Conditions: Churg-Strauss Syndrome Eosinophilic Granulomatosis With Polyangiitis
Keywords: Eosinophilic Granulomatosis MEA115921 Polyangiitis Long-term access program mepolizumab
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 100
Healthy volunteers: no

Brief summary:
Eosinophilic Granulomatosis with Polyangiitis (EGPA), also referred to as Churg-Strauss syndrome, is a rare hyper-eosinophilic syndrome. Eosinophilia is central to the pathophysiology of EGPA and interleukin-5 (IL-5) is a key cytokine regulating the life-cycle of the eosinophil. Neutralization of IL-5 with mepolizumab, an anti-IL5 monoclonal antibody, therefore offers a potential therapeutic option for EGPA. The objective of study MEA115921 was to investigate the efficacy and safety of mepolizumab compared with placebo wherein the subjects were randomized to receive either: 300 milligram (mg) mepolizumab or Placebo subcutaneous (SC) injection every 4 weeks in addition to their background standard-of-care therapy. Subjects were treated for a period of 52 weeks and then followed up for a further 8 weeks to study completion at Week 60. This is a LAP to support provision of open-label mepolizumab on an individual basis to eligible subjects who participated in clinical study MEA115921 and who require a dose of prednisolone (or equivalent) of \>=5 milligrams per day (mg/day) for adequate control of their EGPA. Eligible subjects can initiate mepolizumab under this LAP within a 6-month period starting from completion of study MEA115921 (that is, at Week 60) or, in case of premature discontinuation from study MEA115921, the subjects will initiate mepolizumab at the time point that would have been Week 60 if the subject had completed the study. Eligible subjects will receive subcutaneously administered mepolizumab at a dose of 300 mg SC every 4 weeks. Eligible subjects will continue to receive mepolizumab under this LAP until mepolizumab is commercially licensed for the treatment of EGPA in the relevant country or until GlaxoSmithKline (GSK) discontinues the program or until the subject meets any of the withdrawal/stopping criteria.

Detailed description:

Arms:
arm 1: Subjects who participated in clinical study MEA115921 and who require a dose of prednisolone (or equivalent) of 5 mg/day for adequate control of their EGPA will be included. Eligible subjects will receive subcutaneously administered mepolizumab at a dose of 300 mg SC every 4 weeks.

Interventions: intervention 1: Mepolizumab intervention 2: Prednisolone
Intervention descriptions: intervention 1: Mepolizumab will be available as lyophilized powder for injection to be reconstituted with sterile water for injection, prior to use. Subjects will be dosed with mepolizumab at a dose of 300 mg which will be administered as three separate 100 mg SC injections every 4 weeks. The injections will be administered into any of the upper arm, thigh or anterior abdominal wall. intervention 2: Subjects who require a dose of prednisolone (or equivalent) of 5 mg/day for adequate control of their EGPA will be included.

Protocol document:
Prot_000.pdf: 
2014N201870_05 
CONFIDENTIAL 
 
GlaxoSmithKline group of companies 
 
MEA116841 
 
1 
TITLE PAGE 
Division:  Worldwide Development 
Information Type: Protocol Amendment 
 
Title: 
Mepolizumab Long-term Access Programme for Subjects who 
Participated in Study MEA115921 (Placebo-controlled Study of 
Mepolizumab in the Treatment of Eosinophilic Granulomatosis 
with Polyangiitis in Subjects Receiving Standard-of-care 
Therapy) 
 
Compound Number: SB-240563 
Development Phase 
III 
Effective Date: 
30-JUN-2021 
Protocol Amendment Number:  05 
Author(s): 
 
 
 
 
 
 
 
 
 
 
 
 
 
PPD


2014N201870_05 
CONFIDENTIAL 
 
GlaxoSmithKline group of companies 
 
MEA116841 
 
2 
 
Revision Chronology 
GlaxoSmithKline 
Document Number 
Date 
Version 
2014N201870_00 
2014-OCT-29 
Original 
2014N201870_01 
2015-FEB-26 
Amendment No. 1 
Country-specific amendment for the UK: clarification regarding the estimated study end 
date for the UK and clarification regarding definition of abstinence as acceptable method 
of birth control. 
2014N201870_02 
2015-MAR-12 
Amendment No. 2 
Country-specific amendment for the UK: Further clarification regarding the estimated 
study end date for the UK. 
2014N201870_03 
2015-AUG-20 
Amendment No. 3 
Amendment to indicate that use of other biological agents will be permitted on agreement 
with the GSK Medical Monitor. Administrative updates.  
2014N201870_04 
2019-May22 
Amendment No. 4 
Non-substantial amendment for the addition of an interim analyses and an update of 
medical monitor information. Country-specific amendment for the UK: Further 
clarification regarding the estimated study end date for the UK. 
2014N201870_05 
2021-Jun-30 
Amendment No. 5 
Non-substantial amendment for the addition of a Country-specific amendment for the 
UK: Further clarification regarding the estimated study end date for the UK. 
 
Copyright 2019 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited. 


2014N201870_04 
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3 
SPONSOR SIGNATORY: 
 
Namhee Kwon MD 
Physician, Medicine Delivery Unit 
 
Date 
 


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4 
MEDICAL MONITOR/SPONSOR INFORMATION PAGE 
Medical Monitor/SAE Contact Information:  
Role 
Name 
Day Time Phone Number and 
email address 
After-hours 
Phone/Cell/ 
Pager 
Number 
Fax 
Number 
Site 
Address 
Primary 
Medical 
Monitor  
n/a 
GSK 
980 Great 
West 
Road, 
Brentford, 
Middlese
x, TW8 
9GS, 
United 
Kingdom 
Secondary 
Medical 
Monitor 
n/a 
GSK 
Upper 
Providenc
e, PA, 
USA 
 
SAE 
contact 
information  
 
 
Clinical 
Investigatio
n Lead - 
CIL 
n/a 
GSK 
980 Great 
West 
Road, 
Brentford, 
Middlese
x, TW8 
9GS, 
United 
Kingdom 
Operations 
& Science 
Lead-OSL 
n/a 
GSK 
Homebas
ed Spain 
 
Data 
Manager 
Lead 
n/a 
TCS 
Maharash
tra, India 
 
 
PPD


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5 
Sponsor Legal Registered Address:  
GlaxoSmithKline Research & Development Limited 
980 Great West Road 
Brentford 
Middlesex, TW8 9GS 
UK 
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate 
Company (or designee). If applicable, the details of the alternative Sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application.    
Regulatory Agency Identifying Number(s):  
 BBIND 006971 
EudraCT number 2014-003162-25 


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INVESTIGATOR PROTOCOL AGREEMENT PAGE 
• 
I confirm agreement to conduct the study in compliance with the protocol. 
• 
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study. 
• 
I agree to ensure that all associates, colleagues and employees assisting in the 
conduct of the study are informed about their obligations. Mechanisms are in place 
to ensure that site staff receives the appropriate information throughout the study. 
 
Investigator Name: 
 
Investigator Address: 
 
 
Investigator Phone Number: 
 
 
 
Investigator Signature 
Date 
 
 


2014N201870_04 
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TABLE OF CONTENTS 
PAGE 
1. 
PROTOCOL SYNOPSIS FOR STUDY MEA116841 ................................................ 9 
2. 
INTRODUCTION .................................................................................................... 11 
2.1. 
Study Rationale .......................................................................................... 11 
2.2. 
Brief Background ........................................................................................ 11 
3. 
OBJECTIVE ........................................................................................................... 12 
4. 
STUDY DESIGN .................................................................................................... 12 
4.1. 
Overall Design ............................................................................................ 12 
4.2. 
Type and Number of Subjects ..................................................................... 14 
4.3. 
Dose Justification ........................................................................................ 14 
4.4. 
Benefit:Risk Assessment ............................................................................ 14 
4.4.1. 
Risk Assessment ......................................................................... 15 
4.4.2. 
Benefit Assessment ..................................................................... 19 
4.4.3. 
Overall Benefit:Risk Conclusion ................................................... 19 
5. 
SELECTION OF POPULATION AND WITHDRAWAL CRITERIA .......................... 20 
5.1. 
Inclusion Criteria ......................................................................................... 20 
5.2. 
Exclusion Criteria ........................................................................................ 21 
5.3. 
Withdrawal/Stopping Criteria....................................................................... 22 
5.4. 
Subject and Study Completion .................................................................... 23 
6. 
STUDY TREATMENT ............................................................................................ 23 
6.1. 
Investigational Product and Other Study Treatment .................................... 23 
6.2. 
Packaging and Labelling ............................................................................. 24 
6.3. 
Preparation/Handling/Storage/Accountability .............................................. 24 
6.4. 
Treatment of Mepolizumab Overdose ......................................................... 24 
6.5. 
Concomitant Medications and Non-Drug Therapies .................................... 25 
6.5.1. 
Permitted Medications and Non-Drug Therapies .......................... 25 
7. 
ASSESSMENTS AND PROCEDURES .................................................................. 25 
7.1. 
Time and Events Table ............................................................................... 26 
7.2. 
Screening and Critical Baseline Assessments ............................................ 27 
7.3. 
Safety ......................................................................................................... 27 
7.3.1. 
Adverse Events (AE) and Serious Adverse Events (SAEs) .......... 27 
7.3.1.1. 
Time period and Frequency for collecting AE 
and SAE information ................................................... 27 
7.3.1.2. 
Method of Detecting AEs and SAEs ........................... 28 
7.3.1.3. 
Follow-up of AEs and SAEs ........................................ 28 
7.3.1.4. 
Cardiovascular and Death Events .............................. 28 
7.3.1.5. 
Regulatory Reporting Requirements for SAEs ............ 29 
7.3.2. 
Pregnancy ................................................................................... 29 
8. 
DATA MANAGEMENT ........................................................................................... 30 
9. 
STATISTICAL CONSIDERATIONS AND DATA ANALYSES ................................. 30 
9.1. 
Interim Analysis .......................................................................................... 30 


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10. STUDY GOVERNANCE CONSIDERATIONS ........................................................ 30 
10.1. 
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................ 30 
10.2. 
Quality Control (Study Monitoring) .............................................................. 31 
10.3. 
Quality Assurance ....................................................................................... 31 
10.4. 
Study and Site Closure ............................................................................... 32 
10.5. 
Records Retention ...................................................................................... 32 
10.6. 
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication ................. 33 
10.7. 
Review Committees .................................................................................... 33 
11. REFERENCES ....................................................................................................... 34 
12. APPENDICES ........................................................................................................ 36 
12.1. 
Appendix 1 – Abbreviations and Trademarks .............................................. 36 
12.2. 
Appendix 2 - Anaphylaxis Criteria ............................................................... 37 
12.3. 
Appendix 3 – Acceptable Birth Control ........................................................ 38 
12.4. 
Appendix 4 - Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events ............................ 40 
12.4.1. 
Definition of Adverse Events ........................................................ 40 
12.4.2. 
Definition of Serious Adverse Events ........................................... 41 
12.4.3. 
Definition of Cardiovascular Events ............................................. 42 
12.4.4. 
Recording of AEs and SAEs ........................................................ 43 
12.4.5. 
Evaluating AEs and SAEs ............................................................ 43 
12.4.6. 
Reporting of SAEs to GSK ........................................................... 45 
12.5. 
Appendix 5 - Country Specific Requirements .............................................. 46 
12.6. 
Appendix 6 – Protocol Changes .................................................................. 47 
12.6.4 Protocol Amendment 04 ................................................................... 53 
9.1 
Interim Analysis .......................................................................................... 53 
 


2014N201870_04 
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9 
1. 
PROTOCOL SYNOPSIS FOR STUDY MEA116841 
Rationale 
Eosinophilia is central to the pathophysiology of Eosinophilic Granulomatosis with 
Polyangiitis (EGPA) and interleukin-5 (IL-5) is a key cytokine regulating the life-cycle of 
the eosinophil. Neutralisation of IL-5 with mepolizumab, an anti-IL5 monoclonal 
antibody, therefore offers a potential therapeutic option for EGPA. This was shown by 
data from two investigator-sponsored studies which attest to the clinical utility/proof-of-
concept of mepolizumab in the treatment of EGPA by demonstrating the potential for 
mepolizumab to allow safe reduction in corticosteroid dose while maintaining clinical 
stability (study CRT109797) and for induction of remission (study MHE109435) in 
subjects with EGPA. These studies supported the subsequent initiation of a randomised, 
double-blind, phase 3 study (MEA115921) investigating the efficacy and safety of 
mepolizumab (300 mg subcutaneously [SC] every 4 weeks) compared with placebo over 
a 52-week study treatment period (with 8-week follow-up) in subjects with relapsing or 
refractory EGPA receiving standard-of-care therapy including background corticosteroid 
therapy with or without immunosuppressive therapy.  
The purpose of this protocol is to support provision of open-label mepolizumab from 
GlaxoSmithKline (GSK), on an individual basis, to eligible subjects who participated in 
study MEA115921 and satisfy specific requirements, including requiring a dose of 
prednisolone (or equivalent) of 5 mg/day for adequate control of their EGPA. This will 
be referred to as a ‘Long-term access programme (LAP)’ and this protocol outlines the 
procedures to support treatment with mepolizumab in appropriate subjects. 
Objective 
The objective of this protocol is to provide a mechanism to supply mepolizumab on an 
individual subject basis to eligible subjects who previously participated in GSK-
sponsored study MEA115921. 
Overall Design 
This is a Long-term Access Programme (LAP) to support provision of open-label 
mepolizumab on an individual basis to eligible subjects who participated in clinical study 
MEA115921 and who require a dose of prednisolone (or equivalent) of 5 mg/day for 
adequate control of their EGPA. Eligible subjects can initiate mepolizumab under this 
LAP within a 6-month period starting from completion of study MEA115921 (i.e., at 
Week 60) or, if the subject discontinued study MEA115921 prematurely, from the time-
point that would have been Week 60 if the subject had completed the study. Initiation of 
mepolizumab treatment under this LAP more than 6 months after the MEA115921 Week 
60 time-point will be considered on an individual subject basis by the GSK Medical 
Monitor. 
After IRB/Ethics Committee approval is received for this protocol, the treating physician 
will be required to complete a ‘Long-term Access Programme’ Subject Application 
Form’ if he/she identifies a subject who may be eligible for treatment. The completed 
application form must be sent to GSK for review and approval by the GSK Medical 


2014N201870_04 
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MEA116841 
 
10 
Monitor to confirm the subject is eligible for treatment with mepolizumab under this 
LAP. Approval will be communicated to the treating physician and mepolizumab 
supplies provided for initiation of treatment. 
Individual investigators will be responsible for identifying subjects from MEA115921 
who may be eligible for treatment with mepolizumab under this LAP and for ensuring the 
necessary approval is obtained from GSK. In the event a subject is deemed appropriate 
for treatment with mepolizumab the investigator will then be responsible for ongoing 
benefit:risk evaluation to support continued treatment with mepolizumab irrespective of 
oral corticosteroid dose. It is expected that the treating physician will monitor subjects as 
per standard-of-care therapy (including any requirements for blood and urine tests). 
Eligible subjects will receive subcutaneously administered mepolizumab at a dose of 
300 mg SC every 4 weeks.  
Information including demography, cardiovascular risk, date of randomization and last 
visit in study MEA115921 will be collected from participating subjects. Study visits will 
include assessment of adverse events and serious adverse events and recording of 
corticosteroid use. Based on regular standard-of-care management, at each visit the 
investigator will be required to make an overall assessment of benefit:risk for treatment 
with mepolizumab prior to administration. To support continued supply of mepolizumab, 
the investigator is required to record the overall assessment of benefit risk every 
12 weeks. Urine pregnancy tests will be conducted on females of child-bearing potential. 
In the event a subject discontinues treatment, for any reason, a follow-up assessment will 
be required 12 weeks after the last dose of mepolizumab. 
Eligible subjects can continue to receive mepolizumab under this LAP until mepolizumab 
is commercially licensed for the treatment of EGPA in the relevant country or until the 
Sponsor discontinues development in EGPA or until the subject meets any of the 
withdrawal/stopping criteria. United Kingdom (UK) only clarification: Eligible subjects 
can continue to receive mepolizumab under this LAP until July 2022 or until the Sponsor 
discontinues development in EGPA or until the subject meets any of the 
withdrawal/stopping criteria. 
 


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2. 
INTRODUCTION 
2.1. 
Study Rationale 
GlaxoSmith Kline (GSK) is sponsoring a randomised, double-blind, phase 3 study 
(MEA115921) investigating the efficacy and safety of mepolizumab (300 mg 
subcutaneously [SC] every 4 weeks) compared with placebo over a 52-week study 
treatment period in subjects with relapsing or refractory EGPA receiving standard-of-care 
therapy including background corticosteroid therapy with or without immunosuppressive 
therapy [GlaxoSmithKline Document Number 2012N142276_02].  
The purpose of this protocol is to support provision of mepolizumab from GSK, on an 
individual compassionate basis, to eligible subjects who have participated in study 
MEA115921 and who satisfy specific requirements, including requiring a dose of 
prednisolone (or equivalent) of 5 mg/day for adequate control of their EGPA. This 
mechanism will be referred to as a ‘Long-term Access Programme’ (LAP) in this 
protocol and outlines procedures to support treatment with mepolizumab in appropriate 
subjects. 
2.2. 
Brief Background 
Eosinophilic Granulomatosis with Polyangiitis (EGPA), also referred to as Churg-Strauss 
syndrome (CSS), is a rare hypereosinophilic syndrome characterised by small vessel 
vasculitis in association with asthma, sinusitis, and pulmonary infiltrates. Multiple organs 
can be affected including the heart, lungs, skin, gastrointestinal tract, kidneys, and 
nervous system [Keogh, 2006; Vaglio, 2012; Holle, 2009]. 
Eosinophilia is central to the pathophysiology of Eosinophilic Granulomatosis with 
Polyangiitis (EGPA) and interleukin-5 (IL-5) is a key cytokine regulating the life-cycle of 
the eosinophil [Keogh, 2006; Vaglio, 2012; Holle, 2009; Clutterbuck, 1989; Lopez, 1988; 
Rothenberg, 2006]. Neutralisation of IL-5 with mepolizumab, an anti-IL5 monoclonal 
antibody, therefore offers a potential therapeutic option for EGPA. 
Mepolizumab is a fully humanized monoclonal antibody (IgG1, kappa, mAb) which is 
specific for human IL-5 and which blocks binding of human IL-5 (hIL-5) to the alpha 
chain of the IL-5 receptor complex expressed on the eosinophil cell surface. In patients 
with conditions where eosinophilia is considered to play an important part in the 
pathology, a consistent reduction in eosinophil number is observed in association with 
mepolizumab administration, with concomitant clinical improvement [Haldar, 2009; 
Pavord, 2012; Stein, 2006; Rothenberg, 2008; Nair, 2009]. 
Data from two investigator-sponsored studies attested to the clinical utility/proof-of-
concept of mepolizumab in the treatment of EGPA having demonstrated the potential for 
mepolizumab to allow safe reduction in corticosteroid dose while maintaining clinical 
stability (study CRT109797; [Kim, 2010; IB; GlaxoSmithKline Document Number: 
CM2003/00010/08]) and for induction of remission (study MHE109435; [Moosig, 2011; 
IB; GlaxoSmithKline Document Number: CM2003/00010/08]) in subjects with EGPA. 


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This has supported initiation of a phase 3, double-blind, randomised, placebo-controlled 
study, MEA115921 [GlaxoSmithKline Document Number 2012N142276_02].  
The objective of study MEA115921 is focussed on investigating the efficacy and safety 
of mepolizumab plus standard-of-care compared with placebo plus standard-of-care. In 
this study, 130 subjects are randomised in a 1:1 ratio to receive either: 300 mg 
mepolizumab SC every 4 weeks (n=65) or Placebo SC every 4 weeks (n=65) in addition 
to their background standard-of-care therapy including corticosteroid therapy with or 
without immunosuppressive therapy. Subjects are treated for a period of 52 weeks and 
then followed up for a further 8 weeks to study completion at Week 60.  
3. 
OBJECTIVE 
The objective of this protocol is to provide a mechanism to supply mepolizumab on an 
individual subject basis to eligible subjects who previously participated in GSK-
sponsored study MEA115921. 
4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a LAP to support provision of open-label mepolizumab on an individual basis to 
eligible subjects who participated in clinical study MEA115921 who satisfy specific 
requirements, including requiring a dose of prednisolone (or equivalent) of 5 mg/day for 
adequate control of their EGPA. Eligible subjects can initiate mepolizumab under this 
LAP within a 6-month period starting from completion of study MEA115921 (i.e., at 
Week 60) or, if the subject discontinued study MEA115921 prematurely, from the time-
point that would have been Week 60 if the subject had completed the study. Initiation of 
mepolizumab treatment under this LAP more than 6 months after the MEA115921 Week 
60 time-point will be considered on an individual subject basis by the GSK Medical 
Monitor.  
After IRB/Ethics Committee approval is received for this protocol, the treating physician 
will be required to complete a ‘Long-term Access Programme Subject Application Form’ 
if he/she identifies a subject who may be eligible for treatment (a copy will be provided 
in the Study Reference Manual). The completed application form must be sent to GSK 
for review and approval by the GSK Medical Monitor to confirm the subject is eligible 
for treatment with mepolizumab under this LAP. Approval will be communicated to the 
treating physician and mepolizumab supplies provided for initiation of treatment. 
Individual investigators will be responsible for identifying subjects from MEA115921 
who may be eligible for treatment with mepolizumab under this LAP and for ensuring the 
necessary approval is obtained from GSK. In the event a subject is deemed appropriate 
for treatment with mepolizumab the investigator will then be responsible for ongoing 
benefit:risk evaluation to support continued treatment with mepolizumab irrespective of 
oral corticosteroid dose. It is expected that the treating physician will monitor subjects as 
per standard-of-care therapy (including any requirements for blood and urine tests). 


2014N201870_04 
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Eligible subjects will receive subcutaneously administered mepolizumab at a dose of 
300 mg SC every 4 weeks.  
Information including demography, cardiovascular risk, date of randomization and last 
visit in study MEA115921 will be collected from participating subjects. Study visits will 
include assessment of adverse events and serious adverse events and recording of 
corticosteroid use. Based on regular standard-of-care management, at each visit the 
investigator will be required to make an overall assessment of benefit:risk for treatment 
with mepolizumab prior to administration. To support continued supply of mepolizumab, 
the investigator is required to record the overall assessment of benefit risk every 
12 weeks. Urine pregnancy tests will be conducted on females of child-bearing potential 
(FCBP). In the event a subject discontinues treatment, for any reason, a follow-up 
assessment will be required 12 weeks after the last dose of mepolizumab. 
Eligible subjects can continue to receive mepolizumab under this LAP until mepolizumab 
is commercially licensed for the treatment of EGPA in the relevant country or until the 
Sponsor discontinues development in EGPA or until the subject meets any of the 
withdrawal/stopping criteria. 
UK only clarification: Eligible subjects can continue to receive mepolizumab under this 
LAP until July 2022 or until the Sponsor discontinues development in EGPA or until the 
subject meets any of the withdrawal/stopping criteria. 
A summary of the study design is provided in Figure 1. 
Figure 1 
Study Design 
 
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, review blinded and unblinded (i.e., from open-label trials) 
safety data from ongoing clinical studies with mepolizumab on a regular basis and 
conduct 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 re-assessment 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 Independent 


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Data Monitoring Committee (IDMC) will be utilized until completion of the lead study 
MEA115921; their primary focus will be the monitoring of cardiovascular safety and all 
cause mortality.   
Furthermore, GSK has 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.    
4.2. 
Type and Number of Subjects 
Any subject who participated in study MEA115921 who requires a dose of prednisolone 
(or equivalent) of 5 mg/day for adequate control of their EGPA will be eligible to be 
considered for treatment with mepolizumab under the LAP outlined in this protocol. 
4.3. 
Dose Justification 
The dose of mepolizumab for this LAP is the same as that investigated in the lead clinical 
study, MEA115921, i.e., 300 mg mepolizumab SC every 4 weeks. 
4.4. 
Benefit:Risk Assessment 
Summaries of findings from both clinical and non-clinical studies conducted with SB-
240563, mepolizumab, can be found in the Investigator’s Brochure IB and Supplement 
[GlaxoSmithKline Document Number: CM2003/00010/08 and GlaxoSmithKline 
Document Number 2014N200212_00]. 
 


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15 
4.4.1. 
Risk Assessment 
Potential Risk of Clinical 
Significance 
Data/Rationale for Risk 
Mitigation Strategy 
Investigative Medicinal Product (IMP): Mepolizumab 
Pre-Clinical and Clinical Findings 
Risk of Systemic Allergic and 
Non-allergic Reactions, 
including Anaphylaxis 
• Biopharmaceutical products may elicit ADA and NAB, 
which have the potential to modulate PK, 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 and Supplement; see 
‘Special Warnings and Special Precautions for Use’ 
section located in Section 6 titled ‘Summary of Data and 
Guidance for the Investigator’. [GlaxoSmithKline 
Document Number: CM2003/00010/08 and 
GlaxoSmithKline Document Number: 2014N200212_00]. 
• Daily monitoring of SAEs by medical monitor; 
regular systematic review of AE/SAE data from 
ongoing studies by a GSK safety review team.  
• Independent Data Monitoring Committee (IDMC) 
will be utilized during study until completion of 
the lead study MEA115921. 
• Specific Case Report Form (CRF) pages utilized 
for targeted collection of reactions data. 
• Utilization of Joint NIAID/FAAN 2nd Symposium 
on Anaphylaxis to collect data on reports of 
anaphylaxis (see Error! Reference source not 
found.). 
• Subjects are monitored in clinic for 1 hour 
following dosing (first 3 administrations only) 
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 Information for the 
Investigator’ section located in Section 6 titled ‘Summary 
• 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 
Investigative Medicinal Product (IMP): Mepolizumab 
Pre-Clinical and Clinical Findings 
of Data and Guidance for the Investigator’. 
Potential risk for adverse 
cardiovascular (CV) effects 
• Mepolizumab binding restricted to human lymphoid 
tissues in an immunohistochemistry tissue binding study 
suggesting a low likelihood of non-pharmacologic effects 
on CV function.   
• No adverse effects on 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 a 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 
subsequently completed placebo-controlled severe 
asthma trials did not show an increased risk of serious 
• 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: 
• Enhanced baseline collection of CV risk 
factors & functional status; 
• Baseline evaluation of clinical symptoms of 
ischemic heart disease, if clinically indicated; 
• 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); 
• Use of an IDMC and external adjudication 
panel for CV events (until completion of the 
lead study MEA115921) 


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Potential Risk of Clinical 
Significance 
Data/Rationale for Risk 
Mitigation Strategy 
Investigative Medicinal Product (IMP): Mepolizumab 
Pre-Clinical and Clinical Findings 
ischemic cardiac events; there were no new reports in 
any treatment groups including placebo 
Potential risk for increase in 
infections – 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 and 
Supplement; 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  
• IDMC will be utilized during study (until 
completion of the lead study MEA115921). 
 


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Potential Risk of Clinical 
Significance 
Data/Rationale for Risk 
Mitigation Strategy 
Investigative Medicinal Product (IMP): Mepolizumab 
Pre-Clinical and Clinical Findings 
[GlaxoSmithKline Document Number: CM2003/00010/08 
and GlaxoSmithKline Document Number 
2014N200212_00]. 
Potential risk for increase in 
malignancies – theoretical 
concern with biologics; 
however, blockade of IL-5 is 
not associated with generalized 
 nform-suppression or impaired 
host resistance. 
• Role of IL-5 and eosinophils in tumour surveillance is not 
fully characterised in the literature.   
• No evidence of defective tumour 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  
• IDMC will be utilized during study (until 
completion of the lead study MEA115921). 
 
 


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4.4.2. 
Benefit Assessment 
Data from two investigator-sponsored studies attested to the clinical utility/proof-of-
concept of mepolizumab in the treatment of EGPA having demonstrated the potential for 
mepolizumab to allow safe reduction in corticosteroid dose while maintaining clinical 
stability (study CRT109797; [Kim, 2010; IB; GlaxoSmithKline Document Number: 
CM2003/00010/08]) and for induction of remission (study MHE109435; [Moosig, 2011; 
IB; GlaxoSmithKline Document Number: CM2003/00010/08]) in subjects with EGPA. 
Furthermore, mepolizumab has also demonstrated clinical benefit in other conditions 
where eosinophilia is considered to play an important part in the pathology, e.g., severe 
asthma [Haldar, 2009; Nair, 2009; Pavord, 2012], hypereosinophilic syndrome 
[Rothenberg, 2008] and eosinophilic esophagitis [Stein, 2006]. 
Study MEA115921 is a phase 3, double-blind, randomised, placebo-controlled study 
investigating the efficacy and safety of mepolizumab in the treatment of EGPA in 
subjects receiving standard-of-care therapy.  
The Sponsor considers that the available data support provision of mepolizumab to 
subjects who participated in study MEA115921 and who require a dose of prednisolone 
(or equivalent) of 5 mg/day for adequate control of their EGPA, as outlined in the 
eligibility criteria for supply of mepolizumab as outlined in this protocol/’LAP’. 
4.4.3. 
Overall Benefit:Risk Conclusion 
Current data from mepolizumab preclinical and clinical development indicate the ability 
of mepolizumab to inhibit IL-5, with demonstration of the potential for clinical utility in 
the treatment of conditions associated with hypereosinophilia such as EGPA. To date, the 
safety profile of mepolizumab has been favourable and Aes reported commonly are non-
serious and manageable with minimal supportive care. Furthermore, there have been no 
safety concerns identified or signals observed with mepolizumab that would preclude 
investigation in EGPA. The Sponsor therefore considers that the available data and 
overall benefit/risk profile support treatment of subjects who participated in study 
MEA115921. 


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5. 
SELECTION OF POPULATION AND WITHDRAWAL 
CRITERIA 
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the Investigator’s Brochure 
and Supplement [GlaxoSmithKline Document Number: CM2003/00010/08 and 
GlaxoSmithKline Document Number: 2014N200212_00]. 
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize regulatory acceptability or subject safety. Therefore, adherence to 
the criteria as specified in the protocol/LAP is essential. 
All requests for continued treatment will be submitted to GSK using the LAP Application 
Form. The Lead Mepolizumab Medical Advisor for the mepolizumab EGPA programme, 
reserves the right to review the necessary information to confirm whether each subject, in 
the opinion of GSK, meets the required eligibility criteria and may be approved for 
treatment with mepolizumab under this LAP. Approval will be based on review of the 
eligibility criteria outlined below, in addition to any other information (if required), with 
careful consideration of each individual case.  
5.1. 
Inclusion Criteria 
Subjects will be required to satisfy the specified inclusion and exclusion criteria 
requirements listed below to be eligible to receive mepolizumab under the LAP. In 
addition, GSK may request additional information, not specified here, to support approval 
of mepolizumab supply. 
A subject will be eligible for the LAP only if all of the following criteria apply: 
[1] MEA115921 PARTICIPATION 
1. Subject participated in study MEA115921 
 
[2] MEA115921 COMPLETION  
2. Subject has either:  
i. 
completed study MEA115921 to Week 60, i.e., completion of follow up period,  
or  
ii. 
if the subject was withdrawn prematurely from study MEA115921, the subject 
has reached the date of what would have been the Week 60 if the subject had 
completed the study, i.e., 60 weeks from Baseline (Visit 2). 
 
[3] SUBJECT REQUIRES PREDNISOLONE (OR EQUIVALENT) 5 MG/DAY 
3. At or up to 6 months after the MEA115921 Week 60 time- point the subject requires 
a dose of prednisolone (or equivalent) of 5 mg/day for adequate control of their 
EGPA. 


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Note: Inclusion of subjects >6 months after the MEA115921 Week 60 time-point will 
be considered on an individual subject basis by the GSK Medical Monitor. 
 
[4] PHYSICIAN ASSESSMENT SUPPORTS MEPOLIZUMAB TREATMENT 
4. The treating physician requesting mepolizumab under this Long-term Access 
Programme considers the benefits of treatment with mepolizumab outweigh the risks 
for the individual subject. 
 
[5] FEMALE SUBJECTS 
5. To be eligible for mepolizumab treatment under this Long-term Access Programme, 
females of childbearing potential (FCBP) must commit to consistent and correct use 
of an acceptable method of birth control, as summarised in Appendix 2 – 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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6. Appendix 3, beginning with consent, for the duration of the treatment with 
mepolizumab and for 4 months after the last mepolizumab administration. 
 
[6] INFORMED CONSENT 
7. The subject consents to receiving treatment with mepolizumab under this Long-term 
Access Programme. 
5.2. 
Exclusion Criteria 
A subject will not be eligible for the LAP if any of the following criteria apply: 
[1] MALIGNANCY 
1. A current malignancy or history of cancer in remission for less than 12 months 
(Subjects who had localized carcinoma (i.e., basal or squamous cell) of the skin 
which was resected for cure will not be excluded). 
 
[2] OTHER CLINICALLY SIGNIFICANT MEDICAL CONDITIONS  
2. Subject has other clinically significant medical conditions uncontrolled with standard-
of-care therapy not associated with EGPA, e.g., unstable liver disease, uncontrolled 
cardiovascular disease, ongoing active infectious disease requiring systemic 
treatment. 
 
[3] PREGNANCY 
3. Subject is pregnant or breastfeeding. Subjects should not be considered for continued 
treatment if they plan to become pregnant during the course of treatment with 
mepolizumab. 
 
[4] HYPERSENSITIVITY 
4. Subject has a known allergy or intolerance to a monoclonal antibody or biologic 
therapy including mepolizumab. 
 
[5] PREMATURE WITHDRAWAL OF STUDY TREATMENT IN MEA115921 
5. Subject had an adverse event (serious or non-serious) considered related to study 
treatment whilst participating in study MEA115921 which resulted in permanent 
withdrawal of study treatment. 
 
[6] OTHER BIOLOGICAL THERAPY 
6. Subject is receiving treatment with another biological therapy such as a monoclonal 
antibody therapy or IV immunoglobulin therapy without prior agreement from the 
GSK Medical Monitor. 
 
[7] OTHER INVESTIGATIONAL PRODUCTS 
7. Subjects who have received treatment with an investigational drug within the past 


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30 days or 5 terminal phase half-lives of the drug whichever is longer, prior to 
initiation of mepolizumab treatment under this Long-term Access Programme (this 
also includes investigational formulations of marketed products). 
 
[8] OTHER CLINICAL STUDY 
8. Subject is currently participating in any other interventional clinical study. 
 
5.3. 
Withdrawal/Stopping Criteria 
GSK must be advised of any permanent discontinuations of mepolizumab under the LAP. 
Any subject discontinuing mepolizumab should be assessed 12 weeks after receiving 
their last dose at a follow-up/end of study visit. If the subject is lost to follow-up an Early 
Withdrawal form should be completed.  
Subjects may continue to receive mepolizumab until any of the following apply: 
• 
The physician determines that the subject is no longer deriving clinical benefit 
from treatment with mepolizumab or the benefit:risk evaluation does not support 
continued treatment. 
• 
Subject experiences a treatment-limiting adverse event(s), i.e., an event that 
results in permanent discontinuation of mepolizumab treatment. 
• 
Subject becomes pregnant or is planning to become pregnant. 
• 
GSK discontinues clinical development of mepolizumab in EGPA. Note, under 
these circumstances, provision of mepolizumab will be discontinued for all 
subjects regardless of individual patient benefit received during MEA115921 or 
116841. 
• 
Mepolizumab becomes commercially licensed for the treatment of EGPA in the 
relevant country. UK only clarification: Eligible subjects can continue to receive 
mepolizumab under this LAP until July 2022. 
5.4. 
Subject and Study Completion 
Supply of mepolizumab under the LAP will continue until mepolizumab is commercially 
available in the relevant country. UK only clarification: Eligible subjects can continue to 
receive mepolizumab under this LAP until July 2022. 
Treating physicians are responsible for the individual benefit:risk assessments and safety 
monitoring in support of continued mepolizumab treatment. 
6. 
STUDY TREATMENT 
6.1. 
Investigational Product and Other Study Treatment 
The term ‘study treatment’ is used throughout the protocol to describe open-label 
mepolizumab supply. 


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Study Treatment 
Product name: 
SB-240563 (mepolizumab) 
Formulation description: 
Mepolizumab 100mg vial for injection contains target quantities 
of 10.3mg Sodium Phosphate Dibasic Heptahydrate, 0.96 mg 
Polysorbate 80 and 230.4mg Sucrose per vial. 
Dosage form: 
Lyophilized powder for injection reconstituted with Sterile Water 
for Injection, just prior to use.   
Unit dose 
strength(s)/Dosage level(s): 
100 mg/300 mg 
Route of Administration:  
Subcutaneous injection 
Dosing instructions: 
Subjects will be dosed with 300 mg SC injection administered 
as three separate 100 mg SC injections every 4 weeks. 
 
Injections should be administered into any of the upper arm, 
thigh or anterior abdominal wall. It is recommended that 
individual injection sites are separated by at least 5 cm. 
Physical description: 
Mepolizumab will be provided as a lyopholised cake in sterile 
vials for individual use.  
 
Safety monitoring of subjects is required during SC administration and for 1 hour after 
the end of the injections for the first three administrations, i.e., at baseline, and Weeks 4 
and 8. Such monitoring will include general safety monitoring including monitoring for 
both systemic hypersensitivity (i.e., allergic/IgE-mediated and non-allergic) and local site 
reactions. From Week 12 onwards, subjects can be monitored following mepolizumab 
administration in accordance with standard of care at the site. 
Trained rescue personnel and rescue medications/equipment must be available for use at 
all times, see Error! Reference source not found. for further information. 
6.2. 
Packaging and Labelling 
The contents of the label will be in accordance with all applicable regulatory 
requirements. 
6.3. 
Preparation/Handling/Storage/Accountability 
A description of the methods and materials required for reconstitution of mepolizumab 
will be detailed in the Study Reference Manual (SRM) which will be accompanied by a 
Quality Agreement. 
• 
Only subjects enrolled in the study may receive study treatment and only authorized 
site staff may supply or administer study treatment.  
• 
Mepolizumab must be stored in a secure environmentally controlled and monitored 
(manual or automated) area in accordance with the labelled storage conditions with 
access limited to the investigator and authorized site staff.  


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• 
The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (i.e. receipt, reconciliation and final disposition records).   
• 
Study treatment/mepolizumab must be stored in a secure area under the appropriate 
physical conditions for the product. Access to study treatment will be limited to the 
investigator’s authorized site staff. Mepolizumab must be stored under the 
appropriate physical conditions which includes storage in a refrigerator or at a 
temperature of 2-8C and protected from light. Maintenance of a temperature log 
(manual or automated) is required. Study treatment must be dispensed or 
administered only to subjects enrolled in the study and in accordance with the 
protocol. 
• 
Further guidance and information for final disposition of unused study treatment are 
provided in the SRM.  
• 
Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff. Take adequate precautions to 
avoid direct eye or skin contact and the generation of aerosols or mists. In the case of 
unintentional occupational exposure notify the monitor, Medical Monitor and/or 
GSK study contact. 
• 
A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from 
GSK. 
6.4. 
Treatment of Mepolizumab 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. 
6.5. 
Concomitant Medications and Non-Drug Therapies 
6.5.1. 
Permitted Medications and Non-Drug Therapies 
Other concomitant therapy for the treatment of EGPA is permitted. 
Use of corticosteroids (excluding inhaled and topical steroids) will be captured. 
 
Concomitant therapy with another biological therapy (e.g., monoclonal antibodies or IV 
immunoglobulin therapy) should be discussed with the GSK Medical Monitor prior to 
beginning therapy.  If allowed, therapy should not be administered at the same time as the 
mepolizumab injection(s) and physicians should take measures to separate administration 
of another biological therapy as long as possible from administration of mepolizumab. 


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7. 
ASSESSMENTS AND PROCEDURES 
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the assessment requirements, including those specified 
in the Time and Events Table, are essential and required for study conduct. 
This section lists the procedures and parameters of each planned assessment. The exact 
timing of each assessment is listed in the Time and Events Table Section 7.1.  
 


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7.1. 
Time and Events Table 
Visits and Assessments 
Screening 
(up to 
4 weeks) 
Baseline 
Week 4 
(±7 days) 
Week 8 
(±7 days) 
Week 12 
 (±7 days) 
Week 16  
(±7 days) 
Week 20 
 (±7 days) 
Week 24 
(±7 days)  
Every 4 week treatment cycle/assessments  
repeated until End of Treatment 
Early 
withdrawal3 
End of 
Treatment3/ 
Follow-up  
(12 weeks 
post-last 
dose) 
Application Form sent to GSK for 
approval 
X 
 
 
 
 
 
 
 
 
 
Written Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Demography and CV risk 
assessment 
X 
 
 
 
 
 
 
 
 
 
Eligibility assessment: inclusion 
& exclusion criteria review 
X 
 
 
 
 
 
 
 
 
 
Baseline information 
 
X 
 
 
 
 
 
 
 
 
Dosing with mepolizumab1,2 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Corticosteroid use 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE/SAE review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine pregnancy test (FCBP) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Documentation of Benefit:risk 
evaluation to support continued 
supply of mepolizumab1 
X 
X 
 
 
X 
 
 
X 
 
 
1. The treating physician should make a benefit:risk evaluation to confirm continued treatment with mepolizumab is appropriate prior to each administration. This will be documented 
every 12 weeks to support continued supply. Note: it is expected that the treating physician will monitor subjects as per standard-of-care therapy (including any requirements for 
blood and urine tests).  
2. Safety monitoring of subjects is required during SC administration and for 1 hour after the end of the injections for the first three administrations, i.e., at baseline, and Weeks 4 and 
8. From Week 12 onwards, subjects can be monitored following mepolizumab administration in accordance with standard of care at the site. 
3. See Section 5.3  
 


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7.2. 
Screening and Critical Baseline Assessments 
The subject’s informed consent will be obtained at the Screening visit. 
Review of inclusion/exclusion criteria will be conducted at the Screening visit. 
The investigator will make a benefit:risk evaluation to confirm treatment with 
mepolizumab is appropriate for the subject.  
The subject’s identification number from study MEA115921 will be recorded in addition 
to their current oral corticosteroid dose. 
Cardiovascular medical history/risk factors (as detailed in the CRF) will be assessed at 
screening. 
The following demographic parameters will be captured: year of birth, sex, race and 
ethnicity. 
7.3. 
Safety 
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1).   
The treating physician should make a benefit:risk evaluation to confirm treatment with 
mepolizumab is appropriate prior to each administration. This will be documented every 
12 weeks to support continued supply. It is expected that the treating physician will 
monitor subjects as per standard-of-care therapy (including any requirements for blood 
and urine tests). 
7.3.1. 
Adverse Events (AE) and Serious Adverse Events (SAEs) 
The definitions of an AE or SAE can be found in Appendix 4. Additionally, because 
mepolizumab is a monoclonal antibody administered subcutaneously, systemic (i.e., 
allergic/hypersensitivity and non-allergic) reactions and local injection site reactions will 
be reported and recorded throughout the treatment and follow-up period. Hypersensitivity 
reactions will be monitored using the diagnostic criteria for anaphylaxis as outlined by 
the 2006 Joint NIAID/FAAN Second Symposium on Anaphylaxis [Sampson, 2006] 
(Error! Reference source not found.). 
The treating physician and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE.  
7.3.1.1. 
Time period and Frequency for collecting AE and SAE information 
• 
Aes and SAEs will be collected from administration of the first dose of mepolizumab 
and will continue indefinitely, see minimum schedule of assessments, Time and 
Events Table (Section 7.1) 
• 
Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK product 


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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 recorded and reported to GSK within 24 hours, as indicated in 
Appendix 4. The treating physician is not obligated to actively seek Aes or SAEs in 
former study subjects. However, if the investigator learns of any SAE, including a 
death, at any time after a subject has discontinued mepolizumab treatment under the 
LAP, and he/she considers the event reasonably related to the study treatment or 
study participation, the investigator must promptly notify GSK. 
NOTE: The method of recording, evaluating and assessing causality of Aes and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 4 
 
7.3.1.2. 
Method of Detecting Aes and SAEs 
Care will be taken not to introduce bias when detecting Aes and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence. Appropriate questions include: 
• 
“How are you feeling?”  
• 
“Have you had any (other) medical problems since your last visit/contact?”  
• 
“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?”  
7.3.1.3. 
Follow-up of Aes and SAEs 
After the initial AE/SAE report, the treating physician is required to proactively follow 
each subject at subsequent visits/contacts. All SAEs, and non-serious Aes of special 
interest (as defined in Section 4.4.1) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up 
(as defined in Section 5.3). Further information on follow-up procedures is given in 
Appendix 4. 
7.3.1.4. 
Cardiovascular and Death Events 
Investigators will be required to fill out the specific CV event page of the CRF for the 
cardiovascular Aes and SAEs, as listed in Appendix 4: Section 12.4.3. 
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 non-cardiovascular death. 
This information should be recorded within one week of when the death is first reported. 


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7.3.1.5. 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the treating physician to GSK of SAEs and non-serious Aes 
related to study treatment (even for non- interventional post-marketing studies) is 
essential so that legal obligations and ethical responsibilities towards the safety of 
subjects and the safety of a product under clinical investigation are met.  
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation. GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators. 
Treating physician 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. 
A treating physician who receives an investigator safety report describing a SAE(s) or 
other specific safety information (e.g., summary or listing of SAEs) from GSK will file it 
with the IB and will notify the IRB/IEC, if appropriate according to local requirements. 
7.3.2. 
Pregnancy 
Urine pregnancy tests in FCBP will be conducted as indicated in the Time and Events 
Table (Section 7.1).  
Details of all pregnancies in female subjects will be collected after the start of dosing and 
until 12 weeks post last dose. If a pregnancy is reported then the investigator should 
inform GSK within 2 weeks of learning of the pregnancy and should follow the 
procedures outlined below. 
• 
Treatment with mepolizumab should be discontinued in the event of pregnancy. . 
• 
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. 
 


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8. 
DATA MANAGEMENT 
• 
For this study (1-eDM) subject data will be entered into GSK defined CRFs, 
transmitted electronically to GSK.  
• 
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 
(Medical Dictionary for Regulatory Activities) and an internal validated medication 
dictionary, GSKDrug. 
9. 
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES 
No statistical analysis will be conducted for this study. Reported data will be 
summarized. 
9.1. 
Interim Analysis 
When required, an interim analysis will be performed in order to provide open-label 
safety data to inform the risk-benefit assessment of mepolizumab in EGPA. 
10. 
STUDY GOVERNANCE CONSIDERATIONS 
10.1. 
Regulatory and Ethical Considerations, Including the 
Informed Consent Process 
Prior to initiation of a site, GSK will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements. 
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy. 
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki. This includes, but is not limited to, the following: 
• 
IRB/IEC review and favourable opinion/approval of the study protocol and 
amendments as applicable 
• 
Signed informed consent to be obtained for each subject before participation in the 
study (and for amendments as applicable) 
• 
Investigator reporting requirements (e.g. reporting of Aes/SAEs/protocol deviations 
to IRB/IEC) 
• 
GSK will provide full details of the above procedures, either verbally, in writing, or 
both. 


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• 
Signed informed consent must be obtained for each subject prior to participation in 
the study 
• 
The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.  
• 
Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.  
• 
Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities. In this situation, written 
approval of the clinical protocol should state that approval of optional assessments is 
being deferred and the study, with the exception of the optional assessments, can be 
initiated. 
10.2. 
Quality Control (Study Monitoring) 
• 
In accordance with applicable regulations including GCP, and GSK procedures, 
GSK monitors will contact the site prior to the start of the study to review with the 
site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and GSK requirements.  
• 
When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the CRF will 
serve as the source document. 
GSK will monitor the study and site activity to verify that the: 
• 
Data are authentic, accurate, and complete. 
• 
Safety and rights of subjects are being protected. 
• 
Study is conducted in accordance with the currently approved protocol and any other 
study agreements, GCP, and all applicable regulatory requirements. 
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents 
10.3. 
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. 


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10.4. 
Study and Site Closure 
• 
Upon completion or premature discontinuation of the study, the GSK monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and GSK Standard Operating 
Procedures. 
• 
GSK reserves the right to temporarily suspend or prematurely discontinue this study 
at any time for reasons including, but not limited to, safety or ethical issues or severe 
non-compliance. For  nformation studies, this can occur at one or more or at all 
sites.  
• 
If GSK determines such action is needed, GSK will discuss the reasons for taking 
such action with the investigator or the head of the medical institution (where 
applicable). When feasible, GSK will provide advance notification to the investigator 
or the head of the medical institution, where applicable, of the impending action. 
• 
If the study is suspended or prematurely discontinued for safety reasons, GSK will 
promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action.  
• 
If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation. 
10.5. 
Records Retention 
• 
Following closure of the study, the investigator or the head of the medical institution 
(where applicable) must maintain all site study records (except for those required by 
local regulations to be maintained elsewhere), in a safe and secure location.   
• 
The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review in 
conjunction with assessment of the facility, supporting systems, and relevant site 
staff.   
• 
Where permitted by local laws/regulations or institutional policy, some or all of these 
records can be maintained in a format other than hard copy (e.g., microfiche, 
scanned, electronic); however, caution needs to be exercised before such action is 
taken.   
• 
The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, including 
re-generating a hard copy, if required. Furthermore, the investigator must ensure 
there is an acceptable back-up of these reproductions and that an acceptable quality 
control process exists for making these reproductions. 
• 
GSK will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements. The minimum retention time 
will meet the strictest standard applicable to that site for the study, as dictated by any 


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institutional requirements or local laws or regulations, GSK standards/procedures, 
and/or institutional requirements.   
• 
The investigator must notify GSK of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of ownership 
of the records in the event the investigator is no longer associated with the site. 
10.6. 
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location. 
GSK will also provide the investigator with the full summary of the study results. The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate. 
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy. 
10.7. 
Review Committees 
An IDMC will be utilized until completion of the lead study MEA115921; their primary 
focus will be the monitoring of cardiovascular safety and all cause mortality. 


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11. 
REFERENCES 
Clutterbuck E, Hirst E, Sanderson C. Human interleukin-5 (IL-5) regulates the production 
of  nformation in human bone marrow cultures: comparison and interaction with IL-1, 
IL-3, IL-6 and GMCSF. Blood 1989;73:1504-12. 
GlaxoSmithKline Document Number 2012N142276_02: Protocol MEA115921: A 
Double-blind, Randomised, Placebo-controlled Study to Investigate the Efficacy and 
Safety of Mepolizumab in the Treatment of Eosinophilic Granulomatosis with 
Polyangiitis in Subjects Receiving Standard of Care Therapy. Date: 27-Aug-2014. 
GlaxoSmithKline Document Number 2014N200212_00. Supplement to Mepolizumab 
(SB-240563) Investigator’s Brochure. Supplement No.: 01 IB Version 12. Date: 22-May-
2014. 
GlaxoSmithKline Document Number CM2003/00010/08 Mepolizumab (SB-240563) 
Investigator’s brochure. Version 12, Report Date 08-Apr-2013. 
Haldar P, Brightling C, Hargadon B, et al. Mepolizumab and exacerbations of refractory 
eosinophilic asthma. N Engl J Med 2009;360:973-84.  
Holle J, Moosig F, Gross WL. Diagnostic and therapeutic management of Churg-Strauss. 
Expert Rev Clin Immunol 2009;5:813-23.  
Keogh KA, Specks U. Churg-Strauss Syndrome. Semin Respir Crit Care Med 
2006;27:148-57.  
Kim S, Marigowda G, Oren E, Israel E, Wechsler M. Mepolizumab as a steroid-sparing 
treatment option in patients with Churg-Strauss Syndrome. J Allergy Clin Immunol 
2010;125:1336-43.  
Lopez A, Sanderson C, Gamble J, et al. Recombinant human interleukin 5 is a selective 
activator of human eosinophil function. J Exp Med 1988;167:219-24. 
Moosig F, Gross WL, Herrmann K, Bremer JP. Targeting interleukin-5 in refractory and 
relapsing Churg–Strauss Syndrome. Ann Int Med 2011;155:341-3. 
Nair P, Pizzichini M, Kjarsgaard M, et al. Mepolizumab for prednisone-dependent 
asthma with sputum eosinophilia. N Engl J Med 2009;360:985-93. 
Pavord ID, Korn S, Howarth P, et al. Mepolizumab for severe eosinophilic asthma 
(DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet 2012;380:651–9. 
Rothenberg ME, Hogan SA. The eosinophil. Annu Rev Immunol 2006;24:147–74. 
Rothenberg ME, Klion AD, Roufosse FE, et al. Treatment of patients with 
hypereosinophilic syndrome with mepolizumab. N Engl J Med 2008;358:1215-28.  


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Sampson HA, Muñoz-Furlong A, Campbell R, 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;117:391-7. 
Stein ML, Collins MH, Villanueva JM, et al. Anti-IL-5 (mepolizumab) therapy for 
eosinophilic esophagitis. J Allergy Clin Immunol 2006;118:1312-9.  
Vaglio A, Moosig F, Zwerina J. Churg–Strauss syndrome: update on pathophysiology 
and treatment. Curr Opin Rheumatol 2012;24:24–30. 
 


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12. 
APPENDICES 
12.1. 
Appendix 1 – Abbreviations and Trademarks 
Abbreviations 
ADA 
Anti-drug antibody 
AE 
Adverse Event 
ALT 
Alanine transaminase 
CRF 
Case Report Form 
CV 
Cardiovascular 
DCSI 
Developmental Core Safety Information 
ECG 
Electrocardiogram 
EGPA 
Eosinophilic Granulomatosis with Polyangiitis 
FCBP 
Female of childbearing potential 
GCP 
Good Clinical Practice 
GSK 
GlaxoSmithKline 
HRT 
Hormone replacement therapy 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
IDMC 
Independent data monitoring committee 
IEC 
Independent Ethics Committee 
IL 
Interleukin 
IRB 
Institutional review Board 
IUD 
Intrauterine device 
IV 
Intravenous(ly) 
kg 
kilogram 
LAP 
Long-term Access Programme 
mAb 
Monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligrams 
MSDS 
Material Safety Data Sheet 
NAB 
Neutralizing antibodies 
SAE 
Serious Adverse Event 
SC 
Subcutaneous(ly) 
SOC 
System organ class 
SRM 
Study reference manual 
SRT 
Safety review team 
ULN 
Upper limit of normal 
UK 
United Kingdom 
Trademark Information 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
NONE 
 
None 


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12.2. 
Appendix 2 – 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: 
4) 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: 
c) Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced PEF, hypoxemia)  
d) Reduced BP or associated symptoms of end-organ dysfunction (e.g., 
hypotonia [collapse], syncope, incontinence) 
5) Two or more of the following that occur rapidly after exposure to a likely allergen 
for that patient (minutes to several hours): 
e) Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, 
swollen lips-tongue-uvula) 
f) Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced PEF, hypoxemia) 
g) Reduced BP or associated symptoms (e.g., hypotonia [collapse], syncope, 
incontinence) 
h) Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting) 
6) Reduced BP after exposure to known allergen for that patient (minutes to several 
hours): 
c) Infants and children: low systolic BP (age specific) or greater than 30% 
decrease in systolic BP 
d) Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from 
that person’s baseline 
 


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12.3. 
Appendix 3 – Acceptable Birth Control 
To be eligible for entry into the study, females of childbearing potential (FCBP) 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 mepolizumab 
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. 
• 
UK only clarification: True abstinence from penile-vaginal intercourse when 
this is in line with the preferred and usual lifestyle of the subject. 
• 
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) 
• 
Male condom combined with a female diaphragm, either with or without a 
vaginal spermicide (foam, gel, film, cream, or suppository) 
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  nformat to confirm childbearing potential.   


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Females on 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 enrolment. 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 foetus 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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12.4. 
Appendix 4 – Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events 
12.4.1. 
Definition of Adverse Events 
Adverse Event Definition: 
• 
An AE is any untoward medical occurrence in a patient or clinical investigation 
subject, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product. 
• 
NOTE: An AE can therefore be any unfavourable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product. 
 
Events meeting AE definition include: 
• 
Any abnormal laboratory test results (haematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator. 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent. This should be reported regardless of sequelae). 
• 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. However, the signs and symptoms and/or clinical 
sequelae resulting from lack of efficacy will be reported if they fulfil the definition 
of an AE or SAE. 
 
Events NOT meeting definition of an AE include: 
• 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 
condition. 


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• 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE. 
• 
Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
 
12.4.2. 
Definition of Serious Adverse Events 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc). 
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose: 
a. Results in death 
b. Is life-threatening 
NOTE: 
The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the 
subject was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
c. 
Requires hospitalization or prolongation of existing hospitalization 
NOTE: 
• 
In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting. Complications that occur during hospitalization are Aes. 
If a complication prolongs hospitalization or fulfils any other serious criteria, the 
event is serious. When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious. 
• 
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
d. Results in disability/incapacity 
NOTE: 
• 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhoea, influenza, 


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and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday 
life functions but do not constitute a substantial disruption 
e. 
Is a congenital anomaly/birth defect 
f. 
Other situations: 
• 
Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition. These should also be considered 
serious. 
• 
Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse 
g. Is associated with liver injury and impaired liver function defined as: 
• 
ALT  3xULN and total bilirubin*  2xULN (>35% direct), or 
• 
ALT  3xULN and INR** > 1.5. 
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick. If fractionation is unavailable and ALT  3xULN 
and total bilirubin  2xULN, then the event is still to be reported as an SAE. 
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants. If INR measurement is obtained, the value is to be 
recorded on the SAE form. 
 
12.4.3. 
Definition of Cardiovascular Events 
Cardiovascular Events (CV) Definition: 
Investigators will be required to fill out the specific CV event page of the CRF for the 
following Aes and SAEs: 
• 
Myocardial infarction/unstable angina 
• 
Congestive heart failure 
• 
Arrhythmias 
• 
Valvulopathy 
• 
Pulmonary hypertension 
• 
Cerebrovascular events/stroke and transient ischemic attack 
• 
Peripheral arterial thromboembolism 


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• 
Deep venous thrombosis/pulmonary embolism 
• 
Revascularization 
 
12.4.4. 
Recording of Aes and SAEs 
Aes and SAE Recording: 
• 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event. 
• 
The investigator will then record all relevant information regarding an AE/SAE in 
the CRF 
• 
It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to GSK in lieu of completion of the GSK, AE/SAE CRF page. 
• 
There may be instances when copies of medical records for certain cases are 
requested by GSK. In this instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to 
submission of to GSK. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms. 
 
12.4.5. 
Evaluating Aes and SAEs 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories: 
• 
Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities. 
• 
Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities 
• 
Severe:  An event that prevents normal everyday activities. – an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for rating 
the intensity of an event; and both Aes and SAEs can be assessed as severe. 
• 
An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE. 
 


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Assessment of Causality 
• 
The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE. 
• 
A “reasonable possibility” is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
out. 
• 
The investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated. 
• 
The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of his/her assessment. 
• 
For each AE/SAE the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality. 
• 
There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK. However, it is very important 
that the investigator always make an assessment of causality for every event 
prior to the initial transmission of the SAE data to GSK. 
• 
The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly. 
• 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-up of Aes and SAEs 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE. 
• 
The investigator is obligated to assist. This may include additional laboratory tests or 
investigations, histopathological examinations or consultation with other health care 
professionals. 
• 
If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide GSK with a copy of any post-mortem findings, 
including histopathology. 
• 
New or updated information will be recorded in the originally completed CRF. 
• 
The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames. 


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12.4.6. 
Reporting of SAEs to GSK 
SAE reporting to GSK via electronic data collection tool 
• 
Primary mechanism for reporting SAEs to GSK will be the electronic data collection 
tool 
• 
If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax it to the Medical Monitor or the SAE 
coordinator. 
• 
Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available. 
• 
After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) will be taken off-line to prevent the entry of new data or changes to 
existing data. 
• 
If a site receives a report of a new SAE from a study subject or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, the site can report this information on a paper SAE form or to the Medical 
Monitor or the SAE coordinator by telephone. 
• 
Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page. 
 


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12.5. 
Appendix 5 – Country Specific Requirements 
Amendments 01, 02 and 04 include a country-specific local amendment generated for the 
United Kingdom (UK).  
The UK regulatory authority has requested the following clarifications highlighted in 
bold italics. 
Overall study design (Section 1: Protocol Synopsis for Study MEA115921, Overall 
Design, paragraph 6 and Section 4.1: Overall Design, paragraph 6): 
UK only clarification: Eligible subjects can continue to receive mepolizumab under this 
LAP until June 2018 or until the Sponsor discontinues development in EGPA or until the 
subject meets any of the withdrawal/stopping criteria. 
Section 5.3: Withdrawal/Stopping Criteria, paragraph 2, bullet 5 and Section 5.4: Subject 
and Study Completion 
 
UK only clarification: Eligible subjects can continue to receive mepolizumab under 
this LAP until June 2018. 


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12.6. 
Appendix 2 – 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: 
7) 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: 
e) Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced PEF, hypoxemia)  
f) Reduced BP or associated symptoms of end-organ dysfunction (e.g., 
hypotonia [collapse], syncope, incontinence) 
8) Two or more of the following that occur rapidly after exposure to a likely allergen 
for that patient (minutes to several hours): 
i) Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, 
swollen lips-tongue-uvula) 
j) Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
reduced PEF, hypoxemia) 
k) Reduced BP or associated symptoms (e.g., hypotonia [collapse], syncope, 
incontinence) 
l) Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting) 
9) Reduced BP after exposure to known allergen for that patient (minutes to several 
hours): 
e) Infants and children: low systolic BP (age specific) or greater than 30% 
decrease in systolic BP 
f) Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from 
that person’s baseline 
 
Appendix 3 – Acceptable Birth Control: 
UK only clarification: True abstinence from penile-vaginal intercourse when this is in 
line with the preferred and usual lifestyle of the subject. 
Overall study design (Section 1: Protocol Synopsis for Study MEA115921, Overall 
Design, paragraph 6 and Section 4.1: Overall Design, paragraph 6): 
UK only Clarification: Eligible subjects can continue to receive mepolizumab under this 
LAP until June 2021 or until the Sponsor discontinues development in EGPA or until the 
subject meets any of the withdrawal/stopping criteria. 


2014N201870_04 
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49 
Section 5.3: Withdrawal/Stopping Criteria, paragraph 2, bullet 5 and Section 5.4: Subject 
and Study Completion 
UK only clarification: Eligible subjects can continue to receive mepolizumab under 
this LAP until June 2021. 
UK only clarification: Eligible subjects can continue to receive mepolizumab under 
this LAP until July 2022. 


2014N201870_04 
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50 
12.7. 
Appendix 6 – Protocol Changes 
12.6.1  
Protocol Amendment 01 
This amendment applies to sites in the UK only. 
List of protocol changes: 
Text which has been added to the protocol is highlighted in bold, italic typeface. Text 
which has been deleted from the protocol is indicated by strike-through format. 
Change  Section, Text affected, and Rationale 
1.  
Section 1: Protocol Synopsis for Study MEA115921, Overall Design, 
paragraph 6. 
Section 4.1: Overall Design, paragraph 6. 
Added: 
United Kingdom (UK) only clarification: Eligible subjects can continue to 
receive mepolizumab under this LAP until June 2018 unless mepolizumab 
is commercially licensed for the treatment of EGPA in the relevant country 
prior to this date or until the Sponsor discontinues development in EGPA 
or until the subject meets any of the withdrawal/stopping criteria. 
Rationale: Clarification requested by the UK regulatory authority. 
2.  
Appendix 1 – Abbreviations and Trademarks 
Added: 
UK: United Kingdom 
3.  
Appendix 3– Acceptable Birth Control; bullet 3 
Modified: 
UK only: True abstinence from penile-vaginal intercourse when this is in 
line with the preferred and usual lifestyle of the subject. 
Rationale: Clarification requested by the UK regulatory authority. 
4.  
Appendix 5 – Country Specific Requirements: 
Changed from: 
No country-specific requirements exist. 


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51 
Change  Section, Text affected, and Rationale 
Changed to: 
Amendment 01 includes a country-specific local amendment generated for 
the United Kingdom (UK).  
The UK regulatory authority has requested the following clarifications 
highlighted in bold italics. 
Overall study design (Section 1: Protocol Synopsis for Study MEA115921, 
Overall Design, paragraph 6 and Section 4.1: Overall Design, paragraph 6): 
UK only clarification: Eligible subjects can continue to receive 
mepolizumab under this LAP until June 2018 unless mepolizumab is 
commercially licensed for the treatment of EGPA in the relevant country 
prior to this date or until the Sponsor discontinues development in EGPA or 
until the subject meets any of the withdrawal/stopping criteria. 
Appendix 3 – Acceptable Birth Control: 
UK only clarification: True abstinence from penile-vaginal intercourse 
when this is in line with the preferred and usual lifestyle of the subject. 
 


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52 
12.6.2  
Protocol Amendment 02 
This amendment applies to sites in the UK only. 
List of protocol changes: 
Text which has been added to the protocol is highlighted in bold, italic typeface. Text 
which has been deleted from the protocol is indicated by strike-through format. 
Change  Section, Text affected, and Rationale 
1.  
Section 1: Protocol Synopsis for Study MEA115921, Overall Design, 
paragraph 6. 
Section 4.1: Overall Design, paragraph 6: 
Deleted: 
United Kingdom (UK) only clarification: Eligible subjects can continue to 
receive mepolizumab under this LAP until June 2018 unless mepolizumab is 
commercially licensed for the treatment of EGPA in the relevant country 
prior to this date or until the Sponsor discontinues development in EGPA or 
until the subject meets any of the withdrawal/stopping criteria. 
Rationale: Clarification requested by the UK regulatory authority. 
2.  
Section 5.3: Withdrawal/Stopping Criteria, paragraph 2, bullet 5. 
Section 5.4: Subject and Study Completion, paragraph 1 
 
Added: 
UK only clarification: Eligible subjects can continue to receive 
mepolizumab under this LAP until June 2018. 
Rationale: Clarification requested by the UK regulatory authority. 
3.  
Appendix 5 – Country Specific Requirements: 
Added and deleted: 
Amendments 01 and 02 includes a country-specific local amendment 
generated for the United Kingdom (UK).  
UK only clarification: Eligible subjects can continue to receive 
mepolizumab under this LAP until June 2018 unless mepolizumab is 
commercially licensed for the treatment of EGPA in the relevant country 
prior to this date or until the Sponsor discontinues development in EGPA or 
until the subject meets any of the withdrawal/stopping criteria. 


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53 
Change  Section, Text affected, and Rationale 
Section 5.3: Withdrawal/Stopping Criteria, paragraph 2, bullet 5 and 
Section 5.4: Subject and Study Completion 
 
Added: 
UK only clarification: Eligible subjects can continue to receive 
mepolizumab under this LAP until June 2018. 
Rationale: Clarification requested by the UK regulatory authority. 
 


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12.6.3  
Protocol Amendment 03 
This amendment applies to all countries. 
List of protocol changes: 
Text which has been added to the protocol is highlighted in bold, italic typeface. Text 
which has been deleted from the protocol is indicated by strike-through format. 
Change  Section, Text affected, and Rationale 
1.  
TITLE PAGE: Authors 
Deleted/Added: 
Rationale: 
Change in team personnel. 
2.  
MEDICAL MONITOR/SPONSOR INFORMATION PAGE 
Deleted: 
Secondary Medical Monitor: 
 BSc MBChB FRCA PhD 
Rationale: 
Dr 
 has left GSK. 
3.  
Section 5.2: Exclusion Criteria, Exclusion #6: Other Biological Therapy, 
Section 6.5.1 Permitted Medications and Non-Drug Therapies and Section 
6.5.2: Prohibited Medications and Non-Drug Therapies 
Added:  
Section 5.2: Exclusion Criteria, Exclusion #6 
5. Subject is receiving treatment with another biological therapy such as 
a monoclonal antibody therapy or IV immunoglobulin therapy 
without prior agreement from the GSK Medical Monitor. 
Section 6.5.1 Permitted Medications and Non-Drug Therapies 
Concomitant therapy with another biological therapy (e.g., monoclonal 
antibodies or IV immunoglobulin therapy) should be discussed with the 
GSK Medical Monitor prior to beginning therapy.  If allowed, therapy 
PPD
PPD
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55 
Change  Section, Text affected, and Rationale 
should not be administered at the same time as the mepolizumab 
injection(s) and physicians should take measures to separate 
administration of another biological therapy as long as possible from 
administration of mepolizumab. 
Deleted: 
 
Section 6.5.2: Prohibited Medications and Non-Drug Therapies 
Section 6.5.2  Prohibited Medications and Non-Drug Therapies 
• 
Concomitant administration of other biological therapies such as 
monoclonal antibodies or IV immunoglobulin therapy. 
Rationale: It is recognised that there may be occasions when physicians 
may want to administer another biological therapy for a condition other than 
EGPA while a patient is being treated with mepolizumab.  The GSK Medical 
Monitor will need to assess each drug’s safety profile and any potential 
safety concern with the combination and thus as a precaution, use of another 
biologic therapy in addition to mepolizumab will require approval from the 
GSK Medical Monitor.  In addition, the treating physician will be asked to 
take measures to separate administration of another biological therapy as 
long as possible from administration of mepolizumab. 
 
 
 
 
 
 
 
 
 
 
 


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56 
12.6.4 Protocol Amendment 04  
Amendment changes 1 and 2 apply to all countries. Amendment change 3 and 4 apply to 
sites in the UK only. 
List of protocol changes: 
Text which has been added to the protocol is highlighted in bold, italic typeface. 
Chan
ge  
Section, Text affected, and Rationale 
1.      Section 9 Statistical Considerations and Data Analyses 
Added: 
9.1 
Interim Analysis 
When required, an interim analysis will be performed in order to provide open-
label safety data to inform the risk-benefit assessment of mepolizumab in 
EGPA. 
2.  
 
 
 
 
 
 
 
 
 
 
MEDICAL MONITOR/SPONSOR INFORMATION PAGE 
Role 
Name 
Day Time Phone 
Number and email 
address 
After-hours 
Phone/Cell/ 
Pager 
Number 
Fax 
Numb
er 
Site 
Address 
Primary 
Medical 
Monitor  
n/a 
GSK 
Upper 
Providen
ce, PA, 
USA 
 
Secondar
y Medical 
Monitor 
n/a 
GSK 
Researc
h 
Triangle 
Park, 
NC, USA 
 
SAE 
contact  
 informat
ion  
Medica
l 
monito
r as 
above 
 
 
 
 
3.  
Section 1: Protocol Synopsis for Study MEA115921, Overall Design, 
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Chan
ge  
Section, Text affected, and Rationale 
paragraph 6. 
Section 4.1: Overall Design, paragraph 6. 
Added: 
UK only Clarification: Eligible subjects can continue to receive mepolizumab 
under this LAP until June 2021 or until the Sponsor discontinues development 
in EGPA or until the subject meets any of the withdrawal/stopping criteria. 
Rationale: Clarification requested by the UK regulatory authority. 
4.  
Section 5.3: Withdrawal/Stopping Criteria, paragraph 2, bullet 5. 
Section 5.4: Subject and Study Completion, paragraph 1 
 
Added: 
UK only clarification: Eligible subjects can continue to receive mepolizumab 
under this LAP until June 2021. 
Rationale: Clarification requested by the UK regulatory authority. 
 
 
 
 
 
 
 
 
 
 
 


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12.7.5. 
Protocol Amendment 05 
Amendment changes 1 and 2 apply to all countries. Amendment change 3, 4 and 5 apply 
to sites in the UK only. 
List of protocol changes: 
TEXT WHICH HAS BEEN ADDED TO THE PROTOCOL IS HIGHLIGHTED IN BOLD, 
ITALIC TYPEFACE 
 
Chan
ge  
Section, Text affected, and Rationale 
1.  
MEDICAL MONITOR/SPONSOR INFORMATION PAGE 
Role 
Name 
Day Time Phone 
Number and email 
address 
After-hours 
Phone/Cell/ 
Pager 
Number 
Fax 
Numb
er 
Site 
Address 
Primary 
Medical 
Monitor  
n/a 
GSK 
980 Great 
West 
Road, 
Brentford
, 
Middlese
x, TW8 
9GS, 
United 
Kingdom 
Secondat
y Medical 
Monitor 
n/a 
GSK 
Upper 
Providen
ce, PA, 
USA 
 
SAE 
contact  
informati
on  
Medic
al 
monito
r as 
above 
 
 
 
 
PPD


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59 
Chan
ge  
Section, Text affected, and Rationale 
Clinical 
Investiga
tion Lead 
- CIL 
n/a 
GSK 
980 Great 
West 
Road, 
Brentford
, 
Middlese
x, TW8 
9GS, 
United 
Kingdom 
Operatio
ns & 
Science 
Lead-
OSL 
n/a 
GSK 
Homebas
ed Spain 
 
Data 
Manager 
Lead 
n/a 
TCS 
Maharash
tra, India 
2.  
Section 1: Protocol Synopsis for Study MEA115921, Overall Design, 
paragraph 6. 
Section 4.1: Overall Design, paragraph 6. 
Added: 
UK only Clarification: Eligible subjects can continue to receive mepolizumab 
under this LAP until July 2022 or until the Sponsor discontinues development 
in EGPA or until the subject meets any of the withdrawal/stopping criteria. 
Rationale: Clarification requested by the UK regulatory authority. 
3.  
Section 5.3: Withdrawal/Stopping Criteria, paragraph 2, bullet 5. 
Section 5.4: Subject and Study Completion, paragraph 1 
 
Added: 
UK only clarification: Eligible subjects can continue to receive mepolizumab 
under this LAP until July 2022. 
Rationale: Clarification requested by the UK regulatory authority. 
4.  
Appendix 5 – Country Specific Requirements 
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Chan
ge  
Section, Text affected, and Rationale 
Added: 
UK only clarification: Eligible subjects can continue to receive mepolizumab 
under this LAP until July 2022. 
 

SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
MEA116841
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for MEA116841 and 201607: 
Long-term Access Programme for mepolizumab in subjects 
with Eosinophilic Granulomatosis with Polyangiitis (EGPA))
Compound Number 
:
SB-240563
Effective Date 
:
01-Aug-2019
Description:
The purpose of this RAP is to describe the planned analyses and output to be included in 
the Clinical Study Report for the Long-term Access Programme (LAP) for mepolizumab 
in EGPA. The LAP comprises a clinical trial (MEA116841) and compassionate use 
programme (201607). Planned outputs also include periodic interim analyses conducted 
after the effective date of this RAP, as necessary.
RAP Author(s):
Author
Date
18-JUL-2019
Project Statistician (Biostatistics)
Copyright 2019 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD


CONFIDENTIAL
The GlaxoSmithKline group of companies
MEA116841
2
RAP Team Review Confirmations (Method: E-mail)
Reviewer
Date
Project Physician Lead (PPL)
18-JUL-2019
Clinical Investigation Lead (CIL)
24-JUL-2019
Operations Study Lead (OSL)
25-JUL-2019
Data Quality Lead (DQL)
18-JUL-2019
(SERM)
18-JUL-2019
(Regulatory)
24-JUL-2019
Lead Programmer (Clinical Programming)
24-JUL-2019
Clinical Statistics and Clinical Programming Line Approvals (Method: Pharma 
TMF eSignature):
Approver
Date
01-Aug-2019
31-Jul-2019
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


CONFIDENTIAL
MEA116841
3
TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................5
1.1.
RAP Amendments ........................................................................................5
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................7
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................7
2.2.
Study Objective(s) and Endpoint(s)...............................................................7
2.3.
Study Design ................................................................................................8
2.4.
Statistical Hypotheses / Statistical Analyses .................................................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.....................................................................................................11
5.1.
Study Treatment and Subgroup Display Descriptors...................................11
5.2.
Examination of Subgroups..........................................................................11
5.3.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................12
6.
STUDY POPULATION ANALYSES .......................................................................13
6.1.
Overview of Planned Study Population Analyses........................................13
7.
SAFETY ANALYSES .............................................................................................14
7.1.
Adverse Events...........................................................................................14
7.2.
Adverse Events of Special Interest .............................................................14
7.3.
Other Safety Analyses ................................................................................15
8.
REFERENCES.......................................................................................................16
9.
APPENDICES........................................................................................................17
9.1.
Appendix 1: Schedule of Activities ..............................................................17
9.1.1.
Protocol Defined Schedule of Events...........................................17
9.2.
Appendix 2: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................18
9.2.1.
Study Phases ..............................................................................18
9.3.
Appendix 3: Data Display Standards & Handling Conventions....................19
9.3.1.
Reporting Process .......................................................................19
9.3.2.
Reporting Standards....................................................................19
9.4.
Appendix 4: Derived and Transformed Data ...............................................21
9.4.1.
General........................................................................................21
9.4.2.
Study Population..........................................................................21
9.4.3.
Safety ..........................................................................................21
9.5.
Appendix 5: Reporting Standards for Missing Data.....................................23
9.5.1.
Premature Withdrawals................................................................23


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MEA116841
4
9.5.2.
Handling of Missing Data.............................................................23
9.5.2.1.
Handling of Missing and Partial Dates ........................23
9.6.
Appendix 6: Abbreviations & Trade Marks ..................................................24
9.6.1.
Abbreviations...............................................................................24
9.6.2.
Trademarks .................................................................................25
9.7.
Appendix 7: List of Data Displays ...............................................................26
9.7.1.
Data Display Numbering..............................................................26
9.7.2.
Mock Example Shell Referencing ................................................26
9.7.3.
Deliverables.................................................................................26
9.7.4.
Study Population Tables..............................................................27
9.7.5.
Safety Tables...............................................................................29
9.7.6.
ICH Listings .................................................................................38


CONFIDENTIAL
MEA116841
5
1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses and
planned outputs to be included in the Clinical Study Report for the Long-term Access 
Programme (LAP) for mepolizumab in EGPA. The LAP comprises a clinical trial 
(MEA116841) and compassionate use programme (201607).  This document also 
describes the planned outputs to be included in periodic interim analyses, conducted after 
the effective date of this RAP, as appropriate
This RAP is based on MEA116841 study protocol amendment 4 issued 18-Jun-2019
(GlaxoSmithKline Document Number 2014N201870_04) and has been amended 
following the previous RAP version which has been used to provide the analyses required 
for the previous Interim Clinical Study Report (ICSRs).
The clinical data base for the LAP consists of the following subjects:

Subjects recruited into study MEA116841

Subjects recruited as part of the named patient supply guidance program 201607
Available data from the above subjects will be included in the analyses specified in this 
RAP. Combined summaries will be produced from the clinical trial data base for 
MEA116841 and the NPS guidance program.
1.1.
RAP Amendments
All revisions since the previous approved RAP (dated 26-Sep-2016) are listed below:
RAP Section
Amendment Details
All
Formatting changes to fit RAP_Template_Master_v2 (8-Aug-2017)
3.1 Interim Analyses
Details of previous interim analysis (5-Sep-2016 cut-off date) were added
4.1 Protocol Deviations
Reference added to updated PDMP
7.1 Safety Analyses
Added text providing additional information regarding adverse event 
reporting for MEA116841 and 201607
9.7.4 Study Population 
Tables

Removed “Summary of Reasons for Screen and Run-In Failure“ 
(Rationale: there was only one occurrence and these data are included 
in the listings)

Removed “Summary of Inclusion/Exclusion Criteria” (Rationale: there 
was only one occurrence and these data are included in the listings)

Added “Summary of Age Ranges” (Required as per revised RAP 
template)

Added “Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Participants and Occurrences)” 
(Required for disclosure purposes).


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6
RAP Section
Amendment Details

Added “Summary of Non-Serious Drug-Related Adverse Events by 
Overall Frequency” (Required for Plain language Summaries)

Added “Summary of Non-Serious Drug-Related Adverse Events by 
Overall Frequency” (Required for Plain language Summaries)


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MEA116841
7
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.
2.2.
Study Objective(s) and Endpoint(s)
Objective
Endpoints
The objective of this protocol is to provide a mechanism to supply 
mepolizumab on an individual subject basis to eligible subjects who 
previously participated in GSK sponsored study MEA115921.
N/A


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MEA116841
8
2.3.
Study Design
Overview of Study Design and Key Features
Design 
Features
See figure above.
Dosing
Eligible subjects will receive subcutaneously administered mepolizumab at a dose 
of 300 mg SC every 4 weeks.
Treatment 
Assignment
All eligible subjects will receive mepolizumab as described above.
2.4.
Statistical Hypotheses / Statistical Analyses
No statistical hypotheses are defined for this study.


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MEA116841
9
3.
PLANNED ANALYSES
3.1.
Interim Analyses
A summary of integrated safety data from MEA116841 and 201607 (compassionate use 
programme) was conducted to support mepolizumab EGPA submissions in the US and 
Japan, using a cut-off date of 05-SEP-2016 (GlaxoSmithKline Document Number: 
2017N320079_00). 
Further interim analyses may be conducted, as required.
This RAP contains details of analyses proposed for future interim analyses as well as the 
final study report. Access to the results from such interim analyses will not be
confidential. Specifically the results will be provided to the study team and GSK 
governance boards, and may be provided to external investigators and to regulatory 
authorities.
3.2.
Final Analyses
The final planned primary analyses will be performed after the completion of the 
following sequential steps:
1.
All participants have completed the study as defined in the protocol 
2.
All required database cleaning activities have been completed and final database 
release (DBR) and database freeze (DBF) has been declared by Data Management.
4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
All Subjects 
Enrolled
Comprises all subjects enrolled and for whom a 
record exists on the study database. This 
population will be used for summarising reasons 
for screen and run-in failures.
Study Population
Safety
Comprise of all subjects who receive at least one 
dose of mepolizumab

Study Population

Safety
4.1.
Protocol Deviations
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, failure to report pregnancy and SAEs and informed consent) will be summarised 
and listed.
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan [version 5.0, 05-June-2019].
o Data will be reviewed prior to freezing the database to ensure all important 
deviations are captured and categorised on the protocol deviations dataset. 


CONFIDENTIAL
MEA116841
10
o This dataset will be the basis for the summaries and listings of protocol 
deviations.
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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MEA116841
11
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
5.1.
Study Treatment and Subgroup Display Descriptors
Summaries will be presented for all subjects receiving open-label mepolizumab. In 
addition, summaries will also be presented by the actual treatment the participant 
received in the randomised double-blind study (MEA115921).
Treatment group descriptors will be assigned as follows:
Treatment Group Descriptions
RandAll NG from Study MEA115921
Data Displays for Reporting 
Code
Description
Description
Order [1]
P
Placebo
300mg SC Prev. Placebo
1
A
Mepolizumab 300mg SC
300mg SC Prev. Mepo
2
N/A
N/A
300mg SC Total
3
5.2.
Examination of Subgroups
The following subgroups are defined for this study:
Subgroups
Age group:

<65 years

65 years
Sex

Male

Female
Race

African American/African Heritage

White

Asian

Other


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MEA116841
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5.3.
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
9.2
Appendix 2: Study Phases and Treatment Emergent Adverse Events
9.3
Appendix 3: Data Display Standards & Handling Conventions
9.4
Appendix 4: Derived and Transformed Data
9.5
Appendix 5: Reporting Standards for Missing Data


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MEA116841
13
6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
The study population analyses will be based on the Safety population.
Study population analyses including analyses of subject’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
and exposure and treatment compliance will be based on GSK Core Data Standards.  
Details of the planned displays are presented in Appendix 7: List of Data Displays.


CONFIDENTIAL
MEA116841
14
7.
SAFETY ANALYSES
The safety analyses will be based on the Safety population, unless otherwise specified.
The LAP comprises a clinical trial (MEA116841) and compassionate use programme 
(201607) restricted to subjects who participated in MEA115921. The compassionate use 
programme (CUP) was conducted under a guidance document which mirrored the 
objectives of MEA116841. Since 201607 was run as a CUP, the treating physician was 
the responsible party. Per local legal requirements, serious adverse event reporting was 
required at a minimum. Furthermore, GSK did not monitor CUP 201607, and therefore 
verification that all non-serious adverse events (AEs) were reported is not possible.
For this reason, summaries of adverse events are reported separately for MEA116841 and 
201607, with the exception of serious adverse events, which are additionally reported 
using combined MEA116841 and 201607 data.
7.1.
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 date/time and the AE onset 
date/time. 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, run-in failures or subjects who were enrolled but did not 
receive treatment will be classified as pre-treatment SAEs. 
The most frequent on-treatment AEs will be defined as AEs with frequency ≥3% in any 
treatment group.
7.2.
Adverse Events of Special Interest
The following Adverse Events of Special Interest in mepolizumab clinical development 
have been defined:

Systemic Allergic/Hypersensitivity and Non-allergic Reactions 

Local injection site reactions

Alteration in immune response (infections)

Alteration in immune response (malignancies)

Alteration in cardiovascular safety

Immunogenicity
The methods by which these events will be identified are detailed in the Program Safety 
Analysis Plan for Mepolizumab (PSAP), version 5 (effective 1-Apr-2019), Section 10.3.2


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15
The details of the planned displays are provided in Appendix 7: List of Data Displays.
7.3.
Other Safety Analyses
Details of listings of corticosteroid usage are provided in Appendix 7: List of Data 
Displays.


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16
8.
REFERENCES

GlaxoSmithKline Document Number 2014N201870_04 Study ID MEA116841.
Mepolizumab Long-term Access Programme for Subjects who Participated in Study 
MEA115921 (Placebo-controlled Study of Mepolizumab in the Treatment of 
Eosinophilic Granulomatosis with Polyangiitis in Subjects Receiving Standard-of-
care Therapy). Protocol Amendment 4, Effective Date 18-Jun-2019.

GlaxoSmithKline Document Number 2017N320079_00. Mepolizumab Long-term 
Access Programme for Subjects who Participated in Study MEA115921 (Placebo-
controlled Study of Mepolizumab in the Treatment of Eosinophilic Granulomatosis
with Polyangiitis in Subjects Receiving Standard-of-care Therapy). Interim Clinical 
Study Report, Effective 12-Jun-2017

Program Safety Analysis Plan for Mepolizumab (SB240563) (PSAP). Version 5, 
Effective 1-April 2019. Author: Bhabita Mayer.


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17
9.
APPENDICES
9.1.
Appendix 1: Schedule of Activities
9.1.1.
Protocol Defined Schedule of Events


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MEA116841
18
9.2.
Appendix 2: Study Phases and Treatment Emergent 
Adverse Events
9.2.1.
Study Phases
Treatment State
Definition
Pre-Treatment
AE Start Date/Time < Study Treatment Start Date/Time
On-Treatment
Study Treatment Start Date/Time  ≤ AE Start Date/Time ≤ Study Treatment Stop Date 
+ 28 days
Post-Treatment
AE Start Date > Study Treatment Stop Date + 28 days
NOTES: 

If the study treatment stop date is missing then the AE will be considered to be On-Treatment.


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9.3.
Appendix 3: Data Display Standards & Handling 
Conventions
9.3.1.
Reporting Process
Software

The currently supported versions of SAS software will be used.
Reporting Area
HARP Server
HARP Compound
Analysis Datasets 

Analysis datasets will be created according to CDISC standards (SDTM IG version 3.1.3 & ADaM IG 
version 1.0).

For creation of ADaM datasets (ADC1/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.
9.3.2.
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 

Do not include subject level listings in the main body of the GSK Clinical Study Report. All subject level 
listings should be located in the modular appendices as ICH or non-ICH listings
Formats

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for reporting of 
data based on the raw data collected, but may be adjusted to a clinically interpretable number of 
DPs. 
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses:

Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled visit days 
on the analyses and interpretation of the results will be assessed as appropriate.

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 Visits

Unscheduled or unplanned readings will be presented within the subject’s listings. 

Visits outside the protocol defined time-windows (ie. recorded as protocol deviations) will be 
included in listings but omitted from figures, summaries and statistical analyses.
CCI


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20
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.


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9.4.
Appendix 4: Derived and Transformed Data
9.4.1.
General
Study Day

Calculated as the number of days from First treatment:

Ref Date = Missing              → Study Day = Missing 

Ref Date < Date of first treatment → Study Day = Ref Date – Date of first treatment

Ref Data ≥ Date of first treatment → Study Day = Ref Date – (Date of first treatment) + 1    
9.4.2.
Study Population
Extent of Exposure

Number of days of exposure to study drug will be calculated based on the formula:  
Duration of Exposure in Days = Treatment Stop Date – (Treatment Start Date) + 29

Participants who were randomized but did not report a treatment start date will be categorised as 
having zero days of exposure. 

If there are any treatment breaks during the study, exposure data will be adjusted accordingly.
9.4.3.
Safety
Adverse Events
Drug Related AEs
AEs with relationship marked ‘YES’.
AEs Leading to Permanent Discontinuation from Study Treatment or Withdrawal from the Study 
AEs with action marked “Study treatment withdrawn” or withdrawn from study status marked 
“YES”, or a response to either of these questions is missing.
AEs on Day of Dosing
AEs with an onset date equal to a study treatment dosing date and an onset time on or after the 
study treatment dosing time.
AE Time Since First Dose

If AE onset time is missing, calculate in days as follows:-
o
If AE start date < Date of first dose of study treatment then 
Time since first dose = AE start date - Date of first dose of study treatment 
o
If AE start date ≥ Date of first dose of study treatment then 
Time since first dose = AE start date – Date of first dose of study treatment +1
o
Missing if AE start date or date of first dose of study treatment is missing.

If AE onset time is present, calculate in days, hours, minutes as 
Time since first dose = AE start date/time – Date/time of first dose of study 
treatment 


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22
AE Duration (Days)

If AE onset time is missing, calculate in days as
AE end date – AE start date + 1

If AE onset time is present, calculate in days, hours and minutes as
AE end date/time – AE start date/time

Missing if AE start date or end date is missing.
AEs of Special Interest

See Section 7.2.


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MEA116841
23
9.5.
Appendix 5: Reporting Standards for Missing Data
9.5.1.
Premature Withdrawals
Element
Reporting Detail
General
All available data from subjects in the Safety population who withdrew from 
mepolizumab will be listed and all available planned data will be included in 
summary tables and figures, unless otherwise specified.
9.5.2.
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 table. 
o
Answers such as “Not applicable” and “Not evaluable” are not 
considered to be missing data and should be displayed as such.
9.5.2.1.
Handling of Missing and Partial Dates
Element
Reporting Detail
Adverse 
Events

Completely missing start or end dates will remain missing, with no imputation 
applied.  Consequently, time to onset and duration of such events with be 
missing.

The eCRF allows for the possibility of partial dates (i.e., only month and year) to 
be recorded for AE start and end dates; that is, the day of the month may be 
missing. In such a case, the following conventions will be applied for calculating 
the time to onset and the duration of the event:
o
Missing Start Day: First of the month will be used unless this is before 
the start date of study treatment; in this case the study treatment start 
date will be used and hence the event is considered On-treatment as 
per Appendix 2: Treatment States and Phases.
o
Missing Stop Day: Last day of the month will be used, unless this is 
after the stop date of study treatment; in this case the study treatment 
stop date will be used.

The recorded partial date will be displayed in listings.
Concomitant 
medications

Partial dates for any concomitant medications recorded in the CRF will be 
imputed using the following convention:
o
If the partial date is a start date, a '01' will be used for the day and 'Jan' 
will be used for the month
o
If the partial date is a stop date, a '28/29/30/31' will be used for the day 
(dependent on the month and year) and 'Dec' will be used for the 
month.

The recorded partial date will be displayed in listings.


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24
9.6.
Appendix 6: Abbreviations & Trade Marks
9.6.1.
Abbreviations
Abbreviation
Description
ADaM
Analysis Data Model
AE
Adverse Event
AESI
Adverse Event of Special Interest
A&R
Analysis and Reporting 
CDISC
Clinical Data Interchange Standards Consortium
CS
Clinical Statistics
CSR
Clinical Study Report
CTR
Clinical Trial Register
CVT
Cardiac, Vascular and Thromboembolic
DOB
Date of Birth
DP
Decimal Places
eCRF
Electronic Case Record Form
EGPA
Eosinophilic Granulomatosis with Polyangiitis
FCBP
Female of Childbearing Potential
IA
Interim Analysis
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee 
IDSL
Integrated Data Standards Library
IP
Investigational Product
GSK
Glaxo SmithKline
GUI
Guidance
LAP
Long-term Access Programme
LOC
Last Observation Carries Forward
MedDRA
Medical Dictionary for Regulatory Activities
OSL
Operations and Science Lead
PCI
Potential Clinical Importance 
PDMP
Protocol Deviation Management Plan
PP
Per Protocol
QC
Quality Control
RAP
Reporting & Analysis Plan
SAC
Statistical Analysis Complete
SDTM
Study Data Tabulation Model
SMQ
Standardised MedDRA Queries
SOP
Standard Operation Procedure
TA
Therapeutic Area
TFL
Tables, Figures & Listings 


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25
9.6.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
None
Sas


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MEA116841
26
9.7.
Appendix 7: List of Data Displays
9.7.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.n
1.1 to 1.n
Safety
3.1 to 3.n
3.1 to 3.n
Section
Listings
ICH Listings
1 to x
9.7.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided.
Section
Figure
Table
Listing
Study Population
POP_Fn
POP_Tn
POP_Ln
Safety
SAFE_Fn
SAFE_Tn
SAFE_Ln
NOTES: 

Non-Standard displays are indicated in the ‘IDSL /  Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’
9.7.3.
Deliverables
Delivery  [1]
Description
IA SAC
Interim Analysis SAC (as appropriate)
SAC
Final SAC


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27
9.7.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.1.
Safety
ES1
Summary of Subject Disposition 

MEA116841

201607

MEA116841 + 201607
IA , SAC 
1.2.
Safety
SD1
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment

MEA116841

201607

MEA116841 + 201607
IA , SAC 
1.3.
All Subjects 
Enrolled
NS1
Summary of Number of Participant by Country and Site ID

MEA116841

201607

MEA116841 + 201607
IA , SAC 
Protocol Deviation
1.4.
Safety
DV1
Summary of Important Protocol Deviations

MEA116841 
IA , SAC 
Population Analysed
1.5.
All Subjects 
Enrolled
mid_mepo_egpa_lap
/interim1
Table 1.1
Summary of Study Populations 

MEA116841

201607

MEA116841 + 201607
IA , SAC 
Demographic and Baseline Characteristics
1.6.
Safety
DM1
Summary of Demographic Characteristics

MEA116841

201607

MEA116841 + 201607
IA , SAC 


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MEA116841
28
Study Population Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
1.7.
All Subjects 
Enrolled
DM11
Summary of Age Ranges

MEA116841

201607

MEA116841 + 201607
IA , SAC 
1.8.
Safety
DM5
Summary of Race and Racial Combinations

MEA116841

201607

MEA116841 + 201607
IA , SAC 
1.9.
Safety
mid_mepo_egpa_lap
/interim1
Table 1.10
Summary of Race and Racial Combinations Details

MEA116841

201607

MEA116841 + 201607
IA , SAC
1.10.
Safety
mid_mepo_egpa_lap
/interim1
Table 1.11
Summary of Cardiovascular Assessments – Screening 
Questions

MEA116841

201607

MEA116841 + 201607
IA , SAC 
1.11.
Safety
mid_mepo_egpa_lap
/interim1
Table 1.12
Summary of Cardiovascular Assessments – Family History

MEA116841

201607

MEA116841 + 201607
IA , SAC 
1.12.
Safety
mid_mepo_egpa_lap
/interim1
Table 1.13
Summary of Oral Corticosteroid Therapy Taken Before the 
Treatment Period

MEA116841

201607

MEA116841 + 201607
IA , SAC 
1.13.
Safety
mid_mepo_egpa_lap
/interim1
Table 1.14
Summary of Oral Corticosteroid Therapy Taken During the 
Treatment Period

MEA116841

201607

MEA116841 + 201607
IA , SAC 


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29
9.7.5.
Safety Tables
Safety: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Exposure
3.1.
Safety
mid_mepo_egpa_lap
/interim1
Table 3.1
Summary of Exposure to Study Treatment

MEA116841

201607

MEA116841 + 201607
IA , SAC 
3.2.
Safety
mid_mepo_egpa_lap
/interim1
Table 3.2
Summary of Number of Treatment Administered

MEA116841

201607

MEA116841 + 201607
IA , SAC 
Adverse Events (AEs)
3.3.
Safety
AE1
Summary of On-Treatment Adverse Events by System 
Organ Class and Preferred Term

MEA116841

201607
IA , SAC 
3.4.
Safety
AE1
Summary of Post-Treatment Adverse Events by System 
Organ Class and Preferred Term

MEA116841

201607
IA , SAC 
3.5.
Safety
AE3
Summary of Common (>=3%) Adverse Events by 
Preferred Term

MEA116841

201607
IA , SAC 
3.6.
Safety
AE1
Summary All Drug-Related Adverse Events by System 
Organ Class and Preferred Term

MEA116841

201607As 3.1 notes
IA , SAC 
3.7.
Safety
AE3
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from 
Study by Preferred Term

MEA116841

201607For studies with few 
events/participants, listing is 
sufficient.
IA , SAC 


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MEA116841
30
Safety: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.8.
Safety
AE15
Summary of Common (>=3%) Non-serious Adverse Events 
by System Organ Class and Preferred Term (Number of 
Participant and Occurrences)

MEA116841

201607Common’ to be defined 
by study/project team. For 
studies with very few 
events/participants, listing is 
sufficient: discuss this option 
with your disclosure 
representative.
IA , SAC 
3.9.
Safety
AE5A
Summary of On-Treatment Adverse Events by System 
Organ Class and Preferred Term and Maximum Intensity

MEA116841

201607Common’ to be defined 
by study/project team. For 
studies with very few 
events/participants, listing is 
sufficient: discuss this option 
with your disclosure 
representative.
IA , SAC 
Serious and Other Significant Adverse Events
3.10.
Safety
AE1
Summary of Pre-Treatment Serious Adverse Events by 
System Organ Class and Preferred Term

MEA116841

201607For studies with few 
events/participants listing is 
sufficient: discuss this option 
with your disclosure 
representative.

MEA116841 + 201607
IA , SAC 


CONFIDENTIAL
MEA116841
31
Safety: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.11.
Safety
AE1
Summary of On-Treatment Serious Adverse Events by 
System Organ Class and Preferred Term

MEA116841

201607For studies with few 
events/participants listing is 
sufficient: discuss this option 
with your disclosure 
representative.

MEA116841 + 201607
IA , SAC
3.12.
Safety
AE1
Summary of Post-Treatment Serious Adverse Events by 
System Organ Class and Preferred Term

MEA116841

201607For studies with few 
events/participants listing is 
sufficient: discuss this option 
with your disclosure 
representative.

MEA116841 + 201607
IA , SAC 
3.13.
Safety
AE16
Summary of Serious Adverse Events by System Organ 
Class and Preferred Term (Number of Participants and 
Occurrences)
Required for data disclosure

MEA116841

201607For studies with few 
events/participants listing is 
sufficient: discuss this option 
with your disclosure 
representative.

MEA116841 + 201607
IA , SAC 


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MEA116841
32
Safety: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.14.
Safety
AE1
Summary of On-Treatment Non-Fatal Serious Adverse 
Events by System Organ Class and Preferred Term

MEA116841

201607For studies with few 
events/participants listing is 
sufficient: discuss this option 
with your disclosure 
representative.

MEA116841 + 201607
IA , SAC 
3.15.
Safety
AE1
Summary of Fatal Serious Adverse Events by System 
Organ Class and Preferred Term

MEA116841

201607For studies with few 
events/participants listing is 
sufficient: discuss this option 
with your disclosure 
representative.

MEA116841 + 201607
IA , SAC 
3.16.
Safety
AE1
Summary of Drug-Related Non-Fatal Serious  Adverse 
Events by System Organ Class and Preferred Term

MEA116841

201607For studies with few 
events/participants listing is 
sufficient: discuss this option 
with your disclosure 
representative.

MEA116841 + 201607
IA , SAC 


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MEA116841
33
Safety: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.17.
Safety
AE1
Summary of Drug-Related Fatal  Adverse Events by 
System Organ Class and Preferred Term

MEA116841

201607For studies with few 
events/participants listing is 
sufficient: discuss this option 
with your disclosure 
representative.

MEA116841 + 201607
IA , SAC 
3.18.
Safety
AE3
Summary of Non-Serious Drug-Related Adverse Events by 
Overall Frequency
Required for Plain Language 
Summary 

MEA116841

201607For studies with few 
events/participants listing is 
sufficient: discuss this option 
with your disclosure 
representative.

MEA116841 + 201607
IA , SAC 
3.19.
Safety
AE3
Summary of Serious Drug-Related Adverse Events by 
Overall Frequency
Required for Plain Language 
Summary 

MEA116841

201607For studies with few 
events/participants listing is 
sufficient: discuss this option 
with your disclosure 
representative.

MEA116841 + 201607
IA , SAC 


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34
Safety: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.20.
Safety
mid_mepo_egpa_lap
/interim1
Table 3.16
Summary of All Cardiovascular Events Reported by the 
Investigator

MEA116841

201607For studies with few 
events/participants listing is 
sufficient: discuss this option 
with your disclosure 
representative.

MEA116841 + 201607
IA , SAC 
Adverse Events of Special Interest
3.21.
Safety
mid_mepo_egpa_lap
/interim1
Table 3.17
Summary of On-Treatment Adverse Events of Special 
Interest: Systemic Reactions 

MEA116841

201607
IA , SAC 
3.22.
Safety
mid_mepo_egpa_lap
/interim1
Table 3.18
Summary of On-Treatment Adverse Events of Special 
Interest: Systemic Reactions, by Whether Related to 
Investigational Product 

MEA116841

201607
IA , SAC 
3.23.
Safety
mid_mepo_egpa_lap
/interim1
Table 3.19
Summary of Systemic Reactions Experienced on Day of 
Dosing 

MEA116841

201607
IA , SAC 
3.24.
Safety
mid_mepo_egpa_lap
/interim1
Table 3.20
Summary of On-Treatment Adverse Events of Special 
Interest: Systemic Hypersensitivity Reactions 

MEA116841

201607
IA , SAC 
3.25.
Safety
mid_mepo_egpa_lap
/interim1
Table 3.21
Summary of On-Treatment Adverse Events of Special 
Interest: Systemic Non-Allergic Reactions  

MEA116841

201607
IA , SAC 


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35
Safety: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.26.
Safety
mid_mepo_egpa_lap
/interim1
Table 3.22
Summary of On-Treatment Adverse Events of Special 
Interest: Local Injection Site Reactions 

MEA116841

201607
IA , SAC 
3.27.
Safety
mid_mepo_egpa_lap
/interim1
Table 3.23
Summary of On-Treatment Adverse Events of Special 
Interest: Local Injection Site Reactions, by Whether 
Related to Investigational Product 

MEA116841

201607
IA , SAC 
3.28.
Safety
mid_mepo_egpa_lap
/interim1
Table 3.24
Summary of On-Treatment Adverse Events of Special 
Interest: Systemic Reactions That According to Investigator 
Met Criteria for Anaphylaxis 

MEA116841

201607
IA , SAC 
3.29.
Safety
mid_mepo_egpa_lap
/interim1
Table 3.25
Summary of On-Treatment Adverse Events of Special 
Interest: Potential Opportunistic Infections 

MEA116841

201607
IA , SAC 
3.30.
Safety
mid_mepo_egpa_lap
/interim1
Table 3.26
Summary of On-Treatment Adverse Events of Special 
Interest: Malignancies 

MEA116841

201607
IA , SAC 
3.31.
Safety
mid_mepo_egpa_lap
/interim1
Table 3.27
Summary of On-Treatment Adverse Events of Special 
Interest: Serious Cardiac, Vascular and Thromboembolic

MEA116841

201607
IA , SAC 
3.32.
Safety
mid_mepo_egpa_lap
/interim1
Table 3.28
Summary of On-Treatment Adverse Events of Special 
Interest by Cardiovascular History or Risk: Serious 
Cardiac, Vascular and Thromboembolic 

MEA116841

201607
IA , SAC 
3.33.
Safety
mid_mepo_egpa_lap
/interim1
Table 3.29
Summary of On-Treatment Adverse Events of Special 
Interest: Serious Ischemic Events 

MEA116841

201607
IA , SAC 


CONFIDENTIAL
MEA116841
36
Safety: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.34.
Safety
mid_mepo_egpa_lap
/interim1
Table 3.30
Summary Profile of On-Treatment Adverse Events of 
Special Interest: Systemic Reactions

MEA116841

201607
IA , SAC 
3.35.
Safety
mid_mepo_egpa_lap
/interim1
Table 3.31
Summary Profile of On-Treatment Adverse Events of 
Special Interest: Systemic Hypersensitivity Reactions

MEA116841

201607
IA , SAC 
3.36.
Safety
mid_mepo_egpa_lap
/interim1
Table 3.32
Summary Profile of On-Treatment Adverse Events of 
Special Interest: Systemic Non-Allergic Reactions

MEA116841

201607
IA , SAC 
3.37.
Safety
mid_mepo_egpa_lap
/interim1
Table 3.33
Summary Profile of On-Treatment Adverse Events of 
Special Interest: Local Injection Site Reactions

MEA116841

201607
IA , SAC 
3.38.
Safety
mid_mepo_egpa_lap
/interim1
Table 3.34
Summary Profile of On-Treatment Adverse Events of 
Special Interest: Potential Opportunistic Infections

MEA116841

201607
IA , SAC 
3.39.
Safety
mid_mepo_egpa_lap
/interim1
Table 3.35
Summary Profile of On-Treatment Adverse Events of 
Special Interest: Malignancies

MEA116841

201607
IA , SAC 
3.40.
Safety
mid_mepo_egpa_lap
/interim1
Table 3.36
Summary Profile of On-Treatment Adverse Events of 
Special Interest: Serious Cardiac, Vascular and 
Thromboembolic

MEA116841

201607
IA , SAC 
3.41.
Safety
mid_mepo_egpa_lap
/interim1
Table 3.37
Summary Profile of On-Treatment Adverse Events of 
Special Interest: Serious Ischemic Events

MEA116841

201607
IA , SAC 


CONFIDENTIAL
MEA116841
37
Safety: Tables
No.
Population
IDSL / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Exposure-Adjusted Adverse Events
3.42.
Safety
mid_mepo_egpa_lap
/interim1
Table 3.38
Summary of Exposure Adjusted On-Treatment Adverse 
Events 

MEA116841

201607
IA , SAC 
3.43.
Safety
mid_mepo_egpa_lap
/interim1
Table 3.39
Summary of Exposure Adjusted Most Frequent On-
Treatment Adverse Events Reported by 3% or More 
Subjects In Any Treatment Group 

MEA116841

201607
IA , SAC 
3.44.
Safety
mid_mepo_egpa_lap
/interim1
Table 3.40
Summary of Exposure Adjusted Drug Related Adverse 
Events 

MEA116841

201607
IA , SAC 
3.45.
Safety
mid_mepo_egpa_lap
/interim1
Table 3.41
Summary of Exposure Adjusted On-Treatment Adverse 
Events Leading To Permanent Discontinuation of Study 
Drug or Withdrawal From Study

MEA116841

201607
IA , SAC 
3.46.
Safety
mid_mepo_egpa_lap
/interim1
Table 3.42
Summary of Exposure Adjusted On-Treatment Serious 
Adverse Events 

MEA116841

201607
IA , SAC 
3.47.
Safety
mid_mepo_egpa_lap
/interim1
Table 3.43
Summary of On-Treatment Adverse Events by Age 
Category

MEA116841

201607
IA , SAC 
3.48.
Safety
mid_mepo_egpa_lap
/interim1
Table 3.44
Summary of On-Treatment Adverse Events by Sex

MEA116841

201607
IA , SAC 
3.49.
Safety
mid_mepo_egpa_lap
/interim1
Table 3.45
Summary of On-Treatment Adverse Events by Race

MEA116841

201607201607
IA , SAC 


CONFIDENTIAL
MEA116841
38
9.7.6.
ICH Listings
All listings will include the following study IDs unless otherwise specified:

MEA116841

201607
ICH: Listings
No.
Population
IDSL / Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.
All Subjects 
Enrolled
ES7
Listing of Reasons for Screen Failure
IA , SAC 
2.
All Subjects 
Enrolled
ES2 / ES3
Listing of Reasons for Study Withdrawal
IA , SAC 
3.
Safety
SD2/SD3
Listing of Reasons for Study Treatment Discontinuation
IA , SAC 
Protocol Deviations
4.
Safety
DV2
Listing of Important Protocol Deviations 

MEA116841 only
IA , SAC 
5.
Safety
IE3
Listing of Participants with Inclusion/Exclusion Criteria 
Deviations

MEA116841 only
IA , SAC 
Populations Analysed
6.
Safety
SP3/SP3a
Listing of Participants Excluded from Any Population
Subjects screened but not 
included in Safety Population
IA , SAC 
Demographic and Baseline Characteristics
7.
Safety
DM2 / DM4
Listing of Demographic Characteristics
IA , SAC 
8.
Safety
DM9 / DM10
Listing of Race
IA , SAC 


CONFIDENTIAL
MEA116841
39
ICH: Listings
No.
Population
IDSL / Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Exposure and Treatment Compliance
9.
Safety
See 
mid_mepo_egpa_lap/interim1
Listing 10
Listing of Exposure Data
IA , SAC 
10.
Safety
See 
mid_mepo_egpa_lap/interim1
Listing 26
Listing of Current and Previous Treatment
IA , SAC
Adverse Events
11.
Safety
AE8
Listing of All Adverse Events
IA , SAC 
12.
Safety
AE7
Listing of Subject Numbers for Individual Adverse Events
IA , SAC 
13.
Safety
AE2
Listing of Relationship Between Adverse Event System 
Organ Classes, Preferred Terms, and Verbatim Text
IA , SAC 
Serious and Other Significant Adverse Events
14.
Safety
AE8
Listing of Fatal Serious Adverse Events
IA , SAC 
15.
Safety
AE8
Listing of Non-Fatal Serious Adverse Events
IA , SAC 
16.
Safety
AE14
Listing of Reasons for Considering as a Serious Adverse 
Event
IA , SAC 
17.
Safety
AE8
Listing of Adverse Events Leading to Withdrawal from Study 
/ Permanent Discontinuation of Study Treatment
IA , SAC 
18.
Safety
See 
mid_mepo_egpa_lap/interim1
Listing 19
Listing of Adverse Events Defined by the Investigator as a 
Systemic (Non-Allergic or Allergic/Hypersensitivity) Injection 
Reaction
IA , SAC 


CONFIDENTIAL
MEA116841
40
ICH: Listings
No.
Population
IDSL / Example Shell
Title
Programming Notes
Deliverable 
[Priority]
19.
Safety
See 
mid_mepo_egpa_lap/interim1
Listing 20
Listing of Adverse Events Defined by the Investigator as a 
Local Injection Site Reaction
IA , SAC 
20.
Safety
See 
mid_mepo_egpa_lap/interim1
Listing 21
Listing of AEs of Systemic Reactions Meeting Anaphylaxis 
Criteria 
IA , SAC 
21.
Safety
See 
mid_mepo_egpa_lap/interim1
Listing 22
Listing of Potential Opportunistic Infections
IA , SAC 
22.
Safety
See 
mid_mepo_egpa_lap/interim1
Listing 23
Listing of Serious Ischemic AEs
IA , SAC 
23.
Safety
See 
mid_mepo_egpa_lap/interim1
Listing 24
Listing of Malignancies
IA , SAC 
Corticosteroid Medication
24.
Safety
See 
mid_mepo_egpa_lap/interim1
Listing 11
Listing of Corticosteroid Therapy
IA , SAC