Conditions: Asthma
Keywords: extension study Severe refractory asthma safety SB-240563 mepolizumab eosinophils
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 347
Healthy volunteers: no

Brief summary:
This is a multi-centre, open-label long term safety study of 100 milligrams (mg) mepolizumab administered subcutaneously (SC) in addition to standard of care in subjects who participated in the MEA112997 study. At each clinic visit, adverse events will be assessed and exacerbations will also be reviewed.

Detailed description:

Arms:
arm 1: Subjects will receive 100 mg of mepolizumab (in 1ml polypropylene syringe) injected subcutaneously (SC) approximately every 4 weeks.

Interventions: intervention 1: Mepolizumab
Intervention descriptions: intervention 1: 100 mg of mepolizumab will be injected subcutaneously (SC) once every 4 weeks

Protocol document:
Prot_000.pdf: 
2012N139436_03
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The GlaxoSmithKline group of companies
MEA115666
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
MEA115666: A multi-centre, open-label, long term safety study
of mepolizumab in asthmatic subjects who participated in the
MEA112997 trial.
Compound Number:
SB-240563
Development Phase:
IIIa
Effective Date:
19-JUN-2015
Protocol Amendment Number:  03
Author (s):
Copyright 2015 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2012N139436_00
2012-MAY-31
Original
2012N139436_01
2012-AUG-21
Amendment No.: 1

To clarify that the rationale and objective of the study includes long-term provision 
of mepolizumab therapy to subjects who have severe asthma and participated in 
MEA112997

To clarify that only monoclonal antibodies are excluded, rather than all biologics

To clarify reason for more frequent safety monitoring at the start of the study 

To correct Inclusion criterion 5 from Randomisation Visit to Visit 2

To add exclusion criterion for significant cardiovascular disease

To correct inconsistencies between protocol text and the Time and Events Table

To correct bilirubin exclusion criterion at visit 2

To expand on requirements for designating a subject as lost to follow-up

To add visit window for the follow-up visit

To move baseline spirometry from the screen visit to the baseline visit

To clarify that all subjects will have an immunogenicity test 12 weeks after last dose

To correct Section 8.3.5.2 wording “Efficacy” to “Safety”

To add reference to support Appendix 6 and remove 3 references which are not cited 
in the protocol.

To add Appendix 5 and Appendix 6 and amended Section 6.1 and Section 6.3.9. to 
support the determination of exclusion criteria 4
2012N139436_02
2013-MAR-06
Amendment No.02

To add two additional immunogenicity sample assessment time points when the 
100mg vial is introduced. 

To allow other syringe sizes for study drug administration

To allow for study drug administration in the upper thigh or the arm

To add the prohibited non-drug therapies to Section 5.7.2

To list Adverse Events and Serious Adverse Events on the same line in Table 3

To correct a formatting error for Section 4.6
 
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
To remove specific test name for confirming Hepatitis C positive sample

To delete redundant text in Section 6.3.3.1

To remove from Section 6.3.7 the requirement to report outcome of pregnancy in 
female partners of male subjects

To include analyses of immunogenicity data in Section 8.3 and to clarify when 
interim analyses will be performed
2012N139436_03
2015-JUN-19
Amendment No. 3

To reduce the Follow-up visit period from 12 weeks to 4 weeks post last dose of IP 

To update the time limit from reconstitution to administration of IP
 
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SPONSOR INFORMATION PAGE
Clinical Study Identifier:
MEA115666
Sponsor Legal Registered Address
GlaxoSmithKline Research & Development Limited
Iron Bridge Road
Stockley Park West , Uxbridge , Middlesex , UB11 1BU , UK
Telephone:  
GlaxoSmithKline Research & Development Limited
Five Moore Drive
P.O. 13398
Research Triangle Park , NC 27709-3398 , USA
Telephone: 
Sponsor Global Medical Monitor Contact Information:  
 MD (Director, Respiratory & Immuno-Inflammation Medicine 
Development Centre)
Tel: 
Mobile: 
Sponsor Global Back-up Medical Monitor Contact Information:  
 MD (Director, Respiratory & Immuno-Inflammation Medicine 
Development Centre)
Tel:
Mobile: 
Sponsor Serious Adverse Events (SAE) Contact Information: 
Case Management Group, Global Clinical Safety and Pharmacovigilance (GCSP)
Email: 
Fax: 
Regulatory Agency Identifying Number(s): IND No. 006971, 
EudraCT No. 2012-001643-51
 
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number MEA115666
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date
 
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TABLE OF CONTENTS
PAGE
LIST OF ABBREVIATIONS...........................................................................................10
PROTOCOL SUMMARY...............................................................................................12
1.
INTRODUCTION....................................................................................................15
1.1.
Background ................................................................................................15
1.2.
Rationale ....................................................................................................15
2.
OBJECTIVE(S) ......................................................................................................16
3.
INVESTIGATIONAL PLAN.....................................................................................16
3.1.
Study Design ..............................................................................................16
3.2.
Discussion of Design ..................................................................................17
4.
SUBJECT SELECTION AND WITHDRAWAL CRITERIA.......................................18
4.1.
Number of Subjects ....................................................................................18
4.2.
Inclusion Criteria.........................................................................................18
4.3.
Exclusion Criteria........................................................................................19
4.4.
Visit 2 Criteria .............................................................................................20
4.5.
Withdrawal Criteria .....................................................................................21
4.6.
Screening/Run-in Failures ..........................................................................21
5.
STUDY TREATMENTS..........................................................................................22
5.1.
Investigational Product................................................................................22
5.2.
Dosage and Administration.........................................................................22
5.3.
Treatment Assignment................................................................................23
5.4.
Blinding.......................................................................................................23
5.5.
Product Accountability ................................................................................23
5.6.
Treatment Compliance................................................................................23
5.7.
Concomitant Medications and Non-Drug Therapies....................................23
5.7.1.
Permitted Medications and Non-Drug Therapies..........................23
5.7.2.
Prohibited Medications and Non-Drug Therapies.........................23
5.8.
Treatment after the End of the Study ..........................................................24
5.9.
Treatment of Study Treatment Overdose....................................................24
6.
STUDY ASSESSMENTS AND PROCEDURES .....................................................25
6.1.
Critical Baseline Assessments....................................................................28
6.2.
Efficacy.......................................................................................................29
6.2.1.
Efficacy Endpoints .......................................................................29
6.2.1.1.
Exacerbations.............................................................29
6.2.1.2.
Pulmonary Function Testing.......................................29
6.2.1.3.
Asthma Control Questionnaire-5 (ACQ)......................29
6.3.
Safety .........................................................................................................30
6.3.1.
Safety Endpoints..........................................................................30
6.3.2.
Liver chemistry stopping and follow up criteria.............................30
6.3.3.
Adverse Events............................................................................33
6.3.3.1.
Definition of an AE......................................................33
6.3.3.2.
Definition of a SAE .....................................................34
 
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6.3.4.
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs.........................................................35
6.3.5.
Cardiovascular Events.................................................................36
6.3.6.
Death Events...............................................................................36
6.3.7.
Pregnancy ...................................................................................36
6.3.8.
Time Period and Frequency of Detecting AEs and SAEs.............37
6.3.9.
Prompt Reporting of Serious Adverse Events and Other 
Events to GSK.............................................................................37
6.3.9.1.
Regulatory reporting requirements for SAEs ..............39
6.3.10.
Other Safety Outcomes ...............................................................39
6.3.10.1.
Vital Signs ..................................................................39
6.3.10.2.
Twelve-lead electrocardiogram...................................39
6.3.10.3.
Clinical Laboratory Parameters...................................40
6.4.
Immunogenicity...........................................................................................40
7.
DATA MANAGEMENT ...........................................................................................40
8.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS...................................41
8.1.
Hypotheses.................................................................................................41
8.2.
Study Design Considerations......................................................................41
8.2.1.
Sample Size Assumptions ...........................................................41
8.2.2.
Sample Size Sensitivity................................................................41
8.2.3.
Sample Size Re-estimation..........................................................41
8.3.
Data Analysis Considerations .....................................................................41
8.3.1.
Analysis Populations....................................................................41
8.3.2.
Analysis Data Sets.......................................................................41
8.3.3.
Treatment Comparisons ..............................................................41
8.3.3.1.
Primary Comparisons of Interest ................................41
8.3.3.2.
Other Comparisons of Interest....................................42
8.3.4.
Interim Analysis ...........................................................................42
8.3.5.
Key Elements of Analysis Plan ....................................................42
8.3.5.1.
Efficacy Analyses .......................................................42
8.3.5.2.
Safety Analyses..........................................................42
8.3.5.3.
Immunogenicity Analyses...........................................42
9.
STUDY CONDUCT CONSIDERATIONS ...............................................................42
9.1.
Posting of Information on Publicly Available Clinical Trial Registers............42
9.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................42
9.3.
Quality Control (Study Monitoring) ..............................................................43
9.4.
Quality Assurance.......................................................................................44
9.5.
Study and Site Closure ...............................................................................44
9.6.
Records Retention......................................................................................44
9.7.
Provision of Study Results to Investigators, Posting of Information 
on Publicly Available Clinical Trials Registers and Publication....................45
9.8.
Independent Data Monitoring Committee (IDMC) .......................................45
10. REFERENCES.......................................................................................................46
11. APPENDICES........................................................................................................48
11.1.
Appendix 1: Country Specific Requirements...............................................48
11.2.
Appendix 2: Acceptable Birth Control..........................................................49
 
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11.3.
Appendix 3: Liver Chemistry Stopping and Followup Criteria......................51
11.4.
Appendix 4: Anaphylaxis Criteria ................................................................52
11.5.
Appendix 5: Cardiovascular Screening Questions ......................................53
11.6.
Appendix 6: New York Heart Association Functional Classification 
of Congestive Heart Failure ........................................................................54
11.7.
Appendix 7: Protocol Changes....................................................................55
 
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LIST OF ABBREVIATIONS
ACQ
Asthma Control Questionnaire
AE
Adverse Event
ALT
Alanine transaminase
AST
Aspartate transaminase
ATS
American Thoracic Society
CIB
Clinical Investigator Brochure
CPAP
Continuous Positive Airway Pressure
CS
Corticosteroid
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic Case report form
ED
Emergency Department
ERS
European Respiratory Society
FEV1
Forced expiratory volume in 1 second
FVC
Forced vital capacity
GCP
Good clinical practice
GCSP
Global Clinical Safety and Pharmacovigilance
GINA
Global Initiative for Asthma
GSK
GlaxoSmithKline
HBsAg
Hepatitis B Surface Antigen
HIV
Human Immunodeficiency Virus
IDMC
Independent Data Monitoring Committee
IC50
Inhibitory Concentration 50%
ICS
Inhaled corticosteroids
ICU
Intensive Care Unit
IEC
Independent ethics committee
Ig
Immunoglobulin
IL
Interleukin
IM
Intramuscular
IP
Investigational Product
IRB
Institutional review board
ITT
Intent to Treat
IUD
Intrauterine Device
IV
Intravenous
IVRS
Interactive voice response system
LABA
Long-acting beta-2-agonists
LTRA
Leukotriene receptor antagonist
MedDRA
Medicinal dictionary for regulatory activities
mcg
Micrograms
MDI
Metered Dose Inhaler
mg
Milligram
N/A
Not applicable
NHANES
National Health and Nutrition Examination Survey
NHLBI
National Heart Lung and Blood Institute
OCS
Oral corticosteroids
OLE
Open Label Extension Study
 
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PEF
Peak expiratory flow
RAP
Reporting and Analysis Plan
SABA
Short-acting beta-2-agonists
SAE
Serious adverse event
SC
Subcutaneous
SPM
Study procedures manual
ULN
Upper Limit of Normal
Trademark Information
Trademarks of the GlaxoSmithKline
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
Xolair
 
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PROTOCOL SUMMARY
RATIONALE
This study will provide long term safety and immunogenicity data when mepolizumab is 
administered subcutaneously (SC) in subjects with severe, refractory asthma and a history 
of eosinophilic inflammation.  Additionally, this study will inform on the safety and 
immunogenicity profile when mepolizumab therapy is reinstituted in subjects following a 
cessation in drug therapy. 
This trial also provides subjects who participated in the MEA112997 study, and meet the 
current trial eligibility criteria, the option of receiving treatment with mepolizumab, as an 
add-on to their standard of care treatment for severe asthma. 
OBJECTIVE(S)
PRIMARY
The primary objective of this study is to describe the long-term safety profile of 
mepolizumab. 
SECONDARY
To provide long-term treatment with mepolizumab to subjects who participated in 
MEA112997
To evaluate the effects of mepolizumab on a range of clinical markers of asthma control 
STUDY DESIGN
This is a multi-centre, open-label, long term, safety study of mepolizumab100 mg 
administered SC in addition to standard of care in subjects with severe, refractory asthma 
and a history of eosinophilic inflammation.  Subjects who participated in the 
MEA112997 trial will be offered the opportunity to consent for this study. All subjects 
will have experienced a gap of at least 10 months since receiving their last double-blind 
study medication in MEA112997.
At Visit 1, subjects will undergo an initial screening to assess their eligibility to 
participate in this study.  This screening will include: informed consent, vital signs, 
update of medical history, immunogenicity status based on MEA112997 data, smoking 
status, prior monoclonal antibody use, and exacerbations post completion of 
MEA112997.  Subjects meeting the Visit 1 eligibility criteria will enter the run-in period.  
The purpose of the run-in period is to allow for receipt and review of lab results and the 
ECG over-read.  Visit 2, will mark the end of the run-in period.
 
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Those subjects meeting all the inclusion criteria and none of the exclusion criteria will 
receive their first mepolizumab dose at Visit 2.  Subjects will continue to receive 
mepolizumab SC injections approximately every 4 weeks until either:

The risk/benefit profile for the subject is no longer positive in the opinion of the 
investigator or

the subject’s physician withdraws the subject or 

the subject withdraws consent or

the sponsor discontinues development of mepolizumab or 

the sponsor discontinues the study in the relevant participating country or 

mepolizumab becomes commercially available in the relevant participating 
country
Subjects will remain on standard of care asthma therapy, which may be adjusted during 
the study, at the discretion of their physician. The use of Xolair (omalizumab) or any 
other monoclonal antibody will not be permitted during the course of the study. 
Subjects will be monitored in the clinic approximately every 4 weeks to assess adverse 
events and asthma status.  The Asthma Control Questionnaire-5 (ACQ) will be used to 
assist the investigator in assessing the subject’s asthma status along with spirometry at 
regular intervals.  As some subjects may have previously received placebo while 
participating in the MEA112997 study and are naive to mepolizumab, safety lab 
monitoring will be more frequent at the start of the study.  Appropriate safety labs will be 
drawn prior to starting treatment and then at week 4, 8, 12, 24, 36 and 48.  Thereafter, 
these will be collected every 24 weeks.  Labs will also be obtained at 4 weeks after 
discontinuing mepolizumab.  Subjects discontinuing mepolizumab treatment should be 
monitored for exacerbation of their asthma.
Serum samples for anti-mepolizumab antibody measurements will be obtained from all 
subjects at Weeks 0, 4, 24 and 48 of the initial year, week 24 and 48 for every additional 
year, as well as at the Follow-up Visit. Any anti-mepolizumab antibody positive sample 
will be tested for neutralization antibody.
A maximum of two additional anti-mepolizumab antibody samples will be obtained; one 
immediately prior to the first dose and the other prior to the second dose with the 100mg 
mepolizumab vial. If the first or second dose coincides with a visit where an 
immunogenicity sample is already required, it is not necessary to obtain an additional 
sample.
The number of subjects participating in this trial will be no greater than the number of 
subjects randomised into MEA112997 who also received 2 doses of study medication 
which is 608 subjects.
The study closure process will begin, on a country by country basis, as mepolizumab 
becomes commercially available for prescription.  Please see the SPM for more details.
 
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Study Endpoints/Assessments
Primary Endpoint

Adverse Events
Secondary Endpoints

Frequency of positive anti-mepolizumab binding antibodies and neutralizing 
antibodies

Annualized rate of exacerbations

Asthma Control Questionnaire score

FEV1 measured by clinic spirometry

Number of withdrawals due to lack of efficacy

Number of withdrawals due to adverse events

Number of hospitalizations due to adverse events including asthma exacerbations

Frequency of both systemic (i.e., allergic/IgE-mediated and non-allergic)  and local 
site  reactions

