Clinical trial NCT02654145
Conditions: Asthma
Keywords: mepolizumab Omalizumab SGRQ severe eosinophilic asthma ACQ exacerbations
Sponsor: GlaxoSmithKline
Start date: 2016-03-17; Completion date: 2017-05-31
Enrollment: 145 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Mepolizumab is an anti-interleukin-5 ( IL-5) monoclonal antibody that neutralizes IL-5 and reduces eosinophil counts in both sputum and blood. Omalizumab an anti-immunoglobulin E (IgE) monoclonal antibody (mAb) is effective in the treatment of moderate to severe allergic asthma. The aim of this study is to investigate whether subjects not optimally controlled on their current omalizumab treatment, who are eligible for therapy with mepolizumab can be effectively and safely switched to treatment with mepolizumab to improve asthma control. The study will provide data on the efficacy, safety, immunogenicity, and tolerability of mepolizumab when switched directly from omalizumab without any wash-out. The learnings from this study may help guide physicians when substituting one biologic with another for the treatment of patients with severe eosinophilic asthma.

The study will be a multi-centre, open-label single arm trial. Patients with severe eosinophilic asthma who are receiving omalizumab, but are not optimally controlled will be eligible to participate. Subjects will remain on their current maintenance therapy including omalizumab throughout the run-in period for a minimum of one week and up to 4 weeks. At Visit 2 (week 0) subjects will discontinue their omalizumab treatment and be switched to mepolizumab 100 mg subcutaneous (SC) every 4 weeks for 28 weeks. The treatment period is 32 weeks, including an Exit Visit/Early Withdrawal Visit, 4 weeks following the subject's last dose of mepolizumab.

Detailed description:

Arms: arm 1: Subjects with severe eosinophilic asthma who are receiving omalizumab will enter a run-in period for a minimum of one week and a up to 4 weeks. Subjects will remain on their current maintenance therapy throughout the run-in period, including omalizumab. At Visit 2 (week 0) subjects will discontinue omalizumab treatment and will be switched to receiving mepolizumab 100 mg SC every 4 weeks for 28 weeks. Except for omalizumab, subjects will remain on their current maintenance therapy throughout the open-label treatment period. Albuterol/salbutamol metered dose inhalers (MDIs) will be provided as rescue medication during treatment period.
Interventions: intervention 1: Mepolizumab 100mg SC intervention 2: Albuterol/salbutamol MDIs intervention 3: Omalizumab
Intervention descriptions: intervention 1: At Visit 2 (Week 0) eligible subjects will receive mepolizumab 100mg SC into the upper arm or thigh every 4 weeks over a period of 28 weeks. intervention 2: Albuterol/salbutamol metered dose inhalers (MDIs) will be provided as rescue medication during treatment period. intervention 3: Subjects receiving omalizumab will enter in a run-in period and will continue to receive omalizumab throughout the run-in period. At Visit 2 (week 0) subjects will discontinue omalizumab.

Protocol documents:
Prot_001.pdf: 
2015N243304_01
CONFIDENTIAL
The GlaxoSmithKline group of companies
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1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A multi-centre, open-label,single arm, 32-week treatment study 
in subjects with severe eosinophilic asthma not optimally 
controlled with current omalizumab treatment who are switched 
from omalizumab to mepolizumab 100mg subcutaneous (study 
number204471-the OSMO study)
Compound Number: SB-240563
Development Phase:
IIIB/IV
Effective Date:
23-MAR-2016
Protocol Amendment Number:  01
Author(s):PPD
 
Copyright 2016the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.


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Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2015N243304_00
2015-OCT-19
Original
2015N243304_01
2016-MAR-23
Amendment No. 1
This protocol amendment was created to make the following changes:
Secondary Medical Monitor details updated to reflect changesin personnel. 
IND Number added.
Section 1 andSection3 Objective(s)/Endpoints: The wording of the primary objective 
was revised to reflect the pragmatic approach of the study. “To determine whether there 
is an improvement in asthma control whendirectly switched to mepolizumab,in subjects 
with a severe eosinophilic asthma phenotype not optimally controlled on omalizumab” 
changed to:“To describe in a pragmatic settingwhether there is an improvement in 
asthma control,from the beginning to the end of the study, when directly switchedfrom 
omalizumabto mepolizumab, in subjects with a severe eosinophilic asthma phenotype 
not optimally controlled on omalizumab.
Section 4.6.1 Table 3:  Risk assessment. “Subjects are to be monitored post-injection for 
one hour” was changed to “Subjects are to be monitored post-injection for one hour for 
the first 3 injections, then per institutional guidelines”.
Section 5.1, Inclusion criterion 6, was updated to include long-acting anticholinergic 
(tiotropium bromide). 
Section 5.3, Required Criteria to Start Treatment. No. 2, “run-in” was added for 
consistency.
Section 5.5.3,Liver Chemistry Stopping Criteria“Appendix 2”was correctedto 
“Appendix 5”as this was a typographical error.
Section 5.5.4,QTc Stopping Criteria“change from baseline (Visit 2)”, was replaced with 
“change from screening (Visit 1)”. In addition, “Baseline (Visit 2)” was changed to 
“Screening (Visit 1)” as this was a typographical error. 
Section 6.1,Investigational Product and Other Study Treatment.Ventolin Diskus for 
Sweden was added to reflect its use as a rescue medication in Sweden. “MDI”, was 
replaced by “rescue inhaler”
Section 7,Time and Event Table was updated. The “x”, in Dispense paper 
diary/worksheet row for The Exit Visit/Early withdrawal Visit column, was removed to 
correct a typographical error.  In addition, in the table footnote the assay for Hepatitis C 
was updated.


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Section 7.3.2.3.1, Pre and post bronchodilator FEV1, “long-acting anticholinergic 
(LAMA)” was added.
Section 7.4.7,Clinical Safety Laboratory Assessments Table 5 footnote, “Appendix 2”, 
was changed to “Appendix 5”as this was typographical error.
Section 7.5,Biomarker(s)/Pharmacodynamic Markers,a sentence referring to the 
blinding of eosinophil counts was removed.
Section 12.7 Appendix 7 Sub-section 12.7.2 last bullet point, Appendix 2 was replaced 
by Appendix 5 to correct a typographical error.
Typographical errors have been corrected throughout the document.


PPD
PPD


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MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information: 
Ro
le
Name
Day T
ime Phone 
Number and ema
i
l 
address
After-hours 
Phone/Ce
l
l/
Pager 
Number
Fax 
Number
S
ite Address
Pr
imary 
Med
ica
l 
Mon
itor 
 
Te
lephone:
Ce
l
l: 
Fax:  
 G
laxoSm
ithK
l
ine
F
ive Moore 
Dr
ive
Research 
Tr
iang
le Park, 
NC 27709-3998, 
USA
Secondary 
Med
ica
l 
Mon
itor
 Te
lephone:
 Ce
l
l: 
 
 
Fax: 
 
G
laxoSm
ithK
l
ine
Stock
ley Park 
West, 1-3 
Ironbr
idge 
Road, 
Heathrow, 
Uxbr
idge, 
M
idd
lesex, 
UB11 1BT, 
Un
ited K
ingdom
SAE 
contact  
informat
ion 
 
Te
lephone:
Ce
l
l: 
Fax:  
 G
laxoSm
ithK
l
ine
F
ive Moore
Dr
ive
Research 
Tr
iang
le Park, 
NC 27709-3998, 
USA
Sponsor Legal Registered Address: 
PP
D
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):  EudraCT no.2015-003697-32,IND 
no.006971
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 204471
Iconfirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I amresponsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date


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TABLE OF CONTENTS
PAGE
1. PROTOCOL SYNOPSIS FOR STUDY 204471......................................................11
2. INTRODUCTION....................................................................................................14
2.1.
Study Rationale..........................................................................................14
2.2.
Brief Background........................................................................................15
3. OBJECTIVE(S) AND ENDPOINT(S)......................................................................16
4. STUDY DESIGN....................................................................................................18
4.1.
Overall Design............................................................................................18
4.2.
Treatment Arms and Duration.....................................................................19
4.2.1. 
Exit Interview...............................................................................20
4.3.
Type and Number of Subjects.....................................................................20
4.4.
Design Justification.....................................................................................20
4.5.
Dose Justification........................................................................................20
4.6.
Benefit: Risk Assessment...........................................................................21
4.6.1.
Risk Assessment.........................................................................21
4.6.2.
Benefit Assessment.....................................................................26
4.6.3.
Overall Benefit: Risk Conclusion..................................................26
5. SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA.............26
5.1.
Inclusion Criteria.........................................................................................27
5.2.
Exclusion Criteria........................................................................................29
5.3.
Continuation to Treatment Criteria..............................................................32
5.4.
Pre-Screening/ Screening/Run-in Failures..................................................32
5.5.
Withdrawal/Stopping Criteria.......................................................................33
5.5.1.
Withdrawal from Study Treatment................................................33
5.5.2.
Withdrawal from the Study...........................................................34
5.5.3.
Liver Chemistry Stopping Criteria................................................34
5.5.3.1.
Study Treatment Restart orRechallenge....................35
5.5.4.
QTc Stopping Criteria..................................................................35
5.6.
Subject and Study Completion....................................................................36
6. STUDY TREATMENT............................................................................................36
6.1.
Investigational Product and Other Study Treatment....................................36
6.2.
Treatment Assignment................................................................................37
6.3.
Packaging andLabeling..............................................................................37
6.4.
Preparation/Handling/Storage/Accountability..............................................37
6.5.
Compliance with Study Treatment Administration.......................................38
6.6.
Treatment of Study Treatment Overdose....................................................38
6.7.
Treatment after the End of the Study..........................................................38
6.8.
Concomitant Medications and Non-Drug Therapies....................................38
6.8.1.
Permitted Medications and Non-Drug Therapies..........................38
6.8.2.
Prohibited Medications and Non-Drug Therapies.........................39
7. STUDY ASSESSMENTS AND PROCEDURES.....................................................39
7.1.
Time and Events Table...............................................................................40
7.2.
Screening and Critical Baseline Assessments............................................43


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7.2.1.
Pre-screening Visit.......................................................................43
7.2.2. 
Critical procedures performed at Screening (Visit 1)....................43
7.2.3.
Critical procedures performed at first treatment Visit 
(Baseline Visit 2)..........................................................................44
7.3.
Efficacy.......................................................................................................44
7.3.1.
Efficacy Endpoints.......................................................................44
7.3.2. 
Efficacy assessments..................................................................45
7.3.2.1.
Questionnaires...........................................................45
7.3.2.1.1.
Asthma Control Questionnaire 
(ACQ).....................................................45
7.3.2.1.2.
St. George’s Respiratory 
Questionnaire (SGRQ)...........................45
7.3.2.1.3.
Clinician/Subject Rated Response 
to Therapy..............................................46
7.3.2.1.4.
Treatment Satisfaction 
Questionnaire for Medication 
(TSQM-9)...............................................46
7.3.2.2.
Exit Interview..............................................................46
7.3.2.3.
Pulmonary Function test.............................................46
7.3.2.3.1.
Pre-and post bronchodilator 
FEV1......................................................47
7.3.2.4.
Clinically Significant Asthma Exacerbation.................47
7.4. 
Safety.........................................................................................................47
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........47
7.4.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................48
7.4.2.
Method of Detecting AEs and SAEs.............................................48
7.4.2.1.
Follow-up of AEs and SAEs........................................48
7.4.2.2.
Cardiovascular and Death Events..............................49
7.4.2.2.1.
Cardiovascular events............................49
7.4.2.2.2. Death Events..........................................49
7.4.2.3.
Regulatory Reporting Requirements for SAEs............49
7.4.3.
Pregnancy...................................................................................49
7.4.4.
Physical Exams...........................................................................50
7.4.5.
Vital Signs....................................................................................50
7.4.6.
Electrocardiogram (ECG).............................................................50
7.4.7.
Clinical Safety Laboratory Assessments......................................50
7.4.8. 
Paper worksheet..........................................................................52
7.5.
Biomarker(s)/Pharmacodynamic Markers...................................................52
7.6.
Immunogenicity...........................................................................................52
7.7.
Genetics.....................................................................................................52
8. DATA MANAGEMENT...........................................................................................53
9. STATISTICAL CONSIDERATIONS AND DATA ANALYSES.................................53
9.1.
Hypotheses.................................................................................................53
9.2.
Sample Size Considerations.......................................................................53
9.2.1.
Sample Size Assumptions...........................................................53
9.2.2.
Sample Size Sensitivity................................................................54
9.3.
Data Analysis Considerations.....................................................................54
9.3.1.
Analysis Populations....................................................................54
9.3.2.
Interim Analysis...........................................................................55


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9.4.
Key Elements of Analysis Plan...................................................................55
9.4.1.
Primary Analyses.........................................................................55
9.4.2.
Secondary Analyses....................................................................55
9.4.3.
Other Analyses............................................................................56
9.4.3.1.
Other Efficacy Analyses.............................................56
9.4.3.2.
Safety Analyses..........................................................56
9.4.3.2.1.
Extent of Exposure.................................56
9.4.3.2.2.
Adverse Events......................................56
9.4.3.2.3.
Clinical Laboratory Evaluations...............56
9.4.3.2.4.
Other Safety Measures...........................57
9.4.3.2.5.
Immunogenicity......................................57
10. STUDY GOVERNANCE CONSIDERATIONS........................................................57
10.1. Posting of Information on Publicly Available Clinical Trial Registers............57
10.2. Regulatory and Ethical Considerations, Including the Informed 
Consent Process........................................................................................57
10.2.1. Written Informed Consent/Assent................................................58
10.3. Quality Control (Study Monitoring)..............................................................58
10.4. Quality Assurance.......................................................................................58
10.5. Study and Site Closure...............................................................................59
10.6. Records Retention......................................................................................59
10.7. Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication.................60
11.REFERENCES.......................................................................................................61
12.APPENDICES........................................................................................................65
12.1. Appendix 1 –Abbreviations and Trademarks..............................................65
12.2. Appendix 2: Anaphylaxis Criteria................................................................68
12.3. Appendix 3: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in FRP and Collection of Pregnancy Information.......................69
12.3.1. Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP)..............69
12.3.2. Collection of Pregnancy Information............................................70
12.4. Appendix 4: New York Heart Association Functional Classification 
of Congestive Heart Failure........................................................................71
12.5. Appendix 5: Liver Safety Required Actions and Follow up 
Assessments..............................................................................................72
12.6. Appendix 6: Cardiovascular Screening Questions......................................75
12.7. Appendix 7: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................76
12.7.1. Definition of Adverse Events........................................................76
12.7.2. Definition of Serious Adverse Events...........................................77
12.7.3. Definition of Cardiovascular Events.............................................79
12.7.4. Recording of AEs and SAEs........................................................79
12.7.5. Evaluating AEs and SAEs............................................................80
12.7.6. Reporting of SAEs to GSK...........................................................81
12.8. Appendix 8-Asthma control Questionnaire.................................................82
12.9. Appendix 9-St.Geroge’s Respiratory Questionnaire...................................84
12.10.Appendix 10-Subject Rated Response to Therapy.....................................90
12.11.Appendix 11-Clinician rated response to Therapy......................................91


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12.12.Appendix 12-Treatment Satisfaction Questionnaire for Medication 
(TSQM-9)....................................................................................................92
12.13.Appendix 13–Exit Interview Guide.............................................................95
12.14.Appendix 14: Genetic Research.................................................................97
12.15.Appendix 15-Country Specific Requirements...........................................100
12.16.Appendix 16: Protocol changes................................................................101


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1.
PROTOCOL SYNOPSIS FOR STUDY 204471
Rationale
Severe asthma is associated with substantial morbidity and mortality and a large fraction 
of the health care cost among patients withasthma. Eosinophilic airways are associated 
with high risk of asthma exacerbations.  Mepolizumab is an anti-interleukin-5 ( IL-5) 
monoclonal antibody that neutralizesIL-5 and reduceseosinophil countsin both sputum 
and blood.Clinical trials have shown that mepolizumab reduces asthma symptoms, 
exacerbations, improves quality of life and is a promising intervention to manage patients 
with severe eosinophilic asthma.
Omalizumab an anti-immunoglobulin E (IgE) monoclonal antibody (mAb) is effective in 
the treatment of moderate to severe allergic asthma.  However there are some patients 
who continue to have asthma that is not optimally controlled with omalizumab treatment. 
Allergic and eosinophilic severe asthma are recognized as two distinctive phenotypes 
with a degree of overlap(~30%), but with differences in their associationswith 
inflammatory biomarkers. Mepolizumab has been shown to be effective in subjects with 
both atopic and non-atopic asthma. 
The aim of this study is to investigate whether subjects not optimally controlledon their 
current omalizumab treatment, who are eligible for therapy with mepolizumab can be 
effectively and safelyswitched to treatment with mepolizumabto improve asthma 
control.As this is a single arm study, comparisons will be made back to baseline.
The study will provide data on the efficacy, safety, immunogenicity,and tolerability of 
mepolizumab when switched directly from omalizumab without any wash-out.  In 
clinical practice, mepolizumab would likely be started 2-4 weeks after the last dose of 
omalizumab. The learnings from this study may help guide physicians when substituting 
one biologic with another for the treatment of patients with severeeosinophilic asthma.
Objective(s)/Endpoint(s)
Objectives
Endpoints
Primary
To describe in a pragmatic setting
whether there is an improvement in 
asthma control,from the beginning to the 
end of the study, when directly switched
from omalizumabto mepolizumab in 
subjects with a severe eosinophilic 
asthma phenotypenot optimally 
controlled on omalizumab
Mean change from baseline in 
Asthma Control Questionnaire-5 
(ACQ-5) score at Week 32
Secondary
To determinewhether there is an 
Mean change from baseline in St. 


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Objectives
Endpoints
improvement in Health related Quality of 
Life (HR-QoL)whendirectly switchedto 
mepolizumab, in subjects with a severe 
eosinophilic asthma phenotype not 
optimally controlled on omalizumab
George’s Respiratory Questionnaire 
(SGRQ)score at Week 32
To determine the frequency of asthma 
exacerbations, whendirectlyswitched to 
mepolizumab, insubjects with a severe 
eosinophilic asthma phenotype not 
optimally controlled on omalizumab. 
Frequency of clinically significant 
asthma exacerbationsover 32 week 
treatment
To evaluate the pharmacodynamic effects 
when directlyswitched to mepolizumab,
in subjects with a severe eosinophilic
asthma phenotype not optimally 
controlled on omalizumab.

Ratio to baseline in blood 
eosinophils at Week 32
Overall Design
The study will be a multi-centre, open-label single arm trial.  Patients with severe 
eosinophilic asthma who are receiving omalizumab, but are not optimally controlled will 
be eligible to participate and will be identified through the ACQ-5 with a screening (Visit 
1) and baseline (Visit 2) score of ≥1.5 and a history of ≥2 exacerbations in the past 12 
months.  For those subjects receiving omalizumab for 8 months, at least 1 exacerbation 
must be while on omalizumab treatment. 
Subjects meeting all the inclusion/exclusion criteria at screening Visit 1, will enter a run-
in period for a minimum of one week and a up to 4 weeks.
Subjects will remain on their current maintenance therapy including omalizumab 
throughout the run-in period. At Visit 2 subjects will discontinue their omalizumab 
treatment and be switched to mepolizumab 100mg subcutaneous (SC) every 4 weeks. 
The treatment period is 32 weeks, including an Exit Visit/Early Withdrawal Visit, 4 
weeks following the subject’s last dose of mepolizumab. Except for omalizumab, 
subjects will remain on their current maintenance therapy throughout the treatment
period.
Efficacy and safety assessments include blood tests, physical exam, ECGs, vital signs, 
pulmonary function tests (PFTs)and questionnaires(including ACQ-5, SGRQ, 
Treatmentsatisfaction questionnaireandpatient and physician rated response to therapy).
An optional Exit interview will be conducted during the Exit Visit/Early Withdrawal 
Visit in a subset of participating sites and in a subset of patients who consent to 
participate.


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The investigator is responsible for ensuring that consideration has been given to the post-
study care of the patient’s medical condition. At the end of the study, subjects may be 
prescribed appropriate alternative asthma therapy if needed and as determined by the 
study Investigator.
The study design is shown in the figure below
Treatment Arms and Duration
Eligible patients will receive mepolizumab 100 mg SC every 4 weeks for 28 weeksand 
will be requested to participate in the study for a maximum of 38weeks inclusive of the 
Exit Visit.
Approximately 155subjects will be screened to achieve 120 treated with mepolizumab. 
Assuming a 15% withdrawal rate, this will result in approximately 100 evaluable subjects 
completing 32 weeks of mepolizumab treatment.
Sample Size and Analysis
With a sample size of 120 treated subjects, it is estimated that this study has over 90% 
power to detect a statistically significant improvement from baseline. Further it is 
estimated that a significant improvement over the ‘placebo effect’ of -0.55 from baseline 
in ACQ score will be observed at the two-sided 5% level of significance if the observed 
change from baseline is at least -0.74 units.
If the true change from baseline is -0.86 units, then the study has a probability of 90% of 
observing a change from baseline of at least -0.74 unitsand therefore the study has 90% 
power for declaring statistical significance over the ‘placebo effect’  
Analysis of change from baseline in ACQ score will be performed usingmixed models 
repeated measures (MMRM) analysis, allowing for covariates of baseline ACQ score, 
region, baseline maintenance oral corticosteroid (OCS)therapy, exacerbations in the year 
prior to the study (as an ordinal variable), visit and aninteraction term for visit by 
baselineACQ score.


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2.
INTRODUCTION
Eosinophilic inflammation of the airways specifically plays a central role in the 
pathogenesis of asthma [Kim, 2004].  Eosinophils are not present in healthy lungs, and 
are thought to play a major role in maintaining airway inflammation [Walsh,2010;
Wadsworth, 2011].  Studies inthe severe asthma patients have shown that more than half 
of these patients have persistent eosinophilic (>3%sputum eosinophils) airway 
inflammation despite corticosteroid therapy [Wenzel, 2005;ENFUMOSA, 2003].
Of the inflammatory mediators postulated to contribute to the regulation of eosinophil 
trafficking and degranulation, interleukin-5 (IL-5)hasbeen identified as the main 
cytokine to selectively regulate eosinophil function[Sumitas, 2011].IL-5 specifically 
promotes the differentiation of eosinophils in the bone marrow and stimulates the release 
of eosinophils from the bone marrow into peripheral circulation[Sanderson1992; 
Collins, 1995]. Binding of IL-5 to eosinophil-expressingIL-5 receptors results in 
enhanced adhesion of eosinophils to endothelial cells and increased eosinophil survival 
and activation [Lopez, 1988].
Mepolizumab is a humanized anti-interleukin 5 (anti-IL5) immunoglobulin G (IgG
Kappa) monoclonal antibody (mAb)that binds to and inactivatesIL-5. Mepolizumabhas 
completed a phase III program and is under regulatory review for market authorization in 
a number of countries. 
Recently completed studies in severe eosinophilic asthma have demonstrated 
mepolizumab to be effective in reducing asthma symptoms and exacerbations and in 
improving respiratory quality of life [Pavord, 2012; Ortega, 2014b; Bel, 2014].
2.1.
Study Rationale
Severe asthma is associated with substantial morbidity andmortality and a large fraction 
of the health care cost among patients of asthma[Wenzel, 2012]. Eosinophilic airways, 
and high eosinohil count blood is associated with frequent asthma exacerbations (Tran, 
2014). Completed clinical trials have shown that mepolizumab,neutralizesIL-5 and 
reduceseosinophil countsin both sputum and blood(Pavord, 2012)and is a promising 
intervention to managepatients with severe eosinophilic asthma.
Omalizumab an anti-immunoglobulin E (IgE) monoclonal antibody (mAb) is effective in 
the treatment of moderate to severe allergic asthma. [European medicines Agency 
EMEA, 2015] summary of product characteristics (SmPC);XolairUS prescribing 
information, 2014].However there are some patients who continue to have asthma that is 
not optimally controlled with omalizumab treatment. 
The key principal of treatment management is to achieve asthma control with a goal of 
improving symptoms and reducing future risk [Chung, 2014]. Due to the heterogeneous 
nature of asthma, no single clinical parameter completely reflects asthma control. 
Multiple measures are important as each may assess different domains of disease, 
including health related quality of life.


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Allergic and eosinophilic severe asthma are recognized as two distinctive phenotypes 
with a degree of overlap(~30 %)butwith also differences in their associationswith 
inflammatory biomarkers [Chung, 2014].  Mepolizumab has been shown to be effective 
in subjects with both atopic and non-atopic asthma [Ortega, 2014a]. With the availability 
of mAbs with different mechanismsofaction,the opportunity for personalized and 
specifically targeted treatment becomes possible.
The aim of the present study is to investigate whether subjects not optimally controlled
on their current omalizumab treatment, who are eligible for therapy with mepolizumab 
can be effectively and safelyswitched to treatment with mepolizumabto improve asthma 
control.As this is a single arm study, comparisons will be made back to baseline.
The study will provide data on the efficacy, safety, immunogenicity,and tolerability of 
mepolizumab when switched directly from omalizumab without a wash-out period of 
approximately 4.5 months. In clinical practice, mepolizumab would likely be started 2-4 
weeks after the last dose of omalizumab. The learningsfrom this study may help 
physicianswhen substituting one biologic with another for the treatment of patients with 
severe eosinophilic asthma. 
2.2.
Brief Background
Severe asthma represents approximately 5-10% of the asthma population and is 
associated with a greater frequency of asthma exacerbations, and a greater symptom 
burden [Chung, 2014; Moore, 2007]. Asthma is a heterogeneous condition characterized 
by airflow obstruction, bronchial hyper responsiveness and underlying inflammation. 
Eosinophils are major effector cells involved in the initiation and propagation of diverse 
inflammatory responses and are considered a central mediator of asthma pathology 
[Catley, 2011].  An increase in eosinophils is associated with cough, airway remodelling, 
worse lung function and asthma exacerbations which are, in-turn, associated with a more 
rapid decline in forced expiratory volume in 1 second(FEV
1)[Desai, 2012; O’Byrne, 
2011].
Mepolizumab is a humanised monoclonal antibody that binds to and inactivate 
interleukin-5, a cytokine that recruits eosinophils from the bone marrow and promotes the 
persistence and activation of these cells [Sumitas, 2011; Pavord, 2012].
Completed phase III studies with mepolizumab have demonstrated the efficacy of 
mepolizumab and support the use of mepolizumab 100mg subcutaneous(SC)every 4 
weeks as an add-on therapy for the treatment of severe eosinophilic asthma. Compared 
with placebo, mepolizumab has been shown to: 
Reduce the rate of clinically significant exacerbations by approximately 50%.  
[Pavord, 2012, Ortega, 2014b].
Reduce the rate of exacerbations requiring hospitalisations and/or Emergency 
Department (ED) visits, with reductions ranging from 32% to 61% [Pavord, 2012, 
Ortega, 2014b].


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Produce statistically significant and/or clinically relevant improvements in lung 
function based on FEV1,improvement in Asthma Control Questionnaire(ACQ-5), 
St. George’s Respiratory Questionnaire(SGRQ)and clinician and subject-rated 
overall response to therapy [Ortega, 2014b, Bel, 2014]
Consistently reduce blood eosinophil levels detected at Week4 and sustained for the 
duration of treatment [Pavord, 2012, Ortega, 2014b, Bel, 2014].
Additional details of the pharmacology, efficacy and safety can be found in the 
Investigator Brochure (IB).
3.
OBJECTIVE(S) AND ENDPOINT(S)
Table1
Study Objectives and Endpoints
Objectives
Endpoints
Primary
To descr
ibe 
in a pragmat
ic sett
ingwhether 
there 
is an 
improvement 
in asthma 
contro
l,from the beg
inn
ing to the end of the 
study, when d
irect
ly sw
itchedfrom 
oma
l
izumabto mepo
l
izumabin sub
jects w
ith 
a severe eos
inoph
i
l
ic asthma phenotype not 
opt
ima
l
ly contro
l
led on oma
l
izumab
Mean change from baseline in ACQ-
5 score at Week 32
Secondary
To determinewhether there is an 
improvement in Health related Quality of 
Life(HR-QoL)whendirectly switchedto 
mepolizumab, in subjects with a severe 
eosinophilic asthma phenotype not 
optimally controlled on omalizumab
Mean change from baseline in 
SGRQ score at Week 32
To determine the frequency of asthma 
exacerbations, when directlyswitched to 
mepolizumab, insubjects with a severe 
eosinophilic asthma phenotype not 
optimally controlled on omalizumab. 
Frequency of clinically significant 
asthma exacerbationsover 32 week 
treatment
To evaluate the pharmacodynamic effects 
whendirectlyswitched to mepolizumab,
in subjects with a severe eosinophilic
asthma phenotype not optimally 
controlled on omalizumab.

Ratio to baseline in blood 
eosinophils at Week 32
Others
To determine the response to asthma 
clinical parameters when directly 
switched to mepolizumabin subjects 
Percentage of subjects achieving a 
0.5-point or greater reduction from 


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Objectives
Endpoints
with a severe eosinophilic asthma 
phenotype not optimally controlled on 
omalizumab.
baseline in ACQ-5score at Week 32
Percentage of subjects achieving a 4-
point or greater reduction from 
baseline in SGRQ score at Week 32
Mean change from baseline in pre-
and post bronchodilator FEV
1 at 
Week 32
Frequency of exacerbations 
requiring EDvisit/hospitalization 
during the treatment period 

Subject/Clinician rated response to 
therapy

Mean change from baseline in 
treatmentsatisfaction questionnaire
Exploratory
To determine the effect on inflammatory 
biomarkers, when directly switched to 
mepolizumab, in subjectswith a severe 
eosinophilic asthma phenotypenot 
optimally controlled on omalizumab 
To characterize patient treatment benefit 
of mepolizumab
Change from baseline in some 
inflammatory biomarkers expression 
at week 32.
Subject Exit Interviews
Safety
To determine the safety, immunogenicity 
and tolerability of mepolizumab when 
directlyswitched to mepolizumab, in 
subjects with a severe eosinophilic 
asthma phenotype not optimally 
controlled on omalizumab.

Incidence and frequency of 
Adverse/Serious Adverse Events 
(including systemic and injection site 
reactions)

Clinically significant change in 
electrocardiogram(ECGs)

Clinically significant change in vital 
signs
Incidence of immunogenicity


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4.
STUDY DESIGN
4.1.
Overall Design
The study will be a multi-centre, open-label single arm trial. Patients with severe 
eosinophilic asthma who are receiving omalizumab, but are not optimally controlled will 
be eligible to participate and will be identified through the ACQ-5 with a screening (Visit 
1) and baseline(Visit 2)score of ≥1.5 and a history of ≥2 exacerbations in the past 12 
months. For those subjects receiving omalizumab for 8 months, at least 1 exacerbation 
must be while on omalizumab treatment. 
Subjects meeting all the inclusion/exclusion criteria at screening Visit 1, will enter a run-
in period for a minimum of one week and a up to 4 weeks to assess subjects’eligibility 
and compliance with study-related procedures. 
Subjects will remain on their current maintenance therapy throughout the run-in period, 
including omalizumab.  At Visit 2 subjects will discontinue omalizumab treatment and be 
switched to mepolizumab 100 mg SCevery 4 weeks.Except for omalizumab, subjects 
will remain on their current maintenance therapy throughout the open-labeltreatment 
period.
Every subject, including those who withdraw early from the study, will be asked to return 
for an Exit Visit approximately 4 weeks after their last dose of study treatment.  
An Exit interview will be conducted during the Exit Visit or early withdrawal Visit in a 
subset of participating sites and in a subset of patient who consent to participate.
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the patient’s medical condition. At the end of the study, subjects may be 
prescribed appropriate alternative asthma therapy if needed and as determined by the 
study Investigator.
Figure 1
Study Design


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4.2.
Treatment Arms and Duration
Eligible patients will receive mepolizumab 100 mg SC every 4 weeks for 28 weeksand
will be requested to participate in the study for a maximum of 38weeks (Visit 0to the 
ExitVisit(Visit 10), inclusive asdescribed inTable 2.
Table 2
Study phases
Phase
Phase Title
Duration
Description
1
Pre-screening
0to 2 weeks
At the Pre-screening Visit,details about 
the study and procedures will be explained 
through the informed consent process. The 
Pre-screening Visit (Visit 0) can occur on 
the same day as the Screening Visit (Visit 
1) but must be completed prior to 
initiating any Visit 1 procedures. 
2
Screening / 
Run-in
1 to 4 weeks
Subjects who meet all the eligibility 
criteria at Screening, will enter the run-in 
period for a minimum of 1 week and a 
maximum of 4 weeks in order to continue 
to assess the subject’s eligibility for the 
study. Subjects who experience an asthma 
exacerbation during the run-in period 
should receive treatment for their 
exacerbation and remain in the run-in 
period until the investigator considers that 
the subject has returned to their baseline 
asthma status for at least one week.  Those 
subjects that are not eligible to continue in 
the study at the end of the 4 week run-in 
period will be deemed run-in failures (see
Section 5.4).
3
Treatment
32 weeks
At Visit 2 (Week 0) those subjects who 
successfully complete the run-in period as 
well as meet the other pre-defined 
eligibility and continuation to treatment 
criteria (see Section 5.3) will receive 
mepolizumab 100 mg SC every 4 weeks 
for a total of 8 doses. 
The treatment period will conclude with 
subjects completingExit Visit (Visit 10) 
assessments approximately 4 weeks after 
the subject was administered their last 
dose of study treatment at Visit 9. 


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4.2.1.
Exit Interview
A Single optional Exit Interview to characterize the patient experience of change in 
asthma will be conducted at the Exit Visit (Visit 10) or Early Withdrawal Visit in a sub-
set of sites and in a subset of patients  who consent to participate (See Section 7.3.2.2). 
4.3.
Type and Number of Subjects
Approximately 155subjects will be screened to achieve 120treatedwith mepolizumab. 
Assuming a 15% withdrawal rate, this will result in approximately100 evaluable subjects
completing 32 weeks of mepolizumab treatment.
4.4.
Design Justification
The study is designedto investigate whether subjects not optimally controlledon current 
omalizumab can be safelyand effectively switched to treatment with mepolizumab.  
Subjects enrolled into the study will already be receiving omalizumab and therefore have 
previously been identified as suitable for omalizumab treatment according to the product 
label, and any additional criteria applicable in the participating countries.The dose of 
omalizumab should previously have been determined by the subject’s weight and level of 
IgE. 
Subjects with severe asthma who are not optimally controlled on omalizumab will be 
identified through the ACQ-5 with a score of ≥1.5, at both Visits 1 and 2 respectively and 
a history of ≥2 exacerbations in the past 12 months.For those subjects receiving 
omalizumab for 8 months, at least 1 exacerbation must be while on omalizumab 
treatment. 
The treatmentduration of 32 weeks(inclusive of Exit Visit)will enable an adequate time 
to assess the impact of mepolizumab on ACQ-5, lung function and SGRQ after wash-out 
of omalizumab, usually 5 half-lives or 4.5 months.  In addition, safety, immunogenicity 
and tolerability endpoints will be assessed during the study.
An open-label single arm design with a direct switch, i.e. the substitution of one biologic 
with another biologic with no wash-out period,is expected to reflect clinical practice.
4.5.
Dose Justification
The dose selection is based on previousexperience from the mepolizumab Phase III 
program, including two Phase IIIplacebo-controlled studies MEA115588[Ortega, 
2014b]and MEA115575[Bel, 2014]that demonstrated the safety and efficacy of 
mepolizumab at a dose of 100 mg SCevery 4 weeks.


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4.6.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
mepolizumab (SB-240563)can be found in the Investigator’s Brochure.  The following 
section outlines the risk assessment and mitigation strategy for this protocol:  
4.6.1.
Risk Assessment
Across the mepolizumab development program, chronic dosing of mepolizumab up 
to 750mg intravenous (IV) every 4 weekshas been associated with an adverse event 
(AE) profile similar to placebo (both dosed in addition to standard of care therapy), 
in the patient populations studied, including mild to moderate asthma and severe 
refractory asthma.  
The majority of reports of systemic non-allergic and allergic (i.e., hypersensitivity) 
reactions have been non-serious and resolved without sequelae following minimal 
supportive care. There have been rare reports of serious reactions. To date, in the 
phase II and III program in severe asthma there have been no reports of severe life-
threatening anaphylaxis related to mepolizumab.
Anti-drug antibodies (ADA) have been observed infrequently and have not been 
associated with negative clinical outcomes; there has been no evidence of untoward 
or persistent neutralizing antibodies (NaB) at any dose.
Infection rates have been similar across treatment groups. The data to date do not 
support an association between treatment with mepolizumab and an increased risk of 
clinically serious opportunistic or parasitic infections.
Reports of malignancies have been similar between treatment groups in placebo-
controlled trials.  The known biology of IL-5 and eosinophils suggest that blocking 
the binding of IL-5 to its receptor with mepolizumab would not likely induce an 
immuno-suppressive effect that would impair host surveillance against malignancy.
In previous studies patients on omalizumab and other monoclonal antibodies have 
been excluded to minimise the risk of confounding factors. Cytochrome P450 
enzymes, efflux pumps and protein-binding mechanisms are not involved in the 
clearance of mepolizumab; furthermore mepolizumab target is specific (cytokine IL-
5). The potential for drug-drug interactions with mepolizumab is therefore 
considered low. 
Summaries of findings from both clinical and non-clinical studies conducted with 
mepolizumab can be found in the IB.  The following section (Table 3) outlines the risk 
assessment and mitigation strategy for this protocol:


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Table 3
Risk Assessment for mepolizumab
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) mepolizumab
R
isk of System
ic A
l
lerg
ic and Non-a
l
lerg
ic 
React
ions, 
inc
lud
ing Anaphy
lax
is
B
iopharmaceut
ica
l products adm
in
istered 
subcutaneous
ly may e
l
ic
itsystem
ic (e.g. 
hypersens
it
iv
ity) and 
loca
l s
ite react
ions.
React
ions reported to date across the mepo
l
izumab 
program are summar
ized 
in the IB; see 
‘Spec
ia
l 
Warn
ings and Spec
ia
l Precaut
ions for Use
’ sect
ion 
located 
in 
Sect
ion 6 t
it
led 
‘Summary of Data and 
Gu
idance for the Invest
igator
’.
Da
i
ly mon
itor
ing of ser
ious adverse events (SAEs) by 
med
ica
l mon
itor; regu
lar systemat
ic rev
iew of 
adverse event (AE)/SAE data from ongo
ing stud
ies 
by a GSK safety rev
iew team. 
Spec
if
ic case report form (CRF) pages ut
i
l
izedfor 
targeted co
l
lect
ion of react
ions data.
Use of Jo
int Nat
iona
l Inst
itute of A
l
lergy and 
Infect
ious D
iseases(NIAID)/ Food A
l
lergy and 
Anaphy
lax
is Network(FAAN)2nd Sympos
ium on 
Anaphy
lax
is to co
l
lect data on reports of anaphy
lax
is 
(seeAppend
ix 7)
Sub
jects are to be mon
itored post-in
ject
ion for one 
hourfor the f
irst 3 in
ject
ions
, then per 
inst
itut
iona
l 
gu
ide
l
ines.
R
isk of Immunogen
ic
ity
B
iopharmaceut
ica
l products may e
l
ic
it ant
i-drug 
ant
ibody (ADA) and neutra
l
iz
ing ant
ibody (NaB), 
wh
ich has the potent
ia
l to modu
late pharmacok
inet
ic 
(PK), pharmacodynam
ic (PD) or produce adverse 
react
ions. However, human
ized and fu
l
ly human 
ant
ibod
ies are 
less 
immunogen
ic than mouse or 
ch
imer
ic monoc
lona
l ant
ibod
ies.
Immunogen
ic
ity data reported to date across the 
mepo
l
izumab deve
lopment program are summar
ized 
in the IB; See 
‘C
l
in
ica
l Immunogen
ic
ity
’ and a 
summary of 
immunogen
ic
ity f
ind
ings 
in the 
‘Other 
Potent
ia
l
ly C
l
in
ica
l
ly Re
levant Informat
ion for the 
B
lood samp
les are co
l
lected 
in c
l
in
ica
l stud
ies for 
detect
ion of both ADA and NaB
See prev
ious r
isk for m
it
igat
ion strategy re
lated to 
c
l
in
ica
l safety r
isks


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Invest
igator
’ sect
ion t
it
led‘Summary of Data and 
Gu
idance for the Invest
igator
’.
Potent
ia
l r
isk for adverse card
iovascu
lar (CV) effects
Mepo
l
izumab b
ind
ing was restr
icted to human 
lympho
id t
issues 
in an 
immuno
-h
istochem
istry t
issue 
b
ind
ing study suggest
ing a 
low 
l
ike
l
ihood of non-
pharmaco
log
ic effects on card
iovascu
lar (CV) 
funct
ion. 
No AEs concern
ing card
iac conduct
ion or 
repo
lar
izat
ion ev
ident 
in cynomo
lgus monkeys at 
doses at 
least 10-fo
ld 
in excess of humans dosed at 
10 mg/kg or 750 mg.
No c
l
in
ica
l
ly re
levant trends observed 
in ECG data 
in 
humans.
In one study 
in sub
jects w
ith severe refractory 
asthma, card
iac events were reported 
in s
im
i
lar 
frequenc
ies across treatment groups w
ith a sma
l
l 
numer
ica
l 
increase observed 
in ser
ious 
ischem
ic 
card
iac events 
in the mepo
l
izumab-treated groups. 
However, an 
integrated safety ana
lys
is of a
l
l p
lacebo-
contro
l
led mu
lt
ip
le dose asthma tr
ials showed s
im
i
lar 
frequency of SAEs reported overa
l
l from the card
iac 
and vascu
lar system organ c
lass (SOC). Add
it
iona
l
ly, 
s
im
i
lar f
ind
ings were observed 
in other SOCs w
ith 
thrombot
ic events (e.g., stroke 
in the Nervous System 
SOC).
Sub
jects w
ith uncontro
lled, severe or c
l
in
ica
l
ly 
s
ign
if
icant card
iovascu
lar d
isease are exc
luded from 
study part
ic
ipat
ion.
Da
i
ly mon
itor
ing of SAEs by med
ica
l mon
itor; regu
lar 
systemat
ic rev
iew of AE/SAE data from ongo
ing 
stud
ies by a GSK safety rev
iew team.
CV mon
itor
ing for study 
inc
ludes:
ECG mon
itor
ing dur
ing the tr
ia
l
Use of standard
ized case report form (CRFs) to 
co
l
lect re
levant data on CV as per GSK standard 
pract
ice.


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Potent
ia
l r
isk for 
increase 
in 
infect
ions-a theoret
ica
l 
concern w
ith b
io
log
ics 
The pharmaco
log
ica
l propert
ies of mepo
l
izumab 
suggest the r
isk 
is 
low.
No ev
idence of 
increased 
inc
idence of 
infect
ions 
in 
any prec
l
in
ica
l stud
ies.
Mur
ine data demonstrate that IL-5 antagon
ism 
is 
un
l
ike
ly to 
inf
luence ce
l
lu
lar or humora
l 
immun
ity, 
part
icu
lar
ly 
in response to paras
it
ic 
infect
ions.  
No mepo
l
izumab-re
lated effects on 
lymphocyte 
Immunophenotyp
ing 
in monkeys or humans, 
inc
lud
ing T
-ce
l
l act
ivat
ion, d
istr
ibut
ion of (c
luster of 
d
ifferent
iat
ion )CD4/CD8 subtypes or T he
lper ce
l
l 
(Th1/Th2) cytok
ine patterns, B-ce
l
ls, natura
l k
i
l
ler 
(NK) ce
l
ls or γδ-T-ce
l
ls. 
An 
integrated safety ana
lys
is of a
l
l p
lacebo-contro
l
led 
mu
lt
ip
le dose asthma tr
ia
ls showed s
im
i
lar reports of 
infect
ions, 
inc
lud
ing ser
ious and opportun
ist
ic, across 
treatment groups 
inc
lud
ing p
lacebo. 
Infect
ions reported to date across the mepo
l
izumab 
deve
lopment program are summar
ized 
in the IB; see 
‘Spec
ia
l Precaut
ions and Warn
ings
’ (for exc
lus
ion of 
sub
jects w
ith under
ly
ing paras
it
ic 
infect
ions) and 
‘Undes
irab
le Effects
’ (for very common 
infect
ions of 
nasopharyng
it
is, upper resp
iratory tract 
infect
ion 
(URTI), rh
in
it
is and bronch
it
is reported 
in other 
pat
ient popu
lat
ions) sect
ions t
it
led 
‘Summary of Data 
and Gu
idance for the Invest
igator
’.
Da
i
ly mon
itor
ing of SAEs by the med
ica
l mon
itor; 
regu
lar systemat
ic rev
iew ofAE/SAE data from 
ongo
ing stud
ies by a GSK safety rev
iew team.
Standard safety assessments to be conducted as 
out
l
ined 
in protoco
l
Potent
ia
l r
isk for 
increase 
in ma
l
ignanc
ies-theoret
ica
l 
concern w
ith b
io
log
ics. 
B
lockage of IL-5 
is not assoc
iated w
ith genera
l
ized 
immune
-suppress
ion or 
impa
ired host res
istance.
Ro
le of IL-5 and eos
inoph
i
ls 
in tumor surve
i
l
lance 
is 
not fu
l
ly character
ised 
in the 
l
iterature. 
No ev
idence of defect
ive tumor surve
i
l
lance 
in IL-5 or 
Da
i
ly mon
itor
ing of SAEs by med
ica
l mon
itor; regu
lar 
systemat
ic rev
iew of AE/SAE data from ongo
ing 
stud
ies by a GSK safety rev
iew team 
Standard safety assessments to be conducted as 
out
l
ined 
in protoco
l


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
eos
inoph
i
l-def
ic
ient m
ice. 
D
irect assessmentof the carc
inogen
ic potent
ia
l of 
long
-term IL-5 b
lockade 
in rodent mode
ls not 
techn
ica
l
ly feas
ib
le. 
An 
integrated safety ana
lys
is of a
l
l p
lacebo-contro
l
led 
mu
lt
ip
le dose asthma tr
ia
ls showed s
im
i
lar reports of 
ma
l
ignanc
ies across treatment groups 
inc
lud
ing 
p
lacebo.
Ma
l
ignanc
ies reported to date across the 
mepo
l
izumab deve
lopment program are summar
ized 
in the IB.
Potent
ia
l r
isk for rebound eos
inoph
i
l
ia w
ith assoc
iated 
c
l
in
ica
l consequences.
Ear
ly pub
l
ished data w
ith Scher
ing-P
lough ant
i-IL5 
mAb suggested potent
ia
l for rebound eos
inoph
i
l
ia 
and d
isease exacerbat
ion when treatment was 
stopped [K
im, 2004; Gevaert, 2006]; however, no 
standard def
in
it
ion of rebound was used and cr
iter
ia 
for report
ing were var
iab
le. 
There have been no verbat
im reports of 
‘rebound
’ 
from comp
leted c
l
in
ica
l tr
ia
ls of sub
jects w
ith asthma, 
atop
ic dermat
it
is and eos
inoph
i
l
ic esophag
it
is. 
Furthermore, the data do not support an exaggerated 
return of symptoms after cessat
ion of treatment.
Da
i
ly mon
itor
ing of SAEs by med
ica
l mon
itor; regu
lar 
systemat
ic rev
iew of AE/SAE data from ongo
ing 
stud
ies by a GSK safety rev
iew team
Standard safety assessments to be conducted as 
out
l
ined 
in protoco
l.
Study Procedures
Potent
ia
l r
isk for 
in
jury w
ith ph
lebotomy
R
isks w
ith ph
lebotomy 
inc
lude bru
is
ing, b
leed
ing, 
infect
ion, nerve damage.
Procedures to be performed by tra
ined personne
l 
(
i.e., study nurse) 


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4.6.2.
Benefit Assessment
Data from earlierstudies [Haldar2009; Pavord, 2012] attest to the clinical utility of 
mepolizumab in the treatment of severe eosinophilic asthma, as do the data from recently 
completed Phase III studies MEA115575 and MEA115588[Bel, 2014; Ortega, 2014b]. 
In this study, benefit considerations for a subject may include:

Potential benefit of receiving a drug which may have clinical utilityin patients 
with uncontrolled asthma symptoms
Medical evaluations/assessments associated with study procedures
4.6.3.
Overall Benefit: RiskConclusion
Current data from mepolizumab clinical development have demonstrated itsclinical 
utility in the treatment of eosinophilic asthma. Data from the Phase III asthma 
programme with mepolizumab demonstrated, compared to placebo, a reduction in asthma 
exacerbations, improvements in asthma control and quality of life (as measured by the 
ACQ and SGRQ, respectively), improvements in lung function and a reduction in steroid 
use in those subjects on chronic OCStreatment.
To date, the safety profile of mepolizumab has beensimilar to placeboand AEs reported 
commonly are non-serious and manageable with minimal supportive care.  Furthermore, 
there have been no safety concerns identified or signals observed with mepolizumab that 
would preclude further investigation in severe asthma.
Taking into account the measures taken to minimize risk to subjects participating in this 
study, the potential risks identified in association with mepolizumab are justified by the 
anticipated benefits that may be afforded to a subject with severe asthma. Therefore, the 
Sponsor considers that the efficacy, safety and tolerability of mepolizumab is justified in 
study 204471 with a positive benefit/risk ratio. 
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific informationregarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in theIB brochure
Deviations from inclusion and exclusion criteria(see Inclusion CriteriaSection 5.1, 
Exclusion CriteriaSection 5.2and continuation to treatment Section 5.3)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:
AGE
1. At least 12 years of age at the time of signing the informed consent. [For those 
countries where local regulations permit enrolment of adults only, subject recruitment 
will be restricted to those who are 18 years of age]
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. Asthma:A physician diagnosis of asthma for ≥2 years that meetsthe National Heart 
and Lung Institute guidelines [Nationalheart, lung and blood institute(NIH), 2007]or 
GINA guidelines (GINA, 2015]
3. FEV1: Persistent airflow obstruction as indicated by:
For subjects ≥18 years of age at Visit 1, a pre-bronchodilator FEV1<80% predicted 
[Quanjer, 2012] recorded at Visit 1
For subjects 12-17 years of age at Visit 1, a pre-bronchodilator FEV1<90% 
predicted [Quanjer, 2012] recorded at Visit 1
OR
FEV1/FVC ratio <0.8 recorded at Visit 1
4. Eosinophilic asthma:  Airway inflammation characterized as eosinophilic in nature 
as indicated by one of the following:
a.A peripheral blood eosinophilcount of ≥300 cells/µL that is related to asthma 
demonstrated in the past 12 months prior to Visit 1 
OR
b. Aperipheral blood eosinophil count of ≥150 cells/µL at Visit 1 that is related to 
asthma. 
5. Inhaled Corticosteroid: A well-documented requirement forregular treatment 
with high-dose inhaled corticosteroid (ICS) in the 12 months prior to Visit 1 with or 
without maintenance oral corticosteroids (OCS).
For 18 years of age and older: 
ICS dose must be ≥880 mcg/day fluticasone propionate (FP) (ex-actuator) or 
equivalent daily
For ICS/LABA combination preparations, the highest approved maintenance 
dose in the local country will meet this ICS criterion.


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TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
For subjects 12-17 years of age at Visit 1:
ICS dose must be ≥440 mcg/day fluticasone propionate (FP) (ex-actuator) or 
equivalent daily
For ICS/LABA combination preparations, the highest approved maintenance dose 
in the local country will meet this ICS criterion.
6. Controller Medication:  Current treatment with an additional controller 
medication, besides ICS, for at least 3 months or a documented failure in the past 
12 months of an additional controller medication for at least 3 successive months.  
[e.g., long-acting beta-2-agonist (LABA), leukotriene receptor antagonist (LTRA), 
long-acting anticholinergic (tiotropium bromide), or theophylline.]
7. Asthma symptoms not optimally controlled: An ACQ-5 score of ≥1.5 recorded 
at Visit 1.
8. Omalizumab Treatment: Receiving omalizumab, based on weight and IgE levels, 
for at least the 4 months prior to Visit 1. 
9. Exacerbationhistory: Previously confirmed history of two or more exacerbations 
requiring treatment with systemic corticosteroids (intramuscular, intravenous, or 
oral)in the 12 months prior to Visit 1 despite the use of high-dose ICS.  For 
subjects receiving omalizumab for ≥8 months, at least one exacerbation must have 
occurred while on omalizumab treatment.  For subjects receiving maintenance oral 
corticosteroids, the corticosteroid treatment for the exacerbations must have been a 
two-fold dose increase or greater.
SEX
10.Male or eligible Female
Females: 
a. Non-reproductive potential defined as:

Pre-menopausal females with one of the following:
Documented tubal ligation
Documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion 
Hysterectomy
Documented Bilateral Oophorectomy

Postmenopausal defined as 12 months of spontaneous amenorrhea [in 
questionable cases a blood sample with simultaneous follicle stimulating 
hormone (FSH) and estradiol levels consistent with menopause (refer to 
laboratory reference ranges for confirmatory levels)].  Females on hormone 


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SEX
replacement therapy (HRT) and whose menopausal status is in doubt will be 
required to use one of the highly effective contraception methods if they wish to 
continue their HRT during the study.  Otherwise, they must discontinue HRT to 
allow confirmation of post-menopausal status prior to study enrolment.
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) (seeAppendix3)from 30 days prior to the first dose of 
study medication and until at least five terminal half-lives OR until any continuing 
pharmacologic effect has ended, whichever is longer,after the last dose of study 
medication and completion of the Exit visit/Early Withdrawal visit.
The investigator is responsible for ensuring that subjects understand how to properly use 
these methods of contraception.
INFORMED CONSENT
11.Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the consent form and in this protocol.
5.2.
Exclusion Criteria
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL) 
1. Concurrent Respiratory Disease: Presence of a known pre-existing, clinically 
important lung condition other than asthma.  This includes current infection, 
bronchiectasis, pulmonary fibrosis, bronchopulmonary aspergillosis, or diagnoses of 
emphysema or chronic bronchitis (chronic obstructive pulmonary disease other than 
asthma) or a history of lung cancer. 
2. Malignancy: A current malignancy or previous history of cancer in remission for 
less than 12 months prior to screening (subjects that had localized carcinoma of the 
skin which was resected for cure will not be excluded).
3. Liver disease:Subjects must not be enrolled in thestudy if:
At screening (Visit 1) ALT >2xULN;and bilirubin >1.5xULN (isolated bilirubin 
>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%)
Current active liver or biliary disease (with the exception of Gilbert’s syndrome or 
asymptomatic gallstones or otherwise stable chronic liver disease per investigator 
assessment).
NOTES: 
Stable chronic liver disease should generally be defined by the absence of ascites, 
encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, 


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CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL) 
or persistent jaundice, or cirrhosis
4. Hepatitis status: Diagnosis of chronic hepatitis B, as evidenced by positive 
Hepatitis B surface antigen (HBsAg) at Visit 1. Chronic stable hepatitis C 
(e.g.,positive hepatitis C antibody test result at screening(Visit 1)or within 3 months 
prior to first dose of study treatment) are acceptable if subject otherwise meets entry 
criteria.
5. Cardiovascular:Subjects who have severe or clinically significant 
cardiovascular disease uncontrolled with standard treatment. Including but not limited 
to:
a. known ejection fraction of <30% OR
b.severe heart failure meeting New York Heart Association Class IV (see
Appendix 4)classification OR
c. hospitalised in the 12 months prior to Visit 1 for severe heart failure 
meeting New York Heart Association Class III(seeAppendix 4)
OR
d. angina diagnosed less than 3 months prior to Visit 1 or at Visit 1 
6. Subjects with QTc> 450 msecor QTc > 480 msec in subjects with Bundle 
Branch Blockat screening Visit 1
NOTES: 
The QTc is the QT interval corrected for heart rate according to Bazett’s formula 
(QTcB), Fridericia’s formula (QTcF), and/or another method, machine-read or 
manually over-read.
The specific formula that will be used to determine eligibility and discontinuation 
for an individual subject should be determined prior to initiation of the study. In 
other words, several different formulae cannot be used to calculate the QTc for an 
individual subject and then the lowest QTc value used to include or discontinue 
the subject from the trial.
For purposes of data analysis, QTcB, QTcF, another QT correction formula, or a 
composite of available values of QTc will be used as specified in the Reporting 
and Analysis Plan (RAP).
7. Other Concurrent Medical Conditions:Subjects who have known, pre-existing, 
clinically significant endocrine, autoimmune, metabolic, neurological, renal, 
gastrointestinal, hepatic, haematological or any other system abnormalities that are 
uncontrolled with standard treatment. 
8. Eosinophilic Diseases:Subjects with other conditions that could lead to elevated 
eosinophils such as Hypereosinophilic Syndromes, including Churg-Strauss Syndrome 
(Eosinophilic Granulomatosis with Polyangiitis; EGPA), or Eosinophilic Esophagitis.  


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CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL) 
Subjects with a known, pre-existing parasitic infestation within 6 months prior to Visit 
1 are also to be excluded.
9. Immunodeficiency:A known immunodeficiency (e.g., human immunodeficiency 
virus –HIV), other than that explained by the use of corticosteroids taken as therapy 
for asthma.
CONCOMITANT MEDICATIONS
10.Other Monoclonal Antibodies: Subjects who have received any monoclonal 
antibody (other than omalizumab) to treat inflammatory disease within 5 half-lives of 
Visit 1.
RELEVANT HABITS
11.Smoking history:Current smokers or former smokers with a smoking history of 
≥10 pack years (number of pack years = (number of cigarettes per day / 20) x number 
of years smoked).  A former smoker is defined as a subject who quit smoking at least 
6 months prior to Screening Visit 1.
12.Alcohol/Substance Abuse: A history (or suspected history) of alcohol misuse or 
substance abuse within 2 years prior to Visit 1.
13.Adherence:Subjects who have known evidence of lack of adherence to 
controller medications and/or ability to follow physician’s recommendations.
CONTRAINDICATIONS 
14.Hypersensitivity:Subjects with allergy/intolerance to a monoclonal antibody or 
biologic.
History of sensitivity to any of the study medications, or components thereof or a 
history of drug or other allergy that, in the opinion of the investigator or Medical 
Monitor, contraindicates their participation.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
15.Investigator opinion: Omalizumab treatment has provided significant clinical 
benefit despite experiencing 2 exacerbations in the past 12 months, and potential 
benefit from a switch to mepolizumab would not outweigh the potential harm after 
omalizumab withdrawal for the subject.
16.Previous participation:Previously participated in any study with mepolizumab 
and received investigational product (including placebo).


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DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
17.Investigational Medications: Subjects who have received treatment with an
investigational drug within the past 30 days or five terminal phase half-lives ofthe 
drug whichever is longer, prior to Screening (V1)(this also includes investigational
formulations of marketed products).
18.Pregnancy: Subjects who are pregnant or breastfeeding. Patientsshould not be 
enrolled if they plan to become pregnant during the time of study participation.
5.3.
Continuation to Treatment Criteria
AtVisit 2,those subjects who fulfil the inclusion/exclusion criteria and who meet the 
continuation to treatment criteria will commencethe studytreatment phaseuntil the 
target of approximately 120 treated subjects is reached.  
In order to receive study treatment subjects must have completed the run-in period and 
musthavefulfilled all inclusion and exclusion criteria described in Section 5.1and 
Section 5.2. In addition to the following:
REQUIRED CRITERIA TO START TREATMENT
1. Not optimally controlled:An ACQ-5 score of ≥1.5 recorded at Visit 2
2. No Asthma Exacerbation:Subjects with an ongoing asthma exacerbation at 
Baseline (Visit 2) should have their Visit 2 delayed until the investigator 
considers the subject has returned to their baseline asthma status for at least 
one week.If the 4-week screening/run-inperiod has elapsed and subjects 
have not returned to their baseline asthma status, then they should be 
considered a run-in failure. An exacerbation is defined as worsening of asthma 
requiring the use of systemic corticosteroids and/or emergency department 
visit, orhospitalisation (see Section 7.3.2.4Clinically Significant Asthma 
Exacerbation).
3. Maintenance Asthma Therapy: No changes in the dose or regimen of ICS 
and/or additional controller medication (except for treatment of an 
exacerbation) during the run-in period. 
4. Last dose of omalizumab: For subjects receiving omalizumab every 4 weeks, 
their last dose must be 3 to 5 weeks prior to Visit 2.  For subjects receiving 
omalizumab every 2 weeks, their last dose must be between1 to 3 weeks prior 
to Visit 2. 
5.4.
Pre-Screening/Screening/Run-in Failures
A subject will be assigned a subject number at the time the informed consent is signed.


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A subject who is assigned a subject number at Visit 0 but does not have any screening 
Visit 1 procedureswill be considered a pre-screen failure.
The following information will be collected in the eCRF for subjects who are pre-screen 
failures:
Date of ICF signature
Demographic information including race, age and gender
Child bearing status assessment for allfemale subjects of reproductivepotential 
Subject number
Details of asthma medications within 3 months of the pre-screening Visit 0
Details of asthma exacerbations during the pre-screening period
Serious Adverse Event information onlyfor any SAE considered as related to 
study participation (e.g. protocol mandated procedures, invasive tests or change 
in existing therapy) or related to a GSK concomitant medication
Investigator signature page
For the purposes of this study, screening failuresand run-in failureswill be defined as 
follows:
Screening failures: those subjects that complete at least one Visit 1 (Screening) 
procedure but do not enter the run-in period.
Run-in failures: those subjects that enter the run-in period but donot 
subsequently receive study treatment.
Subjects who are pre-screen, screen and run-in failure will be recorded in the eCRF.
5.5.
Withdrawal/Stopping Criteria
5.5.1.
Withdrawal from Study Treatment
Subjects may be withdrawn from study treatment at any time by the Investigator if it is 
considered to be detrimental for them to continue in the study. Reasons for withdrawal 
from study treatment can include: anadverse event (including abnormal liver function 
test or abnormal laboratory results),clinically significant abnormality identified on ECG, 
lost to follow-up,protocol violation, lack of efficacy, sponsor terminated study, non-
compliance, continued in error, pregnancy, or for any other reason. 
Subjects who have permanently withdrawn mepolizumabstudy treatmentare not required 
to withdrawfrom the study. Every effort should be madeto complete all remaining 
protocol specified visits even if they have discontinued mepolizumab treatment provided 
there are no safety concerns with doing so. 


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5.5.2.
Withdrawal from the Study
A subject may withdraw from study 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. 
A reason for the withdrawal from the study must be captured in the eCRF.
A subject will also be withdrawn from the study, in consultation with the medical 
monitor and principal investigator, if any of the following stopping criteria are met:
Laboratory parameters: Clinically important changes in laboratory parameters 
identified
ECG: Clinically significant abnormality identified during the studythat meet the 
QTcstopping criteria describedin Section 5.5.4.
Liver Chemistry: Meets any of the Liver chemistry stopping criteria(See 
Section5.5.3and Appendix 5)
Pregnancy: Positive pregnancy test(see Appendix3)
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. 
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”. 
5.5.3.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteriahave been designed to 
assure subject safety and evaluate liver eventetiology(in alignment with the FDA 
premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf


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Phase III-IVLiver Chemistry Stoppingand Increased Monitoring Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus 
Bilirubin≥2x
ULN (>35% 
direct) or plus
INR>1.5, if 
measured*
Possible  
Hy’sLaw
ALT≥3xULN
ALT
≥8xULN
Plus
Symptoms of 
liver 
injury
or 
hypersensitivity
No
Yes
Yes
Yes
No
No
No
See algorithm 
for continued 
therapy with 
increased liver 
chemistry 
monitoring
Yes
*INR value not 
applicable to subjects on anticoagulants 
ALT 
≥3xULN 
but 
<8xULN
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments section 
in the Appendix
Report as an SAE if possible Hy’sLaw case: 
ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver chemistry stopping criteria and required follow up assessmentsare defined in 
Appendix 5.
5.5.3.1.
Study Treatment Restart orRechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any subject participating in this study is not allowed.
5.5.4.
QTc Stopping Criteria
The sameQT correction formula mustbe used for each individual subjectto 
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 onQTcB, 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 
formulamust 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 averaged QTc values of triplicate electrocardiograms 
obtained over a brief (e.g., 5-10 minutes) recording period.  For example if a routine 
ECG demonstrates a prolonged QT, obtain 2 or more ECGs over a brief period and 
then use the averaged QTc values of the 3 ECGs to determine whether patient should 
be withdrawn from the study.


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A subject who meets either of the bulleted criteriabelow will be withdrawn from the 
study:
QTc > 500 msec OR UncorrectedQT > 600 msec
[Change from screening(Visit 1) of QTc > 60 msec]
For patients with underlying bundle branch block, follow the discontinuation criteria 
listed below:
Screening (Visit 1) QTc with Bundle
Branch Block
Discontinuation QTc with Bundle 
Branch Block
< 450 msec
> 500 msec
450 –480 msec
≥ 530 msec
5.6.
Subject and Study Completion
A subject will be considered to have completed study treatment if he/she receives study 
treatment at Visit 9(Week 28)and completesthe Exit Visit(Week 32). A subject will be 
considered to have completed the study if they continue to participate in the study until 
the Exit Visit assessments have been completed (regardless of whether the subject 
completed the study treatment schedule).
The end of the study is defined as the last subject’s last visit.
6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
The study treatment and investigational product is mepolizumab (SB-240563),a fully 
humanised IgG antibody (IgG1, kappa) with human heavy and light chain frameworks. 
Mepolizumab will be provided as a lyophilised cake in sterile vials for individual use. 
The vial will be reconstituted with Sterile Water forInjection, just prior to use. Further 
information on the preparation and administration of study treatment can be found in 
Section 6.5.
Trade label albuterol/salbutamol metered dose inhalers (MDIs) will be provided locally 
by each country (except for US sites where GSK Global Supply Organisation will supply 
the rescue medication)includingSweden where Ventolin Diskus will be used.Subjects 
will be dispensed a rescue inhalerat the time of screening to be used to primarily treat 
asthma symptoms on an as needed basis but also during pre and post bronchodilator 
spirometryassessments (see Section 7.3.2.3.1).The rescue inhalershould be replacedas 
needed, and collected at the Exit Visit (or Early Withdrawal Visit, as applicable).


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6.2.
Treatment Assignment
This is a single arm open label study. At Visit 2 (Week 0) eligiblesubjects who meet the 
continuation to treatmentcriteriawill receivemepolizumab 100mg SC into the upper arm 
or thighevery 4 weeks over a period of 28 weeks. 
A web based interactivesystem RAMOS NG will be used to dispense mepolizumab from 
Visit 2 to Visit 9.
6.3.
Packaging andLabeling
Thecontents of the label will be in accordance with all applicable regulatory 
requirements.
6.4.
Preparation/Handling/Storage/Accountability
Only subjects enrolled in the study may receive study treatment and only authorized 
site staff may supply or administer study treatment. 
A description of the methods and materials required for the reconstitution of 
mepolizumab will be detailed in the staff manual which is available in the Study 
Reference Manual (SRM).

Study treatment 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).  
The investigator or designated site staff must document the amount of investigational 
product administered to study subjects.
Further guidance and information for final disposition of unused study treatment are 
provided in the SRM. 
Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.  Take adequate precautions to 
avoid direct eye or skin contact and the generation of aerosols or mists. In the case of 
unintentional occupational exposure notify the monitor, Medical Monitor and/or 
GSK study contact.
A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from 
GSK.


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6.5.
Compliance with Study Treatment Administration
When subjects are dosed at the site, they will receive study treatment directly from the 
investigator or designee, under medical supervision.  The date and time of each dose 
administered in the clinic will be recorded in the source documentsand reported in the 
eCRF.  The dose of study treatment and study subject identification will be confirmed at 
the time of dosing by a member of the study site staff other than the person administering 
the study treatment.  
6.6.
Treatment of Study Treatment Overdose
The dose of mepolizumab considered to be an overdose has not been defined. There are 
no known antidotes and GSK does not recommend a specific treatment in the event of a 
suspected overdose. The investigator will use clinical judgement in treating the symptoms 
of a suspected overdose.
6.7.
Treatment after the End of the Study
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition, whether or not GSK is providing specific 
post-study treatment.
There are no plans to routinely provide mepolizumab following study completion, as 
mepolizumab is expected to be commercially available in most countries participating in 
this study.
6.8.
Concomitant Medications and Non-Drug Therapies
6.8.1.
Permitted Medications and Non-Drug Therapies
Throughout the study, subjects are to be maintained on their baseline standard of care 
asthma treatment. The only exception to this is the discontinuation of omalizumab from 
Visit 2 onwards.
Additional asthma medications such as theophyllines or anti-leukotrienes will be 
permitted provided that they have been taken regularly in the 3 months prior to first dose 
of mepolizumab treatment (Visit 2, Week 0).
All concomitant medications taken during the study will be recorded in the eCRF. In 
addition, all medications taken by the patient for the treatment of asthma including 
asthma exacerbations in the 12 months prior to Visit 1 must also be recorded in the 
eCRF. The minimum requirement is that the drug name and the dates of administration 
are recorded.  However, forICS/LABA, omalizumab andOCS, the dose and regimen 
(including any change in doseor regimen) must also be recorded.Continuous Positive 
Airway Pressure (CPAP) for the treatment of obstructive sleep apnea is permitted, if 
initiated prior to the Screening Visit 1.


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6.8.2.
Prohibited Medications and Non-Drug Therapies
The following medications are not allowed prior to screening (Visit 1), according to the 
following schedule, or during the study:
Table 4
Medications not allowed prior to the Screening Visit and throughout 
the study
Medication
Washout Time
Prior to Screening Visit
Invest
igat
iona
l drugs
1 month or 5 ha
lf-l
ives wh
ichever 
is 
longer
Monoc
lona
l ant
ibod
ies**
5 ha
lf-l
ives
Exper
imenta
l ant
i-inf
lammatory drugs (non b
io
log
ica
ls)
3 months
Immunosuppressive medications such as those listed below (not all inclusive)
Regu
lar system
ic (ora
l or parentera
l) cort
icostero
ids for 
the treatment of cond
it
ions other than asthma. Long-
act
ing depotcorticostero
idsif used to treat a cond
it
ion 
other than asthma
3 months
Methotrexate, tro
leandomyc
in, cyc
lospor
in, azath
iopr
ine 1 month
Ora
l go
ld
3 months
Chemotherapy used for cond
it
ions other than asthma
12 months
**= Oma
l
izumab 
is perm
itteddur
ing screen
ing and run-in but must be d
iscont
inue
dat V
is
it 2.
Additionally, Bronchial Thermoplasty and Radiotherapy are excluded for 12 months
prior to Visit 1 and throughout the study.  Neither CPAP nor oxygen therapy may be 
initiated on or after Visit 1.
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 forstudy 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


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7.1.
Time and Events Table
Procedures
Pre-
screen1
Screen
Run-in
Treatment
(visit window is 7days)
Exit Visit/ 
Early withdrawal 
Visit3
Visit
0
1
2
3
4
5
6
7
8
9
10
Week
-6 to -4
-4to -1 
0
4
8
12
16
20
24
28
4 weeks post last 
dose7days 
Informed Consent2
x
Sub
ject Demography
x
Med
ica
l H
istory
x
Asthma H
istory (
inc
lud
ing 
tr
iggers)
x
x
Therapy H
istory4
x
Smok
ing H
istory
x
Card
iovascu
lar H
istory/R
isk 
Factors
x
Inc
lus
ion/Exc
lus
ion Cr
iter
ia
x
Cont
inuat
ion to treatment 
Cr
iter
ia
x
Efficacy Assessments5
ACQ-5
x
x
x
x
x
x
x
x
x
x
Exacerbat
ion rev
iew
x
x
x
x
x
x
x
x
x
x
x
Sp
irometry 
inc
lud
ingpre-and 
post bronchod
i
lator FEV1,
FVC6
x
x
x
x
x
Health Outcome 
Assessments5
SGRQ
x
x
x
x


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Procedures
Pre-
screen1
Screen
Run-in
Treatment
(visit window is 7days)
Exit Visit/ 
Early withdrawal 
Visit3
Visit
0
1
2
3
4
5
6
7
8
9
10
Week
-6 to -4
-4to -1 
0
4
8
12
16
20
24
28
4 weeks post last 
dose7days 
C
l
in
ic
ian& Sub
jectrated 
response to therapy
x
x
x
x
Treatment Sat
isfact
ion w
ith 
Med
icat
ion Quest
ionna
ire 
(TSQM-9) 
x
x
Ex
it Interv
iew7
x
Safety Assessments5
Concom
itant Med
icat
ion
x
x
x
x
x
x
x
x
x
x
x
Phys
ica
l Exam
inat
ion, 
inc
lud
ing nasa
l exam
x
x
V
ita
l S
igns 
x
x
x
x
x
x
x
x
x
x
12 
lead ECG
x
x
x
Adverse Events
x
x
x
x
x
x
x
x
x
x
Ser
ious Adverse Events
x
x
x
x
x
x
x
x
x
x
x
Laboratory Assessments5
Haemato
logy w
ith d
ifferent
ia
l
x
x
x
x 
x
x
x
x
x
x
C
l
in
ica
l Chem
istry(
inc
l. LFT)
x 
x
x
x
x 
x
x 
Paras
it
ic Screen
ing8
x
Pharmacogenet
ic samp
le9
           X              
Pregnancy test10
U
U
U
U
U
U
U
U
U
U
HBsAg and hepat
it
is C 
ant
ibody11
x
Immunogen
ic
itysamp
le
x
x
x
x
B
iomarker samp
le
x
x
x
x


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Procedures
Pre-
screen1
Screen
Run-in
Treatment
(visit window is 7days)
Exit Visit/ 
Early withdrawal 
Visit3
Visit
0
1
2
3
4
5
6
7
8
9
10
Week
-6 to -4
-4to -1 
0
4
8
12
16
20
24
28
4 weeks post last 
dose7days 
Investigational product 
(Mepolizumab) and rescue 
medication
Adm
in
istermepo
l
izumab. 
Contact RAMOS NG to 
reg
ister d
ispens
ing v
is
it. 
x
x
x
x
x
x
x
x
A
lbutero
l/sa
lbutamo
l 
d
ispensed (as needed)
x
x
x
x
x
x
x
x
x
Co
l
lect d
ispensed 
a
lbutero
l/sa
lbutamo
l 
x
x
x
x
x
x
x
x
x
eCRF/
paper diary/worksheet
Comp
lete eCRF
x
x
x
x
x
x
x
x
x
x
x
D
ispense paper 
d
iary/worksheet
x
x
x
x
x
x
x
x
x
x
Co
l
lect/rev
iew paper 
d
iary/worksheet
x
x
x
x
x
x
x
x
x
x
1. Pre-screen V
is
it 0 must be comp
leted pr
ior to V
is
it 1 (Screen
ing). It can be comp
leted on the same day as V
is
it 1 or at up to 2 weeks pr
ior to V
is
it 1.
2. Sub
jects w
i
l
l be ass
igned a sub
ject number at the t
ime ICF s
igned. The ICF must be s
igned before any study procedures 
inc
lud
ing med
icat
ion wash out per
iod(s). 
3. Ex
it V
is
it may be comp
leted 3 to 5 weeks post 
last dose. 
4. Therapy h
istory to 
inc
lude a deta
i
led rev
iew of pr
ior b
io
log
ics rece
ived for treatment of asthma, 
inc
lud
ing oma
l
izumab dose and reg
imen and pr
ior 
invest
igat
iona
l therap
ies e.g 
ant
i-IL5 or ant
i-IL13 preparat
ions.
5. A
l
l study eff
icacy, safety and a
l
l pat
ient reported quest
ionna
ires must be comp
leted pr
ior any study procedure. 
6. Sp
irometry to 
inc
lude pre-and post bronchod
i
lator FEV1 from V2.
7. Ex
it 
interv
iew w
i
l
l be conducted on
ly 
in a subset of s
ites and 
in a subset of sub
jects who choose to part
ic
ipate 
in the Ex
it interv
iew.  Sub
jects must be consented pr
ior to 
interv
iew 
8. Paras
it
ic screen
ing 
is on
ly requ
ired 
in countr
ies w
ith h
igh-r
isk or for sub
jects who have v
is
ited h
igh-r
isk countr
ies 
in the past 6 months. S
ites shou
ld use 
loca
l 
laborator
ies.
9. Pharmacogenet
ic samp
le may be drawn at V
is
it 2 or any v
is
it after.
10.Pregnancy test, U= ur
ine 
11.Hepat
it
is B Surface Ant
igen and Hepat
it
is C ant
ibody. (
if hepat
it
is C ant
ibody 
is pos
it
ive, hepat
it
is C w
i
l
l be conf
irmed by PCR).


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7.2.
Screening and Critical Baseline Assessments
7.2.1.
Pre-screening Visit
Subjects can perform the Pre-screening Visit (Visit 0) up to 2 weeks prior to or on the 
same day as the Screening Visit (Visit 1).  A subject number will be assigned at the time 
the informed consent form (ICF) is signed.  During the Pre-screening Visit, study 
designated personnel must provide informed consent (including informed consent for the 
optional pharmacogenetics part of the study, as applicable) to study participants.
Once the informed consent document has been signed, pre-screening assessments can be 
conducted. The following demographic parameters will be captured: year of birth, sex, 
race and ethnicity.In addition, Asthma history and concomitant medications will be 
assessed. From the pre-screening visit onwards concomitant medications, exacerbations 
and SAEs (considered as related to study participation) must be reported
7.2.2.
Critical procedures performed atScreening (Visit 1)
Medical history including smoking status, history of sinusitis,nasalpolyposis, 
aspirin sensitivity,current treatment, duration of asthma, courses of rescue 
corticosteroidsin the past 12 months, history of previous intubations,asthma 
exacerbation history in the previous 12 months, asthma triggersand smoking history
Therapy history, including use of omalizumab or previous biologics in the past 12 
months (see Section 6.8.1)
Cardiovascular medical history/risk factors (as detailed in the eCRFand Appendix
6). This assessment must include a review of the subject responses to the 
cardiovascular assessment questions and height, weight, blood pressure, smoking 
history, medical conditions, and family history of premature cardiovascular disease.
Asthma control questionnaire-5 (ACQ-5)(see Section 7.3.2.1.1)
Treatment Satisfaction Questionnaire with Medication (TSQM-9) (See Section 
7.3.2.1.4)
Vital signs (see Section 7.4.5)
Resting 12-lead ECG (see Section 7.4.6)
Physical exam (see Section 7.4.4)
Nasal exam to check for presence or absence of nasal polyps (if no documented 
historical assessment in the past 12 months)
Pulmonary function tests (see Section 7.3.2.3)
Laboratory tests (see Section 7.4.7). This should include:
Chemistry
Haematology with differential count
Hepatitis B Surface Antigen and hepatitis C antibody


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
Urine pregnancy test-for all women of child bearing potential

FSH will be assessed to confirm child-bearing status (if applicable)

Parasitic screening (only in countries with a high-risk or in subjects who have 
visited a high-risk country)
Review of Inclusion/Exclusion criteria
Review exacerbations, AEs, SAEs
7.2.3.
Critical procedures performed at first treatment Visit (Baseline 
Visit 2)
Asthma Control Questionnaire (ACQ-5) (see Section 7.3.2.1.1) 
St George’s Respiratory Questionnaire (SGRQ) (see Section 7.3.2.1.2)
Vital signs (see Section 7.4.5)
Laboratory tests (see Section 7.4.7). This should include

Clinical Chemistry

Haematology with differential

Blood for baseline immunogenicity

Blood for baseline biomarkers

Urine pregnancy test for all females of childbearing potential
Pulmonary function tests including pre and post-bronchodilator FEV1and FVC.  
(may be repeated at this visit, (see Section 7.3.2.3)
Review exacerbations, concomitant medications, AEs, SAEs
Review of continuation to treatment criteria (see Section 5.3).
7.3.
Efficacy
7.3.1.
Efficacy Endpoints
Mean change from baseline in Asthma Control Questionnaire-5 (ACQ-5) score at 
Week 32
Mean change from baseline in St. George’s Respiratory Questionnaire (SGRQ)score 
at Week 32
Frequency of clinically significant asthma exacerbations
Ratio to baseline in blood eosinophils at Week 32


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Percentage of subjects achieving a 0.5-point or greater reduction in ACQ-5score at 
Week 32
Percentage of subjects achieving a 4-point or greater reduction in SGRQ score at 
Week 32
Mean change from baseline in pre-and post-bronchodilator FEV1 at Week 32
Frequency of exacerbations requiring ED visit or hospitalization.
Subject/Clinician ratedresponse to therapy
Mean change from baseline in treatmentsatisfaction questionnaireat Week 32
7.3.2.
Efficacy assessments
The timings of all efficacy assessments are documented in the Time and Events Schedule 
(Section 7.1)
7.3.2.1.
Questionnaires
It is requested that questionnairesareadministered at the same time of day during each 
visit (as applicable). They should be presented to the subject in a consistent order at each 
study visit.  To avoid influencing the subject’s response, the subjects should not be told 
the results of diagnostic tests prior to completing the questionnaires and the 
questionnairesshould be completed before any procedures are performed on the subject. 
All questionnaires will be completed using an electronic device at clinic. Adequate time 
shouldbe allowed to complete all items on the questionnaires and the questionnaires 
must be reviewedby the investigator or designated study stafffor completeness and, if 
necessary, the subject must be encouraged to complete any missing items.
Instructions for completing the questionnaires can be found in the SRM.
7.3.2.1.1. Asthma Control Questionnaire (ACQ)
The ACQ-5 is a five-item questionnaire, which has been developed as a measure of 
subject’ asthma control that can be quickly and easily completed [Juniper1999; Juniper, 
2005].  The questions are designed to be self-completed by the subject.  The five 
questions (concerning nocturnal awakening, waking in the morning, activity limitation, 
shortness of breath and wheeze) enquire about the frequency and/or severity of symptoms 
over the previous week.  The response options for all these questions range fromzero 
(no impairment/limitation) to six (total impairment/ limitation) scale ( see Appendix 8)
7.3.2.1.2. St. George’s Respiratory Questionnaire (SGRQ)
The St. George’s Respiratory Questionnaire is a well established instrument, comprising 
50 questions designed to measure Quality of Life in patients with diseases of airway 
obstruction, measuring symptoms, impact, and activity. The questions are designed to be 


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self-completed by the subject [Jones, 1992] with a recall over the past 4 weeks(see 
Appendix 9). 
7.3.2.1.3. Clinician/Subject Rated Response to Therapy
This is an overall evaluation of response to mepolizumab treatment, conducted separately 
by the investigator and the subject using a rating scale. In this rating scale, a seven-point 
scale score is used with the following definitions: 1= significantly improved; 2= 
moderately improved; 3 = mildly improved; 4 = no change; 5 = mildlyworse; 6 = 
moderately worse; and 7 = significantly worse. Subjects will enter their response in an 
electronic deviceprovided to the site as described in the SRM ( see Appendix 10and 
Appendix 11)
7.3.2.1.4. Treatment Satisfaction Questionnaire for Medication (TSQM-9)
The Treatment Satisfaction Questionnaire for Medication(TSQM-9) measures 
satisfaction with medication on 3 domains of effectiveness, convenience and global 
satisfaction[Atkinson, 2004; Bharmal, 2009]. The TSQM-9 has been demonstrated to be 
a reliable and valid measure of satisfaction with medication.  Each of the 9 items is 
scored by the subject on a 5 or 7 point scale with theends representing extreme 
dissatisfaction to extreme satisfaction.  The total score is reported as score of 0 to 100 
with higher scores representing higher satisfaction. Questions are framed to ask about 
current satisfaction with medication ( see Appendix 12) .
7.3.2.2.
Exit Interview
Exit interviews will be conducted as shown in the Schedule of Events table (Section 7.1) 
to explore subjects’ experience with study treatment.  Exit interviews are qualitative 
interviews conducted with study subjects to capture subject experiences in drug 
development on completion of participation in a clinical study.  Interview questions are 
designed to fully assess a subject’s experience with a study medication and are 
administered in a semi-structured format by a trained interviewer. Subject feedback will 
be captured in a data collection sheet as well as being audio-taped for subsequent 
transcription and qualitative analysis. The Exit interview technique and questions will be 
described in the SRM and training as well as training material references will be provided 
to site personnel who will administer the Exit interviews ( see Appendix 13) .
7.3.2.3.
Pulmonary Function test
Spirometry will be performed using the investigator spirometry equipments.The 
investigator is responsible for ensuring that all spirometryprocedures and evaluations 
follow the recommendations of the American Thoracic Society (ATS)/European 
Respiratory Society (ERS) Task force: Standardization of Lung Function Testing [Miller, 
2005].


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7.3.2.3.1. Pre-and post bronchodilator FEV1
Only pre-bronchodilator assessments are required at Visit 1. Both pre-bronchodilator and 
post-bronchodilator assessments are required from Visit 2 onwards. At each visit, 
spirometry assessments should be performed at the same time of day (1hour) as the 
assessment performed at Visit 2 (the baseline assessment). Subjects should withhold 
short-acting beta-2-agonists(SABAs) for 6 hours ,LABAs for 12 hours and their 
dose of long-acting anticholinergic (LAMA) prior to the clinic visit.
7.3.2.4.
Clinically Significant Asthma Exacerbation
Clinically significant exacerbationsof asthma are defined by:
Worsening of asthma which requires use of systemic corticosteroids
1and/or 
hospitalisation and/or Emergency Department (ED) visits.
1For all subjects, i.v. or oral steroid (e.g., prednisone) for at least 3 days or a single IM 
CS dose is required. For subjects on maintenance systemic corticosteroids, at least 
double the existing maintenance dose for at least 3 days is required. 
Exacerbation data will be included in the analysis from Visit 2 until Exit Visit(Week 32) 
approximately 4 weeks after the last dose of study treatment.  For those subjects that stop 
study treatment early or withdraw early from the study altogether, the time period for 
collection of exacerbation data will be from Visit 2 until no greater than approximately 4 
weeks post-last-dose of mepolizumab.  For consistency, exacerbations separated by less 
than 7 days will be treated as a continuation of the same exacerbation.
7.4.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1)
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Section 12.7, Appendix 7
Adverse Events including systemic (i.e., allergic/IgE-mediated and non-allergic) and
local injection site reactions will be reported throughout the 32-week treatment period. 
NOTE: Hypersensitivity reactions will be monitored using the diagnostic criteria for 
anaphylaxis as outlined by the Second Symposium on Anaphylaxis[Sampson, 2006] and 
(Appendix 7).
Information will be also collectedfrom subjects to help with the assessment of potential 
localised injection site reactions.
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 


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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 Exit Visitat the time-
points specified in the Time and Events Table (Section7.1).
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 Conditionssection of the CRF.
All SAEs will be recorded and reported to GSK within 24 hours, as indicated in
Appendix 7
Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects. However, if the investigator learnsof any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the study treatment or study participation, the investigator 
must promptly notify GSK.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in
Section 12.7, Appendix 7.
7.4.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:
“How are you feeling?”
“Have you had any (other) medical problems since your last visit/contact?” 
“Have you taken any new medicines, other than those provided in this study, 
since your last visit/contact?” 
7.4.2.1.
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 4.6.1) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up 
(as defined in Section 5.5). Further information on follow-up procedures is given in 
Appendix 7)


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7.4.2.2.
Cardiovascular and Death Events
7.4.2.2.1. Cardiovascular events
Cardiovascular-related AEs and SAEs that will require the investigator to complete event 
specific pages in the eCRF are listed in Section 12.7.3, Appendix 4.
Cardiovascular events information should be recorded on the corresponding eCRF pages 
within one week of when the AE/SAE(s) are first reported.  Please refer toAppendix 4
for timelines for reporting AE/SAEs
7.4.2.2.2. Death Events
In addition, all deaths will require completion of a specific death data collection page in 
the eCRF.  The death data collection page in the eCRF includes questions regarding 
cardiovascular (including sudden cardiac death) and non-cardiovascular death.
Death information should be recorded on the death eCRF page within one week of when 
the death is first reported.
Please refer to Section 12.7, Appendix 7or timelines for reporting SAEs.
7.4.2.3.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK of SAEs related to study treatment (even 
for non-interventional post-marketing studies) is essential so that legal obligations and 
ethical responsibilities towards the safety of subjects and the safety of a product under 
clinical investigation are met. 
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
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.
7.4.3.
Pregnancy
Details of all pregnancies of female participants in the study will be collected after 
the start of dosing and until theExit Visit.


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If a pregnancy is reported then the investigator should inform GSK within 2 weeks 
of learning of the pregnancy and should follow the procedures outlined in Appendix
3.
7.4.4.
Physical Exams
A complete physical examination will include, at a minimum, assessment of the 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
7.4.5.
Vital Signs
As detailed inthe Time and Events Schedule Table (Section 7.1) vital signs will be 
measured in semi-supine position after 5 minutes rest and will include systolic and 
diastolic blood pressure and pulse rate.
Vital signs assessments will be taken before measurement of any clinic lung function 
tests or ECGs at the specified time point.
Height and weight will also be measured and recordedat Visit 1.
7.4.6.
Electrocardiogram (ECG)
A single12-lead ECG will be obtained at each time-point as specified in the Time 
and event schedule (see Section 7.1) using an ECG machine that automatically 
calculates the heart rate and measures PR, QRS, QT, and QTcintervals. 
If aroutine singleECG demonstrates a prolonged QT interval, obtain two more 
ECGs over a brief period, and then use the averaged QTc values of the three ECGs to 
determine whether the patient should be discontinued from the study.Refer to 
Section 5.5.4for QTcwithdrawal criteria and additional QTcreadings that may be 
necessary.
ECG measurements will be made after the subject has rested in the supine position 
for 5minutes.  The ECG should be obtained after the vital signs assessments but 
before lung function testing and followed by other study procedures.  ECG 
measurements shortly after a meal or during sleep should be avoided since QT 
prolongation can occur at these times.
7.4.7.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in(Table 5)must be conducted 
in accordance with the Laboratory Manual, and Protocol Time and Events Schedule.
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 


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detailed in the laboratory manual.All blood samples must be taken pre-injection of 
mepolizumab.  In case of any Screening assessment (Visit1) occurring on the same day as 
omalizumab injection, all assessments must be performed pre omalizumab injection.  
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.
Refer to the SRM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws.
Haematology, clinical chemistry and additional parameters to be tested are listed in Table 
5.
Table 5
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
P
late
let Count
RBC Ind
ices: WBC count w
ith D
ifferent
ia
l:
RBC Count
MCV
Neutroph
i
ls
Hemog
lob
in
MCH
Lymphocytes
Hematocr
it
Monocytes
Eos
inoph
i
ls
Basoph
i
ls
Clinical 
Chemistry 
1
BUN
Potass
ium AST (SGOT)
Tota
l and d
irect 
b
i
l
irub
in
Creat
in
ine
Sod
ium
ALT (SGPT)
Tota
l Prote
in
G
lucose 
Ca
lc
ium
A
lka
l
ine phosphat
ise A
lbum
in
Other Screening 
Tests
Hepatitis B (HBsAg)
Hepatitis C (Hep C antibody)
FSH and estradiol (as needed in women of non-child bearing 
potential only)
Alcohol and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines)
UrinehCG Pregnancy test (as needed for women of child bearing 
potential) 2


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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 inSection 5.5.3
andAppendix 5
2. Local urine testing will be standard for the protocol unless serum testing is 
required by local regulation or ethics committee.
All laboratory tests with values that are considered clinically significantly abnormal 
during participation in the study should be repeated until the values return to normal or 
baseline.  If such values do not return to normal within a period judged reasonable by the 
investigator, theetiologyshould be identified and the sponsor notified.
7.4.8.
Paperworksheet
Subjects will be issued with a paper worksheet to record adverse events, changes in 
concomitant medications and any visits to general practioner, hospital and/or emergency 
department during the study.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.
7.5.
Biomarker(s)/Pharmacodynamic Markers
Blood eosinophil counts will be recorded as partof the standard haematological 
assessments performed at the visits specified in the Time and Events Schedule(Section 
7.1).  Additional blood samplesfor exploratory biomarkers of type 2 helper T cells (Th2) 
response,will be collected at Visits 1, 2, 4 and 10.  Details on collecting and handling of 
biomarker samples can be found in the SRM.
7.6.
Immunogenicity
Blood samples will be collected for the determination of anti-mepolizumab antibodies, 
prior to dosing, as detailed in the Time and Events Schedule (Section 7.1)
Details for sample collection and processing may be found in the SRM.
7.7.
Genetics
Information regarding genetic research is included in Appendix14.  IEC/IRB and, where 
required, the applicable regulatory agency must approve the genetic assessments before 
these can be conducted at the site.  The approval(s) must be in writing and will clearly 
specify approval of the genetic assessments (i.e., approval of Appendix3.  In some cases, 
approval of the genetic assessments can occur after approval is obtained for the rest of the 
study.  If so, then the written approval will clearly indicate approval of the genetic 
assessments is being deferred and the study, except for PGx and genetic assessments, can 


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be initiated.  When genetic assessments will not be approved, then the approval for the 
rest of the study will clearly indicate this and therefore, genetic assessments will not be 
conducted
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.  
Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., 
removing errors and inconsistencies in the data.
Adverse events and concomitant medications terms will be coded using Medical 
Dictionary for Regulatory Activities(MedDRA)and an internal validated medication 
dictionary, GSKDrug.  
CRFs (including queries and audit trails) will be retained by GSK, and copies will be 
sent to the investigator to maintain as the investigator copy.  Subject initials will not 
be collected or transmitted to GSK according to GSK policy.
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1.
Hypotheses
This study is designed to investigate whether subjects not optimally controlledon 
omalizumab can be effectively and safelyswitched to treatment with mepolizumabto 
improve asthma control.As there is no control arm in this study, comparisons in ACQ 
score will be made back to baseline.  
9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
The primary analysis will utilise within-subject changes from baseline.As this study is 
uncontrolled, the potential of a ‘placebo effect’ within the mepolizumab treated subjects 
will be considered.A meta-analysis of two previous severe asthma studies with 
mepolizumab (MEA115588 and MEA112997) estimated a change from baseline at Week 
32of -0.55 and -0.88 in the placebo and mepolizumab groups respectively, with 
mepolizumab presenting a benefit of -0.34 over placebo. 
The following sample size estimates are based on a residual standard deviation of 0.96 
units and are based upon the aforementioned meta-analysis.These estimates assume that 
15% of subjects will prematurely withdraw from the study and therefore have missing 


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data at Week 32. This primary analysis will use the “missing at random” assumption for 
missing data.
With a sample size of 120 treated subjects, it is estimated that this study has over 90% 
power to detect a statistically significant improvement from baseline. Further it is 
estimated that a significant improvement over the ‘placebo effect’ of -0.55 from baseline 
in ACQ score will be observed at the two-sided 5% level of significance if the observed 
change from baseline is at least -0.74 units.
If the true change from baseline is -0.86 units, then the study has a probability of 90% of 
observing a changefrom baseline of at least -0.74 unitsand therefore the study has 90% 
power for declaring statistical significance over the ‘placebo effect’.  
9.2.2.
Sample Size Sensitivity
If either the actual change from baseline or variability are different from the values 
assumed in Section 9.2.1, the power to detect a change in ACQ score will be affected.
Table 6illustrates the estimated power which would be obtained with different values of 
change from baseline and standard deviation, assuming 120 patients are treated. 
Table 6
Power for various changes from baseline and standard deviations
Mean change 
from 
Baseline
Standard deviation
0.85
0.90
0.95
1.00
1.05
-0.75
65% 
60% 
56% 
52% 
48%
-0.80
84% 
79% 
75% 
71% 
66%
-0.85
94% 
92% 
88% 
85% 
82%
-0.90
98% 
97% 
96% 
94% 
92%
-0.95
>99%
99% 
99% 
98% 
97%
-1.00
>99% 
>99% 
>99%
99% 
99%
9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations
All Subjects Enrolled (ASE) Population
The ASE population will compriseall subjects enrolled and for whom a record exists on
the study database. This population will be used for summarising reasons for screen and
run-in failures.
Intent-to-Treat(ITT)Population


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This population will consist of all subjects who receive at least one dose of mepolizumab, 
and will be the primary population for all analyses of efficacy measures and safety 
measures.  
Per Protocol (PP) Population
The Per Protocol (PP) population will consist of all subjects in the Intent-to-Treat 
population who have not been identified as full protocol deviators with respect to criteria 
that are considered to impact the primary efficacy analysis. The decision to exclude a 
subject from the PP population or exclude part of their data from the PP population 
analyses will be made prior to freezing thestudy database. The PP population will be 
used for a supplementary analysis of the primary endpoint.
9.3.2.
Interim Analysis
No interim analysis is planned for this study.
9.4.
Key Elements of Analysis Plan
All pre-specified analyseswill be described in a full Reporting and Analysis Plan (RAP) 
which will be finalised prior to freezing thestudy database.  Any changes to what is 
detailed in the protocol will also be described in the RAP.
The study database will be frozen once the final subject has completed the Exitvisitand 
all queries for data collected up to this time are resolved.
9.4.1.
Primary Analyses
Analysis of change from baseline in ACQ score will be performed usinga mixed models 
repeated measures (MMRM) analysis, allowing for covariates of baseline ACQ score, 
region, baseline maintenance OCS therapy, exacerbations in the year prior to the study 
(as an ordinal variable), visit and aninteraction term for visit by baselineACQ score. The 
primary comparison will be Week 32 vs. Baseline and all data collected up to and 
including Week 32 from patients, including those who have discontinued study treatment, 
will be included in the analysis.
The primary population for analysis will be the ITT population. A supporting analysis of 
the PP population will also be performed. 
9.4.2.
Secondary Analyses
The secondary efficacy endpoints are listed below and their link to the study objectives is 
detailed within Section 3:
Mean change from baseline in SGRQ 
Frequency of clinically significant exacerbations


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Ratio tobaseline in blood eosinophils 
Mean change from baseline in SGRQ and blood eosinophils will be analyzed using
mixed models repeated measures analysis, allowing for the aforementioned covariates 
within the primary analysis. A log-transformation will be applied to blood eosinophil 
counts prior to analysis.
The frequency of clinically significant exacerbations will be analyzed using a generalized 
linear model, assuming the number of exacerbationshas a negative binomial probability 
distribution and that its mean is related to covariate factors with a ‘log link’ function. The 
logarithm of time on treatment will be used as an offset variable. The model will include 
covariates for region, baseline maintenance OCS therapy andnumber of exacerbations in 
the year prior to the study (as an ordinal variable).   
9.4.3.
Other Analyses
9.4.3.1.
Other Efficacy Analyses
See Section 3for a list of all other efficacy endpoints. Full details of any analyses to be
performed on these endpoints will be provided in the RAP.
9.4.3.2.
Safety Analyses
Summaries of data will be reported according to the nominal visit for which it was
recorded. Further details will be provided in the RAP.
9.4.3.2.1. Extent of Exposure
The number of subjects administeredinvestigational product, the number of treatments 
administered and the number of days over which treatment was administered will be 
summarised.
9.4.3.2.2. Adverse Events
Adverse Events (AEs)will be coded using the standard Medical Dictionary for 
Regulatory Activities (MedDRA) and will be grouped by system organ class.AEs will be
summarised by frequency and percentage of subjects, by system organ class and
preferred term. Separate summaries will be presentedfor all AEs, drug-related AEs, 
SAEs, AEs leading to permanent discontinuation of investigational product or withdrawal 
from the studyand for any AEs of special interest.
9.4.3.2.3. Clinical Laboratory Evaluations
Haematology (including blood eosinophils) and clinical chemistry data will be 
summarized at each scheduled assessment. The proportion of values outside of the 
normal reference range and those meeting the criteria for potential clinical significance 
will also be summarised. Further details will be provided in the RAP.


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9.4.3.2.4. Other Safety Measures
Actual values and change from baseline for other scheduled safety assessments will be 
summarized at each visit per the Time and Events schedule (Section 7.1).Further details 
will be provided in the RAP.
9.4.3.2.5. Immunogenicity
Immunogenicity data will be summarised using appropriate descriptive statistics.
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 beforeenrollmentof 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 accordancewith ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki.  This includes, but is not limited to, the following:
IRB/IEC review andfavorableopinion/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.


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10.2.1.
Written Informed Consent/Assent
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 theeCRFwill 
serve as the source document.
GSK will monitor the study and site activity to verify that the:
Data are authentic, accurate, and complete.
Safety and rights of subjects are being protected.
Study is conducted in accordance with the currently approved protocol and any other 
study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents
10.4.
Quality Assurance
To ensure compliance with GCP and all applicable regulatory requirements, GSK 
may conduct a quality assurance assessment and/or audit of the site records, and the 
regulatory agencies may conduct a regulatory inspection at any time during or after 
completion of the study. 
In the event of an assessment, audit or inspection, the investigator (and institution) 
must agree to grant the advisor(s), auditor(s) and inspector(s) direct access toall 
relevant documents and to allocate their time and the time of their staff to discuss the 


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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 oneor 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 orthe head of the medical institution 
(where applicable) must maintain all site study records (except for those required by 
local regulations to be maintained elsewhere), in a safe and secure location.  
The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review in 
conjunction with assessment of the facility, supporting systems, and relevant site 
staff.  
Where permitted by local laws/regulations or institutional policy, some or all of these 
records can be maintained in a format other than hard copy (e.g., microfiche, 
scanned, electronic); however, caution needs to be exercised before such action is 
taken.  
The investigator must ensure that all reproductionsare 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 reproductionsand that an acceptable quality 
control process exists for making these reproductions.


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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.
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be inaccordance with GSK Policy.


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Chung KF, Wenzel SE, Brozek JC,et al. International ERS/ATS guidelines on definition, 
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Global Initiative forAsthma (GINA) 2015.Global Strategy for Asthma Management 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
ASE
All Subjects Enrolled
AST
Aspartate Transaminase
ATS
American Thoracic Society
BMI
Body Mass Index
BP
Blood pressure
CD
Cluster of differentiation
CI
Confidence Interval
CPAP
Continuous Positive Airway Pressure
CS
Corticosteroid
CV
Cardiovascular
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
(e)CRF
(Electronic) Case Report Form
ED
Emergency Department
eDiary
Electronic Diary
EGPA
Eosinophilic Granulomatosis with Polyangiitis
EMEA
European Medicines Agency
ERS
European Respiratory Society
FAAN
Food Allergy and Anaphylaxis Network
FDA
Food and Drug Administration
FEV1
Forcedexpiratory volume in 1 second
FP
Fluticasone Propionate
FRP
Females of Reproductive Potential
FSH
Follicle Stimulating Hormone
FVC
Forced Vital Capacity
g/gm
grams
GCP
Good clinical practice
GCSP
Global Clinical Safety and Pharmacovigilance
GINA
Global Initiative for Asthma
GSK
GlaxoSmithKline
HBsAg
Hepatitis B Surface Antigen
hCG
Human Chorionic Gonadotropin
HES
Hypereosinophilic Syndrome
HIV
Human Immunodeficiency Virus
HPLC
High Performance Liquid Chromatography
HR-QoL
Health-Related Quality of Life


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HRT
Hormone replacement therapy
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization
ICS
Inhaled Corticosteroids
ICU
Intensive Care Unit
IEC
Independent Ethics Committee
Ig
Immunoglobulin
IL
Interleukin
IM
Intramuscular
INR
International Normalized Ratio
IP
Investigational Product
IRB
Institutional Review Board
ITT
Intent to Treat
IV
Intravenous
IVRS
Interactive Voice Response System
kg
Kilogram
L/min
Liters per minute
LABA
Long-Acting Beta-2-Agonists
LTRA
Leukotriene Receptor Antagonist
mAb
Monoclonal Antibody
MedDRA
Medicinal dictionary for regulatory activities
MCID
Minimal Clinically Important Difference
mcg (g)
Microgram
mcL (L)
Microliter
MDI
Metered Dose Inhaler
mg
Milligram
ml
Milliliter
MMRM
Mixed Models Repeated Measures
mm Hg
Milliliterof Mercury
MSDS
Material Safety Data Sheet
N/A
Not Applicable
NaB
Neutralizing Antibodies
NHLBI
National Heart Lung and Blood Institute
NIAID
National Institute of Allergyand Infectious Diseases
NK
Natural killer Cell
OCS
Oral Corticosteroids
p.a.
Per annum
PD
Pharmacodynamic
PCR
Polymerase Chain Reaction
PEF
Peak Expiratory Flow
PGx
Pharmacogenetics
PFT
Pulmonary function tests
PK
Pharmacokinetic
PP
Per Protocol
QTc
QT interval corrected for heart rate


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QTcB
QT interval corrected for heart rate by Bazett’s formula
QTcF
QT interval corrected for heart rate by Fridericia’s formula
RAP
Reporting and Analysis Plan
RNA
Ribonucleic acid
SABA
Short-Acting Beta-2-Agonists
SAE
Serious Adverse Event
SC
Subcutaneous
SGRQ
St. George’s Respiratory Questionnaire
SmPC
Summary of Product characteristics
SOC
System Organ Class
Th
T Helper cells
TSQM
Treatment Satisfaction Questionnaire for Medication
Visit
V
ULN
Upper Limit of Normal
URTI
Upper Respiratory Tract Infection
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
Omalizumab (Xolair)


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12.2.
Appendix 2: Anaphylaxis Criteria
Joint NIAID/FAAN Second Symposium on Anaphylaxis [Sampson, 2006]. The criteria 
do not make a distinction based on underlying mechanism. These criteria are summarized 
as follows:
1) Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, swollen lips-
tongue-uvula), and at least one of the following:
a) Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced PEF, hypoxemia) 
b) Reduced blood pressure (BP)or associated symptoms of end-organ 
dysfunction (e.g., hypotonia [collapse], syncope, incontinence)
2) Two or more of the following that occur rapidly after exposure to a likely allergen 
for that patient (minutes to several hours):
a) Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, 
swollen lips-tongue-uvula)
b) Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced PEF, hypoxemia)
c) Reduced BP or associated symptoms (e.g., hypotonia [collapse], syncope, 
incontinence)
d) Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting)
3) Reduced BP after exposure to known allergen for that patient (minutes to several 
hours):
a) Infants and children: low systolic BP (age specific) orgreater than 30% 
decrease in systolic BP
b) Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from 
that person’s baseline


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12.3.
Appendix3: Modified List of Highly Effective Methods for 
Avoiding Pregnancy in FRP and Collection of Pregnancy 
Information
12.3.1.
Modified List of Highly Effective Methods for Avoiding Pregnancy 
in Females of Reproductive Potential (FRP)
This list does not apply to FRP with same sex partners, when this is their preferred and 
usual lifestyle or for subjects who are and will continue to be abstinent from penile-
vaginal intercourse on a long term and persistent basis.  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. Oral Contraceptive. Combined estrogen and progestogen oral contraceptive
[Hatcher, 2007] 
4. Injectable progestogen [Hatcher, 2007]
5. Contraceptive vaginal ring [Hatcher, 2007]
6. Percutaneous contraceptive patches [Hatcher, 2007]
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, 2007].  
This is an all inclusive list of those methods that meet the GSK definition of highly 
effective: having a failure rate of less than 1% per year when used consistently and, 
correctly and, when applicable, in accordance with the product label.  For non-product 
methods (e.g.  male sterility), the investigator determines what is consistent and correct 
use. The GSK definition is based on the definition provided by the ICH [ICH, M3 (R2) 
2009].
Based on the absence of an identified reproductive hazard from preclinical studies, 
absence of a genotoxic potential, and very low levels of mepolizumab that might be 
present in semen, there is no recognized risk for mepolizumabto affect human sperm or 
the fetus if transferred to a female partner via semen. Therefore, the use of condoms or 
other methods of contraception in the male study subject is not required.
The investigator is responsible for ensuring that subjects understand how to properly use 
these methods of contraception.


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12.3.2.
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.
A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK 
as described in Appendix 4. While the investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.
Any female subject who becomes pregnant while participating in the study will 
immediately discontinue study medication 


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12.4.
Appendix 4: New York Heart Association Functional 
Classification of Congestive Heart Failure
CLASS
PATIENT SYMPTOMS
I
Patients withcardiac disease butresulting 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.If any physical 
activity is undertaken, discomfort increases
Adapted fromAmerican Heart Association, 2011]


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12.5.
Appendix 5: Liver Safety Required Actions and Follow up 
Assessments
Phase III-IVliver chemistry stopping and increased monitoringcriteriahave 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
Liver chemistry stoppingcriteria and required followup assessments
Liver Chemistry StoppingCriteria-Liver Stopping Event
ALT-absolute
ALT 8xULN
ALT Increase
ALT 5xULN but <8xULN  pers
ists for 2 weeks
ALT 3xULN but <5xULN  pers
ists for 4 weeks
Bilirubin1, 2
ALT 3xULN andb
i
l
irub
in 2xULN (>35% d
irect b
i
l
irub
in) 
INR
2
ALT 3xULN andINR>1.5, 
if INR measured
Cannot Monitor ALT 5xULN but <8xULN and cannot be mon
itored week
ly for 2 weeks
ALT 3xULN but <5xULN and cannot be mon
itored week
ly for 4 weeks
Symptomatic3
ALT  3xULN assoc
iated w
ith symptoms (new or worsen
ing) be
l
ieved to be 
re
lated to  l
iver 
in
jury or hypers
ens
it
iv
ity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments
Immed
iate
ly d
iscont
inue  study treatment 
Report the event to GSKwithin 24 hours
Comp
lete the 
l
iver event CRF and comp
lete an 
SAE data co
l
lect
ion too
l 
if the event a
lso meets 
the cr
iter
ia for an SAE
2
Perform 
l
iver event fo
l
low up assessments 
Mon
itor the sub
ject unt
i
l 
l
iver chem
istr
ies 
reso
lve , stab
i
l
ize, or return to w
ith
in base
l
ine 
(see MONITORINGbe
low)
V
ira
l hepat
it
is sero
logy
4
On
ly 
in those w
ith under
ly
ing chron
ic 
hepat
it
is B at study entry (
ident
if
ied by 
pos
it
ive hepat
it
is B surface ant
igen)
quant
itat
ive hepat
it
is B DNA and 
hepat
it
is de
lta ant
ibody
5.
B
lood samp
le for pharmacok
inet
ic (PK) 
ana
lys
is, obta
ined w
ith
in 4 weeksafter 
last dose
6
Serum creat
ine phosphok
inase (CPK) 


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Do not restart/rechallengesub
ject w
ith study 
treatment.  Permanently discontinue study 
treatment and may continuesub
ject 
in the 
study for any protoco
l spec
if
ied follow up 
assessments
MONITORING:
For bilirubin or INR criteria:
Repeat liver chem
istr
ies (
inc
lude ALT, AST, 
a
lka
l
ine phosphatase, b
i
l
irub
in)and perform 
l
iver event fo
l
low up assessments w
ith
in  
24 
hrs
Mon
itor sub
jects tw
ice week
ly unt
i
l 
l
iver 
chem
istr
ies reso
lve, stab
i
l
ize or return to w
ith
in 
base
l
ine
A spec
ia
l
ist or hepato
logy consu
ltat
ion 
is 
recommended
For All other criteria:
Repeat 
l
iver chem
istr
ies(inc
lude 
ALT, AST,
a
lka
l
ine phosphatase, b
i
l
irub
in)andperform
l
iver event fo
l
low up assessments w
ith
in  
24-72 
hrs 
Mon
itor sub
jects week
ly unt
i
l 
l
iver chem
istr
ies 
reso
lve, stab
i
l
ize or return to w
ith
in base
l
ine
and 
lactate dehydrogenase (LDH).
Fract
ionate b
i
l
irub
in, 
if tota
l 
b
i
l
irub
in2xULN
Obta
in comp
lete b
lood count w
ith 
d
ifferent
ia
l to assess eos
inoph
i
l
ia
Record the appearance or worsen
ing of 
c
l
in
ica
l symptoms of l
iver 
in
jury
, or 
hypersens
it
iv
ity, on the AE report form
Record use of concom
itant med
icat
ions 
on the concom
itant med
icat
ions report 
forminc
lud
ing 
acetam
inophen, herba
l 
remed
ies, other over the counter 
med
icat
ions.
Record a
lcoho
l use on the 
l
iver event 
a
lcoho
l 
intake case report form
For bilirubin or INR criteria:
Ant
i-nuc
lear ant
ibody, ant
i-smooth 
musc
le ant
ibody, Type 1 ant
i-l
iver k
idney 
m
icrosoma
l ant
ibod
ies, and quant
itat
ive 
tota
l 
immunog
lobu
l
in G (IgG or gamma 
g
lobu
l
ins).
Serum acetam
inophen adduct h
igh 
performance 
l
iqu
id chromatography 
(HPLC)assay (quant
if
ies potent
ia
l 
acetam
inophen contr
ibut
ion to 
l
iver 
in
jury 
in sub
jects w
ith def
in
ite or 
l
ike
ly 
acetam
inophen use 
in the preced
ing 
week [James,2009]). NOTE: not 
required in China
L
iver 
imag
ing (u
ltrasound, magnet
ic 
resonance, or computer
ised 
tomography)and /or 
l
iver b
iopsyto 
eva
luate 
l
iver d
isease; comp
lete L
iver 
Imag
ing and/or L
iver B
iopsy CRF forms.
1. Serum b
i
l
irub
in fract
ionat
ion shou
ld be performed 
if test
ing is ava
i
lab
le. 
If serum b
i
l
irub
in fract
ionat
ion 
is not 
immed
iate
ly ava
i
lab
le, d
iscont
inue study treatment for that sub
ject 
if ALT 3xULN andb
i
l
irub
in 2xULN. 
Add
it
iona
l
ly, 
ifserum b
i
l
irub
in fract
ionat
iontest
ing 
is unava
i
lab
le, record presence of detectable urinary 
bilirubin on dipstick, 
ind
icat
ing d
irect b
i
l
irub
in e
levat
ions and suggest
ing 
l
iver 
in
jury. 


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2. A
l
l events of ALT 3xULN andb
i
l
irub
in 2xULN (>35% d
irect b
i
l
irub
in) or ALT 3xULN andINR>1.5, 
if 
INR measured wh
ich may 
ind
icate severe 
l
iver 
in
jury (poss
ib
le ‘
Hy
’sLaw
’), must be reported as an SAE 
(excluding studies of hepatic impairment or cirrhosis); INR measurement 
is not requ
ired and the 
thresho
ld va
lue stated w
i
l
l not app
ly to sub
jects rece
iv
ing ant
icoagu
lants
3. New or worsen
ing symptomsbe
l
ieved to be re
lated to l
iver 
in
jury(such as fat
igue, nausea, vom
it
ing, r
ight 
upper quadrant pa
in or tenderness, or 
jaund
ice) or be
l
ieved to be re
lated to hypersens
it
iv
ity (such as fever, 
rash or eos
inoph
i
l
ia)   
4. Inc
ludes: Hepat
it
is A IgM ant
ibody; Hepat
it
isB surface ant
igen and Hepat
it
is B Core Ant
ibody (IgM); 
Hepat
it
is C RNA; Cytomega
lov
irus IgM ant
ibody;  Epste
in-Barr v
ira
l caps
id ant
igen IgM ant
ibody (or 
if 
unava
i
lab
le, obta
in heteroph
i
le ant
ibody or monospot test
ing);  Hepat
it
is E IgM ant
ibody 
5. If hepat
it
is de
lta ant
ibody assay cannot be performed,, 
it can be rep
laced w
ith a PCR of hepat
it
is D RNA 
v
irus (where needed) [Le Ga
l, 2005].
6. PK samp
le may not be requ
ired for sub
jects known to be rece
iv
ing p
lacebo or non-GSK comparator 
treatments.  Record the date/t
ime of the PK b
lood samp
le draw and the date/t
ime of the 
last dose of study 
treatment pr
ior to b
lood samp
le draw on the CRF. If the date or t
ime of the 
last dose 
is unc
lear, prov
ide the 
sub
ject
’s best approx
imat
ion. If the date/t
ime of the 
last dose cannot be approx
imated OR a PK samp
le 
cannot be co
l
lected 
in the t
ime per
iod 
ind
icated above, do not obta
in a PK samp
le. Instruct
ions for samp
le 
hand
l
ing and sh
ipp
ing are 
in the SRM.  
Liver Chemistry Increased Monitoring Criteria –Liver Monitoring Event
Criteria
Actions
ALT 5xULN and<8xULN and
b
i
l
irub
in <2xULN withoutsymptoms
be
l
ieved to be re
lated to 
l
iver 
in
jury or 
hypersens
it
iv
ity, andwho can be 
mon
itored week
ly for 2weeks.
OR
ALT 3xULN and<5xULN and
b
i
l
irub
in <2xULN withoutsymptoms
be
l
ieved to be re
lated to 
l
iver 
in
jury or 
hypersens
it
iv
ity, andwho can be 
mon
itored week
ly for 4 weeks.
Not
ify the GSK med
ica
l mon
itor within 24 hours
of 
learn
ing of the abnorma
l
ity to d
iscuss sub
ject 
safety. 
Sub
ject can cont
inue study treatment  
Sub
ject must return week
ly for repeat 
l
iver 
chem
istr
ies (ALT, AST, a
lka
l
ine phosphatase, 
b
i
l
irub
in) unt
i
l they reso
lve, stab
i
l
ise or return to 
w
ith
in base
l
ine 
If at any t
ime sub
ject meets the 
l
iver chem
istry 
stopp
ing cr
iter
ia, proceed as descr
ibed above
If ALT decreases from ALT 5xULN and<8xULN 
to ≥3xULN but <5xULN, cont
inue to mon
itor 
l
iver 
chem
istr
ies week
ly. 
If, after 4 weeks of mon
itor
ing, ALT <3xULN and 
b
i
l
irub
in <2xULN, mon
itor sub
jects tw
ice month
ly 
unt
i
l 
l
iver chem
istr
ies norma
l
ize or return to w
ith
in 
base
l
ine.


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12.6.
Appendix6: Cardiovascular Screening Questions
At screening each subject should be asked the following:
Unrelated to the symptoms you experience with your asthma:
1) Do you have any pain or discomfort (such as pressure) in your chest? 
If yes, does this pain/discomfort/pressure go to other areas of your body such as 
neck, jaw, throat, or down your arms (including a numbness feeling in your 
arm) when it occurs?
2) When you walk at an ordinary pace on a level surface does this produce chest 
pain?If yes, respond to a and b:
a) Does this chest pain or discomfort occur when you are not doing any 
activities such as resting in bed or sitting in a chair?  
b) Has this chest pain/discomfort been more frequent or more intense or last 
longer or come on with less exertion lately?
3) When you walk uphill or hurry does this produce chest pain/discomfort?
4) Do you use or have you been previously prescribed nitroglycerine to relieve 
the discomfort?
If yes, have you needed to increase the number of pills or frequency of using the 
pills recently?
If the subject responds “yes” to any of the above questions a study physician should 
further assess for the presence of undiagnosed or unrecognized angina when 
evaluating Exclusion Criterion 5(seeExclusion CriteriaSection 5.2).  


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12.7.
Appendix 7: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.7.1.
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 anyunfavorableand unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.
Events meetingAE 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.
The signs and symptoms and/or clinical sequelae resulting from lack of efficacy will 
be reported if they fulfil the definition of an AE orSAE.  Also, "lack of efficacy" or 
"failure of expected pharmacological action" also constitutes an AE or SAE.


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Events NOTmeeting definition of an AE include:
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessmentswhich 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 
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.
12.7.2.
Definition of Serious Adverse Events
If an event is not an AE perdefinition 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-patientsetting.  Complications that occur during hospitalization are 
AEs.  If a complication prolongs hospitalization orfulfillsany 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 


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Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any 
dose:
from baseline is not considered an AE.
d. Results in disability/incapacity
NOTE:
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
This definition is not intended to include experiences of relatively minor medical 
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. Isa 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 andimpaired 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.
** INRtesting 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 Appendix 5for the required liver chemistry follow-up instructions


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12.7.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:
Myocardial infarction/unstable angina
Congestive heart failure
Arrhythmias
Valvulopathy
Pulmonary hypertension
Cerebrovascular events/stroke and transient ischemic attack
Peripheral arterial thromboembolism
Deep venous thrombosis/pulmonary embolism
Revascularization
12.7.4.
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 notacceptable 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.


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12.7.5.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:
Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.
Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities
Severe:  An event that prevents normal everyday activities. -an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe.
An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
Assessment of Causality
The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.
A "reasonable possibility" is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
out.
The investigator will use clinical judgment to determine the relationship.
Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.
The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of his/her assessment.
For each AE/SAE the investigator mustdocument 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 
priorto the initial transmission of the SAE data to GSK.
The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.


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Follow-up of AEs and SAEs
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.
The investigator is obligated to assist.  This may include additional laboratory tests 
or investigations, histopathological examinations or consultation with other health 
care professionals.
If a subject dies during participation in the study 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.
12.7.6.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool
Primary mechanism for reporting SAEs to GSK will be the electronic data collection 
tool.
If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax it to the Medical Monitor or the SAE 
coordinator.
Site will enter the serious adverse event data intothe electronic system as soon as it 
becomes available.
The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of 
the SAE.
After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) will be taken off-line to prevent the entry of new data or changes to 
existing data
If a site receives a report of a new SAE from a study subject or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, the site can report this information on a paper SAE form or to the Medical 
Monitor or the SAE coordinator by telephone.
Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.


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CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by 
third party copyright laws and therefore have been excluded.
12.8.
Appendix 8-Asthma control Questionnaire


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CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by 
third party copyright laws and therefore have been excluded.
12.9.
Appendix 9-St.Geroge’s Respiratory Questionnaire


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12.10.
Appendix 10-Subject Rated Response to Therapy
Evaluate your response to therapy since you started this study.
only one:
[1] Significantly Improved
[2] Moderately Improved
[3] Mildly Improved
[4] No Change
[5] Mildly Worse
[6] Moderately Worse
[7] Significantly Worse


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12.11.
Appendix 11-Clinician rated response to Therapy
Evaluate the subject’s response to therapy since the start of the study by placing a in the 
appropriate box below:
only one:
[1] Significantly Improved
[2] Moderately Improved
[3] Mildly Improved
[4] No Change
[5] Mildly Worse
[6] Moderately Worse
[7] Significantly Worse


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CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by 
third party copyright laws and therefore have been excluded.
12.12.
Appendix 12-Treatment Satisfaction Questionnaire for 
Medication (TSQM-9)


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12.13.
Appendix 13–Exit Interview Guide
1. Please tell me about your asthma over the past 6 months, during this trial. Has it improved, 
stayed the same, or gotten worse?
a. Please tell me about your symptomssince you’ve been in the trial compared to before 
the trial.  
Probes: 

Describe your symptoms before and during the trial. Symptoms during the day? 
Symptoms at night?

What symptoms? How often?
b. Please tell me about good days and bad dayswith respect to your asthma since you’ve 
been in the trial compared to before the trial.  
Probes: 

Describe good and bad days before and during the trial. 
c. Please tell me about activities or things you do day-to-daysince you’ve been in the trial 
compared to before the trial.  
Probes: 

Describe your activities or things you do day-to-day before and during the trial. 

Is there anything you avoid doing or worry about doing because of your asthma?  
Has this changed since you’ve been in the trial? 
d. Please tell me about how asthma impacted or affected your life since you’ve been in the 
trial compared to before the trial.  
Probes: 

Describe the impact of asthma before and during the trial. 
e. Please tell me about your asthma triggers, things that make your asthma worse,since 
you’ve been in the trial compared to before the trial.  
Probes: 

Describe your triggers before and during the trial. 
f. Please tell me about any unplanned visits to your doctor, emergency room or hospital
since you’ve been in the trial compared to before the trial.  
Probes: 

Describe any unplanned visits before and during the trial.


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2. Now let’s talk (more) about your asthma exacerbations over the past 6 months, during this 
trial.  Exacerbations are also sometimes called asthma attacks and might mean that you 
needed to take more medication, new medication like steroids, or were admitted to the 
hospital or emergency room. Would you say your exacerbations have improved, stayed the 
same, or gotten worse?
a. Please tell me about the number of asthma exacerbationssince you’ve been in the trial 
compared to before the trial.  
Probes: 

Describe your exacerbations. 

How often did you have exacerbations before and during the trial?
b. Please tell me about your asthma exacerbations in terms of how long they lastedsince 
you’ve been in the trial compared to before the trial.  
Probes: 

Describe your exacerbations. 

How long did they last before and during the trial?
c. Please tell me about your asthma exacerbations in terms of how severe or bad they were
since you’ve been in the trial compared to before the trial.  
Probes: 

Describe your exacerbations. 

What symptoms were most severe or most affected you? 

What symptoms were least severe or least affected you? 

Did they interfere with your normal activities? If “yes”, what activities? Tell me more 
about those.

Did you always seek care from a doctor?  Or go to an emergency room or hospital? If 
“yes”, tell me more about those.

Did you have exacerbations you took care of yourself?  Without contacting a doctor? 
If “yes”, tell me more about those.
3. Do you feel that the study treatment worked for you?
a. What makes you say that the treatment [subject’s response; worked or didn’t work]?
Probes: 

What is most important to you in terms of your asthma to say that a treatment works? 


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12.14.
Appendix14: 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 medicineor any concomitant medicines;
Asthma 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 Reporting and Analysis Plan 
(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 anallogeneicbone 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 priorihypothesis 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 Deoxyribonucleic acid (DNA) extraction. A blood 
sample is collected at the baseline (Visit 2) or any other later visit, after the subject has 
provided informed consent for genetic research. 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 an inability to utilize the original sample.  
The genetic sample is labelled (or “coded”) with the same study specific number used to 
label other samples and data in thestudy.   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 purpose stated in this protocol and in the informedconsent 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 bloodbeing 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. 
Genotype data may be generated during the study or after completion of the study and 
may be analyzed during the study or storedfor future analysis. 


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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 
tobe stored and used, as appropriate. 
Initiation of study treatment not met
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.


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12.15.
Appendix 15-Country Specific Requirements
No country-specific requirements exist.


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12.16.
Appendix 16:Protocol changes
Scope:
This amendment applies to all sites.
Protocol Changes specified in Amendment No.1 are summarised below.
Strike throughtextrefers to deleted textand underlined refersto added text.
Protocol Changes
Medical Monitors/Sponsor information Page
Secondary Medical Monitor details
Rationale for change:  Contact detailsupdateto reflect change in personnel. 
Revisedtext:
Ro
le
Name
Day T
ime Phone 
Number and ema
i
l 
address
After-hours 
Phone/Ce
l
l/
Pager 
Number
Fax 
Number
S
ite Address
Pr
imary 
Med
ica
l 
Mon
itor 
 
 MD
Te
lephone: 
Ce
l
l:  
Fax 
 G
laxoSm
ithK
l
ine
F
ive Moore 
Dr
ive
Research 
Tr
iang
le Park, 
NC 27709-3998, 
USA
Secondary 
Med
ica
l 
Mon
itor
 
 
 MD
Te
lephone:
 
Te
lephone:  
 
Ce
l
l:
 
 
Ce
l
l:  
 
Fax
 
Fax:  
G
laxoSm
ithK
l
ine
Stock
ley Park 
West, 1-3 
Ironbr
idge 
Road, 
Heathrow, 
Uxbr
idge, 
M
idd
lesex, 
UB11 1BT, 
Un
ited K
ingdom
SAE 
contact  
informat
ion 
 
 MD
Te
lephone: 
Ce
l
l:  
G
laxoSm
ithK
l
ine
F
ive Moore 
Dr
ive
Research 
Tr
iang
le Park, 
NC 27709-3998, 
USA
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
P
P
D
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Sponsor Legal Registered Address
Rationale for change: Mepolizumab IND numberadded
Revised text:
Regulatory Agency Identifying Number(s):  EudraCT no.2015-003697-32, IND 
no.006971
Section 1 andSection3 Objective(s)/Endpoints
Rationale for change: The wording of the primary objective was revised to reflect the 
pragmatic approach of the study.
Revised text: 
Primary objective: To determine To describe in a pragmatic settingwhether there is an 
improvement in asthma control,from the beginning to the end of the study,whendirectly 
switched to mepolizumabin subjects with a severe eosinophilic asthma phenotype not 
optimally controlled on omalizumab.
Section 4.6.1 Table3 Risk Assessment for mepolizumab
Rationale for change: To clarify that subjectsshould be monitored for 1 hr post 
injection for the first 3 injectionsand later per institutional guidelines.
Revised text
Subjects are to be monitored post-injection for one hourfor the first 3 injections, then per 
institutional guidelines.
Section 5.1Inclusion Criteria No.6
Rationale for change: To add long-acting anticholinergic (tiotropium bromide)
Revised text:
Controller medication:Current treatment with an additional controller medication, 
besides ICS, for at least 3 months or a documented failure in the past 12 months of an 
additional controller medication for at least 3 successive months.  [e.g., long-acting beta-
2-agonist (LABA), leukotriene receptor antagonist (LTRA), long-acting anticholinergic 
(tiotropium bromide), or theophylline.]
Section 5.3 Required Criteria to Start Treatment. Criterion No. 2
Rationale for change: “run-in” is added for consistency
Revised text:
No Asthma Exacerbation: Subjects with an ongoing asthma exacerbation at Baseline 
(Visit 2) should have their Visit 2 delayed until the investigator considers the subject has 


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returned to their baseline asthma status for at least one week.If the 4-week 
screening/run-inperiod has elapsed and subjects have not returned to their baseline 
asthma status, then they should be considered a run-in failure. An exacerbation is defined 
as worsening of asthma requiring the use of systemic corticosteroids and/or emergency 
departmentvisit, or hospitalisation (see Section 7.3.2.4Clinically Significant Asthma 
Exacerbation).
Section 5.5.3Liver Chemistry Stopping Criteria
Phase III-IV Liver Chemistry Stopping and Increased Monitoring Algorithm
Rationale for change: To change“Appendix 2”to “Appendix 5”as this was a 
typographical error.
Revised text
Liver chemistry stopping criteria and required follow up assessmentsare defined in 
Appendix 2Appendix5.
Section 5.5.4QTc Stopping Criteria
Last bullet point
Rationale for change: To correcttypographical errors. Change from baseline (Visit 2), 
was replaced with “change from screening (Visit 1)”. In addition, “Baseline (Visit 
2)” was changed to “Screening (Visit 1)”. 
Revised Text
[Change from baselinescreening (Visit 21) of QTc > 60 msec]
For patients with underlying bundle branch block, follow the discontinuation criteria 
listed below:
BaselineScreening (Visit 21) QTc with 
Bundle Branch Block
Discontinuation QTc with Bundle 
Branch Block
< 450 msec
> 500 msec
450 –480 msec
≥ 530 msec
Section 6.1 Investigational Product and Other Study Treatment
Second paragraph
Rationale for change: Ventolin Diskus for Sweden was added to reflect its use as a 
rescue medication in Sweden. “MDI”, was replaced by “rescue inhaler”
Revised text


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Trade label albuterol/salbutamol metered dose inhalers (MDIs) will be provided locally 
by each country (except for US sites where GSK Global Supply Organisation will supply 
the rescue medication)including Swedenwhere Ventolin Diskus will be used.Subjects 
willbe dispensedan MDIa rescue inhalerat the time of screening to be used to primarily 
treat asthma symptoms on an as needed basis but also during pre and post bronchodilator 
spirometryassessments (see Section 7.3.2.3.1).TheMDIrescue inhalershould be 
replacedas needed, and collected at the Exit Visit (or Early Withdrawal Visit, as 
applicable).
Section 7.1Time and Events Table
Rationale for change:  To make minor changes, the “x”, in Dispense paper 
diary/worksheet row for The Exit Visit/Early withdrawal Visit column, was removed 
to correct a typographical error.  In addition, in the table footnote the assay for 
Hepatitis C was updated.
Revised text


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Procedures
Pre-
screen1
Screen
Run-in
Treatment
(visit window is 7days)
Exit Visit/ 
Early withdrawal 
Visit3
Visit
0
1
2
3
4
5
6
7
8
9
10
Week
-6 to -4
-4to -1 
0
4
8
12
16
20
24
28
4 weeks post last 
dose7days 
Informed Consent2
x
Sub
ject Demography
x
Med
ica
l H
istory
x
Asthma H
istory (
inc
lud
ing 
tr
iggers)
x
x
Therapy H
istory4
x
Smok
ing H
istory
x
Card
iovascu
lar H
istory/R
isk 
Factors
x
Inc
lus
ion/Exc
lus
ion Cr
iter
ia
x
Cont
inuat
ion to treatment 
Cr
iter
ia
x
Efficacy Assessments5
ACQ-5
x
x
x
x
x
x
x
x
x
x
Exacerbat
ion rev
iew
x
x
x
x
x
x
x
x
x
x
x
Sp
irometry 
inc
lud
ingpre-and 
post bronchod
i
lator FEV1,
FVC6
x
x
x
x
x
Health Outcome 
Assessments5
SGRQ
x
x
x
x
C
l
in
ic
ian& Sub
jectrated 
response to therapy
x
x
x
x
Treatment Sat
isfact
ion w
ith 
Med
icat
ion Quest
ionna
ire 
(TSQM-9) 
x
x
Ex
it Interv
iew7
x


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Procedures
Pre-
screen1
Screen
Run-in
Treatment
(visit window is 7days)
Exit Visit/ 
Early withdrawal 
Visit3
Visit
0
1
2
3
4
5
6
7
8
9
10
Week
-6 to -4
-4to -1 
0
4
8
12
16
20
24
28
4 weeks post last 
dose7days 
Safety Assessments5
Concom
itant Med
icat
ion
x
x
x
x
x
x
x
x
x
x
x
Phys
ica
l Exam
inat
ion, 
inc
lud
ing nasa
l exam
x
x
V
ita
l S
igns 
x
x
x
x
x
x
x
x
x
x
12 
lead ECG
x
x
x
Adverse Events
x
x
x
x
x
x
x
x
x
x
Ser
ious Adverse Events
x
x
x
x
x
x
x
x
x
x
x
Laboratory Assessments5
Haemato
logy w
ith d
ifferent
ia
l
x
x
x
x 
x
x
x
x
x
x
C
l
in
ica
l Chem
istry(
inc
l. LFT)
x 
x
x
x
x 
x
x 
Paras
it
ic Screen
ing8
x
Pharmacogenet
ic samp
le9
            X              
Pregnancy test10
U
U
U
U
U
U
U
U
U
U
HBsAg and hepat
it
is C 
ant
ibody11
x
Immunogen
ic
itysamp
le
x
x
x
x
B
iomarker samp
le
x
x
x
x


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Procedures
Pre-
screen1
Screen
Run-in
Treatment
(visit window is 7days)
Exit Visit/ 
Early withdrawal 
Visit3
Visit
0
1
2
3
4
5
6
7
8
9
10
Week
-6 to -4
-4to -1 
0
4
8
12
16
20
24
28
4 weeks post last 
dose7days 
Investigational product 
(Mepolizumab) and rescue 
medication
Adm
in
istermepo
l
izumab. 
Contact RAMOS NG to 
reg
ister d
ispens
ing v
is
it. 
x
x
x
x
x
x
x
x
A
lbutero
l/sa
lbutamo
l 
d
ispensed (as needed)
x
x
x
x
x
x
x
x
x
Co
l
lect d
ispensed 
a
lbutero
l/sa
lbutamo
l 
x
x
x
x
x
x
x
x
x
eCRF/
paper diary/worksheet
Comp
lete eCRF
x
x
x
x
x
x
x
x
x
x
x
D
ispense paper 
d
iary/worksheet
x
x
x
x
x
x
x
x
x
x
x
Co
l
lect/rev
iew paper 
d
iary/worksheet
x
x
x
x
x
x
x
x
x
x
1. Pre-screen V
is
it 0 must be comp
leted pr
ior to V
is
it 1 (Screen
ing). It can be comp
leted on the same day as V
is
it 1 or at up to 2 weeks pr
ior to V
is
it 1.
2. Sub
jects w
i
l
l be ass
igned a sub
ject number at the t
ime ICF s
igned. The ICF must be s
igned before any study procedures 
inc
lud
ing med
icat
ion wash out per
iod(s). 
3. Ex
it V
is
it may be comp
leted 3 to 5 weeks post 
last dose. 
4. Therapy h
istory to 
inc
lude a deta
i
led rev
iew of pr
ior b
io
log
ics rece
ived for treatment of asthma, 
inc
lud
ing oma
l
izumab dose and reg
imen and pr
ior 
invest
igat
iona
l therap
ies e.g 
ant
i-IL5 or ant
i-IL13 preparat
ions.
5. A
l
l study eff
icacy, safety and a
l
l pat
ient reported quest
ionna
ires must be comp
leted pr
ior any study procedure. 
6. Sp
irometry to 
inc
lude pre-and post bronchod
i
lator FEV1 from V2.
7. Ex
it 
interv
iew w
i
l
l be conducted on
ly 
in a subset of s
ites and 
in asubset of sub
jects who choose to part
ic
ipate 
in the Ex
it 
interv
iew.  Sub
jects must be consented pr
ior to 
interv
iew 
8. Paras
it
ic screen
ing 
is on
ly requ
ired 
in countr
ies w
ith h
igh-r
isk or for sub
jects who have v
is
ited h
igh-r
isk countr
ies 
in the past 6 months.S
ites shou
ld use 
loca
l 
laborator
ies.
9. Pharmacogenet
ic samp
le may be drawn at V
is
it 2 or any v
is
it after.
10.Pregnancy test, U= ur
ine 
11.Hepat
it
is B Surface Ant
igen and Hepat
it
is C ant
ibody. (
if hepat
it
is C ant
ibody 
is pos
it
ive,a RIBA 
immunob
lot assay shou
ld beref
lex
ive
ly performed on the serum samp
le to 
conf
irm the resu
lts hepat
it
is C w
i
l
l be conf
irmed by PCR).  


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Section 7.3.2.3.1 Pre and post bronchodilator FEV1
Rationale for change: To add “morning long-acting anticholinergic (LAMA)”
Revised text
Only pre-bronchodilator assessments are required at Visit 1. Both pre-bronchodilator and 
post-bronchodilator assessments are required from Visit 2 onwards. At each visit, 
spirometry assessments should be performed at the same time of day (1hour) as the 
assessment performed at Visit 2 (the baseline assessment). Subjects should withhold 
short-acting beta-2-agonists (SABAs) for 6 hours and LABAs for 12 hours and their 
dose of long-acting anticholinergic (LAMA)prior to the clinic visit.if possible.
Section 7.4.7 Clinical Safety Laboratory Assessments
Table 5 Protocol Required Safety Laboratory Assessments
Rationale for change: to correct a typographical errorin appendix No.
Revised text
Laboratory 
Assessments
Parameters
Haematology
P
late
let Count
RBC Ind
ices: WBC count w
ith D
ifferent
ia
l:
RBC Count
MCV
Neutroph
i
ls
Hemog
lob
in
MCH
Lymphocytes
Hematocr
it
Monocytes
Eos
inoph
i
ls
Basoph
i
ls
Clinical 
Chemistry 
1
BUN
Potass
ium AST (SGOT)
Tota
l and d
irect 
b
i
l
irub
in
Creat
in
ine
Sod
ium
ALT (SGPT)
Tota
l Prote
in
G
lucose 
Ca
lc
ium
A
lka
l
ine phosphat
ise A
lbum
in
Other Screening 
Tests
Hepatitis B (HBsAg)
Hepatitis C (Hep C antibody)
FSH and estradiol (as needed in women of non-child bearing 
potential only)
Alcohol and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines)
UrinehCG Pregnancy test (as needed for women of child bearing 
potential) 2


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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 inSection 5.5.3
andAppendix 2Appendix 5
2. Local urine testing will be standard for the protocol unless serum testing is 
required by local regulation or ethics committee.
Section 7.5 Biomarker(s)/Pharmacodynamic Markers
Rationale for change: To clarify that eosinophil count is not blinded
Revised text
Blood eosinophil counts will be recorded as part of the standard haematological 
assessments performed at the visits specified in the Time and Events Schedule(Section 
7.1).  From Visit 2 onwards, blood eosinophil counts will not be communicated to 
investigators, in order not to bias the investigator assessment of patient response to 
treatment. Additional blood samplesfor exploratory biomarkers of type 2 helper T cells 
(Th2) response,will be collected at Visits 1, 2, 4 and 10.  Details on collecting and 
handling of biomarker samples can be found in the SRM.
Section 12.7 Appendix 7 Sub-section 12.7.2 last bullet point
Revised text 
Rationale for change: To correct the Appendix No as it was a typographical error
Revised text: Refer to Appendix 2 Appendix 5forthe required liver chemistry follow-up 
instructions

SAP_000.pdf: 
2017N328770_00
CONFIDENTIAL
The GlaxoSmithKline group of companies
204471
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for Study 204471, A multi-
centre, open label, single arm, 32-week treatment study in 
subjects with severe eosinophilic asthma not optimally 
controlled with current omalizumab treatment who are 
switched from omalizumab to mepolizumab 100mg 
subcutaneous (the OSMO study).
Compound Number :
SB-240563
Effective Date 
:
08-MAY-2017
Description :

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report (CSR) for Protocol 204471.

The critical components RAP was completed on the 10th February 2016.  This 
document represents the final RAP and will be provided to the study team 
members to convey the content of the Statistical Analysis Complete (SAC) 
deliverable.
Author’s Name and Functional Area: 
03-MAY-2017
Statistician, RD PCPS QSci Clinical Statistics
Agreed by core RAP team (via email):
 (Project Physician Lead, Respiratory Therapeutic Unit)
 (Global Medical Affairs Lead, Respiratory Franchise)
 (Clinical Investigation Leader, Respiratory Therapeutic Unit)
 (Medical Director, Safety Evaluation & Risk Management)
 (Manager, Clinical Programming)
Approved by: 
 
08-MAY-2017
Director, RD PCPS QSci Clinical Statistics
Copyright 2017 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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TABLE OF CONTENTS
PAGE
1.
REPORTING & ANALYSIS PLAN SYNPOSIS.........................................................4
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................6
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................6
2.2.
Study Objectives and Endpoints ...................................................................7
2.3.
Study Design ................................................................................................9
2.4.
Statistical Hypotheses...................................................................................9
3.
PLANNED ANALYSES ..........................................................................................10
3.1.
Interim Analyses .........................................................................................10
3.2.
Final Analyses ............................................................................................10
4.
ANALYSIS POPULATIONS ...................................................................................11
4.1.
Protocol Deviations.....................................................................................11
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................12
6.
STUDY POPULATION ANALYSES .......................................................................13
6.1.
Overview of Planned Analyses ...................................................................13
7.
PRIMARY STATISTICAL ANALYSES....................................................................15
7.1.
Efficacy Analyses........................................................................................15
7.1.1.
Overview of Planned Efficacy Analyses .......................................15
7.1.2.
Planned Efficacy Statistical Analyses...........................................16
7.1.3.
Analysis Comparing Against A Historical Placebo Effect..............17
8.
SECONDARY STATISTICAL ANALYSES .............................................................18
8.1
Efficacy Analyses........................................................................................18
8.1.1.
Overview of Planned Efficacy Analyses .......................................18
8.1.2.
Secondary Efficacy Statistical Analyses.......................................20
8.2.
Safety Analyses..........................................................................................24
8.2.1.
Overview of Planned Analyses ....................................................24
8.2.2.
Adverse Events of Special Interest ..............................................25
8.2.3.
Overview of Planned Clinical Laboratory Analyses ......................26
8.2.4.
Overview of Planned Other Safety Analyses................................27
8.2.4.1.
Immunogenicity ..........................................................28
9.
REFERENCES.......................................................................................................30
10. APPENDICES........................................................................................................31
10.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................32
10.1.1.
Exclusions from Per Protocol Population .....................................32
10.2.
Appendix 2: Time & Events.........................................................................34
10.2.1.
Protocol Defined Time & Events ..................................................34
10.3.
Appendix 3: Assessment Windows & Visit Slotting .....................................37
10.3.1.
Assessment Windows..................................................................37
10.3.2.
Early Withdrawal / Treatment Discontinuation Visits ....................37


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10.3.3.
Unscheduled Visits ......................................................................37
10.4.
Appendix 4: Treatment Phases...................................................................38
10.4.1.
Treatment Phases (Exacerbations)..............................................38
10.4.2.
Treatment Phases (Visit Based Efficacy Data).............................38
10.4.3.
Treatment Phases (Adverse Events) ...........................................38
10.4.3.1.
Adverse Event Data Derivations.................................39
10.4.4.
Treatment Phases (Concomitant Medications) ............................39
10.5.
Appendix 5: Data Display Standards & Handling Conventions....................41
10.5.1.
Study Treatment & Subgroup Display Descriptors .......................41
10.5.2.
Baseline Definition & Derivations .................................................41
10.5.2.1.
Baseline Definition......................................................41
10.5.2.2.
Derivations and Handling of Missing Baseline 
Data ...........................................................................41
10.5.3.
Reporting Process & Standards...................................................41
10.6.
Appendix 6: Derived and Transformed Data ...............................................44
10.6.1.
General........................................................................................44
10.6.2.
Study Population..........................................................................44
10.6.3.
Efficacy........................................................................................46
10.6.4.
Safety ..........................................................................................48
10.7.
Appendix 7: Premature Withdrawals & Handling of Missing Data ...............50
10.7.1.
Premature Withdrawals................................................................50
10.7.2.
Handling of Missing Data.............................................................50
10.7.2.1.
Handling of Missing or Partial Dates...........................51
10.8.
Appendix 8: Values of Potential Clinical Importance ...................................52
10.8.1.
Laboratory Values........................................................................52
10.9.
Appendix 9: Multicenter Studies..................................................................53
10.9.1.
Methods for Handling Centres .....................................................53
10.10. Appendix 10: Examination of Covariates and Subgroups............................54
10.10.1. Handling of Covariates.................................................................54
10.10.2. Handling of Subgroups ................................................................54
10.11. Appendix 11: Model Checking and Diagnostics for Statistical 
Analyses.....................................................................................................55
10.11.1. Statistical Analysis Assumptions..................................................55
10.12. Appendix 12: Abbreviations & Trade Marks ................................................56
10.12.1. Abbreviations...............................................................................56
10.12.2. Trademarks .................................................................................57
10.13. Appendix 13: List of Data Displays..............................................................58
10.13.1. Data Display Numbering..............................................................58
10.13.1.1. Study Population Tables.............................................59
10.13.1.2. Study Population Figures............................................62
10.13.1.3. Efficacy Tables...........................................................63
10.13.1.4. Efficacy Figures..........................................................68
10.13.1.5. Safety Tables .............................................................70
10.13.1.6. Safety Figures ............................................................75
10.13.1.7. ICH Listings................................................................76
10.14. Appendix 14: Example Mock Shells for Data Displays ................................81


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1.
REPORTING & ANALYSIS PLAN SYNPOSIS
Overview
Key Elements of the RAP
Purpose

This reporting and analysis plan (RAP) details all planned analyses and outputs 
required for the final Clinical Study Report (CSR) of study 204471.

The critical components RAP was completed on the 10th February 2016.  This 
document represents the final RAP and will be provided to the study team 
members to convey the content of the Statistical Analysis Complete (SAC) 
deliverable.
Protocol

This RAP is based on protocol amendment 1 (Dated: 23-MAR-2016) for study 
204471 (GSK Document No.: 2015N243304_01) and the latest version of the 
electronic Case Report Form (eCRF) [eCRF Version 2.1].
Primary 
Objective 

To determine in a pragmatic setting whether there is an improvement in asthma 
control, from the beginning to the end of the study, when directly switched from 
omalizumab to mepolizumab in subjects with a severe eosinophilic asthma 
phenotype not optimally controlled on omalizumab.
Primary 
Endpoint

Mean change from baseline in ACQ-5 score at Week 32
Study 
Design

An open label, single arm, 32-week treatment, multi-center study in subjects with 
severe eosinophilic asthma not optimally controlled with current omalizumab 
treatment who are switched from omalizumab to mepolizumab 100mg 
administered subcutaneously (SC) every 4 weeks.

Approximately 120 subjects are expected to be treated with open label 
mepolizumab.
Planned 
Analyses

No interim analysis of data is planned for this study.

A complete analysis in accordance with all study objectives and endpoints will be 
performed after all subjects have completed the study.

Decisions regarding the analyses, specified in this RAP document, will be made 
prior to Database Freeze of the study data.
Analysis 
Populations

The ‘All Subjects Enrolled’ population will be used to summarise Screen and run-
in failures.

The ‘Intent-to-Treat’ population will be used as the primary population to
summarise the study population, and to evaluate efficacy, safety and 
PD/Biomarkers. 

The ‘Per Protocol’ population will also be used as a supporting population to 
evaluate efficacy. Subjects excluded will have protocol deviations considered to 
potentially have an effect on efficacy.
Hypothesis

As there is no control arm within this study, comparisons in ACQ score will be 
made back to baseline. 

The potential of a ‘placebo effect’ within the mepolizumab treated subjects was 
considered when the study was designed and was estimated as an improvement 
of -0.55 from baseline in ACQ score, based on placebo subjects within historical 
mepolizumab severe asthma studies. However, when only previous Xolair users 
were considered, an improvement of -0.11 from baseline in ACQ score was 
observed. 

This study is designed to test the superiority of mepolizumab 100 mg SC 


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Overview
Key Elements of the RAP
treatment vs. baseline.  Improvements will also be assessed against the
historical ‘placebo effects’ estimated from previous mepolizumab studies. 
Significance tests will be performed at the two-sided 5% alpha level (one-sided 
2.5%).
Primary 
Analyses

ACQ-5 score will be analysed using a mixed models repeated measures 
analyses allowing for covariates of region, use of baseline maintenance oral 
corticosteroids therapy (OCS vs no OCS), exacerbations in the year prior to the 
study (as an ordinal variable), and visit (including baseline visit).
Secondary 
Analyses

SGRQ score will be analysed using a mixed models repeated measures analysis 
as for ACQ-5.

Frequency of clinically significant asthma exacerbations will be analysed using a 
negative binomial regression analysis 

Blood eosinophil count will be analysed using a mixed model repeated measures 
analysis after log transformation
Safety 
Analysis

Safety data including adverse events, vital signs, clinical laboratory, 
electrocardiogram (ECG), and immunogenicity data will be summarised 
descriptively.


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2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
Statistical analysis changes to the originally planned statistical analysis specified in the 
protocol amendment 1 (Dated: 23-MAR-2016) (GSK Document No.: 2015N243304_01)
are outlined in Table 1. 
Table 1
Changes to Protocol Defined Statistical Analysis Plan
Protocol 
Reporting & Analysis Plan 
Statistical Analysis Plan
Statistical Analysis Plan
Rational for Changes

Analysis of change from baseline 
in ACQ, SQRQ scores will be 
performed using a mixed models 
repeated measures (MMRM) 
analysis, allowing for covariates of 
baseline ACQ score, region, 
baseline maintenance OCS 
therapy, exacerbations in the year 
prior to the study (as an ordinal 
variable), visit and an interaction 
term for visit by baseline ACQ 
score.

Clinically significant exacerbations 
will be analyzed using a 
generalized linear model with 
covariates for region, baseline 
maintenance OCS therapy and 
number of exacerbations in the 
year prior to the study (as an 
ordinal variable).

Baseline values will be 
included as a data point in the 
analysis, and there will be no 
covariate adjustment made in 
the model. The change from 
the baseline at Visit X will be 
calculated by:
Estimated  Score at Visit X 
minus  Estimated Score at
Baseline.

Clinically significant 
exacerbations will be examined 
using a generalized estimating 
equation (GEE) with no 
adjustments for covariates.

This is a single 
treatment arm study 
and comparisons are 
being made directly to 
the baseline values.

Generalised 
estimating equations 
(GEEs) will compare 
the on-treatment 
exacerbation rate to 
the rate within the 12 
months prior to study.


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2.2.
Study Objectives and Endpoints
The below objectives and endpoints will be assessed when subjects with a severe 
eosinophilic asthma phenotype who are not optimally controlled on omalizumab are 
directly switched from omalizumab to mepolizumab:
Objectives
Endpoints
Primary Objectives
Primary Endpoints

To describe in a pragmatic 
situation/setting whether there is 
an improvement in asthma 
control from the beginning to the 
end of the study 

Mean change from baseline in Asthma Control 
Questionnaire-5 (ACQ-5) score at Week 32
Secondary Objectives
Secondary Endpoints

To determine whether there is an 
improvement in Health related 
Quality of Life (HR-QoL)

Mean change from baseline in St. George’s 
Respiratory Questionnaire (SGRQ) score at Week 32

To determine the frequency of 
asthma exacerbations

Frequency of clinically significant asthma 
exacerbations over 32 week treatment

To evaluate the pharmacodynamic 
effects 

Ratio to baseline in blood eosinophils at Week 32
Other Objectives
Other Endpoints

To determine the response to 
asthma clinical parameters 

Percentage of subjects achieving a 0.5-point or 
greater reduction from baseline in ACQ-5 score at 
Week 32

Percentage of subjects achieving a 4-point or greater 
reduction from baseline in SGRQ score at Week 32

Mean change from baseline in pre- and post 
bronchodilator FEV1 at Week 32

Frequency of exacerbations requiring ED 
visit/hospitalization during the treatment period 

Subject/Clinician rated  response to therapy

Mean change from baseline in treatment satisfaction 
questionnaire
Exploratory Objectives
Exploratory Endpoints

To determine the effect on 
inflammatory biomarkers 

To characterize patient treatment 
benefit of mepolizumab

Change from baseline in some inflammatory 
biomarkers expression at week 32

Subject Exit Interviews
Safety Objectives
Safety Endpoints

To determine the safety, 
immunogenicity and tolerability of 
mepolizumab 

Incidence and frequency of Adverse/Serious 
Adverse Events (including systemic and injection site 
reactions)

Clinically significant change in electrocardiogram 
(ECGs)

Clinically significant change in vital signs


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Objectives
Endpoints

Incidence of immunogenicity


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2.3.
Study Design
Overview of Study Design and Key Features
Design 
Features

An open label, single arm, 32-week treatment, multi-center study in subjects 
with severe eosinophilic asthma not optimally controlled with current 
omalizumab treatment who are switched from omalizumab to mepolizumab 
100mg administered subcutaneously (SC) every 4 weeks.

Patients with severe eosinophilic asthma who are receiving omalizumab, but 
are not optimally controlled will be eligible to participate and will be identified 
through the ACQ-5 with a screening (Visit 1) and baseline (Visit 2) score of 
≥1.5 and a history of ≥2 exacerbations in the past 12 months.
Dosing

Subjects will remain on their current maintenance therapy throughout the run-in 
period, including Omalizumab. At Visit 2 subjects will discontinue their 
Omalizumab treatment and be switched to open-label mepolizumab (100 mg 
SC) every 4 weeks for 32 weeks (there is no wash-out period between the 
therapies). If patients require any additional maintenance therapy (except for 
omalizumab), they will remain receiving it throughout the treatment period.
Treatment 
Assignment

At week 0 (Visit 2) approximately 120 eligible subjects who meet the 
continuation to treatment criteria will receive open-label mepolizumab 100 mg 
SC into the upper arm or thigh every 4 weeks with the last dose being given at 
week 28 (Visit 9). A web based interactive system RAMOS NG will be used to 
dispense mepolizumab from Visit 2 to Visit 9.
Planned 
Analysis

No interim analysis of data is planned for this study.

A complete analysis in accordance with all study objectives and endpoints will 
be performed after all subjects have completed the study.

Decisions regarding the analyses, specified in this RAP document, will be 
made prior to Database Freeze of the study data.
2.4.
Statistical Hypotheses
This study is designed to investigate whether subjects not optimally controlled on 
omalizumab can be effectively and safely switched to treatment with mepolizumab to 
improve asthma control. As there is no control arm in this study, comparisons in ACQ-5 
score will be made to baseline. The first hypothesis to be tested will be for superiority of 
mepolizumab 100 mg SC treatment vs. baseline. 


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The potential of a ‘placebo effect’ within the mepolizumab treated subjects has been 
considered.  In the protocol this was estimated as an improvement of -0.55 (SE: 0.05)  
from baseline in ACQ-5 score, based on the  placebo effect observed in mepolizumab 
subjects from Phase 3 severe asthma studies (meta-analysis of double-blind studies 
MEA112997 and MEA115588). Improvements from baseline in ACQ-5 score will be 
assessed against this historical ‘placebo effect’. For further information regarding this 
historical ‘placebo effect’ please refer to Section 7.1.3.
Significance tests will be performed at the two-sided 5% alpha level (one-sided 2.5%).
3.
PLANNED ANALYSES
3.1.
Interim Analyses
No interim analysis of data is planned for this study.
3.2.
Final Analyses
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 and database freeze has been declared by Data Management.


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4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
All Subjects 
Enrolled (ASE) 
Population

Comprised of all subjects enrolled and for 
whom a record exists on the study database.

Screen and run-in 
failures
Intent-to-Treat
(ITT) Population

Comprised of all subjects who receive at least 
one dose of mepolizumab. 

Study Population

Efficacy

Safety
Per Protocol (PP) 
Population

Comprised of all subjects in the ITT population 
who have not been identified as full protocol 
deviators with respect to criteria that are 
considered to 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 freezing the study database. 
Protocol deviations that would exclude 
subjects from the PP population are defined in 
Section 4.1 (Protocol Deviations) and 
(Appendix 1: Protocol Deviation Management 
and Definitions for Per Protocol Population).

Supplementary 
analysis of the 
primary endpoint
NOTES : 

Please refer to Appendix 13: List of Data Displays which details the population to be used for each displays being 
generated.
4.1.
Protocol Deviations

All protocol deviations will be tracked by the study team throughout the conduct of 
the study in accordance with the Protocol Deviation Management Plan.
o
Data will be reviewed prior to freezing the database to ensure all important 
deviations and deviations which may lead to exclusion from the Per Protocol 
analysis are captured and categorised on the protocol deviations dataset. 
o
This dataset will be the basis for the summaries and listings of protocol 
deviations.

Important protocol deviations (including deviations related to study 
inclusion/exclusion criteria, conduct of the trial, patient management or patient 
assessment) will be summarised and listed.

Important deviations which result in exclusion from the Per Protocol population will 
also be summarised and listed. (Please refer to Appendix 1: Protocol Deviation 
Management and Definitions for Per Protocol Population).

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.


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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS
Table 2 provides an overview of appendices within the RAP for outlining general 
considerations for data analyses and data handling conventions. 
Table 2
Overview of Appendices
Section
Component
10.1
Appendix 1: Protocol Deviation Management and Definitions for Per Protocol 
Population
10.2
Appendix 2: Time & Events
10.3
Appendix 3: Assessment Windows & Visit Slotting
10.4
Appendix 4: Treatment Phases
10.5
Appendix 5: Data Display Standards & Handling Conventions
10.6
Appendix 6: Derived and Transformed Data
10.7
Appendix 7: Premature Withdrawals & Handling of Missing Data
10.8
Appendix 8: Values of Potential Clinical Importance
10.9
Appendix 9: Multicenter Studies
10.10
Appendix 10: Examination of Covariates and Subgroups
10.11
Appendix 11: Model Checking and Diagnostics for Statistical Analyses
Other RAP Appendices
10.12
Appendix 12: Abbreviations & Trade Marks
10.13
Appendix 13: List of Data Displays
10.14
Appendix 14: Example Mock Shells for Data Displays


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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Analyses
The study population analyses will be based on the Intent-To-Treat (ITT) population, 
unless otherwise specified.
Table 3 provides an overview of the planned study population analyses, with full details 
of data displays being presented in Appendix 13: List of Data Displays.
Table 3
Overview of Planned Study Population Analyses
Endpoint / Parameter / Display Type
Data Displays Generated
Table
Figure
Listing
Subject Disposition
Analysis Populations
Y
Reasons for Screen and Run-in Failure
Y
Y
Failed Inclusion/Exclusion/Continuation criteria
Y
Y
Subjects by Region, Country and Site
Y
Reasons for Subject Withdrawal From Study
Y
Y
Reasons for Subject Withdrawal From Investigational Product
Y
Y
Time to Withdrawal From Investigational Product
Y[1]
Demographic and Baseline Characteristics
Demographic Characteristics
Y
Y
Age Ranges
Y
Race and Racial Combinations
Y
Y[2]
Race and Racial Combination Details
Y
Demographic and Baseline Disease Characteristics
Asthma History and Baseline Disease Characteristics
Y
Previous Exacerbation History
Y
History of Tobacco Use
Y
Baseline Lung Function Results
Y
Past and Current Medical Conditions
Y
Cardiovascular Assessments (Family History/Screen Questions)
Y
Prior and Concomitant Medications
History Xolair Use (including regime, duration of treatment)
Y
Asthma Concomitant Medications by Respiratory Medication 
Class
Y
Non-Asthma Concomitant Medications Taken During 
Treatment
Y
Relationship between ATC level 1, Ingredient and verbatim 
text
Y


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Endpoint / Parameter / Display Type
Data Displays Generated
Table
Figure
Listing
Protocol Deviations
Important Protocol Deviations
Y
Y
Protocol Deviations Resulting in Exclusion from PP Population
Y
NOTES : Y = Yes display generated. [1] Kaplan Meier plot; [2] Listing of race as collected in eCRF.


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7.
PRIMARY STATISTICAL ANALYSES
7.1.
Efficacy Analyses
7.1.1.
Overview of Planned Efficacy Analyses
The primary efficacy analyses will be based on the Intent-To-Treat (ITT) population. 
Additional sensitivity analysis will be performed on the Per Protocol population.
Table 4 provides an overview of the planned efficacy analyses, with full details of data 
displays being presented in Appendix 13: List of Data Displays.
Table 4
Overview of Planned Efficacy Analyses
Endpoint
Absolute [1]
Change from Baseline [1]
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
Primary Endpoint
Asthma Control Questionnaire (ACQ-5)
On-treatment & Off-
treatment [2] [3]
Y[4]
Y
Y[4]
Y[5]
Y
Y
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
1.
Absolute and change from baseline summaries combined into a single display.
2.
To be generated for Intent-To-Treat (ITT) population and Per-Protocol (PP) population.
3.
Subgroup analyses to be repeated for Intent-To-Treat (ITT) population and all subgroups listed within Section 
10.10.2.
4.
Table to include both Least Square Means and Least Square Mean Changes and estimated treatment difference 
(Mepolizumab-Historical Placebo) and 95% confidence interval at each visit from Mixed Model Repeated 
Measures (MMRM) Analysis.
5.
Figure to present Least Square Mean Changes and corresponding 95% confidence intervals at each visit from 
MMRM Analysis 


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7.1.2.
Planned Efficacy Statistical Analyses
Primary Statistical Analyses
Endpoint(s)

Mean change from baseline in ACQ-5 score at Week 32 (ADaM Dataset : ADACQ5)
Model Specification

Endpoint will be analysed using a mixed models repeated measures (MMRM) analysis

Dependent variable will be ACQ-5 score at each visit including the baseline

Terms fitted in the MMRM analysis will include:
Fixed Categorical Covariates :
Region, Baseline maintenance OCS use,  Visit 
Fixed Continuous Covariates :
Exacerbations in the year prior to study (as an ordinal 
variable), 
Repeated :
Visit
See Section 10.10.1 for further details around model covariates.
Model Checking & Diagnostics

Refer to Appendix 11: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation

Adjusted means and the corresponding 95% confidence intervals will be presented by visit. 

The estimated adjusted means will be presented using the observed marginal distribution of 
the sample covariates (OM option in LSMEANS statement).

The Kenward and Roger method for approximating the denominator degrees of freedom and 
correcting for bias in the estimated variance-covariance of the fixed effects will be used 
(DDMF=KR). 

An unstructured covariance structure for the R matrix will be used by specifying ‘type=UN’ on 
the REPEATED line.

Change from the baseline at each Visit X will be calculated by (Estimated Score at Visit X 
minus Estimated Score at Baseline) and the corresponding 95% confidence intervals.  
Adjusted means at each visit will also be presented.

Plots of LS means change from baseline in ACQ-5 Score and 95% confidence intervals from 
the model will be generated by visit.

Adjusted mean and corresponding standard error of mean will be presented, together with 
estimated between treatment difference (Mepolizumab – Historical Placebo) and the 
corresponding 95% confidence intervals at Week 32. 
Treatment Phase

All subjects in the ITT population will be included within this analysis.

All data collected up to and including Week 32 from patients, including those who have 
discontinued study treatment, will be included in the analysis.
Sensitivity and Supportive Statistical Analyses

Additional comparisons to historical placebo effect will be presented at Week 32 (refer to 
Section 7.1.3 for more details). 

A supporting sensitivity analysis of the Per Protocol (PP) population will also be performed.

Subgroup analyses of the primary endpoint will be performed for all subgroups listed within 
Section 10.10.2.


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7.1.3.
Analysis Comparing Against A Historical Placebo Effect
We will perform two separate analyses of the primary endpoint comparing to a historical 
‘placebo effect’. 
Firstly, as specified in the protocol, a meta-analysis of previous exacerbation double-
blind studies, MEA112997 and MEA115588, gave an estimate of -0.55 (SE: 0.05), for 
the improvement in the ACQ-5 score for placebo subjects at Week 32 compared to 
baseline. The observed improvement in this study for following mepolizumab treatment
will be compared to this historical improvement on placebo.
Secondly, a meta-analysis has been performed of subjects within studies MEA115588 
and 200862 who reported previous Xolair use, which may represent a more comparable 
population for this study. Study 200862 has completed since the protocol was finalised 
and previous Xolair usage was not collected in study MEA112997. 
At Week 32 an estimate of -0.29 (SE: 0.248) was reported in the MEA115588 study 
while at Week 24 study 200862 reported an estimate of -0.03 (SE: 0.164) for the 
improvement in the ACQ-5 score for placebo subjects who previously used Xolair. 
Weighted meta-analysis was performed on these values to get the combined estimate of   
-0.11 (SE: 0.14) for the historical placebo effect (Figure 1). This shows a reduction in the 
ACQ-5 score, but not as large as that specified in the protocol. The observed 
improvement in this study for mepolizumab vs. baseline will be also compared to this 
historical improvement on placebo.
Figure 1
Meta-analysis of ACQ-5 Placebo Effect in Previous Xolair Users


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8.
SECONDARY STATISTICAL ANALYSES
8.1
Efficacy Analyses
8.1.1.
Overview of Planned Efficacy Analyses
The secondary efficacy analyses will be based on the Intent-To-Treat (ITT) population, 
unless otherwise specified in Appendix 13: List of Data Displays. 
Table 5 provides an overview of the planned efficacy analyses, with further details of 
data displays being presented in Appendix 13: List of Data Displays.
Table 5
Overview of Planned Efficacy Analyses
Endpoint
Absolute [1]
Change from Baseline [1] [2]
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
Secondary Endpoints
St George’s Respiratory Questionnaire (SGRQ)
On-treatment & Off-
treatment 
Y
Y
Y
Y
Y
Y
Blood Eosinophil Count
On-treatment & Off-
treatment 
Y
Y
Y
Y
Y
On-treatment [3]
Y
Y
Other Endpoints
>= 0.5-point reduction from baseline in ACQ-5 score at Week 32
On-treatment & Off-
treatment 
Y
Y
>= 4-point or greater reduction from baseline in SGRQ Total  score at Week 32
On-treatment & Off-
treatment 
Y
Y
Pre-Bronchodilator FEV1
On-treatment & Off-
treatment 
Y
Y
Y
Y
Y
Post-Bronchodilator FEV1
On-treatment & Off-
treatment 
Y
Y
Y
Y
Y
Subject/Clinician Rated Response to Therapy
On-treatment [3]
Y
Treatment Satisfaction Questionnaire for Medication (TSQM-9)
On-treatment [3]
Y
Y
Biomarkers
On-treatment 
Y
Y


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Endpoint 
Incidence of Events
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
Secondary Endpoints
Clinically Significant Exacerbations
On-treatment & Off-
treatment 
Y[4]
Y
Y
Y
On-treatment [3]
Y[4]
Exacerbations requiring ED visit/hospitalization
On-treatment & Off-
treatment 
Y[4]
Y
Y
On-treatment [3]
Y[4]
Exacerbations requiring hospitalization
On-treatment & Off-
treatment 
Y[4]
Y
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
1.
Absolute and change from baseline summaries combined into a single display.
2.
Ratio to Baseline to be shown for Blood Eosinophil Count and Biomarker data.
3.
To analyse data collected whilst On-Treatment, not considering any data collected following treatment 
discontinuation (see Section 10.4).
4.
Table to include annualised exacerbation rate and 95% confidence intervals from negative binomial model.


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8.1.2.
Secondary Efficacy Statistical Analyses
Secondary Statistical Analyses
Secondary Endpoint(s)

Mean change from baseline in SGRQ at Week 32
Model Specification

See Primary Efficacy Statistical Analysis, Section 7.1.2
Model Checking & Diagnostics

Refer to Appendix 11: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation

Adjusted means and the corresponding 95% confidence intervals will be presented by visit. 

The estimated adjusted means will be presented using the observed marginal distribution of 
the sample covariates (OM option in LSMEANS statement).

The Kenward and Roger method for approximating the denominator degrees of freedom and 
correcting for bias in the estimated variance-covariance of the fixed effects will be used 
(DDMF=KR). 

An unstructured covariance structure for the R matrix will be used by specifying ‘type=UN’ on 
the REPEATED line.

Change from the baseline at each Visit X will be calculated by (Estimated Score at Visit X 
minus Estimated Score at Baseline) and the corresponding 95% confidence intervals.  
Adjusted means at each visit will also be presented. 

Plots of LS means change from baseline in SGRQ Score and 95% confidence intervals from 
the model will be generated by visit.
On-treatment Phase

See Primary Efficacy Statistical Analysis, Section 7.1.2
Secondary Statistical Analyses
Secondary Endpoint(s)

Frequency of clinically significant asthma exacerbations over 32 week treatment

Frequency of exacerbations requiring ED visit/hospitalization during the 32 week treatment 
period

Frequency of exacerbations requiring hospitalization during the 32 week treatment period
Model Specification

The frequency of clinically significant exacerbations will be analysed using Negative Binomial 
regression via generalised estimating equations with a covariate of time period (pre-, post-
mepolizumab).

Exacerbations separated by less than 7 days will be treated as a continuation of the same 
exacerbation.

The pre-mepolizumab exacerbation values (in the 12 months prior) will be obtained at 
screening, while the post-meplizumab exacerbation values will be observed during the study. 

The variance of the mean estimate will be corrected for within-subject correlation. The 
logarithm of time on treatment will be used as an offset variable.
Model Checking & Diagnostics

Refer to Appendix 11: Model Checking and Diagnostics for Statistical Analyses.


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Secondary Statistical Analyses
Model Results Presentation

Adjusted exacerbation rate and the corresponding 95% confidence interval will be presented. 
On-treatment Phase

All subjects in the ITT population will be included within this analysis.

All data collected up to and including Week 32 from patients, including those who have 
discontinued study treatment, will be included in the analysis.

An On-Treatment “de jure” analysis will also be performed which does not consider any data 
collected following treatment discontinuation (see On-Treatment definition within Section 10.4).
Sensitivity and Supportive Statistical Analyses

The On-Treatment “de jure” analysis will be also performed with a subset of patients who were 
on omalizumab for more than 12 months.
Secondary Statistical Analyses
Secondary Endpoint(s)

Ratio to baseline in blood eosinophil count at week 32 
Model Specification

See Primary Efficacy Statistical Analysis, Section 7.1.2

A log-transformation will be applied to blood eosinophil count data prior to analysis. 

If a blood eosinophil count of zero is reported, it will be imputed with half of the lowest possible  
blood eosinophil count, where applicable, prior to log transforming the data (Note: this  
imputation has typically been 0.5 * 0.01 GI/L = 0.005 GI/L for previous mepolizumab studies).
Model Checking & Diagnostics

Refer to Appendix 11: Model Checking and Diagnostics for Statistical Analyses..
Model Results Presentation

Adjusted means and the corresponding 95% confidence intervals will be presented by visit. 

Plots of LS means ratio to baseline in blood eosinophil count and 95% confidence intervals 
from the model will be generated by visit.
On-treatment Phase

All subjects in the ITT population will be included within this analysis.

All data collected up to and including Week 32 from patients, including those who have 
discontinued study treatment, will be included in the analysis.

An On-Treatment “de jure” analysis will also be performed which does not consider any data 
collected following treatment discontinuation (see On-Treatment definition within Section 10.4.
Other Statistical Analyses
Other Endpoint

Percentage of subjects achieving a 0.5-point or greater reduction from baseline in ACQ-5 score 
at Week 32
Results Presentation

The number and percentage of subjects achieving a 0.5-point or greater reduction in ACQ-5 
Score compared to baseline will be presented for each visit.

The number of subjects with a missing ACQ-5 Score at each visit will be presented in a 
separate category.


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On-treatment Phase

See Primary Efficacy Statistical Analysis, Section 7.1.2
Other Statistical Analyses
Other Endpoint

Percentage of subjects achieving a 4-point or greater reduction from baseline in SGRQ score 
at Week 32
Results Presentation

The number and percentage of subjects achieving a 4-point or greater reduction in SGRQ 
Total score compared to baseline will be presented for each visit.

The number of subjects with a missing SGRQ Total Score at each visit will be presented in a 
separate category.
On-treatment Phase

See Primary Efficacy Statistical Analysis, Section 7.1.2
Other Statistical Analyses
Other Endpoint

Mean change from baseline in pre- and post- bronchodilator FEV1 at Week 32
Model Specification

See Primary Efficacy Statistical Analysis, Section 7.1.2
Model Checking & Diagnostics

Refer to Appendix 11: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation

Adjusted means and the corresponding 95% confidence intervals will be presented by visit 

The estimated adjusted means will be presented using the observed marginal distributions of 
the sample covariates (OM option in LSMEANS statement).

The Kenward and Roger method for approximating the denominator degrees of freedom and 
correcting for bias in the estimated variance-covariance of the fixed effects will be used 
(DDMF=KR). 

An unstructured covariance structure for the R matrix will be used by specifying ‘type=UN’ on 
the REPEATED line.

Change from the baseline at each Visit X will be calculated by (Estimated Score at Visit X 
minus Estimated Score at Baseline) and the corresponding 95% confidence intervals.  
Adjusted means at each visit will also be presented. 

Plots of Least Squares (LS) mean change from baseline pre- and post bronchodilator FEV1 
and 95% confidence intervals from the model will be generated at each visit.
On-treatment Phase

See Primary Efficacy Statistical Analysis, Section 7.1.2
Other Statistical Analyses
Other Endpoint

Subject rated response to therapy at Week 32

Clinician rated response to therapy at Week 32
Results Presentation


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
The number and percentage of subjects in each response category will be presented for each 
visit.

The number of subjects with a missing responses at each visit will be presented in a separate 
category.
On-treatment Phase

An On-Treatment “de jure” analysis will also be performed which does not consider any data 
collected following treatment discontinuation (see On-Treatment definition within Section 10.4).
Other Statistical Analyses
Other Endpoint

Mean change from baseline in Treatment Satisfaction Questionnaire for Medication (TSQM-9)
Model Specification

The Mean Change at Week 32 will be tested to see if it is significantly different from zero using 
Wilcoxon signed-rank test
Model Checking & Diagnostics

Check for the extreme outliers by plotting the differences between TSQM-9 at Week 32 and 
Baseline
Model Results Presentation

Summary Statistics will be represented by study visit

The mean change at Week 32 will presented with the corresponding 95% CI and p-value in the 
table

The mean change at Week 32 will presented with the corresponding 95% CI in the figure
On-treatment Phase

An On-Treatment “de jure” analysis will also be performed which does not consider any data 
collected following treatment discontinuation (see On-Treatment definition within Section 10.4)
Other Statistical Analyses
Other Endpoint

Change from baseline in inflammatory biomarkers expression at week 32. 
The following biomarker parameters will be reported: 
CCL13, CCL17, ECP, EDN, Eotaxin1, Total IL-5, IL-13, MDC, Periostin, TSLP
Model Results Presentation

A log-transformation will be applied to each biomarker parameter prior to analysis. 

Summary Statistics will be represented by study visit, including ratio to baseline

See Section 10.6.4 for further information regarding biomarker results below the lower limit of 
quantification
On-treatment Phase

An On-Treatment “de jure” analysis will also be performed which does not consider any data 
collected following treatment discontinuation (see On-Treatment definition within Section 10.4).


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8.2.
Safety Analyses
8.2.1.
Overview of Planned Analyses
The safety analyses will be based on the Intent-To-Treat (ITT) population, unless 
otherwise specified in Appendix 13: List of Data Displays. The safety displays to be 
created as part of the RAP include all the required and relevant displays identified as per 
the RAP Core Safety Reporting Template Version 1.0.
Table 6 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 13: List of Data Displays.
Adverse events will be coded using the latest version of the Medical Dictionary for
Regulatory Activities (MedDRA).
Table 6
Overview of Planned Adverse Event Analyses
Endpoint / Parameter/ Display Type
Absolute
Summary
Individual
T
F
L
Exposure
Number of treatments administered and time on-treatment
Y
Y
Adverse Events (AEs)
Overview of Adverse Events
Y
AEs by SOC and Maximum Intensity
Y
Y
Common Adverse Events by Overall Frequency [1]
Y
All Drug-Related AEs by SOC and Maximum Intensity
Y
AEs on the Day of Dosing 
Y
AEs by the Age Group (<18 year, ≥18 years)
Y
AEs by Highest Antidrug Antibody Result At Any Time Post Baseline
Y
Number of subjects & occurrences of common[1] non-serious AEs by SOC and 
PT
Y
Subject Numbers for Individual AEs
Y
Relationship between AE SOCs, PT & verbatim text
Y
Serious and Other Significant AEs
Fatal Serious AEs
Y
Y
Non-Fatal Serious AEs
Y
Y
Serious AEs by SOC
Y
Reasons for Considering as a Serious AE
Y
Drug-Related Serious AEs by SOC and Maximum Intensity
Y
AEs Leading to Withdrawal from Study / Permanent Discontinuation of Study 
Treatment by Overall Frequency
Y
Y
Number of Subjects and Occurrences of Serious, Drug-Related Serious, Fatal 
Serious, and Drug-Related Fatal Serious AEs
Y
Adverse Events of  Special Interest (AESI) (On-Treatment) [2]
Anaphylaxis
Y
Y
Systemic Allergic/Hypersensitivity and Non-allergic Reactions
Y
Y


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Endpoint / Parameter/ Display Type
Absolute
Summary
Individual
T
F
L
Systemic Allergic/Hypersensitivity Reactions
Y
Systemic Non-allergic Reactions
Y
Local Injection Site Reactions
Y
Y
Opportunistic Infections
Y
Y
Malignancies
Y
Y
Serious Cardiac, Vascular and Thromboembolic Events
Y
Y
Serious Ischemic Events 
Y
Y
Cardiovascular Events
All Cardiovascular Events
Y
Y
NOTES:

T = Table, F = Figures, L = Listings, Y = Display generated, SOC=System Organ Class, PT=Preferred Term.

Summary = Represents TF related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data. 
[1] Common AEs will be defined as AEs with frequency ≥3% (prior to rounding to nearest percent).
[2] On-treatment Summary Profiles of each type of AE of Special Interest will also be presented.
8.2.2.
Adverse Events of Special Interest
Adverse events of special interest (AESIs) are adverse events associated with the 
identified and potential risks of mepolizumab. AESIs of anaphylaxis reactions, systemic 
reactions, and local injection site reactions are collected via targeted eCRF within the 
study. Events captured on the eCRF as systemic reactions will be further categorized as 
allergic/hypersensitivity reactions or non-allergic reactions. Events with preferred terms 
such as injection related reaction or administration related reaction will be considered 
non-allergic reactions. All remaining events will be considered allergic/hypersensitivity 
reactions. 
AESIs of opportunistic infections, malignancies, serious CVT events and serious 
ischemic events will be identified from a list of relevant preferred terms maintained 
within a project level reference dataset created based on the MedDRA dictionary 
available at the time of database freeze 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. Information will be reported as 
part of the standard AE tables for AESIs of infections, serious infections, neoplasms, 
cardiac disorders and serious cardiac disorders. 
For each type of AESI a profile summary table will be produced containing information 
which would include, but not be limited to, the number of occurrences of the event, event 
characteristics, time to onset, intensity, outcome and action taken. 
A listing of any subjects with systemic events identified by the investigators as meeting 
the criteria for anaphylaxis as outlined by the 2006 Joint National Institute of Allergy and 
Infectious Disease/Food Allergy and Anaphylaxis Network Second Symposium on 


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Anaphylaxis [Sampson , 2006] will be provided. Adverse events experienced on a day of 
dosing will be summarised and presented by SOC and preferred term. 
A listing of all adverse events experienced by subjects who have had at least one 
investigator defined systemic reaction will be provided. 
Cardiovascular events will be captured on targeted CV event pages of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
8.2.3.
Overview of Planned Clinical Laboratory Analyses
Safety analyses will be based on the Intent-To-Treat (ITT) population, unless otherwise 
specified in Appendix 13: List of Data Displays. The safety displays to be created as part 
of the RAP include all the required and relevant displays identified as per the RAP Core 
Safety Reporting Template Version 1.0.
Table 7 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 13: List of Data Displays.
Table 7
Overview of Planned Clinical Laboratory Analyses
Endpoint / Parameter/ Display Type
Absolute
Change from BL
Summary
Individual
Summary
Individual
T
F
L
T
F
L
Chemistry
Change from Baseline in Clinical Chemistry by Visit
Y
Chemistry Results (Change from Baseline Relative to 
Normal Range)
Y
Y
Hematology
Change From Baseline in Haematology by Visit
Y
Haematology Results (Change from Baseline Relative to 
Normal Range)
Y
Y
Hepatobiliary (Liver)
Liver Monitoring/Stopping Event Reporting
Y
Chemistry Results for Subjects Meeting Liver 
Y


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Endpoint / Parameter/ Display Type
Absolute
Change from BL
Summary
Individual
Summary
Individual
T
F
L
T
F
L
Monitoring/Stopping Event Criteria
Medical Conditions for Subjects with Liver Stopping 
Events
Y
Alcohol Intake for Subjects with Liver Stopping Events
Y
Hepatobiliary Laboratory Abnormalities
Y
Y
Scatter Plot of Maximum Post-Baseline vs. Baseline for 
ALT
Y
Scatter Plot of Maximum Post-Baseline ALT vs 
Maximum Post-Baseline Total Bilirubin
Y
All Laboratory
All Laboratory Data for Subjects with any Value of 
Potential Clinical Concern
Y
NOTES:

T = Table, F = Figures, L = Listings, Y = Yes display generated, PCI = Potential Clinical Importance

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
8.2.4.
Overview of Planned Other Safety Analyses
The safety analyses will be based on the Intent-To-Treat (ITT) population, unless 
otherwise specified in Appendix 13: List of Data Displays. The safety displays to be 
created as part of the RAP include all the required and relevant displays identified as per 
the RAP Core Safety Reporting Template Version 1.0.
Table 8 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 13: List of Data Displays.
Table 8
Overview of Planned Other Safety Analyses
Endpoint / Parameter/ Display Type
Absolute
Change from BL
Summary
Individual
Summary
Individual
T
F
L
T
F
L
ECG
ECG Findings
Y
Y
Change from Baseline in ECG Values by Visit
Y
Actual and Change From Baseline QTc(F) Values by 
Category
Y
Y
Actual and Change From Baseline QTc(B) Values by 
Category
Y
Y


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Endpoint / Parameter/ Display Type
Absolute
Change from BL
Summary
Individual
Summary
Individual
T
F
L
T
F
L
Vital Signs
Change from Baseline in Vital Signs by Visits
Y
Immunogenicity 
Immunogenicity (ADA and NAb results)
Y
Y
Treatment Emergent ADA results
Y
NOTES:

T = Table, F = Figures, L = Listings, Y = Yes display generated, PCI = Potential Clinical Importance

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
8.2.4.1.
Immunogenicity
Immunogenicity is a measure of the immune response to a therapeutic drug (e.g. a 
monoclonal antibody) resulting in generation of anti-drug antibodies. Clinical samples 
are tested in a sequence of binding anti-drug antibody (ADA) and neutralising antibody 
assays:
a) Screening assay. Each sample is tested for the presence of anti-drug antibodies 
(ADA assay) and initially declared positive or negative according to assay cut-off 
criteria. Negative samples are not tested further.Positive samples are then tested in 
the confirmation ADA assay. 
b) Confirmation assay. Each positive sample from the screening assay is either 
confirmed positive in this assay (ADA assay), or is declared negative and are not 
tested further. Positive ADA samples are then tested in the titer assay and 
neutralization (NAb) assay.
c) Titration assay. Each positive sample from the ADA confirmation assay is serially 
diluted to provide a titre, corresponding to the highest dilution factor that still 
yields a positive test result.
d) Neutralising assay. Each positive sample from the ADA confirmation assay is 
tested with the neutralising antibody assay and found as either positive or negative 
in this assay (NAb assay).
The mepolizumb ADA (screening/confirmation/titration) assay version 2011N122789 is 
performed at a Alliance Pharma (method 120711M01.V02). The  mepolizumb Nab assay 
version 2011n129752 is being performed within GSK.

A table will be produced summarising the number and percentage of negative and 
confirmed positive subjects ADA samples by treatment group and visit in the ITT 
population. The table will also summarise the highest assay result obtained post-
baseline for each subject.

A similar table will also be produced summarising results for the neutralising 
antibody assay in the ITT Population, by treatment group and visit. 


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
An additional summary of treatment emergent positive confirmatory binding antibody 
assay and  results in the subset of subjects who did not have a positive confirmatory 
binding antibody assay result prior to the first dose of study treatment will also be 
presented.  

All immunogenicity results (i.e. ADA screening and confirmatory assay results, titre 
values, neutralising antibody results and observed mepolizumab concentration) will 
be listed.


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9.
REFERENCES
GlaxoSmithKline Document Number 2015N243304_00 Study ID 204471. A multi-
centre, open label, single arm, 32-week treatment study in subjects with severe 
eosinophilic asthma not optimally controlled with current omalizumab treatment who are 
switched from omalizumab to mepolizumab 100mg subcutaneous (study number 204471-
the OSMO study). Report Date 19-OCT-2015. 
GlaxoSmithKline Document Number 2015N243304_01 Study ID 204471. A multi-
centre, open label, single arm, 32-week treatment study in subjects with severe 
eosinophilic asthma not optimally controlled with current omalizumab treatment who are 
switched from omalizumab to mepolizumab 100mg subcutaneous (study number 204471-
the OSMO study). Report Date 23-MAR-2016. 
GlaxoSmithKline Document Number n/a Study ID Across Studies. Program Safety 
Analysis Plan for Mepolizumab (SB240563). Report Date 31-Mar-2017. 
Juniper EF, O'Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of 
a questionnaire to measure asthma control. Eur Respir J. 1999;14:902–907. 
Juniper EF, Svensson K, Mork AC, Stahl E. Measurement properties and interpretation of 
three shortened versions of the asthma control questionnaire. Respiratory Medicine. 
2005;99:553–558. 
Quanjer P., Stanojevic S., Cole T., Baur X., Hall G., Culver B., Enright P., Hankinson J., 
Ip M., Zheng J., Stocks J., & ERS Global Lung Function Initiative. Multi-ethnic 
reference values for spirometry for the 3-95-yr age range: The global lung function 2012 
equations. European Respiratory Journal. 2012;40(6):1324-1343. 
Quanjer P., Stanojevic S., Cole T., Baur X., Hall G., Culver B., Enright P., Hankinson J., 
Ip M., Zheng J., Stocks J., & ERS Global Lung Function Initiative. Multi-ethnic 
reference values for spirometry for the 3-95-yr age range: The global lung function 2012 
equations - Supplemental Material. European Respiratory Journal. 2012;40(6):1324-
1343. 
Sampson HA, Munoz-Furlong A, Campbell RL et al. Second Symposium on the 
definition and management of anaphylaxis: Summary Report.Second National Institute of 
Allergy and Infectious Disease / Food Allergy and Anaphylaxis Network Symposium. 
Journal of Allergy and Clinical Immunology. 2006;117:391-397. 
Winthrop KL, Novosad SA, Baddley JW, et al. Opportunistic infections and biologic 
therapies in immune-mediated inflammatory diseases - consensus recommendations for 
infection reporting during clinical trials and postmarketing surveillance. Ann Rheum Dis. 
2015;0:1–10. 
Atkinson MJ, Kumar R, Cappelleri JC, Hass SL. Hierarchical construct validity of the 
treatment satisfaction questionnaire for medication (TSQM version II) among outpatient 
pharmacy consumers. Value Health. 2005;8(Suppl 1):S9-S24. 


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10.
APPENDICES
Section
Appendix
RAP Section 4 : Analysis Populations
Section 10.1
Appendix 1: Protocol Deviation Management and Definitions for Per Protocol 
Population
RAP Section 5 : General Considerations for Data Analyses & Data Handling Conventions
Section 10.2
Appendix 2: Time & Events
Section 10.3
Appendix 3: Assessment Windows & Visit Slotting
Section 10.4
Appendix 4: Treatment Phases
Section 10.5
Appendix 5: Data Display Standards & Handling Conventions

Study Treatment & Subgroup Display Descriptors

Baseline Definitions & Derivations

Reporting Process & Standards
Section 10.6
Appendix 6: Derived and Transformed Data

General

Study Population

Efficacy

Safety
Section 10.7
Appendix 7: Premature Withdrawals & Handling of Missing Data

Premature Withdrawals

Handling of Missing Data
Section 10.8
Appendix 8: Values of Potential Clinical Importance

Laboratory Values
Section 10.9
Appendix 9: Multicenter Studies
Section 10.10
Appendix 10: Examination of Covariates and Subgroups
Section 10.11
Appendix 11: Model Checking and Diagnostics for Statistical Analyses
Other RAP Appendices
Section 10.12
Appendix 12: Abbreviations & Trade Marks
Section 10.13
Appendix 13: List of Data Displays
Section 10.14
Appendix 14: Example Mock Shells for Data Displays


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10.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population
10.1.1.
Exclusions from Per Protocol Population
Subjects with protocol deviations considered to potentially have an effect on efficacy will 
be excluded from the Per Protocol (PP) population. Determination of the Per Protocol 
population will be performed before the database is frozen. The reason for the exclusion 
of any subject will be documented.
A subject meeting any of the following criteria will be excluded from the Per Protocol 
population:
Number
Exclusion Description
01
Inclusion criteria # 2 – Insufficient evidence of asthma for ≥2 years that meets the National 
Heart and Lung Institute guidelines or GINA guidelines
02
Inclusion criteria # 3 – No persistent airflow obstruction as indicated by For subjects ≥18 
years of age at Visit 1, a pre-bronchodilator FEV1 <80% predicted [Quanjer, 2012] 
recorded at Visit 1. For subjects 12-17 years of age at Visit 1, a pre-bronchodilator FEV1 
<90% predicted [Quanjer, 2012] OR FEV1/FVC ratio <0.8 recorded at Visit 1.
03
Inclusion criteria # 4 – No eosinophilic airway inflammation as defined by:

Peripheral blood eosinophil level of ≥300 cells/μL that is related to asthma 
demonstrated in the 12 months prior to visit 1 OR

Peripheral blood eosinophil level of ≥150 cells/μL demonstrated at Visit 1 that is 
related to asthma
04
Inclusion criteria # 5 – Absence of evidence of a well-documented requirement for regular 
treatment with high dose ICS (equivalent to ≥880μg/day fluticasone propionate (FP) (ex-
actuator) or equivalent daily in adults and ≥440μg/day FP (ex-actuator) or equivalent daily 
for subjects aged 12-17) in the 12 months prior to Visit 1 
[Note: For ICS/LABA combination preparations, the highest approved maintenance dose in 
the local country will meet this ICS criterion.]
05
Inclusion criteria #  6 – Absence of current treatment with an additional controller  
medication, besides ICS, for at least 3 months or a documented failure in the past 12 
months of an additional controller medication for at least 3 successive months
[e.g., long-acting beta-2-agonist (LABA), leukotriene receptor antagonist (LTRA), or 
theophylline]
06
Inclusion criteria # 7 – Asthma symptoms not uncontrolled at Visit 1, as defined by an ACQ-
5 score of <1.5.
07
Inclusion criteria # 8 – Not receiving Omalizumab treatment based on weight and IgE 
levels, for at least the 4 months prior to Visit 1.
08
Inclusion criteria # 9 – No history of two or more exacerbations requiring treatment with 
systemic corticosteroids (intramuscular, intravenous, or oral) in the 12 months prior to Visit 
1 despite the use of high-dose ICS.
[Note: For subjects receiving omalizumab for ≥8 months, at least one exacerbation must 
have occurred while on omalizumab treatment. For subjects receiving maintenance oral 
corticosteroids, the corticosteroid treatment for the exacerbations must have been a two-
fold dose increase or greater.]
09
Continuation to treatment criteria # 1 – Asthma symptoms not uncontrolled at Visit 2, as 


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Number
Exclusion Description
defined by an ACQ-5 score of <1.5.
10
Continuation to treatment criteria # 2 – Subjects who experience an asthma exacerbation 
during run-in who have not returned to their baseline asthma status within one week of Visit 
2.
11
Continuation to treatment criteria # 3 – Any subject with changes in the dose or regimen of 
ICS, and/or additional controller medication (except for treatment of an
exacerbation) during the run-in period.
12
Continuation to treatment criteria # 4 – Subjects who do not receive their last dose of 
Omalizumab during the correct period, as defined by:

For subjects receiving omalizumab every 4 weeks, their last dose is received <3 
or >5 weeks prior to Visit 2.

For subjects receiving omalizumab every 2 weeks, their last dose is received <1 
or >3 weeks prior to Visit 2.
13
Any subject with changes in the dose or regimen of baseline ICS, and/or additional 
controller medication during open-label treatment.
N.B. This excludes the use of OCS for the treatment of an asthma exacerbation.
14
Use of any prohibited medication during the study [1].
15
Receiving the incorrect study treatment at any point during the study. 
NOTES:

[1] See Protocol Section 6.8.2 for the list of prohibited medications within this study.


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10.2.
Appendix 2: Time & Events
10.2.1.
Protocol Defined Time & Events
Table 9
Time and Events Table
Procedures
Pre-
screen1
Screen
Run-in
Treatment
(visit window is 7days)
Exit Visit/ 
Early withdrawal 
Visit3
Visit
0
1
2
3
4
5
6
7
8
9
10
Week
-6 to -4 
-4 to -1 
0
4
8
12
16
20
24
28
4 weeks post last 
dose 7 days 
Informed Consent 2
x
Subject Demography
x
Medical History
x
Asthma History (including 
triggers)
x
x
Therapy History4
x
Smoking History
x
Cardiovascular History/Risk 
Factors
x
Inclusion/Exclusion Criteria
x
Continuation to treatment 
Criteria
x
Efficacy Assessments5
ACQ-5 
x
x
x
x
x
x
x
x
x
x
Exacerbation review
x
x
x
x
x
x
x
x
x
x
x
Spirometry including pre- and 
post bronchodilator FEV1, 
FVC 6
x
x
x
x
x
Health Outcome 
Assessments5
SGRQ
x
x
x
x


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Procedures
Pre-
screen1
Screen
Run-in
Treatment
(visit window is 7days)
Exit Visit/ 
Early withdrawal 
Visit3
Visit
0
1
2
3
4
5
6
7
8
9
10
Week
-6 to -4 
-4 to -1 
0
4
8
12
16
20
24
28
4 weeks post last 
dose 7 days 
Clinician & Subject rated 
response to therapy
x
x
x
x
Treatment Satisfaction with 
Medication Questionnaire 
(TSQM-9) 
x
x
Exit Interview7
x
Safety Assessments5
Concomitant Medication
x
x
x
x
x
x
x
x
x
x
x
Physical Examination, 
including nasal exam
x
x
Vital Signs 
x
x
x
x
x
x
x
x
x
x
12 lead ECG
x
x
x
Adverse Events
x
x
x
x
x
x
x
x
x
x
Serious Adverse Events
x
x
x
x
x
x
x
x
x
x
x
Laboratory Assessments5
Haematology with differential
x
x
x
x 
x
x
x
x
x
x
Clinical Chemistry (incl. LFT)
x 
x
x
x
x 
x
x 
Parasitic Screening8
x
Pharmacogenetic sample9
X
Pregnancy test10
U
U
U
U
U
U
U
U
U
U
HBsAg and hepatitis C 
antibody11
x
Immunogenicity sample
x
x
x
x
Biomarker sample
x
x
x
x


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Procedures
Pre-
screen1
Screen
Run-in
Treatment
(visit window is 7days)
Exit Visit/ 
Early withdrawal 
Visit3
Visit
0
1
2
3
4
5
6
7
8
9
10
Week
-6 to -4 
-4 to -1 
0
4
8
12
16
20
24
28
4 weeks post last 
dose 7 days 
Investigational product 
(Mepolizumab) and rescue 
medication
Administer mepolizumab. 
Contact RAMOS NG to 
register dispensing visit. 
x
x
x
x
x
x
x
x
Albuterol/salbutamol 
dispensed (as needed)
x
x
x
x
x
x
x
x
x
Collect dispensed 
albuterol/salbutamol 
x
x
x
x
x
x
x
x
x
eCRF/
paper diary/worksheet
Complete eCRF
x
x
x
x
x
x
x
x
x
x
x
Dispense paper 
diary/worksheet
x
x
x
x
x
x
x
x
x
x
Collect/review paper 
diary/worksheet
x
x
x
x
x
x
x
x
x
x
1.
Pre-screen Visit 0 must be completed prior to Visit 1 (Screening). It can be completed on the same day as Visit 1 or at up to 2 weeks prior to Visit 1.
2.
Subjects will be assigned a subject number at the time ICF signed. The ICF must be signed before any study procedures including medication wash out period(s). 
3.
Exit Visit may be completed 3 to 5 weeks post last dose. 
4.
Therapy history to include a detailed review of prior biologics received for treatment of asthma, including omalizumab dose and regimen and prior investigational therapies e.g 
anti-IL5 or anti-IL13 preparations.
5.
All study efficacy, safety and all patient reported questionnaires must be completed prior any study procedure. 
6.
Spirometry to include pre- and post bronchodilator FEV1 from V2.
7.
Exit interview will be conducted only in a subset of sites and in a subset of subjects who choose to participate  in the Exit interview.  Subjects must be consented prior to interview 
8.
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.
9.
Pharmacogenetic sample may be drawn at Visit 2 or any at any visit after.
10. Pregnancy test, U= urine 
11. Hepatitis B Surface Antigen and Hepatitis C antibody. (if hepatitis C antibody is positive, hepatitis C will be confirmed by PCR)


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10.3.
Appendix 3: Assessment Windows & Visit Slotting
10.3.1.
Assessment Windows
Clinic visits are scheduled to take place as specified in Appendix 2: Time & Events. 
Measurements outside visit windows will not be excluded from analyses. For all clinic 
visits, nominal visit days and times will be used for reporting, such that if a subject 
recorded values that were outside of the ±7 day window for a visit they will still be 
reported under that visit.
10.3.2.
Early Withdrawal / Treatment Discontinuation Visits
If a subject withdraws from the study at a scheduled visit (i.e. completes an Early 
Withdrawal or Treatment Discontinuation Visit), where endpoint data were scheduled to 
be collected, the data will be summarised and analysed (as appropriate) together with data 
from subjects who did not withdraw from the study. If a subject withdraws from the study 
at a scheduled visit at which endpoint data were not scheduled to be collected, or if a 
subject withdraws between scheduled visits, data will be slotted to the nearest adjacent 
visit where the endpoint data was scheduled to be collected (if data at that visit were not 
recorded) according to the Time and Events schedule (Appendix 2: Time & Events). 
For example, if a subject prematurely withdraws from the study and completed the Early 
Withdrawal Visit at Visit 6 (Week 16) and completes an Early Withdrawal Visit which 
includes an FEV1 assessment, the FEV1 data collected will need to be re-assigned to an 
adjacent visit where FEV1 data is scheduled for collection. In this case the FEV1 data will 
be reassigned to Visit 5 (Week 12) (if data at that visit were not recorded) as this is the 
closest nominal visit at which collection of FEV1 data is scheduled.
10.3.3.
Unscheduled Visits
For unscheduled visits, similar logic will be applied. If a subject has an unscheduled 
assessment then this data would be slotted to the closest adjacent scheduled visit but only 
if information already exists at that visit. If an unscheduled visit occurred between two 
scheduled visits for which data has been reported, then the data from the unscheduled 
visit will remain in the unscheduled visit and will not be used in summary tables and 
analyses (except for endpoints using any post-baseline data) but will be presented in any 
relevant listings. 


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10.4.
Appendix 4: Treatment Phases
10.4.1.
Treatment Phases (Exacerbations)
Exacerbation data will be classified according to time of occurrence/assessment relative 
to the first and last date of mepolizumab and the attendance dates of specific visits.
Treatment Phase
Definition
Pre-Treatment 
Date & time < First dose of mepolizumab
On-Treatment
Subjects completing treatment and completing the study:
First dose of mepolizumab ≤ Date & time ≤ Visit 10 (Exit Visit)* visit date
Subjects discontinuing study treatment/withdrawing early from the study:
First dose of mepolizumab ≤ Date & time ≤ Earliest of (1) Last dose of mepolizumab + 
28 days or (2) Early Withdrawal/Treatment Discontinuation visit date
Off-Treatment
Subjects completing treatment and completing the study:
Date & time > Visit 10 (Exit Visit)* visit date
Subjects discontinuing study treatment/withdrawing early from the study:
Date & time > Earliest of :
(1) Last dose of mepolizumab + 28 days or
(2) Early Withdrawal/Treatment Discontinuation visit date
* Data may be considered off treatment if beyond acceptable protocol defined limits.
10.4.2.
Treatment Phases (Visit Based Efficacy Data)
Efficacy data collected at scheduled visits (including: Questionnaires, PFT, Blood 
Eosinophils and Biomarkers) will be classified according to time of 
occurrence/assessment relative to the first and last date of mepolizumab and the 
attendance dates of specific visits.
Treatment Phase
Definition
Pre-Treatment 
Visit date/time ≤ First dose of mepolizumab
On-Treatment
Subjects completing treatment and completing the study:
Visit date/time < First dose of mepolizumab ≤ Visit 10 (Exit Visit)* visit date/time
Subjects discontinuing study treatment/withdrawing early from the study:
Visit date/time < First dose of mepolizumab ≤ Earliest of (1) Last dose of mepolizumab 
+ 28 days or (2) Early Withdrawal/Treatment Discontinuation visit date date/time
Off-Treatment
Subjects completing treatment and completing the study:
Date & time > Visit 10 (Exit Visit)* visit date/time
Subjects discontinuing study treatment/withdrawing early from the study:
Date & time > Earliest of:
(1) Last dose of mepolizumab + 28 days or
(2)  Early Withdrawal/Treatment Discontinuation visit date/time
* Data may be considered off treatment if beyond acceptable protocol defined limits.
10.4.3.
Treatment Phases (Adverse Events)
Adverse events will be classified according to time of occurrence relative to the first and 
last date of the study treatment.


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Treatment Phase
Definition
Pre-Treatment 
AE Onset Date & time < First dose of mepolizumab
If mepolizumab treatment is never started then all AEs will be classified as pre-
treatment.
On- Treatment 
First dose of mepolizumab ≤ AE Onset Date & time ≤ Last dose of mepolizumab + 28
days
If an AE start date is missing or partial then the AE will be considered on-treatment 
unless there is evidence to the contrary (e.g. month/year of onset date is present and is 
earlier than the month/year of First dose of mepolizumab).
Post-treatment
AE Onset Date & time > Last dose of mepolizumab + 28 days
10.4.3.1.
Adverse Event Data Derivations
Treatment State
Definition
Onset Time  
Since 1st Dose 
(Days)
If Treatment Start Date ˃  AE Onset Date = AE Onset Date - First dose of mepolizumab
If Treatment Start Date ≤ AE Onset Date = AE Onset Date - First dose of mepolizumab 
+1
If Treatment Start Date or AE Onset Date is missing = missing.
Duration (Days) 
AE Resolution Date – AE Onset Date + 1
Drug-related
If relationship is marked ‘YES’ on Inform/eCRF OR value is missing.
10.4.4.
Treatment Phases (Concomitant Medications)
Concomitant medications will be classified according to time of occurrence relative to the 
first and last date of the study treatment.
Treatment/Study 
Phase
Definition
Taken Before the 
Run-in 
If Con-med Start Date < Date of Visit 1
Taken During the 
Run-in

If Con-med Start Date < Date of Visit 1 and Con-med Stop Date ≤ Date of Visit 1,
or

If Date of Visit 1 ≤ Con-med Start Date < First dose of mepolizumab
Taken During 
Treatment 

If Con-med Start Date < First dose of mepolizumab and Con-med Stop Date ≥ 
First dose of mepolizumab
or

If First dose of mepolizumab≤ Con-med Start Date ≤ Last dose of mepolizumab+ 
28 days

If the con-med start or stop date is missing or partial then the con-med will be 
considered on-treatment unless there is evidence to the contrary (e.g. month/year 
of con-med stop date is present and is before the month/year of the first dose of 
mepolizumab).
Started During 
Treatment 
Subset of con-meds Taken During Treatment for which:
First dose of mepolizumab ≤ Con-med Start Date ≤ Last dose of mepolizumab + 28 
days
Taken Post 
Treatment 

Last dose of mepolizumab + 28 days < Con-med Stop Date
A medication will be summarised in every treatment/study phase in which it was taken, 


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so for example a medication that was started in the run-in and stopped during treatment 
will appear in both the during the run-in and during treatment tables.


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10.5.
Appendix 5: Data Display Standards & Handling 
Conventions
10.5.1.
Study Treatment & Subgroup Display Descriptors
Treatment Group Descriptions
RandAll NG 
Data Displays for Reporting 
Code
Description
Description
Order [1]
1
Mepolizumab 100mg SC
Mepolizumab 100mg SC
1
NOTES:
1.
Order represents treatments being presented in TFL, as appropriate.
10.5.2.
Baseline Definition & Derivations
10.5.2.1.
Baseline Definition

Baseline will be defined for all subjects who are within the ITT population.

For all endpoints the baseline values for each assessment will be the latest available 
assessment prior to first dose of mepolizumab. 

Measurements on the same date as the first administration of mepolizumab will be considered 
within the baseline derivation if measurement time is not captured. Where the measurement 
time is captured this should be compared against the time of first receiving mepolizumab.
10.5.2.2.
Derivations and Handling of Missing Baseline Data
Definition
Reporting Details
Change from Baseline
= Visit Value – Baseline
Ratio to Baseline
= Visit Value / Baseline
NOTES :

Unless otherwise specified, the baseline definitions specified in Section 10.5.2.1 Baseline Definitions will be used 
for endpoints / parameters and indicated on summaries and listings.

Unless otherwise stated, if baseline data is missing no derivation will be performed and will be set to missing.
10.5.3.
Reporting Process & Standards
Reporting Process
Software

The currently supported versions of SAS software will be used.
Reporting Area
HARP Server
: uk1salx00175
HARP Area
: /arenv/arprod/sb240563/mid204471/final01
Quality Control 
(QC) Spread sheet
: /arenv/arprod/sb240563/mid204471/final01/documents


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Reporting Process
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 only for summary tables.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated:
o
4.03 to 4.23: General Principles
o
5.01 to 5.08: Principles Related to Data Listings
o
6.01 to 6.11: Principles Related to Summary Tables
o
7.01 to 7.13: Principles Related to Graphics 
Formats

All data will be reported according to the actual treatment the subject received unless 
otherwise stated.

The reported precision (decimal places) will follow the IDSL statistical principles but may be 
adjusted to a clinically interpretable number of decimal places. 
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses :

Nominal visits (planned time relative to dosing) will be used in figures, summaries, 
statistical analyses and calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled 
visit days on the analyses and interpretation of the results will be assessed as appropriate.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to 
IDSL Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject’s listings. 

Scheduled visits outside the protocol defined time-windows (i.e. recorded as protocol 
deviations) will be included in listings, summaries and statistical analyses.
Unscheduled Visits

When possible unscheduled assessments will be slotted to the closest adjacent scheduled 
visit. If an unscheduled visit occurs between two completed scheduled visits, the data from the 
unscheduled visit will not be used in summary tables which are based on by-visit assessments. 
The information from the unscheduled visit will be included in ‘any time post-baseline’ 
summaries and will also be presented in any relevant listings. See Section 10.3 for further 
details.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N (number of subjects in the treatment group), n (number of subjects with 


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Reporting Standards
non-missing values), frequency, %
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.


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10.6.
Appendix 6: Derived and Transformed Data
10.6.1.
General
Multiple Measurements at One Time Point

There are no scheduled multiple measurements, however, if multiple measurements are 
recorded at a given time point the following process will be followed, unless a process for
selection of the measurement for the visit is specified:

Mean of the measurements will be calculated and used in any derivation of summary statistics
but if listed, all data will be presented.

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.
Study Day

Calculated as the number of days from date of first dose of mepolizumab:

Ref Date = Missing                       
→ 
Study Day = Missing 

Ref Date < Date of first dose of mepolizumab   
→ 
Study Day = Ref Date – Date of first dose of mepolizumab

Ref Data ≥ Date of first dose of mepolizumab   
→ 
Study Day = Ref Date – (Date of first dose of mepolizumab) + 1    
10.6.2.
Study Population
Demographics
Age

Only year of birth was collected for subjects; actual birth data was not collected.

GSK standard IDSL algorithms will be used for calculating age where the birth date of all 
subjects will be imputed as ‘30th June’.

Birth date will be presented in listings as ‘YYYY’.

Each subject’s derived age will be calculated as an integer value based on their imputed date of 
birth relative to the date of the subject’s screening visit (Visit 1).
[(30th June of the year of birth reported on eCRF – date of Screening)/365.25]
Body Mass Index (BMI)

Calculated as Weight (kg) / Height (m)2
Percent Predicted FEV1

FEV1 % of predicted normal will be derived using the Global Lung Function Initiative 2012 look-
up tables which are based on the Quanjer equations [Quanjer, 2012] according to the 
Race/Ethnicity designations specified below:
Collected Race[1]
Quanjer Designation
African American/African Heritage 
African-American calculation will be applied
American Indian or Alaskan Native 
Other calculation will be applied


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Demographics
Asian-Central/South Asian Heritage 
South East Asian calculation will be applied
Asian-East Asian Heritage 
North East Asian calculation will be applied
Asian-Japanese Heritage 
Other calculation will be applied
Asian- Southeast Heritage 
South East Asian calculation will be applied
Native Hawaiian or Other Pacific Islander 
Other calculation will be applied
White-Arabic/North African Heritage 
Caucasian calculation will be applied
White-White/Caucasian/European Heritage 
Caucasian calculation will be applied
NOTES:
1.
If multiple races are selected for a single subject then the “Other” calculation will be applied.
FEV1/FVC Ratio

Pre- and post-bronchodilator FEV1/FVC ratio will be calculated as the ratio of the FEV1 and FVC 
values.
Length of Omalizumab (Xolair) Use

Number of days exposed to Omalizumab (Xolair) will be calculated based on the formula:  
For subjects receiving Omalizumab (Xolair) monthly:
Duration of Exposure in Days = Last Omalizumab dose – (First Omalizumab dose) + 29
For subjects receiving Omalizumab (Xolair) twice monthly:
Duration of Exposure in Days = Last Omalizumab dose – (First Omalizumab dose) + 15
Baseline OCS daily dose

Only corticosteroids administered via oral, intravenous (IV) and intramuscular (IM) routes are to 
be considered when calculating a subject’s total daily prednisone/prednisolone asthma 
maintenance dose at baseline. All steroids administered via a sublingual route will also be 
considered as oral. 

The corticosteroid conversion factors shown below will be used, regardless of the route of 
administration, to scale each corticosteroid dose to a prednisone equivalent dose. These three 
routes of administration (oral, IV and IM) are to be considered equivalent as it has been noted 
that the bioavailability of methylprednisolone is considered to be roughly equivalent following 
administration as an oral, IV or IM steroid.
Standardised Medication Name
Scaling Factor
Betamethasone
8.33
Betamethasone Dipropionate
8.33
Betamethasone Sodium Phosphate
8.33
Cortisone
0.2
Cortisone Acetate
0.2
Cortivazol
17
Deflazacort 
0.833
Dexamethasone 
6.67
Dexamethasone Sodium Phosphate 
6.67
Fludrocortisone Acetate 
0
Hydrocortisone 
0.25
Hydrocortisone Sodium Succinate 
0.25


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Demographics
Hydrocortisone Sodium Phosphate 
0.25
Meprednisone
1
Methylprednisolone
1.25
Methylprednisolone Acetate
1.25
Methylprednisolone Sodium Succinate
1.25
Methylprednisone 
1.25
Methylprednisone Acetate 
1.25
Methylprednisolone Sodium Succinate 
1.25
Methylprednisone
1.25
Methylprednisone Acetate 
1.25
Prednisolone 
1
Prednisolone Acetate 
1
Prednisolone Hemisuccinate 
1
Prednisolone Sodium Succinate 
1
Prednisone 
1
Prednisone Acetate 
1
Triamcinolone 
1.25
Triamcinolone Acetonide 
1.25
10.6.3.
Efficacy
Patient Reported Outcomes/Questionnaires
ACQ-5

Each question on the ACQ-5 is scored on a 7-point scale from 0 = no impairment to 6 =
maximum impairment. The questions are equally weighted and the ACQ-5 score will be the 
mean of the 5 questions, thus giving a score between 0 (totally controlled) and 6 (severely 
uncontrolled) [Juniper, 1999; Juniper, 2005].

If a subject does not complete 1 of the 5 questions at a visit, then the ACQ-5 score will be the
mean of the responses to the remaining 4 questions at that visit.

If a subject does not complete more than 1 of the 5 questions at a visit, then their ACQ-5 score
will be set to missing at that visit.

A subject will be deemed a responder if the subject has a ≥0.5 reduction in ACQ score from 
Baseline. ACQ-5 Responder/Non-responder category will be missing if the overall ACQ-5 score 
is missing.
St George’s Respiratory Questionnaire (SGRQ)

The SGRQ comprises 50 questions with a recall period of 4 weeks.

Scores are expressed as the percentage of overall impairment with 100 equal to the worst 
possible health and 0 the best.

Scoring of each domain of the SGRQ (Symptoms, Activity, Impacts) and the Total score are 
described in the St George’s Respiratory Questionnaire Manual (Version 2.3).


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Patient Reported Outcomes/Questionnaires
Treatment Satisfaction with Medication Questionnaire (TSQM-9)

TSQM Scale scores range from 0 to 100, with higher scores indicating higher satisfaction. No 
computed score should be lower or higher than these limits. [Atkinson, 2005] 

Effectiveness scale: ([(Item 1 + Item 2 + Item 3) − 3] divided by 18) × 100
If one item is missing: ([(Sum of Item 1 + Item 2 + Item 3)) − 2] divided by (12) × 100

Convenience scale: ([Sum of Item 4 to Item 6) − 3] divided by 18) × 100
If one item is missing: ([(Sum of Item 4 to Item 6)) − 2] divided by (12) × 100

Overall Satisfaction scale: First recode Item 9 = (Item 9 - 1) x 5/6

Then: ([Sum of Item 7 to Item 9) - 3] divided by (12) × 100
If any one Item is missing: ([Sum of Item 7 to Item 9) - 2] divided by (8) x 100
Exacerbations
An exacerbation of asthma as defined as:
Worsening of asthma which requires use of systemic corticosteroids1and/or hospitalisation and/or 
Emergency Department (ED) visits.

1For all subjects, i.v. or oral steroid (e.g., prednisone) for at least 3 days or a single IM CS dose 
is required. For subjects on maintenance systemic corticosteroids, at least double the existing 
maintenance dose for at least 3 days is required.

Within each subject, exacerbations that occurred less than seven days apart will be collapsed 
into a single exacerbation. Exacerbations for which the collapsing has already been performed
will be included in the summaries and analyses. Exacerbations will be displayed in listings as 
captured within the eCRF. Exacerbations which are collapsed into a single exacerbation will be 
highlighted.

The collapsed exacerbation records will be constructed as follows: 
o
Start date (ASTDT) is the start date of the first exacerbation in the series 
o
End date (AENDT) is the end date of the last exacerbation in the series 
o
Outcome (CEOUT) is the worst outcome in the series (worst to best is Fatal, Not 
Resolved, Resolved) 
o
Cause (EBCAUSE) is the cause associated with the first exacerbation in the series 
o
Withdrawal due to exacerbation (EBWD), OCS taken for exacerbation (OCSEXB), 
corticosteroids taken for exacerbation (CTSEXB), hospitalization due to 
exacerbation (HSPEXB), emergency visit due to exacerbation (EREXB), and 
intubation for exacerbation (INTUBEXB) are set to ‘Y’ if any value for the respective 
variable in the series equals ‘Y’ 
o
Number of telephone calls (TPCNUM), home day visits (HMDYVSN), home night 
visits (HMNTVSN), home day+night visits (HMDYNTV), office visits (OFCVSN), 
urgent care/outpatient visits (UCOUTVSN), emergency room visits (ERVSN), days 
in intensive care (ICSDYNUM), days in general ward (GWDYNUM) and days 
hospitalized (HSPDYNUM) are the sum of all of the values in the series for each 
respective variable
Blood Eosinophils

Blood eosinophils will be log-transformed prior to analysis. Summary statistics will include 
geometric mean, and a measure of spread (SD or SE) on the natural log scale.


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
If a blood eosinophil count of zero is reported, it will be imputed with half of the lowest possible 
blood eosinophil count, where applicable, prior to log transforming the data (Note: this 
imputation has typically been 0.5 * 0.01 GI/L =  0.005 GI/L for previous mepolizumab studies). 
10.6.4.
Safety
Extent of Exposure

Number of days of exposure to study drug will be calculated based on the formula:  
Duration of Exposure in Days = Last mepolizumab dose – (First mepolizumab dose) + 29

The extent of exposure will also be summarised as the number of study treatments 
administered 
Adverse Events
Adverse Events of Special Interest
Section 8.2.2 provides a full list of AEs of special interest for this compound.
Adverse events of special interest (AESIs) of anaphylaxis reactions, systemic reactions, and local 
injection site reactions are collected via targeted eCRF.  Systemic reactions with preferred terms 
such as injection related reaction or administration related reaction will be considered non-allergic 
reactions; those with other preferred terms will be considered allergic/hypersensitivity reactions.
The AESIs of opportunistic infections, malignancies, serious CVT events and serious ischemic 
events will be identified from a list of relevant preferred terms maintained within a project level 
reference dataset; created based on the latest version of the MedDRA dictionary available at the 
time of database freeze for this study (See Program Safety Analysis Plan for additional details).
ECG Parameters
RR Interval
All ECG parameters required in this study will be databased, and therefore, further derivations will 
not be performed by Stats and Programming. The definitions of these parameters are given in this 
section.

If RR interval (msec) is not databased, then RR can be derived as :
[1] If QTcB is machine read & QTcF is not provided, then :
[2] If QTcF is machine read and QTcB is not provided, then: 

If ECGs are manually read, the RR value should be a collected value and will not be derived.
Corrected QT Intervals

When not databased, corrected QT intervals by Bazett’s (QTcB) and Fredericia’s (QTcF) 
formulas will be calculated, in msec, depending on the availability of other measurements.

If RR interval (msec) is provided then missing QTcB and/or QTcF will be derived as : 


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ECG Parameters

Individual maximum QTc(F) and QTc(B) values will also be summarised by treatment group for 
each scheduled study visit to show the number of subjects with maximum values (msec) in the 
following categories:

<= 450

450 < to <= 480

480 < to <= 500

> 500 

Additionally, individual maximum changes from baseline in QTc(F) and QTc(B) values will be 
summarised by treatment group for each scheduled study visit to show the number of subjects 
with maximum changes (msec) in the following categories: 

< -60

≥ -60 to < -30

≥ -30 to < 0

≥  0 to < 30

≥  30 to < 60

≥ 60
Laboratory Parameters

If a laboratory value which is expected to have a numeric value for summary purposes, has a 
non-detectable level reported in the database (values below the lower limit of quantification), 
where the numeric value is missing, but typically a character value starting with ‘<x’ or ‘>x’ (or 
indicated as less than x or greater than x in the comment field) is present, the lower limit of 
quantification for that particular parameter will be used to impute the corresponding numeric 
value as half the lower limit of quantification for that measure (LLQ/2).

The above imputation of half the lower limit of quantification for that measure (LLQ/2) will also 
be applied to all biomarker parameters.

Regarding blood eosinophil laboratory data please reference Section 10.6.3.


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10.7.
Appendix 7: Premature Withdrawals & Handling of Missing 
Data
10.7.1.
Premature Withdrawals
Element
Reporting Detail
General

A subject will be considered to have completed study treatment if he/she 
receives study treatment at Visit 9 (Week 28) and completes the Visit 10/Exit 
Visit (Week 32). 

A subject will be considered to have completed the study if they continue to 
participate in the study until the Exit Visit assessments have been completed 
(regardless of whether the subject completed the study treatment schedule).

Subjects who discontinue study treatment or withdraw early will not be replaced 
in the study.

The number of subjects who discontinue study treatment or withdraw early will 
be summarised and listed.

All available data from subjects who were withdrawn from the study will be listed 
and all available data up to and including the date of early withdrawal will be 
included in summary tables and figures, unless otherwise specified.
Pre-Screen 
Failures, 
Screen 
Failures 
and Run-in 
Failures
For the purposes of this study pre-screen failures, screen failures and run-in failures 
will be defined as follows:

Subjects will be assigned a study number at the time of signing the informed 
consent (Pre-screen Visit). Subjects who do not progress to the Screening Visit 
will be deemed a pre-screen failure.

Those subjects that complete at least one additional Visit 1 (Screening) 
procedure but do not enter the run-in period will be designated as screen 
failures.

Those subjects that enter the run-in but do not subsequently receive study 
treatment will be designated as run-in failures.
10.7.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank 
fields on the collection instrument :
o These data will be indicated by the use of a “blank” in subject listing displays. 
Unless all data for a specific visit are missing in which case the data is 
excluded from the listing. 
o Answers such as “Not applicable” and “Not evaluable” are not considered to 
be missing data and should be displayed as missing. 
o Results which are found to be below the limit of quantification (BLQ) are not 
missing data and will be included in all displays. See Section 10.6 for the 
handling of this data.

The ACQ-5 score will be considered as missing if <4 items of the questionnaire 


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Element
Reporting Detail
are completed at a visit. ACQ-5 Responder/Non-responder category will be 
missing if the overall ACQ-5 score is missing.

If a blood eosinophil count of zero is reported, it will be imputed with half of the 
lowest possible blood eosinophil count, where applicable, prior to log 
transforming the data (Note: this imputation has typically been 0.5 * 0.01 GI/L = 
0.005 GI/L for previous mepolizumab studies).

Missing values will not be imputed for any of the other endpoints.
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.
10.7.2.1.
Handling of Missing or Partial Dates
Element
Reporting Detail
General

The eCRF allows for the possibility of missing or partial dates (i.e., only month
and year is captured) to be recorded for event start and end dates.

The recorded missing or partial date will be displayed in listings as captured.
Concomitant 
Medications

Partial dates for any concomitant medications recorded in the CRF will be 
imputed using the following convention: 
o
If the partial date is a start date, a '01' 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. 
Adverse 
Events, 
Exacerbations

Any partial dates for adverse events and exacerbations will be raised to data 
management. If the full date cannot be ascertained, the following assumptions 
will be made:
o
If the partial date is a start date, a '01' will be used for the day and 'Jan' will 
be used for the month. 
o
However, if these result in a date prior to the start of treatment and the 
event could possibly have occurred during treatment from the partial 
information, then the study treatment start date will be assumed to be the 
start date and hence the event is considered On-treatment (worst case), 
as per Appendix 4: Treatment Phases.
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 above listed imputations will also be applied when calculating the time to 
onset and the duration of the event containing missing or partial start and end 
dates.

Start or end dates which are completely missing (i.e. no year specified) will 
remain missing, with no imputation applied. Consequently, time to onset and 
duration of such events will be missing.


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10.8.
Appendix 8: Values of Potential Clinical Importance
10.8.1.
Laboratory Values
Chemistry Values of Potential Clinical Concern
ANALYTE
Age
Sex
SI Units
F3 low
F3 high
SODIUM
0+
Both
MMOL/L
120
160
POTASSIUM
3+
Both
MMOL/L
2.8
6.5
CALCIUM
3+
Both
MMOL/L
1.50
3.24
PHOSPHORUS, 
INORG
3+
Both
MMOL/L
0.32
GLUCOSE
1+
Both
MMOL/L
2.2
27.8
ALT (SGPT)
3-12
Both
U/L
>143 (and 
Total Bilirubin 
> 43)
ALT (SGPT)
13+
Both
U/L
>239 (and 
Total Bilirubin 
> 43)
Haematology Values of Potential Clinical Concern
ANALYTE
Age
Sex
SI Units
F3 low
F3 high
HAEMOGLOBIN
12+
Both
G/L
71
199
HAEMATOCRIT
12+
Both
1
0.201
0.599
PLATELET 
COUNT
1+
Both
GI/L
31
1499
WHITE CELL 
COUNT
12+
Both
GI/L
1.1


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10.9.
Appendix 9: Multicenter Studies
10.9.1.
Methods for Handling Centres

In this multicentre global study, enrolment will be presented pooled across 
investigative sites and countries.

For the purposes of covariate adjustment in the statistical analysis centres will be 
grouped into regions. The following regions are defined with consideration for 
standard of care medical practice, number of subjects enrolled and regulatory 
considerations:
Region
Countries
European Union
Belgium, France, Germany, Netherlands, Spain, Sweden
Rest of World
Argentina, Canada, United States


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10.10.
Appendix 10: Examination of Covariates and Subgroups
10.10.1.
Handling of Covariates

The following is a list of covariates that will be used in all model-based statistical 
analyses. 
Category
Subgroups
Region
Europe, Rest of World (See Section 10.9 for further details)
Exacerbations in the year prior 
to study (to be included as an 
ordinal variable)
2,3,4+
Use of baseline maintenance 
oral corticosteroids
OCS use, no OCS use

Additional covariates of clinical interest may also be considered. 

If the percentage of subjects is small within a particular subgroup, then the subgroup 
categories may be refined prior to database freeze.  

If the category cannot be refined further, then descriptive rather than statistical 
comparisons may be performed for the particular subgroup.
10.10.2.
Handling of Subgroups
The following subgroups are of interest within 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.  
The following subgroups are of interest for the primary efficacy endpoint: 

Exacerbations in previous year: <=2, 3, 4+ exacerbations

Baseline blood eosinophils: <150, ≥150-<300,  ≥300-<500, ≥500 cells/µl


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10.11.
Appendix 11: Model Checking and Diagnostics for 
Statistical Analyses
10.11.1.
Statistical Analysis Assumptions
Endpoint(s)

Mean change from baseline in ACQ-5 score at Week 32 

Mean change from baseline in SGRQ at Week 32

Ratio to baseline in blood eosinophil count at Week 32

Mean change Pre- and Post- bronchodilator FEV1 at Week 32
Analysis

Mixed Model Repeated Measures (MMRM)

In the event that this model fails to converge, the list of covariates may be adjusted and/or 
reduced.

If there are any important departures from the distributional assumptions, transformations of 
covariates may be considered or alternative models may be explored as supporting analysis.
Endpoint(s)

Frequency of clinically significant asthma exacerbations over 32 week treatment

Frequency of exacerbations requiring ED visit/hospitalization during the 32 
week treatment period

Frequency of exacerbations requiring hospitalization during the 32 week 
treatment period
Analysis

Negative binomial regression analysis

In the event that this model fails to converge, the list of covariates may be adjusted and/or 
reduced.

Distributional assumptions underlying the model used for analysis will be examined by:
o
assessing if a sufficient number of events occurred within covariate categories.

If there are any important departures from the distributional assumptions, transformations of 
covariates may be considered or alternative models may be explored as supporting analysis.


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10.12.
Appendix 12: Abbreviations & Trade Marks
10.12.1.
Abbreviations
Abbreviation
Description
ACQ
Asthma Control Questionnaire
ADA
Anti-drug Antibody
ADaM
Analysis Data Model
AE
Adverse Event
AESI
Adverse Event of Special Interest
AIC
Akaike's Information Criteria
ALT
Alanine Transaminase
ASE
All Subjects Enrolled
ATC
Anatomical Therapeutic Chemical
BLQ
Below Limit of Quantification
BMI
Body Mass Index
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
CIL
Clinical Investigation Leader
CPMS
Clinical Pharmacology Modelling & Simulation
CS
Corticosteroid
CSR
Clinical Study Report
DBF
Database Freeze
DBR
Database Release
DOB
Date of Birth
DP
Decimal Places
ECG
Electrocardiogram
eCRF
Electronic Case Record Form
ED
Emergency Department
EW
Early Withdrawal
FEV1
Forced expiratory volume in 1 second
FVC
Forced Vital Capacity
GCSP
Global Clinical Safety and Pharmacovigilance
GSK
GlaxoSmithKline
HbsAg
Hepatitis B Surface Antigen
ICH
International Conference on Harmonisation
ICS
Inhaled Corticosteroids
IDSL
Integrated Data Standards Library
IG
Implementation Guide
IM
Intramuscular
IP
Investigational Product
IPDISC
Investigational Product Discontinuation
IRT
Interactive Response Technology
ITT
Intent-To-Treat
IV
Intravenous


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Abbreviation
Description
LFT
Liver Function Test
LLQ
Lower Limit of Quantification
MMRM
Mixed Model Repeated Measures
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
NAb
Neutralising Antibody
OCS
Oral Corticosteroids
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
PP
Per Protocol
PT
Preferred Term
QC
Quality Control
QTcF
Frederica’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
RAMOS NG
Randomization & Medication Ordering System Next Generation
RAP
Reporting and Analysis Plan
RTF
Rich Text File
SAC
Statistical Analysis Complete
SAE
Serious Adverse Event
SAS
Statistical Analysis Software
SC
Subcutaneous
SD
Standard Deviation
SDTM
Study Data Tabulation Model
SE
Standard Error
SGRQ
St. George’s Respiratory Questionnaire
SMQ
Standard MedDRA Query
SOC
System Organ Class
SRM
Study Reference Manual
TFL
Tables, Figures & Listings 
TST
Therapeutic Standards Team
TSQM
Treatment Satisfaction with Medication Questionnaire
VS
Versus/against
10.12.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
NONE
SAS
Xolair


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10.13.
Appendix 13: List of Data Displays
10.13.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.25
1.1
Efficacy
2.1 to 2.46
2.1 to 2.11
Safety
3.1 to 3.56
3.1 to 3.2
Section
Listings
ICH and Other Listings
1 to 44


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10.13.1.1. Study Population Tables
Study Population: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable[1]
[Priority]
Population Analysed
1.1.
ASE
SP1
Summary of Study Populations
IDSL
Include All Subjects Enrolled, Intention 
to Treat, Per Protocol
SAC
Subject Disposition
1.2.
ASE
ES6
Summary of Reasons for Screening and/or Run-In Failures
Journal Requirements
SAC 
1.3.
ASE
IE2
Summary of Failed Inclusion/Exclusion/Continuation Criteria for 
Screening or Run-in Failures
SAC
1.4.
ASE
IE2
Summary of Failed Inclusion/Exclusion/Continuation Criteria for 
Subjects within the Intent to Treat Population
SAC
1.5.
ITT
NS1/SHELL
Summary of Number of Subjects by Region, Country and Centre
Add in a column for region, add a total 
for regions and a total for country
EudraCT
SAC 
1.6.
ITT
ES1
Summary of Subject Disposition
ICH E3, GSK CTR, FDAAA, EudraCT
SAC 
1.7.
ITT
SD1/SHELL
Summary of Reasons for Withdrawal From Investigational 
Product
SAC 
Demographic and Baseline Characteristics
1.8.
ITT
DM1
Summary of Demographic Characteristics
ICH E3, GSK CTR, FDAAA, EudraCT
SAC
1.9.
ASE
DM11
Summary of Age Ranges
EMA, keep row ≥12-17, ≥18-<64, ≥65-
<84, ≥85
SAC
1.10.
ITT
DM5
Summary of Race and Racial Combinations
ICH E3, FDA, GSK CTR, FDAAA, 
EudraCT
SAC
1.11.
ITT
DM6
Summary of Race and Racial Combination Details
ICH E3, FDA
SAC


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Study Population: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable[1]
[Priority]
1.12.
ITT
SHELL
Summary of Asthma History and Baseline Disease 
Characteristics
Include GERD, CCI, mMRC
SAC
1.13.
ITT
SHELL
Summary of Previous Exacerbation History
SAC
1.14.
ITT
SU1/SHELL
Summary of History of Tobacco Use
SAC
1.15.
ITT
SHELL
Summary of Screening and Baseline Lung Function Tests
Include FEV1, FVC, FEV/FVC, 
%Predicted, Reversibility
SAC
Medical Conditions
1.16.
ITT
MH4
Summary of Past Medical Conditions
ICH E3 
SAC
1.17.
ITT
MH4
Summary of Current Medical Conditions
ICH E3 
SAC
1.18.
ITT
FH1
Summary of Cardiovascular Assessments – Family History
Note: Family history in women <65 
years or men < 55 years (first degree 
relatives only).  Half siblings considered 
first degree relatives
SAC
1.19.
ITT
FH1
Summary of Cardiovascular Assessments – Screening 
Questions
SAC
Prior and Concomitant Medications
1.20.
ITT
SHELL
Summary of Use of Omalizumab Therapy Prior to Treatment
SAC


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Study Population: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable[1]
[Priority]
1.21.
ITT
CM1
Summary of Asthma Concomitant Medications Started Prior to 
Treatment by Respiratory Medication Class Group
ICH E3
Footnote: Includes all Asthma 
medications started before the first 
dose of investigational product.
Multi-component medications displayed 
under the respiratory medication  class 
of each component
Programming note: Display RMC and 
ingredient as previous Asthma studies
SAC
1.22.
ITT
CM1
Summary of Asthma Concomitant Medications Taken During 
Treatment by Respiratory Medication Class Group
Footnote: Multi-component medications 
displayed under the respiratory 
medication  class of each component
Programming note: Display RMC and 
ingredient as previous Asthma studies
SAC
1.23.
ITT
CM1
Summary of Asthma Concomitant Medications Taken Post-
Treatment by Respiratory Medication Class Group
Footnote: Multi-component medications 
displayed under the respiratory 
medication  class of each component
Programming note: Display RMC and 
ingredient as previous Asthma studies
SAC
1.24.
ITT
CM1
Summary of Non-Asthma Medications Taken During Treatment
Footnote: Medications may be 
displayed under more than one ATC 
classification
SAC
Protocol Deviation
1.25.
ITT
DV1B
Summary of Protocol Deviations
ICH E3
SAC


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10.13.1.2. Study Population Figures
Study Population: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition 
1.1
ITT
SHELL
Time to Subject Withdrawal From Investigation Product 
See Study Population Table 1.1 
(MEA117113 ‘final’ reporting effort), 
but exclude ‘Placebo’ and Mepo 
300mg SC
SAC


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10.13.1.3. Efficacy Tables
Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Asthma Control Questionnaire (ACQ-5) Endpoints 
2.1.
ITT
SHELL
Summary of Asthma Control Questionnaire (ACQ-5) Score
See Efficacy Table 2.34 
(MID200862 ‘final’ reporting effort), 
but exclude ‘Placebo’ column 
Include screening visit in addition to 
baseline and post-baseline visits
SAC
2.2.
ITT
SHELL
Analysis of Change from Baseline in Asthma Control 
Questionnaire (ACQ-5)  Score Mixed Model Repeated Measures
SAC
2.3.
PP
SHELL
Sensitivity Analysis of Asthma Control Questionnaire (ACQ-5)  
Score Responders: Subjects With At Least 0.5-point 
Improvement from Baseline (Per Protocol Population only)
SAC
2.4.
ITT
SHELL
Analysis of Change from Baseline in Asthma Control 
Questionnaire (ACQ-5)  by number of exacerbations in previous 
year
SAC
2.5.
ITT
SHELL
Analysis of Change from Baseline in Asthma Control 
Questionnaire (ACQ-5)  by baseline blood eosinophils
SAC
2.6.
ITT
SHELL
Summary of Asthma Control Questionnaire (ACQ-5)  Score 
Responders: Subjects With At Least 0.5-point Improvement from 
Baseline
See Efficacy Table 2.41 
(MID200862 ‘final’ reporting effort), 
but exclude ‘Placebo’ column, and 
rename ‘Odd Ratio to Historical 
Placebo’
SAC
St. George’s Respiratory Questionnaire (SGRQ) Endpoints
2.7.
ITT
SHELL
Summary of St George’s Respiratory Questionnaire (SGRQ) 
Total Score
See Efficacy Table 2.01 
(MID200862 ‘final’ reporting effort), 
but exclude ‘Placebo’ column
SAC


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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.8.
ITT
SHELL
Analysis of Change from Baseline in St George’s Respiratory 
Questionnaire (SGRQ) Total Score Mixed Model Repeated 
Measures
SAC
2.9.
ITT
SHELL
Summary of St. George's Respiratory Questionnaire (SGRQ) 
Symptom Domain Score 
SAC
2.10.
ITT
SHELL
Analysis of Change From Baseline in St. George's Respiratory 
Questionnaire (SGRQ) Symptom Domain Score 
SAC
2.11.
ITT
SHELL
Summary of St. George's Respiratory Questionnaire (SGRQ) 
Activity Domain Score 
SAC
2.12.
ITT
SHELL
Analysis of Change From Baseline in St. George%'s Respiratory 
Questionnaire (SGRQ) Activity Domain Score 
SAC
2.13.
ITT
SHELL
Summary of St. George's Respiratory Questionnaire (SGRQ) 
Impacts Domain Score 
SAC
2.14.
ITT
SHELL
Analysis of Change From Baseline in St. George's Respiratory 
Questionnaire (SGRQ) Impacts Domain Score 
SAC
2.15.
ITT
SHELL
Summary of St George’s Respiratory Questionnaire (SGRQ) 
Responders: Subjects With At Least 4-point Improvement in 
Total Score from Baseline
See Efficacy Table 2.24 
(MID200862 ‘final’ reporting effort), 
but exclude ‘Placebo’ column, and 
rename ‘Odd Ratio to Historical 
Placebo’
SAC
Exacerbations 
2.16.
ITT
SHELL
Overview of Exacerbations
See Efficacy Table 2.61 
(MID200862 ‘final’ reporting effort), 
but exclude ‘Placebo’ column
SAC


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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.17.
ITT
SHELL
Summary of Frequency of Clinically Significant Exacerbations
See Efficacy Table 2.62 
(MID200862 ‘final’ reporting effort), 
but exclude ‘Placebo’ column
SAC
2.18.
ITT
SHELL
Annualised Rate of Clinically Significant Exacerbations
SAC
2.19.
ITT
SHELL
Analysis of Time to First Clinically Significant Exacerbation
See Efficacy Table 2.68 
(MID200862 ‘final’ reporting effort), 
but exclude ‘Placebo’ column and 
Hazard Ration Analysis 
SAC
2.20.
ITT
SHELL
Sensitivity Analysis of Annualised Rate of Clinically Significant 
Exacerbations  (on–treatment data only)
SAC
2.21.
ITT
SHELL
Sensitivity Analysis of Annualised Rate of Clinically Significant 
Exacerbations (Patients with at least 12 months of prior 
omalizumab use)
SAC
2.22.
ITT
SHELL
Summary of Frequency of Exacerbations Requiring
Hospitalisation or Emergency Department visits
See Efficacy Table 2.64 
(MID200862 ‘final’ reporting effort), 
but exclude ‘Placebo’ column
SAC
2.23.
ITT
SHELL
Annualised Rate of Exacerbations Requiring Hospitalisation or
Emergency Department visits
SAC
2.24.
ITT
SHELL
Sensitivity Analysis of Annualised Rate of Exacerbations 
Requiring Hospitalisation or Emergency Department visits (on–
treatment data only)
SAC
2.25.
ITT
SHELL
Summary of Frequency of Exacerbations Requiring
Hospitalisation
See Efficacy Table 2.66 
(MID200862 ‘final’ reporting effort), 
but exclude ‘Placebo’ column
SAC
2.26.
ITT
SHELL
Annualised Rate of Exacerbations Requiring Hospitalisation
SAC
Blood Eosinophils


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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.27.
ITT
SHELL
Summary of Blood Eosinophils (109/L)
See Efficacy Table 2.73 
(MID200862 ‘final’ reporting effort), 
but exclude ‘Placebo’ column
SAC
2.28.
ITT
SHELL
Analysis of Change from Baseline in Blood Eosinophils (109/L)
SAC
2.29.
ITT
SHELL
Analysis of Change from Baseline in Blood Eosinophils (109/L) 
(on–treatment data only)
SAC
Pre – Bronchodilator and Post – Bronchodilator FEV1 
2.30.
ITT
SHELL
Summary of Clinic Pre-Bronchodilator FEV1 (mL)
See Efficacy Table 2.27 
(MID200862 ‘final’ reporting effort), 
but exclude ‘Placebo’ column
SAC
2.31.
ITT
SHELL
Analysis of Change From Baseline in Clinic Pre-Bronchodilator
FEV1 (mL)
See Efficacy Table 2.28 
(MID200862 ‘final’ reporting effort), 
but exclude ‘Placebo’ column and 
Difference Analysis
SAC
2.32.
ITT
SHELL
Summary of Clinic Post-Bronchodilator FEV1 (mL)
See Efficacy Table 2.49 
(MID200862 ‘final’ reporting effort), 
but exclude ‘Placebo’ column
SAC
2.33.
ITT
SHELL
Analysis of Change From Baseline in Clinic Post-Bronchodilator
FEV1 (mL)
See Efficacy Table 2.68 
(MID200862 ‘final’ reporting effort), 
but exclude ‘Placebo’ column and 
Difference Analysis
SAC
Response to Therapy 
2.34.
ITT
SHELL
Summary of Subject Rated Overall Evaluation of Response to 
Therapy (on–treatment data only)
See Efficacy Table 2.47 
(MID200862 ‘final’ reporting effort), 
but exclude ‘Placebo’ column and 
Odds Ratio Analysis
SAC


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Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.35.
ITT
SHELL
Summary of Clinician Rated Overall Evaluation of 
Response to Therapy (on–treatment data only)
SAC
Treatment Satisfaction Questionnaire for Medication (TSQM–9)
2.36.
ITT
SHELL
Summary of Treatment Satisfaction Questionnaire for 
Medication (TSQM – 9) (on–treatment data only)
Summarise the Effectiveness, 
Convenience and Overall Satisfaction 
scales separately
SAC
Biomarkers
2.37.
ITT
SHELL
Summary of CCL13 (on–treatment data only)
SAC
2.38.
ITT
SHELL
Summary of CCL17 (on–treatment data only)
SAC
2.39.
ITT
SHELL
Summary of ECP (on–treatment data only)
SAC
2.40.
ITT
SHELL
Summary of EDN (on–treatment data only)
SAC
2.41.
ITT
SHELL
Summary of Eotaxin1 (on–treatment data only)
SAC
2.42.
ITT
SHELL
Summary of Total IL-5 (on–treatment data only)
SAC
2.43.
ITT
SHELL
Summary of IL-13 (on–treatment data only)
SAC
2.44.
ITT
SHELL
Summary of MDC (on–treatment data only)
SAC
2.45.
ITT
SHELL
Summary of Periostin (on–treatment data only)
SAC
2.46.
ITT
SHELL
Summary of TSLP (on–treatment data only)
SAC


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10.13.1.4. Efficacy Figures
Efficacy: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Asthma Control Questionnaire (ACQ-5) Endpoints
2.1.
ITT
SHELL
Figure of Analysis of Asthma Control Questionnaire ( ACQ-5) 
Score at  Each Visit: Mean Change from Baseline
See format of Efficacy Figure 2.11 
(MID200862 ‘final’ reporting effort), 
but exclude ‘Placebo’ 
SAC
2.2.
ITT
SHELL
Cumulative Distribution Function for Change from Baseline in
Asthma Control Questionnaire ( ACQ-5) Score at Week 32
See format of Efficacy Figure 2.14 
(MID200862 ‘final’ reporting effort), 
but exclude ‘Placebo’
SAC
2.3.
ITT
SHELL
Figure of Asthma Control Questionnaire ( ACQ-5) Responders: 
Subjects With At Least  0.5-point Improvement in the Score from 
Baseline
SAC
St. George’s Respiratory Questionnaire (SGRQ) Endpoints
2.4.
ITT
SHELL
Figure of Analysis of St George’s Respiratory Questionnaire 
(SGRQ) Total Score at Each Visit: Mean Change from Baseline
See format of Efficacy Figure 2.01 
(MID200862 ‘final’ reporting effort), 
but exclude ‘Placebo’
SAC
2.5.
ITT
SHELL
Figure of St George’s Respiratory Questionnaire (SGRQ) Total 
Score: Change from Baseline At Week 52: Cumulative 
Distribution Function
See format of Efficacy Figure 2.07 
(MID200862 ‘final’ reporting effort), 
but exclude ‘Placebo’
SAC
2.6.
ITT
SHELL
Figure of Analysis of SGRQ by Domain (Mean Change from 
Baseline at Each Visit) 
SAC
2.7.
ITT
SHELL
Figure of St George’s Respiratory Questionnaire  (SGRQ) 
Responders: Subjects With At Least 4-point Improvement in 
Total Score from Baseline
SAC
Exacerbations


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Efficacy: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.8.
ITT
SHELL
Kaplan-Meier Cumulative Incidence Curve for Time to First  
Clinically Significant Exacerbations 
See format of Efficacy Figure 2.07 
(MID200862 ‘final’ reporting effort), 
but exclude ‘Placebo’
SAC
Blood Eosinophils
2.9.
ITT
SHELL
Figure of Analysis of Blood Eosinophils Ratio Compared to 
Baseline
See format of Efficacy Figure 6.18 
(MEA 115588 ‘final’ reporting effort), 
but exclude ‘Placebo’ and mepo 75 
mg IV
SAC
Pre – bronchodilator and post – bronchodilator FEV1
2.10.
ITT
SHELL
Figure of Analysis of Pre-Bronchodilator FEV1 (mL) Mean 
Change From Baseline at Each Visit 
See format of Efficacy Figure 2.09 
(MID200862 ‘final’ reporting effort), 
but exclude ‘Placebo’
SAC
2.11.
ITT
SHELL
Figure of Analysis of Post-Bronchodilator FEV1 (mL) Mean 
Change From Baseline at Each Visit
See format of Efficacy Figure 2.09 
(MID200862 ‘final’ reporting effort), 
but exclude ‘Placebo’
SAC


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10.13.1.5. Safety Tables
Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
Exposure 
3.1
ITT
SHELL
Summary of Number of Treatments Administered and Time On-
Treatment 
See format of Study Population
Table 1.28 (200862 ‘final’ reporting
effort).
SAC 
Adverse Events
3.2
ITT
SHELL
Overview of All Adverse Events
Add a Total column across all severities
SAC 
3.3
ITT
AE1
Summary of All On-Treatment Adverse Events by System Organ 
Class 
SAC 
3.4
ITT
AE5
Summary of All On-Treatment Adverse Events by System Organ 
Class and Maximum Intensity 
Add a Total column across all severities
SAC 
3.5
ITT
AE1
Summary of All Post-Treatment Adverse Events by System 
Organ Class 
SAC 
3.6
ITT
AE5
Summary of All Post-Treatment Adverse Events by System 
Organ Class and Maximum Intensity
Add a Total column across all severities
SAC 
3.7
ITT
AE3
Summary of Common On-Treatment Adverse Events (>=3% in
Any Treatment Group) by Overall Frequency
GSK CTR; ≥3% (prior to rounding 
to nearest percent)
SAC
3.8
ITT
AE1
Summary of All On-Treatment Drug-Related Adverse Events by 
System Organ Class 
SAC
3.9
ITT
AE5
Summary of All On-Treatment Drug-Related Adverse Events by 
System Organ Class and Maximum Intensity
Add a Total column across all severities
SAC
3.10
ITT
AE1
Summary of Adverse Events Reported on Day of Dosing by
System Organ Class
SAC
3.11
ITT
SHELL
Summary of All On-Treatment Adverse Events by Age Group 
Add a Total column across all severities
SAC 


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Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
3.12
ITT
SHELL
Summary of On-Treatment Adverse Events by Highest Anti Drug 
Antibody Result At Any Time Post Baseline 
SAC
3.13
ITT
SHELL
Summary of Post-Treatment Adverse Events by Highest Anti 
Drug Antibody Result At Any Time Post Baseline 
SAC
3.14
ITT
AE15
Summary of Number of Subjects and Occurrences of Common 
non-Serious Adverse Events by System Organ Class and 
Preferred Term
GSK CTR; ≥3% (prior to rounding 
to nearest percent)
SAC
Serious and Other Significant AEs
3.15
ITT
AE1
Summary of Fatal Serious Adverse Events 
SAC
3.16
ITT
AE1
Summary of Non-Fatal Serious On-Treatment Adverse Events
by System Organ Class
SAC
3.17
ITT
AE1
Summary of Non-Fatal Serious Post-Treatment Adverse Events
by System Organ Class 
SAC
3.18
ITT
AE1
Summary of Serious Adverse Events by System Organ Class 
(Pre-Treatment)
SAC 
3.19
ITT
AE1
Summary of Serious Adverse Events by System Organ Class 
(On-Treatment)
SAC
3.20
ITT
AE1
Summary of Serious Adverse Events by System Organ Class 
(Post-Treatment)
SAC 
3.21
ITT
AE1
Summary of Drug-Related Fatal Serious Adverse Events by 
System Organ Class
SAC 
3.22
ITT
AE1
Summary of Drug-Related Serious Adverse Events by System 
Organ Class and Maximum Intensity
Add a Total column across all severities
SAC 


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Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
3.23
ITT
AE3
Summary of Adverse Events Leading to Permanent
Discontinuation of Study Treatment or Withdrawal from Study by
Overall Frequency
SAC 
3.24
ITT
AE16
Summary of Number of Subjects and Occurrences of Serious 
Adverse Events by System Organ Class and Preferred Term
SAC 
Adverse Events of Special Interest
3.25
ITT
AE1
Summary of AEs meeting Anaphylaxis Criteria (On-Treatment)
Present by Anaphylactic Criterion 1, 2 
and 3 rather than SOC as shown in 
AE1 
SAC 
3.26
ITT
SHELL
Summary Profile of AEs meeting Anaphylaxis Criteria (On-
Treatment)
SAC
3.27
ITT
AE1
Summary of AEs Defined by the Investigator as being Systemic 
(non-allergic or allergic/hypersensitivity) Reactions (On-
Treatment)
SAC 
3.28
ITT
SHELL
Summary Profile of Systemic (non-allergic or 
allergic/hypersensitivity) Reactions (On-Treatment)
SAC
3.29
ITT
SHELL
Summary Profile of Systemic Allergic Reactions (On-Treatment)
SAC
3.30
ITT
SHELL
Summary Profile of Systemic Non-Allergic Reactions (On-
Treatment)
SAC
3.31
ITT
AE1
Summary of AEs Defined by the Investigator as being Local 
Injection Site Reactions (On-Treatment)
SAC 
3.32
ITT
AE1
Summary of AEs Defined by the Investigator as being Local 
Injection Site Reactions by Relation to IP (On-Treatment)
SAC 
3.33
ITT
SHELL
Summary Profile of Local Injection Site Reactions (On-
Treatment)
SAC 


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Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
3.34
ITT
AE3
Summary of Opportunistic Infections (On-Treatment)
SAC 
3.35
ITT
SHELL
Summary Profile of Opportunistic Infections (On-Treatment)
SAC
3.36
ITT
AE3
Summary of Malignancies (On-Treatment)
SAC 
3.37
ITT
SHELL
Summary Profile of Malignancies (On-Treatment)
SAC
3.38
ITT
AE1
Summary of Serious Cardiac, Vascular and Thromboembolic 
Adverse Events (On-Treatment)
SAC 
3.39
ITT
SHELL
Summary Profile of Serious Cardiac, Vascular and 
Thromboembolic Adverse Events (On-Treatment)
SAC
3.40
ITT
AE1
Summary of Serious Ischemic AEs (On-Treatment)
SAC 
3.41
ITT
SHELL
Summary Profile of Serious Ischemic AEs (On-Treatment)
SAC
3.42
ITT
SHELL
Summary of Serious AEs and AEs of Special Interest
See format of Safety Table 7.32 
(MEA115588 ‘final’ reporting effort)
SAC 
Cardiovascular Events
3.43
ITT
SHELL
Summary of All Cardiovascular Events Reported by the 
Investigator
SAC 
Laboratory: Chemistry
3.44
ITT
LB1
Summary of Changes from Baseline in Chemistry Data
Include Baseline values.
SAC 
3.45
ITT
LB3
Summary of Chemistry Results (Changes from Baseline
Relative to the Normal Range)
See also format of Safety Table 7.36 
(MEA115588 ‘final reporting effort)
SAC 
Laboratory: Haematology
3.46
ITT
LB1
Summary of Changes From Baseline in Haematology Data
Include Baseline values
SAC 
3.47
ITT
LB3
Summary of Haematology Results (Changes from Baseline
Relative to the Normal Range)
See also format of Safety Table 7.42 
(MEA115588 ‘final reporting effort)
SAC 


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Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
Hepatobiliary (Liver)
3.48
ITT
LIVER10
Summary of Subjects Meeting Emergent Hepatobiliary 
Laboratory Abnormality Criteria 
SAC
ECGs
3.49
ITT
EG1
Summary of ECG Findings
SAC 
3.50
ITT
EG2
Summary of Change from Baseline in ECG Values by Visit
Include Baseline values
SAC 
3.51
ITT
SHELL
Summary of Actual and Change From Baseline QTc(F) Values 
by Category (msec)
SAC 
3.52
ITT
SHELL
Summary of Actual and Change From Baseline QTc(B) Values 
by Category (msec)
Vital Signs
3.53
ITT
VS1
Summary of Change From Baseline in Vital Signs by Visit
Include Baseline values
SAC 
Immunogenicity
3.54
ITT
SHELL
Summary of ADA Assay Results
See format of Other Assessments 
Table 8.01 (MEA115588 ‘final’ reporting 
effort)
SAC 
3.55
ITT
SHELL
Summary of Treatment Emergent ADA Assay Results
SAC
3.56
ITT
SHELL
Summary of NAb Assay Results
See format of Other Assessments 
Table 8.02 (MEA115588 ‘final’ reporting 
effort)
SAC 


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10.13.1.6. Safety Figures
Safety : Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
Laboratory
3.1
ITT
LIVER9
Scatter Plot of Maximum Post-Baseline vs. Baseline for ALT 
SAC
3.2
ITT
LIVER9
Scatter Plot of Maximum Post-Baseline ALT vs. Maximum Post-
Baseline Total Bilirubin 
SAC


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10.13.1.7. ICH Listings
ICH Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
Subject Disposition
1.
ASE
ES7
Listing of Reasons for Screening Failure or Run-In 
Failure
SAC 
2.
ASE
IE3
Listing of Failed Inclusion/Exclusion/Continuation 
criteria
SAC
3.
ITT
ES2
Listing of Reasons  for Premature Study Withdrawal
SAC 
4.
ITT
ES2
Listing of Reasons for Premature Discontinuation of 
Study Treatment
SAC 
Demographics
5.
ITT
DM2
Listing of Demographic Characteristics
SAC 
6.
ITT
DM9
Listing of Race
SAC 
Medication Use
7.
ITT
CM6
Relationship Between ATC Level 1, Ingredient and 
Verbatim Text
SAC 
Protocol Deviations
8.
ITT
DV2
Listing of Important Protocol Deviations
Listing also includes Per-Protocol analysis population 
exclusions
SAC 
Efficacy


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ICH Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
9.
ITT
SHELL
Listing of ACQ-5 Data
SAC 
10.
ITT
SHELL
Listing of Exacerbations
See format of Efficacy Listing 6.01 (MEA115588 
‘final’ reporting effort)
SAC 
Exposure
11.
ITT
EX3
Listing of Exposure Data
SAC 
Adverse Events
12.
ASE
AE8
Listing of All Adverse Events
SAC 
13.
ASE
AE7
Listings of Subject Numbers for Individual Adverse 
Events
SAC 
14.
ASE
AE2
Listing of Relationship Between Adverse Event 
System Organ Classes, Preferred Terms, and 
Verbatim Text
SAC 
Serious and Other Significant AEs
15.
ASE
AE8
Listing of all Fatal Adverse Events
SAC 
16.
ASE
AE8
Listing of Non-Fatal Serious Adverse Events
SAC 
17.
ASE
AE14
Listing of Reasons for Considering as a Serious 
Adverse Event
SAC 
18.
ITT
AE8
Listing of Adverse Events Leading to Withdrawal from 
Study / Permanent Discontinuation of Study 
Treatment
SAC 


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ICH Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
Adverse Events of Special Interest
19.
ITT
SHELL
Listing of AEs meeting Anaphylaxis Criteria
See format of Safety Listing 7.10 (MEA115588 ‘final’ 
reporting effort)
SAC
20.
ITT
SHELL
Listing of Adverse Events Defined by the Investigator 
as a Systemic (non-allergic or 
allergic/hypersensitivity) Reaction
See format of Safety Listing 7.07 (MEA115588 ‘final’ 
reporting effort). Also add a column stating whether 
AE is related to IP.
SAC 
21.
ITT
SHELL
Listing of All Adverse Events Experienced by 
Subjects with at least one Adverse Event Defined 
by the Investigator as a Systemic (non-allergic or 
allergic/hypersensitivity) Reaction
SAC
22.
ITT
SHELL
Listing of Adverse Events Defined by the Investigator 
as a Local Injection Site Reaction
See format of Safety Listing 7.09 (MEA115588 ‘final’ 
reporting effort). Also add a column stating whether 
AE is related to IP.
SAC 
23.
ITT
SHELL
Listing of Opportunistic Infections
See format of Safety Listing 7.10 (MEA115588 ‘final’ 
reporting effort)
SAC 
24.
ITT
SHELL
Listing of Malignancies
See format of Safety Listing 2.03 (mid_mepo_iss 
‘iss_nda’ reporting effort)
SAC 
25.
ITT
SHELL
Listing of Serious Cardiac, Vascular and 
Thromboembolic (CVT) AEs
See format of Safety Listing 7.10 (MEA115588 ‘final’ 
reporting effort)
SAC 
26.
ITT
SHELL
Listing of Serious Ischemic AEs
See format of Safety Listing 7.10 (MEA115588 ‘final’ 
reporting effort)
SAC 
Cardiovascular Events


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ICH Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
27.
ITT
SHELL
Listing of Investigator Reported Cardiovascular 
Events: Arrhythmias
See format of Safety Listing 7.11 (MEA115588 
‘final’ reporting effort)
SAC 
28.
ITT
SHELL
Listing of Investigator Reported Cardiovascular 
Events: Congestive Heart Failure
See format of Safety Listing 7.12 (MEA115588 
‘final’ reporting effort)
SAC 
29.
ITT
SHELL
Listing of Investigator Reported Cardiovascular 
Events: Cerebrovascular Events/Stroke
See format of Safety Listing 7.13 (MEA115588 
‘final’ reporting effort)
SAC 
30.
ITT
SHELL
Listing of Investigator Reported Cardiovascular 
Events: Deep venous Thrombosis/Pulmonary 
Embolism
See format of Safety Listing 7.14 (MEA115588 
‘final’ reporting effort)
SAC 
31.
ITT
SHELL
Listing of Investigator Reported Cardiovascular 
Events: Myocardial Infarction/Unstable Angina
See format of Safety Listing 7.15 (MEA115588 
‘final’ reporting effort)
SAC 
32.
ITT
SHELL
Listing of Investigator Reported Cardiovascular 
Events: Peripheral Arterial Thrombosis Embolism
See format of Safety Listing 7.16 (MEA115588 
‘final’ reporting effort)
SAC 
33.
ITT
SHELL
Listing of Investigator Reported Cardiovascular 
Events: Pulmonary Hypertension
See format of Safety Listing 7.17 (MEA115588 
‘final’ reporting effort)
SAC 
34.
ITT
SHELL
Listing of Investigator Reported Cardiovascular 
Events: Revascularisation
See format of Safety Listing 7.18 (MEA115588 
‘final’ reporting effort)
SAC 
35.
ITT
SHELL
Listing of Investigator Reported Cardiovascular 
Events: Valvulopathy
See format of Safety Listing 7.19 (MEA115588 
‘final’ reporting effort)
SAC 
36.
ITT
SHELL
Listing of Investigator Reported Cardiovascular 
Events: All Cause Deaths
See format of Safety Listing 7.20 (MEA115588 
‘final’ reporting effort)
SAC 


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ICH Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
Hepatobiliary (Liver)
37.
ITT
LIVER5
Listing of Liver Monitoring/Stopping Event Reporting
SAC
38.
ITT
LB5
Chemistry Results for Subjects Meeting Liver 
Monitoring/Stopping Event Criteria
SAC
39.
ITT
MH2
Listing of Medical Conditions for Subjects with Liver 
Stopping Events
SAC 
40.
ITT
SU2
Listing of Substance Use for Subjects with Liver 
Stopping Events
See format of Safety Listing 7.22 (MEA112997 ‘final’ 
reporting effort)
SAC 
41.
ITT
LIVER13
Listing of Subjects Meeting Hepatobiliary Laboratory 
Criteria Post-Baseline
SAC
All Laboratory
42.
ITT
LB5
Listing of Laboratory Data for Subjects with 
Abnormalities of Potential Clinical Concern
SAC 
ECG
43.
ITT
EG6
Listing of ECG Findings for Abnormal Interpretations
SAC 
Immunogenicity
44.
ITT
SHELL
Listing of Immunogenicity Results
See format of Other Assessments Listing 8.01 
(MEA115588 ‘final’ reporting effort)
SAC 


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10.14.
Appendix 14: Example Mock Shells for Data Displays
The data display shells are contained in separate documents which are available on request.