Clinical trial NCT02135692
Conditions: Asthma
Keywords: Severe eosinophilic asthma Extension study Expanded access Safety Mepolizumab Eosinophils
Sponsor: GlaxoSmithKline
Start date: 2014-05-29; Completion date: 2017-10-05
Enrollment: 339 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a multi-center, open-label, long-term study of subcutaneously (SC) administered mepolizumab 100mg in addition to standard of care (SOC), in subjects with severe eosinophilic asthma. This study will enroll a subset of subjects from Study MEA115661 who have demonstrated clear benefit from therapy and who without continuation of mepolizumab therapy are individuals at greatest risk of serious deterioration of their health status. In order to target individuals at greatest risk for serious deterioration of their health status, only subjects from the MEA115661 study with a history of life-threatening or seriously debilitating asthma, will be allowed to participate. Subjects meeting all of the eligibility criteria for the study will be offered the opportunity to consent for this study of up to 128 weeks in length (including the Follow-Up Visit). This study will give opportunity to extend the collection of clinical data for long-term use and further assess the sustainability of efficacy in a population likely to experience significant loss of asthma control and the need for higher doses of systemic steroids if returned to SOC only.

Detailed description:

Arms: arm 1: All subjects will receive mepolizumab 100mg administered SC into the upper arm or thigh approximately every 4 weeks.
Interventions: intervention 1: Mepolizumab intervention 2: SOC
Intervention descriptions: intervention 1: Mepolizumab is a fully humanised IgG antibody (IgG1, kappa) with human heavy and light chain frameworks. Mepolizumab will be supplied as a lyophilised cake in sterile vials for individual use. intervention 2: Standard of Care (SOC) will differ by participant, however it will generally include oral corticosteroids and an inhaled controller medicine (an inhaled corticosteroid plus a long acting beta agonist) and/or short acting beta agonists

Protocol documents:
Prot_000.pdf: 
2013N187987_04
CONFIDENTIAL
The GlaxoSmithKline group of companies
201312
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
Study 201312: A Multi-Centre, Open-Label, Study of
Mepolizumab in a Subset of Subjects with a History of Life
Threatening/Seriously Debilitating Asthma Who Participated in
the MEA115661 Trial
Compound Number:
SB-240563
Development Phase:
IIIb
Effective Date:
06-JUL-2015
Protocol Amendment Number:  03
Author (s):
Copyright 2015 the GlaxoSmithKline group of companies.  All rights reserved. 
Unauthorised copying or use of this information is prohibited.
PPD


2013N187987_04
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The GlaxoSmithKline group of companies
201312
2
Revision Chronology
GlaxoSmithKline 
Document Number
Date
Version
2013N187987_00
2014-FEB-11
Original
2013N187987_01
2014-JUN-27
Amendment No. 1
The primary purpose of Amendment 01 is to change three entry criteria to ensure those 
subjects with a history of seriously debilitating asthma and a history of improved disease 
control continue to receive mepolizumab in 201312.  The amendment also includes a 
number of additional corrections and edits (Appendix 7).
2013N187987_02
2014-NOV-14
Amendment No. 2
The primary reason for Amendment 2 is to insert entry criterion No. 8.  There are also 
minor changes to clarify the subject scenarios added during Amendment 1 and an 
administrative change to update the Medical Monitors.
2013N187987_03
2015-JUN-19
Amendment No. 3
The primary reason for Amendment 3 is to increase the treatment duration and to remove 
the Follow-up visit.  There is also a change to the IP administration process and 
clarification to the IP post dose monitoring process.  The amendment also includes a 
standardisation of the collection of concomitant medications (Appendix 9).
2013N187987_04
2015-JUL-06
Republishing Protocol 
Amendment 3 
To correct some errors in Appendix 9 to reflect the amendments made within the main 
protocol.


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SPONSOR INFORMATION PAGE
Clinical Study Identifier: 201312
Sponsor Legal Registered Address:
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Sponsor Contact Address
GlaxoSmithKline Research & Development Limited
Iron Bridge Road 
Stockley Park West, Uxbridge, Middlesex, UB11 1BU, UK
Telephone: 
 
GlaxoSmithKline Research & Development Limited
Five Moore Drive 
P.O. 13398
Research Triangle Park, NC 27709-3398, USA
Telephone: 
Sponsor Global Medical Monitor Contact Information: 
 MA MSc. MBBS FFPM (Clinical Development Physician)
Tel: 
Mobile: 
Sponsor Global Back-up Medical Monitor Contact Information: 
 MD (Clinical Development Physician)
Tel: 
Mobile: 
Sponsor Serious Adverse Events (SAE) Contact Information:
 MD (Clinical Development Physician)
Tel: 
Mobile: 
Regulatory Agency Identifying Number(s):
IND No. 006971; EudraCT No. 2014-000314-54
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 201312
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date


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TABLE OF CONTENTS
PAGE
LIST OF ABBREVIATIONS.............................................................................................9
PROTOCOL SUMMARY...............................................................................................11
1.
INTRODUCTION....................................................................................................14
1.1.
Background ................................................................................................14
1.2.
Rationale ....................................................................................................15
1.3.
Benefit:Risk Assessment ............................................................................15
1.3.1.
Risk Assessment .........................................................................16
1.3.2.
Benefit Assessment.....................................................................20
1.3.3.
Overall Benefit:Risk Conclusion...................................................20
2.
OBJECTIVE(S) ......................................................................................................21
3.
INVESTIGATIONAL PLAN.....................................................................................21
3.1.
Study Design ..............................................................................................21
3.2.
Discussion of Design ..................................................................................23
4.
SUBJECT SELECTION AND WITHDRAWAL CRITERIA.......................................24
4.1.
Number of Subjects ....................................................................................24
4.2.
Inclusion Criteria.........................................................................................24
4.3.
Exclusion Criteria........................................................................................26
4.4.
Withdrawal Criteria .....................................................................................27
4.4.1.
Subject Compliance with Visit Schedule ......................................27
4.4.2.
Lost To Follow-Up........................................................................27
4.4.3.
Withdrawal By Investigator ..........................................................27
4.4.3.1.
General Withdrawal Requirements.............................27
4.4.3.1.1.
ECGs......................................................28
4.4.3.1.2.
Other Basis for Withdrawal .....................28
4.4.4.
Subject Self-Withdrawal...............................................................28
4.4.5.
Withdrawal Documentation ..........................................................28
5.
STUDY TREATMENTS..........................................................................................29
5.1.
Investigational Product................................................................................29
5.1.1.
Medication Preparation and Handling ..........................................29
5.1.2.
Storage........................................................................................29
5.2.
Dosage and Administration.........................................................................29
5.3.
Treatment Assignment................................................................................30
5.4.
Blinding.......................................................................................................30
5.5.
Product Accountability ................................................................................30
5.6.
Treatment Compliance................................................................................30
5.7.
Concomitant Medications and Non-Drug Therapies....................................30
5.7.1.
Permitted Medications and Non-Drug Therapies..........................30
5.7.2.
Prohibited Medications.................................................................31
5.8.
Treatment after the End of the Study ..........................................................31
5.9.
Treatment of Study Treatment Overdose....................................................31
6.
STUDY ASSESSMENTS AND PROCEDURES .....................................................31


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6.1.
Critical Baseline Assessments....................................................................31
6.2.
Efficacy Endpoints ......................................................................................33
6.2.1.
Efficacy Data Capture/Instruments...............................................33
6.2.1.1.
Exacerbations.............................................................33
6.2.1.2.
Asthma Control Questionnaire-5 (ACQ-5) ..................33
6.2.1.3.
Pulmonary Function Testing.......................................33
6.3.
Safety .........................................................................................................34
6.3.1.
Liver Chemistry Stopping and Follow-Up Criteria.........................34
6.3.1.1.
Criteria for Liver Chemistry Stopping ..........................34
6.3.1.2.
Actions .......................................................................35
6.3.1.3.
Follow-Up Assessments .............................................36
6.3.1.4.
Restarting Investigational Product ..............................38
6.3.1.4.1.
Drug Restart/Rechallenge 
Following Liver Events that are 
Possibly Related to IP.............................38
6.3.1.4.2.
Drug Restart Following Transient 
Resolving Liver Events Not 
Related to IP...........................................38
6.3.2.
Adverse Events............................................................................39
6.3.2.1.
Definition of an AE......................................................39
6.3.2.2.
Definition of an SAE ...................................................40
6.3.2.3.
Sentinel Events ..........................................................41
6.3.3.
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs.........................................................41
6.3.4.
Cardiovascular Events.................................................................41
6.3.5.
Death Events...............................................................................42
6.3.6.
Pregnancy ...................................................................................42
6.3.7.
Time Period and Frequency of Detecting AEs and SAEs.............42
6.3.8.
Method of Detecting AEs and SAEs.............................................43
6.3.9.
Prompt Reporting of Serious Adverse Events and Other 
Events to GSK.............................................................................43
6.3.9.1.
Regulatory Reporting Requirements for SAEs............45
6.3.10.
Other Safety Outcomes ...............................................................46
6.3.10.1.
Laboratory Assessments ............................................46
6.3.10.2.
Physical Examination .................................................46
6.3.10.3.
Vital Signs ..................................................................47
6.3.10.4.
Twelve-lead electrocardiogram...................................47
6.4.
Immunogenicity...........................................................................................47
7.
DATA MANAGEMENT ...........................................................................................47
8.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS...................................48
8.1.
Hypothesis..................................................................................................48
8.2.
Study Design Considerations......................................................................48
8.2.1.
Sample Size Assumptions ...........................................................48
8.3.
Data Analysis Considerations .....................................................................48
8.3.1.
Analysis Populations....................................................................48
8.3.2.
Analysis Data Sets.......................................................................48
8.3.3.
Treatment Comparisons ..............................................................48
8.3.4.
Interim Analysis ...........................................................................48
8.3.5.
Key Elements of Analysis Plan ....................................................48
8.3.5.1.
Efficacy Analyses .......................................................49


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8
8.3.5.2.
Safety Analyses..........................................................49
9.
STUDY CONDUCT CONSIDERATIONS ...............................................................49
9.1.
Posting of Information on Publicly Available Clinical Trial Registers............49
9.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................49
9.3.
Quality Control (Study Monitoring) ..............................................................49
9.4.
Quality Assurance.......................................................................................50
9.5.
Study and Site Closure ...............................................................................50
9.6.
Records Retention......................................................................................50
9.7.
Provision of Study Results to Investigators, Posting of Information 
on Publicly Available Clinical Trials Registers and Publication....................51
10. REFERENCES.......................................................................................................52
11. APPENDICES........................................................................................................54
11.1.
Appendix 1: Time and Events Table ...........................................................54
11.2.
Appendix 2: Acceptable Birth Control..........................................................58
11.3.
Appendix 3: Country Specific Requirements...............................................60
11.4.
Appendix 4: Liver Chemistry Stopping and Follow-up Criteria.....................61
11.5.
Appendix 5: Liver Safety Drug Restart or Rechallenge Guidelines..............62
11.6.
Appendix 6: Anaphylaxis Criteria ................................................................67
11.7.
Appendix 7: Protocol Amendment 01 Changes...........................................68
11.8.
Appendix 8: Protocol Amendment 02 Changes...........................................86
11.9.
Appendix 9: Protocol Amendment 03 Changes...........................................91


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LIST OF ABBREVIATIONS
ACQ-5
Asthma Control Questionnaire-5
AE
Adverse Event
ALT
Alanine transaminase
AST
Aspartate transaminase
ATS
American Thoracic Society
CIB
Clinical Investigator Brochure
CPAP
Continuous Positive Airway Pressure
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic Case report form
ED
Emergency Department
FEV1
Forced expiratory volume in 1 second
FVC
Forced vital capacity
GCP
Good clinical practice
GCSP
Global Clinical Safety and Pharmacovigilance
GINA
Global Initiative for Asthma
GSK
GlaxoSmithKline
IC50
Inhibitory Concentration 50%
ICS
Inhaled corticosteroids
IEC
Independent ethics committee
IL
Interleukin
IM
Intramuscular
IP
Investigational Product
IRB
Institutional review board
IUD
Intrauterine Device
IV
Intravenous
IVRS
Interactive voice response system
MedDRA
Medicinal dictionary for regulatory activities
mg
Milligram
N/A
Not applicable
NHLBI
National Heart Lung and Blood Institute
OLE
Open Label Extension Study
PEF
Peak expiratory flow
RAP
Reporting and Analysis Plan
SABA
Short-acting Beta Agonist
SAE
Serious adverse event
SC
Subcutaneous
SGRQ
St. George’s Respiratory Questionnaire
SPM
Study procedures manual
ULN
Upper Limit of Normal


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


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PROTOCOL SUMMARY
Rationale
Study 201312 is a study of subcutaneously (SC) administered mepolizumab 100mg that 
will enroll a subset of subjects from Study MEA115661 who have demonstrated clear 
benefit from therapy and who without continuation of mepolizumab therapy are 
individuals at greatest risk of serious deterioration of their health status. In order to target 
individuals at greatest risk for serious deterioration of their health status, only subjects 
from the MEA115661 study with a history of life-threatening or seriously debilitating 
asthma, as defined by this protocol, will be allowed to participate in Study 201312. 
Providing treatment to these subjects offers the opportunity to extend the collection of 
clinical data for long-term use and further assess the sustainability of efficacy in a 
population likely to experience significant loss of asthma control and the need for higher 
doses of systemic steroids if returned to standard of care (SOC) only.
Objectives
Primary Objective

To provide extended treatment with mepolizumab to subjects with a history of life-
threatening or seriously debilitating asthma and a history of improved disease control 
while receiving mepolizumab as defined by this protocol.
Secondary Objective

To further describe the long-term clinical experience of mepolizumab in a subset of 
subjects who demonstrated significant clinical benefit since receiving mepolizumab 
Study Design
This is a multi-center, open-label, long-term study of mepolizumab 100mg administered 
SC, in addition to standard of care (SOC), in subjects with severe eosinophilic asthma. 
Only subjects who complete the MEA115661 Exit Visit (Visit 14) will be offered the 
opportunity to consent for this study. Subjects meeting all of the eligibility criteria will be 
offered the opportunity to consent for this study of up to 172 weeks.  
It is expected that the majority of eligible subjects will enter 201312 within 8 weeks of 
completing the Exit Visit (Visit 14) in MEA115661.  
To reduce the burden of repeated procedures during the ending of MEA115661 and the 
start of 201312, subjects will start the study according to a specific “scenario”.  This 
depends on when their Visit 1 occurs in relation to the Visit 14 of the MEA115661 study. 
Scenario 1 is when Visit 1 of 201312 is performed on the same day (or less than or equal 
to 8 weeks) from when Visit 14 of study MEA115661 is performed.
Scenario 2a is when Visit 1 of 201312 is performed greater than 8 weeks after Visit 14 
of MEA115661 AND when Visit 1 of 201312 is performed on the same day as the 
Follow-up visit (Visit 15) of study MEA115661. 


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Scenario 2b is when Visit 1 of 201312 is performed greater than 8 weeks after Visit 14 
of MEA115661 AND Visit 1 of 201312 is performed after the Follow-up visit (Visit 15) 
of study MEA115661 has taken place.
All applicable procedures for scenario 1, and 2a and 2b subjects are listed in Section 6.1. 
Critical Baseline Assessments.  
All eligible subjects should be enrolled into 201312 within 4 weeks of receiving all 
applicable approvals.
After giving informed consent for this study, eligibility will be assessed via multiple 
evaluations, including physical examination, vital signs, electrocardiogram (ECG), and 
an updated medical history. Subjects whose health status remains appropriate for the 
study will then be assessed based on the inclusion and exclusion criteria. Those subjects 
meeting all study eligibility requirements will receive their first dose of mepolizumab at 
Visit 1. Mepolizumab will then be administered approximately every 4 weeks with the 
last dose at Week 168 (Visit 43).  Forty three doses will provide therapeutic coverage for 
172 weeks (4 weeks following the last dose). Subjects will continue to receive 
mepolizumab 100mg SC injections for up to 172 weeks or until one of the following 
occurs: 

the risk/benefit profile for the subject is no longer positive in the opinion of 
the investigator or

the subject’s physician withdraws the subject or

the subject withdraws consent or

the sponsor discontinues development of mepolizumab or

the sponsor discontinues the study in the relevant participating country or

mepolizumab becomes commercially available in the local country.
The study closure process will begin, on a country by country basis, as mepolizumab
becomes commercially available for prescription.  Some subjects will complete the 
original 120 week treatment period (as specified in the previous protocol) prior to 
mepolizumab being available for prescription.  To ensure these subjects do not have a 
treatment gap the treatment period will be extended for an additional 52 weeks to a total 
of 172 weeks.
Subjects will remain on standard of care asthma therapy throughout the study. Asthma 
medications may be adjusted at any time during the study at the discretion of the 
investigator. All changes in asthma therapy will be captured in the source documents and 
the electronic case report form (eCRF). At each clinic visit, adverse events will be 
assessed and subjects will be questioned regarding the occurrence of any exacerbations 
since their last clinic visit. The Asthma Control Questionnaire-5 (ACQ-5) will be 
performed every 12 weeks during the study and at the Exit/Early Withdrawal Visit to 
assist the investigator in monitoring the subject’s asthma status along with spirometry 
assessments every 6 months and at the Exit/Early Withdrawal Visit. 


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Safety labs (hematology, chemistry, and liver analytes) will be drawn at Visit 1 and then 
approximately every 6 months thereafter. Hematology and chemistry labs will also be 
obtained 4 weeks after the subject’s last dose of mepolizumab. Serum samples for anti-
mepolizumab antibody measurements will also be obtained from subjects at baseline 
(Visit 1), Weeks 48, 96, 144 and at the Exit Visit/Early Withdrawal Visit. Any serum 
sample testing positive for anti-mepolizumab antibody will also be tested for neutralizing 
antibody. Subjects discontinuing mepolizumab treatment will be monitored for 
exacerbation of their asthma during the subsequent 4 weeks after their last dose.
Study Endpoints/Assessments
Primary Endpoints

Annualized rate of exacerbations

Frequency of adverse events
Secondary Endpoints

Asthma Control Questionnaire-5 score

Forced expiratory volume in 1 second (FEV1) 

Number of withdrawals due to lack of efficacy

Number of withdrawals due to adverse events

Number of hospitalizations due to adverse events including asthma exacerbations

Frequency of both systemic (i.e., allergic and non-allergic) and local site reactions

12-lead ECG parameters

Vital signs

Frequency of positive anti-mepolizumab binding antibodies/neutralizing antibodies

Clinical Laboratory Parameters


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1.
INTRODUCTION
1.1.
Background
Asthma is a disease characterised by chronic airway inflammation, bronchial hyper-
reactivity and variable airflow obstruction. Eosinophils are usually prominent in the 
airway inflammation seen in asthma and are considered a central cause in the 
pathogenesis of asthma [Wardlaw, 2000]. The expression of interleukin (IL)-5 is elevated 
in bronchoalveolar lavage (BAL) fluid and bronchial biopsies in patients with asthma 
[Hamid, 1991]. Moreover, the level of IL-5 in BAL fluid and the bronchial mucosa 
correlates with disease severity [Robinson, 1992; Robinson, 1993; Humbert, 1997]. The 
cytokine IL-5 promotes eosinophil differentiation, recruitment, and survival [Clutterbuck, 
1989; Wang, 1989]. Thus, a therapeutic strategy which blocks IL-5, thereby suppressing 
eosinophilic inflammation, may have therapeutic benefit in asthma.
Currently available therapies are highly effective at controlling asthma symptoms and 
airway inflammation in the majority of patients [Bateman, 2004]. Severe refractory 
asthma encompasses wide ranges in both clinical symptoms and in natural history. This 
population can be defined on the basis of medication requirements, asthma symptoms, 
degree of airflow limitation, and frequency of asthma exacerbations. In terms of 
exacerbations, three or more steroid-treated exacerbations have been considered part of 
the typical clinical features in this patient population [ATS, 2000].
Inhaled corticosteroids reduce airway inflammation and sputum eosinophils in most 
asthmatics [Kips, 2002]. However, a proportion of asthma patients remain uncontrolled 
despite appropriate therapy with high dose inhaled corticosteroids (ICS) or ICS with 
additional controller therapy [National Heart Lung and Blood Institute (NHLBI) 
Guidelines for the Diagnosis and Treatment of Asthma [NHLBI, 2007]; Global Initiative 
for Asthma guidelines [GINA, 2008]. This severe, uncontrolled, refractory population 
suffers from persistent symptoms and acute exacerbations of their asthma. 
Patients with severe asthma have significant morbidity and mortality risk; they contribute 
disproportionately to health care and societal costs of the disease with particularly high 
costs occurring in those with frequent exacerbations. In MEA112997, subjects had 
features of severe, refractory asthma, as described in the American Thoracic Society 
(ATS) workshop on refractory asthma [ATS, 2000], and also demonstrated markers of 
eosinophilic inflammation [Pavord, 2012]. Together, these criteria were useful to identify 
a severe eosinophilic asthma population that continued to exacerbate despite maximal 
therapy with currently marketed asthma medications. This severe, eosinophilic 
population is the subset of asthmatics most likely to benefit from treatment with 
mepolizumab. 
Subjects who are eligible for participation in 201312 will be subjects who have life-
threatening or seriously debilitating asthma, who have been previously treated with 
mepolizumab, and who have demonstrated clear clinical benefit from the treatment. 
Subjects entering 201312 through MEA115588 and MEA115661 could have been treated 
for up to 20 months. Subjects entering the study through MEA115575 and MEA115661 


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could have been treated for up to 18 months. At a minimum, subjects entering the study 
will have already been treated for at least 12 months.
1.2.
Rationale
Study 201312 is a study of subcutaneously (SC) administered mepolizumab 100mg that 
will enroll a subset of subjects from Study MEA115661 who have demonstrated clear 
benefit from therapy and who without continuation of mepolizumab therapy are 
individuals at greatest risk of serious deterioration of their health status. In order to target 
individuals at greatest risk for serious deterioration of their health status, only subjects 
from the MEA115661 study with a history of life-threatening or seriously debilitating 
asthma, as defined by this protocol, will be allowed to participate in Study 201312. 
Providing treatment to these subjects offers the opportunity to extend the collection of 
clinical data for long-term use and further assess the sustainability of efficacy in a 
population likely to experience significant loss of asthma control and the need for higher 
doses of systemic steroids if returned to standard of care (SOC) only.
1.3.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
mepolizumab (SB240563) can be found in the Investigator’s Brochure.
Serious adverse events (SAEs) reported from ongoing clinical studies with mepolizumab 
are reviewed daily by the project Medical Monitor. Additionally, regular, systematic 
reviews of emerging safety data from all clinical studies are conducted by an in-house 
multi disciplinary Safety Review Team (SRT) which provides a central and dedicated 
forum for review of emerging data which could impact subject safety. The SRT, which 
includes the project Medical Monitor, other physicians assigned to the project, clinical 
scientists and a statistician reviews blinded and unblinded (i.e., from open-label trials) 
safety data from ongoing clinical studies with mepolizumab on a regular basis and 
conducts a comprehensive evaluation of the safety data upon completion of each study. 
Moreover, an integrated analysis of safety across the program is completed annually 
when additional safety data are available from completed studies. A reassessment of 
benefit risk and the current Developmental Core Safety Information (DCSI) is completed 
at each SRT meeting subsequent to review of new data. 
Additionally, an adjudication committee will be utilized during the study to assess 
cardiovascular events. There is also a standard and comprehensive process for the 
reporting and management of Sentinel Events. (A Sentinel Event is an SAE that is not 
necessarily drug-related, but that has been associated historically with adverse reactions 
for other drugs, and is therefore worthy of heightened pharmacovigilance. Sentinel 
Events include acquired long QT syndrome, agranulocytosis, anaphylactic and 
anaphylactoid reactions, hepatotoxicity, renal failure, seizures, and Stevens Johnson 
syndrome/toxic epidermal necrolysis.) Subsequent to the reporting of a Sentinel Event, 
the Medical Monitor promptly notifies the SRT and the GSK Global Safety Board and 
leads a thorough and comprehensive follow-up of the Sentinel Event with collection of 
all relevant data. 


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The following section outlines the risk assessment and mitigation strategy for this 
protocol: 
1.3.1.
Risk Assessment
Table 1
Assessment of Risk
Potential Risk of Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) SB 240563
Risk of Systemic Allergic and 
Non-allergic Reactions, 
including Anaphylaxis
Reactions reported to date 
across the mepolizumab 
program are summarized in 
the IB; see ‘Special Warnings 
and Special Precautions for 
Use’ section located in Section 
6 titled ‘Summary of Data and 
Guidance for the Investigator’.
Daily monitoring of serious 
adverse events (SAEs) by 
medical monitor; regular 
systematic review of adverse 
event (AE)/SAE data from 
ongoing studies by a GSK 
safety review team. 
Specific case report form 
(CRF) pages utilized for 
targeted collection of reactions 
data.
Use of Joint NIAID/FAAN 
2nd Symposium on 
Anaphylaxis to collect data on 
reports of anaphylaxis 
(Appendix 6 Anaphylaxis 
Criteria).
Subjects are to be monitored 
based on institutional 
practices. 
Risk of Immunogenicity
Biopharmaceutical products 
may elicit anti-drug antibody 
(ADA) and neutralizing 
antibody (NAB), which have 
the potential to modulate 
pharmacokinetic (PK), 
pharmacodynamic (PD) or 
produce adverse reactions. 
However, humanized and fully 
human antibodies are less 
immunogenic than mouse or 
chimeric monoclonal 
antibodies.
Immunogenicity data reported 
to date across the 
Blood samples are collected in 
clinical studies for detection of 
both ADA and NAB.
See previous risk for 
mitigation strategy related to 
clinical safety risks.


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Potential Risk of Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
mepolizumab development 
program are summarized in 
the IB; See Section 5.4 
‘Clinical Immunogenicity’ and 
a summary of immunogenicity 
findings in the ‘Other 
Potentially Clinically Relevant 
Information for the 
Investigator’ section located in 
Section 6.titled ‘Summary of 
Data and Guidance for the 
Investigator’s Brochure.
Potential risk for adverse 
cardiovascular (CV) effects
Mepolizumab binding was 
restricted to human lymphoid 
tissues in an 
immunohistochemistry tissue 
binding study suggesting a 
low likelihood of non-
pharmacologic effects on 
cardiovascular (CV) function. 
No AEs concerning cardiac 
conduction or repolarization 
evident in cynomolgus 
monkeys at doses at least 10-
fold in excess of humans 
dosed at 10 mg/kg or 750 mg.
No clinically relevant trends 
observed in ECG data in 
humans.
In one study in subjects with 
severe refractory asthma, 
cardiac events were reported 
in similar frequencies across 
treatment groups with a small 
numerical increase observed in 
serious ischemic cardiac 
events in the mepolizumab-
treated groups. However, an 
integrated safety analysis of all 
placebo-controlled multiple 
dose asthma trials showed 
similar frequency of SAEs 
reported overall from the 
cardiac and vascular system 
organ class (SOC). 
Daily monitoring of SAE by 
medical monitor; regular 
systematic review of AE/SAE 
data from ongoing studies by a 
GSK safety review team.
CV monitoring for study 
includes:

ECG monitoring during 
the trial

Use of standardized CRFs 
to collect relevant data on 
CV events of interest (i.e., 
myocardial infarction, 
hospitalization for 
unstable angina and 
congestive heart failure, 
arterial thrombosis, 
pulmonary embolism and 
deep vein thrombosis);

Adjudication of 
cardiovascular events


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Potential Risk of Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
Additionally, similar findings 
were observed in other SOCs 
with thrombotic events (e.g., 
stroke in the Nervous System 
SOC). Data from 2 
subsequently completed 
placebo-controlled severe 
asthma trials did not show an 
increased risk of serious 
ischemic cardiac events; there 
were no new reports in any 
treatment groups including 
placebo.
Potential risk for increase in 
infections – a theoretical 
concern with biologics; 
however, the pharmacological 
properties of mepolizumab 
suggest the risk is low.
No evidence of increased 
incidence of infections in any 
preclinical studies.
Murine data demonstrate that 
IL-5 antagonism is unlikely to 
influence cellular or humoral 
immunity, particularly in 
response to parasitic 
infections.  
No mepolizumab-related 
effects on lymphocyte 
Immunophenotyping in 
monkeys or humans, including 
T-cell activation, distribution 
of CD4/CD8 subtypes or 
Th1/Th2 cytokine patterns, B-
cells, NK cells or γδ-T-cells. 
An integrated safety analysis 
of all placebo-controlled 
multiple dose asthma trials 
showed SAEs reported in the 
infection and infestation SOC 
were 5/345 (1%) in placebo 
subjects and 18/754 (2%) in 
mepolizumab subjects.
Infections reported to date 
across the mepolizumab 
development program are 
summarized in the IB; see 
‘Special Precautions and 
Warnings’ (for exclusion of 
Daily monitoring of SAE by 
medical monitor; regular 
systematic review of AE/SAE 
data from ongoing studies by a 
GSK safety review team 
Standard safety assessments to 
be conducted as outlined in 
protocols


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Potential Risk of Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
subjects with underlying 
parasitic infections) and 
‘Undesirable Effects’ (for very 
common infections of 
nasopharyngitis, URTI, 
rhinitis and bronchitis reported 
in other patient populations) 
sections located in Section 6 
titled ‘Summary of Data and 
Guidance for the Investigator’.
Potential risk for increase in 
malignancies - theoretical 
concern with biologics; 
however, blockade of IL-5 is 
not associated with 
generalized immuno-
suppression or impaired host 
resistance.
Role of IL-5 and eosinophils 
in tumor surveillance is not 
fully characterised in the 
literature. 
No evidence of defective 
tumor surveillance in IL-5 or 
eosinophil-deficient mice. 
Direct assessment of the 
carcinogenic potential of long-
term IL-5 blockade in rodent 
models not technically 
feasible. 
Malignancies reported to date 
across the mepolizumab 
development program are 
summarized in the IB.
Daily monitoring of SAE by 
medical monitor; regular 
systematic review of AE/SAE 
data from ongoing studies by a 
GSK safety review team 
Standard safety assessments to 
be conducted as outlined in 
protocols
Potential risk for rebound 
eosinophilia with associated 
clinical consequences
Early published data with 
Schering-Plough anti- IL5 
mAb suggested potential for 
rebound eosinophilia and 
disease exacerbation when 
treatment was stopped [Kim, 
2004; Gevaert, 2006]; 
however, no standard 
definition of rebound was used 
and criteria for reporting were 
variable. 
There have been no verbatim 
reports of ‘rebound’ from 
completed clinical trials of 
subjects with asthma, atopic 
dermatitis and eosinophilic 
esophagitis. Furthermore, the 
Daily monitoring of SAE by 
medical monitor; regular 
systematic review of AE/SAE 
data from ongoing studies by a 
GSK safety review team 
Standard safety assessments to 
be conducted as outlined in 
protocols


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Potential Risk of Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
data do not support an 
exaggerated return of 
symptoms after cessation of 
treatment.
Study Procedures
Potential risk for injury with 
phlebotomy 
Risks with phlebotomy 
include bruising, bleeding, 
infection, nerve damage.
Procedures to be performed by 
trained personnel (i.e., study 
nurse) 
1.3.2.
Benefit Assessment
Study 201312 will provide extended use of mepolizumab to subjects with a history of 
life-threatening or seriously debilitating asthma while collecting data to evaluate the 
long-term continuous use of mepolizumab. This population of asthma subjects has been 
evaluated as having received benefit from at least one year’s treatment with mepolizumab 
(Study MEA115661) in addition to standard of care asthma treatment. This study will 
assess the incidence of adverse events and the rate of exacerbations to establish the long-
term safety and sustained efficacy of the treatment in this population.
Exacerbations are a major concern to asthma patients and lead to a worsening of the 
quality of life for subjects. Interventions in at risk populations that can reduce or 
eliminate serious exacerbations will improve a patient’s quality of life and may reduce 
hospitalizations. Subjects participating in this study will be required to attend visits 
approximately every 4 weeks and therefore may benefit from the additional monitoring to 
their current standard asthma care.
1.3.3.
Overall Benefit:Risk Conclusion
Data from mepolizumab preclinical and clinical development demonstrate the ability of 
mepolizumab to inhibit IL-5 and, consequently, treat inflammatory conditions linked to 
an eosinophilic signal, such as asthma subjects predisposed to exacerbations. To date, the 
safety profile of mepolizumab across other mepolizumab studies has been favorable for 
all the patient populations studied. Adverse events (AEs) reported commonly have been 
manageable with minimal medical intervention. Furthermore, preclinical data and the 
observed safety profile to date in over 1200 clinical trial subjects, as well as the history of 
mepolizumab use for at least one year in this patient population already, has not 
identified a safety concern that would preclude continued use. Therefore, investigation of 
the long-term safety, efficacy, and tolerability of mepolizumab is thereby justified in 
Study 201312.


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2.
OBJECTIVE(S)
Primary Objective

To provide extended treatment with mepolizumab to subjects with a history of life-
threatening or seriously debilitating asthma and a history of improved disease control 
while receiving mepolizumab as defined by this protocol
Secondary Objective

To further describe the long-term clinical experience of mepolizumab in a subset of 
subjects who demonstrated significant clinical benefit since receiving mepolizumab 
3.
INVESTIGATIONAL PLAN
3.1.
Study Design
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct. 
This is a multi-center, open-label, long-term study of mepolizumab 100mg administered 
SC, in addition to standard of care (SOC), in subjects with severe eosinophilic asthma. 
Only subjects who complete the MEA115661 Exit Visit (Visit 14) will be offered the 
opportunity to consent for this study. Subjects meeting all of the eligibility criteria for the 
study will be offered the opportunity to consent for this study of up to 172 weeks in 
length.  
It is expected that the majority of eligible subjects will enter 201312 within 8 weeks of 
completing the Exit Visit (Visit 14) in MEA115661.  
To reduce the burden of repeated procedures during the ending of MEA115661 and the 
start of 201312, subjects will start the study according to a specific “scenario”.  This 
depends on when their Visit 1 occurs in relation to the Visit 14 of the MEA115661 study. 
Scenario 1 is when Visit 1 of 201312 is performed on the same day (or less than or equal 
to 8 weeks) from when Visit 14 of study MEA115661 is performed. 
Scenario 2a is when Visit 1 of 201312 is performed greater than 8 weeks after Visit 14 
of MEA115661 AND when Visit 1 of 201312 is performed on the same day as the 
Follow-up visit (Visit 15) of study MEA115661. 
Scenario 2b is when Visit 1 of 201312 is performed greater than 8 weeks after Visit 14 
of MEA115661 AND Visit 1 of 201312 is performed after the Follow-up visit (Visit 15) 
of study MEA115661 has taken place.
All applicable procedures for scenario 1, and 2a and 2b subjects are listed in Section 6.1. 
Critical Baseline Assessments.  
All eligible subjects should be enrolled into 201312 within 4 weeks of receiving all 
applicable approvals.


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After giving informed consent for this study, eligibility will be assessed via multiple 
evaluations, including physical examination, vital signs, electrocardiogram (ECG), and 
an updated medical history. Subjects whose health status remains appropriate for the 
study will then be assessed based on the inclusion and exclusion criteria. Those subjects 
meeting all of the eligibility requirements will receive their first dose of mepolizumab at 
Visit 1. Mepolizumab will be administered approximately every 4 weeks with the last 
dose at Week 168 (Visit 43).  Forty three doses will provide therapeutic coverage for 172
weeks (4 weeks following the last dose). Subjects will then continue to receive 
mepolizumab 100mg SC injections for up to 172 weeks or until one of the following 
occurs: 

the risk/benefit profile for the subject is no longer positive in the opinion of 
the investigator or

the subject’s physician withdraws the subject or

the subject withdraws consent or

the sponsor discontinues development of mepolizumab or

the sponsor discontinues the study in the relevant participating country or

mepolizumab becomes commercially available in the local country.
The study closure process will begin, on a country by country basis, as mepolizumab 
becomes commercially available for prescription.  Some subjects will complete the 
original 120 week treatment period (as specified in the previous protocol) prior to 
mepolizumab being available for prescription.  To ensure these subjects do not have a 
treatment gap the treatment period will be extended for an additional 52 weeks to a total 
of 172 weeks.
Subjects will remain on standard of care asthma therapy throughout the study. Asthma 
medication may be adjusted at any time during the study at the discretion of the 
investigator. All changes in asthma therapy will be captured in the source documents and 
the electronic case report form (eCRF). At each clinic visit, adverse events will be 
assessed and subjects will be questioned regarding the occurrence of any exacerbations 
since their last clinic visit. The Asthma Control Questionnaire-5 (ACQ-5) will be 
performed every 12 weeks during the study and at the Exit/Early Withdrawal Visit to 
assist the investigator in monitoring the subject’s asthma status along with spirometry 
assessments every 6 months and at the Exit/Early Withdrawal Visit. 
Safety labs (hematology, chemistry, liver analytes) will be drawn at Visit 1 and then 
approximately every 6 months thereafter. Hematology and chemistry labs will also be 
obtained 4 weeks after the last dose of mepolizumab. Serum samples for anti-
mepolizumab antibody measurements will also be obtained from subjects at baseline 
(Visit 1), Weeks 48, 96 144 and at the Exit Visit/Early Withdrawal Visit. Any serum 
sample testing positive for anti-mepolizumab antibody will also be tested for neutralizing 
antibody. Subjects discontinuing mepolizumab treatment will be monitored for 
exacerbation of their asthma during the subsequent 4 weeks after their last dose.


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Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Procedures Manual (SPM). The SPM will provide 
the site personnel with administrative and detailed technical information that does not 
impact subject safety.
3.2.
Discussion of Design
The design for this study is an open-label continuation of treatment to allow and 
characterize longer-term experience in subjects with severe asthma who completed the 
MEA115661 study (through Visit 14). Subjects must have a history of life-threatening 
asthma and received significant clinical benefit from mepolizumab for one year or more. 
As mepolizumab is administered approximately every 4 weeks, this design will achieve 
the objectives of the study by providing appropriate monitoring and data capture at each 
visit. 
The dose for Study 201312, mepolizumab 100mg SC, will be a continuation of the same 
dose administered in MEA115661. The dose rationale for the mepolizumab 100mg SC 
dose is based on the efficacy and safety profile observed in the MEA112997 study and is 
additionally supported by a PK/PD model developed for mepolizumab. The MEA112997 
study investigated a 10-fold dose range with doses of 75mg, 250mg, and 750mg 
administered intravenously (IV) every 4 weeks. All three doses resulted in a clinically 
significant reduction in the frequency of severe exacerbations when compared to placebo, 
with a reduction of 48% occurring in the 75mg treatment arm. These three doses also 
produced a marked and sustained suppression of blood eosinophils throughout the dose 
interval with a similar safety profile across all treatment arms [Clinical Investigator’s 
Brochure [CIB], GlaxoSmithKline Document Number CM2003/00010/07]. 
The mepolizumab PK/PD model, developed from 5 prior asthma studies and 1 healthy 
volunteer study, included 2 studies of mepolizumab administered subcutaneously. This 
model described the relationship between plasma mepolizumab concentrations and 
eosinophil counts (irrespective of the route of administration) by an IC50 of 226ng/mL 
[CIB, GlaxoSmithKline Document Number CM2003/00010/07]. (IC50 is the half-
maximal inhibitory concentration or the concentration at which 50% of the eosinophil 
population is inhibited.) Based on prior PK studies, the bioavilability of mepolizumab has 
been determined to be approximately 75% and 71% when administered SC into the upper 
arm and thigh, respectively [GlaxoSmithKline Document Number CM2003/00010/07].
Therefore, a dose of 100mg SC is anticipated to provide similar exposure to the 75mg IV 
dose studied in MEA112997. Additionally, this dose will provide plasma concentrations 
of mepolizumab well above the IC50 for the entire dosage interval. 
Further details on the PK/PD model can be in found in the CIB [GlaxoSmithKline 
Document Number CM2003/00010/07].


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4.
SUBJECT SELECTION AND WITHDRAWAL CRITERIA
4.1.
Number of Subjects
Approximately 375 subjects are estimated to be eligible to take part in this study. As the 
study is open-label, no randomization will occur. Attrition/withdrawal is expected to be 
less than 10% of enrolled subjects. 
4.2.
Inclusion Criteria
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the Clinical Investigator’s 
Brochure [GlaxoSmithKline Document Number CM2003/00010/07].
Deviations from inclusion criteria are not allowed because they can potentially jeopardise 
the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential.  
Subjects eligible for enrolment in the study must additionally meet all of the following 
criteria:
1.
Informed Consent: Prior to commencing any study related activities, subjects must 
be able and willing to provide written informed consent.
2.
Male or Eligible Female Subjects:
To be eligible for the study, females of child-bearing potential must commit to 
consistent and correct use of an acceptable method of birth control and for 4 months 
after the last study drug administration. Methods of acceptable birth control and the 
definitions for child-bearing and non-child bearing potential are provided in 
Appendix 2.
A urine pregnancy test is required of all females of childbearing potential at the   
initial Baseline Visit (Visit 1). 
3.
French Subjects Only: In France, a subject will be eligible for inclusion in this 
study only if either affiliated to or a beneficiary of a social security category.
4.
MEA115661 Participation: Subjects must have completed Visit 14 of MEA115661.
5.
Current Anti-Asthma Therapy: The subject’s asthma has been treated with an ICS 
controller medication for the last 8 months with fluticasone propionate (FP) ≥500 
mcg/day (or equivalent).
6.
Disease Severity: Subjects must be assessed as having life-threatening asthma or 
serious debilitating asthma in order to enroll.  
Life threatening asthma is defined by the following: 
Subjects enrolled in MEA115588 must meet one of the following criteria:
a) Subject has a history of at least one intubation during their lifetime 


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b) ≥3 asthma exacerbations in the 12 months prior to screening for MEA115588
c) ≥1 or more hospitalization for asthma exacerbation in the 12 months prior to 
screening for MEA115588. 
Subjects enrolled in MEA115575 must meet one of the following criteria:
d) Subject has a history of at least one intubation during their lifetime 
e) Their optimized dose at randomization in MEA115575 was ≥10mg of 
prednisone 
f)
≥1 or more hospitalization for asthma exacerbation in the 12 months prior to 
screening for MEA115575
Those subjects that do not meet the definition of potentially life threatening asthma 
must be assessed as having serious debilitating asthma.   
Subjects enrolled in MEA115588 or MEA115575 must meet the following criteria:
At randomisation of MEA115588 or MEA115575 must have:
g) A % predicted FEV1 of ≤50% and either
h) ACQ5 score of ≥3 or
i)
SGRQ score of ≥60 
7.
Clinical Benefit: Subjects must have experienced documented clinical benefit to 
enroll. Subjects must meet the following criteria demonstrating clinical benefit:
Subjects enrolled in MEA115588 who received mepolizumab must meet all of the 
following criteria:
a) Subject must have had a reduction in their exacerbation frequency by ≥50% 
during MEA115588. The baseline for comparison is the total number of 
exacerbations reported in the 12 months prior to screening for MEA115588.
b) The investigator confirms that the subject demonstrated improvement during 
MEA115588. 
Subjects enrolled in MEA115588 who received placebo must meet all of the 
following criteria:
c) Subject must have had a reduction in their exacerbation frequency by ≥50% 
during the first 8 months of MEA115661. The baseline for comparison is the total 
number of exacerbations reported in the 12 months prior to screening for 
MEA115588.
d) The investigator confirms that the subject demonstrated improvement during 
MEA115661 


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Subjects enrolled in MEA115575 who received mepolizumab must meet all of the 
following criteria:
e) Subject must have reduced their oral corticosteroid dose by ≥ 50% during 
MEA115575. The baseline for comparison is the subject’s optimized OCS dose at 
randomization in MEA115575
f)
The investigator confirms that the subject demonstrated improvement during 
MEA115575. 
Subjects enrolled in MEA115575 who received placebo must meet all of the 
following criteria:
g) Subject must have reduced their oral corticosteroid dose at randomization by 
≥50% in the first 6 months of MEA115661. The baseline for comparison is the 
subject’s optimized OCS dose at randomization in MEA115575.
h) The investigator confirms that the subject demonstrated improvement during 
MEA115661. 
8.
Subjects at Significant Safety Risk: If either criteria 6 or 7 are not met, subjects 
who are considered to be at risk of experiencing a life-threatening event, or whose 
functional health status will become significantly worse if returned to standard of 
care, as judged by the investigator and agreed by GSK.
4.3.
Exclusion Criteria
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardise the scientific integrity of the study, regulatory acceptability or subject safety. 
Therefore, adherence to the criteria as specified in the protocol is essential. 
Subjects meeting any of the following criteria must not be enrolled in the study:
1. Health Status: Clinically significant change in health status during MEA115661 
which in the opinion of the investigator would make the subject unsuitable for 
participation in this long-term study.
2. Pregnancy: Subjects who are pregnant or breastfeeding. Subjects should not be 
enrolled if they plan to become pregnant during the time of study participation.
3. Exacerbation History: Subjects who received placebo in MEA115588 and had NO 
exacerbations during the study.
4. Oral Corticosteroid Use: Subjects who received placebo in MEA115575 and were 
able to discontinue oral corticosteroid therapy by the end of the study.
5. Smoking Status: Current smokers
6. Previous Significant Protocol Deviation: Subjects who were excluded from the per 
protocol analysis due to a significant protocol deviation in either study MEA115575 


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or MEA115588 which is deemed by the GSK Medical Monitor to put the subject at 
risk from further participation.
7. ECG Assessment: A clinically significant ECG abnormality as determined by the 
investigator.
4.4.
Withdrawal Criteria
4.4.1.
Subject Compliance with Visit Schedule
Should a subject fail to attend the clinic for a required study visit, the site should attempt 
to contact the subject and re-schedule the missed visit as soon as possible. The site should 
also 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 based 
on previous non-compliance. 
4.4.2.
Lost To Follow-Up
In cases where the subject does not return for the rescheduled visit or cannot be reached 
to reschedule the missed visit, the site should make every effort to regain contact with the 
subject (3 telephone calls and, if necessary, a letter to the subject’s last known mailing 
address) so that they can appropriately be withdrawn from the study. These contact 
attempts should be documented in the subject’s medical record. Should the subject 
continue to be unreachable, then and only then will he/she be considered to have 
withdrawn from the study with a primary reason of “Lost to Follow-up”. For all other 
subjects withdrawing from the study, an alternative reason for discontinuation should be 
recorded in the eCRF.
4.4.3.
Withdrawal By Investigator
4.4.3.1.
General Withdrawal Requirements
Subjects may be withdrawn from study treatment at anytime by the investigator if it is 
deemed detrimental for them to continue in the study. Reasons for withdrawal can 
include: an adverse event, lost to follow-up, protocol violation, lack of efficacy, sponsor 
terminated study, non-compliance, abnormal laboratory results (Section 6.3.3), or for any 
other reason. 
Subjects may also be withdrawn from this study if mepolizumab becomes commercially 
available in the respective country, if marketing of mepolizumab is no longer being 
sought in the respective country, or upon decision of the sponsor to discontinue further 
development of mepolizumab. Every effort should be made to have the subject complete 
the Exit/Early Withdrawal Visit.
A subject must be permanently discontinued from IP if any of the following stopping 
criteria are met: 

Liver Chemistry: Meets any of the protocol-defined liver chemistry stopping 
criteria (Section 11.4). 


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
Pregnancy: Positive pregnancy test
4.4.3.1.1.
ECGs
Discontinuation is required if any of the following ECG criteria are met during the study:

QTcF >500 msec

Uncorrected QT >600 msec
These criteria should be based on the average QTc(F) value of triplicate ECGs. For 
example, if an ECG demonstrates a prolonged QT interval, obtain two more ECGs over a 
brief period, and then use the averaged QTc(F) values of the three ECGs to determine 
whether the patient should be discontinued from the study. 
For subjects with underlying Bundle Branch Block: 
Baseline QTc(F) with Bundle Branch Block
Discontinuation QTc(F) with Bundle Branch 
Block
<450 msec
>500 msec
450-480 msec
530 msec
4.4.3.1.2.
Other Basis for Withdrawal
Subjects may also be withdrawn from the study if mepolizumab becomes commercially 
available in the respective country or upon decision of the sponsor to discontinue further 
development of mepolizumab in the respective country.
4.4.4.
Subject Self-Withdrawal
Subjects are free to discontinue participation in the study at anytime. Every effort should 
be made to have the subject return for an Exit/Early Withdrawal visit 4 weeks post last 
mepolizumab injection. In those instances where the subject specifies the reason for 
withdrawal of consent, this information will be captured in the eCRF.
4.4.5.
Withdrawal Documentation
The primary reason for withdrawal will be recorded in the eCRF and any data collected 
up until the point of withdrawal will be used in the data analyses. A subject should only 
be designated as lost to follow-up if the site is unable to establish contact with the subject 
after 3 documented attempts via 2 different methods (phone, text, e-mail, certified letter, 
etc). These efforts should be documented in the clinic notes at the site. For those subjects 
that are lost to follow-up, every effort will be made to contact the subject to assure their 
safety.


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5.
STUDY TREATMENTS
5.1.
Investigational Product
Mepolizumab (SB-240563) is a fully humanised IgG antibody (IgG1, kappa) with human 
heavy and light chain frameworks. Mepolizumab will be provided as a lyophilised cake 
in sterile vials for individual use. The contents of the label will be in accordance with all 
applicable regulatory requirements.
5.1.1.
Medication Preparation and Handling
The vial will be reconstituted with Sterile Water for Injection, just prior to use. Details 
for dose preparation and administration of mepolizumab for injection 100mg/vial are 
provided in the Study Procedures Manual (SPM).
Under normal conditions of handling and administration, investigational product 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. Notify the monitor of 
any unintentional occupational exposure. A Material Safety Data Sheet (MSDS) 
describing the occupational hazards and recommended handling precautions will be 
provided to site staff if required by local laws or will otherwise be available from GSK 
upon request.
5.1.2.
Storage
Mepolizumab must be stored in a refrigerator or at a temperature of 2-8C and protected 
from light. Maintenance of a temperature log (manual or automated) is required. 
Investigational product must be stored in a secure area under the appropriate physical 
conditions for the product. Access to and administration of the investigational product 
will be limited to the investigator and authorised site staff. Investigational product must 
be dispensed or administered only to subjects enrolled in the study and in accordance 
with the protocol.
5.2.
Dosage and Administration
Prior to administration, each vial of mepolizumab will need to be reconstituted and 
swirled gently to enable complete dissolution of the product. Detailed instructions can be 
found within the SPM.
Once the mepolizumab vial is reconstituted, 100mg of mepolizumab should be drawn 
into a polypropylene syringe and administered according to the instructions in the SPM. 
The dose may be given subcutaneously in the upper arm or thigh. The administration site 
should be documented for each dose given.
Safety monitoring of subjects will be according to local site policy. Such monitoring will 
include general safety monitoring including monitoring for both systemic (i.e., allergic 
and non-allergic) and local injection-site reactions. Trained rescue personnel and rescue 
medications/equipment must be available for use at all times. 


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5.3.
Treatment Assignment
All subjects will receive mepolizumab 100mg administered subcutaneously into the 
upper arm or thigh approximately every 4 weeks.
5.4.
Blinding
This will be an open-label study.
5.5.
Product Accountability
In accordance with local regulatory requirements, the investigator, designated site staff, 
or head of the medical institution (where applicable) must document the amount of 
investigational product dispensed and/or administered to study subjects, the amount 
returned by study subjects (where applicable), and the amount received from and returned 
to GSK, when applicable. Product accountability records must be maintained throughout 
the course of the study.
5.6.
Treatment Compliance
All doses administered within the study will be administered under the supervision of the 
investigator or appropriately qualified designee (e.g., study nurse). 
Drug dispensing/accountability logs will be maintained by a member of the study team 
designated by the Investigator.
5.7.
Concomitant Medications and Non-Drug Therapies
5.7.1.
Permitted Medications and Non-Drug Therapies
Subjects will be required to continue ICS controller therapy for the duration of this study. 
For corticosteroids, the dose must be recorded as well as any dose changes
Details of asthma-related concomitant medications administered from the first dose of 
mepolizumab in 201312 until the Exit/Early Withdrawal visit or last subject visit will be 
recorded in the electronic case report form (eCRF). In addition, any asthma-related 
medications started prior to first dose in 201312, but were ongoing during the first dose 
will also be recorded. The minimum requirement is that drug name, unit dose, and the 
dates of administration are to be recorded.


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Details of  non-asthma-related concomitant medications administered from the first dose 
of mepolizumab in 201312 until the Exit/Early Withdrawal visit or last subject visit will 
be recorded in the electronic case report form (eCRF).Additional medications to treat 
asthma are permitted, as are medications to treat other disease states, with the exception 
of those listed as prohibited in Table 2. Oxygen and Continuous Positive Airway Pressure 
(CPAP) are permitted for the treatment of obstructive sleep apnea.
5.7.2.
Prohibited Medications
Table 2 lists those medications that are prohibited from use during the study.
Table 2
Prohibited Medications
Medication

Investigational drugs other than mepolizumab

Experimental anti-inflammatory drugs (non biologicals)

Immunosuppressive medications1

Methotrexate, troleandomycin, cyclosporin, azathioprine 

Oral gold

Chemotherapy used for conditions other than asthma

Regular systemic (oral or parenteral) corticosteroids for the treatment of conditions 
other than asthma or for treatement of hypoadrenalism
1.
The list of immunosuppressives provided contains commonly used example medications. The list is not all-
inclusive and other known immunosuppressive medications not listed are also prohibited.
5.8.
Treatment after the End of the Study
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the patient’s medical condition whether or not GSK is providing specific 
post study treatment. 
5.9.
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.
STUDY ASSESSMENTS AND PROCEDURES
The Time and Events Table is provided in Appendix 1. 
6.1.
Critical Baseline Assessments
Baseline assessments performed for scenario 1 subjects in study 201312:
1. Demographic information review and update for 201312


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2. General medical history review and update in 201312
3. Physical examination and update in 201312
4. Assessment of Inclusion/Exclusion criteria. 
5. Urine pregnancy test for females of childbearing potential (Appendix 2: 
Acceptable Birth Control)
Baseline assessments performed for scenario 2a subjects in study 201312:
1. Demographic information review and update for 201312
2. General medical history review and update in 201312
3. Physical examination and update in 201312
4. Pulmonary function tests and assessment 
5. Assessment of Inclusion/Exclusion criteria. 
6. Urine pregnancy test for females of childbearing potential (Appendix 2: 
Acceptable Birth Control)
For scenario 2b subjects in study 201312, the following assessments should be 
performed:
1. Demographic information review and update for 201312
2. General medical history review and update in 201312
3. Physical examination and update in 201312
4. Pulmonary function tests and assessment 
5. Assessment of Inclusion/Exclusion criteria. 
6. Asthma Control Questionnaire-5 (Section 6.2.1.2)
7. Vital signs (Section 6.3.10.3)
8. 12-lead ECG (Section 6.3.10.4)
9. Blood sampling for the following:

Clinical chemistry 

Hematology

Liver Analytes

Immunogenicity
10. Urine pregnancy test for females of childbearing potential (Appendix 2: 
Acceptable Birth Control)
Please see the SPM for more detail around the required baseline assessments.


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6.2.
Efficacy Endpoints

Annualized rate of exacerbations

Asthma Control Questionnaire-5 score

Forced expiratory volume in 1 second (FEV1) 
6.2.1.
Efficacy Data Capture/Instruments
6.2.1.1.
Exacerbations
Subjects will be questioned at each visit regarding the occurrence of any exacerbations 
since their last visit. Numerical occurrences will be captured via the eCRF. 
Exacerbations will be defined as worsening of asthma which requires use of systemic 
corticosteroids and/or hospitalisation and/or Emergency Department (ED) visits.
For all subjects, use of systemic corticosteroids is defined as IV or oral steroids (e.g., 
prednisone) for at least 3 days or a single intramuscular (IM) CS dose. For subjects on 
maintenance systemic corticosteroids, use of systemic corticosteroids is defined as at 
least double the existing maintenance dose for at least 3 days. 
Exacerbations where the courses of systemic CS are separated by <7 days will be 
considered as one exacerbation for consistency across the program.
6.2.1.2.
Asthma Control Questionnaire-5 (ACQ-5)
The ACQ-5 is a five-item questionnaire used to measures a subject’s asthma control that 
can be quickly and easily completed [Juniper, 2005]. The questions are designed to be 
self-completed by the subject. The five questions enquire about the frequency and/or 
severity of symptoms (nocturnal awakening on waking in the morning, activity 
limitation, and shortness of breath, wheeze). The response options for all these questions 
consist of a zero (no impairment/limitation) to six (total impairment/ limitation) scale.
The ACQ-5 will be administered at Visit 1 and approximately every 12 weeks afterwards. 
It is recommended that the ACQ-5 be administered at the same time during each visit. To 
avoid biasing responses, the subjects should not be told the results of diagnostic tests 
prior to completing the questionnaire and should be completed before any procedures are 
performed on the subject to avoid influencing the subject’s response. Adequate time 
should be allowed to complete all items on the ACQ-5. The questionnaire will be 
administered every 12 weeks throughout the study. 
6.2.1.3.
Pulmonary Function Testing
Spirometry to assess subjects’ FEV1 will be performed approximately every 24 weeks 
beginning at Visit 1 using the site’s own equipment (Appendix 1 Time and Events 
Table). The spirometer should meet American Thoracic Society standards and produce a 
printout of all data generated, which should be stored in the subject’s notes. The 
spirometer should be calibrated in accordance with the manufacturer’s instructions and a 


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calibration log maintained. Spirometry should be performed within 1 hour of the 
baseline assessment. Subjects should try to withhold short-acting beta2-agonists (SABA) 
for ≥6 hours and LABAs for 12 hours prior to clinic visit, if possible. Assessments to be 
recorded will include FEV1 and forced vital capacity (FVC).
6.3.
Safety

Incidence of adverse events including systemic (i.e., allergic/IgE mediated and non-
allergic) and local site injection-related reactions reported throughout the treatment 
period.
o
Systemic reactions can be allergic or non-allergic in nature and are typically mild 
to moderate in intensity, generally develop within several hours of the injection, 
and are most commonly associated with a complex of symptoms including chills, 
fever, nausea, vomiting, asthenia, headache, skin rash, pruritus, urticaria, 
arthralgia/myalgia, hypotension/hypertension, dizziness, bronchospasm, dyspnea 
or cough. 
o
Anaphylaxis, the most severe form of hypersensitivity reactions will be assessed 
using the diagnostic criteria outlined by the 2006 Joint NIAID/FAAN Second 
Symposium on Anaphylaxis [Sampson, 2006; Appendix 6 Anaphylaxis Criteria].

A 12-lead ECG will be performed to derive the following endpoints:
o
Mean change from baseline in the QTc(F) (QT interval corrected by Friderica’s 
method) 
o
Mean change from baseline in QTc(B) (QT interval corrected by Bazett's method)
o
Maximum change from baseline for QTc(F) and QTc(B)

Clinical laboratory parameters

Vital signs
6.3.1.
Liver Chemistry Stopping and Follow-Up Criteria
6.3.1.1.
Criteria for Liver Chemistry Stopping
Phase III-IV liver chemistry stopping and follow up criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). 


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Phase III-IV liver chemistry stopping criteria 1-5 are defined below and are 
presented in a figure in Appendix 4:
Criterion 1:
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) (or ALT 
3xULN and INR>1.5, if INR measured)
NOTE: if serum bilirubin fractionation is not immediately available, 
withdraw study drug for that subject if ALT 3xULN and bilirubin 
2xULN. Serum bilirubin fractionation should be performed if testing is 
available. If testing is unavailable, record presence of detectable 
urinary bilirubin on dipstick, indicating direct bilirubin elevations and 
suggesting liver injury.
Criterion 2:
ALT 8xULN.
Criterion 3:
ALT 5xULN but <8 xULN persists for 2 weeks
Criterion 4:
ALT 3xULN if associated with symptoms (new or worsening) believed 
to be related to hepatitis (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or hypersensitivity (such as 
fever, rash or eosinophilia).
Criterion 5:
ALT 5xULN but <8 xULN and cannot be monitored weekly for 2 
weeks
6.3.1.2.
Actions
When any of the liver chemistry stopping Criteria 1-5 is met, do the following:

Immediately withdraw investigational product for that subject

Report the event to GSK within 24 hours of learning its occurrence

Complete the liver event CRF and SAE data collection tool if the event also meets
the criteria for an SAE. All events of ALT 3xULN and bilirubin 2xULN (>35% 
direct) (or ALT   3xULN and INR>1.5, if INR measured); INR measurement is not 
required and the threshold value stated will not apply to patients receiving 
anticoagulants), termed ‘Hy’s Law’, must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis). 
NOTE: if serum bilirubin fractionation is not immediately available, withdraw study 
drug for that subject if ALT    3xULN and bilirubin   2xULN. Serum bilirubin 
fractionation should be performed if testing is available. If testing is unavailable, 
record presence of detectable urinary bilirubin on dipstick, indicating direct 
bilirubin elevations and suggesting liver injury.

Complete the liver imaging and/or liver biopsy CRFs if these tests are performed

Perform liver event follow up assessments, and monitor the subject until liver 
chemistries resolve, stabilise, or return to baseline values as described below. 


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
Withdraw the subject from the study (unless further safety follow-up is required) 
after completion of the liver chemistry monitoring as described 

Do not restart investigational product unless written approval for drug restart is 
granted by GSK Medical Governance (Section 6.3.1.4).
In addition, for Criterion 1:

Make every reasonable attempt to have subjects return to clinic within 24 hours for 
repeat liver chemistries, liver event follow up assessments (see below), and close 
monitoring

A specialist or hepatology consultation is recommended

Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) resolve, stabilise or return to within baseline values
For Criteria 2, 3, 4 and 5:

Make every reasonable attempt to have subjects return to clinic within 24-72 hrs for 
repeat liver chemistries and liver event follow up assessments (see below)

Monitor subjects weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilise or return to within baseline values; criterion 5 subjects 
should be monitored as frequently as possible.
Subjects with ALT 5xULN and <8xULN which exhibit a decrease to ALT x3xULN, 
but <5xULN and bilirubin <2xULN without hepatitis symptoms or rash, and who can be 
monitored weekly for 4 weeks:

Notify the GSK medical monitor within 24 hours of learning of the abnormality to 
discuss subject safety

Can continue investigational product 

Must return weekly for repeat liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to within baseline 

If at any time these subjects meet the liver chemistry stopping criteria, proceed as 
described above

If, after 4 weeks of monitoring, ALT <3xULN and bilirubin <2xULN, monitor 
subjects twice monthly until liver chemistries normalise or return to within baseline 
values. 
6.3.1.3.
Follow-Up Assessments
For Criteria 1-5, make every attempt to carry out the liver event follow up assessments
described below:

Viral hepatitis serology including:


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
Hepatitis A IgM antibody;

Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); 

Hepatitis C RNA; 

Cytomegalovirus IgM antibody; 

Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing); 

Hepatitis E IgM antibody 

Blood sample for PK analysis, obtained within 4 weeks of last dose. Record the 
date/time of the PK blood sample draw and the date/time of the last dose of 
investigational product prior to blood sample draw on the CRF. If the date or time of 
the last dose is unclear, provide the subject’s best approximation. If the date/time of 
the last dose cannot be approximated OR a PK sample cannot be collected in the 
time period indicated above, do not obtain a PK sample. Instructions for sample 
handling and shipping are in the SPM. 

Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total bilirubin   2xULN.

Obtain complete blood count with differential to assess eosinophilia.

Record the appearance or worsening of clinical symptoms of hepatitis or 
hypersensitivity, such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever rash or eosinophilia as relevant on the AE report form.

Record use of concomitant medications, acetaminophen, herbal remedies, other over 
the counter medications, or putative hepatotoxins, on the concomitant medications 
report form.

Record alcohol use on the liver event alcohol intake case report form.
The following are required for subjects with ALT 3xULN and bilirubin 2xULN 
(>35% direct) but are optional for other abnormal liver chemistries:

Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney 
microsomal antibodies and quantitative total immunoglobulin G (IgG or gamma 
globulins).

Serum acetaminophen adduct HPLC assay (quantifies potential acetaminophen 
contribution to liver injury in subjects with definite or likely acetaminophen use in 
the preceding week. 

Only in those with underlying chronic hepatitis B at study entry (identified by 
positive hepatitis B surface antigen): quantitative hepatitis B DNA and hepatitis delta 
antibody. NOTE: if hepatitis delta antibody assay cannot be performed,, it can be 
replaced with a PCR of hepatitis D RNA virus (where needed) [Legal, 2005].

Liver imaging (ultrasound, magnetic resonance, or computerised tomography) to 
evaluate liver disease.


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6.3.1.4.
Restarting Investigational Product
6.3.1.4.1.
Drug Restart/Rechallenge Following Liver Events that are Possibly 
Related to IP
Approval by GSK for drug restart can be considered where:

The subject is receiving compelling benefit, benefit of drug restart exceeds risk, and 
no effective alternative therapy is available. Ethics Committee or Institutional 
Review Board approval of drug restart/rechallenge must be obtained, as required.

If the restart/rechallenge is approved by GSK in writing, the subject must be 
provided with a clear description of the possible benefits and risks of drug 
administration, including the possibility of recurrent, more severe liver injury or 
death. 

The subject must also provide signed informed consent specifically for the IP 
restart/rechallenge. Documentation of informed consent must be recorded in the 
study chart. 

Study drug must be administered at the dose specified by GSK.

Subjects approved by GSK for restart/rechallenge of IP must return to the clinic 
twice a week for liver chemistry tests until stable, liver chemistries have been 
demonstrated and then laboratory monitoring may resume as per protocol. 
6.3.1.4.2.
Drug Restart Following Transient Resolving Liver Events Not Related 
to IP
Approval by GSK for drug restart can be considered where:

Liver chemistries have a clear underlying cause (e.g., biliary obstruction, 
hypotension and liver chemistries have improved to normal or are within 1.5 x 
baseline and ALT <3xULN). Ethics Committee or Institutional Review Board 
approval of drug restart/rechallenge must be obtained, as required.

If restart of drug is approved by GSK in writing, the subject must be provided with a 
clear description of the possible benefits and risks of drug administration, including 
the possibility of recurrent, more severe liver injury or death. 

The subject must also provide signed informed consent specifically for the restart. 
Documentation of informed consent must be recorded in the study chart. 

Study drug must be administered at the dose specified by GSK.

Subjects approved by GSK for restarting IP must return to the clinic once a week for 
liver chemistry tests until stable, liver chemistries have been demonstrated and then 
laboratory monitoring may resume as per protocol. If protocol defined stopping 
criteria for liver chemistry elevations are met, study drug must be stopped.


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6.3.2.
Adverse Events
The investigator or site staff will be responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE.
6.3.2.1.
Definition of an AE
Any untoward medical occurrence in a patient or clinical investigation subject, 
temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product.
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product. For marketed medicinal products, this 
also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse.
Events meeting the definition of an AE include:

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study

Signs, symptoms, or the clinical sequelae of a suspected interaction

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE) unless this is an intentional overdose taken with possible suicidal/self-
harming intent. This should be reported regardless of sequelae.
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. However, the signs and symptoms and/or clinical sequelae 
resulting from lack of efficacy will be reported if they fulfil the definition of an AE or 
SAE. 
Events that do not meet the definition of an AE include:

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

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


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6.3.2.2.
Definition of an SAE
A serious adverse event is 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 hospitalisation or prolongation of existing hospitalisation
NOTE: In general, hospitalisation signifies that the subject has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward for
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting. Complications that occur during hospitalisation are AEs. 
If a complication prolongs hospitalisation or fulfills any other serious criteria, the 
event is serious. When in doubt as to whether “hospitalisation” occurred or was 
necessary, the AE should be considered serious.
Hospitalisation for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d. Results in disability/incapacity, or
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.
Is a congenital anomaly/birth defect
f.
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 hospitalisation but may jeopardise 
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 hospitalisation, or development of drug dependency 
or drug abuse.
g. All events of possible drug-induced liver injury with hyperbilirubinaemia defined as 
ALT 3xULN and bilirubin 2xULN (>35% direct) (or ALT 3xULN and 
INR>1.5, if INR measured) termed ‘Hy’s Law’ events (INR measurement is not 
required and the threshold value stated will not apply to patients receiving 
anticoagulants).
NOTE: bilirubin fractionation is performed if testing is available. If testing is 
unavailable, record presence of detectable urinary bilirubin on dipstick indicating 


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direct bilirubin elevations and suggesting liver injury. If testing is unavailable and a 
subject meets the criterion of total bilirubin 2xULN, then the event is still reported 
as an SAE. If INR is obtained, include values on the SAE form. INR elevations >1.5 
suggest severe liver injury.
6.3.2.3.
Sentinel Events
A Sentinel Event is a GSK-defined SAE that is not necessarily drug-related but has been 
associated historically with adverse reactions for other drugs and is therefore worthy of 
heightened pharmacovigilance. Medical monitor review of all SAEs for possible Sentinel 
Events is mandated at GSK. The GSK medical monitor may request additional clinical 
information on an urgent basis if a possible Sentinel Event is identified on SAE review. 
The current GSK-defined Sentinel Events are listed below:

Acquired Long QT Syndrome

Agranulocytosis/Severe Neutropenia 

Anaphylaxis & Anaphylactoid Reactions 

Hepatotoxicity

Acute Renal Failure

Seizure

Stevens Johnson syndrome/Toxic epidermal necrosis
6.3.3.
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs
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 are to be recorded as AEs or SAEs. 
However, any clinically significant safety assessments that are associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the subject’s condition, are not to be reported as AEs or SAEs.
6.3.4.
Cardiovascular Events
Investigators will be required to fill out event specific data collection tools for the 
following AEs and SAEs: 

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension


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
Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularisation
This information should be recorded in the specific cardiovascular eCRF within one week 
of when the AE/SAE(s) is/are first reported.
6.3.5.
Death Events
In addition, all deaths will require a specific death data collection tool to be completed. 
The death data collection tool includes questions regarding cardiovascular (including 
sudden cardiac death) and noncardiovascular death.
This information should be recorded in the specific death eCRF within one week of when 
the death is first reported.
6.3.6.
Pregnancy
A urine pregnancy test will be performed for all females of child bearing potential prior 
to enrollment, during each scheduled study visit prior to the injection of investigational 
product, and during the Exit/Early Withdrawal Visit.
Any pregnancy that occurs during study participation must be reported using a clinical 
trial pregnancy form. To ensure subject safety, each pregnancy must be reported to GSK 
within 2 weeks of learning of its occurrence. The pregnancy must be followed up to 
determine outcome (including premature termination) and status of mother and child. 
Pregnancy complications and elective terminations for medical reasons must be reported 
as an AE or SAE. Spontaneous abortions must be reported as an SAE.
Any SAE occurring in association with a pregnancy, brought to the investigator’s 
attention after the subject has completed the study and considered by the investigator as 
possibly related to the study treatment, must be promptly reported to GSK.
6.3.7.
Time Period and Frequency of Detecting AEs and SAEs
The investigator or site staff is responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE.
AEs will be collected from the start of study treatment and until the follow up contact. 
SAEs will be collected over the same time period as stated above for AEs. However, any 
SAEs assessed as related to study participation (e.g., study treatment, protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK concomitant 
medication, will be recorded from the time a subject consents to participate in the study 
up to and including any follow up contact. All SAEs will be reported to GSK within 24 
hours, as indicated in Section 6.3.9. 


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6.3.8.
Method of Detecting AEs and SAEs
Care must be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence. Appropriate questions include:
“How are you feeling?” or for paediatric studies, “How does your child seem to feel?”
“Have you had any (other) medical problems since your last visit/contact?” or for 
paediatric studies, “Has your child had any (other) medical problems or seem to act 
differently in any way since his/her last visit/contact?”
“Have you taken any new medicines, other than those provided in this study, since your 
last visit/contact?” or for paediatric studies, ”Has your child needed to take any 
medicines, other than those provided in this study, since his/her last visit/contact?”
6.3.9.
Prompt Reporting of Serious Adverse Events and Other Events 
to GSK
SAEs, pregnancies, medical device incidents, and liver function abnormalities meeting 
pre-defined criteria will be reported promptly by the investigator to GSK as described in 
the following table once the investigator determines that the event meets the protocol 
definition for that event.
The investigator is obligated to assess the relationship between investigational product 
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 
conclusion that a relationship to the investigational product 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 investigational product will be 
considered and investigated. The investigator will also consult the Investigator Brochure 
(IB) to assist in the determination of his/her assessment.


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Initial Reports
Follow-up Information on a Previous 
Report
Type of Event
Time Frame
Documents
Time Frame
Documents
All SAEs
24 hours
“SAE” data 
collection tool
24 hours
Updated “SAE” 
data collection tool
Cardiovascular or 
death event
Initial and 
follow up 
reports to be 
completed 
within one 
week of when 
the 
cardiovascular 
event or death 
is reported 
“CV events” 
and/or “death” 
data collection 
tool(s) if 
applicable
Initial and follow 
up reports to be 
completed within 
one week of when 
the cardiovascular 
event or death is 
reported
Updated “CV 
events” and/or 
“death” data 
collection tool(s) if 
applicable
Pregnancy
2 weeks
“Pregnancy 
Notification Form”
2 weeks
“Pregnancy Follow-
up Form”
Liver chemistry abnormalities for Phase I to IV:
ALT3xULN and
Bilirubin2xULN 
(>35% direct) (or 
ALT3xULN and
INR>1.5, if INR 
measured)1
24 hours2
“SAE” data 
collection tool. 
“Liver Event CRF” 
and “Liver 
Imaging” and/or 
“Liver Biopsy” 
CRFs, if 
applicable3
24 hours
Updated “SAE” 
data collection 
tool/“Liver Event” 
Documents3
Remaining liver chemistry abnormalities Phase III to IV:
ALT8xULN; 
ALT3xULN with 
hepatitis or rash or 
3xULN and <5xULN 
that persists4 
weeks
24 hours2
“Liver Event” 
Documents 
(defined above) 3
24 hours
Updated “Liver 
Event” Documents3


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Initial Reports
Follow-up Information on a Previous 
Report
Type of Event
Time Frame
Documents
Time Frame
Documents
ALT5xULN plus 
bilirubin <2xULN
24 hours2
“Liver Event” 
Documents 
(defined above) 
do not need 
completing unless 
elevations persist 
for 2 weeks or 
subject cannot be 
monitored weekly 
for 2 weeks3
24 hours
Updated “Liver 
Event” Documents, 
if applicable3
ALT5xULN and 
bilirubin <2xULN that 
persists 2 weeks
24 hours2
“Liver Event” 
Documents 
(defined above) 3
24 hours
Updated “Liver 
Event” Documents3
ALT3xULN and <5x 
ULN and bilirubin 
<2xULN
24 hours2
“Liver Event” 
Documents 
(defined above) 
do not need 
completing unless 
elevations persist 
for 4 weeks or 
subject cannot be 
monitored weekly 
for 4 weeks3
24 hours
Updated “Liver 
Event” Documents, 
if applicable3
1.
INR measurement is not required; if measured, the threshold value stated will not apply to patients receiving 
anticoagulants.
2.
GSK must be contacted at onset of liver chemistry elevations to discuss subject safety
3.
Liver Event Documents (i.e., “Liver Event CRF” and “Liver Imaging CRF” and/or “Liver Biopsy CRF”, as 
applicable) should be completed as soon as possible.
The method of recording, evaluating and follow-up of AEs and SAEs plus procedures for 
completing and transmitting SAE reports to GSK are provided in the SPM. Procedures 
for post-study AEs/SAEs are provided in the SPM.
6.3.9.1.
Regulatory Reporting Requirements for SAEs
Prompt notification of SAEs by the investigator to GSK is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects 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.


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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.
6.3.10.
Other Safety Outcomes
6.3.10.1.
Laboratory Assessments
All protocol required laboratory assessments, as defined in the Time and Events Table 
(Appendix 1 Time and Events Table), will be taken pre-dosing and will be sent to the 
central laboratory, Quest Diagnostics for analysis (details provided in the SPM). 
Laboratory assessments must be conducted in accordance with the Central 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 Quest Diagnostics. Reference ranges for all safety 
parameters will be provided to the site by Quest Diagnostics. The central laboratory will 
fax laboratory results to the Investigator and will transmit the results electronically to 
GSK.
At the discretion of the Investigator, additional samples may be taken for safety reasons. 
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in patient management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the subject’s CRF. Refer to the SPM for 
appropriate processing and handling of samples to avoid duplicate and/or additional 
blood draws.
6.3.10.2.
Physical Examination
A detailed physical examination including, but not limited to, an evaluation of the lungs 
and cardiovascular system will be conducted as outlined in Time and Events Table 
(Appendix 1 Time and Events Table). For the US, licensed practitioners who are listed on 
the Form 1572 can complete the physical examination. A licensed physician on the Form 
1572 must sign off on the physical examinations completed by non-physicians. In 
countries outside of the US, the physical examination should be conducted by a medically 
qualified person; however, if the physical examination is conducted by non-physicians, a 
medically qualified person must sign off. 
Results of the examinations will be recorded in the subject’s clinic notes. The same 
person should perform both examinations, if possible.


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6.3.10.3.
Vital Signs
Sitting pulse rate and blood pressure measurements will be performed by the investigator 
or qualified site staff as outlined in Time and Events Table (Appendix 1 Time and Events 
Table). Measurements will be done pre-injection with the subject sitting, having rested in 
this position for at least 5 minutes before each reading. They will be taken before 
measurement of any clinic lung function tests or ECGs at the specified time point.
At the baseline visit, height and weight will also be measured.
6.3.10.4.
Twelve-lead electrocardiogram
Twelve-lead ECGs will be performed at the visits specified in the Time and Events Table 
(Appendix 1 Time and Events Table). 
Investigators will be provided with ECG machines by GSK through a designated central 
laboratory. Paper ECG traces will be recorded at a standard paper speed of 25mm/sec and 
gain of 10mm/mV, with a lead II rhythm strip. There will be electronic capture and 
storage of the data by a validated method, with subsequent transferral to the central 
laboratory for manual reading and calculation of the electrocardiographic parameters. 
Paper traces are required to be maintained at the site with other source documents.
Electrocardiogram measurements will be made after the subject has rested in the supine 
position for 5 minutes. The ECG should be obtained before lung function testing 
followed by other study procedures. Collection shortly after a meal or during sleep should 
be avoided since QT prolongation can occur at these times.
6.4.
Immunogenicity
Blood samples will be collected for the determination of anti-mepolizumab antibodies 
just prior to administration of mepolizumab at the time points identified in the Time and 
Events Table (Appendix 1 Time and Events Table). Samples that test positive for anti-
mepolizumab antibodies will be further tested for the presence of neutralizing antibody.
7.
DATA MANAGEMENT
For this study, subject data will be entered into GSK defined electronic case report forms 
(eCRFs), 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 MedDRA and an internal validated medication dictionary, GSKDrug. 
An appropriate medical dictionary that covers all approved drugs in studies where Japan 
is participating will be referenced. eCRFs (including queries and audit trails) will be 
retained by GSK and copies will be sent to the investigator to maintain as the investigator 
copy. In all cases, subject initials will not be collected or transmitted to GSK according to 
GSK policy.


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8.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS
8.1.
Hypothesis
Because the study has a single treatment arm, statistical analyses of treatment effect will 
not be performed. Therefore no hypotheses have been defined for this study.
8.2.
Study Design Considerations
8.2.1.
Sample Size Assumptions
There is no sample size calculation for this study. The sample size will be determined by 
the number of available subjects who were enrolled into study MEA115661 and are 
eligible for the current study based on inclusion and exclusion criteria.
8.3.
Data Analysis Considerations
All pre-specified analyses will be described in a full Reporting and Analysis Plan (RAP) 
which will be finalised prior to database freeze.
8.3.1.
Analysis Populations
The All Subjects Enrolled population will comprise all subjects for whom a record exists 
on the database. 
The As Treated population will consist of all subjects who received at least one dose of 
open label mepolizumab within study 201312.
8.3.2.
Analysis Data Sets
All analyses will be performed using all available data as outlined in the Reporting and 
Analysis Plan.
8.3.3.
Treatment Comparisons
No treatment comparisons will be performed.
8.3.4.
Interim Analysis
Interim analysis will be performed as needed in order to provide open-label safety data to 
inform the risk-benefit assessment of mepolizumab in severe asthma.
8.3.5.
Key Elements of Analysis Plan
Details of the analysis plan will be fully described in the RAP.


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8.3.5.1.
Efficacy Analyses
All efficacy endpoints will be summarized using descriptive statistics. Further details will 
be provided in the RAP.
8.3.5.2.
Safety Analyses
All safety endpoints will be summarized using descriptive statistics. Further details will 
be provided in the RAP.
9.
STUDY CONDUCT CONSIDERATIONS
9.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrolment of subjects begins.
9.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a study site, GSK will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements.
The study will be conducted in accordance with ICH GCP, all applicable subject privacy 
requirements, and the ethical principles that are outlined in the Declaration of Helsinki 
2008, including, but not limited to:

Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review 
and favourable opinion/approval of study protocol and any subsequent 
amendments.

Subject informed consent.

Investigator reporting requirements.
GSK will provide full details of the above procedures, either verbally, in writing, or both.
Written informed consent must be obtained from each subject prior to participation in the 
study.
9.3.
Quality Control (Study Monitoring)
In accordance with applicable regulations, 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 include 


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identification, agreement and documentation of data items for which the CRF will serve 
as the source document.
GSK will monitor the study to ensure 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.
9.4.
Quality Assurance
To ensure compliance with GCP and all applicable regulatory requirements, GSK may 
conduct a quality assurance assessment and/or audit of the site records, and the regulatory 
agencies may conduct a regulatory inspection at any time during or after completion of 
the study. In the event of an assessment, audit or inspection, the investigator (and 
institution) must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to 
all relevant documents and to allocate their time and the time of their staff to discuss the 
conduct of the study, any findings/relevant issues and to implement any corrective and/or 
preventative actions to address any findings/issues identified.
9.5.
Study and Site Closure
Upon completion or termination of the study, the GSK monitor will conduct site closure 
activities with the investigator or site staff (as appropriate), in accordance with applicable 
regulations, GCP, and GSK Standard Operating Procedures.
GSK reserves the right to temporarily suspend or terminate the study at any time for 
reasons including (but not limited to) safety issues, ethical issues, or severe non-
compliance. If GSK determines that such action is required, GSK will discuss the reasons 
for taking such action with the investigator or head of the medical institution (where 
applicable). When feasible, GSK will provide advance notice to the investigator or head 
of the medical institution of the impending action.
If a study is suspended or terminated for safety reasons, GSK will promptly inform all 
investigators, heads of the medical institutions (where applicable),and/or institutions 
conducting the study. GSK will also promptly inform the relevant regulatory authorities 
of the suspension/termination along with the reasons for such action. Where required by 
applicable regulations, the investigator or head of the medical institution must inform the 
IRB/IEC promptly and provide the reason(s) for the suspension/termination.
9.6.
Records Retention
Following closure of the study, the investigator or head of the medical institution (where 
applicable) must maintain all site study records (except for those required by local 


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regulations to be maintained elsewhere) in a safe and secure location. The records must 
be easily accessible 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 the 
records may be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution must be exercised before such action is taken. The 
investigator must ensure that all reproductions are legible and are a true and accurate 
copy of the original. In addition, they must meet accessibility and retrieval standards, 
including regeneration of a hard copy, if required. The investigator must also ensure that 
an acceptable back-up of the reproductions exists and that there is an acceptable quality 
control procedure in place for creating the reproductions.
GSK will inform the investigator of the time period for retaining the site records in order 
to comply with all applicable regulatory requirements. The minimum retention time will 
meet the strictest standard applicable to a particular site, as dictated by local 
laws/regulations, GSK standard operating procedures, and/or institutional requirements.
The investigator must notify GSK of any changes in the archival arrangements, including, 
but not limited to archival of records at an off-site facility or transfer of ownership of the 
records in the event that the investigator is no longer associated with the site.
9.7.
Provision of Study Results to Investigators, Posting of 
Information on Publicly 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 results summary will be posted to the Clinical Study Register no later than eight 
months after the final primary completion date, the date that the final subject was 
examined or received an intervention for the purposes of final collection of data for the 
primary outcome. In addition, a manuscript will be submitted to a peer reviewed journal 
for publication no later than 18 months after the last subject’s last visit (LSLV). When 
manuscript publication in a peer reviewed journal is not feasible, a statement will be 
added to the register to explain the reason for not publishing.


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10.
REFERENCES
American Heart Association. Classes of Heart Failure. Available at: 
http://www.heart.org/HEARTORG/Conditions/HeartFailure/AboutHeartFailure/Classes-
of-Heart-Failure_UCM_306328_Article.jsp. Accessed 14 August 2012.
Bateman ED, Boushey HA, Bousquet J, Busse WW, Clark TJ, Pauwels RA, Pedersen SE. 
Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma Control 
study. Am J Respir Crit Care Med 2004;170:836-844.
Clutterbuck EJ, Hirst EM, Sanderson CJ. Human interleukin-5 (IL-5) regulates the 
production of eosinophils in human bone marrow cultures: comparison and interaction 
with IL-1, IL-3, IL-6, and GMCSF. Blood 1989;73:1504-1512.
Gevaert, P at al. Nasal IL-5 levels determine the response to anti–IL-5 treatment in 
patients with nasal polyps. J Allergy Clin Immunol. 2006;118:1133-41.
GlaxoSmithKline Document Number CM2003/00010/07 Compound ID SB-240563. 
Investigator’s Brochure for Mepolizumab. Report date 23-MAY-2012.
Global Initiative for Asthma (GINA): Global Strategy for Asthma Management and 
Prevention, revised 2008. http://www.ginasthma.org/guidelines-gina-report-global-
strategy-for-asthma.html
Hamid Q, Azzawi M, Ying S, Moqbel R, Wardlaw AJ, Corrigan CJ, Bradley B, Durham 
SR, Collins JV, Jeffery PK et al. Expression of mRNA for interleukin-5 in mucosal 
bronchial biopsies from asthma. J Clin Invest 1991;87:1541-1546.
Humbert M, Corrigan CJ, Kimmitt P, Till SJ, Kay AB, Durham SR. Relationship 
between IL-4 and IL-5 mRNA expression and disease severity in atopic asthma. Am J 
Respir Crit Care Med 1997;156:704-708.
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of acetaminophen protein adducts in adults with acetaminophen
overdose and acute liver failure. Drug Metab Disp 2009;37:1779-84.
Juniper EF, Svensson K, Mőrk AC, Ståhl E. Measurement properties and interpretation of 
three-shortened versions of the asthma control questionnaire. Resp Med 2005;99:553-
558.
Kim Y.-J., Prussin C., Martin B., Law M.A., Haverty T.P., Nutman T.B., Klion A.D. 
Rebound eosinophilia after treatment of hypereosinophilic syndrome and eosinophilic 
gastroenteritis with monoclonal anti-IL-5 antibody SCH55700. Journal of Allergy and 
Clinical Immunology 2004; 114:6 (1449-1455)
Kips JC, Inman MD, Jayaram L, Bel EH, Parameswaran K, Pizzichini MM, Pavord ID, 
Djukanovic R, Hargreave FE, Sterk PJ. The use of induced sputum in clinical trials. Eur 
Respir J Suppl 2002;37:47s-50s.


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Legal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P, Gault E.  Quantification of 
Hepatitis Delta Virus RNA in Serum by Consensus Real-Time PCR Indicates Different 
Patterns of Virological Response to Interferon Therapy in Chronically Infected Patients.  
J Clin Microbiol. 2005;43(5):2363–2369. 
National Institutes of Health. National Heart, Lung, and Blood Institute (NHLBI). 
National Asthma Education and Prevention Program. Expert Panel Report 3: guidelines 
for the diagnosis and management of asthma. August 2007. NIH publication no. 07-4051 
Available at: http://www.nhlbi.nih.gov/guidelines/asthma/index.htm. Accessed 
November, 10, 2008.
Pavord ID, Korn S, Howarth P, et al. Mepolizumab for severe eosinophilic asthma 
(DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet 2012;380:651-
59.
Proceedings of the ATS workshop on refractory asthma: current understanding, 
recommendations, and unanswered questions. Am J Respir Crit Care Med
2000;162:2341-2351.
Robinson DS, Hamid Q, Ying S, Tsicopoulos A, Barkans J, Bentley AM, Corrigan C, 
Durham SR, Kay AB. Predominant TH2-like bronchoalveolar T-lymphocyte population 
in atopic asthma. N Engl J Med 1992;326:298-304.
Robinson DS, Ying S, Bentley AM, Meng Q, North J, Durham SR, Kay AB, Hamid Q. 
Relationships among numbers of bronchoalveolar lavage cells expressing messenger 
ribonucleic acid for cytokines, asthma symptoms, and airway methacholine 
responsiveness in atopic asthma. J Allergy Clin Immunol 1993;92:397-403.
Sampson HA, Munoz-Furlong A, Campbell RL, et al. Second symposium on the 
definition and management of anaphylaxis: summary report--Second National Institute of 
Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J 
Allergy Clin Immunol 2006;117:391-397.
Wang JM, Rambaldi A, Biondi A, Chen ZG, Sanderson CJ, Mantovani A. Recombinant 
human interleukin 5 is a selective eosinophil chemoattractant. Eur J Immunol
1989;19:701-705.
Wardlaw AJ, Brightling C, Green R, Woltmann G, Pavord I. Eosinophils in asthma and 
other allergic diseases. Br Med Bull 2000;56:985-1003.


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11.
APPENDICES
11.1.
Appendix 1: Time and Events Table
Procedures
Week 52 of 
MEA1156611
Treatment Period (Visit Window is 1 week)
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Week of study 
0
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
Written Informed Consent
X
Medical History Changes
X
Smoking Status
X
Inclusion/Exclusion 
Criteria
X
Safety Assessments
Concomitant Medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examination
X
Vital Signs 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG 
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serious Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments2
Immunogenicity
X
X
Hematology
X
X
X
Chemistry 
X
X
X
Liver Analytes
X
X
X
Pregnancy Test3
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
Efficacy Assessments
Exacerbation review 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Asthma Control 
Questionnaire-5
X
X 
X 
X
X
X
Spirometry
X
X
X


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55
Procedures
Week 52 of 
MEA1156611
Treatment Period (Visit Window is 1 week)
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Week of study 
0
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
Worksheets/IP/eCRF
Administer Mepolizumab 
100mg SC
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense paper 
worksheet
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect paper worksheet
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Register IVRS/IWRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete eCRF
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
1.
Before entry in to study 201312, determine which scenario the subject is best classified as and perform the relevant procedures as defined in Section 6.1 and the SPM. 
2.
All laboratory assessments to be completed prior to dosing
3.
Pregnancy test (all females of childbearing potential) U = Urine


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11.1
Appendix 1: Time and Events Table (Continued)
Procedures
Treatment Period (Visit Window is 1 week)
Visit
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
Week of study 
64
68
72
76
80
84
88
92
96
100
104
108
112
116
120
Safety Assessments
Concomitant Medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examination
Vital Signs 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG 
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serious Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments2
Immunogenicity
X
Hematology
X
X
X
Chemistry 
X
X
X
Liver Analytes
X
X
X
Pregnancy Test3
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
Efficacy Assessments
Exacerbation review 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Asthma Control 
Questionnaire-5
X 
X 
X
X
X
Spirometry
X
X
X
Worksheets/IP/eCRF
Administer Mepolizumab 
100mg SC
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense paper 
worksheet
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect paper worksheet
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Register IVRS/IWRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete eCRF
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
2.
All laboratory assessments to be completed prior to dosing
3.
Pregnancy test (all females of childbearing potential) U = Urine


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11.1
Appendix 1: Time and Events Table (Continued)
Procedure
Treatment Period (Visit Window is 1 Week)
Exit/ EW Visit4
Visit
32
33
34
35
36
37
38
39
40
41
42
43
44
Week of study 
124
128
132
136
140
144
148
152
156
160
164
168
172
Safety Assessments
Concomitant Medication
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examination
X 
Vital Signs 
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG 
X
X
X 
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
Serious Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments2
Immunogenicity
X
X
Hematology
X
X
X
Chemistry 
X
X
X
Liver Analytes
X
X
X
Pregnancy Test3
U
U
U
U
U
U
U
U
U
U
U
U
U
Efficacy Assessments
Exacerbation review 
X
X
X
X
X
X
X
X
X
X
X
X
X
Asthma Control 
Questionnaire-5
X
X
X
X
X
Spirometry
X
X
X
Worksheets/IP/eCRF
Administer Mepolizumab 
100mg SC
X
X
X
X
X
X
X
X
X
X
X
X
Dispense Paper Worksheet
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect Paper Worksheet
X
X
X
X
X
X
X
X
X
X
X
X
X
Register IVRS/IWRS
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete eCRF
X
X
X
X
X
X
X
X
X
X
X
X
X
2.
All laboratory assessments to be completed prior to dosing
3.
Urine pregnancy test for all females of childbearing potential,  U = Urine
4.
In the event a subject withdraws early at a scheduled visit, all study procedures scheduled for the Exit Visit (Visit 44) should be performed at this visit instead. In the event a subject 
withdraws between visits, the subject should be asked to return to the clinic as soon as possible to complete the Exit Visit procedures.


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11.2.
Appendix 2: Acceptable Birth Control
To be eligible for entry into the study, females of childbearing potential must commit 
to consistent and correct use of an acceptable method of birth control from the time 
of consent, for the duration of the trial, and for 4 months after the last study drug 
administration.

Male partner who is sterile prior to the female subject’s entry into the study and 
is the sole sexual partner for that female subject 

Abstinence from penile-vaginal intercourse

Implants of levonorgestrel or etonogestrel 

Injectable progestogen

Oral contraceptive (either combined or progestogen alone)

Estrogenic vaginal ring

Percutaneous contraceptive patches

Any intrauterine device (IUD) with a documented failure rate of less than 1% 
per year.

Male condom combined with a vaginal spermicide (foam, gel, film, cream, or 
suppository). The vaginal spermicide must be specified for use with the chosen 
male condom

Male condom combined with a female diaphragm, either with or without a 
vaginal spermicide (foam, gel, film, cream, or suppository).  The vaginal 
spermicide must be specified for use with the chosen male condom
Females of childbearing potential are defined as females with functioning ovaries (i.e., 
post-menarche, premenopausal women with no documented impairment of oviductal or 
uterine function that would cause sterility). This category includes females with 
oligomenorrhea, females who are peri-menopausal, and young females who have begun 
to menstruate (adolescents). The information on the lack of impairment of oviductal or 
uterine function that would cause sterility, can come from the site personnel’s:

Review of subject’s medical records

Medical examination of the subject

Interview with the subject on her medical history.
Females of non-childbearing potential are defined as females with functioning ovaries 
and with a documented tubal ligation or hysterectomy; or females who are 
postmenopausal defined as 12 months of spontaneous amenorrhea with an appropriate 
clinical profile, e.g. age appropriate, >45 years, in the absence of hormone replacement 
therapy (HRT).
In questionable cases a blood sample for follicle stimulating hormone (FSH) and estradiol 
will be obtained and analyzed to confirm childbearing potential. 


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Females on hormone replacement therapy (HRT) and whose menopausal status is in 
doubt will be required to use one of the contraception methods listed above for females of 
childbearing potential 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 enrollment. For most forms of HRT, at least 2-4 weeks should elapse between the 
cessation of therapy and the blood draw; this interval depends on the type and dosage of 
HRT. Following confirmation of their post-menopausal status, they can resume use of 
HRT during the study without use of a contraceptive method.
Based on the absence of an identified reproductive hazard from preclinical studies, 
absence of a genotoxic potential, and very low levels of mepolizumab that might be 
present in semen, there is no recognized risk for mepolizumab to affect human sperm or 
the fetus if transferred to a female partner via semen. Therefore, the use of condoms or 
other methods of contraception in the male study subject is not required.


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11.3.
Appendix 3: Country Specific Requirements
No country-specific requirements exist.


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11.4.
Appendix 4: Liver Chemistry Stopping and Follow-up 
Criteria
Phase III-IV Liver Safety Algorithms
ALT>3xULN
plus 
bilirubin >2x 
ULN (>35%
direct) (or plus
INR >1.5, if   
measured)*
No
Yes
Yes
•Instruct subject to stop investigational product (IP)
•Notify GSK within 24h and arrange clinical followup 
within 24-72h
•Perform liver chemistries and liver event follow up 
assessments (serology, PK sample etc as in protocol) 
•Complete liver event CRF, SAE data collection tool if 
appropriate, and liver imaging and/or biopsy CRFs if  
tests performed.
•Obtain weekly liver chemistries [**as far as possible in 
these subjects] until resolved, stabilised or returned to 
baseline 
•Withdraw subject from study after monitoring 
complete unless protocol has option to restart drug
•Instruct subject to stop investigational product (IP)
•Notify GSK and arrange clinical followup within 24h
•Perform liver chemistries and liver event follow up 
assessments (serology, PK sample etc as in protocol) 
•Report as SAE (excl. hepatic impairment or cirrhosis 
studies) and complete liver event CRF, SAE data 
collection tool, and liver imaging and/or biopsy CRFs if 
tests performed.
•Obtain twice weekly liver chemistries until resolved, 
stabilised or returned to baseline values
•Consultation with hepatologist/specialist recommended
•Withdraw subject from study after monitoring 
complete unless protocol has option to restart drug
Hepatitis 
symptoms
or rash?
No
Able to 
monitor 
weekly for 
4 weeks?
Yes
No**
Yes
Continue IP
Obtain twice 
monthly liver 
chemistries until 
normalised or 
back to baseline 
values
Yes
Yes
ALT<3xULN 
+ bilirubin 
<2xULN 
after ≤ 4 
wks?
Yes
ALT 
>5xULN 
but 
<8xULN
No
ALT  
>8xULN
Yes
ALT >5 
and 
<8xULN 
for > 2 
wks
Yes
No
ALT>3xULN 
but <5xULN + 
bilirubin 
<2xULN+no 
symptoms
No
Able to 
monitor 
weekly for 
> 2 wks?
No
No
Notify GSK within 24h 
to discuss subject 
safety; continue IP;
check liver chemistry 
weekly for 4 weeks
Yes
No
*INR value not applicable to subjects on anticoagulants


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11.5.
Appendix 5: Liver Safety Drug Restart or Rechallenge 
Guidelines
1.
Drug restart may be considered for a subject exhibiting compelling benefit for a 
critical medicine following drug-induced liver injury, if favorable benefit: risk and 
no alternative medicine available. It applies to Phase I-IV studies (excluding healthy 
volunteer studies; example of phase I studies are oncology studies). 
2.
In Phase III-IV, drug restart may be considered for liver safety events with a clear 
underlying cause (e.g. biliary, pancreatic events, hypotension, acute viral hepatitis), 
if not associated with drug-induced liver injury, alcoholic hepatitis, or 
hypersensitivity (fever, rash or eosinophilia) and drug not associated with HLA 
genetic marker of liver injury, when liver chemistries have improved to normal or 
are within 1.5x baseline and ALT<3xULN.
Liver Events Possibly Related to IP - Drug Restart/Rechallenge Following Possible 
Drug-induced Liver Injury Challenge Guidelines
Following drug-induced liver injury, drug restart or rechallenge is associated with a 
13% mortality across all drugs in prospective studies1 Clinical outcomes vary by 
drug, with nearly 50% fatality with halothane readministered in one month of initial 
injury. However, some drugs seldom result in recurrent liver injury or fatality. Risk 
factors for a fatal drug restart/rechallenge outcome include: hypersensitivity1 with initial 
liver injury (e.g. fever, rash, eosinophilia), jaundice or bilirubin 2xULN or INR>1.5 
suggesting severe liver injury, prior IP-related severe or fatal drug restart/rechallenge2,3 or 
evidence of drug-related preclinical liability / mitochondrial impairment3
GSK Decision Process for Drug Restart Approval or Disapproval (also see Figure 1)

Principal Investigator (PI) requests consideration of drug restart for a subject 
receiving compelling benefit from a critical or life-saving drug, who exhibits liver 
chemistry elevation meeting subject stopping criteria, with no alternative treatment

GSK Medical Monitor & Clinical Safety Physician.to review the subject’s 
restart/rechallenge risk factors & complete checklist (Table 3).


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Table 3
Checklist for drug rechallenge for critical medicine (Following drug-
induced liver injury, drug rechallenge is associated with 13% 
mortality across all drugs in prospective studies)
Yes
No
Compelling benefit of the investigational product (IP) for this subject and no 
alternative therapy. Provide brief explanation:
Relative benefit-risk favorable for drug restart/rechallenge, after considering 
the following high risk factors:

Initial liver injury event included: 
o
fever, rash, eosinophilia, or hypersensitivity
o
or bilirubin>2xULN (direct bilirubin >35% of total)

Subject currently exhibits ALT 3xULN, bilirubin 2xULN (direct bilirubin 
>35% of total, if available), or INR 1.5

Severe or fatal restart/rechallenge has earlier been observed with IP If yes, 
please provide brief explanation:

IP associated with known preclinical hepatic liability/ injury  
*Principal Investigator (PI) Actions:

The PI must obtain Ethics Committee or Institutional Review Board review of drug 
reinitiation, as required. 

PI must discuss the possible benefits and risks of drug reinitiation with the subject.

The subject must sign informed consent with a clear description of possible benefits 
and risks of drug administration, including recurrent liver injury or death. Consent 
must be recorded in the study chart.

The drug must be reinitiated at GSK approved dose(s). 

Liver chemistries should be followed twice weekly until stable.

The Ethics Committee or Institutional Review Board must be informed of the 
subject’s outcome, as required.

GSK to be notified of any adverse events, as per Section 6.3.2-Section 6.3.3. 


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Figure 1
GSK process for drug restart after possible drug-induced liver injury
References:
1.
Andrade RJ, Robles M, Lucena MI. Rechallenge in drug-induced liver injury: the 
attractive hazard. Expert Opin Drug Saf. 2009;8:709-714.
2.
Hunt, CM. Mitochondrial and immunoallergic injury increase risk of positive drug 
rechallenge after drug-induced liver injury: A systematic review. Hepatol. 
2010;52:2216-2222.
3.
Papay JI, Clines D, Rafi R, Yuen N, Britt SD, Walsh JS, Hunt CM. Drug-induced 
liver injury following positive drug rechallenge. Regul Tox Pharm. 2009;54:84-90. 


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Drug Restart Guidelines
GSK Decision Process for Drug Restart Approval or Disapproval (also see Figure 2)

Principal Investigator (PI) requests consideration of drug reinitiation for a subject 
stable or improving on investigational product (IP), who exhibits liver chemistry 
elevation meeting subject stopping criteria, which is transient, non-drug-related, and 
resolves. 

GSK Medical Monitor & Clinical Safety Physician to review the subject’s diagnosis, 
restart risk factors & complete checklist (Table 4).
Table 4
Checklist for Phase III drug restart after well-explained liver injury 
(e.g. biliary, pancreatic, hypotensive events, CHF, acute viral 
hepatitis), liver chemistries improving to normal, or 1.5x baseline 
and ALT<3xULN
Yes
No
Is subject stable or improving on the investigational product (IP)?
Do not restart if the following risk factors at initial liver injury:
fever, rash, eosinophilia, or hypersensitivity 
drug-induced liver injury 
alcoholic hepatitis (AST>ALT, typically <10xULN)  
IP associated with liver injury and an HLA genetic marker (e.g. 
lapatinib, abacavir, amoxicillin/clavulanate)  
*Principal Investigator (PI) Actions

The PI must obtain Ethics Comm. or Institutional Review Board review of drug 
reinitiation, as required. 

PI must discuss the benefits and risks of drug reinitiation with the subject.

The subject must sign informed consent with a clear description of possible benefits 
and risks of drug administration, including recurrent liver injury or death. Consent 
must be recorded in the study chart. 

Liver chemistries should be followed weekly until stable.

The Ethics Committee or Institutional Review Board must be informed of the 
patient’s outcome, as required.

GSK to be notified of any adverse or serious adverse events, as per Section 6.3.2-
Section 6.3.3. 


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Figure 2
GSK process for drug restart approvals
References

Andrade RJ, Robles M, Lucena MI. Rechallenge in drug-induced liver injury: the 
attractive hazard. Expert Opin Drug Saf. 2009;8:709-714.

Hunt, CM. Mitochondrial and immunoallergic injury increase risk of positive drug 
rechallenge after drug-induced liver injury: A systematic review. Hepatol. 
2010;52:2216-2222. 

Papay JI, Clines D, Rafi R, Yuen N, Britt SD, Walsh JS, Hunt CM. Drug-induced 
liver injury following positive drug rechallenge. Regul Tox Pharm. 2009;54:84-90.


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11.6.
Appendix 6: Anaphylaxis Criteria
Hypersensitivity reactions will be monitored using the diagnostic criteria for anaphylaxis 
as outlined by the Joint NIAID/FAAN Second Symposium on Anaphylaxis [Sampson
2006]. The criteria do not make a distinction based on underlying mechanism. These 
criteria are summarized as follows:
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, swollen lips-
tongue-uvula), and at least one of the following:
a.
Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced PEF, hypoxemia) 
b. Reduced BP or associated symptoms of end-organ dysfunction (e.g., 
hypotonia [collapse], syncope, incontinence)
2. Two or more of the following that occur rapidly after exposure to a likely allergen 
for that patient (minutes to several hours):
a.
Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, 
swollen lips-tongue-uvula)
b. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced PEF, hypoxemia)
c.
Reduced BP or associated symptoms (e.g., hypotonia [collapse], syncope, 
incontinence)
d. Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting)
3. Reduced BP after exposure to known allergen for that patient (minutes to several 
hours):
a.
Infants and children: low systolic BP (age specific) or greater than 30% 
decrease in systolic BP
b. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from 
that person’s baseline


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11.7.
Appendix 7: Protocol Amendment 01 Changes
Scope: this applies to all sites
Protocol Changes specified in Amendment No. 01 are summarised below:
Change 1: Study Design (Page 10) and 3.1 Study Design (page 20).
To ensure subjects are monitored according to best practice if the time between Visit 14 
in MEA115661 and the start of study medication in 201312 exceeds 8 weeks.  
Original Text: 
This is a multi-center, open-label, long-term study of mepolizumab 100mg administered 
SC, in addition to standard of care (SOC), in subjects with severe eosinophilic asthma. 
Only subjects who complete the MEA115661 Exit Visit (Visit 14) will be offered the 
opportunity to consent for this study. Subjects meeting all of the eligibility criteria for the 
study will be offered the opportunity to consent for this study of up to 128 weeks in 
length (including the Follow-Up Visit). The Exit Visit (Visit 14) in MEA115661 will 
serve as the baseline visit (Visit 1) for this study (Study 201312). For sites not receiving 
regulatory and/or ethics approval prior to Visit 14, the window for Visit 1 can be up to 8 
weeks after V14. Subjects who consent to participate in Study 201312 and who fulfill 
entry criteria will not perform the Follow-Up Visit for MEA115661. 
Revised Text:
This is a multi-center, open-label, long-term study of mepolizumab 100mg administered 
SC, in addition to standard of care (SOC), in subjects with severe eosinophilic asthma. 
Only subjects who complete the MEA115661 Exit Visit (Visit 14) will be offered the 
opportunity to consent for this study. Subjects meeting all of the eligibility criteria for the 
study will be offered the opportunity to consent for this study of up to 128 weeks in 
length (including the Follow-Up Visit). 
It is expected that the majority of eligible subjects will enter 201312 within 8 weeks of 
completing, the Exit Visit (Visit 14) in MEA115661. In this scenario (scenario 1), this 
Exit Visit will serve as the baseline visit (Visit 1) for this study (201312). The invasive 
procedures, e.g. blood draw, spirometry and ECG are not repeated and data from these 
procedures performed at the Exit Visit (Visit 14) of MEA115661 will be used for the 
baseline analysis.  All other safety related procedures will be performed.  Eligible 
subjects in scenario 1 will not perform the Follow-Up Visit (Visit 15) for MEA115661.  
If the window between the Exit Visit (Visit 14) of MEA115661 and Visit 1 of 201312 is 
greater than 8 weeks, the subject should complete MEA115661 by performing the 
Follow-up visit (Visit 15).  Once approvals for 201312 are received, eligible subject will 
begin study 201312 and perform all procedures listed for Visit 1.  In this scenario 
(scenario 2), Visit 1 of 201312 will serve as the baseline visit. 
All applicable procedures for scenario 1 and 2 are listed in Section 6.1. Critical Baseline 
Assessments.  


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All eligible subjects should be enrolled into 201312 within 4 weeks of receiving all 
applicable approvals.
Change 2: 4.2 Inclusion Criteria. Edit of entry criterion number 6 Disease Severity 
(page 23).  
To introduce a definition of serious debilitating asthma.
Original Text: 
6.
Disease Severity: Subjects must be assessed as having life-threatening /serious 
debilitating asthma in order to enroll, as defined by the following: 
Subjects enrolled in MEA115588 must meet one of the following criteria:
a) Subject has a history of at least one intubation during their lifetime 
b) ≥3 asthma exacerbations in the 12 months prior to screening for MEA115588
c) ≥1 or more hospitalization for asthma exacerbation in the 12 months prior to 
screening for MEA115588.
Subjects enrolled in MEA115575 must meet one of the following criteria:
d) Subject has a history of at least one intubation during their lifetime 
e) Their optimized dose at randomization in MEA115575 was ≥10mg of prednisone 
f)
≥1 or more hospitalization for asthma exacerbation in the 12 months prior to 
screening for MEA115575
Revised Text:
6.
Disease Severity: Subjects must be assessed as having life-threatening asthma or  
serious debilitating asthma in order to enroll.  
Life threatening asthma is defined by the following: 
Subjects enrolled in MEA115588 must meet one of the following criteria:
a) Subject has a history of at least one intubation during their lifetime 
b) ≥3 asthma exacerbations in the 12 months prior to screening for MEA115588
c) ≥1 or more hospitalization for asthma exacerbation in the 12 months prior to 
screening for MEA115588.
Subjects enrolled in MEA115575 must meet one of the following criteria:
d) Subject has a history of at least one intubation during their lifetime 
e) Their optimized dose at randomization in MEA115575 was ≥10mg of prednisone 
f)
≥1 or more hospitalization for asthma exacerbation in the 12 months prior to 
screening for MEA115575
Those subjects that do not meet the definition of potentially life threatening asthma 
must be assessed as having serious debilitating asthma.   


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Subjects enrolled in MEA115588 or MEA115575 must meet all of the following 
criteria:
At randomisation of MEA115588 or MEA115575 must have:
g) A % predicted FEV1 of ≤50% and either
h) ACQ5 score of ≥3 or
i)
SGRQ score of ≥60 
Change 3: 4.2 Inclusion Criteria. Edit of entry criterion number 7 Clinical Benefit (page 
23).  
To remove the Clinical-Rated Response to Therapy assessment and replace with an 
investigator confirmed demonstrated improvement whilst receiving mepolizumab.
Original Text: 
7.
Clinical Benefit: Subjects must have experienced documented clinical benefit to 
enroll. Subjects must meet the following criteria demonstrating clinical benefit:
Subjects enrolled in MEA115588 who received mepolizumab must meet all of the 
following criteria:
a) Subject must have had a reduction in their exacerbation frequency by ≥50% 
during MEA115588. The baseline for comparison is the total number of 
exacerbations reported in the 12 months prior to screening for MEA115588.
b) The investigator response on the “Clinician-Rated Response to Therapy” 
questionnaire at Visit 10 was either: mildly improved, moderately improved or 
significantly improved.
Subjects enrolled in MEA115588 who received placebo must meet all of the 
following criteria:
c) Subject must have had a reduction in their exacerbation frequency by ≥50% 
during the first 8 months of MEA115661. The baseline for comparison is the total 
number of exacerbations reported in the 12 months prior to screening for 
MEA115588.
d) The investigator confirms that the subject demonstrated improvement during 
MEA115661. 
Subjects enrolled in MEA115575 who received mepolizumab must meet all of the 
following criteria:
e) Subject must have reduced their oral corticosteroid dose by ≥ 50% during 
MEA115575. The baseline for comparison is the subject’s optimized OCS dose at 
randomization in MEA115575.
f)
The investigator response on the “Clinician-Rated Response to Therapy” 
questionnaire at Visit 9 was either: mildly improved, moderately improved or 
significantly improved.


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Subjects enrolled in MEA115575 who received placebo must meet all of the 
following criteria:
g) Subject must have reduced their oral corticosteroid dose at randomization by 
≥50% in the first 6 months of MEA115661. The baseline for comparison is the 
subject’s optimized OCS dose at randomization in MEA115575.
h) The investigator confirms that the subject demonstrated improvement during 
MEA115661. 
Revised Text:
7.
Clinical Benefit: Subjects must have experienced documented clinical benefit to 
enroll. Subjects must meet the following criteria demonstrating clinical benefit:
Subjects enrolled in MEA115588 who received mepolizumab must meet all of the 
following criteria:
a) Subject must have had a reduction in their exacerbation frequency by ≥50% 
during MEA115588. The baseline for comparison is the total number of 
exacerbations reported in the 12 months prior to screening for MEA115588.
b) The investigator confirms that the subject demonstrated improvement during 
MEA115588. 
Subjects enrolled in MEA115588 who received placebo must meet all of the 
following criteria:
c) Subject must have had a reduction in their exacerbation frequency by ≥50% 
during the first 8 months of MEA115661. The baseline for comparison is the total 
number of exacerbations reported in the 12 months prior to screening for 
MEA115588.
d) The investigator confirms that the subject demonstrated improvement during 
MEA115661. 
Subjects enrolled in MEA115575 who received mepolizumab must meet all of the 
following criteria:
e) Subject must have reduced their oral corticosteroid dose by ≥ 50% during 
MEA115575. The baseline for comparison is the subject’s optimized OCS dose at 
randomization in MEA115575
f)
The investigator confirms that the subject demonstrated improvement during 
MEA115575. 
Subjects enrolled in MEA115575 who received placebo must meet all of the 
following criteria:
g) Subject must have reduced their oral corticosteroid dose at randomization by 
≥50% in the first 6 months of MEA115661. The baseline for comparison is the 
subject’s optimized OCS dose at randomization in MEA115575.
h) The investigator confirms that the subject demonstrated improvement during 
MEA115661. 


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Change 4: Section 4.3 Exclusion Criteria No. 7.  (page 25) Clarification to ensure that 
subjects with a clinically significant abnormal ECG are not entered into 201312.
Original Text: 7. ECG Assessment: A clinically significant ECG abnormality at the exit 
visit of MEA115661, as determined by the investigator.
Revised Text: 7. ECG Assessment: A clinically significant ECG abnormality as 
determined by the investigator.
Change 5: 4.3 Exclusion Criteria. To clarify exclusion criterion number 6 Previous 
Significant Protocol Deviation (page 25). 
Original Text: 
6. Previous Significant Protocol Deviation: Subjects who were excluded from the 
per protocol analysis due to significant protocol deviations in either study 
MEA115575 or MEA115588.
Revised Text:
6. Previous Significant Protocol Deviation: Subjects who were excluded from the 
per protocol analysis due to a significant protocol deviation in either study 
MEA115575 or MEA115588 which is deemed by the GSK Medical Monitor to 
put the subject at risk from further participation.
Change 6: 6.3.10.2. Physical Examination (page 45). To remove the examination for 
nasal polyps.
Original Text:
A detailed physical examination including, but not limited to, an evaluation of the 
lungs and cardiovascular system will be conducted at Visit 1, Exit/Early Withdrawal 
and the Follow-Up Visit. This examination should also include observation of the
nasal cavities for the presence of nasal polyps. For the US, licensed practitioners who 
are listed on the Form 1572 can complete the physical examination. A licensed 
physician on the Form 1572 must sign off on the physical examinations completed by 
non-physicians. In countries outside of the US, the physical examination should be 
conducted by a medically qualified person; however, if the physical examination is 
conducted by non-physicians, a medically qualified person must sign off.
Revised Text: 
A detailed physical examination including, but not limited to, an evaluation of the 
lungs and cardiovascular system will be conducted at Visit 1, Exit/Early Withdrawal 
and the Follow-Up Visit. For the US, licensed practitioners who are listed on the Form 
1572 can complete the physical examination. A licensed physician on the Form 1572 
must sign off on the physical examinations completed by non-physicians. In countries 
outside of the US, the physical examination should be conducted by a medically 


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qualified person; however, if the physical examination is conducted by non-
physicians, a medically qualified person must sign off.
Change 7: 6.1 Critical Baseline Assessments (page 31). To clarify the process and which 
assessments are required in 201312 if there is a delay of greater than 8 weeks between the 
Exit visit (Visit 14) of MEA115661 and the start of participation in 201312.  Clarification 
of No. 5 for scenario 1 and scenario 2 by removing the bulleted sentence.
Original Text: 
Baseline assessments at Visit 1 will be comprised of the following in the list below. 
Assessments performed as part of the Exit Visit for MEA115661 do not have to be 
repeated for Visit 1 of 201312 as results will be transferred accordingly.  
1. Demographic information review 
2. General medical history review and update
3. Physical examination 

To include a nasal exam to check for nasal polyps
4. Pulmonary function tests and assessment 
5. Assessment of Inclusion/Exclusion criteria. 

Results of laboratory tests and the ECG over-read results from Visit 1 will be 
reviewed at Visit 2.
6. Asthma Control Questionnaire-5 (Section 6.2.1.2)
7. Vital signs (Section 6.3.10.3)
8. 12-lead ECG (Section 6.3.10.4)
9. Blood sampling for the following:

Clinical chemistry 

Hematology

Liver Analytes

Immunogenicity
10. Urine pregnancy test for females of childbearing potential (Appendix 2: 
Acceptable Birth Control)
Revised Text:
For scenario 1 subjects, i.e. those that have a window of less than or equal to 8 weeks 
between the Exit Visit (Visit 14) of MEA115661 and the start of participation in 201312, 
certain assessments performed as part of the Exit Visit for MEA115661 do not have to be 
repeated. 


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For scenario 2 subjects, i.e. those that have a window of greater than 8 weeks, must 
perform the Follow-up visit (Visit 15) of MEA115661 and when approvals for 201312 
are in place, must complete all procedures listed for Visit 1. Baseline assessments 
performed for scenario 1 subjects:
1. Demographic information review 
2. General medical history review and update
3. Physical examination
4. Assessment of Inclusion/Exclusion criteria. 
5. Asthma Control Questionnaire-5 (Section 6.2.1.2)
6. Vital signs (Section 6.3.10.3)
7. Urine pregnancy test for females of childbearing potential (Appendix 2: 
Acceptable Birth Control)
Baseline assessments performed for scenario 2 subjects:
1. Demographic information review 
2. General medical history review and update
3. Physical examination 
4. Pulmonary function tests and assessment 
5. Assessment of Inclusion/Exclusion criteria. 
6. Asthma Control Questionnaire-5 (Section 6.2.1.2)
7. Vital signs (Section 6.3.10.3)
8. 12-lead ECG (Section 6.3.10.4)
9. Blood sampling for the following:

Clinical chemistry 

Hematology

Liver Analytes

Immunogenicity
10. Urine pregnancy test for females of childbearing potential (Appendix 2: 
Acceptable Birth Control)
Change 8: 11.1. Appendix 1: Time and Events Table, footnote no. 1 (page 53-56).
To clarify the process if the delay between MEA115661 and 201312 is greater than 8 
weeks.


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Original Text: 
1. Visit 1 is the same as Visit 14 of MEA115661 however for sites not receiving 
regulatory and/or ethics approval prior to Visit 14, the window for Visit 1 is + 8 
weeks after V14; Assessments performed as part of the exit visit for MEA115661 do 
not have to be repeated for Visit 1 of 201312 as results will be transferred 
accordingly.
Revised Text:
1. For scenario 1 subjects, that is when the window between Visit 14 and Visit 1 is ≤8 
weeks all procedures should be performed except laboratory tests from blood (urine 
pregnancy test must be performed), spirometry and ECG.  For scenario 2 subjects, 
that is when the window between Visit 14 and Visit 1 is >8 weeks, the subject should 
complete the Follow-up visit (Visit 15) for MEA115661.  Once approvals are 
received the subject can only then begin 201312 and must perform all procedures 
listed for Visit 1 above.  
Change 9: Figure 1: GSK process for drug restart after possible drug-induced liver injury 
(page 63): Duplicate diagram removed.
Change 10: Figure 2: GSK process for drug restart approvals (page 67): Duplicate 
diagram removed.
Change 11: Section 5.5 Product Accountability, (page 29).  Added “where applicable” to 
clarify that where rescue medicine is provided to the subject, it should be accounted for.
Original Text:
In accordance with local regulatory requirements, the investigator, designated site staff, 
or head of the medical institution (where applicable) must document the amount of 
investigational product dispensed and/or administered to study subjects, the amount 
returned by study subjects, and the amount received from and returned to GSK, when 
applicable. Product accountability records must be maintained throughout the course of 
the study.
Revised Text:
In accordance with local regulatory requirements, the investigator, designated site staff, 
or head of the medical institution (where applicable) must document the amount of 
investigational product dispensed and/or administered to study subjects, the amount 
returned by study subjects (where applicable), and the amount received from and returned 
to GSK, when applicable. Product accountability records must be maintained throughout 
the course of the study.


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Change 12: Section 6.2. Efficacy Endpoints, (page 32).  To add the Forced expiratory 
volume in 1 second (FEV1), which was missing from this section only due to an 
oversight.  
Orignal Text: 

Annualized rate of exacerbations

Asthma Control Questionnaire-5 score
Revised Text: 

Annualized rate of exacerbations

Asthma Control Questionnaire-5 score

Forced expiratory volume in 1 second (FEV1)
Change 13: A change of Sponsor Global Back-up Medical Monitor Contact Information 
page 3):
Original Text:
 MD (Director, Respiratory Medicine Development Centre)
Tel: 
Mobile: 
Revised Text:
 MD (Director, Respiratory Medicine Development Centre)
Tel: 
Mobile: 
Change 14: Section 11.2 Appendix 2: Acceptable Birth Control (page 57).  The addition 
of text to ensure that the vaginal spermicide used is specified for use with the chosen 
male condom.
Original Text: 

Male condom combined with a vaginal spermicide (foam, gel, film, cream, or 
suppository).  

Male condom combined with a female diaphragm, either with or without a 
vaginal spermicide (foam, gel, film, cream, or suppository).  
Revised Text:

Male condom combined with a vaginal spermicide (foam, gel, film, cream, or 
suppository).  The vaginal spermicide must be specified for use with the chosen 
male condom, 
PPD
PPD
PPD
PPD
PPD
PPD


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
Male condom combined with a female diaphragm, either with or without a 
vaginal spermicide (foam, gel, film, cream, or suppository).  The vaginal 
spermicide must be specified for use with the chosen male condom
Change 15: Section 1.3.1 Risk Assessment, (page 15, Table 1).  Table updated with new 
information and some text reorganised.
Original Text:  
Potential Risk of Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) SB 240563
Risk of Systemic Allergic and 
Non-allergic Reactions, 
including Anaphylaxis
Biopharmaceutical products 
may elicit anti-drug antibody 
(ADA) and neutralizing 
antibody (NAB), which have 
the potential to modulate 
pharmacokinetic (PK), 
pharmacodynamic (PD) or 
produce adverse reactions. 
However, humanized and fully 
human antibodies are less 
immunogenic than mouse or 
chimeric monoclonal 
antibodies.
Reactions reported to date 
across the mepolizumab 
program are summarized in 
the IB; see ‘Special Warnings 
and Special Precautions for 
Use’ section located in Section 
6 titled ‘Summary of Data and 
Guidance for the Investigator’.
Daily monitoring of serious 
adverse events (SAEs) by 
medical monitor; regular 
systematic review of adverse 
event (AE)/SAE data from 
ongoing studies by a GSK 
safety review team. 
Specific case report form 
(CRF) pages utilized for 
targeted collection of reactions 
data.
Use of Joint NIAID/FAAN 
2nd Symposium on 
Anaphylaxis to collect data on 
reports of anaphylaxis 
(Appendix 6 Anaphylaxis 
Criteria).
Subjects are to be monitored 
based on institutional 
practices. 
Risk of Immunogenicity
See previous risk for 
background information in 
literature.
Immunogenicity data reported 
to date across the 
mepolizumab development 
program are summarized in 
the IB; See Section 5.4 
‘Clinical Immunogenicity’ and 
a summary of immunogenicity 
findings in the ‘Other 
Potentially Clinically Relevant 
Blood samples are collected in 
clinical studies for detection of 
both ADA and NAB.
See previous risk for 
mitigation strategy related to 
clinical safety risks.


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Potential Risk of Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
Information for the 
Investigator’ section located in 
Section 6.titled ‘Summary of 
Data and Guidance for the 
Investigator’s Brochure.
Potential risk for adverse 
cardiovascular (CV) effects
Mepolizumab binding was 
restricted to human lymphoid 
tissues in an 
immunohistochemistry tissue 
binding study suggesting a 
low likelihood of non-
pharmacologic effects on 
cardiovascular (CV) function. 
No AEs concerning cardiac 
conduction or repolarization 
evident in cynomolgus 
monkeys at doses at least 10-
fold in excess of humans 
dosed at 10 mg/kg or 750 mg.
No clinically relevant trends 
observed in ECG data in 
humans.
In one study in subjects with 
severe refractory asthma, 
cardiac events were reported 
in similar frequencies across 
treatment groups with a small 
numerical increase observed in 
serious ischemic cardiac 
events in the mepolizumab-
treated groups. However, an 
integrated safety analysis of all 
placebo-controlled multiple 
dose asthma trials showed 
similar frequency of SAEs 
reported overall from the 
cardiac and vascular system 
organ class (SOC). 
Additionally, similar findings 
were observed in other SOCs 
with thrombotic events (e.g., 
stroke in the Nervous System 
SOC).
Daily monitoring of SAE by 
medical monitor; regular 
systematic review of AE/SAE 
data from ongoing studies by a 
GSK safety review team.
CV monitoring for study 
includes:

ECG monitoring during 
the trial

Use of standardized CRFs 
to collect relevant data on 
CV events of interest (i.e., 
myocardial infarction, 
hospitalization for 
unstable angina and 
congestive heart failure, 
arterial thrombosis, 
pulmonary embolism and 
deep vein thrombosis);

Adjudication of 
cardiovascular events


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Potential Risk of Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
Potential risk for increase in 
infections – a theoretical 
concern with biologics; 
however, the pharmacological 
properties of mepolizumab 
suggest the risk is low.
No evidence of increased 
incidence of infections in any 
preclinical studies.
Murine data demonstrate that 
IL-5 antagonism is unlikely to 
influence cellular or humoral 
immunity, particularly in 
response to parasitic 
infections.  
No mepolizumab-related 
effects on lymphocyte 
Immunophenotyping in 
monkeys or humans, including 
T-cell activation, distribution 
of CD4/CD8 subtypes or 
Th1/Th2 cytokine patterns, B-
cells, NK cells or γδ-T-cells. 
An integrated safety analysis 
of all placebo-controlled 
multiple dose asthma trials 
showed SAEs reported in the 
infection and infestation SOC 
were 5/345 (1%) in placebo 
subjects and 18/754 (2%) in 
mepolizumab subjects.
Infections reported to date 
across the mepolizumab 
development program are 
summarized in the IB; see 
‘Special Precautions and 
Warnings’ (for exclusion of 
subjects with underlying 
parasitic infections) and 
‘Undesirable Effects’ (for very 
common infections of 
nasopharyngitis, URTI, 
rhinitis and bronchitis reported 
in other patient populations) 
sections located in Section 6 
titled ‘Summary of Data and 
Guidance for the Investigator’.
Daily monitoring of SAE by 
medical monitor; regular 
systematic review of AE/SAE 
data from ongoing studies by a 
GSK safety review team 
Standard safety assessments to 
be conducted as outlined in 
protocols


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Potential Risk of Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
Potential risk for increase in 
malignancies - theoretical 
concern with biologics; 
however, blockade of IL-5 is 
not associated with 
generalized immuno-
suppression or impaired host 
resistance.
Role of IL-5 and eosinophils 
in tumor surveillance is not 
fully characterised in the 
literature. 
No evidence of defective 
tumor surveillance in IL-5 or 
eosinophil-deficient mice. 
Direct assessment of the 
carcinogenic potential of long-
term IL-5 blockade in rodent 
models not technically 
feasible. 
Malignancies reported to date 
across the mepolizumab 
development program are 
summarized in the IB.
Daily monitoring of SAE by 
medical monitor; regular 
systematic review of AE/SAE 
data from ongoing studies by a 
GSK safety review team 
Standard safety assessments to 
be conducted as outlined in 
protocols
Potential risk for rebound 
eosinophilia with associated 
clinical consequences
Early published data with 
Schering-Plough anti- IL5 
mAb suggested potential for 
rebound eosinophilia and 
disease exacerbation when 
treatment was stopped [Kim, 
2004; Gevaert, 2006]; 
however, no standard 
definition of rebound was used 
and criteria for reporting were 
variable. 
There have been no verbatim 
reports of ‘rebound’ from 
completed clinical trials of 
subjects with asthma, atopic 
dermatitis and eosinophilic 
esophagitis. Furthermore, the 
data do not support an 
exaggerated return of 
symptoms after cessation of 
treatment.
Daily monitoring of SAE by 
medical monitor; regular 
systematic review of AE/SAE 
data from ongoing studies by a 
GSK safety review team 
Standard safety assessments to 
be conducted as outlined in 
protocols
Study Procedures
Potential risk for injury with 
phlebotomy 
Risks with phlebotomy 
include bruising, bleeding, 
infection, nerve damage.
Procedures to be performed by 
trained personnel (i.e., study 
nurse) 


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Revised Text:
Potential Risk of Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) SB 240563
Risk of Systemic Allergic and 
Non-allergic Reactions, 
including Anaphylaxis
Reactions reported to date 
across the mepolizumab 
program are summarized in 
the IB; see ‘Special Warnings 
and Special Precautions for 
Use’ section located in Section 
6 titled ‘Summary of Data and 
Guidance for the Investigator’.
Daily monitoring of serious 
adverse events (SAEs) by 
medical monitor; regular 
systematic review of adverse 
event (AE)/SAE data from 
ongoing studies by a GSK 
safety review team. 
Specific case report form 
(CRF) pages utilized for 
targeted collection of reactions 
data.
Use of Joint NIAID/FAAN 
2nd Symposium on 
Anaphylaxis to collect data on 
reports of anaphylaxis 
(Appendix 6 Anaphylaxis 
Criteria).
Subjects are to be monitored 
based on institutional 
practices. 
Risk of Immunogenicity
Biopharmaceutical products 
may elicit anti-drug antibody 
(ADA) and neutralizing 
antibody (NAB), which have 
the potential to modulate 
pharmacokinetic (PK),
pharmacodynamic (PD) or 
produce adverse reactions. 
However, humanized and fully 
human antibodies are less 
immunogenic than mouse or 
chimeric monoclonal 
antibodies.
Immunogenicity data reported 
to date across the 
mepolizumab development 
program are summarized in 
the IB; See Section 5.4 
‘Clinical Immunogenicity’ and 
a summary of immunogenicity 
Blood samples are collected in 
clinical studies for detection of 
both ADA and NAB.
See previous risk for 
mitigation strategy related to 
clinical safety risks.


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Potential Risk of Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
findings in the ‘Other 
Potentially Clinically Relevant 
Information for the 
Investigator’ section located in 
Section 6.titled ‘Summary of 
Data and Guidance for the 
Investigator’s Brochure.
Potential risk for adverse 
cardiovascular (CV) effects
Mepolizumab binding was 
restricted to human lymphoid 
tissues in an 
immunohistochemistry tissue 
binding study suggesting a 
low likelihood of non-
pharmacologic effects on 
cardiovascular (CV) function. 
No AEs concerning cardiac 
conduction or repolarization 
evident in cynomolgus
monkeys at doses at least 10-
fold in excess of humans 
dosed at 10 mg/kg or 750 mg.
No clinically relevant trends 
observed in ECG data in 
humans.
In one study in subjects with 
severe refractory asthma, 
cardiac events were reported 
in similar frequencies across 
treatment groups with a small 
numerical increase observed in 
serious ischemic cardiac 
events in the mepolizumab-
treated groups. However, an 
integrated safety analysis of all 
placebo-controlled multiple 
dose asthma trials showed 
similar frequency of SAEs 
reported overall from the 
cardiac and vascular system 
organ class (SOC). 
Additionally, similar findings 
were observed in other SOCs 
with thrombotic events (e.g., 
stroke in the Nervous System 
SOC). Data from 2 
Daily monitoring of SAE by 
medical monitor; regular 
systematic review of AE/SAE 
data from ongoing studies by a 
GSK safety review team.
CV monitoring for study 
includes:

ECG monitoring during 
the trial

Use of standardized CRFs 
to collect relevant data on 
CV events of interest (i.e., 
myocardial infarction, 
hospitalization for 
unstable angina and 
congestive heart failure, 
arterial thrombosis, 
pulmonary embolism and 
deep vein thrombosis);

Adjudication of 
cardiovascular events


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Potential Risk of Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
subsequently completed 
placebo-controlled severe 
asthma trials did not show an 
increased risk of serious 
ischemic cardiac events; there 
were no new reports in any 
treatment groups including 
placebo.
Potential risk for increase in 
infections – a theoretical 
concern with biologics; 
however, the pharmacological 
properties of mepolizumab 
suggest the risk is low.
No evidence of increased 
incidence of infections in any 
preclinical studies.
Murine data demonstrate that 
IL-5 antagonism is unlikely to 
influence cellular or humoral 
immunity, particularly in 
response to parasitic 
infections.  
No mepolizumab-related 
effects on lymphocyte 
Immunophenotyping in 
monkeys or humans, including 
T-cell activation, distribution 
of CD4/CD8 subtypes or 
Th1/Th2 cytokine patterns, B-
cells, NK cells or γδ-T-cells. 
An integrated safety analysis 
of all placebo-controlled 
multiple dose asthma trials 
showed SAEs reported in the 
infection and infestation SOC 
were 5/345 (1%) in placebo 
subjects and 18/754 (2%) in 
mepolizumab subjects.
Infections reported to date 
across the mepolizumab 
development program are 
summarized in the IB; see 
‘Special Precautions and 
Warnings’ (for exclusion of 
subjects with underlying 
parasitic infections) and 
‘Undesirable Effects’ (for very 
common infections of 
nasopharyngitis, URTI, 
Daily monitoring of SAE by 
medical monitor; regular 
systematic review of AE/SAE 
data from ongoing studies by a 
GSK safety review team 
Standard safety assessments to 
be conducted as outlined in 
protocols


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Potential Risk of Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
rhinitis and bronchitis reported 
in other patient populations) 
sections located in Section 6 
titled ‘Summary of Data and 
Guidance for the Investigator’.
Potential risk for increase in 
malignancies - theoretical 
concern with biologics; 
however, blockade of IL-5 is 
not associated with 
generalized immuno-
suppression or impaired host 
resistance.
Role of IL-5 and eosinophils 
in tumor surveillance is not 
fully characterised in the 
literature. 
No evidence of defective 
tumor surveillance in IL-5 or 
eosinophil-deficient mice. 
Direct assessment of the 
carcinogenic potential of long-
term IL-5 blockade in rodent 
models not technically 
feasible. 
Malignancies reported to date 
across the mepolizumab 
development program are 
summarized in the IB.
Daily monitoring of SAE by 
medical monitor; regular 
systematic review of AE/SAE 
data from ongoing studies by a 
GSK safety review team 
Standard safety assessments to 
be conducted as outlined in
protocols
Potential risk for rebound 
eosinophilia with associated 
clinical consequences
Early published data with 
Schering-Plough anti- IL5 
mAb suggested potential for 
rebound eosinophilia and 
disease exacerbation when 
treatment was stopped [Kim, 
2004; Gevaert, 2006]; 
however, no standard 
definition of rebound was used 
and criteria for reporting were 
variable. 
There have been no verbatim 
reports of ‘rebound’ from 
completed clinical trials of 
subjects with asthma, atopic 
dermatitis and eosinophilic 
esophagitis. Furthermore, the 
data do not support an 
exaggerated return of 
symptoms after cessation of 
treatment.
Daily monitoring of SAE by 
medical monitor; regular 
systematic review of AE/SAE 
data from ongoing studies by a 
GSK safety review team 
Standard safety assessments to 
be conducted as outlined in 
protocols


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Potential Risk of Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
Study Procedures
Potential risk for injury with 
phlebotomy 
Risks with phlebotomy 
include bruising, bleeding, 
infection, nerve damage.
Procedures to be performed by 
trained personnel (i.e., study
nurse) 


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11.8.
Appendix 8: Protocol Amendment 02 Changes
Scope: this applies to all sites
Protocol changes specified in Amendment No. 02 are summarised below:
Change No. 1: The addition of an Inclusion criterion to Section 4.2 Inclusion Criteria: 
Additional Text: 
8.
If criteria 6 and 7 are not met, subjects who are considered to be at risk of 
experiencing a life-threatening event or whose functional health status will become 
significantly worse if returned to standard of care, as judged by the investigator and 
agree by GSK.
Change 2: The addition of a third subject scenario when entering 201312 from 
MEA115661.  Multiple sections are clarified, including the same change made to 
Protocol Summary, Study Design (page 11) and to Section 3.1. Study Design (page 20).  
Additionally, Section 6.1 Critical Baseline Assessments and Appendix 1: Time and 
Events Schedule, footnote 1.
Original Text:
3.1 Study Design
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct. 
This is a multi-center, open-label, long-term study of mepolizumab 100mg administered 
SC, in addition to standard of care (SOC), in subjects with severe eosinophilic asthma. 
Only subjects who complete the MEA115661 Exit Visit (Visit 14) will be offered the 
opportunity to consent for this study. Subjects meeting all of the eligibility criteria for the 
study will be offered the opportunity to consent for this study of up to 128 weeks in 
length (including the Follow-Up Visit).  
It is expected that the majority of eligible subjects will enter 201312 within 8 weeks of 
completing the Exit Visit (Visit 14)  in MEA115661.  In this scenario (scenario 1), this 
Exit Visit will serve as the baseline visit (Visit 1) for this study (201312). The invasive 
procedures, e.g. blood draw, spirometry and ECG are not repeated and data from these 
procedures performed at the Exit Visit (Visit 14) of MEA115661 will be used for the 
baseline analysis.  All other safety related procedures will be performed.  Eligible 
subjects in scenario 1 will not perform the Follow-Up Visit (Visit 15) for MEA115661.
If the window between the Exit Visit (Visit 14) of MEA115661 and Visit 1 of 201312 is 
greater than 8 weeks, the subject should complete MEA115661 by performing the 
Follow-up visit (Visit 15).  Once approvals for 201312 are received, eligible subjects will 
begin 201312 and perform all procedures stated for Visit 1. In this scenario (scenario 2), 
Visit 1 of 201312 will serve as the baseline visit. 


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All applicable procedures for scenario 1 and 2 are listed in Section 6.1. Critical Baseline 
Assessments.  
Changed To:  
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct. 
This is a multi-center, open-label, long-term study of mepolizumab 100mg administered 
SC, in addition to standard of care (SOC), in subjects with severe eosinophilic asthma. 
Only subjects who complete the MEA115661 Exit Visit (Visit 14) will be offered the 
opportunity to consent for this study. Subjects meeting all of the eligibility criteria for the 
study will be offered the opportunity to consent for this study of up to 128 weeks in 
length (including the Follow-Up Visit).  
It is expected that the majority of eligible subjects will enter 201312 within 8 weeks of 
completing the Exit Visit (Visit 14) in MEA115661.  
To reduce the burden of repeated procedures during the ending of MEA115661 and the 
start of 201312, subjects will start the study according to a specific “scenario”.  This 
depends on when their Visit 1 occurs in relation to the Visit 14 of the MEA115661 study. 
Scenario 1 is when Visit 1 of 201312 is performed on the same day (or less than or equal 
to 8 weeks) from when Visit 14 of study MEA115661 is performed. 
Scenario 2a is when Visit 1 of 201312 is performed greater than 8 weeks after Visit 14 
of MEA115661 AND when Visit 1 of 201312 is performed on the same day as the 
Follow-up visit (Visit 15) of study MEA115661. 
Scenario 2b is when Visit 1 of 201312 is performed greater than 8 weeks after Visit 14 
of MEA115661 AND Visit 1 of 201312 is performed after the Follow-up visit (Visit 15) 
of study MEA115661 has taken place.
All applicable procedures for scenario 1, and 2a and 2b subjects are listed in Section 6.1. 
Critical Baseline Assessments.  
Change 3: Clarification of the subject scenarios in Section 6.1 Critical Baseline 
Assessments
Original Text: 
For scenario 1 subjects, i.e. those that have a window of less than or equal to 8 weeks 
between the Exit Visit (Visit 14) of MEA115661 and the start of participation in 201312, 
certain assessments performed as part of the Exit Visit for MEA115661 do not have to be 
repeated. 
For scenario 2 subjects, i.e. those that have a window of greater than 8 weeks, must 
perform the Follow-up visit (Visit 15) of MEA115661 and when approvals for 201312 


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are in place, must complete all procedures listed for Visit 1. Baseline assessments 
performed for scenario 1 subjects:
1. Demographic information review 
2. General medical history review and update
3. Physical examination 
4. Assessment of Inclusion/Exclusion criteria. 
5. Asthma Control Questionnaire-5 (Section 6.2.1.2)
6. Vital signs (Section 6.3.10.3)
7. Urine pregnancy test for females of childbearing potential (Appendix 2: 
Acceptable Birth Control)
Baseline assessments performed for scenario 2 subjects:
1. Demographic information review 
2. General medical history review and update
3. Physical examination 
4. Pulmonary function tests and assessment 
5. Assessment of Inclusion/Exclusion criteria. 
6. Asthma Control Questionnaire-5 (Section 6.2.1.2)
7. Vital signs (Section 6.3.10.3)
8. 12-lead ECG (Section 6.3.10.4)
9. Blood sampling for the following:

Clinical chemistry 

Hematology

Liver Analytes

Immunogenicity
10. Urine pregnancy test for females of childbearing potential (Appendix 2: 
Acceptable Birth Control)
Amended Text: 
Baseline assessments performed for scenario 1 subjects in study 201312:
1. Demographic information review and update for 201312
2. General medical history review and update in 201312
3. Physical examination and update in 201312
4. Assessment of Inclusion/Exclusion criteria. 


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5. Urine pregnancy test for females of childbearing potential (Appendix 2: 
Acceptable Birth Control)
Baseline assessments performed for scenario 2a subjects in study 201312:
1. Demographic information review and update for 201312
2. General medical history review and update in 201312
3. Physical examination and update in 201312
4. Pulmonary function tests and assessment 
5. Assessment of Inclusion/Exclusion criteria. 
6. Urine pregnancy test for females of childbearing potential (Appendix 2: 
Acceptable Birth Control)
For scenario 2b subjects in study 201312, the following assessments should be 
performed:
1. Demographic information review and update for 201312
2. General medical history review and update in 201312
3. Physical examination and update in 201312
4. Pulmonary function tests and assessment 
5. Assessment of Inclusion/Exclusion criteria. 
6. Asthma Control Questionnaire-5 (Section 6.2.1.2)
7. Vital signs (Section 6.3.10.3)
8. 12-lead ECG (Section 6.3.10.4)
9. Blood sampling for the following:

Clinical chemistry 

Hematology

Liver Analytes

Immunogenicity
10. Urine pregnancy test for females of childbearing potential (Appendix 2: 
Acceptable Birth Control)
Please see the SPM for more detail around the required baseline assessments.
Change 4: A change to footnote one of the T&E schedule (Appendix 1)
Original Text: 
1. For scenario 1 subjects, that is when the window between Visit 14 and Visit 1 is ≤8 
weeks, all procedures should be performed except laboratory tests from blood (urine 
pregnancy test must be performed), spirometry and ECG.  For scenario 2 subjects, that is 
when the window between Visit 14 and Visit 1 is >8 weeks, the subject should complete 


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the Follow-up visit (Visit 15) for MEA115661.  Once approvals are received the subject 
can only then begin 201312 and must perform all procedures listed for Visit 1 above.  
Amended Text: 
1. Before entry in to study 201312, determine which scenario the subject is best classified 
as and perform the relevant procedures as defined in Section 6.1 and the SPM.
Change 5: An administrative change of the Medical Monitors details on page 3:
Original Text:
Sponsor Global Medical Monitor Contact Information: 
 MD (Director, Respiratory Medicine Development Centre)
Tel: 
Mobile: 
Sponsor Global Back-up Medical Monitor Contact Information: 
 MD (Director, Respiratory Medicine Development Centre)
Tel: 
Mobile: 
Sponsor Serious Adverse Events (SAE) Contact Information:
 MD (Director, Respiratory Medicine Development Centre)
Tel: 
Mobile: 
Amended Text: 
Sponsor Global Medical Monitor Contact Information: 
 MA MSc. MBBS FFPM (Clinical Development Physician)
Tel: 
Mobile: 
Sponsor Global Back-up Medical Monitor Contact Information: 
 MD (Clinical Development Physician)
Tel: 
Mobile: 
Sponsor Serious Adverse Events (SAE) Contact Information:
 MD (Clinical Development Physician)
Tel: 
Mobile: 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


2013N187987_04
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91
11.9.
Appendix 9: Protocol Amendment 03 Changes
Scope: this applies to all sites
Protocol changes specified in Amendment No. 03 are summarised below:
Change No. 1: Increasing the duration of IP from 2 to 3 years. This occurs in multiple 
sections of the protocol listed below.  The rationale is that 201312 will begin to close on a 
country by country basis when mepolizumab becomes commercially available.  Some 
subjects will complete the 2 year treatment period before commercial availability and to 
ensure that all subjects have a seamless transition from IP to commercially available 
mepolizumab the study treatment duration is increased to three years. 
Change No. 2: Removal of the Follow-up Visit.  This occurs in multiple sections of the 
protocol listed below.  The rationale is that the original reason for the Follow-up visit was 
to collect the final immunogenicity sample 12 weeks after the last dose of IP.  The 
sensitivity of the immunogenicity test has since improved and the immunogenicity 
sample at the Exit visit is now sufficient.   
Study Design 
Original text:
Subjects meeting all of the eligibility criteria will be offered the opportunity to consent 
for this study of up to 128 weeks (including Follow-Up).  
Changed to:
Subjects meeting all of the eligibility criteria will be offered the opportunity to consent 
for this study of up to 172 weeks.  
Study Design
Original text:
Mepolizumab will then be administered approximately every 4 weeks with the last dose 
at Week 116 (Visit 30).  Thirty doses will provide therapeutic coverage for 120 weeks (4 
weeks following the last dose). ). Subjects will continue to receive mepolizumab 100mg 
SC injections for up to 116 weeks or until one of the following occurs:
Changed to:
Mepolizumab will then be administered approximately every 4 weeks with the last dose 
at Week 168 (Visit 43).  Forty three doses will provide therapeutic coverage for 172 
weeks (4 weeks following the last dose). Subjects will continue to receive mepolizumab 
100mg SC injections for up to 172 weeks or until one of the following occurs:


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Additional paragraph added to Study Design
The study closure process will begin, on a country by country basis, as mepolizumab 
becomes commercially available for prescription.  Some subjects will complete the 
original 120 week treatment period (as specified in the previous protocol) prior to 
mepolizumab being available for prescription.  To ensure these subjects do not have a 
treatment gap the treatment period will be extended for an additional 52 weeks to a total 
of 172 weeks.
Study Design
Original text:
The Asthma Control Questionnaire-5 (ACQ-5) will be performed every 12 weeks during 
the study, at the Exit/Early Withdrawal Visit, and Follow-Up Visit to assist the 
investigator in monitoring the subject’s asthma status along with spirometry assessments 
every 6 months and at the Exit/Early Withdrawal Visit. 
Safety labs (hematology, chemistry, and liver analytes) will be drawn at Visit 1 and then 
approximately every 6 months thereafter. Hematology and chemistry labs will also be 
obtained 12 weeks after the subject’s last dose of mepolizumab. Serum samples for anti-
mepolizumab antibody measurements will also be obtained from subjects at baseline 
(Visit 1), Weeks 48, 96, Exit Visit/Early Withdrawal Visit and the Follow-Up Visit. Any 
serum sample testing positive for anti-mepolizumab antibody will also be tested for 
neutralizing antibody. Subjects discontinuing mepolizumab treatment will be monitored 
for exacerbation of their asthma during the subsequent 12 weeks after their last dose.
Changed to:
The Asthma Control Questionnaire-5 (ACQ-5) will be performed every 12 weeks during 
the study and at the Exit/Early Withdrawal Visit to assist the investigator in monitoring 
the subject’s asthma status along with spirometry assessments every 6 months and at the 
Exit/Early Withdrawal Visit. 
Safety labs (hematology, chemistry, and liver analytes) will be drawn at Visit 1 and then 
approximately every 6 months thereafter. Hematology and chemistry labs will also be 
obtained 4 weeks after the subject’s last dose of mepolizumab. Serum samples for anti-
mepolizumab antibody measurements will also be obtained from subjects at baseline 
(Visit 1), Weeks 48, 96, 144 and at the Exit Visit/Early Withdrawal Visit. Any serum 
sample testing positive for anti-mepolizumab antibody will also be tested for neutralizing 
antibody. Subjects discontinuing mepolizumab treatment will be monitored for 
exacerbation of their asthma during the subsequent 4 weeks after their last dose.
Section 3.1 Study Design
Original text: 
Subjects meeting all of the eligibility criteria will be offered the opportunity to consent 
for this study of up to 128 weeks in length (including the Follow-Up visit).  


2013N187987_04
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93
Changed to:
Subjects meeting all of the eligibility criteria will be offered the opportunity to consent 
for this study of up to 172 weeks in length.  
Section 3.1 Study Design
Original text:
Mepolizumab will then be administered approximately every 4 weeks with the last dose 
at Week 116 (Visit 30).  Thirty doses will provide therapeutic coverage for 120 weeks (4 
weeks following the last dose). ). Subjects will continue to receive mepolizumab 100mg 
SC injections for up to 116 weeks or until one of the following occurs:
Changed to:
Mepolizumab will then be administered approximately every 4 weeks with the last dose 
at Week 168 (Visit 43).  Forty three doses will provide therapeutic coverage for 172 
weeks (4 weeks following the last dose). Subjects will continue to receive mepolizumab 
100mg SC injections for up to 172 weeks or until one of the following occurs:
Additional paragraph added to Section 3.1 Study Design
The study closure process will begin, on a country by country basis, as mepolizumab 
becomes commercially available for prescription.  Some subjects will complete the 
original 120 week treatment period (as specified in the previous protocol) prior to 
mepolizumab being available for prescription.  To ensure these subjects do not have a 
treatment gap the treatment period will be extended for an additional 52 weeks to a total 
of 172 weeks.
Section 3.1 Study Design
Original text:
The Asthma Control Questionnaire-5 (ACQ-5) will be performed every 12 weeks during 
the study, at the Exit/Early Withdrawal Visit, and Follow-Up Visit to assist the 
investigator in monitoring the subject’s asthma status along with spirometry assessments 
every 6 months and at the Exit/Early Withdrawal Visit. 
Safety labs (hematology, chemistry, and liver analytes) will be drawn at Visit 1 and then 
approximately every 6 months thereafter. Hematology and chemistry labs will also be 
obtained 12 weeks after the subject’s last dose of mepolizumab. Serum samples for anti-
mepolizumab antibody measurements will also be obtained from subjects at baseline 
(Visit 1), Weeks 48, 96, Exit Visit/Early Withdrawal Visit and the Follow-Up Visit. Any 
serum sample testing positive for anti-mepolizumab antibody will also be tested for 
neutralizing antibody. Subjects discontinuing mepolizumab treatment will be monitored 
for exacerbation of their asthma during the subsequent 12 weeks after their last dose.


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Changed to:
The Asthma Control Questionnaire-5 (ACQ-5) will be performed every 12 weeks during 
the study and at the Exit/Early Withdrawal Visit to assist the investigator in monitoring 
the subject’s asthma status along with spirometry assessments every 6 months and at the 
Exit/Early Withdrawal Visit. 
Safety labs (hematology, chemistry, and liver analytes) will be drawn at Visit 1 and then 
approximately every 6 months thereafter. Hematology and chemistry labs will also be 
obtained 4 weeks after the subject’s last dose of mepolizumab. Serum samples for anti-
mepolizumab antibody measurements will also be obtained from subjects at baseline 
(Visit 1), Weeks 48, 96, 144 and at the Exit Visit/Early Withdrawal Visit. Any serum 
sample testing positive for anti-mepolizumab antibody will also be tested for neutralizing 
antibody. Subjects discontinuing mepolizumab treatment will be monitored for 
exacerbation of their asthma during the subsequent 4 weeks after their last dose.
Section 4.4.3.1. General Withdrawal Requirements
Original text:
Subjects may also be withdrawn from this study if mepolizumab becomes commercially 
available in the respective country, if marketing of mepolizumab is no longer being 
sought in the respective country, or upon decision of the sponsor to discontinue further 
development of mepolizumab. Every effort should be made to have the subject complete 
the Exit/Early Withdrawal and Follow-Up Visits.
Changed to:
Subjects may also be withdrawn from this study if mepolizumab becomes commercially 
available in the respective country, if marketing of mepolizumab is no longer being 
sought in the respective country, or upon decision of the sponsor to discontinue further 
development of mepolizumab. Every effort should be made to have the subject complete 
the Exit/Early Withdrawal Visit.
Section 4.4.4 Subject Self-Withdrawal
Original text: 
Every effort should be made to have the subject return for a follow-up visit 12 weeks post 
last mepolizumab injection.
Changed to: 
Every effort should be made to have the subject return for an Exit/Early Withdrawal visit 
4 weeks post last mepolizumab injection.


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Section 6.3.6 Pregnancy
Original text:
A urine pregnancy test will be performed for all females of child bearing potential prior 
to enrollment, during each scheduled study visit prior to the injection of investigational 
product, and during the Follow-up Visit.
Changed to:
A urine pregnancy test will be performed for all females of child bearing potential prior 
to enrollment, during each scheduled study visit prior to the injection of investigational 
product, and during the Exit/Early Withdrawal Visit.
Section 6.3.10.2 Physical Examination
Original text:
A detailed physical examination including, but not limited to, an evaluation of the lungs 
and cardiovascular system will be conducted at Visit 1, Exit/Early Withdrawal and the 
Follow-Up Visit..
Changed to:
A detailed physical examination including, but not limited to, an evaluation of the lungs 
and cardiovascular system will be conducted outlined in Time and Events Table 
(Appendix 1 Time and Events Table).
Section 11.1 Appendix 1: Time and Events Table
Original text:
Multiple changes made. See over page.


2013N187987_04
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96
Procedures
Week 52 of 
MEA1156611
Treatment Period (Visit Window is 1 week)
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Week of study 
0
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
Written Informed Consent
X
Medical History Changes
X
Smoking Status
X
Inclusion/Exclusion 
Criteria
X
Safety Assessments
Concomitant Medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examination
X
Vital Signs 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG 
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serious Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments2
Immunogenicity
X
X
Hematology
X
X
X
Chemistry 
X
X
X
Liver Analytes
X
X
X
Pregnancy Test3
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
Efficacy Assessments
Exacerbation review 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Asthma Control 
Questionnaire-5
X
X 
X 
X
X
X
Spirometry
X
X
X


2013N187987_04
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97
Procedures
Week 52 of 
MEA1156611
Treatment Period (Visit Window is 1 week)
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Week of study 
0
4
8
12
16
20
24
28
32
36
40
44
48
52
56
60
Worksheets/IP/eCRF
Administer Mepolizumab 
100mg SC
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense paper 
worksheet
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect paper worksheet
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Register IVRS/IWRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete eCRF
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
1.
Before entry in to study 201312, determine which scenario the subject is best classified as and perform the relevant procedures as defined in Section 6.1 and the SPM. 
2.
All laboratory assessments to be completed prior to dosing
3.
Pregnancy test (all females of childbearing potential) U = Urine
Procedure
Treatment Period (Visit Window is 1 Week)
Exit/ 
EW 
Visit4
Follow-
Up
Visit5
Visit
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
Week of study 
64
68
72
76
80
84
88
92
96
100
104
108
112
116
120
128
Safety Assessments
Concomitant Medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examination
X 
X
Vital Signs 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG 
X
X
X 
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serious Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments2
Immunogenicity
X
X
X
Hematology
X
X
X
X
Chemistry 
X
X
X
X
Liver Analytes
X
X
X
X


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Procedure
Treatment Period (Visit Window is 1 Week)
Exit/ 
EW 
Visit4
Follow-
Up
Visit5
Visit
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
Week of study 
64
68
72
76
80
84
88
92
96
100
104
108
112
116
120
128
Pregnancy Test3
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
Efficacy Assessments
Exacerbation review 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Asthma Control 
Questionnaire-5
X
X
X
X
X
X
Spirometry
X
X
X
Worksheets/IP/eCRF
Administer Mepolizumab 
100mg SC
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense Paper Worksheet
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect Paper Worksheet
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Register IVRS/IWRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete eCRF
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
1.
Before entry in to study 201312, determine which scenario the subject is best classified as and perform the relevant procedures as defined in Section 6.1 and the SPM.   
2.
All laboratory assessments to be completed prior to dosing
3.
Urine pregnancy test for all females of childbearing potential,  U = Urine
4.
In the event a subject withdraws early at a scheduled visit, all study procedures scheduled for the Exit Visit (Visit 31) should be performed at this visit instead. In the event a 
subject withdraws between visits, the subject should be asked to return to the clinic as soon as possible to complete the Exit Visit procedures.
5.
Follow-up visit is to occur approximately 12 weeks after the last injection of mepolizumab. The visit window is ±1 week.


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Changed to:
Procedures
Treatment Period (Visit Window is 1 week)
Visit
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
Week of study 
64
68
72
76
80
84
88
92
96
100
104
108
112
116
120
Safety Assessments
Concomitant Medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examination
Vital Signs 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG 
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serious Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments2
Immunogenicity
X
Hematology
X
X
X
Chemistry 
X
X
X
Liver Analytes
X
X
X
Pregnancy Test3
U
U
U
U
U
U
U
U
U
U
U
U
U
U
U
Efficacy Assessments
Exacerbation review 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Asthma Control 
Questionnaire-5
X 
X 
X
X
X
Spirometry
X 
X
X


2013N187987_04
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100
Procedures
Treatment Period (Visit Window is 1 week)
Visit
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
Week of study 
64
68
72
76
80
84
88
92
96
100
104
108
112
116
120
Worksheets/IP/eCRF
Administer Mepolizumab 
100mg SC
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense paper 
worksheet
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect paper worksheet
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Register IVRS/IWRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete eCRF
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
2.
All laboratory assessments to be completed prior to dosing
3.
Pregnancy test (all females of childbearing potential) U = Urine
Procedure
Treatment Period (Visit Window is 1 Week)
Exit/ EW Visit4
Visit
32
33
34
35
36
37
38
39
40
41
42
43
44
Week of study 
124
128
132
136
140
144
148
152
156
160
164
168
172
Safety Assessments
Concomitant Medication
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examination
X 
Vital Signs 
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG 
X
X 
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
Serious Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments2
Immunogenicity
X
X
Hematology
X
X
X
Chemistry 
X
X
X
Liver Analytes
X
X
X
Pregnancy Test3
U
U
U
U
U
U
U
U
U
U
U
U
U
Efficacy Assessments


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101
Procedure
Treatment Period (Visit Window is 1 Week)
Exit/ EW Visit4
Visit
32
33
34
35
36
37
38
39
40
41
42
43
44
Week of study 
124
128
132
136
140
144
148
152
156
160
164
168
172
Exacerbation review 
X
X
X
X
X
X
X
X
X
X
X
X
X
Asthma Control 
Questionnaire-5
X
X
X
X
X
Spirometry
X
X
X
Worksheets/IP/eCRF
Administer Mepolizumab 
100mg SC
X
X
X
X
X
X
X
X
X
X
X
X
Dispense Paper Worksheet
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect Paper Worksheet
X
X
X
X
X
X
X
X
X
X
X
X
X
Register IVRS/IWRS
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete eCRF
X
X
X
X
X
X
X
X
X
X
X
X
X
2.
All laboratory assessments to be completed prior to dosing
3.
Urine pregnancy test for all females of childbearing potential,  U = Urine
4.
In the event a subject withdraws early at a scheduled visit, all study procedures scheduled for the Exit Visit (Visit 44) should be performed at this visit instead. In the event a subject 
withdraws between visits, the subject should be asked to return to the clinic as soon as possible to complete the Exit Visit procedures.


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Change No. 3: The following changes are regarding the change in time from 
reconstitution to administration and the monitoring time after administration of 
mepolizumab.
Section 5.2 Dosage and Administration
Original text:
Once the mepolizumab vial is reconstituted, 100mg of mepolizumab should be drawn 
into a polypropylene syringe and administered immediately
Changed to:
Once the mepolizumab vial is reconstituted, 100mg of mepolizumab should be drawn 
into a polypropylene syringe and administered according to the instructions in the SPM.
Section 6.3 Safety
Original text:
o
Systemic reactions can be allergic or non-allergic in nature and are typically mild 
to moderate in intensity, generally develop within several hours of the injection, 
and are most commonly associated with a complex of symptoms including chills, 
fever, nausea, vomiting, asthenia, headache, skin rash, pruritus, urticaria, 
arthralgia/myalgia, hypotension/hypertension, dizziness, bronchospasm, dyspnea 
or cough. Subjects must be monitored during IP administration and for 1 hour 
post-administration.
Changed to:
o
Systemic reactions can be allergic or non-allergic in nature and are typically mild 
to moderate in intensity, generally develop within several hours of the injection, 
and are most commonly associated with a complex of symptoms including chills, 
fever, nausea, vomiting, asthenia, headache, skin rash, pruritus, urticaria, 
arthralgia/myalgia, hypotension/hypertension, dizziness, bronchospasm, dyspnea 
or cough. 
Change No. 4: The following change is to standardise the collection of concomitant 
medications for subjects moving from MEA115661 to 201312.
Section 5.7.1 Permitted Medications and Non-Drug Therapies
Original text:
Subjects will be required to continue ICS controller therapy for the duration of this study. 
For corticosteroids, the dose must be recorded as well as any dose changes. All other 
concomitant medications taken during the study will also be recorded in the electronic 
case report form (eCRF). The minimum requirement is that drug name and the dates of 
administration are to be recorded.  


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Additional medications to treat asthma are permitted, as are medications to treat other 
disease states, with the exception of those listed as prohibited in Table 2. Oxygen and 
Continuous Positive Airway Pressure (CPAP) are permitted for the treatment of 
obstructive sleep apnea.
Changed to:
Subjects will be required to continue ICS controller therapy for the duration of this study. 
For corticosteroids, the dose must be recorded as well as any dose changes
Details of asthma-related concomitant medications administered from the first dose of 
mepolizumab in 201312 until the Exit/Early Withdrawal visit or last subject visit will be 
recorded in the electronic case report form (eCRF). In addition, any asthma-related 
medications started prior to first dose in 201312, but were ongoing during the first dose 
will also be recorded. The minimum requirement is that drug name, unit dose, and the 
dates of administration are to be recorded.
Details of  non-asthma-related concomitant medications administered from the first dose 
of mepolizumab in 201312 until the Exit/Early Withdrawal visit or last subject visit will 
be recorded in the electronic case report form (eCRF).Additional medications to treat 
asthma are permitted, as are medications to treat other disease states, with the exception 
of those listed as prohibited in Table 2. Oxygen and Continuous Positive Airway Pressure 
(CPAP) are permitted for the treatment of obstructive sleep apnea.

SAP_001.pdf: 
2017N348509_00
CONFIDENTIAL
The GlaxoSmithKline group of companies
201312
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for Study 201312: A Multi-
Centre, Open-Label, Study of Mepolizumab in a Subset of 
Subjects with a History of Life Threatening/Seriously 
Debilitating Asthma Who Participated in the MEA115661 
Trial
Compound Number 
:
SB-240563
Effective Date 
:
25-OCT-2017
Description:

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 201312

This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverable.
RAP Author(s):
Approver
Date
Approval Method
25-OCT-2017
Email
Statistician (Clinical Statistics)
 
Principal Statistician (Clinical Statistics)
25-OCT-2017
Email 
Clinical Statistics and Clinical Programming Line Approvals:
Approver
Date
Approval 
Method
24-OCT-2017
Email
Director (Clinical Statistics)
Director (Clinical Programming) 
25-OCT-2017
Email
Copyright 2017 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD
PPD
PPD
PPD


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RAP Team Approvals:
Approver
Date
Approval 
Method
Medical Director (Safety Evaluation & Risk 
Management)
24-OCT-2017
Email
25-OCT-2017
Email
Manager (Clinical Programming)
23-OCT-2017
Email
Project Physician Lead (Respiratory Therapeutic Unit)
24-OCT-2017
Email
Clinical Investigation Leader (Respiratory Therapeutic 
Unit) 
25-OCT-2017
Email
Operational Science Lead (Respiratory Therapeutic Unit)
25-OCT-2017
Email
Data Quality Leader (Clinical Data Management)
PPD
PPD
PPD
PPD
PPD
PPD


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TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................6
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................6
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................6
2.2.
Study Objective(s) and Endpoint(s)...............................................................6
2.3.
Study Design ................................................................................................8
2.4.
Statistical Hypotheses...................................................................................8
3.
PLANNED ANALYSES ............................................................................................9
3.1.
Interim Analyses ...........................................................................................9
3.2.
Final Analyses ..............................................................................................9
4.
ANALYSIS POPULATIONS .....................................................................................9
4.1.
Protocol Deviations.......................................................................................9
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................10
5.1.
Study Treatment & Sub-group Display Descriptors.....................................10
5.2.
Visit 1 Assessments (Copying from MEA115661).......................................10
5.3.
Baseline Definition......................................................................................11
5.3.1.
Derivations and Handling of Missing Baseline Data.....................11
5.4.
Multicentre Studies .....................................................................................11
5.5.
Examination of Subgroups..........................................................................12
5.6.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................12
6.
STUDY POPULATION ANALYSES .......................................................................13
6.1.
Overview of Planned Study Population Analyses........................................13
6.2.
Subject Disposition .....................................................................................13
6.3.
Demographic and Baseline Characteristics.................................................13
6.3.1.
Demography and Race................................................................13
6.3.2.
Baseline Lung Function Tests......................................................13
6.4.
Medical Conditions .....................................................................................14
6.5.
Concomitant Medications............................................................................14
6.6.
Protocol Deviations.....................................................................................14
7.
SAFETY ANALYSES .............................................................................................15
7.1.
Extent of Exposure .....................................................................................15
7.2.
Adverse Events Analyses ...........................................................................15
7.3.
Adverse Events of Special Interest Analyses..............................................15
7.4.
Clinical Laboratory Analyses.......................................................................16
7.5.
Other Safety Analyses ................................................................................17
7.5.1.
Immunogenicity............................................................................17
8.
EFFICACY ANALYSES..........................................................................................18
8.1.
Primary Efficacy Analyses ..........................................................................18
8.1.1.
Endpoint / Variables.....................................................................18
8.1.2.
Summary Measure ......................................................................18


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8.1.3.
Population of Interest...................................................................18
8.1.4.
Strategy for Intercurrent Events ...................................................18
8.1.5.
Statistical Analyses / Methods .....................................................18
8.1.5.1.
Statistical Methodology Specification..........................18
8.2.
Secondary Efficacy Analyses......................................................................19
8.2.1.
Endpoint / Variables.....................................................................19
8.2.2.
Summary Measure ......................................................................19
8.2.3.
Population of Interest...................................................................19
8.2.4.
Strategy for Intercurrent Events ...................................................19
8.2.5.
Statistical Analyses / Methods .....................................................19
8.2.5.1.
Statistical Methodology Specification..........................20
9.
PHARMACODYNAMIC ANALYSIS........................................................................21
9.1.
Pharmacodynamic Analyses.......................................................................21
9.1.1.
Endpoint / Variables.....................................................................21
9.1.2.
Summary Measure ......................................................................21
9.1.3.
Population of Interest...................................................................21
9.1.4.
Strategy for Intercurrent (Post-Randomization) Events ................21
9.1.5.
Statistical Analyses / Methods .....................................................21
9.1.5.1.
Statistical Methodology Specification..........................21
10. REFERENCES.......................................................................................................22
11. APPENDICES........................................................................................................24
11.1.
Appendix 1: Schedule of Activities ..............................................................24
11.2.
Appendix 2: Assessment Windows .............................................................28
11.2.1.
Assessment Windows..................................................................28
11.2.2.
Early Withdrawal Visits ................................................................28
11.2.3.
Unscheduled Visits ......................................................................28
11.3.
Appendix 3: Treatment Phases...................................................................29
11.3.1.
Treatment Phases (Efficacy Data) ...............................................29
11.3.2.
Treatment Phases (Adverse Events) ...........................................29
11.3.2.1.
Adverse Events Data Derivations ...............................29
11.3.3.
Treatment Phases (Concomitant Medications) ............................30
11.4.
Appendix 4: Data Display Standards & Handling Conventions....................31
11.4.1.
Reporting Process .......................................................................31
11.4.2.
Reporting Standards....................................................................31
11.5.
Appendix 5: Derived and Transformed Data ...............................................33
11.5.1.
General........................................................................................33
11.5.2.
Study Population..........................................................................34
11.5.3.
Efficacy........................................................................................36
11.5.4.
Safety ..........................................................................................37
11.5.5.
Pharmacodynamic.......................................................................39
11.6.
Appendix 6: Reporting Standards for Missing Data.....................................40
11.6.1.
Premature Withdrawals................................................................40
11.6.2.
Handling of Missing Data.............................................................41
11.6.2.1.
Handling of Missing and Partial Dates ........................41
11.7.
Appendix 7: Values of Potential Clinical Importance ...................................43
11.7.1.
Laboratory Values........................................................................43
11.8.
Appendix 8: Model Checking and Diagnostics for Statistical 
Analyses.....................................................................................................44
11.8.1.
Statistical Analysis Assumptions..................................................44


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11.9.
Appendix 9: Abbreviations & Trade Marks ..................................................45
11.9.1.
Abbreviations...............................................................................45
11.9.2.
Trademarks .................................................................................46
11.10. Appendix 10: List of Data Displays..............................................................47
11.10.1. Data Display Numbering..............................................................47
11.10.2. Mock Example Shell Referencing ................................................47
11.10.3. Deliverables.................................................................................47
11.10.4. Study Population Tables..............................................................48
11.10.5. Study Population Figures.............................................................50
11.10.6. Safety Tables...............................................................................50
11.10.7. Safety Figures .............................................................................56
11.10.8. Efficacy Tables ............................................................................57
11.10.9. Efficacy Figures ...........................................................................58
11.10.10.Pharmacodynamic Tables ...........................................................58
11.10.11.ICH Listings .................................................................................59
11.11. Appendix 11: Example Mock Shells for Data Displays ................................64


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1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol 201312.
Revision Chronology:
GSK Document Number
DD-MMM-YYYY
Version
2013N187987_00
11-FEB-2014
Original
2013N187987_01
27-JUN-2014
Amendment No. 1
2013N187987_02
14-NOV-2014
Amendment No. 2
2013N187987_03
19-JUN-2015
Amendment No. 3
2013N187987_04
06-JUL-2015
Republishing Protocol Amendment 3
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
There were no changes or deviations to the originally planned statistical analysis 
specified in the protocol amendment 3 (Dated: 06/JUL/2015).
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints
To provide extended 
treatment with mepolizumab 
to subjects with a history of 
life-threatening or seriously 
debilitating asthma and a 
history of improved disease 
control while receiving 
mepolizumab as defined in 
the protocol.

Annualized rate of exacerbations

Frequency of adverse events
Secondary Objectives
Secondary Endpoints
To further describe the long-
term clinical experience of 
mepolizumab in a subset of 
subjects who demonstrated 
significant clinical benefit 
since receiving mepolizumab

Asthma Control Questionnaire-5 score

Forced expiratory volume in 1 second (FEV1)

Number of withdrawals due to lack of efficacy

Number of withdrawals due to adverse events

Number of hospitalizations due to adverse events 
including asthma exacerbations

Frequency of both systemic (i.e., allergic and non-
allergic) and local site reactions

12-lead ECG parameters

Vital signs

Frequency of positive anti-mepolizumab binding 
antibodies/neutralizing antibodies


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Objectives
Endpoints

Clinical Laboratory Parameters


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2.3.
Study Design
Overview of Study Design and Key Features
Design
Features
Study 201312 is a study of subcutaneously (SC) administered 
mepolizumab 100mg that will enrol a subset of subjects from Study 
MEA115661 who have demonstrated clear benefit from therapy and who 
without continuation of mepolizumab therapy are individuals at greatest 
risk of serious deterioration of their health status. 
This is a multi-centre, open-label, long-term study of mepolizumab 100mg 
administered SC, in addition to standard of care (SOC), in subjects with 
severe eosinophilic asthma. Only subjects who complete the MEA115661 
Exit Visit (Visit 14) and meeting all eligibility criteria will be offered the 
opportunity to consent for this study of up to 172 weeks.
Dosing
Mepolizumab 100 mg SC will be administered approximately every 4 
weeks with the first dose administered at Week 0 (Visit 1) and the last dose 
administered at Week 168 (Visit 43). 
Forty-three doses will provide therapeutic coverage for 172 weeks (4 
weeks following the last dose).
Subjects will continue to receive mepolizumab 100mg SC injections for up 
to 172 weeks or until one of the following occurs:

the risk/benefit profile for the subject is no longer positive in the 
opinion of the investigator or 

the subject’s physician withdraws the subject or

the subject withdraws consent or

the sponsor discontinues development of mepolizumab or

the sponsor discontinues the study in the relevant participating 
country or

mepolizumab becomes commercially available in the local country.
The study closure process will begin, on a country by country basis, as 
mepolizumab becomes commercially available for prescription.
Time & 
Events
Refer to Appendix 1: Schedule of Activities
Treatment 
Assignment
All subjects are assigned to 100 mg SC mepolizumab.
Interim 
Analysis
No interim analysis was conducted.
2.4.
Statistical Hypotheses
Since the study has a single treatment arm, statistical analyses of treatment effect will
not be performed. Therefore, no hypotheses have been defined for this study.


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3.
PLANNED ANALYSES
3.1.
Interim Analyses
While the protocol allowed for interim analyses to be performed as needed in order to 
provide open-label safety data to inform the risk-benefit assessment of mepolizumab in 
severe asthma, no interim analysis was required or conducted.
3.2.
Final Analyses
The final planned primary analyses will be performed after the completion of the
following sequential steps:
1. All subjects have been withdrawn from 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.
4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
All Subjects Enrolled
(ASE) 
The population will comprise all subjects for whom a 
record exists on the database.

Screen failures
As Treated (AT)
The population will consist of all subjects who received at 
least one dose of an open label mepolizumab within 
study 201312.

Study Population

Efficacy

Pharmacodynamic

Safety
Refer to Appendix 10: List of Data Displays which details the population used for each display.
4.1.
Protocol Deviations
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan [Version 4 
(24/AUG/2017)].
o Data will be reviewed prior to freezing the database to ensure all important 
deviations and deviations 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.
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
5.1.
Study Treatment & Sub-group 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.
5.2.
Visit 1 Assessments (Copying from MEA115661)
Subjects will enter this study (201312) after completion of the MEA115661 study. To 
reduce the burden of repeated procedures during the ending of MEA115661 and the start 
of 201312, some baseline assessments will be copied from MEA115661. Detailed 
conditions for copying assessments are listed below:
Definition 1. 
Condition: 
i) Visit 1 Date is less than/equal to 8 weeks apart from the MEA115661 Visit 14 (Exit 
Visit) Date;
ii) MEA115661 Visit 15 (Follow Up) Visit assessment is not available;
Action: Copy assessment from MEA115661 Visit 14 (Exit Visit)
Definition 2. 
Condition: 
i) Visit 1 Date is less than/equal to 8 weeks apart from the MEA115661 Visit 14 (Exit 
Visit) Date;
ii) MEA115661 Visit 15 (Follow Up) Visit assessment is available;
Action: Copy assessment from MEA115661 Visit 15 (Follow Up) Visit
Definition 3. 
Condition: 
i) Visit 1 Date is greater than 8 weeks apart from the MEA115661 Visit 14 (Exit Visit)
Date;
ii) MEA115661 Visit 15 (Follow Up) Visit Date is equal to the Visit 1 Date;
Action: Copy assessment from MEA115661 Visit 15 (Follow Up) Visit
Definition 4. 
Condition: 
i) Visit 1 Date is greater than 8 weeks apart from the MEA115661 Visit 14 (Exit Visit)
Date;
ii) Visit 1 Date is after the MEA115661 Visit 15 (Follow Up) Visit Date 
Action: New assessments to be performed at Visit 1, no copying from MEA115661 will 
be performed


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Under definitions 1-3, a number of the following baseline assessments will be copied 
from either MEA115661 Visit 14 (Exit Visit) or MEA115661 Visit 15 (Follow Up Visit)
where available:
o
Pulmonary function test data (including FEV1 and FVC)
o
Asthma Control Questionnaire-5 (ACQ-5)
o
Vital Sign data
o
ECG data
o
Laboratory data (including Haematology, Chemistry and Liver Event test 
panels)
o
Immunogenicity data
The remaining baseline assessments will need to be performed at Visit 1 of the 201312 
study, in which case, no copying from MEA115661 study will be performed. A list of the 
remaining baseline assessments based on each definition can be found in Appendix 5: 
Derived and Transformed Data. 
5.3.
Baseline Definition
Baseline will be defined for all subjects who are within the AT population.
The baseline assessment for each subject will be derived as the latest assessment prior to 
first dose of mepolizumab in this study. If the measurements are taken on the same date 
as the first administration of mepolizumab, they 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.
5.3.1.
Derivations and Handling of Missing Baseline Data
Definition
Reporting Details
Change from Baseline
= Visit Value – Baseline Value
Ratio to Baseline
= Visit Value / Baseline Value
NOTES :

Unless otherwise specified, the baseline definitions specified in Section 5.3 (Baseline Definition) 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.
5.4.
Multicentre Studies
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, Czech-Republic, France, Germany, Italy, Netherlands, 
Poland, Spain, Ukraine, United Kingdom
Rest of World
Argentina, Australia, Canada, Chile, Japan, Russia, South 
Korea, United States


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5.5.
Examination of Subgroups
The list of subgroups may be used in descriptive summaries and safety analyses.
Additional subgroups of clinical interest may also be considered.
Subgroup
Categories 
Age group
12-17,18-64, >=65 years
5.6.
Other Considerations for Data Analyses and Data Handling 
Conventions
Other considerations for data analyses and data handling conventions are outlined in the 
appendices:
Section
Component
11.1
Appendix 1: Schedule of Activities
11.2
Appendix 2: Assessment Windows
11.3
Appendix 3: Treatment Phases
11.4
Appendix 4: Data Display Standards & Handling Conventions
11.5
Appendix 5: Derived and Transformed Data
11.6
Appendix 6: Reporting Standards for Missing Data
11.7
Appendix 7: Values of Potential Clinical Importance
11.8
Appendix 8: Model Checking and Diagnostics for Statistical Analyses


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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
The study population analyses will be based on the As Treated (AT) population, unless 
otherwise specified.
Study population analyses including analyses of subject’s disposition, demographic and 
baseline characteristics, medical history, concomitant medications and protocol 
deviations will be based on GSK Core Data Standards.  Details of the planned displays
are presented Appendix 10: List of Data Displays. 
6.2.
Subject Disposition
A summary of the number of subjects included in each population will be produced.
The proportion of screen failures, the proportion who reported each reason for screen
failure and the proportion who failed each eligibility criteria will be presented for the All 
Subject Enrolled (ASE) population.
The proportion of subjects in the AT population at each site and within each country and 
region will be presented. 
The proportion of subjects in the AT population who withdrew from the study, and the
reported reasons for withdrawal, will be presented. A Kaplan-Meier plot presenting the
percentage of subjects withdrawing from the study over time will be produced for the AT
Population.
6.3.
Demographic and Baseline Characteristics
6.3.1.
Demography and Race
Demographic characteristics (age, sex, ethnicity, height, weight and body mass index)
will be summarised and listed.
The proportion of subjects reporting each race and racial combination will be presented. 
Race will also be listed.
6.3.2.
Baseline Lung Function Tests
The following Baseline (as defined for this study) clinic lung function results will be 
summarised:

Pre-bronchodilator FEV1 (mL)

Pre-bronchodilator percent predicted FEV1 (%)

Pre-bronchodilator Forced Vital Capacity (FVC) (mL)

Pre-bronchodilator FEV1/FVC


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6.4.
Medical Conditions
An update in each subject’s medical history since the medical history form in the 
MEA115661 trial will be collected at Visit 1. If a subject reports no change in medical 
history, the respective subject’s medical history information will be copied over from the 
MEA115661 trial.
The proportion of subjects who report medical conditions in each medical condition class
will be presented, for past and current conditions separately.
6.5.
Concomitant Medications
The proportion of subjects reporting each concomitant medication will be presented.
Multi-ingredient medications will be presented according to their combination ATC
classification rather than the classifications of the ingredients. Summaries will be split
into asthma and non-asthma concomitant medications, as well as into those taken during 
treatment and post-treatment (as described in Appendix 3: Treatment Phases). Asthma
medication outputs will not display ATC grouping.
Classification of a medication as during or post-treatment will be made with reference to 
the study treatment start and stop dates and the medication start and stop dates. If the 
medication start date is missing or partial then the medication will be considered on-
treatment unless there is evidence to the contrary (e.g. the month of the start date is 
present and is less than the month of the first dose of study medication).
A listing of the relationship between ATC level 1, ingredient and verbatim term will be
produced.
6.6.
Protocol Deviations
Important protocol deviations will be summarised and listed for the AT Population. More 
details are in Appendix 10: List of Data Displays. 


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7.
SAFETY ANALYSES
The main interest of the study is to investigate the long-term safety and these analyses 
will be based on the As Treated (AT) population, unless otherwise specified.
7.1.
Extent of Exposure
The number of treatments administered and the time spent on-treatment will be 
summarised and listed.
Additionally, the overall exposure will be summarised from study 201312 and preceding 
mepolizumab studies where the same subjects participated (MEA115588, MEA115575 
and MEA115661).
7.2.
Adverse Events Analyses
Adverse events analyses including the analysis of adverse events (AEs), Serious (SAEs) 
and other significant AEs will be based on GSK Core Data Standards. 
AEs occurring during pre-treatment, on-treatment and post-treatment phase will be
summarised separately. Adverse events will be coded using the latest version of the 
Medical Dictionary for Regulatory Activities (MedDRA).
The number and percentage of subjects experiencing at least one AE will be summarised.
Exposure adjusted rates of AEs will also be presented to account for the length of 
exposure within the trial. For the definition of exposure adjusted AEs, see Appendix 5: 
Derived and Transformed Data.
The details of the planned displays are provided in Appendix 10: List of Data Displays.
7.3.
Adverse Events of Special Interest Analyses
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).


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Separate summary tables showing the number and percent of subjects with each type of 
AESI, broken down by preferred term will be created. Information will be reported as 
part of the standard AE tables for AESIs of infections, serious infections, neoplasms, 
cardiac disorders and serious cardiac disorders. 
For each type of AESI a profile summary table will be produced containing information 
which would include, but not be limited to, the number of occurrences of the event, event 
characteristics, time to onset, intensity, outcome and action taken. 
A listing of any subjects with systemic events identified by the investigators as meeting 
the criteria for anaphylaxis as outlined by the 2006 Joint National Institute of Allergy and 
Infectious Disease/Food Allergy and Anaphylaxis Network Second Symposium on 
Anaphylaxis [Sampson , 2006] will be provided. Adverse events experienced on a day of 
dosing will be summarised and presented by SOC and preferred term. 
Cardiovascular events will also be captured on targeted CV event pages of the CRF
following AEs and SAEs. The following cardiovascular event listings will be produced 
for all investigator reported events: 

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
Equivalent listings will be produced for all CEC adjudicated events. Note that 
Arrhythmias, pulmonary hypertension, revascularisation and valvulopathy events will not 
be sent for adjudication by the CEC, hence for such events listings will only be produced 
for investigator reported events.
Summaries of events which were reported and confirmed (or not) as cardiovascular 
following adjudication by the trial Clinical Endpoint Committee (CEC) will be 
summarised. 
The details of the planned displays are provided in Appendix 10: List of Data Displays.
7.4.
Clinical Laboratory Analyses
Laboratory evaluations including the analyses of Chemistry laboratory tests, Hematology 
laboratory tests, and liver function tests will be based on GSK Core Data Standards. The 
details of the planned displays are in Appendix 10: List of Data Displays.


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7.5.
Other Safety Analyses
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified. The details of the 
planned displays are presented in Appendix 10: List of Data Displays.
7.5.1.
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 mepolizumab ADA (screening/confirmation/titration) assay version 
2011N122789_03 is performed at Alliance Pharma (method 120711M01.V02). The 
mepolizumab Nab assay version 2011N129752_03 is being performed within GSK.

A table will be produced summarising the number and percentage of negative and 
confirmed positive subjects ADA samples by visit in the AT 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 AT Population, by visit. 

An additional summary of treatment emergent positive confirmatory binding antibody 
assay and results in the subset of subjects who did not have a positive confirmatory 
binding antibody assay result 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 and neutralising antibody results) will be listed.
The details of the planned Immunogenicity displays are presented in Appendix 10: List of 
Data Displays.


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8.
EFFICACY ANALYSES
8.1.
Primary Efficacy Analyses
8.1.1.
Endpoint / Variables
The primary efficacy analyses endpoint is the annualized rate of exacerbations.
8.1.2.
Summary Measure
The frequency of exacerbations of asthma collected during the on-treatment phase 
(Appendix 3: Treatment Phases) will be summarised.
8.1.3.
Population of Interest 
The primary efficacy analyses will be based on the AT population, unless otherwise 
specified.
8.1.4.
Strategy for Intercurrent Events
For the primary analyses, only on-treatment exacerbations will be summarised. More 
details about phases can be found in Appendix 3: Treatment Phases.
8.1.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK data standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 8.1 will be 
summarised using descriptive statistics.
8.1.5.1.
Statistical Methodology Specification
Endpoint / Variables

Annualized rate of on-treatment exacerbations
Model Specification

The frequency of exacerbations will be analysed using Negative Binomial generalised linear 
model.

Exacerbations separated by less than 7 days will be treated as a continuation of the same 
exacerbation.

The logarithm of time on treatment will be used as an offset variable.
Model Checking & Diagnostics

Refer Appendix 8: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation

The estimated mean rate per year and corresponding 95% confidence interval will be 
presented


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Sensitivity and Supportive Analyses

An additional analysis will be performed only for the subjects enrolled into study 201312 from 
previous exacerbation study MEA115588. This analysis will present the exacerbation rate 
during the current and preceding study periods (from studies MEA115588 and MEA115661) to 
assess if the exacerbation rate reduction has been maintained.
8.2.
Secondary Efficacy Analyses
8.2.1.
Endpoint / Variables
The secondary efficacy analysis consists of:

Time to First Exacerbation

Annualized rate of Exacerbations Requiring Hospitalisation or Emergency 
Department (ED) visit

Annualized rate of Exacerbations Requiring Hospitalisation

Asthma Control Questionnaire-5 Score

Forced expiratory volume in 1 second (FEV1)

Oral Corticosteroid Dose (mg/day)
8.2.2.
Summary Measure
The frequency of exacerbations requiring hospitalisation/hospitalisation or ED visit 
collected during the on-treatment phase (Appendix 3: Treatment Phases) will be 
summarised.
Asthma Control Questionnaire (ACQ-5) score (absolute value and change from baseline) 
and Pre-bronchodilator FEV1 (absolute value and change from baseline (mL)) will be 
summarised by visit. 
Additionally, OCS use will be summarised only for the subjects enrolled into study 
201312 from previous OCS reduction study MEA115575. This analysis will present the
median OCS Dose (mg/day) during the current and preceding study periods (from studies 
MEA115575 and MEA115661) to assess if the reduction in OCS use has been 
maintained.
8.2.3.
Population of Interest
The secondary efficacy analyses will be based on the AT population, unless otherwise 
specified.
8.2.4.
Strategy for Intercurrent Events
Only subjects who have on-treatment data will be included. 
8.2.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK data standards and statistical principles.


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Unless otherwise specified, endpoints / variables defined in Section 8.2.1 will be 
summarised using descriptive statistics and graphically presented (where appropriate).
8.2.5.1.
Statistical Methodology Specification
Endpoint / Variables

Time to First Exacerbation
Results Presentation

Kaplan-Meier estimates will be summarised by study visit and presented graphically.
Endpoint / Variables

Annualized rate of Exacerbations Requiring Hospitalisation or Emergency Department visits

Annualized rate of Exacerbations Requiring Hospitalisation
Results Presentation

See Section 8.1.5.1 for details of the analysis model.
Endpoint / Variables

Asthma Control Questionnaire-5 (ACQ-5) score
Results Presentation

ACQ-5 score (absolute value and change from baseline) will be summarised by visit.
Endpoint / Variables

Forced expiratory volume in 1 second (FEV1)
Results Presentation

Pre-bronchodilator FEV1 (absolute value and changes from baseline (mL)) will be summarised 
by visit. 
Endpoint / Variables

Oral Corticosteroid Dose (mg/day)
Results Presentation

OCS use will be summarised only for the subjects enrolled into study 201312 from previous 
OCS reduction study MEA115575. This analysis will present the median OCS Dose (mg/day) 
during the current and preceding study periods (from studies MEA115575 and MEA115661) to 
assess if the reduction in OCS use has been maintained.


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9.
PHARMACODYNAMIC ANALYSIS
9.1.
Pharmacodynamic Analyses
9.1.1.
Endpoint / Variables
The pharmacodynamic variable considered is blood eosinophils. 
9.1.2.
Summary Measure
Blood eosinophil count and ratio to baseline will be summarised by visit.
9.1.3.
Population of Interest
The pharmacodynamic analyses will be based on the AT population, unless otherwise 
specified.
9.1.4.
Strategy for Intercurrent (Post-Randomization) Events
Only on-treatment blood eosinophils will be analysed (See Section 11.3.1). 
9.1.5.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK Data Standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 9.1.1 will be 
summarised using descriptive statistics.
9.1.5.1.
Statistical Methodology Specification
Endpoint / Variables

Ratio to baseline in blood eosinophil count
Data Specification

A log-transformation will be applied to blood eosinophil count data prior to summarising the 
data.

If a blood eosinophil count of zero is reported, it will be imputed with half of the lowest possible 
blood eosinophil count, where applicable, prior to log transforming the data (Note: this 
imputation has typically been 0.5 * 0.01 GI/L = 0.005 GI/L for previous mepolizumab studies).
Results Presentation

Blood eosinophil count and ratio to baseline will be summarised by visit.

Geometric mean and standard deviation (on natural log scale) will be summarised.


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10.
REFERENCES
GlaxoSmithKline Document Number 2011N122789_03 Study ID Across Studies. 
Electrochemiluminescent Immunoassay Method for the Detection of anti-SB240563 
(Mepolizumab) Antibodies in Human Serum (6th Generation Assay). Report Date 09-
Jun-2016. 
GlaxoSmithKline Document Number 2011N129752_03 Study ID Across Studies. 
Indirect Ligand-Binding Assay for the Detection of Neutralizing Antibody Against SB-
240563 in Human Serum. Report Date 07-Nov-2016. 
GlaxoSmithKline Document Number 2013N187987_00 Study ID 201312. Study 201312: 
A Multi-Centre, Open-Label, Study of Mepolizumab in a Subset of Subjects with a 
History of Life Threatening/Seriously Debilitating Asthma Who Participated in the 
MEA115661 Trial. Original Report Date 2014-FEB-11.
GlaxoSmithKline Document Number 2013N187987_01 Study ID 201312. Study 201312: 
A Multi-Centre, Open-Label, Study of Mepolizumab in a Subset of Subjects with a 
History of Life Threatening/Seriously Debilitating Asthma Who Participated in the 
MEA115661 Trial. Amendment No. 1 Report Date 2014-JUN-27.
GlaxoSmithKline Document Number 2013N187987_02 Study ID 201312. Study 201312: 
A Multi-Centre, Open-Label, Study of Mepolizumab in a Subset of Subjects with a 
History of Life Threatening/Seriously Debilitating Asthma Who Participated in the 
MEA115661 Trial. Amendment No. 2 Report Date 2014-NOV-14.
GlaxoSmithKline Document Number 2013N187987_03 Study ID 201312. Study 201312: 
A Multi-Centre, Open-Label, Study of Mepolizumab in a Subset of Subjects with a 
History of Life Threatening/Seriously Debilitating Asthma Who Participated in the 
MEA115661 Trial. Amendment No. 3 Report Date 2015-JUN-19.
GlaxoSmithKline Document Number 2013N187987_04 Study ID 201312. Study 201312: 
A Multi-Centre, Open-Label, Study of Mepolizumab in a Subset of Subjects with a 
History of Life Threatening/Seriously Debilitating Asthma Who Participated in the 
MEA115661 Trial. Republished Amendment 3 Report Date 2015-JUL-06.
GlaxoSmithKline Document Number n/a Study ID Across Studies. Program Safety 
Analysis Plan for Mepolizumab (SB240563) Version 3. 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 


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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.


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11.
APPENDICES
11.1.
Appendix 1: Schedule of Activities
Table 1
Time and Events Table
1. Before entry in to study 201312, determine which scenario the subject is best classified as and perform the relevant procedures as defined in Section 11.5.1 of the Protocol and the 
SPM.
2. All laboratory assessments to be completed prior to dosing
3. Pregnancy test (all females of childbearing potential) U = Urine


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1. Before entry in to study 201312, determine which scenario the subject is best classified as and perform the relevant procedures as defined in Section 11.5.1 of the Protocol and the 
SPM.
2. All laboratory assessments to be completed prior to dosing
3. Pregnancy test (all females of childbearing potential) U = Urine


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2. All laboratory assessments to be completed prior to dosing
3. Pregnancy test (all females of childbearing potential) U = Urine


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2. All laboratory assessments to be completed prior to dosing 
3. Pregnancy test (all females of childbearing potential) U = Urine
4. In the event a subject withdraws early at a scheduled visit, all study procedures scheduled for the Exit Visit (Visit 44) should be performed at this visit instead. In the event a subject
withdraws between visits, the subject should be asked to return to the clinic as soon as possible to complete the Exit Visit procedures.


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11.2.
Appendix 2: Assessment Windows
11.2.1.
Assessment Windows 
In some circumstances certain Visit 1 assessments will not be performed and assessments 
will be copied from either Visit 14 (Exit Visit) or Visit 15 (Follow Up) from the 
preceding study MEA115661. Refer to Section 5.2 for more details.
All other 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.
11.2.2.
Early Withdrawal Visits
If a subject withdraws from the study at a scheduled visit (i.e. completes an Early
Withdrawal), 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 1: Schedule of Activities).
For example, if a subject prematurely withdraws from the study and completed the Early
Withdrawal Visit at Visit 6 (Week 20) 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 7 (Week 24) (if data at that visit were not recorded) as this is the 
closest nominal visit at which collection of FEV1 data is scheduled.
11.2.3.
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 does not 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.
After Visit 31 (Week 120) all the visits will be collected in an unscheduled manner. As a 
result, all assessments following Visit 31 will be slotted to the appropriate scheduled visit 
using the closest assessment to the expected/target visit date. 


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11.3.
Appendix 3: Treatment Phases
11.3.1.
Treatment Phases (Efficacy Data)
Exacerbation data and efficacy data collected at scheduled visits (including: ACQ-5 
Questionnaire, PFT and Blood Eosinophils) will be classified according to time of 
occurrence/assessment relative to the first and last date of mepolizumab in study 201312 
and the attendance dates of specific visits.
Treatment Phase
Definition
Pre-Treatment 
Date & Time < First dose of mepolizumab Date & Time in study 201312
On-Treatment
First dose of mepolizumab in study 201312 ≤Date & Time ≤Earliest of (1) or (2):
(1) Last dose of mepolizumab Date in study 201312 + 28 days or 
(2) Early Withdrawal Visit Date
Post-Treatment
Date & Time > Earliest of (1) or (2): 
(1) Last dose of mepolizumab in study 201312 + 28 days or
(2) Early Withdrawal Visit Date
11.3.2.
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 in study 201312.
Treatment Phase
Definition
Pre-Treatment 
AE Onset Date & time < First dose of mepolizumab in study 201312
If mepolizumab treatment in study 201312 is never started then all AEs will be 
classified as pre-treatment.
On-Treatment
First dose of mepolizumab in study 201312 ≤AE Onset Date & Time ≤Last dose of 
mepolizumab in study 201312 + 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 in study 201312).
Post-Treatment 
AE Onset Date & time > Last dose of mepolizumab in study 201312 + 28 days
11.3.2.1.
Adverse Events Data Derivations 
Treatment Phase
Definition
Onset Time
Since 1st Dose
(Days)
If First dose of mepolizumab in study 201312 ˃ AE Onset Date = AE Onset Date - First 
dose of mepolizumab in study 201312
If First dose of mepolizumab in study 201312 ≤AE Onset Date = AE Onset Date - First 
dose of mepolizumab in study 201312 +1 day
If First dose of mepolizumab in study 201312 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.


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11.3.3.
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 in study 201312.
A medication will be summarised in every treatment/study phase in which it was taken, 
so for example a medication that was started during treatment and stopped post treatment 
will appear in both the during treatment and post treatment tables.
Treatment Phase
Definition
Taken During
Treatment
If Con-med Start Date < First dose of mepolizumab in study 201312 and Con-med 
Stop Date ≥First dose of mepolizumab in study 201312
or
If First dose of mepolizumab in study 201312 ≤Con-med Start Date ≤Last dose of 
mepolizumab in study 201312+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 in study 201312).
Started During
Treatment
Subset of con-meds taken during Treatment for which:
First dose of mepolizumab in study 201312 ≤Con-med Start Date ≤Last dose of 
mepolizumab in study 201312 + 28
days
Taken Post
Treatment
Last dose of mepolizumab in study 201312+ 28 days < Con-med Stop Date


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11.4.
Appendix 4: Data Display Standards & Handling 
Conventions
11.4.1.
Reporting Process
Software

The currently supported versions of SAS software will be used.
Reporting Area
HARP Server
: uk1salx00175
HARP Compound
: /arenv/arprod/sb240563/ mid201312 /final
Quality Control
(QC) Spread sheet
: /arenv/arprod/sb240563/ mid201312/final/documents
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.
11.4.2.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated
(IDSL Standards Location: https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx)

4.03 to 4.23: General Principles

5.01 to 5.08: Principles Related to Data Listings

6.01 to 6.11: Principles Related to Summary Tables

7.01 to 7.13: Principles Related to Graphics 
Formats

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for reporting of 
data based on the raw data collected, unless otherwise stated.

Numeric data will be reported at the precision collected on the eCRF.

The reported precision (decimal places) 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 start of 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.


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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. 
Note additionally all assessments following Visit 31 will be slotted to the appropriate scheduled 
visit. See Appendix 2: Assessment Windows for further details.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N (number of subjects in the treatment group), n (number of subjects with non-
missing values), frequency, %
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.


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11.5.
Appendix 5: Derived and Transformed Data
11.5.1.
General
Multiple Measurements at One Analysis 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 in study 201312:
Ref Date = Missing → 
Study Day = Missing 

Ref Date < Date of first dose of mepolizumab in study 201312→ 
Study Day = Ref Date – Date of first dose of mepolizumab in study 201312

Ref Data ≥ Date of first dose of mepolizumab → 

Study Day = Ref Date – (Date of first dose of mepolizumab in study 201312) + 1


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Critical Baseline Assessments
Subjects meeting Baseline Definition 1 from Section 5.2:
1.
Demographic information review and update for 201312
2.
General medical history review and update in 201312
3.
Physical examination and update in 201312
4.
Assessment of Inclusion/Exclusion criteria.
5.
Urine pregnancy test for females of childbearing potential (Protocol Appendix 2: Acceptable Birth 
Control)
Subjects meeting Baseline Definition 2 and 3 from Section 5.2:
1.
Demographic information review and update for 201312
2.
General medical history review and update in 201312
3.
Physical examination and update in 201312
4.
Pulmonary function tests and assessment
5.
Assessment of Inclusion/Exclusion criteria.
6.
Urine pregnancy test for females
Subjects meeting Baseline Definition 4 from Section 5.2:
1.
Demographic information review and update for 201312
2.
General medical history review and update in 201312
3.
Physical examination and update in 201312
4.
Pulmonary function tests and assessment
5.
Assessment of Inclusion/Exclusion criteria.
6.
Asthma Control Questionnaire-5 (Protocol Section 6.2.1.2)
7.
Vital signs (Protocol Section 6.3.10.3)
8.
12-lead ECG (Protocol Section 6.3.10.4)
9.
Blood sampling for the following:
o
Clinical chemistry
o
Haematology
o
Liver Analytes
o
Immunogenicity
10. Urine pregnancy test for females
11.5.2.
Study Population
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 Visit 1 date.
[(30th June of the year of birth reported on eCRF – date of Visit 1)/365.25]
Body Mass Index (BMI)

Calculated as Weight (kg) / Height2 (m2)


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Percent Predicted FEV1
FEV1 % of predicted normal will be derived using the Global Lung Function Initiative 2012 lookup
tables which are based on the Quanjer equations [Quanjer, 2012] according to the
Race/Ethnicity designations specified below:
Collected Race[1]
Quanjer Designation
African American/African Heritage 
African-American calculation will be applied
American Indian or Alaskan Native 
Other calculation will be applied
Asian-Central/South Asian Heritage 
South East Asian calculation will be applied
Asian-East Asian Heritage 
North East Asian calculation will be applied
Asian-Japanese Heritage 
Other calculation will be applied
Asian- 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-bronchodilator FEV1/FVC ratio will be calculated as the ratio of the FEV1 and FVC values.
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
Hydrocortisone Sodium Phosphate 
0.25
Meprednisone
1


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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
11.5.3.
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.
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 


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Exacerbations 
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
11.5.4.
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 in study 201312 – (First 
mepolizumab dose in study 201312) + 29 days

The extent of exposure will also be summarised as the number of study treatments 
administered 
Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities
(MedDRA) coding dictionary. Classification of an AE as pre-, on- or post-treatment will
be made with reference to the study treatment start and stop dates and the AE onset date.
If the AE onset date is missing or partial then the AE will be considered on-treatment
unless there is evidence to the contrary (e.g. the month of the onset date is present and is
less than the month of the first dose of study medication). AEs with onset up to 4 weeks
after the last dose of treatment will be considered on-treatment. AEs with onset after this
period will be considered post-treatment but will be assigned to the treatment previously
received.
Any SAEs for screen failures or run-in failures will be classified as pre-treatment SAEs.
The most frequent on-treatment AEs will be defined as AEs with frequency ≥3% (prior to
rounding).


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Adverse Events of Special Interest
Section 7.3 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).
Exposure Adjusted Adverse Events
The number of events per 1000 subject-years of exposure will be calculated as:
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: 

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


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ECG Parameters

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).

Regarding blood eosinophil laboratory data please reference Section 11.5.5.
11.5.5.
Pharmacodynamic 
Laboratory Assessments
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.
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).


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11.6.
Appendix 6: Reporting Standards for Missing Data
11.6.1.
Premature Withdrawals
Element
Reporting Detail
General

Subjects will receive mepolizumab 100 mg SC every for weeks, but it is expected that 
subjects would withdraw before the Exist Visit due to NUCALA becoming commercially 
available before the end of the study. Thus, this study will not have any completers and 
all subjects will eventually withdraw (See Section 2.3). 

Withdrawn subjects will not replaced in the study.

All available data from subjects who were withdrawn from the study will be listed and all 
available planned data up to and including the date of early withdrawal will be included 
in summary tables and figures, unless otherwise specified.

The number of subjects who withdraw early will be summarised and listed.

Early withdrawal visits will be slotted as per Appendix 2: Assessment Windows.
Screen 
Failures 
For the purposes of this study screen failures will be defined as follows:

Subjects will be assigned a study number at the time of signing the informed consent 
(Baseline Visit).
Those subjects that complete at least one Visit 1 (Baseline Visit) procedure but do not 
subsequently receive study treatment will be designated as screen failures.


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11.6.2.
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. 
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 11.5.4 for the 
handling of this data.

The ACQ-5 score will be considered as missing if <4 items of the questionnaire 
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.
11.6.2.1.
Handling of Missing and Partial Dates
Element
Reporting Detail
General

The eCRF allows for the possibility of missing or partial dates (i.e., only month 
and year is captured) to be recorded for event start and end dates.

The recorded missing or partial date will be displayed in listings as captured.
Concomitant 
Medications

Partial dates for any concomitant medications recorded in the CRF will be 
imputed using the following convention: 
o
If the partial date is a start date, a '01' 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), 


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Element
Reporting Detail
as per Appendix 3: 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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11.7.
Appendix 7: Values of Potential Clinical Importance
11.7.1.
Laboratory Values
Haematology
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Hematocrit 
Ratio of 
1
Aged 12+
0.201
0.599
Haemoglobin 
g/L
Aged 12+
71
199
Platelet Count 
x109/ L
Aged 1+
31
1499
While Blood Cell Count (WBC)
x109/ L
Aged 12+
1.1
-
Clinical Chemistry
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Calcium
mmol/L
Aged 3+
1.50
3.24
Glucose
mmol/L
Aged 1+
2.2
27.8
Phosphorus
mmol/L
Aged 3+
0.32
-
Potassium
mmol/L
Aged 3+
2.8
6.5
Sodium
mmol/L
Aged 0+
120
160
Liver Function
Test Analyte
Units
Category
Clinical Concern Range
ALT/SGPT 
U/L
Aged 3-12
>143 (and Total Bilirubin > 43)
ALT/SGPT
U/L
Aged 13+
>239 (and Total Bilirubin > 43)


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11.8.
Appendix 8: Model Checking and Diagnostics for Statistical 
Analyses
11.8.1.
Statistical Analysis Assumptions
Endpoint(s)

Frequency of asthma exacerbations during the treatment period
Analysis

Negative binomial regression analysis

In the event that this model fails to converge, the model will be reviewed and alternatives 
explored.

Distributional assumptions underlying the model used for analysis will be examined by:
o
assessing if a sufficient number of events occurred.

If there are any important departures from the distributional assumptions, transformations of 
covariates may be considered or alternative models may be explored as supporting analyses.


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11.9.
Appendix 9: Abbreviations & Trade Marks
11.9.1.
Abbreviations
Abbreviation
Description
ACQ
Asthma Control Questionnaire
ADA
Anti-drug Antibody
ADaM
Analysis Data Model
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine Transaminase
ASE
All Subjects Enrolled
AT
As Treated
ATC
Anatomical Therapeutic Chemical
BLQ
Below Limit of Quantification
BMI
Body Mass Index
AIC
Akaike's Information Criteria
A&R
Analysis and Reporting 
CDISC
Clinical Data Interchange Standards Consortium
CEC
Clinical Endpoint Committee
CI
Confidence Interval
CIL
Clinical Investigation Leader
CPMS
Clinical Pharmacology Modelling & Simulation
CS
Corticosteroid
CSR
Clinical Study Report
CTR
Clinical Trial Register
DBF
Database Freeze
DBR
Database Release
DOB
Date of Birth
DP
Decimal Places
ECG
Electrocardiogram
eCRF
Electronic Case Record Form
ED
Emergency Department
EMA
European Medicines Agency
EW
Early Withdrawal
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Clinical Results Disclosure Requirements
FEV1
Forced expiratory volume in 1 second
FVC
Forced Vital Capacity
GCSP
Global Clinical Safety and Pharmacovigilance
GSK
GlaxoSmithKline
ICH
International Conference on Harmonization
ICS
Inhaled Corticosteroids
IDSL
Integrated Data Standards Library
IG
Implementation Guide
IM
Intramuscular


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Abbreviation
Description
IMMS
International Modules Management System
IP
Investigational Product
IV
Intravenous
LFT
Liver Function Test
LLQ
Lower Limit of Quantification
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
PK
Pharmacokinetic
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
Randomization & Medication Ordering System 
RAP
Reporting & Analysis Plan
RTF
Rich Text File
SAC
Statistical Analysis Complete
SAE
Serious Adverse Event
SAS
Statistical Analysis Software
SC
Subcutaneous
SD
Standard Deviation
SDSP
Study Data Standardization Plan
SDTM
Study Data Tabulation Model
SE
Standard Error
SMQ
Standard MedDRA Query
SOC
System Organ Class
SOP
Standard Operation Procedure
SRM
Study Reference Manual
TA
Therapeutic Area
TFL
Tables, Figures & Listings 
TST
Therapeutic Standards Team
11.9.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
HARP
SAS


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11.10.
Appendix 10: List of Data Displays
11.10.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.17
1.1
Safety
2.1 to 2.67
2.1 to 2.2
Efficacy
3.1 to 3.12
3.1
Pharmacodynamic
4.1
N/A
Section
Listings
ICH Listings
1 to 50
11.10.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays will be provided on request. 
11.10.3.
Deliverables
Delivery 
Description
SAC
Final Statistical Analysis Complete


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11.10.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
Populations Analysed
1.1.
ASE
SP1
Summary of Study Populations
IDSL
Include All Subjects Enrolled and As 
Treated Populations
SAC
Subject Disposition
1.2.
ASE
ES6
Summary of Screening Status and Reasons for Screen Failure
Journal Requirements
SAC
1.3.
ASE
IE2
Summary of Failed Inclusion/Exclusion/Continuation Criteria for 
Screen Failures
SAC
1.4.
AT
IE2
Summary of Failed Inclusion/Exclusion/Continuation Criteria for 
Subjects within the As Treated Population
SAC
1.5.
AT
NS1
Summary of Number of Subjects by Region, Country and Site
Add in a column for region, add a total 
for regions and a total for country
EudraCT/Clinical Operations
SAC
1.6.
AT
ES1
Summary of Disposition and Reasons for Study Withdrawal
ICH E3, FDAAA, EudraCT
SAC
Demographic and Baseline Characteristics
1.7.
AT
DM1
Summary of Demographic Characteristics
ICH E3, FDAAA, EudraCT
SAC
1.8.
ASE
DM11
Summary of Age Ranges
EudraCT, keep rows ≥12-17, ≥18-<64, 
≥65-<84, ≥85
SAC
1.9.
AT
DM5
Summary of Race and Racial Combinations
ICH E3, FDA, FDAAA, EudraCT
SAC
1.10.
AT
DM6
Summary of Race and Racial Combinations Details 
ICH E3, FDA
SAC
1.11.
AT
SHELL
Summary of Baseline Lung Function Tests
Include FEV1, FVC, FEV/FVC, 
%Predicted
SAC


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Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
Medical Conditions
1.12.
AT
MH4
Summary of Past Medical Conditions
ICH E3
SAC
1.13.
AT
MH4
Summary of Current Medical Conditions
ICH E3 
SAC
Concomitant Medications
1.14.
AT
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
1.15.
AT
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
1.16.
AT
CM1
Summary of Non-Asthma Medications Taken During Treatment
Footnote: Medications may be 
displayed under more than one ATC 
classification
SAC
Protocol Deviation
1.17.
AT
DV1
Summary of Important Protocol Deviations
ICH E3
SAC


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11.10.5.
Study Population Figures
Study Population: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
Subject Disposition 
1.1
AT
SHELL
Time to End of Study 
See Study Population Figure 1.1 
(MEA117113 ‘final’ reporting effort), but 
exclude ‘Placebo’ and Mepo 300mg SC
SAC
11.10.6.
Safety Tables
Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
Exposure
2.1.
AT
SHELL
Summary of Exposure to Study Medication
ICH E3
See format of Study Population Table 
1.28 (200862 ‘final’ reporting effort).
SAC
2.2.
AT
SHELL
Summary of Exposure to Study Medication (Therapeutic 
Coverage) From Studies MEA115588, MEA115575, 
MEA115661 and 201312
See format of Study Population Table 
7.74 (MEA115661 ‘manuscript1’ 
reporting effort).
SAC
Adverse Events (AEs)
2.3.
AT
SHELL
Overview of Adverse Events
SAC
2.4.
AT
AE1
Summary of On-Treatment Adverse Events by System Organ 
Class and Preferred Term
ICH E3
SAC
2.5.
AT
SHELL
Summary of Exposure Adjusted On-Treatment Adverse Events 
by System Organ Class and Preferred Term
SAC


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Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
2.6.
AT
AE5
Summary of On-Treatment Adverse Events by Maximum 
Intensity by System Organ Class and Preferred Term
ICH E3
Add a Total column across all severities
SAC
2.7.
AT
AE1
Summary of Post-Treatment Adverse Events by System Organ 
Class and Preferred Term
SAC
2.8.
AT
AE5
Summary of Post-Treatment Adverse Events by Maximum 
Intensity by System Organ Class and Preferred Term
ICH E3
Add a Total column across all severities
SAC
2.9.
AT
AE3
Summary of Common (>=3%) On-Treatment Adverse Events by 
Overall Frequency
ICH E3
≥3% (prior to rounding to nearest 
percent)
SAC
2.10.
AT
SHELL
Summary of Exposure Adjusted On-Treatment Common (>=3%) 
Adverse Events by System Organ Class and Preferred Term
≥3% (prior to rounding to nearest 
percent)
SAC
2.11.
AT
AE1
Summary of On-Treatment Drug-Related Adverse Events by 
System Organ Class and Preferred Term
ICH E3
SAC
2.12.
AT
SHELL
Summary of Exposure Adjusted On-Treatment Drug-Related 
Adverse Events by System Organ Class and Preferred Term
SAC
2.13.
AT
AE5
Summary of On-Treatment Drug-Related Adverse Events by 
System Organ Class and Preferred Term and Maximum 
Intensity
Add a Total column across all severities
SAC
2.14.
AT
AE1
Summary of Adverse Events Reported on Day of Dosing by
System Organ Class and Preferred Term
SAC
2.15.
AT
SHELL
Summary of On-Treatment Adverse Events by Age Group (12-
17, 18-64, >=65 years)
SAC
2.16.
AT
SHELL
Summary of On-Treatment Adverse Events by Highest Anti Drug 
Antibody Result At Any Time Post Baseline 
SAC
2.17.
AT
SHELL
Summary of Post-Treatment Adverse Events by Highest Anti 
Drug Antibody Result At Any Time Post Baseline 
SAC


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Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
2.18.
AT
AE15
Summary of Common (>=3%) Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of Subjects 
and Occurrences)
FDAAA, EudraCT
≥3% (prior to rounding to nearest 
percent)
SAC
Serious and Other Significant Adverse Events
2.19.
AT
AE1
Summary of Pre-Treatment Serious Adverse Events by System 
Organ Class and Preferred Term
SAC
2.20.
AT
AE1
Summary of On-Treatment Serious Adverse Events by System 
Organ Class and Preferred Term
SAC
2.21.
AT
AE1
Summary of Post-Treatment Serious Adverse Events by System 
Organ Class and Preferred Term
SAC
2.22.
AT
SHELL
Summary of Exposure Adjusted On-Treatment Serious Adverse 
Events by System Organ Class and Preferred Term
SAC
2.23.
AT
SHELL
Summary of On-Treatment Serious Adverse Events by Age 
Group (12-17, 18-64, >=65 years)
SAC
2.24.
AT
AE1
Summary of Fatal Serious Adverse Events
SAC
2.25.
AT
SHELL
Summary of Fatal Serious Adverse Events by Age Group (12-
17, 18-64, >=65 years)
SAC
2.26.
AT
AE1
Summary of Non-Fatal Serious On-Treatment Adverse Events
by System Organ Class and Preferred Term
SAC
2.27.
AT
AE1
Summary of Non-Fatal Serious Post-Treatment Adverse Events
by System Organ Class and Preferred Term
SAC
2.28.
AT
SHELL
Summary of Exposure Adjusted On-Treatment Non-Fatal 
Serious Adverse Events by System Organ Class and Preferred 
Term
SAC


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Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
2.29.
AT
AE1
Summary of Drug-Related Fatal Serious Adverse Events by 
System Organ Class and Preferred Term
SAC
2.30.
AT
AE5
Summary of Drug-Related Serious Adverse Events by System 
Organ Class and Preferred Term and Maximum Intensity
Add a Total column across all severities
SAC
2.31.
AT
AE3
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study by 
System Organ Class and Preferred Term /by Overall Frequency
IDSL
SAC
2.32.
AT
SHELL
Summary of Exposure Adjusted On-Treatment Adverse Events 
Leading to Permanent Discontinuation of Study Treatment or 
Withdrawal from Study by System Organ Class and Preferred 
Term
SAC
2.33.
AT
AE16
Summary of On-Treatment Serious Adverse Events by System 
Organ Class and Preferred Term (Number of Subjects and 
Occurrences)
FDAAA, EudraCT
SAC
Adverse Events of Special Interest
2.34.
AT
AE1
Summary of On-Treatment Adverse Events Meeting 
Anaphylaxis Criteria 
Present by Anaphylactic Criterion 1, 2 
and 3 rather than SOC as shown in 
AE1
Insert footnote: “Events displayed are a 
subset of reactions defined by the 
Investigator as being systemic”
SAC
2.35.
AT
SHELL
Summary Profile of On-Treatment Adverse Events Meeting 
Anaphylaxis Criteria 
Insert footnote: “Events displayed are a 
subset of reactions defined by the 
Investigator as being systemic”
SAC
2.36.
AT
AE1
Summary of On-Treatment Adverse Events Defined by the 
Investigator as Being Systemic (non-allergic or 
allergic/hypersensitivity) Reactions 
SAC


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Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
2.37.
AT
SHELL
Summary Profile of On-Treatment Systemic (non-allergic or 
allergic/hypersensitivity) Reactions 
SAC
2.38.
AT
SHELL
Summary Profile of On-Treatment Systemic Allergic Reactions 
SAC
2.39.
AT
SHELL
Summary Profile of On-Treatment Systemic Non-Allergic 
Reactions 
SAC
2.40.
AT
AE1
Summary of On-Treatment Adverse Events Defined by the 
Investigator as being Local Injection Site Reactions 
SAC
2.41.
AT
SHELL
Summary Profile of On-Treatment Local Injection Site Reactions 
SAC
2.42.
AT
AE1
Summary of On-Treatment Opportunistic Infections
SAC
2.43.
AT
SHELL
Summary Profile of On-Treatment Opportunistic Infections 
SAC
2.44.
AT
AE1
Summary of On-Treatment Malignancies 
SAC
2.45.
AT
SHELL
Summary Profile of On-Treatment Malignancies
SAC
2.46.
AT
AE1
Summary of On-Treatment Serious Cardiac, Vascular and 
Thromboembolic Adverse Events
SAC
2.47.
AT
SHELL
Summary Profile of On-Treatment Serious Cardiac, Vascular 
and Thromboembolic Adverse Events 
SAC
2.48.
AT
AE1
Summary of On-Treatment Serious Ischemic Adverse Events 
SAC
2.49.
AT
SHELL
Summary Profile of Serious Ischemic Adverse Events 
SAC
2.50.
AT
SHELL
Summary of Serious Adverse Events and Adverse Events of 
Special Interest
SAC
Cardiovascular Events
2.51.
AT
SHELL
Summary of All Cause Deaths and Cardiovascular Events 
Reported by the Investigator
SAC


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Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
2.52.
AT
SHELL
Summary of CEC Adjudicated All Cause Deaths and 
Cardiovascular Events of Interest
SAC
Laboratory: Chemistry 
2.53.
AT
LB1
Summary of Chemistry Changes from Baseline 
ICH E3
Includes Baseline values.
SAC
2.54.
AT
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
2.55.
AT
LB3
Summary of Chemistry Results (Changes from Baseline
Relative to the Reference Range [Potential Clinical Importance])
See also format of Safety Table 7.36 
(MEA115588 ‘final reporting effort)
SAC
Laboratory: Haematology
2.56.
AT
LB1
Summary of Haematology Changes from Baseline
ICH E3
Includes baseline values.
SAC
2.57.
AT
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
2.58.
AT
LB3
Summary of Haematology Results (Changes from Baseline
Relative to the Reference Range [Potential Clinical Importance])
See also format of Safety Table 7.42 
(MEA115588 ‘final reporting effort)
SAC
Laboratory: Hepatobiliary (Liver)
2.59.
AT
LIVER10
Summary of Subjects Meeting Emergent Hepatobiliary 
Laboratory Abnormality Criteria
IDSL
SAC
ECG
2.60.
AT
EG1
Summary of ECG Findings 
IDSL
SAC
2.61.
AT
EG2
Summary of Change from Baseline in ECG Values by Visit
Includes baseline values.
SAC
2.62.
AT
SHELL
Summary of Actual and Change From Baseline QTc(F) Values 
by Category (msec)
SAC


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Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
2.63.
AT
SHELL
Summary of Actual and Change From Baseline QTc(B) Values 
by Category (msec)
SAC
Vital Signs
2.64.
AT
VS1
Summary of Change from Baseline in Vital Signs
ICH E3
Includes Baseline values.
SAC
Immunogenicity
2.65.
AT
SHELL
Summary of ADA Assay Results
See format of Other Assessments 
Table 8.01 (MEA115588 ‘final’ reporting 
effort)
SAC
2.66.
AT
SHELL
Summary of Treatment Emergent ADA Assay Results
SAC
2.67.
AT
SHELL
Summary of NAb Assay Results
See format of Other Assessments 
Table 8.02 (MEA115588 ‘final’ reporting 
effort)
SAC
11.10.7.
Safety Figures
Safety: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Laboratory
2.1.
AT
LIVER14
Scatter Plot of Maximum Post-Baseline vs. Baseline for ALT
IDSL
SAC
2.2.
AT
LIVER9
Scatter Plot of Maximum Post-Baseline ALT vs. Maximum Post-
Baseline Total Bilirubin
IDSL
SAC


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11.10.8.
Efficacy Tables
Efficacy: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Exacerbations
3.1
AT
SHELL
Overview of All Exacerbations
See Efficacy Table 2.61 (200862 ‘final’ 
reporting effort)
SAC
3.2
AT
SHELL
Summary of Frequency of All Exacerbations
See Efficacy Table 2.62 (200862 ‘final’ 
reporting effort)
SAC
3.3
AT
SHELL
Annualised Rate of Exacerbations
See Efficacy Table 2.64 (200862 ‘final’ 
reporting effort)
SAC
3.4
AT
SHELL
Overview of Exacerbation Rate by Treatment Allocated Within 
MEA115588 and Study Period (MEA115588, MEA115661 and 
201312 combined)
See Efficacy Table 6.15 (MEA115661 
‘final’ reporting effort)
SAC
3.5
AT
SHELL
Analysis of Time to First Exacerbation
See Efficacy Table 2.68 (200862 ‘final’ 
reporting effort)
SAC
3.6
AT
SHELL
Summary of Frequency of Exacerbations Requiring 
Hospitalisation or Emergency Department visits
See Efficacy Table 2.62 (200862 ‘final’ 
reporting effort)
SAC
3.7
AT
SHELL
Annualised Rate of Exacerbations Requiring Hospitalisation or 
Emergency Department visits
See Efficacy Table 2.64 (200862 ‘final’ 
reporting effort)
SAC
3.8
AT
SHELL
Summary of Frequency of Exacerbations Requiring 
Hospitalisation
See Efficacy Table 2.62 (200862 ‘final’ 
reporting effort)
SAC
3.9
AT
SHELL
Annualised Rate of Exacerbations Requiring Hospitalisation
See Efficacy Table 2.64 (200862 ‘final’ 
reporting effort)
SAC
Asthma Control Questionnaire (ACQ-5) 
3.10
AT
SHELL
Summary of Asthma Control Questionnaire (ACQ-5) Score
See Efficacy Table 2.34 (200862 ‘final’ 
reporting effort)
SAC


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Efficacy: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Pre – Bronchodilator FEV1
3.11
AT
SHELL
Summary of Clinic Pre-Bronchodilator FEV1 (mL)
See Efficacy Table 2.27 (200862 ‘final’ 
reporting effort)
SAC
Oral Corticosteroid Use
3.12
AT
SHELL
Summary of OCS Dose (mg/day) During Each Reporting Period 
by Treatment Allocated Within MEA115575 and Study Period 
(MEA115588, MEA115661 and 201312 combined)
See Efficacy Table 6.16 (MEA115661 
‘final’ reporting effort)
SAC
11.10.9.
Efficacy Figures
Efficacy: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Exacerbations
3.1
AT
SHELL
Kaplan-Meier Cumulative Incidence Curve for Time to First 
Exacerbation
See Efficacy Figure 2.15 (200862 ‘final’ 
reporting effort)
SAC
11.10.10. Pharmacodynamic Tables
Pharmacodynamic: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Blood Eosinophils
4.1.
AT
SHELL
Summary of Blood Eosinophils (109/L)
See Efficacy Table 2.73 (200862 ‘final’ 
reporting effort), but exclude ‘Placebo’ 
column
SAC


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11.10.11. ICH Listings
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.
ASE
ES7
Listing of Reasons for Screen Failure
Journal Guidelines
SAC
2.
ASE
IE3
Listing of Failed Inclusion/Exclusion criteria
ICH E3
SAC
3.
AT
ES2
Listing of Reasons for Study Withdrawal
ICH E3
SAC
4.
AT
SHELL
Listing of Current and Previous Treatment
SAC
Demographics
5.
AT
DM2
Listing of Demographic Characteristics
ICH E3
SAC
6.
AT
DM9
Listing of Race
ICH E3
SAC
Medication Use
7.
AT
CM6
Relationship Between ATC Level 1, Ingredient and Verbatim 
Text
SAC
Protocol Deviations
8.
AT
DV2
Listing of Important Protocol Deviations 
ICH E3
SAC
Exposure and Treatment Compliance
9.
AT
EX3
Listing of Exposure Data
ICH E3
SAC
Adverse Events
10.
ASE
AE8
Listing of All Adverse Events
ICH E3
SAC
11.
ASE
AE7
Listing of Subject Numbers for Individual Adverse Events
ICH E3
SAC
12.
ASE
AE2
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text
IDSL
SAC


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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Serious and Other Significant Adverse Events
13.
ASE
AE8
Listing of Fatal Serious Adverse Events
ICH E3
SAC
14.
ASE
AE8
Listing of Non-Fatal Serious Adverse Events
ICH E3
SAC
15.
ASE
AE14
Listing of Reasons for Considering as a Serious Adverse Event
ICH E3
SAC
16.
AT
AE8
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment
ICH E3
SAC
Adverse Events of Special Interest
17.
AT
SHELL
Listing of Adverse Events Meeting Anaphylaxis Criteria
See format of Safety Listing 7.10 
(MEA115588 ‘final’ reporting effort)
Insert footnote: “Events displayed are a 
subset of reactions defined by the 
Investigator as being systemic”
SAC
18.
AT
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
19.
AT
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
20.
AT
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
21.
AT
SHELL
Listing of Opportunistic Infections
See format of Safety Listing 7.10 
(MEA115588 ‘final’ reporting effort)
SAC


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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
22.
AT
SHELL
Listing of Malignancies
See format of Safety Listing 2.03
(mid_mepo_iss ‘iss_nda’ reporting 
effort)
SAC
23.
AT
SHELL
Listing of Serious Cardiac, Vascular and Thromboembolic (CVT) 
Adverse Events
See format of Safety Listing 7.10 
(MEA115588 ‘final’ reporting effort)
SAC
24.
AT
SHELL
Listing of Serious Ischemic Adverse Events
See format of Safety Listing 7.10 
(MEA115588 ‘final’ reporting effort)
SAC
Cardiovascular Events
25.
AT
SHELL
Listing of Investigator Reported Cardiovascular Events: 
Arrhythmias
See format of Safety Listing 7.11 
(MEA115588 ‘final’ reporting effort)
SAC
26.
AT
SHELL
Listing of Investigator Reported Cardiovascular Events: 
Congestive Heart Failure
See format of Safety Listing 7.12 
(MEA115588 ‘final’ reporting effort)
SAC
27.
AT
SHELL
Listing of Investigator Reported Cardiovascular Events: 
Cerebrovascular Events/Stroke
See format of Safety Listing 7.13 
(MEA115588 ‘final’ reporting effort)
SAC
28.
AT
SHELL
Listing of Investigator Reported Cardiovascular Events: Deep 
venous Thrombosis/Pulmonary Embolism
See format of Safety Listing 7.14 
(MEA115588 ‘final’ reporting effort)
SAC
29.
AT
SHELL
Listing of Investigator Reported Cardiovascular Events: 
Myocardial Infarction/Unstable Angina
See format of Safety Listing 7.15 
(MEA115588 ‘final’ reporting effort)
SAC
30.
AT
SHELL
Listing of Investigator Reported Cardiovascular Events: 
Peripheral Arterial Thrombosis Embolism
See format of Safety Listing 7.16 
(MEA115588 ‘final’ reporting effort)
SAC
31.
AT
SHELL
Listing of Investigator Reported Cardiovascular Events: 
Pulmonary Hypertension
See format of Safety Listing 7.17 
(MEA115588 ‘final’ reporting effort)
SAC
32.
AT
SHELL
Listing of Investigator Reported Cardiovascular Events: 
Revascularisation
See format of Safety Listing 7.18 
(MEA115588 ‘final’ reporting effort)
SAC
33.
AT
SHELL
Listing of Investigator Reported Cardiovascular Events:
Valvulopathy
See format of Safety Listing 7.19 
(MEA115588 ‘final’ reporting effort)
SAC


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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
34.
AT
SHELL
Listing of Investigator Reported Cardiovascular Events: All 
Cause Deaths
See format of Safety Listing 7.20 
(MEA115588 ‘final’ reporting effort)
SAC
35.
AT
SHELL
Listing of CEC Adjudicated Cardiovascular Events: Congestive 
Heart Failure
See format of Safety Listing 7.17 
(MEA115666 ‘fina_01l’ reporting 
effort)
SAC
36.
AT
SHELL
Listing of CEC Adjudicated Cardiovascular Events: 
Cerebrovascular Events/Stroke
See format of Safety Listing 7.18 
(MEA115666 ‘fina_01l’ reporting 
effort)
SAC
37.
AT
SHELL
Listing of CEC Adjudicated Cardiovascular Events: Deep venous 
Thrombosis/ Pulmonary Embolism
See format of Safety Listing 7.19 
(MEA115666 ‘fina_01l’ reporting 
effort)
SAC
38.
AT
SHELL
Listing of CEC Adjudicated Cardiovascular Events: Myocardial 
Infarction /Unstable Angina
See format of Safety Listing 7.20 
(MEA115666 ‘fina_01l’ reporting 
effort)
SAC
39.
AT
SHELL
Listing of CEC Adjudicated Cardiovascular Events: Peripheral 
Arterial Thrombosis Embolism
See format of Safety Listing 7.21 
(MEA115666 ‘fina_01l’ reporting 
effort)
SAC
40.
AT
SHELL
Listing of CEC Adjudicated Events: All Cause Deaths
See format of Safety Listing 7.22 
(MEA115666 ‘fina_01l’ reporting 
effort)
SAC
Hepatobiliary (Liver)
41.
AT
LIVER5
Listing of Liver Monitoring/Stopping Event Reporting
SAC
42.
AT
LB5
Chemistry Results for Subjects Meeting Liver 
Monitoring/Stopping Event Criteria
SAC
43.
AT
MH2
Listing of Medical Conditions for Subjects with Liver Stopping 
Events
SAC


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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
44.
AT
SU2
Listing of Substance Use for Subjects with Liver Stopping 
Events
See format of Safety Listing 7.22 
(MEA112997 ‘final’ reporting effort)
SAC
45.
AT
LIVER13
Listing of Subjects Meeting Hepatobiliary Laboratory Criteria 
Post-Baseline
SAC
46.
AT
SHELL
Mepolizumab Concentrations Following Onset of Liver Event
SAC
All Laboratory
47.
AT
LB5
Listing of All Laboratory Data for Subjects with Any Value of 
Potential Clinical Importance
ICH E3
SAC
ECG
48.
AT
EG6
Listing of All ECG Findings for Subjects with an Abnormal ECG 
Interpretations
IDSL
SAC
Immunogenicity
49.
AT
SHELL
Listing of Immunogenicity Results
See format of Other Assessments 
Listing 8.01 (MEA115588 ‘final’ 
reporting effort)
SAC
Efficacy
50.
AT
SHELL
Listing of Exacerbations
See format of Efficacy Listing 6.01 
(MEA115588 ‘final’ reporting effort)
SAC


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11.11.
Appendix 11: Example Mock Shells for Data Displays
The data display shells are available on request.