12 Lead ECG parameters

Vital signs

Clinical Laboratory Parameters
 
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1.
INTRODUCTION
1.1.
Background
Asthma is a disease characterised by chronic airway inflammation, bronchial 
hyperreactivity and variable airflow obstruction. Eosinophils are usually prominent in the 
airway inflammation seen in asthma and are considered a central cause in the 
pathogenesis of asthma [Wardlaw, 2000]. The expression of interleukin (IL)-5 is elevated 
in bronchoalveolar lavage (BAL) fluid and bronchial biopsies in patients with asthma  
[Hamid, 1991]. Moreover, the level of IL-5 in BAL fluid and the bronchial mucosa 
correlates with disease severity [Robinson, 1992; Robinson, 1993; Humbert, 1997]. The 
cytokine IL-5 promotes eosinophil differentiation, recruitment and survival 
[Clutterbuck, 1989; Wang, 1989]. Thus a therapeutic strategy which blocks IL-5, thereby 
suppressing eosinophilic inflammation, may have therapeutic benefit in asthma.
Currently available therapies are highly effective at controlling asthma symptoms and 
airway inflammation in the majority of patients [Bateman, 2004]. Inhaled corticosteroids 
reduce airway inflammation and sputum eosinophils in most asthmatics [Kips, 2002].  
However, a proportion of asthma patients remain uncontrolled despite appropriate 
therapy including high dose inhaled corticosteroids (ICS) plus additional controller 
therapy, i.e. treatment at Step 5/6 and Step 4/5 according to the NHLBI Guidelines for the 
Diagnosis and Treatment of Asthma [NHLBI, 2008] and the Global Initiative for Asthma 
guidelines [GINA, 2008], respectively. This severe uncontrolled, refractory population 
suffers from persistent symptoms and acute exacerbations of their asthma. 
Patients with severe asthma have significant morbidity and mortality risk; they contribute 
disproportionately to health care and societal costs of the disease, and costs are 
particularly high in those with frequent exacerbations. In MEA112997 subjects had 
features of severe, refractory asthma as described in the ATS workshop on refractory 
asthma [ATS workshop, 2000] and additionally demonstrated markers of eosinophilic 
inflammation.  Together these criteria were useful to identify a severe eosinophilic 
asthma population that continued to exacerbate despite maximal therapy with currently 
marketed asthma medications.  This severe, eosinophilic population is the subset of 
asthmatics most likely to benefit from treatment with mepolizumab. Mepolizumab is a 
humanised anti-IL-5 antibody (IgG1 kappa) currently in clinical development. 
1.2.
Rationale
This study will provide long term safety and immunogenicity data when mepolizumab is 
administered subcutaneously (SC) to subjects with severe, refractory asthma with a 
history of eosinophilic inflammation.  Additionally, this study will inform on the safety 
and immunogenicity profile when mepolizumab therapy is reinstituted in subjects 
following a cessation in drug therapy.  
This trial also provides subjects who participated in the MEA112997 study, and meet the 
current trial eligibility criteria, the option of receiving treatment with mepolizumab, as an 
add-on to their standard of care treatment for severe asthma.
 
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2.
OBJECTIVE(S)
Primary Objective
The primary objective of this study is to describe the long-term safety profile of 
mepolizumab. 
Secondary Objectives

To provide long-term treatment with mepolizumab to subjects who participated in 
MEA112997

To evaluate the effects of mepolizumab on a range of clinical markers of asthma 
control 
3.
INVESTIGATIONAL PLAN
3.1.
Study Design
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct. 
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Procedures Manual (SPM). The SPM will provide 
the site personnel with administrative and detailed technical information that does not 
impact subject safety.
This is a multi-centre, open-label long term safety study of 100 mg mepolizumab 
administered SC in addition to standard of care in subjects with severe eosiniophilic 
asthma.  Subjects who participated in the MEA112997 trial will be offered the 
opportunity to consent for this study.  All subjects will have experienced a gap of at least 
10 months since receiving their last double-blind study medication in MEA112997.
At Visit 1, subjects will undergo an initial screening to assess their eligibility to 
participate in this study. This screening will include: informed consent, vital signs, 
update of medical history, immunogenicity status based on MEA112997 data, smoking 
status, prior monoclonal antibody use, and exacerbations post completion of 
MEA112997.  Subjects meeting the Visit 1 eligibility criteria will enter the run-in period.  
The purpose of the run-in period is to allow for receipt and review of lab results and the 
ECG over-read.  Visit 2 will mark the end of the run-in period.
 
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Those subjects meeting all the inclusion criteria and none of the exclusion criteria will 
receive their first mepolizumab dose at Visit 2.  Subjects will continue to receive 
mepolizumab SC injections approximately every 4 weeks until either:

The risk/benefit profile for the subject is no longer positive in the opinion of the 
investigator or

the subject’s physician withdraws the subject or 

the subject withdraws consent or

the sponsor discontinues development of mepolizumab or

the sponsor discontinues the study in the relevant participating country or

mepolizumab becomes commercially available in the relevant participating 
country
All subjects will be dosed with the 250mg vial up until such time that the 100mg vial is 
available at the site.  Once the 100mg vial is available at the site, all subjects will switch 
to dosing with the 100mg vial at the next treatment visit and will be dosed with the100mg 
vial for the remainder of the study.
Subjects will remain on standard of care asthma therapy, which may be adjusted during 
the study, at the discretion of their physician. The use of Xolair (omalizumab) or any 
other monoclonal antibody will not be permitted during the course of the study.  
At each clinic visit, adverse events will be assessed, and appropriate safety labs will be 
obtained as per the Time and Events schedule (see Table 2 and Table 3).  As some 
subjects will be naive to mepolizumab, safety lab monitoring will be more frequent at the 
start of the study.  Exacerbations will also be reviewed at each clinic visit.
The study closure process will begin, on a country by country basis, as mepolizumab 
becomes commercially available for prescription.  Please see the SPM for more details.
3.2.
Discussion of Design
This study will allow subjects that were randomised into MEA112997 study to reinstitute 
(or initiate treatment if a placebo subject) mepolizumab as adjunctive therapy. Subjects in 
MEA112997 could have received mepolizumab or placebo. Thus, the Investigator will 
need to review the randomization code to aid their assessment of whether a subject may 
receive benefit from study participation in MEA115666. For example, subjects receiving 
placebo during MEA112997 may not have demonstrated a positive clinical response, 
nonetheless, may be considered appropriate for the current study as all subjects will 
receive mepolizumab. Investigators should continue subjects on their baseline asthma 
therapy and adjust this therapy as needed in response to improving or worsening asthma. 
All changes in asthma therapy will be captured in the source and eCRF.
Subjects will be evaluated in the clinic approximately every 4 weeks, to assess adverse 
events and asthma status. The Asthma Control Questionnaire (ACQ-5) will be used to 
assist the investigator in assessing the subject’s asthma status along with spirometry.
 
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At a minimum, each subject should have a yearly assessment of risk/benefit of 
mepolizumab therapy performed by the investigator. The investigator should review the 
frequency of exacerbations, blood eosinophil suppression, and the occurrence of 
treatment related adverse events, and any other relevant assessments for each subject.  
Those subjects with an unfavourable risk: benefit ratio, in the opinion of the investigator, 
should be withdrawn from the study.
The dose selected for the current study is based on the results of the MEA112997 study, 
which investigated a 10-fold dose range from 75mg to 750mg administered IV every 4 
weeks.  All 3 doses investigated (75mg, 250mg and 750mg) resulted in a clinically 
significant reduction in the frequency of severe exacerbations when compared to placebo, 
with a reduction of 48% occurring in the 75mg treatment arm.  All 3 doses produced a 
marked and sustained suppression of blood eosinophils throughout the dose interval. The 
safety profile was similar across all treatment arms and was similar to placebo. Further 
details are available in the Clinical Investigator’s Brochure (CIB). [GlaxoSmithKline 
Document Number CM2003/00010/07]. As the SC route is generally preferred by 
patients and a SC route of administration is easy to administer and cost-effective, a SC 
route of administration has been chosen for this study.  
A PK/PD model has been developed for mepolizumab with data obtained from 5 prior 
asthma studies and 1 healthy volunteer study.  Two of these 5 studies, administered 
mepolizumab via the SC route.  The model well describes the relationship between 
plasma mepolizumab concentration and eosinophil counts (irrespective of the route of 
administration), with an IC50 (the concentration at which 50% of the maximum reduction 
of eosinophils) of 226ng/ml [GlaxoSmithKline Document Number CM2003/00010/07].  
Based on prior PK studies, the bioavilability of mepolizumab administered SC into the 
the upper arm is approximately 75% [GlaxoSmithKline Document Number 
CM2003/00010/07], and therefore a dose of 100mg SC is anticipated to provide similar 
exposure to the 75mg IV effective dose from 112997.  Additionally, a dose of 100mg SC 
will provide plasma concentrations of mepolizumab well above the IC50 for the entire 
dosage interval.  In summary, the 100 mg dose via the SC route has been selected for this 
study based primarily on the efficacy and safety profile observed in the MEA112997 
study, and is additionally supported by the previously developed PK/PD model.
4.
SUBJECT SELECTION AND WITHDRAWAL CRITERIA
4.1.
Number of Subjects
In order to qualify for this study, subjects must have been randomised and received at 
least 2 doses of investigational product (IP) in the MEA112997 study.  Therefore, the 
number of subjects in this study will be no greater than 608.
4.2.
Inclusion Criteria
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided [GlaxoSmithKline Document 
Number CM2003/00010/07].
 
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Deviations from inclusion criteria are not allowed because they can potentially jeopardise 
the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential.
Subjects eligible for enrolment in the study must meet all of the following criteria:
1.
Informed Consent: Prior to commencing any study related activities, subjects must 
be able and willing to provide written informed consent.
2.
MEA112997 Study Participation: Received at least 2 doses of double-blind 
investigational product during the MEA112997 trial.
3.
MEA112997 Treatment Assignment: If the subject received mepolizumab, they 
must have had a positive risk: benefit ratio in the opinion of the investigator.
4.
Current Anti-Asthma Therapy: Asthma is currently being treated with a controller 
medication and the subject has been on a controller medication for the past 12 weeks. 
Subjects will be expected to continue controller therapy for the duration of the study.
5.
Male or Eligible Female Subjects:
To be eligible for entry into the study, females of childbearing potential must 
commit to consistent and correct use of an acceptable method of birth control 
(Appendix 2) for the duration of the trial and for 4 months after the last study drug 
administration.
A serum pregnancy test is required of all females. at the initial Screening Visit 
(Visit 1).  In addition, a urine pregnancy test will be performed for all females prior 
to Visit 2, during each scheduled study visit prior to the injection of investigational 
product, and during the Follow-up Visit. 
French subjects: In France, a subject will be eligible for inclusion in this study only if 
either affiliated to or a beneficiary of a social security category.
4.3.
Exclusion Criteria
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. 
Therefore, adherence to the criteria as specified in the protocol is essential. 
Subjects meeting any of the following criteria must not be enrolled in the study:
1.
Immunogenicity: Positive neutralizing antibody status based on the last sample 
obtained during the MEA112997 study.
2.
Hypersensitivity: Report of a hypersensitivity reaction assessed as related to 
mepolizumab that led to patient withdrawal. Subjects who experienced a localized 
injection-site reaction do not need to be excluded.
3.
Health Status: Clinically significant change in health status since completing 
participation in the MEA112997 trial which in the opinion of the investigator would 
make the subject unsuitable for participation in this long term study.
 
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4.
Cardiovascular: Subjects who have severe or clinically significant cardiovascular 
disease uncontrolled with standard treatment. Including but not limited to:

known ejection fraction of <30% OR

severe heart failure meeting New York Heart Association Class IV (see Appendix 
6) classification OR

hospitalised in the 12 months prior to Visit 1 for severe heart failure meeting New 
York Heart Association Class III (see Appendix 6) OR

angina diagnosed less than 3 months prior to Visit 1 or at Visit 1
5.
Malignancy: A current malignancy or previous history of cancer in remission for 
less than 12 months prior to screening (Subjects that had localized carcinoma of the 
skin which was resected for cure will not be excluded). [Note for South Korea: 
Korean subjects with a diagnosis of malignancy within 5 years are excluded]
6.
Prior SAE: For those subjects who had a a SAE in MEA112997 that was assessed 
as possibly related to mepolizumab by the investigator
7.
Pregnancy: Subjects who are pregnant or breastfeeding. Subjects should not be 
enrolled if they plan to become pregnant during the time of study participation.
8.
ECG: Screening ECG which has a clinically significant abnormality or which shows 
QTcF > 450msec or QTcF >480msec for subjects with Bundle Branch Block.
9.
Xolair: Received Xolair (omalizumab) within the past 130 days
10. Clinical trial: Participated in a clinical trial within the past 30 days or have received 
investigational medication within five terminal half-lives of Screen Visit, whichever 
is longer.
11. Smoking status: Current smokers
4.4.
Visit 2 Criteria
Subjects should be excluded if any of the following are met:
1.
Liver Function: Liver Function Tests at screening that meet any of the following: 

ALT ≥2 x ULN (upper limit of normal) 

AST ≥2 x ULN 

Alk Phos ≥2 x ULN 

Bilirubin >1.5 x ULN (isolated bilirubin >1.5x ULN is acceptable if bilirubin is 
fractionated and direct bilirubin is <35%)
2.
Hepatitis Status: Positive Hepatitis B Surface Antigen (HBsAg) screen at Visit 1
3.
ECG Over-read: Clinically significant abnormality identified during the central 
over-read 
4.
Parasitic Infection: Subjects with a known parasitic infection within 6 months of 
Visit 2.
 
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4.5.
Withdrawal Criteria
Subjects may be withdrawn from study treatment at anytime by the Investigator if it is 
considered to be detrimental for them to continue in the study. Reasons for withdrawal 
can include: an adverse event, lost to follow-up, protocol violation, lack of efficacy, 
sponsor terminated study, non-compliance, pregnancy, abnormal liver function test, 
abnormal laboratory results, or for any other reason. Liver chemistry stopping criteria are 
detailed in Section 6.3.2. In addition, QTc discontinuation criteria are listed below:

QTc(F)>500 msec or uncorrected QT>600 msec

Bundle branch block: QTc(F)>530 msec (Note: QTc(F)>500 msec for Korean 
subjects)

Change from baseline: QTc > 60msec
[Based on average QTc(F) value of triplicate ECGs. If an ECG demonstrates a 
prolonged QT interval, obtain 2 more ECGs over a brief period, and then use the 
averaged QTc(F)values of the 3 ECGs to determine whether the patients should be 
discontinued from the study].
Subjects are free to discontinue participation in the study at anytime. Every effort should 
be made to have the subject return for a Follow-up visit 4 weeks post last mepolizumab 
injection. In those instances where the subject specifies the reason for withdrawal of 
consent, this information will be captured in the eCRF.
A subject should only be designated as lost to follow-up if the site is unable to establish 
contact with the subject after 3 documented attempts via 2 different methods (phone, text, 
e-mail, certified letter, etc). These efforts should be documented in the clinic notes at the 
site.
Subjects may also be withdrawn from this study if mepolizumab becomes commercially 
available in the respective country, marketing of mepolizumab is no longer being sought 
in the respective country, or upon decision of the sponsor to discontinue further 
development of mepolizumab.
The primary reason for withdrawal will be recorded in the eCRF and any data collected 
up until the point of withdrawal will be used in the data analyses. 
4.6.
Screening/Run-in Failures
Subjects will be assigned a study number at the time of signing the Informed Consent 
Form.  Those subjects that complete at least one additional Visit 1 (Screen Visit) 
procedure, but do not enter the run-in period will be designated as screen failures.
Those subjects that enter the Run-in period, but do not receive a dose of mepolizumab, 
will be designated as run-in failures.
Information to be collected for screen failure and run-in failures will be detailed in the 
eCRF completion guidelines.
 
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5.
STUDY TREATMENTS
5.1.
Investigational Product
Mepolizumab (SB-240563) is a fully humanised IgG antibody (IgG1, kappa) with human 
heavy and light chain frameworks.  Mepolizumab will be provided as a lyophilised cake 
in sterile vials for individual use.  The vial will be reconstituted with Sterile Water for 
Injection, just prior to use.  Further details of dose preparation and administration can be 
found in the Clinical Investigator’s Brochure (CIB), and the Study Procedures Manual 
(SPM). 
The contents of the label will be in accordance with all applicable regulatory 
requirements.
Under normal conditions of handling and administration, investigational product is not 
expected to pose significant safety risks to site staff.  Take adequate precautions to avoid 
direct eye or skin contact and the generation of aerosols or mists. Notify the monitor of 
any unintentional occupational exposure.  A Material Safety Data Sheet (MSDS) 
describing the occupational hazards and recommended handling precautions will be 
provided to site staff if required by local laws or will otherwise be available from GSK 
upon request.
Investigational product must be stored in a secure area under the appropriate physical 
conditions for the product.  Access to and administration of the investigational product 
will be limited to the investigator’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. Investigational product must be dispensed or 
administered only to subjects enrolled in the study and in accordance with the protocol.
5.2.
Dosage and Administration
Prior to administration, each vial of mepolizumab will need to be reconstituted and 
swirled gently to enable complete dissolution of the product.  Detailed instructions can be 
found within the SPM.
Once the mepolizumab vial is reconstituted, 100 mg of mepolizumab should be drawn 
into a polypropylene syringe, and administered according to the instructions in the SPM.
Safety monitoring of subjects will occur during the SC administration and for one hour 
after the injection for the first 3 doses.  After the first 3 doses, safety monitoring will be 
according to local site policy.  Such monitoring will include general safety monitoring 
including monitoring for both systemic (ie, allergic/IgE-mediated and non-allergic) and 
local injection-site reactions. Trained rescue personnel and rescue medications/equipment 
must be available for use at all times. (See Section 6.3.1)
 
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5.3.
Treatment Assignment
All subjects will receive 100 mg of mepolizumab administered subcutaneously into the 
upper thigh or the upper arm approximately every 4 weeks.  
5.4.
Blinding
This study is open label.
5.5.
Product Accountability
In accordance with local regulatory requirements, the investigator, designated site staff, 
or head of the medical institution (where applicable) must document the amount of 
investigational product dispensed and/or administered to study subjects and the amount 
received from and returned to GSK, when applicable.  Product accountability records 
must be maintained throughout the course of the study.
5.6.
Treatment Compliance
All doses administered within the study unit will be administered under the supervision 
of the Investigator, designee or study nurses.
Drug dispensing/accountability logs will be maintained by a member of the study team 
designated by the Investigator.
5.7.
Concomitant Medications and Non-Drug Therapies
5.7.1.
Permitted Medications and Non-Drug Therapies
All concomitant medications taken during the study will be recorded in the electronic 
case report form (eCRF). The minimum requirement is that drug name and the dates of 
administration are to be recorded. However, for corticosteroids, the dose must be 
recorded as well as well as any dose changes.
Additional medications to treat asthma are permitted, as are medications to treat other 
disease states, with the exception of those listed as prohibited.  Oxygen and Continuous
Positive Airway Pressure (CPAP) are permitted for the treatment of obstructive sleep 
apnea.
5.7.2.
Prohibited Medications and Non-Drug Therapies
The following medications are not allowed prior to screening according to the following 
schedule or during the study:
 
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Table 1
Medications not allowed prior to the screening visit and throughout 
the study
Medication
Washout Time
Prior to Screening Visit
Investigational drugs
1 month or 5 half-lives whichever is 
longer
Omalizumab [Xolair] 
130 days
Other monoclonal antibodies
5 half-lives
Experimental anti-inflammatory drugs (non biologicals)
3 months
Immunosuppressive medications such as those listed below (not all inclusive)

Corticosteroids intramuscular, long-acting depot if 
used to treat a condition other than asthma
3 months

Methotrexate, troleandomycin, cyclosporin, 
azathioprine 
1 month

Oral gold
3 months

Chemotherapy used for conditions other than 
asthma
12 months

Regular systemic (oral or parenteral) corticosteroids 
for the treatment of conditions other than asthma
3 months
Additionally, Bronchial Thermoplasty and Radiotherapy are excluded for 12 months 
prior to Visit 1 and for the duration of the study.  Neither CPAP nor oxygen therapy may 
be initiated after Visit 1.
5.8.
Treatment after the End of the Study
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition whether or not GSK is providing specific 
post study treatment. At the end of the study, subjects should be prescribed appropriate 
alternative asthma therapy if needed and as determined by the study Investigator.
5.9.
Treatment of Study Treatment Overdose
The dose of mepolizumab considered to be an overdose has not been defined. There are 
no known antidotes and GSK does not recommend a specific treatment in the event of a 
suspected overdose. The investigator will use clinical judgement in treating the symptoms 
of a suspected overdose.
 
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6.
STUDY ASSESSMENTS AND PROCEDURES
Table 2
Time and Events Table for the First Year
Procedures
Screen
Baseline
Treatment (window is 1 week)
Follow-up
4 weeks
visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
post last
injection6
Week of study 
-4 to -1
0
4
8
12
16
20
24
28
32
36
40
44
48
Written Informed Consent
X
Medical History changes
X
Assess cardiac risk factors
X
Immunogenicity status
X
Smoking status
X
Prior monoclonal antibody use
X
Parasite screening3
X
Exacerbations post completion 
of  MEA 112997
X
Inclusion/Exclusion Criteria
X
X
Safety Assessments
Concomitant Medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examination
X
X
Vital Signs 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG 
X
X
X 
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serious Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments4
Haematology
X
X
X
X
X
X
X
Chemistry plus lipoproteins5
X
X
Chemistry
X
X
X
X
X
X
X
Pregnancy Test 1
S
U
U
U
U
U
U
U
U
U
U
U
U
U
U
Immunogenicity
X
X
*
X
*
*
*
*
*
X 
X
HbsAg and hepatitis C antibody2
X
Efficacy Assessments
 
 
 
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Procedures
Screen
Baseline
Treatment (window is 1 week)
Follow-up
4 weeks
visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
post last
injection6
Week of study 
-4 to -1
0
4
8
12
16
20
24
28
32
36
40
44
48
Exacerbation review 
X
X
X
X
X
X
X
X
X
X
X
X
X
X 
Asthma Control Questionnaire-5
X
X
X
X
X
X
Spirometry-
X 
 
X
X
X
Worksheets/IP/eCRF
Administer Investigational 
Product.
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense paper worksheet
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect paper worksheet
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Phone IVRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete eCRF
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
1.
Pregnancy test (all females) U = Urine,  S= Serum
2.
Hepatitis B Surface Antigen and Hepatitis C antibody ( if Hepatitis C antibody positive, a hepatitis C confirmatory test should be automatically performed to confirm the result)
3.
Parasitic screening only in countries with a high-risk or for subjects who have visited high-risk countries in the past 6 months.  Sites should utilise local laboratories.
4.
All laboratory assessments to be completed prior to dosing
5.
Subject must be in the fasting state. If subject has not fasted, may return the next business day to obtain this sample
6.
Follow-up visit window is 1 week
* Take additional immunogenicity sample immediately prior to first dose with 100mg vial and prior to the second dose with the 100mg vial. Maximum of 2 additional samples
 
 
 
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Table 3
Time and Events Table for Additional Years
Procedures
Treatment subsequent years
(repeat 48 week cycle for each subsequent year)
Follow-up
4 weeks
visit
15
16
17
18
19
20
21
22
23
24
25
26
27
post last
injection4
Week of study (1 week)
52
56
60
64
68
72
76
80
84
88
92
96
100
Safety Assessments
Assess Risk: Benefit ratio
X
Concomitant Medication
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examination
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG 
X
X
X
Adverse Events/SAEs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments2
Haematology
X
X
X
Chemistry plus lipoproteins3
X
Chemistry
X
X
Pregnancy Test1
U
U
U
U
U
U
U
U
U
U
U
U
U
U
Immunogenicity
*
*
*
*
*
X
*
*
*
*
*
X
X
Efficacy Assessments
Exacerbation review (worksheet)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Asthma Control Questionnaire
X
X
X
X
X
Spirometry-
X
X
IP/eCRF/Worksheets
Administer IP
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense paper diary card
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect paper diary card
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Phone IVRS
X 
X
X
X
X
X
  X
X
X
X
X
X
X
Complete eCRF
X
X
X
X
X
X
  X
X
X
X
X
X
X
X
1.
Pregnancy test (all females) U = Urine
2.
All laboratory tests are to be completed prior to dosing
3.
Subject must be in the fasting state. If subject has not fasted, may return the next business day to obtain this sample
4.
Follow-up visit window is 1 weeks
* Take additional immunogenicity sample immediately prior to first dose with 100mg vial and prior to the second dose with the 100mg vial. Maximum of 2 additional samples
 
 
 
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6.1.
Critical Baseline Assessments
Screening and baseline assessments at Visit 1 or Visit 2 (Week 0) will comprise the 
following:

Demographic information including date of birth

Update medical history

Cardiovascular medical history/risk factors will be assessed at screening. This 
assessment must include a review of the subject responses to the cardiovascular 
assessment questions (See Appendix 5) and height, weight, blood pressure, 
medical conditions, and family history of premature cardiovascular disease.

Therapy history, including review of use of biologics.

Review of immunogenicity status from MEA112997.

Physical examination (including nasal exam to check for the presence or 
absence of nasal polyps.)

Pulmonary function tests and assessment. 

Assessment of Inclusion/Exclusion criteria. (At Visit 2, will need to review the 
results of laboratory tests from Visit 1 and the ECG over-read results)

Asthma Control Questionnaire (ACQ-5). Further details are provided in 
Section 6.2.1.3

Vital signs (further details are provided in Section 6.3.10.1)

12-lead ECG (further details are provided in Section 6.3.10.2)

Blood sampling for the following:
o
Clinical chemistry
o
Clinical chemistry plus lipoproteins at Visit 2 (subject must fast)
o
Haematology
o
Immunogenicity
o
Pregnancy test (all females)
o
HbsAg and hepatitis C antibody

Parasitic screening (only in countries with a high-risk or in subjects who have 
visited a country with a high-risk)
 
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6.2.
Efficacy
6.2.1.
Efficacy Endpoints

Annualized rate of exacerbations

Asthma Control Questionnaire score

FEV1 measured by clinic spirometry
6.2.1.1.
Exacerbations
Exacerbations will be defined as worsening of asthma which requires use of systemic 
corticosteroids1and/or hospitalisation and/or Emergency Department (ED) visits.
1For all subjects, IV. or oral steroid (e.g., prednisone) for at least 3 days or a single IM 
CS dose is required. For subjects on maintenance systemic corticosteroids, at least 
double the existing maintenance dose for at least 3 days is required. 
6.2.1.2.
Pulmonary Function Testing
Spirometry will be conducted, using the site’s own equipment at the visits specified in the 
Time and Events schedule (Table 2 and Table 3).  The spirometer should meet American 
Thoracic Society standards and produce a printout of all data generated, which should be 
stored in the subject’s notes.  The spirometer should be calibrated in accordance with the 
manufacturer’s instructions and a calibration log maintained. Spirometry should be 
performed within 1 hour of the baseline assessment.  Subjects should try to withhold 
short-acting beta-2-agonists (SABAs) for ≥6 hours and LABAs for 12 hours prior to 
clinic visit, if possible. Assessments to be recorded will include FEV1and FVC.
6.2.1.3.
Asthma Control Questionnaire-5 (ACQ)
The ACQ-5 is a five-item questionnaire, which has been developed as a measure of 
subject’ asthma control that can be quickly and easily completed [Juniper, 2005].  The 
questions are designed to be self-completed by the subject.  The five questions enquire 
about the frequency and/or severity of symptoms (nocturnal awakening on waking in the 
morning, activity limitation, and shortness of breath, wheeze).  The response options for 
all these questions consist of a zero (no impairment/limitation) to six (total impairment/ 
limitation) scale.
The subject should be given a quiet area in which to complete the paper questionnaire. 
The investigator should ask the subject to complete the questions as accurately as 
possible.  If the subject requests help or clarification with any of the questions, he/she 
will be asked to re-read the instructions and give the answer that best reflects how he/she 
felt over the previous week.  The subject should be reassured that there are no right or 
wrong answers.  The investigator should not provide the subject with any answer or 
attempt to interpret any portion of a question.  The site-staff will transfer the subject 
responses on paper into the eCRF.
 
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It is recommended that the ACQ be administered at the same time during each visit.  To 
avoid biasing responses, the subjects should not be told the results of diagnostic tests 
prior to completing the questionnaire and should be completed before any procedures are 
performed on the subject to avoid influencing the subject’s response.  Adequate time 
should be allowed to complete all items on the ACQ.
6.3.
Safety
6.3.1.
Safety Endpoints

Adverse Events, including both systemic (ie, allergic/IgE-mediated and non-allergic) 
and local site reactions.
NOTE: Hypersensitivity reactions (ie, allergic or IgE-mediated reactions) will be 
monitored using the diagnostic criteria for anaphylaxis as outlined by the 2006 Joint 
NIAID/FAAN Second Symposium on Anaphylaxis [Sampson, 2006] (Appendix 4).  
Information will be also collected to assess localised site reactions.

12-lead ECG to derive the following endpoints:

Mean change from baseline in the QTc(F) (QT interval corrected by Fridericia's 
method)

Mean change from baseline in QTc(B) (QT interval corrected by Bazett's 
method)

Maximum change from baseline for QTc(F) and QTc(B).

Clinical Laboratory parameters

Vital signs
6.3.2.
Liver chemistry stopping and follow up criteria
Phase III-IV liver chemistry stopping criteria 1-5 are defined below and in Appendix 3:
1.
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) (or ALT 3xULN 
and INR>1.5, if INR measured)
NOTE: if serum bilirubin fractionation is not immediately available, withdraw study 
drug for that subject if ALT 3xULN and bilirubin 2xULN. Serum bilirubin 
fractionation should be performed if testing is available. If testing is unavailable, 
record presence of detectable urinary bilirubin on dipstick, indicating direct 
bilirubin elevations and suggesting liver injury.
2. ALT 8xULN.
3. ALT 5xULN but <8 xULN persists for 2 weeks
4. ALT  3xULN if associated with symptoms (new or worsening) believed to be 
related to  hepatitis (such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, or jaundice) or hypersensitivity (such as fever, rash or eosinophilia).
5. ALT 5xULN but <8 xULN and cannot be monitored weekly for 2 weeks
 
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When any of the liver chemistry stopping criteria 1-5 is met, do the following:

Immediately withdraw investigational product for that subject

Report the event to GSK within 24 hours of learning its occurrence

Complete the liver event CRF and SAE data collection tool if the event also meets 
the criteria for an SAE. All events of ALT 3xULN and bilirubin 2xULN (>35% 
direct) (or ALT 3xULN and INR>1.5, if INR measured); INR measurement is not 
required and the threshold value stated will not apply to patients receiving 
anticoagulants), termed ‘Hy’s Law’, must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis). 
NOTE: if serum bilirubin fractionation is not immediately available, withdraw study 
drug for that subject if ALT 3xULN and bilirubin 2xULN. Serum bilirubin 
fractionation should be performed if testing is available. If testing is unavailable, 
record presence of detectable urinary bilirubin on dipstick, indicating direct 
bilirubin elevations and suggesting liver injury.

Complete the liver imaging and/or liver biopsy CRFs if these tests are performed

Perform liver event follow up assessments, and monitor the subject until liver 
chemistries resolve, stabilize, or return to baseline values as described below. 

Withdraw the subject from the study after completion of the liver chemistry 
monitoring (unless further safety follow up is required)  

Do not re-challenge with investigational product.
In addition, for criterion 1: 

Make every reasonable attempt to have subjects return to clinic within 24 hours for 
repeat liver chemistries, liver event follow up assessments (see below), and close 
monitoring

A specialist or hepatology consultation is recommended

Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) resolve, stabilize or return to within baseline values
For criteria 2, 3, 4 and 5:

Make every reasonable attempt to have subjects return to clinic within 24-72 hrs for 
repeat liver chemistries and liver event follow up assessments (see below)

Monitor subjects weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilize or return to within baseline values; criterion 5 subjects 
should be monitored as frequently as possible.
Subjects with ALT 5xULN and <8xULN which exhibit a decrease to ALT x3xULN, 
but <5xULN and bilirubin <2xULN without hepatitis symptoms or rash, and who can be 
monitored weekly for 4 weeks:

Notify the GSK medical monitor within 24 hours of learning of the abnormality to 
discuss subject safety
 
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
Can continue investigational product 

Must return weekly for repeat liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilize or return to within baseline 

If at any time these subjects meet the liver chemistry stopping criteria, proceed as 
described above

If, after 4 weeks of monitoring, ALT <3xULN and bilirubin <2xULN, monitor 
subjects twice monthly until liver chemistries normalize or return to within baseline 
values. 
For criteria 1-5, make every attempt to carry out the liver event follow up assessments
described below:

Viral hepatitis serology including:

Hepatitis A IgM antibody;

Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); 

Hepatitis C RNA; 

Cytomegalovirus IgM antibody;  

Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  

Hepatitis E IgM antibody 

Blood sample for PK analysis, obtained within 4 weeks of last dose.  Record the 
date/time of the PK blood sample draw and the date/time of the last dose of 
investigational product prior to blood sample draw on the CRF. If the date or time of 
the last dose is unclear, provide the subject’s best approximation. If the date/time of 
the last dose cannot be approximated OR a PK sample cannot be collected in the 
time period indicated above, do not obtain a PK sample. Instructions for sample 
handling and shipping are in the SPM. 

Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total bilirubin 2xULN

Obtain complete blood count with differential to assess eosinophilia

Record the appearance or worsening of clinical symptoms of hepatitis or 
hypersensitivity, such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever rash or eosinophilia as relevant on the AE report form

Record use of concomitant medications, acetaminophen, herbal remedies, other over 
the counter medications, or putative hepatotoxins, on the concomitant medications 
report form.

Record alcohol use on the liver event alcohol intake case report form
 
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The following are required for subjects with ALT 3xULN and bilirubin 2xULN (>35% 
direct) but are optional for other abnormal liver chemistries:

Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney 
microsomal antibodies.

Serum acetaminophen adduct HPLC assay (quantifies potential acetaminophen 
contribution to liver injury in subjects with definite or likely acetaminophen use in 
the preceding week.  

Only in those with underlying chronic hepatitis B at study entry (identified by 
positive hepatitis B surface antigen):  quantitative hepatitis B DNA and hepatitis 
delta antibody.  NOTE:  if hepatitis delta antibody assay cannot be performed,, it can 
be replaced with a PCR of hepatitis D RNA virus (where needed) – as outlined in: 
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1153793/

Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to 
evaluate liver disease.
6.3.3.
Adverse Events
Subject will be issued a paper worksheet to record adverse events during the study
The investigator or site staff will be responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE.
6.3.3.1.
Definition of an AE
Any untoward medical occurrence in a patient or clinical investigation subject, 
temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product.
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.  For marketed medicinal products, this 
also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse.
Events meeting the definition of an AE include:

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study

Signs, symptoms, or the clinical sequelae of a suspected interaction

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE) unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae.
 
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“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 fulfill the definition of an AE or 
SAE.  
Events that do not meet the definition of an AE include:

Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that 
leads to the procedure is an AE

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital)

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen

The disease/disorder being studied, or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 
condition
6.3.3.2.
Definition of a SAE
A serious adverse event is any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:  The term 'life-threatening' in the definition of 'serious' refers to an event in 
which the subject was at risk of death at the time of the event.  It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires hospitalization or prolongation of existing hospitalization
NOTE:  In general, hospitalization signifies that the subject has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting.  Complications that occur during hospitalization are 
AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
 
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d.
Results in disability/incapacity, or
NOTE:  The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions.  This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may 
interfere or prevent everyday life functions but do not constitute a substantial 
disruption.
e.
Is a congenital anomaly/birth defect
f.
Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or 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.
All events of possible drug-induced liver injury with hyperbilirubinaemia defined as 
ALT 3xULN and bilirubin 2xULN (>35% direct) (or ALT 3xULN and 
INR>1.5, if INR measured) termed ‘Hy’s Law’ events (INR measurement is not 
required and the threshold value stated will not apply to patients receiving 
anticoagulants).
NOTE: bilirubin fractionation is performed if testing is available. If testing is 
unavailable, record presence of detectable urinary bilirubin on dipstick indicating 
direct bilirubin elevations and suggesting liver injury. If testing is unavailable and a 
subject meets the criterion of total bilirubin 2xULN, then the event is still reported 
as an SAE. If INR is obtained, include values on the SAE form. INR elevations >1.5 
suggest severe liver injury.
6.3.4.
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs
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 are to be recorded as AEs or SAEs.
However, any clinically significant safety assessments that are associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the subject’s condition, are not to be reported as AEs or SAEs.
 
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6.3.5.
Cardiovascular Events
Investigators will be required to fill out event specific pages in the eCRF 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 thrombosis

Deep Venous Thrombosis

Revascularization
Cardiovascular events information should be recorded on the corresponding eCRF pages 
within one week of when the AE/SAE(s) are first reported. Please refer to Section 6.3.9
for timelines for reporting AE/SAEs.
6.3.6.
Death Events
In addition, all deaths will require completion of a specific death data collection page in 
the eCRF.  The death data collection page in the eCRF includes questions regarding 
cardiovascular (including sudden cardiac death) and non-cardiovascular death.
Death information should be recorded on the death eCRF page within one week of when 
the death is first reported.
Please refer to Section 6.3.9 for timelines for reporting SAEs.
6.3.7.
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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6.3.8.
Time Period and Frequency of Detecting AEs and SAEs
The investigator or site staff is responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE.
AEs will be collected from the start of investigational product (Visit 2) and until the 
follow up visit (4 weeks after the last injection).
SAEs will be collected over the same time period as stated above for AEs. However, any 
SAEs assessed as related to study participation (e.g., study treatment, protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK concomitant 
medication, will be recorded from the time a subject consents to participate in the study 
up to and including any follow up contact. All SAEs will be reported to GSK within 24 
hours, as indicated in Section 6.3.9.
6.3.9.
Prompt Reporting of Serious Adverse Events and Other Events 
to GSK
SAEs, pregnancies, medical device incidents, and liver function abnormalities meeting 
pre-defined criteria will be reported promptly by the investigator to GSK as described in 
the following table once the investigator determines that the event meets the protocol 
definition for that event.
 
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Initial Reports
Follow-up Information on a Previous 
Report
Type of Event
Time Frame
Documents
Time Frame
Documents
All SAEs
24 hours
“SAE” data 
collection tool
24 hours
Updated “SAE” 
data collection tool
“CV events” and/or 
“death” data 
collection tool(
Pregnancy
2 weeks
“Pregnancy 
Notification Form”
2 weeks
“Pregnancy Follow-up 
Form”
Liver chemistry abnormalities for Phase I to IV:
ALT3xULN and
Bilirubin2xULN (>35% 
direct) (or ALT3xULN 
and INR>1.5, if INR 
measured)1
24 hours2
“SAE” data 
collection tool.  
“Liver Event CRF” 
and “Liver Imaging” 
and/or “Liver 
Biopsy” CRFs, if 
applicable3
24 hours
Updated “SAE” data 
collection tool/“Liver 
Event” Documents3
Remaining liver chemistry abnormalities Phase III to IV:
ALT8xULN; 
ALT3xULN with 
hepatitis or rash or 
3xULN and <5xULN 
that persists4 weeks
24 hours2
“Liver Event” 
Documents (defined 
above) 3
24 hours
Updated “Liver Event” 
Documents3
ALT5xULN plus 
bilirubin <2xULN
24 hours2
“Liver Event” 
Documents (defined 
above) do not need 
completing unless 
elevations persist 
for 2 weeks or 
subject cannot be 
monitored weekly 
for 2 weeks3
24 hours
Updated “Liver Event” 
Documents, if 
applicable3
ALT5xULN and 
bilirubin <2xULN that 
persists 2 weeks
24 hours2
“Liver Event” 
Documents (defined 
above) 3
24 hours
Updated “Liver Event” 
Documents3
ALT3xULN and <5x 
ULN and bilirubin 
<2xULN
24 hours2
“Liver Event” 
Documents (defined 
above) do not need 
completing unless 
elevations persist 
for 4 weeks or 
subject cannot be 
monitored weekly 
for 4 weeks3
24 hours
Updated “Liver Event” 
Documents, if 
applicable3
1.
INR measurement is not required; if measured, the threshold value stated will not apply to patients 
receiving anticoagulants.
2.
GSK must be contacted at onset of liver chemistry elevations to discuss subject safety
3.
Liver Event Documents (i.e., “Liver Event CRF” and “Liver Imaging CRF” and/or “Liver Biopsy CRF”, as 
applicable) should be completed as soon as possible.
 
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The method of detecting, recording, evaluating and follow-up of AEs and SAEs plus 
procedures for completing and transmitting SAE reports to GSK are provided in the 
SPM.  Procedures for post-study AEs/SAEs are provided in the SPM.
Procedures for documenting, transmitting and follow-up of medical device incidents 
along with the regulatory reporting requirements for medical devices are provided in the 
SPM.
6.3.9.1.
Regulatory reporting requirements for SAEs
Prompt notification of SAEs by the investigator to GSK is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects are met.
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
6.3.10.
Other Safety Outcomes
6.3.10.1.
Vital Signs
Sitting pulse rate and blood pressure measurements will be performed by the investigator 
or qualified site staff, as outlined in Time and Events Table (see Table 2 and Table 3). 
Measurements will be done pre-injection with the subject sitting, having rested in this 
position for at least 5 minutes before each reading.  They will be taken before 
measurement of any clinic lung function tests or ECGs at the specified time point.
At the Screen visit, height and weight will also be measured.
6.3.10.2.
Twelve-lead electrocardiogram
Twelve-lead ECGs will be performed at the visits specified in the Time and Events Table 
(see Table 2 and Table 3).
Electrocardiogram measurements will be made after the subject has rested in the supine 
position for 5 minutes.  The ECG should be obtained before lung function testing 
followed by other study procedures.  Collection shortly after a meal or during sleep 
should be avoided since QT prolongation can occur at these times.
 
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Investigators will be provided with ECG machines by GSK through a designated central 
laboratory. Paper ECG traces will be recorded at a standard paper speed of 25mm/sec and 
gain of 10mm/mV, with a lead II rhythm strip. There will be electronic capture and 
storage of the data by a validated method, with subsequent transferral to the central 
laboratory for manual reading and calculation of the electrocardiographic parameters.  
ECGs will also be taken at the end of the Follow-up period.
Paper traces are required to be maintained at the site with other source documents.
6.3.10.3.
Clinical Laboratory Parameters
Clinical laboratory tests will be conducted at the visits specified in the Time and Events 
Table (see Table 2 and Table 3). At the discretion of the Investigator, additional samples 
may be taken for safety reasons.
All blood samples, which will be taken pre-dosing will be sent to a central laboratory for 
analysis (details provided in the Study Procedures Manual).  Standard reference ranges 
will be used.  Full details of the collection and shipping requirements for the central 
laboratory are provided in the Central Laboratory Investigator Manual.  The central 
laboratory will fax laboratory results to the Investigator and will transmit the results 
electronically to GSK. 
6.4.
Immunogenicity
Blood samples will be collected for the determination of anti-mepolizumab antibodies, 
just prior to administration of mepolizumab, at the time points identified in the Time and 
Events Table (see Table 2 and Table 3). Samples that test positive for anti-mepolizumab 
antibodies will be further tested for the presence of neutralising antibody.
A maximum of two additional anti-mepolizumab antibody samples will be obtained; one 
immediately prior to the first dose and the other prior to the second dose with the 100mg 
mepolizumab vial. If the first or second dose coincides with a visit where an 
immunogenicity sample is already required, it is not necessary to obtain an additional 
sample.
For all subjects, immunogenicity testing will occur at 4 weeks after the last dose.
7.
DATA MANAGEMENT
For this study subject data will be entered into GSK defined electronic case report forms 
(eCRFs), transmitted electronically to GSK and combined with data provided from other 
sources in a validated data system.  
Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., removing 
errors and inconsistencies in the data.  Adverse events and concomitant medications 
terms will be coded using MedDRA and an internal validated medication dictionary, 
GSKDrug.  In all cases, subject initials will not be collected or transmitted to GSK 
according to GSK policy.
 
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8.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS
8.1.
Hypotheses
Because the study has a single treatment arm, statistical analyses of treatment effect will 
not be performed. Therefore no hypotheses have been defined for this study.
8.2.
Study Design Considerations
8.2.1.
Sample Size Assumptions
There is no sample size calculation for this study. The sample size will be determined by 
the number of available subjects who were randomised into study MEA112997 and are 
eligible for the current study based on inclusion and exclusion criteria.
8.2.2.
Sample Size Sensitivity
Not applicable.
8.2.3.
Sample Size Re-estimation
Not applicable.
8.3.
Data Analysis Considerations
All pre-specified analyses will be described in a full Reporting and Analysis Plan (RAP) 
which will be finalised prior to database freeze.
8.3.1.
Analysis Populations
The All Subjects Enrolled population will comprise all subjects for whom a record exists 
on the database. 
The As Treated population will consist of all subjects who received at least one dose of 
open label mepolizumab.
8.3.2.
Analysis Data Sets
All analyses will be performed using all available data as outlined in the Reporting and 
Analysis Plan.
8.3.3.
Treatment Comparisons
No treatment comparisons will be performed.
8.3.3.1.
Primary Comparisons of Interest
Not applicable.
 
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8.3.3.2.
Other Comparisons of Interest
Not applicable.
8.3.4.
Interim Analysis
Interim analysis will be performed as needed in order to provide open-label safety data to 
inform the risk-benefit assessment of mepolizumab in severe asthma.
8.3.5.
Key Elements of Analysis Plan
Further detail will be fully described in the RAP.
8.3.5.1.
Efficacy Analyses
All efficacy endpoints will be summarised using descriptive statistics. Further details will 
be provided in the RAP.
8.3.5.2.
Safety Analyses
All safety endpoints will be summarised using descriptive statistics. Further details will 
be provided in the RAP.
8.3.5.3.
Immunogenicity Analyses
All immunogenicity endpoints will be summarised using descriptive statistics. The 
number and percentage of subjects with positive neutralizing antibodies before and after 
the introduction of the 100mg mepolizumab vial will be tabulated. Further details will be 
provided in the RAP.
9.
STUDY CONDUCT CONSIDERATIONS
9.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrolment of subjects begins.
9.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a study site, GSK will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements.
The study will be conducted in accordance with ICH GCP, all applicable subject privacy 
requirements, and the ethical principles that are outlined in the Declaration of Helsinki 
2008, including, but not limited to:
 
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
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and 
favourable opinion/approval of study protocol and any subsequent amendments.

Subject informed consent.

Investigator reporting requirements.
GSK will provide full details of the above procedures, either verbally, in writing, or both.
Written informed consent must be obtained from each subject prior to participation in the 
study.
9.3.
Quality Control (Study Monitoring)
In accordance with applicable regulations, GCP, and GSK procedures, GSK monitors 
will contact the site prior to the start of the study to review with the site staff the protocol, 
study requirements, and their responsibilities to satisfy regulatory, ethical, and GSK 
requirements.  When reviewing data collection procedures, the discussion will include 
identification, agreement and documentation of data items for which the CRF will serve 
as the source document.
GSK will monitor the study to ensure that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any other 
study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents.
 
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9.4.
Quality Assurance
To ensure compliance with GCP and all applicable regulatory requirements, GSK may 
conduct a quality assurance assessment and/or audit of the site records, and the regulatory 
agencies may conduct a regulatory inspection at any time during or after completion of 
the study. In the event of an assessment, audit or inspection, the investigator (and 
institution) must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to 
all relevant documents and to allocate their time and the time of their staff to discuss the 
conduct of the study, any findings/relevant issues and to implement any corrective and/or 
preventative actions to address any findings/issues identified.
9.5.
Study and Site Closure
The study will be considered complete when the last subject completes the last visit. 
Upon completion or termination of the study, the GSK monitor will conduct site closure 
activities with the investigator or site staff (as appropriate), in accordance with applicable 
regulations, GCP, and GSK Standard Operating Procedures.
GSK reserves the right to temporarily suspend or terminate the study at any time for 
reasons including (but not limited to) safety issues, ethical issues, or severe non-
compliance.  If GSK determines that such action is required, GSK will discuss the 
reasons for taking such action with the investigator or head of the medical institution 
(where applicable).  When feasible, GSK will provide advance notice to the investigator 
or head of the medical institution of the impending action.
If a study is suspended or terminated for safety reasons, GSK will promptly inform all 
investigators, heads of the medical institutions (where applicable),and/or institutions 
conducting the study.  GSK will also promptly inform the relevant regulatory authorities 
of the suspension/termination along with the reasons for such action.  Where required by 
applicable regulations, the investigator or head of the medical institution must inform the 
IRB/IEC promptly and provide the reason(s) for the suspension/termination.
9.6.
Records Retention
Following closure of the study, the investigator or head of the medical institution (where 
applicable) must maintain all site study records (except for those required by local 
regulations to be maintained elsewhere) in a safe and secure location.  The records must 
be easily accessible when needed (e.g., for a GSK audit or regulatory inspection) and 
must be available for review in conjunction with assessment of the facility, supporting 
systems, and relevant site staff.
Where permitted by local laws/regulations or institutional policy, some or all of the 
records may be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution must be exercised before such action is taken.  The 
investigator must ensure that all reproductions are legible and are a true and accurate 
copy of the original. In addition, they must meet accessibility and retrieval standards, 
including regeneration of a hard copy, if required.  The investigator must also ensure that 
an acceptable back-up of the reproductions exists and that there is an acceptable quality 
control procedure in place for creating the reproductions.
 
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GSK will inform the investigator of the time period for retaining the site records in order 
to comply with all applicable regulatory requirements.  The minimum retention time will 
meet the strictest standard applicable to a particular site, as dictated by local 
laws/regulations, GSK standard operating procedures, and/or institutional requirements.
The investigator must notify GSK of any changes in the archival arrangements, including, 
but not limited to archival of records at an off-site facility or transfer of ownership of the 
records in the event that the investigator is no longer associated with the site.
9.7.
Provision of Study Results to Investigators, Posting of 
Information on Publicly Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
GSK aims to post a results summary to the GSK Clinical Study Register and other 
publicly available registers no later than 8 months after the last subject’s last visit (LSLV) 
[this applies to each data analysis phase for studies with multiple phases, e.g., primary 
analysis, follow up analysis etc]. In addition, the aim is to submit a manuscript to a peer-
reviewed journal for publication within 18 months of LSLV. GSK also aims to publish 
the full study protocol on the GSK Clinical Study Register at the time the results of the 
study are published as a manuscript in the scientific literature. 
When manuscript publication in a peer-reviewed journal is not feasible, further study 
information will be posted to the GSK Clinical Study Register to supplement the results 
summary. 
9.8.
Independent Data Monitoring Committee (IDMC)
An IDMC will be utilized in this study to ensure external objective medical and/or 
statistical review of safety and/or efficacy issues in order to protect the ethical and safety 
interests of subjects and to protect the scientific validity of the study.  The schedule of 
any planned interim analysis and the analysis plan for IDMC review is described in the 
charter, which is available upon request.
 
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10.
REFERENCES
American Heart Association.  Classes of Heart Failure.  Available at: 
http://www.heart.org/HEARTORG/Conditions/HeartFailure/AboutHeartFailure/Classes-
of-Heart-Failure_UCM_306328_Article.jsp.  Accessed 14 August 2012.
Bateman ED, Boushey HA, Bousquet J, Busse WW, Clark TJ, Pauwels RA, Pedersen SE. 
Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma 
ControL study. Am J Respir Crit Care Med 2004;170:836-844.
Clutterbuck EJ, Hirst EM, Sanderson CJ. Human interleukin-5 (IL-5) regulates the 
production of eosinophils in human bone marrow cultures: comparison and interaction 
with IL-1, IL-3, IL-6, and GMCSF. Blood 1989;73:1504-1512.
GlaxoSmithKline Document Number CM2003/00010/07 Compound ID SB-240563. 
Investigator’s brochure for Mepolizumab. Report date 23-MAY-2012.
Global Initiative for Asthma (GINA): Global Strategy for Asthma Management and 
Prevention, revised 2008. http://www.ginasthma.com/Guidelineitem.asp??l1=2&l2= 
Hamid Q, Azzawi M, Ying S, Moqbel R, Wardlaw AJ, Corrigan CJ, Bradley B, Durham 
SR, Collins JV, Jeffery PK et al. Expression of mRNA for interleukin-5 in mucosal 
bronchial biopsies from asthma. J Clin Invest 1991;87:1541-1546.
Humbert M, Corrigan CJ, Kimmitt P, Till SJ, Kay AB, Durham SR. Relationship 
between IL-4 and IL-5 mRNA expression and disease severity in atopic asthma. Am J 
Respir Crit Care Med 1997;156:704-708.
Juniper EF, Svensson K, Mőrk AC, Ståhl E. Measurement properties and interpretation of 
three-shortened versions of the asthma control questionnaire. Resp Med 2005;99:553-
558.
Kips JC, Inman MD, Jayaram L, Bel EH, Parameswaran K, Pizzichini MM, Pavord ID, 
Djukanovic R, Hargreave FE, Sterk PJ. The use of induced sputum in clinical trials. