0 assessment and expressed in 
terms of number of categories of improvement or worsening of symptoms i.e. 4 point 
improvement (-4), 3 point improvement (-3), 2 point improvement (-2), 1 point 
improvement (-1), no change (0), 1 point worsening (1), 2 point worsening (2), 3 point 
worsening (3) or 4 point worsening (4).
7.6.7.2.
Strategy for Intercurrent (Post-Randomization) Events
The treatment effect to be estimated (estimand) will be the ‘treatment policy’ effect of 
initial randomised treatment.  A treatment policy strategy will be used for the intercurrent 
events of a) discontinuation of study medication and b) receipt of alternative HES 
medications. Subjects with missing SSR score at Week 32 will be included in the analysis 
with the largest (i.e. worst) value observed for any subject.
7.6.7.3.
Statistical Analyses / Methods
Summary statistics for the SSR score at each visit will be presented, as well as the change 
from baseline.
Endpoint

Change from baseline in subject-rated symptom severity (SSR) at Week 32.
Model Specification

Wilcoxon Rank Sum test stratified by baseline OCS dose (0-≤20mg/day and >20mg/day 
prednisone or equivalent) and region.

Supplemented by an ordinal logistic regression (proportional odds) analysis adjusting for 
covariates of baseline OCS dose (continuous scale), region and treatment.
Model Results Presentation

Number analysed in each treatment group.

Median change from baseline at Week 32 in each treatment group.

p-value for difference between treatments from Wilcoxon Rank Sum test.

Odds ratio and 95% CI from ordinal logistic regression model.

p-value from ordinal logistic regression model.
Subgroup Analyses

No subgroup analyses will be performed on this endpoint.
Sensitivity and Supportive Statistical Analyses

No sensitivity analyses will be performed.


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7.6.8.
Change from Baseline in Modified Memorial Symptom 
Assessment Scale-Short Form (MSAS-SF) responses at Week 32
7.6.8.1.
Endpoint / Variables
The MSAS-SF questionnaire records the distress or bother in the last week caused by 
each of 32 symptoms on 5-point scale (not at all [0], a little bit [1], somewhat [2], quite a 
bit [3], very much [4]).

Total MSAS-SF score for each visit will be calculated as the mean of the 32 scores 
recorded for that visit. 

MSAS-SF global distress index (GDI) for each visit will be calculated as the mean of 
the scores for the 4 psychological symptoms (feeling sad, worrying, feeling irritable 
and feeling nervous) and 6 physical symptoms (lack of energy, pain, lack of appetite, 
feeling drowsy, constipation, dry mouth).

MSAS-SF physical symptom subscale score for each visit will be calculated as the 
mean of the scores for 12 physical symptoms (lack of energy, pain, lack of appetite, 
feeling drowsy, constipation, dry mouth, nausea, vomiting, change in taste, weight 
loss, feeling bloated, and dizziness).

MSAS-SF psychological symptom subscale score for each visit will be calculated as 
the mean of the scores for 6 psychologic symptoms (worrying, feeling sad, feeling 
nervous, difficulty sleeping, feeling irritable, and difficulty concentrating).
For each score the change from baseline at Week 32 will be calculated from the 
assessment at Week 0 and Week 32.
7.6.8.2.
Strategy for Intercurrent (Post-Randomization) Events
The treatment effect to be estimated (estimand) will be the ‘treatment policy’ effect of 
initial randomised treatment.  A treatment policy strategy will be used for the intercurrent 
events of a) discontinuation of study medication and b) receipt of alternative HES 
medications. Subjects with missing change from baseline MSAS-SF score at Week 32 
will be included in the analysis with the largest (i.e. worst) value observed for any 
subject.
7.6.8.3.
Statistical Analyses / Methods
Summary statistics for MSAS-SF scores at each visit will be presented, including change 
from baseline values.
Endpoint

Change from baseline in Total Modified Memorial Symptom Assessment Scale-Short Form 
(MSAS-SF) score at Week 32.

Change from baseline in Modified Memorial Symptom Assessment Scale-Short Form (MSAS-
SF) global distress index at Week 32.


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
Change from baseline in Modified Memorial Symptom Assessment Scale-Short Form (MSAS-
SF) physical symptom subscale score at Week 32.

Change from baseline in Modified Memorial Symptom Assessment Scale-Short Form (MSAS-
SF) psychological symptom subscale score at Week 32.
Model Specification

Wilcoxon Rank Sum test stratified by median baseline score (baseline score≤median and 
baseline score>median), baseline OCS dose (0-≤20mg/day and >20mg/day prednisone or 
equivalent) and region.
Model Results Presentation

Number analysed in each treatment group.

Median change from baseline at Week 32 in each treatment group.

p-value for difference between treatments from Wilcoxon Rank Sum test.
Subgroup Analyses

No subgroup analyses will be performed on this endpoint.
Sensitivity and Supportive Statistical Analyses

A repeated measures analysis including assessments at Week 4, 8, 16, 24 and 32. In this 
analysis missing data will be assumed to be missing at random and will not be imputed with the 
largest i.e. worst value. A mixed effects model will be fitted with the following specification: 

Time point, treatment and region included as fixed categorical effects.

Baseline score and baseline OCS dose included as continuous fixed covariates. 

Interaction terms for baseline-by-timepoint and treatment-by-time point interaction.

The Kenward and Roger method (DDFM = KR) for approximating the denominator 
degrees of freedom to correct for bias in the estimated variance-covariance matrix.

REPEATED statement with TYPE=UN to specify an unstructured covariance structure for 
the R matrix.

The OBSMARGIN option on the LSMEANS statement in order to compute the adjusted 
geometric means with weights proportional to the input data set.
7.6.9.
Change from Baseline in Physical Function and Sleep (Patient 
Reported Outcome Measurement Information System [PROMIS]) 
at Week 32
7.6.9.1.
Endpoint / Variables

The PROMIS physical function score for each visit will be calculated as the mean of 
the scores for the 12 physical function items recorded for that visit, as long as at least 
6 of the 12 item scores are complete. The change from baseline at Week 32 will be 
calculated from the Week 32 assessment and the Week 0 assessment.

The PROMIS sleep score for each visit will be calculated as the mean of the scores 
for the 2 sleep items recorded for that visit; if either of the items has a missing score, 
the PROMIS sleep score will be assigned as missing for that visit. The change from 


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baseline at Week 32 will be calculated from the Week 32 assessment and the Week 0 
assessment.
7.6.9.2.
Strategy for Intercurrent (Post-Randomization) Events
The treatment effect to be estimated (estimand) will be the ‘treatment policy’ effect of 
initial randomised treatment.  A treatment policy strategy will be used for the intercurrent 
events of a) discontinuation of study medication and b) receipt of alternative HES 
medications. Subjects with missing change from baseline PROMIS score at Week 32 will 
be included in the analysis with the largest (i.e. worst) value observed for any subject.
7.6.9.3.
Statistical Analyses / Methods
Summary statistics for PROMIS physical function and sleep score at each visit will be 
presented, including change from baseline values.
Endpoint

Change from baseline in PROMIS physical function score at Week 32.

Change from baseline in PROMIS sleep score at Week 32.
Model Specification

Wilcoxon Rank Sum test stratified by median baseline score (baseline score≤median and 
baseline score>median), baseline OCS dose (0-≤20mg/day and >20mg/day prednisone or 
equivalent) and region.
Model Results Presentation

Number analysed in each treatment group.

Median change from baseline at Week 32 in each treatment group.

p-value for difference between treatments from Wilcoxon Rank Sum test.
Subgroup Analyses

No subgroup analyses will be performed on this endpoint.
Sensitivity and Supportive Statistical Analyses

A repeated measures analysis including assessments at Week 4, 8, 16, 24 and 32. In this 
analysis missing data will be assumed to be missing at random and will not be imputed with the 
largest i.e. worst value. A mixed effects model will be fitted with the following specification: 

Time point, treatment and region included as fixed categorical effects.

Baseline score and baseline OCS included as continuous fixed covariates. 

Interaction terms for baseline-by-timepoint and treatment-by-time point interaction.

The Kenward and Roger method (DDFM = KR) for approximating the denominator 
degrees of freedom to correct for bias in the estimated variance-covariance matrix.

REPEATED statement with TYPE=UN to specify an unstructured covariance structure for 
the R matrix.

The OBSMARGIN option on the LSMEANS statement in order to compute the adjusted 
geometric means with weights proportional to the input data set.


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8.
HEALTH OUTCOMES ANALYSIS
8.1.
SF-36 v2

Certified scoring of the SF-36 survey will be performed using OPTUMTM software.

The eight domain scores (bodily pain, general health, mental health, physical 
functioning, role emotional, role physical, social functioning and vitality) as well as 
the physical and mental component summary scores provided by the software will be
converted to SDTM and ADaM data sets by GSK Biostatistics.

Domain and component summary scores will be summarised by visit, including 
change from baseline. 

Summaries will be performed on the ITT population.

No statistical analysis of the SF-36 scores will be performed.
8.2.
Healthcare Resource Utilization (HCRU)

Healthcare resource utilisation associated with a HES flare will be summarised by 
treatment group.

Summaries will be performed on the ITT population.

For each resource type, the number of flares using resource, total amount of resource 
and mean (SD) resource per HES flare will be summarised.

No statistical analysis of this endpoint will be performed.
8.2.1.
Work Productivity and Activity Impairment
The following endpoints will be derived and summarised by treatment group and visit for 
the ITT population. Change from baseline will also be derived and summarised.
Endpoint
Derivation
Percentage work time missed due to health
Q2 / (Q2 + Q4)
Percentage impairment while working due to health
Q5 / 10
Percentage overall work impairment due to health
Q2 / (Q2 + Q4) + [(1- (Q2 / (Q2 + Q4))) x (Q5 / 10)]
Percentage activity impairment due to health
Q6 / 10
No statistical analysis of work productivity and activity impairment will be performed.


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9.
POPULATION PHARMACOKINETIC ANALYSES
Refer to Data Display Standards & Handling Conventions (Section 15.5.3 Reporting 
Standards for Pharmacokinetic Data).
In support of the analysis described below, a specific dataset will be generated. 
Specifications for the generation of the dataset will be provided in a separate document.
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK Data Standards and statistical principles.
9.1.
Population of Interest
The population PK analysis will be performed on the PK population.
9.2.
Strategy for Intercurrent (Post-Randomization) Events
For subjects withdrawing prematurely from study treatment, all available data will be 
included in the analysis.
Based on mepolizumab PK knowledge, concentrations below the limit of quantification 
(BLQ) of the assay is considered unlikely at the 300 mg SC dose investigated, in view of 
the PK sampling scheme selected in the study. Thus, any such results will be treated as 
missing.
Outlier data will be assessed for plausibility; however, the aim is to use all available data 
whenever possible. Any decision to exclude data will be fully documented and specified 
in the clinical study report.
9.3.
Population Pharmacokinetic Methodology
Sparse blood sampling is implemented in this study for determination of mepolizumab 
plasma concentration and subsequent data analysis by population PK methods using the 
most recent population pharmacokinetics model (meta-analysis PK model of data across 
indications described in GlaxoSmithKline Document Number 2015N238436_00). Since 
mepolizumab PK following intravenous administration in HES subjects has already been 
evaluated within the population PK meta-analysis (using PK samples collected in 
previous Phase III study MHE100185), the main objectives of this population PK 
analysis are:

To evaluate mepolizumab pharmacokinetics in subjects with HES following the 
subcutaneous administration of a 300 mg dose every 4 weeks.

To investigate the impact of covariates of interest in the studied HES population 
(such as baseline characteristics, co-medication) on specific parameters (e.g. 
clearance) in order to identify potential sources of inter-individual variability in these 
parameters.

To obtain individual plasma concentration predictions for the timepoints at which PD 
is measured to allow the conduct of population PKPD analyses if deemed appropriate.


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Mepolizumab plasma concentration-time data (samples collected at Weeks 4, 16 and 32; 
at the early Withdrawal and the additional follow-up visits (if applicable)) will be 
analysed by population methods using nonlinear mixed-effects modelling. The analysis 
will be carried out using appropriate software (e.g., NONMEM or SAS).
9.3.1.
Base Model
In consideration of the sparse sampling (3 samples post-start of treatment over 32 weeks: 
Week 4, 16 and 32) and the wealth of mepolizumab PK knowledge, the most recent 
population PK model will be applied directly to the dataset without estimation (e.g. 
maxevals=0 in NONMEM) and predictions generated, against which the model will be 
validated prospectively using appropriate goodness of fit tests. For example, the 
Anderson-Darling and Cramér–von Mises tests are accepted methods of comparing 
Empirical Distribution Functions for model and data (i.e., PK concentrations) to evaluate 
whether independent observations (i.e., observed PK concentrations from the study) are 
adequately described by a model (i.e., most recent population PK model).
The following will be obtained:

A description of the key models tested during the model development will be 
provided and tabulated;

Population mepolizumab plasma PK parameter estimates with 95% CI from the final 
model will be tabulated. Goodness of fit plots for the final model will be presented;

Individual post-hoc PK parameter estimates (such as area under the plasma 
concentration-time curve over the dosing interval [AUC (0-)], CAV [AUC (0-)/]) 
will be summarised descriptively and listed;

Individual post-hoc predicted plasma concentrations will be summarised descriptively 
and listed;

Accumulation ratio estimate will be assessed at Week 16 and 32.
The most recent model consists of a two-compartment pharmacokinetic model with first-
order absorption and elimination. Bodyweight is incorporated into the model using 
allometry with fixed physiological allometric exponents of 0.75 and unity for clearance 
and volumes, respectively. Albumin and creatinine clearance are also included as 
covariates of mepolizumab clearance on physiological grounds, however their effects are 
small and not of clinical relevance. Details of the model can be found in report 
GlaxoSmithKline Document Number 2015N238436_00.
9.3.2.
Investigation of Covariates
The impact of the following prospectively selected covariates on mepolizumab exposure 
(e.g. clearance) will be evaluated using the procedures described in Section 9.3.3.
Category
Covariates
Demographics
Weight (included in the structural model), age, race, 
gender, country
Baseline clinical status
Creatinine clearance, albumin (both already included in the 


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Category
Covariates
current model), serum creatinine, alanine aminotransferase, 
aspartate aminotransferase, alkaline phosphatase, bilirubin, 
total protein
Baseline disease status
Flare history, blood eosinophils and baseline OCS dose
Concomitant medications
If data permits*, e.g. immunosuppressant therapies (e.g. 
methotrexate, azathioprine and mycophenolate mofetil), 
proton pump inhibitors, statins, pain relief (e.g. 
paracetamol, NSAIDs), interferon alfa and antihypertensive 
drugs
Others
Presence/absence of anti-drug antibodies and previous 
biologics use (monoclonal antibodies).
*Attempt to investigate those classes of drug will be made providing data permits.
Covariate selection will be based on physiological plausibility, supported by graphical 
evaluation (PK parameters vs. covariates), and formally by automated linear model fitting 
using proc glmselect in SAS 9.2 (or higher). Individual PK parameters and covariates 
will be log-transformed and standardized before analysis. For forward and backward 
selections, significance levels of 0.1 and 0.05 will be applied respectively, in line with 
criteria used in previous analyses. Co-linearity between covariates will be carefully 
considered.
Identified covariates will then be subjected to traditional covariate analysis (with 
estimation step) and will follow the procedures described in Section 9.3.3. If deemed 
appropriate box plots of systemic clearance versus covariates of interest (e.g., 
immunogenicity status) will be provided.
9.3.3.
Covariate Model Selection Procedures
The covariate model building will follow a step-wise process consisting of a forward and 
backward selection procedure. The likelihood ratio test will be used to evaluate the 
significance of incorporating or removing covariates into the population model based on 
alpha levels set a priori. For forward and backward selections, a significance level of 
0.05 and 0.01 for first order conditional estimation with interaction (FOCE-I) will be 
used, respectively, in line with criteria used in previous analyses.

Step-wise forward addition procedure
Each covariate will be included individually in the ‘base model’ to identify covariates 
resulting in a decrease in the objective function value (OFV) of > 3.84, χ2 < 0.05 for 1 
degree of freedom (df) using FOCE-I. The retained covariates will then be added to the 
base model one by one, starting with the most significant ones until all covariates have 
been tested. Note, if a covariate exponent estimate is numerically small, the covariate will 
not be retained; irrespective of objective function. This will also be supported by 
examination of the goodness of fit. This will constitute the full model.


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
Backward elimination procedure
From the full model, the significance of each covariate will be tested individually by 
removing covariates one by one until all non-significant covariates have been excluded. 
A covariate will be retained if upon removal, the OFV increase by more than 6.64 points 
(χ2< 0.01 for 1 df) using FOCE-I. Note, a covariate may be retained in the model despite 
being found non-statistically significant, if there is a strong rationale for its inclusion. 
This will constitute the final model.
Note: centering of continuous covariates may be considered, as appropriate. The mean or 
median value of the subjects included in the analysis may be used for example.
The impact of the presence of anti-mepolizumab antibodies may not be formally tested as 
a covariate in the model, considering the low incidence observed in the mepolizumab 
programme to date. Instead a graphical approach will be used, if deemed appropriate.
9.3.4.
Model Evaluation
The uncertainty in the parameter estimates will be assessed (e.g. from the standard error 
estimates provided by NONMEM or from the 95% CI estimates provided by other 
appropriate analysis conducted using other software). Furthermore, the model 
performance will be investigated using a set of goodness of fit plots as well as Visual 
Predictive Check (VPC) method. Other evaluation methods may be used (e.g., 
bootstrapping) if deemed appropriate.


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10.
PHARMACODYNAMIC ANALYSES
10.1.
Blood Eosinophils
10.1.1.
Population of Interest
Blood eosinophil analyses will be based on the Pharmacodynamic population.
10.1.2.
Endpoint / Variables
Absolute and ratio to baseline blood eosinophil counts at each visit. For blood 
eosinophils, baseline will be defined as the latest blood eosinophil value measured by the 
central laboratory prior to the first dose of study treatment.
10.1.3.
Summary Measure
The difference between mepolizumab and placebo in the ratio to baseline of blood 
eosinophils.
10.1.4.
Strategy for Intercurrent (Post-Randomization) Events
For subjects withdrawing prematurely from study treatment, only the endpoint values up 
to and including 28 days after the last dose of study treatment will be included in the 
analysis (‘while on treatment’ estimand).
10.1.5.
Statistical Analyses / Methods

Blood eosinophil counts will be loge-transformed prior to analysis. Non-detectable 
blood eosinophil values of 0 GI/L, or results below the limit of quantification will be 
replaced by half of the lowest observed detectable (non-zero) value in the study data 
set, prior to log transformation.

Absolute and ratio to baseline blood eosinophil counts will be summarised by 
treatment group and visit. Only results from the central laboratory will be included in 
the summary, however all data will be listed.

Full details of data displays to be presented are given in Appendix 10: List of Data 
Displays.
10.1.5.1.
Statistical Methodology Specification
Endpoint

Ratio to baseline blood eosinophil count
Model Specification

A mixed effects repeated measures model will be fitted to the loge transformed blood 
eosinophil data with the following specification: 

Visit, treatment and region included as fixed categorical effects.


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
Baseline blood eosinophil count (loge scale) and baseline OCS dose included as 
continuous fixed covariates. 

Interaction terms for baseline (screening) blood eosinophil count-by-visit and treatment-by-
visit.

The Kenward and Roger method (DDFM = KR) for approximating the denominator 
degrees of freedom to correct for bias in the estimated variance-covariance matrix.

REPEATED statement with TYPE=UN to specify an unstructured covariance structure for 
the R matrix.

The OBSMARGIN option on the LSMEANS statement in order to compute the adjusted 
geometric means with weights proportional to the input data set.
Model Results Presentation

Number analysed in each treatment group.

LS Mean (SE) and LS Mean ratio to screening (SE) in each treatment group.

Mean treatment ratio, 95% CI and p-value for mepolizumab vs placebo.
Subgroup Analyses

No subgroup analyses will be performed on this endpoint.
Sensitivity and Supportive Statistical Analyses

The MMRM model specified above will also be fitted to the log transformed absolute blood 
eosinophil counts and adjusted mean absolute blood eosinophil counts and 95% CI from this 
model will be plotted.
10.2.
Serum Total IL-5
10.2.1.
Population of Interest
Total IL-5 analyses will be based on the Pharmacodynamic population.
10.2.2.
Endpoint / Variables
Absolute and ratio to baseline total IL-5 at Week 32
10.2.3.
Summary Measure
The difference between mepolizumab and placebo in the ratio to baseline of serum total 
IL-5 at Week 32.
10.2.4.
Strategy for Intercurrent (Post-Randomization) Events
For subjects withdrawing prematurely from study treatment, only the endpoint values up 
to and including 28 days after the last dose of study treatment will be included in the 
analysis (‘while on treatment’ estimand).
10.2.5.
Statistical Analyses / Methods

Total IL-5 values will be loge-transformed prior to analysis. Values below the limit of 
quantification will be replaced by half the limit of quantification, prior to log 


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transformation. Summary statistics will include the number and percentage of BLQ 
values.

Absolute and ratio to baseline total IL-5 values will be summarised by treatment 
group and visit (Baseline and Week 32).

Full details of data displays to be presented are given in Appendix 10: List of Data 
Displays.
10.2.5.1.
Statistical Methodology Specification
Endpoint

Ratio to baseline total IL-5 at Week 32
Model Specification

Wilcoxon Rank Sum test stratified by baseline OCS dose (0-≤20mg/day and >20mg/day 
prednisone or equivalent) and region.
Model Results Presentation

Number analysed in each treatment group.

Median change from baseline at Week 32 in each treatment group.

p-value for difference between treatments from Wilcoxon Rank Sum test.
Subgroup Analyses

No subgroup analyses will be performed on this endpoint.
Sensitivity and Supportive Statistical Analyses

No sensitivity analyses will be performed.


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11.
SAFETY ANALYSES
The safety analyses will be based on the Safety population, unless otherwise specified.
11.1.
Adverse Events Analyses
Adverse events analyses including the analysis of adverse events (AEs), Serious (SAEs)
and other significant AEs will be based on GSK Core Data Standards. Common AEs will 
be defined as AEs with frequency ≥3% (prior to rounding to nearest percent) in either 
treatment group.
The details of the planned displays are provided in Appendix 10: List of Data Displays.
11.1.1.
Adverse Events of Special Interest
Adverse events of special interest (AESIs) reported by the investigator as systemic 
reactions (further categorised by the investigator as either allergic [type I 
hypersensitivity] or other systemic reactions and assessed against Sampson criteria for 
anaphylaxis) are collected via targeted eCRF within the study. Local injection site 
reactions are also collected via targeted eCRF within the study.
AESIs of opportunistic infections, malignancies, serious cardiac, vascular and 
thromboembolic (CVT) events and serious ischemic events will be identified from a list 
of relevant preferred terms maintained within a project level reference dataset created 
based on the MedDRA dictionary available at the time of DBF for this study. Further 
details of how relevant preferred terms are identified are given in the Program Safety 
Analysis Plan (PSAP).
Separate summary tables showing the number and percent of subjects with each type of 
AESI, broken down by preferred term will be created.
For each type of AESI a profile summary table will be produced containing information 
including, but not limited to, the number of occurrences of the event, event 
characteristics, time to onset, intensity, outcome and action taken.
The relative risk of each AESI between mepolizumab and placebo with 95% confidence 
intervals will also be presented.
Separate listings of AESIs identified by the investigator as anaphylaxis, allergic (type I 
hypersensitivity), other systemic reactions and local injection site reactions will be 
produced, as well as listings of opportunistic infections, malignancies, serious CVT 
events and serious ischemic events.
11.2.
Clinical Laboratory Analyses
Laboratory evaluations including the analyses of Chemistry laboratory tests, 
Haematology laboratory tests and liver function tests will be based on GSK Core Data 
Standards. The details of the planned displays are provided in Appendix 10: List of Data 
Displays.


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A scatter plot of maximum ALT vs baseline ALT, and maximum ALT vs total bilirubin 
will be produced. In addition, if any liver stopping or liver monitoring events occur 
during the study, summaries of liver monitoring/stopping event reporting and 
hepatobiliary laboratory abnormalities will be produced.
11.3.
Other Safety Analyses
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified. The details of the 
planned displays are presented in Appendix 10: List of Data Displays.


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12.
IMMUNOGENICITY ANALYSES
12.1.
Overview of Immunogenicity Analyses
For the immunogenicity assessment, two types of anti-drug antibody (ADA) assays will 
be performed, a binding anti-drug antibody assay and a neutralizing antibody assay.
For the binding assay, there will be a three tiered analysis: screening, confirmation and 
titration. The screening assay produces a result of positive or negative relative to a 
screening cut point. Positive samples continue with the confirmation assay, which also 
produces a result of positive or negative relative to a confirmation cut point. For positive 
confirmation samples, a titre value will also be obtained to quantify the degree of binding 
in a titration assay and the sample will be tested with the neutralizing assay, which also 
reports results as positive or negative.
The binding ADA results at each visit will be categorised as negative, transient positive 
(defined as a single confirmatory positive immunogenic response that does not occur at 
the final study assessment) or persistent positive (defined as a confirmatory positive 
immunogenic response for at least 2 consecutive assessments excluding the screening 
visit, or a single result at the final study assessment). In addition, the highest post-
baseline binding ADA confirmatory result obtained for a subject will be summarised. 
Subjects with both positive and negative results will be identified in the positive category. 
Summary statistics for the titre result by visit will also be presented.
A summary of adverse events by highest post-baseline binding ADA confirmatory result 
(as defined above) will be produced.
A summary of treatment emergent positive confirmatory binding ADA results in the 
subset of subjects who did not have a positive confirmatory binding ADA result prior to 
the dosing of study treatment will also be presented. 
Neutralizing antibody assay results will be summarised by visit. In addition, the highest 
post-baseline neutralising antibody assay result during the treatment period of the study 
will be summarised, with subjects with both positive and negative results identified in the 
positive category.
Immunogenicity data will be listed for subjects with at least one positive screening 
binding assay.


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13.
PHARMACOKINETIC / PHARMACODYNAMIC
ANALYSES
In support of the analysis described below, a specific dataset will be generated.
Specifications for the generation of the dataset will be provided in a separate document.
The details of the planned displays are presented in Appendix 10: List of Data Displays.
13.1.
Population of Interest
The population PKPD analysis will be performed on the PK and PD populations.
13.2.
Strategy for Intercurrent (Post-Randomization) Events
For subjects withdrawing prematurely from study treatment, all available data will be 
included in the analysis.
Zero values for the baseline blood eosinophil count as well as for blood eosinophil count 
will be replaced by half of the lowest observed detectable (non-zero) value in the study 
data set (consistent with approaches used in other analyses).
Outlier data will be assessed for plausibility, however the aim is to use all available data 
whenever possible. Any decision to exclude data will be fully documented and specified 
in the clinical study report.
13.3.
Population Pharmacokinetic/Pharmacodynamic 
Methodology
If deemed appropriate, a population pharmacokinetic/pharmacodynamic analysis will be 
conducted.
Blood eosinophil count were measured during the course of the study over the 32 weeks 
treatment period and will be analysed by population methods using the most recent 
population PKPD model (meta-analysis PKPD model of data across indications described 
in GlaxoSmithKline Document Number 2015N238436_00).
The objectives of the population PKPD analysis are:

To evaluate mepolizumab pharmacodynamics in subjects with HES following 
subcutaneous administration of a 300 mg dose every 4 weeks;

To investigate the impact of covariates of interest in the studied HES population 
(such as baseline characteristics, co-medication) on specific parameters (e.g. 
maximum blood eosinophil reduction) in order to identify potential sources of 
inter-individual variability in these parameters.
Mepolizumab blood eosinophil count-time data (samples collected at screening, Week 2, 
Week 4 and every 4 weeks for the remainder of the 32-week treatment period) will be 
analysed by population methods using nonlinear mixed-effects modelling. The analysis 
will be carried out using appropriate software (e.g., NONMEM or SAS).


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13.3.1.
Base Model
The most recent population PKPD model will be applied directly to the dataset without 
estimation (e.g. maxevals=0 in NONMEM) and predictions generated against which the 
model will be validated prospectively using appropriate goodness of fit tests as described 
in Section 9.3.1 (using the observed data from the study).
The following will be obtained:

A description of the key models tested during the model development will be 
provided and tabulated.

The population PD parameter estimates with 95% CI from the final model will be 
tabulated. Goodness of fit plots for the final model will be presented.
The most recent population PKPD model consists of an indirect response model 
parameterised in term of baseline blood eosinophil count (KRO), rate of elimination of 
eosinophils in the blood (Kout), concentration resulting in 50% of maximum drug effect 
(IC50) and maximum effect (Imax). Observed baseline blood eosinophil count is included 
as covariates of both predicted baseline and mepolizumab inhibitory response; and 
disease for predicted baseline blood eosinophil count. Details of the model can be found 
in GlaxoSmithKline Document Number 2015N238436_00 and GlaxoSmithKline 
Document Number 2015N255079_00 (extension of the former report).
13.3.2.
Investigation of Covariates
The impact of the following prospectively selected plausible covariates on relevant 
parameters (i.e., baseline blood eosinophil count and maximum effect) will be evaluated.
Category
Covariates
Demographics
Age, race, gender
Baseline disease status
Flare history, blood eosinophils (already included in the 
current model)
Others
Baseline OCS absolute dose, presence/absence of anti-drug 
antibodies*, immunosuppressant therapies* (e.g. 
methotrexate, azathioprine and mycophenolate mofetil), 
interferon alfa*
*Attempt to investigate those covariates will be made providing data permits.
Covariate selection will be based on physiological plausibility, supported by graphical 
evaluation (PD parameters vs. covariates), and formally by automated linear model fitting 
using proc glmselect in SAS 9.2 (or higher). Individual PD parameters and covariates 
will be log-transformed and standardized before analysis. For forward and backward 
selections, significance levels of 0.1 and 0.05 will be applied respectively, in line with 
criteria used in previous analyses. Co-linearity between covariates will be carefully 
considered.


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Identified covariates will then be subjected to traditional covariate analysis (with 
estimation step) and will follow the same procedures as described in Section 9.3.3 for the 
population PK model.
Model evaluation will be as described in Section 9.3.4 for the population PK model.


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14.
REFERENCES
GlaxoSmithKline Document Number 2013N171550_00 Study ID 200622. A randomised, 
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. Report Date 29-APR-2016. 
GlaxoSmithKline Document Number 2015N238436_00 Study ID N/A. A population PK 
and PKPD meta-analysis of combined intravenous and subcutaneous mepolizumab data. 
Report Date 27-MAY-2015. 
GlaxoSmithKline Document Number 2015N255079_00 Study ID N/A. Supplementary 
outputs from a population PK and PKPD meta-analysis of combined intravenous and 
subcutaneous mepolizumab data. Report Date 04-OCT-2015. 


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15.
APPENDICES
15.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population
Subjects with important protocol deviations considered to potentially have an effect on 
the primary efficacy analysis will be excluded from the Per Protocol (PP) population. The 
decision to exclude a subject from the PP population or exclude part of their data from 
the PP population will be made prior to breaking the blind.
15.1.1.
Exclusions from Per Protocol Population
A subject meeting any of the following criteria will be excluded from the Per Protocol 
population:
Number
Exclusion Description
01
Inclusion #3 – Insufficient evidence that subject has been diagnosed with HES for at least 6 
months at randomization (Visit 2).
02
Inclusion #4 – Subject did not have a history of two or more flares within the past 12 
months prior to screening (Visit 1), with at least one HES flare not related to a decrease in 
HES therapy during the 4 weeks prior to the flare.
03
Inclusion #5 – Subject did not have a blood eosinophil count 1000 cells/L collected 
during screening (within 4 weeks prior to randomization). Investigators were permitted to 
use local laboratory results to meet this inclusion criteria, therefore if the screening 
central laboratory blood eosinophil count is <1000 cells/L but a local laboratory blood 
eosinophil count 1000 cells/L is available during screening the subject will not be 
considered a protocol deviation or excluded from the Per Protocol population.
04
Inclusion #6 – Subject was not on a stable dose of HES therapy for the 4 weeks prior to 
randomization (Visit 2).
05
Incorrect study treatment administered at any point during the study i.e. subject received 
placebo instead of mepolizumab or vice versa.
06
Subject received a medication or herbal remedy which may alter the course of HES or 
interact with the study treatment with the exception of HES therapy to treat an HES flare.


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15.2.
Appendix 2: Schedule of Activities


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15.2.1.
Protocol Defined Schedule of Events
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 
SSR3
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 
scales3
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 (Protocol Table 4) should be obtained pre-dose. 
9. Refer to protocol 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 randomised. 
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 protocol 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 protocol 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 (protocol 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 (protocol 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. 


CONFIDENTIAL
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15.3.
Appendix 3: Assessment Windows
15.3.1.
Definition of Weekly Assessment Windows
Daily assessments of BFI item 3 and HES daily symptoms as well as weekly assessments 
of the full BFI will be assigned a single weekly analysis time point according to the table 
below.
Analysis 
Timepoint
Analysis Window
Beginning 
Timepoint
Ending Timepoint
Special Rules for Handling
Overlapping Timepoints
Week 32
Week 32 (Visit 11) 
visit date – 6 days
Week 32 (Visit 11) visit date
Week 31
Week 32 (Visit 11) 
visit date – 13 days
Week 32 (Visit 11) visit date 
– 7 days
If assessment falls into Week 
31/Week 30/Week 29 and Week 
28, assign assessment as Week 
28.
If assessment date is less than 
Week 28 (Visit 10) visit date, 
assign a relevant timepoint less 
than Week 28.
Week 30
Week 32 (Visit 11) 
visit date – 20 days 
Week 32 (Visit 11) visit date 
– 14 days
Week 29
Week 32 (Visit 11) 
visit date – 27 days
Week 32 (Visit 11) visit date 
– 21 days
Week 28
Week 28 (Visit 10) 
visit date – 6 days
Week 28 (Visit 10) visit date
Week 27
Week 28 (Visit 10) 
visit date – 13 days
Week 28 (Visit 10) visit date 
– 7 days
If assessment falls into Week 
27/Week 26/Week 25 and Week 
24, assign assessment as Week 
24.
If assessment date is less than 
Week 24 (Visit 9) visit date, assign 
a relevant timepoint less than 
Week 24.
Week 26
Week 28 (Visit 10) 
visit date – 20 days 
Week 28 (Visit 10) visit date 
– 14 days
Week 25
Week 28 (Visit 10) 
visit date – 27 days
Week 28 (Visit 10) visit date 
– 21 days
Week 24
Week 24 (Visit 9) visit 
date – 6 days
Week 24 (Visit 9) visit date
Week 23
Week 24 (Visit 9) visit 
date – 13 days
Week 24 (Visit 9) visit date –
7 days
If assessment falls into Week 
23/Week 22/Week 21 and Week 
20, assign assessment as Week 
20.
If assessment date is less than 
Week 20 (Visit 8) visit date, assign 
a relevant timepoint less than 
Week 20.
Week 22
Week 24 (Visit 9) visit 
date – 20 days 
Week 24 (Visit 9) visit date –
14 days
Week 21
Week 24 (Visit 9) visit 
date – 27 days
Week 24 (Visit 9) visit date –
21 days
Week 20
Week 20 (Visit 8) visit 
date – 6 days
Week 20 (Visit 8) visit date
Week 19
Week 20 (Visit 8) visit 
date – 13 days
Week 20 (Visit 8) visit date –
7 days
If assessment falls into Week 
19/Week 18/Week 17 and Week 
16, assign assessment as Week 
16.
If assessment date is less than 
Week 16 (Visit 7) visit date, assign 
a relevant timepoint less than 
Week 18
Week 20 (Visit 8) visit 
date – 20 days 
Week 20 (Visit 8) visit date –
14 days
Week 17
Week 20 (Visit 8) visit 
date – 27 days
Week 20 (Visit 8) visit date –
21 days


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Analysis 
Timepoint
Analysis Window
Beginning 
Timepoint
Ending Timepoint
Special Rules for Handling
Overlapping Timepoints
Week 16.
Week 16
Week 16 (Visit 7) visit 
date – 6 days
Week 16 (Visit 7) visit date
Week 15
Week 16 (Visit 7) visit 
date – 13 days
Week 16 (Visit 7) visit date –
7 days
If assessment falls into Week 
15/Week 14/Week 13 and Week 
12, assign assessment as Week 
12.
If assessment date is less than 
Week 12 (Visit 6) visit date, assign 
a relevant timepoint less than 
Week 12.
Week 14
Week 16 (Visit 7) visit 
date – 20 days 
Week 16 (Visit 7) visit date –
14 days
Week 13
Week 16 (Visit 7) visit 
date – 27 days
Week 16 (Visit 7) visit date –
21 days
Week 12
Week 12 (Visit 6) visit 
date – 6 days
Week 12 (Visit 6) visit date
Week 11
Week 12 (Visit 6) visit 
date – 13 days
Week 12 (Visit 6) visit date –
7 days
If assessment falls into Week 
11/Week 10/Week 9 and Week 8, 
assign assessment as Week 8.
If assessment date is less than 
Week 8 (Visit 5) visit date, assign 
a relevant timepoint less than 
Week 8.
Week 10
Week 12 (Visit 6) visit 
date – 20 days 
Week 12 (Visit 6) visit date –
14 days
Week 9
Week 12 (Visit 6) visit 
date – 27 days
Week 12 (Visit 6) visit date –
21 days
Week 8
Week 8 (Visit 5) visit 
date – 6 days
Week 8 (Visit 5) visit date
Week 7
Week 8 (Visit 5) visit 
date – 13 days
Week 8 (Visit 5) visit date – 7 
days
If assessment falls into Week 
7/Week 6/Week 5 and Week 4, 
assign assessment as Week 4.
If assessment date is less than 
Week 4 (Visit 4) visit date, assign 
a relevant timepoint less than 
Week 4.
Week 6
Week 8 (Visit 5) visit 
date – 20 days 
Week 8 (Visit 5) visit date –
14 days
Week 5
Week 8 (Visit 5) visit 
date – 27 days
Week 8 (Visit 5) visit date –
21 days
Week 4
Week 4 (Visit 4) visit 
date – 6 days
Week 4 (Visit 4) visit date
Week 3
Week 4 (Visit 4) visit 
date – 13 days
Week 4 (Visit 4) visit date – 7 
days
If assessment falls into Week 
3/Week 2/Week 1 and Baseline 
(Week 0) or Screening, assign 
assessment as Baseline (Week 0)
or Screening.
Week 2
Week 4 (Visit 4) visit 
date – 20 days 
Week 4 (Visit 4) visit date –
14 days
Week 1
Week 4 (Visit 4) visit 
date – 27 days
Week 4 (Visit 4) visit date –
21 days
Baseline 
(Week 0)
Date of first dose of 
study treatment – 7
days
Date of first dose of study 
treatment - 1
Screening
N/A
Date of first dose of study 
treatment – 8 days


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15.4.
Appendix 4: Study Phases
Assessments and events will be classified according to the time of occurrence relative to 
the first dose of study treatment.
15.4.1.
Treatment Phases for Adverse Events
Study Phase
Definition
Pre-Treatment 
AE onset date/time < Date/time of first dose of study treatment
On-Treatment
Date/time of first dose of study treatment AE onset date/time Date of last dose of 
study treatment + 28 days
Post-Treatment
AE onset date > Date of last dose of study treatment + 28 days
NOTES: 

Please refer to Section 15.7.2.1 for handling of missing and partial dates for adverse events.
15.4.2.
Study Phases for Concomitant Medication
Study Phase
Definition
Prior
If medication end date is not missing and is before the date of first dose of 
study treatment
Concomitant
Any medication that is not a prior
NOTES: 

Please refer to Section 15.7.2.1 for handling of missing and partial dates for concomitant medications.


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15.5.
Appendix 5: Data Display Standards & Handling 
Conventions
15.5.1.
Reporting Process
Software

The currently supported versions of SAS software will be used.
Reporting Area
HARP Server
: uk1salx00175
HARP Area
: sb240563/mid200622
Analysis Datasets 

Analysis datasets will be created according to CDISC standards.

For creation of ADaM datasets (ADCM/ADAE), the same version of dictionary datasets will be 
implemented for conversion from SI to SDTM.
Generation of RTF Files

RTF files will be generated for the final reporting effort.
15.5.2.
Reporting Standards
General

All data displays (Tables, Figures & Listings) will use the term “Subject” rather than 
“Participant” which reflects CDISC and GSK Data Display Standards terminology.

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: 
https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx):

4.03 to 4.23: General Principles

5.01 to 5.08: Principles Related to Data Listings

6.01 to 6.11: Principles Related to Summary Tables

7.01 to 7.13: Principles Related to Graphics 

Do not include subject level listings in the main body of the GSK Clinical Study Report. All 
subject level listings should be located in the modular appendices as ICH or non-ICH listings
Formats

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DPs) will be adopted for 
reporting of data based on the raw data collected but may be adjusted to a clinically 
interpretable number of DPs.

For FEV1 and FVC, the mean and median (L) will be reported to 3 decimal places (i.e. to the 
nearest mL), SD to 4 decimal places, minimum and maximum to 2 decimal places.
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses:

Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled 
visit days on the analyses and interpretation of the results will be assessed as appropriate.


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
Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to 
IDSL Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject’s listings. 

Visits outside the protocol defined time-windows (i.e. recorded as protocol deviations) will be 
included in listings, summaries and statistical analyses.
Unscheduled Visits

HES flare data collected at unscheduled visits will be included in the derivation of all flare 
related endpoints for summary and analysis.

For summaries by visit, data recorded at an unscheduled visit will be re-assigned in the ADaM 
data sets to the closest nominal visit at which collection of data was scheduled, unless 
information already exists at that visit. Unscheduled data re-assigned to a scheduled visit will 
be included in analyses, summary tables and figures by scheduled visit. Unscheduled data that 
is not re-assigned to a scheduled visit will not be included in analyses, summary tables or 
figures by scheduled visit. Unscheduled data that is not re-assigned to a scheduled visit will be 
considered in the derivation of baseline and highest/worst case post baseline result for relevant 
summary tables.

Data recorded at unscheduled visits will be included in the assessment of maximum or worst 
case post-baseline for relevant endpoints.

All unscheduled visits will be included in listings.
Early Withdrawal Visits

Data recorded at the early withdrawal visit will be re-assigned in the ADaM data sets to the 
next scheduled visit, unless information already exists at that visit. Early withdrawal data re-
assigned to a scheduled visit will be included in analyses, summary tables and figures by 
scheduled visit. Early withdrawal visit data that is not re-assigned to a scheduled visit will not 
be included in analyses, summary tables or figures by scheduled visit.

Data recorded at early withdrawal visits will be included in the assessment of maximum or 
worst case post-baseline for relevant endpoints.

Data from all early withdrawal visits will be included in listings.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.
15.5.3.
Reporting Standards for Pharmacokinetic Data
Pharmacokinetic Concentration Data
Descriptive 
Summary 
Statistics, 
Graphical Displays 
and Listings
Refer to IDSL PK Display Standards.
Refer to IDSL Statistical Principle 6.06.1.
Note: BLQ concentration values will be imputed as per GUI_51487 for 
descriptive summary statistics only. 
NONMEM/Pop PK 
Pop-PK file (CSV and SAS format) for the POP-PK and POP-PKPD 


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File
analyses performed by the Clinical Pharmacology Modelling and Simulation 
function will be created according to the POP-PKPD Dataset Specification 
document.
Pharmacokinetic Parameter Data
Descriptive 
Summary 
Statistics, 
Graphical Displays 
and Listings
Refer to IDSL PK Display Standards.
Refer to IDSL Statistical Principle 6.06.1.


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15.6.
Appendix 6: Derived and Transformed Data
15.6.1.
General
Multiple Measurements at One Analysis Time Point

If there are two results identified at a single visit the latter of the two measurements will be 
flagged and used in any derivation of summary statistics. All values will be presented on 
listings.

Subjects having both High and Low values for Normal Ranges at any post-baseline visits for 
safety parameters will be counted in both the High and Low categories of “Any visit post-
baseline” row of related summary tables. This will also be applicable to relevant Potential 
Clinical Importance summary tables.
Study Day

Calculated as the number of days from the date of the first dose of study treatment:

Ref Date = Missing              → Study Day = Missing 

Ref Date < First Dose Date → Study Day = Ref Date – First Dose Date

Ref Data ≥ First Dose Date → Study Day = Ref Date – (First Dose Date) + 1    
15.6.2.
Change from Baseline Definitions
Definition
Reporting Details
Change from Baseline
= Post-Dose Visit Value – Baseline
% Change from Baseline
= 100 x [(Post-Dose Visit Value – Baseline) / Baseline]
Ratio to Baseline
= Visit Value / Baseline
NOTES :

Unless otherwise specified, the baseline definitions specified in Section 5.2 will be used for derivations for 
endpoints / parameters.

Unless otherwise stated, if baseline data is missing no derivation will be performed and result will be set to 
missing.
15.6.3.
Study Population
Age

GSK standard IDSL algorithms will be used for calculating age where birth day and month will 
be imputed ‘

Birth date will be presented in listings as ‘YYYY’.

Age will be calculated relative to the date of the screening visit (Visit 1).
Body Mass Index (BMI)
Calculated as Weight (kg) / [Height (m)2]
PPD


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Baseline HES Therapy

Baseline oral corticosteroid use and baseline oral prednisone equivalent daily dose will be 
derived as detailed in Section 5.4.1.1.

Cytotoxic therapy/immunosuppressive therapy and other HES therapy will be identified by 
clinical review of the concomitant medications page according to the following criteria:
o
Medication type = “Hypereosinophilic syndrome” 
o
Start date < Date of first dose of study treatment
o
Either “ongoing” or End date Date of first dose of study treatment

Oral budesonide has negligible systemic exposure and will be counted as “Other HES therapy” 
rather than oral corticosteroid therapy.
Duration of HES

Duration of HES in years will be calculated from the date of the screening visit (Visit 1) and the 
date of HES diagnosis as follows:
Duration (years) = (Date of visit 1 – date of HES diagnosis)/365.25

If the date of HES diagnosis is a partial date, a '01' will be used for a missing day and 'Jan' will 
be used for a missing month.
Exposure (therapeutic coverage)

The number of days of exposure (therapeutic coverage) to study drug will be calculated based 
on the formula:  
Duration of exposure in days = Date of last dose of study treatment – date of first dose of study 
treatment + 29.

Exposure in months will be calculated using the formula:  
Exposure (months) = (Exposure in days / 365.25) * 12

Total subject years exposure will be calculated using the formula:  
Total subject-years exposure = (Sum across subjects of exposure in days)/365.25


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15.6.4.
Efficacy
HES Flare
Definition of 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 
- 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 maintenance OCS dose is the dose received during the 4 weeks prior to randomisation i.e. 
baseline OCS therapy, which should be maintained for the duration of the treatment period. If a 
subject has their OCS dose reduced during the treatment period, the maintenance dose will be 
redefined as the new dose they have received for at least 4 weeks. If the OCS dose is 
increased during the treatment period, the maintenance OCS dose will not be redefined and 
will remain as therapy taken during the 4 weeks prior to randomisation.

Flares meeting endpoint definition a) will be captured on the ‘flare details’ form in the eCRF.

An increase in blood eosinophils above the pre-defined threshold level (2 x baseline value or 
baseline value + 2500 cells/L) without any other clinical manifestations during the study will 
lead to administration of blinded active OCS treatment (see Section 2.2). If a subject receives a 
second course of blinded active OCS during the 32-week treatment period, the subject will be 
considered to be experiencing a flare. The container list for the blinded OCS treatment 
(indicating which container numbers contained active OCS and which contained placebo OCS) 
will be used to define HES flares meeting endpoint definition b). This container list will be 
incorporated into the final SDTM data sets at the end of the study, at the same time as the 
randomised treatment information.
HES flare onset and resolution dates

The onset and resolution dates of HES flares meeting endpoint definition a) will be recorded on 
the ‘Flare details’ form in the eCRF.

The start date of HES flares meeting endpoint definition b) is defined as the date of the blood 
draw at which the second course of blinded active OCS was triggered via schedule blood 
sampling for eosinophil monitoring. The resolution date for a flare meeting endpoint definition 
b) is the date of the first blood draw at which blood eosinophil count is below the threshold to 
trigger blinded active OCS (see protocol Section 6.4 for full details of blood eosinophil 
monitoring).
HES flare during Week 20 through Week 32

Defined as an HES flare starting or ongoing on or after the date of the Week 20 visit (Visit 8)
up to and including the date of the Week 32 visit (Visit 11).
Time to First HES Flare

Calculated for each subject as 
(Onset date of first HES flare – Date of first dose of study treatment) + 1


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HES Flare
Rate of HES Flares

For subjects completing the study, the rate of HES flares will be calculated as
365.25 × 
    
   32 (   11) −      $ % + 1

For subjects withdrawing prematurely from the study, the rate of HES flares will be calculated 
as
365.25 × 
    
  ' ( ℎ( −      $ % + 1
The number of HES flares is 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.

For flares meeting endpoint definition b), 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.).
Subjects who have an elevated blood eosinophil level (2 x baseline value or baseline value + 
2500 cells/L) during the 32-week study treatment period

Subjects with elevated blood eosinophils either 2 x baseline value or baseline value + 2500 
cells/L during the 32-week study treatment period will be identified from the central laboratory 
haematology results. Samples taken from the date of first dose of study medication up until the 
date of Visit 11 (Week 32) will be considered in the derivation. Baseline will be defined as in 
Section 5.2.
Worst Level of Fatigue in Past 24 Hours (BFI Item 3)

A BFI item 3 score for baseline and each week of treatment will be derived by taking the mean 
of up to 7 available daily assessments in each week of treatment. 

Assessment windows defining each week will be based on the date recorded for each BFI 
assessment and are defined in Section 15.3.1. 
HES Symptom Severity Based on HES Daily Symptoms (HES-DS)

For each of the 6 symptom domains (muscle/joint pain, chills or sweats, abdominal pain or bloating, 
breathing symptoms, nasal or sinus symptoms and skin symptoms, a symptom score for baseline and 
each week of treatment will be derived by taking the mean of up to 7 available daily assessments in 
each weekly assessment window. 

Assessment windows defining each week will be based on the date recorded for each HES-DS 
assessment and are defined in Section 15.3.1.

A symptom score for most bothersome symptoms will be derived by taking the mean of the symptom 
scores for the up to 3 symptom domains identified by the subject as most bothersome at visit 2 (Week 
0).


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BFI Total Score

The BFI total score (range 0 – 10) will be calculated as the mean of the 9 domain scores 
(range 0 – 10) recorded for the weekly assessment. If less than 4 domain scores are complete, 
the BFI total score will be set to missing.
15.6.5.
Safety
Adverse Events
Drug Related AEs
AEs with relationship marked ‘YES’ or relationship missing.
AEs Leading to Permanent Discontinuation from Study Treatment or Withdrawal from the Study 
AEs with action marked “Study treatment withdrawn” or withdrawn from study status marked 
“YES”, or a response to either of these questions is missing.
AEs on Day of Dosing
AEs with an onset date equal to a study treatment dosing date and an onset time on or after the 
study treatment dosing time.
AE Time Since First Dose

If AE onset time is missing, calculate in days as follows:-
o
If AE start date < Date of first dose of study treatment then 
Time since first dose = AE start date - Date of first dose of study treatment 
o
If AE start date ≥ Date of first dose of study treatment then 
Time since first dose = AE start date – Date of first dose of study treatment +1
o
Missing if AE start date or date of first dose of study treatment is missing.

If AE onset time is present, calculate in days, hours, minutes as 
Time since first dose = AE start date/time – Date/time of first dose of study 
treatment 
AE Duration (Days)

If AE onset time is missing, calculate in days as
AE end date – AE start date + 1

If AE onset time is present, calculate in days, hours and minutes as
AE end date/time – AE start date/time

Missing if AE start date or end date is missing.
AEs of Special Interest

See Section 11.1.1.
ECG

QTc(B) will be derived from QT (uncorrected) and RR interval as


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15.7.
Appendix 7: Reporting Standards for Missing Data
15.7.1.
Premature Withdrawals
Element
Reporting Detail
General

A subject will be considered to have completed study treatment if they receive 
study treatment at week 28 (Visit 10).

For the purpose of the primary endpoint, a subject will be considered to have 
completed the study if they continue to participate in the study until Week 32 
(Visit 11). If a subject’s last dose of study treatment is on Week 24 (Visit 9) or 
Week 28 (Visit 10) and the subject does not continue into the open-label 
extension study 205203 after completing Visit 11 assessments (32 weeks from 
randomization), then the protocol requires an up to 8-week additional follow-up 
period, concluding with the 12-weeks post last dose follow-up visit (Visit 12).
Subjects who continue to participate in the study until Week 32 (Visit 11) but 
withdraw from the study prior to the final follow-up visit (Visit 12) will be 
documented separately in the study disposition table.

Subjects who discontinue study treatment or withdraw early will not be replaced 
in the study.
Pre-Screen 
and 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.

Screen failures are defined as subjects who consent to participate in the 
clinical trial but are never subsequently randomised.
15.7.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank 
fields on the collection instrument. These data will be indicated by the use of a 
“blank” in subject listing displays, unless all data for a specific visit are missing 
in which case the data is excluded from the listing. 

BLQ is not missing data and must be displayed as such and included in all 
listings and summaries. For blood eosinophil and IL-5 data, see Section 10.1.5
and Section 10.2.5 respectively. For PK data, refer to Section 15.5.3.
Outliers

Any subjects excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
15.7.2.1.
Handling of Missing and Partial Dates
Element
Reporting Detail
General

Partial dates will be displayed as captured in subject listing displays.
HES Flare 
and Adverse 
Events

Any partial dates for HES flare and adverse events will be raised to data 
management. If the full date cannot be ascertained, the following assumptions 
will be made:


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Element
Reporting Detail
o
If the partial date is a start date, a '01' will be used for the day and 'Jan' will 
be used for the month. 
o
However, if this imputation results in a date prior to the first dose of study 
treatment and the event could possibly have occurred during treatment from 
the partial information, then the date of the first dose of study treatment will 
be assumed to be the start date.
o
The event will then be considered to start on-treatment (worst case).
o
If the partial date is a stop date, a '28/29/30/31' will be used for the day 
(dependent on the month and year) and 'Dec' will be used for the month.

Completely missing start or end dates will remain missing, with no imputation 
applied. Consequently, time to onset and duration of such events will be 
missing.

The recorded partial date will be displayed in listings.
Concomitant 
Medications

Partial dates for any concomitant medications recorded in the CRF will be 
imputed using the following convention:
o
If the partial date is a start date, a '01' will be used for the day and 'Jan' will 
be used for the month
o
If the partial date is a stop date, a '28/29/30/31' will be used for the day 
(dependent on the month and year) and 'Dec' will be used for the month.

The recorded partial date will be displayed in listings.


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15.8.
Appendix 8: Values of Potential Clinical Importance
15.8.1.
Laboratory Values
Haematology
Laboratory Parameter
Units
Age 
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Hematocrit 
Ratio of 1
12+
0.201 
0.599 
Haemoglobin 
G/L
12+
71
199
Platelet Count 
GI/L
1+
31 
1499 
White Blood Cell Count (WBC)
GI/L
12+
1.1
Clinical Chemistry
Laboratory Parameter
Units
Age
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
ALT
U/L
3-12
>143 (and Total 
Bilirubin >43)
U/L
13+
>239 (and Total 
Bilirubin >43)
Calcium
mmol/L
3+
1.50
3.24
Glucose
mmol/L
1+
2.2
27.8
Phosphorus, Inorg
mmol/L
3+
0.32
Potassium
mmol/L
3+
2.8
6.5
Sodium
mmol/L
0+
120
160
Possible Hy’s Law Cases
Laboratory Parameter
Units
Category
Clinical Concern Range
ALT, Bilirubin
ALT ≥ 3xULN and Bilirubin ≥ 2xULN 
(>35% direct) 
ALT, INR
ALT ≥ 3xULN and INR > 1.5 
NOTES:

ULN = Upper Limit of Normal.
15.8.2.
Urinalysis
As per GSK IDSL display standards, a subject is considered to have urinalysis results of 
PCI if there is an increase in Protein or an increase in Occult Blood results during the 
study, or if microscopy is performed.


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15.9.
Appendix 9: Abbreviations & Trade Marks
15.9.1.
Abbreviations
Abbreviation
Description
ADaM
Analysis Data Model
AE
Adverse Event
A&R
Analysis and Reporting 
BFI
Brief Fatigue Index
BLQ
Below limit of quantification
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
CPMS
Clinical Pharmacology Modelling & Simulation
CS
Clinical Statistics
CSR
Clinical Study Report
DBF
Database Freeze
DBR
Database Release
DOB
Date of Birth
DP
Decimal Places
eCRF
Electronic Case Record Form
FEV1
Forced Expiratory Volume in one second
FVC
Forced Vital Capacity
GSK
GlaxoSmithKline
HCRU
Healthcare Resource Utilisation
HES-DS
HES Daily Symptoms
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee 
IDSL
Integrated Data Standards Library
ITT
Intent-To-Treat
MMRM
Mixed Model Repeated Measures
MSAS-SF
Modified Memorial Symptom Assessment Scale – Short Form
MUGA
Multigated Aquisition
OCS
Oral Corticosteroid
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
PK
Pharmacokinetic
PP
Per Protocol
Pop-PK
Population PK
Pop-PKPD
Population PKPD
PROMIS
Patient Reported Outcome Measurement Information System
QC
Quality Control
QTcF
Frederica’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
RAP
Reporting & Analysis Plan
RMC
Respiratory Medication Class


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Abbreviation
Description
SAC
Statistical Analysis Complete
SAE
Serious Adverse Event
SDTM
Study Data Tabulation Model
SoC
Standard of Care
SSR
Subject-Rated Symptom Severity
TFL
Tables, Figures & Listings 
15.9.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
NONE
NONMEM
SAS


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15.10.
Appendix 10: List of Data Displays
15.10.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.n
1.1 to 1.n
Efficacy
2.1 to 2.n
2.1 to 2.n
Health Outcome Tables
3.1 to 3.n
3.1 to 3.n
Safety
4.1 to 4.n
4.1 to 4.n
Pharmacokinetic
5.1 to 5.n
5.1 to 5.n
Pharmacodynamic and / or Biomarker
6.1 to 6.n
6.1 to 6.n
Pharmacokinetic / Pharmacodynamic
7.1 to 7.n
7.1 to 7.n
Section
Listings
ICH Listings
1 to x
15.10.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Appendix 11: Example Mock Shells for Data Displays.
Section
Figure
Table
Listing
Study Population
POP_Fn
POP_Tn
POP_Ln
Efficacy
EFF_Fn
EFF_Tn
EFF_Ln
Safety
SAFE_Fn
SAFE_Tn
SAFE_Ln
Pharmacokinetic
PK_Fn
PK_Tn
PK_Ln
Population Pharmacokinetic (PopPK)
POPPK_Fn
POPPK_Tn
POPPK_Ln
Pharmacodynamic and / or Biomarker
PD_Fn
PD_Tn
PD_Ln
Pharmacokinetic / Pharmacodynamic
PKPD_Fn
PKPD_Tn
PK/PD_Ln
NOTES: 

Non-Standard displays are indicated in the ‘IDSL /  Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’
15.10.3.
Deliverables
Deliverable
Description
Headline 
Headline results
SAC
Final Statistical Analysis Complete


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15.10.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
Subject Disposition
1.1.
ITT
ES1 
Summary of Subject Disposition
Include Completed, Withdrawn and 
subsets of completed/withdrawn as 
follows:-
Completed, Completed Week 32 and 
entered 205203, Completed Week 32
and Follow-up
Withdrawn, Withdrawn prior to Week 
32, Completed Week 32 and withdrawn
prior to Follow up
SAC
1.2.
ITT
SD1
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment
SAC
1.3.
ITT
POP_T1
Summary of Subject Accountability During 32-Week Treatment 
Period
SAC
1.4.
Screened
ES6
Summary of Screening Status and Reasons for Screen Failure
As a subset of “Enrolled” subjects, also 
include the number of subjects for 
whom inclusion criteria #5 is based on 
local rather than central laboratory 
result. Use text “Inclusion criteria #5 
based on local laboratory result [1]”, 
and add footnote: “[1] The number of 
subjects for whom the screening central 
laboratory blood eosinophil count is 
<1000 cells/uL but a local laboratory 
blood eosinophil count 1000 cells/uL 
was used to meet study inclusion 
criteria.”
SAC


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Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
1.5.
Enrolled
NS1
Summary of Number of Subjects by Country and Site ID
SAC
Protocol Deviation
1.6.
ITT
DV1
Summary of Important Protocol Deviations
SAC
Population Analysed
1.7.
ITT
SP1
Summary of Study Populations 
Headline
1.8.
ITT
SP2
Summary of Exclusions from the Per Protocol Population
SAC 
Demographic and Baseline Characteristics
1.9.
ITT
DM1
Summary of Demographic Characteristics
SAC
1.10.
Enrolled
DM11
Summary of Age Ranges
SAC 
1.11.
ITT
DM5
Summary of Race and Racial Combinations
SAC
1.12.
ITT
POP_T8
Summary of Duration of HES
SAC
Prior and Concomitant Medications/Conditions
1.13.
ITT
POP_T2
Summary of Baseline HES Therapy
SAC
1.14.
ITT
POP_T3
Summary of Baseline Prednisone Equivalent Daily Dose
Headline
1.15.
ITT
CM1
Summary of Concomitant Medications
SAC
1.16.
ITT
MH4
Summary of Current Medical Conditions
SAC
1.17.
ITT
MH4
Summary of Past Medical Conditions
SAC
Exposure and Treatment Compliance
1.18.
ITT
POP_T4
Summary of Exposure (Therapeutic Coverage) to Study 
Treatment
SAC


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Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
1.19.
ITT
POP_T5
Summary of Number of Treatments Administered
SAC
Most Bothersome HES Symptoms
1.20.
ITT
POP_T6
Summary of Most Bothersome HES Related Symptoms
SAC
Steroid Perception Questionnaire
1.21.
ITT
POP_T7
Summary of Steroid Perception Questionnaire
SAC


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15.10.5.
Efficacy Tables
Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
HES Flare
2.1.
ITT
EFF_T1
Overview of HES Flares
SAC
2.2.
ITT
EFF_T2
Summary of Frequency of All HES Flares
SAC 
2.3.
ITT
EFF_T3
Primary Analysis of Proportion of Subjects Who Experience a 
HES Flare During the 32-Week Treatment Period (Treatment 
Policy Estimand)
Headline
2.4.
ITT
EFF_T3a
Supportive Analysis of Proportion of Subjects Who Experience a 
HES Flare During the 32-Week Treatment Period (While on 
Treatment Estimand)
Headline
2.5.
PP
EFF_T3
Supportive Analysis of Proportion of Subjects Who Experience a 
HES Flare During the 32-Week Treatment Period (Treatment 
Policy Estimand, PP Population)
Headline
2.6.
ITT
EFF_T3b
Sensitivity Analysis of Proportion of Subjects Who Experience a 
HES Flare During the 32-Week Treatment Period (Treatment 
Policy Estimand, Alternative Missing Data Imputation Strategy 
#1)
Headline
2.7.
ITT
EFF_T3c
Sensitivity Analysis of Proportion of Subjects Who Experience a 
HES Flare During the 32-Week Treatment Period (Treatment 
Policy Estimand, Alternative Missing Data Imputation Strategy 
#2)
Headline
2.8.
ITT
EFF_T3
Analysis of Proportion of Subjects Who Experience a HES Flare 
During the 32-Week Treatment Period by Age (Treatment Policy 
Estimand)
Descriptive summary only; do not 
present p-values.
SAC


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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
2.9.
ITT
EFF_T3
Analysis of Proportion of Subjects Who Experience a HES Flare 
During the 32-Week Treatment Period by Sex (Treatment Policy 
Estimand)
Descriptive summary only; do not 
present p-values.
SAC
2.10.
ITT
EFF_T3
Analysis of Proportion of Subjects Who Experience a HES Flare 
During the 32-Week Treatment Period by Race (Treatment 
Policy Estimand)
Descriptive summary only; do not 
present p-values.
SAC
2.11.
ITT
EFF_T3
Analysis of Proportion of Subjects Who Experience a HES Flare 
During the 32-Week Treatment Period by Region (Treatment 
Policy Estimand)
Descriptive summary only; do not 
present p-values.
SAC
2.12.
ITT
EFF_T3
Analysis of Proportion of Subjects Who Experience a HES Flare 
During the 32-Week Treatment Period by Baseline OCS 
(Treatment Policy Estimand)
Descriptive summary only; do not 
present p-values.
SAC
2.13.
ITT
EFF_T3
Analysis of Proportion of Subjects Who Experience a HES Flare 
During the 32-Week Treatment Period by Baseline Blood 
Eosinophils (Treatment Policy Estimand)
Descriptive summary only; do not 
present p-values.
SAC
2.14.
ITT
EFF_T4
Analysis of Time to First HES Flare (Treatment Policy Estimand)
Add footnote: “Note: Subjects 
withdrawing from the study prematurely 
are censored at the date of study 
withdrawal.”
Headline
2.15.
ITT
EFF_T4
Sensitivity Analysis of Time to First HES Flare (Treatment Policy 
Estimand, Alternative Missing Data Imputation Strategy #1)
Add footnote: “Note: Subjects 
withdrawing from the study prematurely 
prior to reporting an HES flare are 
included with an HES flare on the date 
of study withdrawal.”
SAC


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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
2.16.
ITT
EFF_T4
Sensitivity Analysis of Time to First HES Flare (Treatment Policy 
Estimand, Alternative Missing Data Imputation Strategy #2)
Add footnote: “Note: Subjects 
withdrawing from the study prematurely 
prior to reporting an HES flare, with 
primary reason for treatment withdrawal 
reported as Adverse Event or Lack of 
Efficacy are included with an HES flare 
on the date of study withdrawal. For 
subjects withdrawing from the study 
prematurely prior to reporting an HES 
flare, with any other reason for 
discontinuation of study treatment, the 
event time will be censored at the date 
of study withdrawal.”
SAC
2.17.
ITT
EFF_T3
Analysis of Proportion of Subjects Who Experience a HES Flare 
During Week 20 Through Week 32 (Treatment Policy Estimand)
SAC
2.18.
ITT
EFF_T3
Sensitivity Analysis of Proportion of Subjects Who Experience a 
HES Flare During Week 20 Through Week 32 (Treatment Policy 
Estimand, Alternative Missing Data Imputation Strategy #1)  
SAC
2.19.
ITT
EFF_T3
Sensitivity Analysis of Proportion of Subjects Who Experience a 
HES Flare During Week 20 Through Week 32 (Treatment Policy 
Estimand, Alternative Missing Data Imputation Strategy #2)  
SAC
2.20.
ITT
EFF_T5
Analysis of Rate of HES Flares (Treatment Policy Estimand)
Add footnote: “Note: For subjects 
withdrawing prematurely from the study 
during the 32-week treatment period, all 
data up to the time of study withdrawal 
is used to calculate the rate of HES 
flares.”
Headline


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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
2.21.
ITT
EFF_T5
Sensitivity Analysis of Rate of HES Flares (Treatment Policy 
Estimand, Alternative Missing Data Imputation Strategy #1)
Add footnote: “Note: For subjects 
withdrawing prematurely from the study 
during the 32-week treatment period, 
the placebo flare rate is imputed for the 
missing time period.”
SAC
2.22.
ITT
EFF_T5
Sensitivity Analysis of Rate of HES Flares (Treatment Policy 
Estimand, Alternative Missing Data Imputation Strategy #2)
Add footnote: “Note: For subjects 
withdrawing prematurely from the study 
with primary reason for treatment 
withdrawal reported as AE or Lack of 
efficacy, the placebo flare rate is 
imputed for the missing time period. For 
all subjects withdrawing prematurely 
from the study with any other primary 
reason for treatment discontinuation, all 
data up to the time of study withdrawal 
is used to calculate the rate of HES 
flares.”
SAC
Daily Fatigue Severity - Worst Level of Fatigue in Past 24 Hours (BFI Item 3)
2.23.
ITT
EFF_T6
Summary of Mean Daily Fatigue Severity - Worst Level of 
Fatigue in Past 24 Hours (BFI Item 3) (Treatment Policy 
Estimand)
Present Baseline (week 0) up Week 32.
SAC
2.24.
ITT
EFF_T7
Analysis of Change from Baseline in Mean Daily Fatigue 
Severity - Worst Level of Fatigue in Past 24 Hours (BFI Item 3) –
at Week 32 (Treatment Policy Estimand)
SAC
2.25.
ITT
EFF_T8
Analysis of Change from Baseline in Mean Daily Fatigue 
Severity - Worst Level of Fatigue in Past 24 Hours (BFI Item 3) 
(Treatment Policy Estimand, Mixed Model Repeated Measures)
SAC
2.26.
ITT
EFF_T9
Summary of P-values for Primary and Secondary Endpoints 
(Treatment Policy Estimand)
SAC


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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
Elevated Blood Eosinophil Level
2.27.
ITT
EFF_T10
Analysis of Proportion of Subjects Who Have an Elevated Blood 
Eosinophil Count (2 x Baseline Value or Baseline Value + 2500 
cells/L) During the 32-Week Treatment Period (Treatment 
Policy Estimand)
SAC
FEV1, FVC, FEV1/FVC Ratio
2.28.
ITT
EFF_T6
Summary of FEV1, FVC and FEV1/FVC
Add a by-line for parameter.
Column header “Visit” rather than 
“Analysis Time Point”.
SAC
2.29.
ITT
EFF_T8
Analysis of Change from Baseline in FEV1 (Treatment Policy 
Estimand, Mixed Model Repeated Measures)
SAC
2.30.
ITT
EFF_T8
Analysis of Change from Baseline in FVC (Treatment Policy 
Estimand, Mixed Model Repeated Measures)
SAC
2.31.
ITT
EFF_T6
Summary of FEV1, FVC and FEV1/FVC - Excluding Data where 
SABA/LABA was Taken Within 6/12 Hours Respectively
Add a by-line for parameter.
Column header “Visit” rather than
“Analysis Time Point”.
SAC
2.32.
ITT
EFF_T8
Analysis of Change from Baseline in FEV1 - Excluding Data 
where SABA/LABA was Taken Within 6/12 Hours Respectively 
(Treatment Policy Estimand, Mixed Model Repeated Measures)
SAC
2.33.
ITT
EFF_T8
Analysis of Change from Baseline in FVC - Excluding Data 
where SABA/LABA was Taken Within 6/12 Hours Respectively 
(Treatment Policy Estimand, Mixed Model Repeated Measures)
SAC
ECHO/MUGA
2.34.
ITT
EFF_T16
Summary of ECHO/MUGA
SAC


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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
HES Symptom Severity (HES-DS)
2.35.
ITT
EFF_T6a
Summary of Most Bothersome HES Symptom Severity Score 
(HES-DS)
Includes number (%) of subjects with 
no reported symptoms.
SAC
2.36.
ITT
EFF_T7
Analysis of Change from Baseline in Most Bothersome HES 
Symptom Severity Score (HES-DS) at Week 32 (Treatment 
Policy Estimand)
Scale 0 = None to 10 = As bad as you 
can imagine.
SAC
2.37.
ITT
EFF_T8
Analysis of Change from Baseline in Most Bothersome HES 
Symptom Severity Score (HES-DS) (Treatment Policy Estimand, 
Mixed Model Repeated Measures)
Scale 0 = None to 10 = As bad as you 
can imagine.
SAC
2.38.
ITT
EFF_T6a
Summary of HES Symptom Severity Score (HES-DS) by 
Symptom
Includes number (%) of subjects with 
no reported symptoms.
Use T_EFF6a with Endpoint = 
Symptom Severity Score and by line for 
symptom domain.
Add footnote “Note: 1. The mean of the 
available assessments on the 7 days 
up to and including the date of each 
study visit is used as the value for that 
visit. For time points between visits i.e 
week 1, 2, 3, 5, 6, 7, 9, 10, 11, 13, 14, 
15, 17, 18, 19, 21, 22, 23, 25, 26, 27, 
29, 30, 31, the number of available 
assessments depends on the elapsed 
time between visits. 2. Scale 0 = None 
to 10 = As bad as you can imagine.”
SAC
2.39.
ITT
EFF_T7
Analysis of Change from Baseline HES Symptom Severity Score 
(HES-DS) by Symptom at Week 32 (Treatment Policy Estimand)
Use T_EFF7 with by line for symptom
domain.
Scale 0 = None to 10 = As bad as you 
can imagine
SAC


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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
2.40.
ITT
EFF_T8
Analysis of Change from Baseline in HES Symptom Severity 
Score (HES-DS) by Symptom (Treatment Policy Estimand, 
Mixed Model Repeated Measures)
Use T_EFF8 with by line for symptom
domain.
Scale 0 = None to 10 = As bad as you 
can imagine.
SAC
Weekly Fatigue Severity – BFI Total Scores
2.41.
ITT
EFF_T6
Summary of Total BFI Score
Present Baseline (week 0) up Week 32.
SAC
2.42.
ITT
EFF_T7
Analysis of Change from Baseline in Total BFI Score at Week 32 
(Treatment Policy Estimand)
SAC
2.43.
ITT
EFF_T8
Analysis of Change from Baseline in Total BFI Score (Treatment 
Policy Estimand, Mixed Model Repeated Measures)
SAC
Clinical- and Subject- Rated Overall Response to Therapy
2.44.
ITT
EFF_T11
Summary of Clinician-Rated Overall Response to Therapy
SAC
2.45.
ITT
EFF_T12
Analysis of Clinician-Rated Overall Response to Therapy 
(Treatment Policy Estimand)
SAC
2.46.
ITT
EFF_T11
Summary of Subject-Rated Overall Response to Therapy
SAC
2.47.
ITT
EFF_T12
Analysis of Subject-Rated Overall Response to Therapy 
(Treatment Policy Estimand)
SAC
Subject-Rated Symptom Severity (SSR) 
2.48.
ITT
EFF_T13
Summary of Subject-Rated Symptom Severity
SAC
2.49.
ITT
EFF_T12
Analysis of Subject-Rated Symptom Severity at Week 32 
(Treatment Policy Estimand)
SAC


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Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
Modified Memorial Symptom Assessment Scale-Short Form (MSAS-SF)
2.50.
ITT
EFF_T6
Summary of MSAS-SF Total and Subscale Scores
Include by line: Total MSAS-SF Score, 
MSAS-SF Global Distress Index, 
MSAS-SF Physical Subscale Score, 
MSAS-SF Psychological Subscale 
Score.
Present Baseline (week 0) up Week 32.
Column header “Visit” rather than 
“Analysis Time Point”.
Add footnote: “Scale 0 = Not at all 
distressed or bothered/No symptoms to 
4 = Very much distressed or 
bothered/Almost constant symptoms.”
SAC
2.51.
ITT
EFF_T7
Analysis of Change from Baseline in MSAS-SF Total and 
Subscale Scores at Week 32 (Treatment Policy Estimand)
Include by line: Total MSAS-SF Score, 
MSAS-SF Global Distress Index, 
MSAS-SF Physical Subscale Score, 
MSAS-SF Psychological Subscale 
Score.
Scale 0 = Not at all distressed or 
bothered/No symptoms to 4 = Very 
much distressed or bothered/Almost 
constant symptoms.
SAC
2.52.
ITT
EFF_T8
Analysis of Change from Baseline in MSAS-SF Total and 
Subscale Scores (Treatment Policy Estimand, Mixed Model 
Repeated Measures)
Include by line: Total MSAS-SF Score, 
MSAS-SF Global Distress Index, 
MSAS-SF Physical Subscale Score, 
MSAS-SF Psychological Subscale 
Score.
Scale 0 = Not at all distressed or 
bothered/No symptoms to 4 = Very 
much distressed or bothered/Almost 
constant symptoms.
SAC


CONFIDENTIAL
200622
94
Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
PROMIS Physical Function and Sleep
2.53.
ITT
EFF_T6
Summary of PROMIS Physical Function Score
Present Baseline (week 0) up Week 32.
Column header “Visit” rather than 
“Analysis Time Point”.
Add footnote: “Scale 1 = Cannot 
do/unable to do to 5 = Not at all/Without 
any difficulty.”
SAC
2.54.
ITT
EFF_T7
Analysis of Change from Baseline in PROMIS Physical Function 
Score at Week 32 (Treatment Policy Estimand)
Scale 1 = Cannot do/unable to do to 5 = 
Not at all/Without any difficulty.
SAC
2.55.
ITT
EFF_T8
Analysis of Change from Baseline in PROMIS Physical Function 
Score (Treatment Policy Estimand, Mixed Model Repeated 
Measures)
Scale 1 = Cannot do/unable to do to 5 = 
Not at all/Without any difficulty.
SAC
2.56.
ITT
EFF_T6
Summary of PROMIS Sleep Score
Present Baseline (week 0) up Week 32.
Column header “Visit” rather than 
“Analysis Time Point”.
Add footnote: “Scale 1 = Not at all 
difficulty in falling asleep /Never trouble 
staying asleep to 5 = Very much 
difficulty in falling asleep /Always 
trouble staying asleep.”
SAC
2.57.
ITT
EFF_T7
Analysis of Change from Baseline in PROMIS Sleep Score at 
Week 32 (Treatment Policy Estimand)
Scale 1 = Not at all difficulty in falling 
asleep /Never trouble staying asleep to 
5 = Very much difficulty in falling asleep 
/Always trouble staying asleep.
SAC
2.58.
ITT
EFF_T8
Analysis of Change from Baseline in PROMIS Sleep Score
(Treatment Policy Estimand, Mixed Model Repeated Measures)
Scale 1 = Not at all difficulty in falling 
asleep /Never trouble staying asleep to 
5 = Very much difficulty in falling asleep 
/Always trouble staying asleep.
SAC


CONFIDENTIAL
200622
95
15.10.6.
Efficacy Figures
Efficacy: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
HES Flare
2.1.
ITT
EFF_F1
Cumulative Number of HES Flares
Headline
2.2.
ITT
EFF_F2
Analysis of Proportion of Subjects with HES Flare During the 32-
Week Treatment Period
Present odds ratios and 95% CI from 5
analyses of the primary endpoint on 
one figure: Primary estimand, While on 
treatment estimand, Per protocol
population, Alternative missing data 
imputation strategy #1, Alternative 
missing data imputation strategy #2.
Headline
2.3.
ITT
EFF_F3
Kaplan-Meier Cumulative Incidence Curve for Time to First HES 
Flare
SAC
2.4.
ITT
EFF_F2
Analysis of Time to First HES Flare (Treatment Policy Estimand)
Present relative risk and 95% CI from 3 
analyses corresponding to 3 missing 
data imputation strategies: Primary 
estimand, Alternative missing data 
imputation strategy #1, Alternative 
missing data imputation strategy #2
SAC
2.5.
ITT
-
Exploratory Modelling of Proportion of Subjects with HES Flare 
During the 32-Week Treatment Period vs Baseline Blood
Eosinophils
SAC
2.6.
ITT
EFF_F2
Analysis of Proportion of Subjects with HES Flare During Week 
20 Through Week 32 (Treatment Policy Estimand)
Present odds ratio and 95% CI from 3 
analyses corresponding to 3 missing 
data imputation strategies: Primary 
estimand, Alternative missing data 
imputation strategy #1, Alternative 
missing data imputation strategy #2
SAC


CONFIDENTIAL
200622
96
Efficacy: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
2.7.
ITT
EFF_F2
Analysis of Rate of HES Flare (Treatment Policy Estimand)
Present rate ratio and 95% CI from 3 
analyses corresponding to 3 missing 
data imputation strategies: Primary 
estimand, Alternative missing data 
imputation strategy #1, Alternative 
missing data imputation strategy #2
SAC
Worst Level of Fatigue in Past 24 Hours (BFI Item 3)
2.8.
ITT
EFF_F6
Cumulative Distribution Plot for the Change from Baseline in 
Mean Daily Fatigue Severity - Worst Level of Fatigue in Past 24 
Hours (BFI Item 3) – at Week 32
SAC
2.9.
ITT
EFF_F4
Change from Baseline in Fatigue Severity - Worst Level of 
Fatigue in Past 24 Hours (BFI Item 3) (Treatment Policy 
Estimand, Mixed Model Repeated Measures)
Present adjusted mean (95% CI) 
change from baseline by time (weeks) 
from repeated measures model – Week 
0, 4, 8, 12, 16, 20, 24, 28, 32.
Add footnote: “Note: Adjusted for 
baseline (week 0) BFI item 3 score and 
region”.
SAC
2.10.
ITT
EFF_F5
Change from Baseline in Fatigue Severity - Worst Level of 
Fatigue in Past 24 Hours (BFI Item 3) - Treatment Difference vs 
Placebo (Treatment Policy Estimand, Mixed Model Repeated 
Measures)
Present adjusted mean treatment 
difference (95% CI) change from 
baseline by time (weeks) from repeated 
measures model – Week 0, 4, 8, 12, 
16, 20, 24, 28, 32.
Add footnote: “Note: Adjusted for 
baseline (week 0) BFI item 3 score and 
region”.
SAC
FEV1 and FVC
2.11.
ITT
EFF_F4
Change from Baseline in FEV1 (Treatment Policy Estimand, 
Mixed Model Repeated Measures)
SAC


CONFIDENTIAL
200622
97
Efficacy: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
2.12.
ITT
EFF_F5
Change from Baseline in FEV1 - Treatment Difference vs
Placebo (Treatment Policy Estimand, Mixed Model Repeated 
Measures)
SAC
2.13.
ITT
EFF_F4
Change from Baseline in FVC (Treatment Policy Estimand, 
Mixed Model Repeated Measures)
SAC
2.14.
ITT
EFF_F5
Change from Baseline in FVC - Treatment Difference vs 
Placebo (Treatment Policy Estimand, Mixed Model Repeated 
Measures)
SAC
HES Symptom Severity (HES-DS)
2.15.
ITT
EFF_F4
Change from Baseline in Most Bothersome HES Symptom 
Severity Score (HES-DS) (Treatment Policy Estimand, Mixed 
Model Repeated Measures)
Present adjusted mean (95% CI) 
change from baseline by time (weeks) 
from repeated measures model – Week 
0, 4, 8, 12, 16, 20, 24, 28, 32.
Add footnote: “Note: Adjusted for 
baseline (week 0) most bothersome 
symptom score and region”.
SAC
2.16.
ITT
EFF_F5
Change from Baseline in Most Bothersome HES Symptom 
Severity Score (HES-DS) - Treatment Difference vs Placebo 
(Treatment Policy Estimand, Mixed Model Repeated Measures)
Present adjusted mean treatment 
difference (95% CI) change from 
baseline by time (weeks) from repeated 
measures model – Week 0, 4, 8, 12, 
16, 20, 24, 28, 32.
Add footnote: “Note: Adjusted for 
baseline (week 0) most bothersome 
symptom score and region”.
SAC


CONFIDENTIAL
200622
98
Efficacy: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
2.17.
ITT
EFF_F4
Change from Baseline in HES Symptom Severity Score (HES-
DS) by Symptom (Treatment Policy Estimand, Mixed Model 
Repeated Measures)
One page per domain with byline.
Present adjusted mean (95% CI) 
change from baseline by time (weeks) 
from repeated measures model – Week 
0, 4, 8, 12, 16, 20, 24, 28, 32.
Add footnote: “Note: Adjusted for 
baseline (week 0) symptom score and 
region”.
SAC
2.18.
ITT
EFF_F5
Change from Baseline in HES Symptom Severity Score (HES-
DS) by Symptom - Treatment Difference vs Placebo (Treatment 
Policy Estimand, Mixed Model Repeated Measures)
One page per domain with byline.
Present adjusted mean treatment 
difference (95% CI) change from 
baseline by time (weeks) from repeated 
measures model – Week 0, 4, 8, 12, 
16, 20, 24, 28, 32.
Add footnote: “Note: Adjusted for 
baseline (week 0) symptom score and 
region”.
SAC
Weekly Fatigue Severity – BFI Total Scores
2.19.
ITT
EFF_F4
Change from Baseline in Total BFI Score (Treatment Policy 
Estimand, Mixed Model Repeated Measures)
Present adjusted mean (95% CI) 
change from baseline by time (weeks) 
from repeated measures model – Week 
0, 4, 8, 12, 16, 20, 24, 28, 32.
Add footnote: “Note: Adjusted for 
baseline (week 0) total BFI score and 
region”.
SAC


CONFIDENTIAL
200622
99
Efficacy: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
2.20.
ITT
EFF_F5
Change from Baseline in Total BFI Score - Treatment Difference 
vs Placebo (Treatment Policy Estimand, Mixed Model Repeated 
Measures)
Present adjusted mean treatment 
difference (95% CI) change from 
baseline by time (weeks) from repeated 
measures model – Week 0, 4, 8, 12, 
16, 20, 24, 28, 32.
Add footnote: “Note: Adjusted for 
baseline (week 0) total BFI score and 
region”.
SAC
Modified Memorial Symptom Assessment Scale-Short Form (MSAS-SF)
2.21.
ITT
EFF_F4
Change from Baseline in MSAS-SF Total and Subscale Scores
(Treatment Policy Estimand, Mixed Model Repeated Measures)
One plot per page, 4 pages with by line: 
Total MSAS-SF Score, MSAS-SF 
Global Distress Index, MSAS-SF 
Physical Subscale Score, MSAS-SF 
Psychological Subscale Score.
Present adjusted mean (95% CI) 
change from baseline by time (weeks) 
from repeated measures model – Week 
0, 4, 8, 16, 24, 32.
Add footnote: “Note: Adjusted for 
baseline (week 0) score and region. 
Scale: 0 = Not at all distressed or 
bothered/No symptoms to 4 = Very 
much distressed or bothered/Almost 
constant symptoms.”
SAC


CONFIDENTIAL
200622
100
Efficacy: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
2.22.
ITT
EFF_F5
Change from Baseline in MSAS-SF Total and Subscale Scores -
Treatment Difference vs Placebo (Treatment Policy Estimand, 
Mixed Model Repeated Measures)
Either one plot per page, 4 pages with 
by line, or 4 lines on one plot, as data 
permit: Total MSAS-SF Score, MSAS-
SF Global Distress Index, MSAS-SF 
Physical Subscale Score, MSAS-SF 
Psychological Subscale Score.
Present adjusted mean treatment 
difference (95% CI) change from 
baseline by time (weeks) from repeated 
measures model – Week 0, 4, 8, 12, 
16, 20, 24, 28, 32.
Add footnote: “Note: Adjusted for 
baseline (week 0) score and region. 
Scale: 0 = Not at all distressed or 
bothered/No symptoms to 4 = Very 
much distressed or bothered/Almost 
constant symptoms.”
SAC


CONFIDENTIAL
200622
101
Efficacy: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
PROMIS Physical Function and Sleep
2.23.
ITT
EFF_F4
Change from Baseline in PROMIS Physical Function and Sleep 
Score (Treatment Policy Estimand, Mixed Model Repeated 
Measures)
One plot per page, 2 pages with by line: 
PROMIS Physical Function Score, 
PROMIS Sleep Score.
Present adjusted mean (95% CI) 
change from baseline by time (weeks) 
from repeated measures model – Week 
0, 4, 8, 16, 24, 32.
Add footnote: “Note: 1. Adjusted for 
baseline (week 0) score and region.
2. Sleep score scale 1 = Not at all 
difficulty in falling asleep /Never trouble 
staying asleep to 5 = Very much 
difficulty in falling asleep /Always 
trouble staying asleep.
3. Physical function scale 0 = Not at all 
distressed or bothered/No symptoms to 
4 = Very much distressed or 
bothered/Almost constant symptoms.”
SAC


CONFIDENTIAL
200622
102
Efficacy: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
2.24.
ITT
EFF_F5
Change from Baseline in PROMIS Physical Function and Sleep 
Score - Treatment Difference vs Placebo (Treatment Policy 
Estimand, Mixed Model Repeated Measures)
Either one plot per page, 2 pages with 
by line, or 2 lines on one plot, as data 
permit: PROMIS Physical Function 
Score, PROMIS Sleep Score.
Present adjusted mean treatment 
difference (95% CI) change from 
baseline by time (weeks) from repeated 
measures model – Week 0, 4, 8, 16, 
24, 32.
Add footnote: “Note: 1. Adjusted for 
baseline (week 0) score and region.
2. Sleep score scale 1 = Not at all 
difficulty in falling asleep /Never trouble 
staying asleep to 5 = Very much 
difficulty in falling asleep /Always 
trouble staying asleep.
3. Physical function scale 0 = Not at all 
distressed or bothered/No symptoms to 
4 = Very much distressed or 
bothered/Almost constant symptoms.”
SAC


CONFIDENTIAL
200622
103
15.10.7.
Health Outcomes Tables
Health Outcomes: Tables
No.
Population
IDSL /  Example 
Shell
Title
Programming Notes
Deliverable
SF-36
3.1.
ITT
EFF_T6
Summary of SF-36 Health Survey Domain Scores
Include change from baseline values. 
Include 95% CIs for the mean.
SAC
3.2.
ITT
EFF_T6
Summary of SF-36 Health Survey Component Summary Scores
Include change from baseline values
Include 95% CIs for the mean.
SAC
Healthcare Resource Utilisation
3.3.
ITT
EFF_T14
Summary of Healthcare Resource Utilisation Associated with 
HES Flare
SAC
Work Productivity and Activity Impairment Questionnaire
3.4.
ITT
EFF_T15
Summary of Work Productivity and Activity Impairment
SAC


CONFIDENTIAL
200622
104
15.10.8.
Safety Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
Adverse Event Overview
4.1.
Safety
SAFE_T1
Adverse Event Overview
SAC
Adverse Events
4.2.
Safety
AE1
Summary of All On-Treatment Adverse Events by System Organ 
Class and Preferred Term
SAC
4.3.
Safety
AE1
Summary of All Post-Treatment Adverse Events by System 
Organ Class and Preferred Term
SAC
4.4.
Safety
AE3
Summary of Common (>=3% Incidence) On-Treatment Adverse 
Events by Overall Frequency
SAC
4.5.
Safety
AE15
Summary of Common (>=3% Incidence) On-Treatment Non-
Serious Adverse Events by System Organ Class and Preferred 
Term (Number of Subjects and Occurrences)
SAC
4.6.
Safety
AE5A
Summary of All On-Treatment Adverse Events by Maximum 
Intensity by System Organ Class and Preferred Term
SAC
4.7.
Safety
AE1
Summary of All Drug-Related Adverse Events by System Organ 
Class and Preferred Term
SAC
4.8.
Safety
AE5A
Summary of All Drug-Related Adverse Events by Maximum 
Intensity by System Organ Class and Preferred Term
SAC
4.9.
Safety
AE1
Summary of Non-Serious Drug-Related Adverse Events by 
System Organ Class and Preferred Term
SAC
4.10.
Safety
AE1
Summary of On-Treatment Adverse Events by Highest Post-
Baseline Binding Antibody Result
Add in row with n in each binding 
antibody result category.
SAC


CONFIDENTIAL
200622
105
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
4.11.
Safety
AE3
Summary of All Adverse Events Leading to Permanent 
Discontinuation from Study Treatment by Overall Frequency
SAC
4.12.
Safety
AE3
Summary of All Adverse Events Leading to Withdrawal from the 
Study by Overall Frequency
SAC
4.13.
Safety
AE1
Summary of Adverse Events Reported on the Day of Dosing by 
System Organ Class and Preferred Term
SAC
4.14.
Safety
AE7
Listing of Subject Numbers for Individual On-Treatment Adverse 
Events
SAC
4.15.
Safety
AE7
Listing of Subject Numbers for Individual Post-Treatment 
Adverse Events
SAC
4.16.
Safety
AE2
Listing of Relationship of Adverse Event, System Organ 
Classes, Preferred Terms and Verbatim Text
SAC
Serious Adverse Events 
4.17.
Safety
AE3
Summary of Fatal Serious Adverse Events by Overall Frequency
Headline
4.18.
Safety
AE3
Summary of Drug-Related Fatal Serious Adverse Events by 
Overall Frequency
SAC
4.19.
Safety
AE3
Summary of Non-Fatal Serious Adverse Events by Overall 
Frequency
SAC
4.20.
Safety
AE3
Summary of All Serious Adverse Events by Overall Frequency
Headline
4.21.
Safety
AE1
Summary of All On-Treatment Serious Adverse Events by 
System Organ Class and Preferred Term
SAC
4.22.
Safety
AE1
Summary of All Post-Treatment Serious Adverse Events by 
System Organ Class and Preferred Term
SAC


CONFIDENTIAL
200622
106
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
4.23.
Safety
AE1
Summary of All Pre-Treatment Serious Adverse Events by 
System Organ Class and Preferred Term
SAC
4.24.
Safety
AE16
Summary of All Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Subjects and Occurrences)
SAC
4.25.
Safety
AE1
Summary of All Drug-Related Serious Adverse Events by 
System Organ Class and Preferred Term
SAC
Adverse Events of Special Interest
4.26.
Safety
SAFE_T5
Summary of On-Treatment Serious AEs and AEs of Special 
Interest
Incidence, Relative Risk and Risk Difference – Mepolizumab 
300mg SC vs Placebo
SAC
4.27.
Safety
AE1
Summary of On-Treatment Adverse Events Reported by the 
Investigator as Meeting the Criteria for Anaphylaxis
SAC
4.28.
Safety
SAFE_T2
Summary Profile of On-Treatment Adverse Events Reported by 
the Investigator as Meeting the Criteria for Anaphylaxis
SAC
4.29.
Safety
AE1
Summary of On-Treatment Adverse Events Defined by the 
Investigator as Systemic Reactions - Allergic (Type I 
Hypersensitivity) and Other Systemic
SAC
4.30.
Safety
SAFE_T2
Summary Profile of On-Treatment Adverse Events Defined by 
the Investigator as Systemic Reactions - Allergic (Type I 
Hypersensitivity) and Other Systemic
SAC
4.31.
Safety
AE1
Summary of On-Treatment Adverse Events Defined by the 
Investigator as Systemic Reactions - Allergic (Type I 
Hypersensitivity)
SAC


CONFIDENTIAL
200622
107
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
4.32.
Safety
SAFE_T2
Summary Profile of On-Treatment Adverse Events Defined by 
the Investigator as Systemic Reactions - Allergic (Type I 
Hypersensitivity)
SAC
4.33.
Safety
AE1
Summary of On-Treatment Adverse Events Defined by the 
Investigator as Systemic Reactions – Other Systemic
SAC
4.34.
Safety
SAFE_T2
Summary Profile of On-Treatment Adverse Events Defined by 
the Investigator as Systemic Reactions - Other Systemic
SAC
4.35.
Safety
AE1
Summary of On-Treatment Adverse Events Defined by the 
Investigator as Local Injection Site Reactions
SAC
4.36.
Safety
SAFE_T2
Summary Profile of On-Treatment Adverse Events Defined by 
the Investigator as Local Injection Site Reactions
SAC
4.37.
Safety
AE1
Summary of On-Treatment Adverse Events Categorised as 
Serious Cardiac, Vascular and Thromboembolic Events
SAC
4.38.
Safety
SAFE_T2
Summary Profile of On-Treatment Adverse Events Categorised 
as Serious Cardiac, Vascular and Thromboembolic Events
SAC
4.39.
Safety
AE1
Summary of On-Treatment Adverse Events Categorised as 
Serious Ischemic Events
SAC
4.40.
Safety
SAFE_T2
Summary Profile of On-Treatment Adverse Events Categorised 
as Serious Ischemic Events
SAC
4.41.
Safety
AE1
Summary of On-Treatment Adverse Events Categorised as 
Malignancies
SAC
4.42.
Safety
SAFE_T2
Summary Profile of On-Treatment Adverse Events Categorised 
as Malignancies
SAC


CONFIDENTIAL
200622
108
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
4.43.
Safety
AE1
Summary of On-Treatment Adverse Events Categorised as 
Opportunistic Infections
SAC
4.44.
Safety
SAFE_T2
Summary Profile of On-Treatment Adverse Events Categorised 
as Opportunistic Infections
SAC
Laboratory – Haematology
4.45.
Safety
LB1
Summary of Haematology Changes from Baseline by Visit
Include baseline values
SAC
4.46.
Safety
LB3
Summary of Haematology Shifts from Baseline Relative to 
Normal Range by Visit
Include worst case post-baseline. If 
there are unscheduled assessments 
add footnote: “Note: Worst case post 
baseline Includes scheduled and 
unscheduled assessments.”
SAC
4.47.
Safety
LB3
Summary of Haematology Shifts from Baseline Relative to PCI 
Criteria by Visit
Include worst case post-baseline. If 
there are unscheduled assessments 
add footnote: “Note: Worst case post 
baseline Includes scheduled and 
unscheduled assessments.”
SAC
Laboratory – Clinical Chemistry
4.48.
Safety
LB1
Summary of Clinical Chemistry Changes from Baseline by Visit
Include baseline values
SAC
4.49.
Safety
LB3
Summary of Clinical Chemistry Shifts from Baseline Relative to 
Normal Range by Visit
Include worst case post-baseline. If 
there are unscheduled assessments 
add footnote: “Note: Worst case post 
baseline Includes scheduled and 
unscheduled assessments.”
SAC


CONFIDENTIAL
200622
109
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
4.50.
Safety
LB3
Summary of Clinical Chemistry Shifts from Baseline Relative to 
PCI Criteria by Visit
Include worst case post-baseline. If 
there are unscheduled assessments 
add footnote: “Note: Worst case post 
baseline Includes scheduled and 
unscheduled assessments.”
SAC
Laboratory – Urinalysis
4.51.
Safety
UR1
Summary of Worst Case Urinalysis Results Post-Baseline 
Relative to Baseline
SAC
Laboratory: Hepatobiliary (Liver)
4.52.
Safety
LIVER1
Summary of Liver Monitoring/Stopping Event Reporting
SAC
4.53.
Safety
LIVER10
Summary of Hepatobiliary Laboratory Abnormalities
SAC
ECG
4.54.
Safety
EG1
Summary of ECG Findings by Visit
Include worst case post-baseline. If 
there are unscheduled assessments 
add footnote: “Note: Worst case post 
baseline Includes scheduled and 
unscheduled assessments.”
SAC
4.55.
Safety
EG2
Summary of Change from Baseline in ECG Values by Visit
Include baseline values
SAC
4.56.
Safety
EG10
Summary of Maximum QTc Values Post-Baseline Relative to 
Baseline by Category
QTc(B) and QTc(F)
If there are unscheduled assessments 
add footnote: “Note: Includes scheduled 
and unscheduled assessments.”
SAC


CONFIDENTIAL
200622
110
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
4.57.
Safety
EG11
Summary of Maximum Increase in QTc Values Post-Baseline 
Relative to Baseline by Category
QTc(B) and QTc(F)
If there are unscheduled assessments 
add footnote: “Note: Includes scheduled 
and unscheduled assessments.”
SAC
Vital Signs
4.58.
Safety
VS1
Summary of Vital Signs by Visit
SAC
4.59.
Safety
VS1
Summary of Change from Baseline in Vital Signs by Visit
Include baseline values
SAC
Immunogenicity
4.60.
Safety
SAFE_T3
Summary of Binding Antibody by Visit
Include highest post baseline result. 
SAC
4.61.
Safety
SAFE_T3
Summary of Binding Antibody By Visit – Subjects Without 
Positive Result Prior to Dosing
Post-Week 0 visits only, plus highest 
post baseline result.
SAC
4.62.
Safety
SAFE_T4
Summary of Neutralising Antibody by Visit
Include highest post baseline result. 
SAC


CONFIDENTIAL
200622
111
15.10.9.
Safety Figures
Safety: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
Adverse Events
4.1.
Safety
AE10
Common (>=3% Incidence) On-Treatment Adverse Events and 
Relative Risk
SAC
4.2.
Safety
SAFE_F1
Relative Risk of On-Treatment Serious Adverse Events and AEs 
of Special Interest
Mepolizumab 300mg SC vs Placebo
SAC
Laboratory
4.3.
Safety
LIVER14
Scatter Plot of Maximum vs Baseline for ALT
If there are unscheduled assessments 
add footnote: “Note: Maximum Value 
includes scheduled and unscheduled 
assessments.”
SAC
4.4.
Safety
LIVER9
Scatter Plot of Maximum Total Bilirubin vs Maximum ALT
If there are unscheduled assessments 
add footnote: “Note: Maximum Value 
includes scheduled and unscheduled 
assessments.”
SAC


CONFIDENTIAL
200622
112
15.10.10. Pharmacokinetic Tables
Pharmacokinetic: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
5.1.
PK
PK01
Summary of Plasma Mepolizumab Concentration-Time Data
(Observed and Predicted)
SAC
5.2.
PK
PK06
Summary Statistics of Individual Model Predicted Plasma 
Mepolizumab Pharmacokinetic Parameters (Non-transformed 
and Log-transformed)
SAC
5.3.
PK
-
Description and Evaluation of Key PK Models Tested
Provided by CPMS
SAC
5.4.
PK
-
Population PK Parameter Estimates with 95% CI of Final PK 
Model
Provided by CPMS
SAC
5.5.
PK
-
Demographics Summary
Provided by CPMS
SAC
5.6.
PK
-
Samples Summary
Provided by CPMS
SAC
5.7.
PK
-
Accumulation Ratio Estimate at Week 16 and 32
Provided by CPMS
SAC


CONFIDENTIAL
200622
113
15.10.11. Pharmacokinetic Figures
Pharmacokinetic: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
5.1.
PK
-
Plasma Mepolizumab Concentration-Time Profiles (by 
Treatment)
Provided by CPMS
SAC
5.2.
PK
-
Model Goodness of Fit Plots
Provided by CPMS
SAC
5.3.
PK
-
Continuous Covariate Correlation Plot
Provided by CPMS
SAC
5.4.
PK
-
Categorical Covariate Correlation Plot
Provided by CPMS
SAC
5.5.
PK
-
Automated Covariate Selection
Provided by CPMS
SAC
5.6.
PK
-
Visual Predictive Check
Provided by CPMS
SAC
5.7.
PK
-
Observed Plasma Mepolizumab Concentration-Time Profiles by 
Anti-Drug Antibody Status
Provided by CPMS
SAC
5.8.
PK
-
Plasma Mepolizumab Observed/Predicted Concentration-Time 
Profiles (by Subject)
Provided by CPMS
SAC
5.9.
PK
-
Box Plot of Systemic Clearance versus Covariates of Interest
Provided by CPMS
SAC


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15.10.12. Pharmacodynamic Tables
Pharmacodynamic: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
Blood Eosinophils
6.1.
PD
PD_T1
Summary of Blood Eosinophil Count
Include absolute blood eosinophils at 
Screening, Baseline and Week 2
through Week 32, and ratio to baseline
values for Week 2 through Week 32.
Number of decimal places as follows: 
geometric mean (2), SD logs (3), 
median (2), min (2), max (2).
SAC
6.2.
PD
PD_T2
Analysis of On-Treatment Ratio to Baseline Blood Eosinophils
(While on Treatment Estimand, Mixed Model Repeated 
Measures)
Include Week 2 through Week 32.
SAC
IL-5
6.3.
PD
PD_T1
Summary of Serum Total IL-5
Include absolute and ratio to baseline 
values.
Include summary statistics for the 
number and % of BLQ values.
SAC
6.4.
PD
PD_T3
Analysis of On-Treatment Ratio to Baseline Serum Total IL-5 at 
Week 32 (While on Treatment Estimand)
SAC


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15.10.13. Pharmacodynamic Figures
Pharmacodynamic: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
Blood Eosinophils
6.1.
PD
EFF_F4
On-Treatment Absolute Blood Eosinophils (While on Treatment 
Estimand, Mixed Model Repeated Measures)
No reference line.
Include screening and baseline
unadjusted geometric mean values 
without 95% CI.
Week 2 onwards adjusted estimates 
from MMRM model with 95% CI.
SAC
6.2.
PD
EFF_F4
On-Treatment Ratio to Baseline Blood Eosinophils (While on 
Treatment Estimand, Mixed Model Repeated Measures)
Reference line at 1.
SAC
6.3.
PD
EFF_F5
On-Treatment Ratio to Baseline Blood Eosinophils – Treatment 
Difference vs Placebo (While on Treatment Estimand, Mixed 
Model Repeated Measures)
Reference line at 1.
SAC
15.10.14. Pharmacokinetic / Pharmacodynamic Tables
Pharmacokinetic / Pharmacodynamic: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
7.1.
PK and PD
-
Description and Evaluation of Key PKPD Models Tested
Provided by CPMS
SAC
7.2.
PK and PD
-
Population PD Parameter Estimates with 95% CI of Final PKPD 
Model
Provided by CPMS
SAC
7.3.
PK and PD
-
Demographics Summary
Provided by CPMS
SAC
7.4.
PK and PD
-
Samples Summary
Provided by CPMS
SAC


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116
15.10.15. Pharmacokinetic / Pharmacodynamic Figures
Pharmacokinetic / Pharmacodynamic: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable
7.1.
PK and PD
-
Blood Eosinophil Count-Time Profiles
Provided by CPMS
SAC
7.2.
PK and PD
-
Model Goodness of Fit Plots
Provided by CPMS
SAC
7.3.
PK and PD
-
Continuous Covariate Correlation Plot
Provided by CPMS
SAC
7.4.
PK and PD
-
Categorical Covariate Correlation Plot
Provided by CPMS
SAC
7.5.
PK and PD
-
Automated Covariate Selection
Provided by CPMS
SAC
7.6.
PK and PD
-
Visual Predictive Check
Provided by CPMS
SAC
7.7.
PK and PD
-
Observed Blood Eosinophil Count -Time Profiles by Anti-Drug 
Antibody Status
Provided by CPMS
SAC
7.8.
PK and PD
-
Observed/Predicted Blood Eosinophil Count-Time Profiles (by 
Subject)
Provided by CPMS
SAC


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15.10.16. ICH Listings
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
Subject Disposition
1.
Screened
ES7
Listing of Reasons for Screen Failure
SAC
2.
ITT
ES2
Listing of Reasons for Study Withdrawal
SAC
3.
ITT
SD2
Listing of Reasons for Study Treatment Discontinuation
SAC
4.
ITT
BL1
Listing of Subjects for Whom the Treatment Blind was Broken
SAC
5.
ITT
TA1
Listing of Planned and Actual Treatments
SAC
Protocol Deviations
6.
ITT
DV2
Listing of Important Protocol Deviations 
SAC
7.
ITT
IE3
Listing of Subjects with Inclusion/Exclusion Criteria Deviations
SAC
Populations Analysed
8.
ITT
SP3
Listing of Subjects Excluded from Any Population
Include Per Protocol, Safety, PK, PD
SAC
Demographic and Baseline Characteristics
9.
ITT
DM2
Listing of Demographic Characteristics
SAC
10.
ITT
DM9
Listing of Race
SAC
11.
ITT
MH2
Listing of Medical Conditions
SAC
Prior and Concomitant Medications
12.
ITT
CP_CM3
Listing of Concomitant Medications
Flag baseline HES therapy on listing.
SAC
Exposure and Treatment Compliance
13.
ITT
EX3
Listing of Exposure Data
Exposure to Mepolizumab/Placebo 
only.
SAC


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118
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
Burden of HES
14.
ITT
POP_L1
Listing of Most Bothersome HES Related Symptoms
SAC
15.
ITT
POP_L2
Listing of Steroid Perception Questionnaire
SAC
Efficacy
16.
ITT
EFF_L1
Listing of Investigator Reported HES Flare
SAC
17.
ITT
EFF_L2
Listing of Blinded OCS Therapy
SAC
18.
ITT
EFF_L3
Listing of Fatigue Severity (BFI)
SAC
19.
ITT
EFF_L4
Listing of FEV1, FVC and FEV1/FVC
SAC
20.
ITT
EFF_L5
Listing of Echocardiogram/MUGA
SAC
21.
ITT
EFF_L6
Listing of Symptom Severity (HES-DS)
SAC
22.
ITT
EFF_L7
Listing of Subject- and Clinician-Rated Overall Response to 
Therapy
SAC
23.
ITT
EFF_L8
Listing of Subject-Rated Symptom Severity
SAC
24.
ITT
EFF_L9
Listing of MSAS-SF Total and Subscale Scores
SAC
25.
ITT
EFF_L10
Listing of PROMIS Physical Function and Sleep Score
SAC
Healthcare Resource Utilisation
26.
ITT
EFF_L11
Listing of SF-36 Health Survey
SAC
27.
ITT
EFF_L12
Listing of Healthcare Resource Utilisation Associated with HES 
Flare
SAC
28.
ITT
EFF_L13
Listing of Work Productivity and Activity Impairment
SAC


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119
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
Adverse Events
29.
Safety
AE8
Listing of All Adverse Events
Add phase: Pre-treatment, on-
treatment, post-treatment.
Include treatment in by-line.
SAC
Serious and Other Significant Adverse Events[1]
30.
Safety
AE8
Listing of Fatal Serious Adverse Events
Add phase: Pre-treatment, on-
treatment, post-treatment.
Include treatment in by-line.
SAC
31.
Safety
AE8
Listing of Non-Fatal Serious Adverse Events
Add phase: Pre-treatment, on-
treatment, post-treatment.
Include treatment in by-line.
SAC
32.
Safety
AE14
Listing of Reasons for Considering as a Serious Adverse Event
Add phase: Pre-treatment, on-
treatment, post-treatment.
Include treatment in by-line.
SAC
33.
Safety
AE8
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment
Add phase: Pre-treatment, on-
treatment, post-treatment.
Include treatment in by-line.
SAC
34.
Safety
AE8
Listing of Adverse Events Reported on the Day of Dosing
Add phase: Pre-treatment, on-
treatment, post-treatment.
Include treatment in by-line.
SAC
35.
Safety
AE8
Listing of Adverse Events Reported by the Investigator as 
Meeting the Criteria for Anaphylaxis
Add phase: Pre-treatment, on-
treatment, post-treatment.
Add injection reaction symptoms and 
number of doses prior to event.
Include treatment in by-line.
SAC


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120
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
36.
Safety
AE8
Listing of Adverse Events Defined by the Investigator as 
Systemic Reactions - Allergic (Type I Hypersensitivity)
Add phase: Pre-treatment, on-
treatment, post-treatment.
Add injection reaction symptoms and 
number of doses prior to event.
Include treatment in by-line.
SAC
37.
Safety
AE8
Listing of Adverse Events Defined by the Investigator as 
Systemic Reactions – Other Systemic
Add phase: Pre-treatment, on-
treatment, post-treatment.
Add injection reaction symptoms and 
number of doses prior to event.
Include treatment in by-line.
SAC
38.
Safety
AE8
Listing of Adverse Events Defined by the Investigator as Local 
Injection Site Reactions
Add phase: Pre-treatment, on-
treatment, post-treatment.
Add injection reaction symptoms and 
number of doses prior to event.
Include treatment in by-line.
SAC
39.
Safety
AE8
Listing of Adverse Events Categorised as Serious Cardiac, 
Vascular and Thromboembolic Events
Add phase: Pre-treatment, on-
treatment, post-treatment.
Include treatment in by-line.
SAC
40.
Safety
AE8
Listing of Adverse Events Categorised as Serious Ischemic 
Events
Add phase: Pre-treatment, on-
treatment, post-treatment.
Include treatment in by-line.
SAC
41.
Safety
AE8
Listing of Adverse Events Categorised as Malignancies
Add phase: Pre-treatment, on-
treatment, post-treatment.
Include treatment in by-line.
SAC


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121
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
42.
Safety
AE8
Listing of Adverse Events Categorised as Opportunistic 
Infections
Add phase: Pre-treatment, on-
treatment, post-treatment.
Include treatment in by-line.
SAC
Hepatobiliary (Liver)
43.
Safety
MH2
Listing of Medical Conditions for Subjects with Liver Stopping 
Events
SAC
44.
Safety
SU2
Listing of Substance Use for Subjects with Liver Stopping 
Events
All Laboratory
45.
Safety
LB5
Listing of Haematology Data for Subjects with Any Value of 
Potential Clinical Importance
SAC 
46.
Safety
LB5
Listing of Clinical Chemistry Data for Subjects with Any Value of 
Potential Clinical Importance
SAC
47.
Safety
LB14
Listing of Laboratory Data with Character Results
SAC
48.
Safety
UR2A
Listing of Urinalysis Data for Subjects with Any Value of 
Potential Clinical Importance
SAC
ECG
49.
Safety
EG3
Listing of All ECG Values for Subjects Meeting Protocol Defined 
QTc Stopping Criteria
SAC
Immunogenicity
50.
Safety
SAFE_L1
Listing of Immunogenicity Data for Subjects with at Least One 
Positive Screening Binding Assay
SAC
Pharmacokinetic
51.
PK
-
Listing of Data and Subjects Excluded from Analysis
Provided by CPMS
SAC


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122
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
52.
PK
-
Final PK Model Listings
Provided by CPMS
SAC
Pharmacodynamic
53.
Safety
PD_L1
Listing of Blood Eosinophils (unit)
SAC
54.
Safety
PD_L2
Listing of Serum Total IL-5 (unit)
SAC
Pharmacokinetic / Pharmacodynamic
55.
PK and PD
-
Listing of Data and Subjects Excluded from Analysis
Provided by CPMS
SAC
56.
PK and PD
-
Final PKPD Model Listings
Provided by CPMS
SAC
[1] For deaths and any cardiovascular events, subject profiles will be produced as per GSK IDSL standard template.


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123
15.11.
Appendix 11: Example Mock Shells for Data Displays
Available upon request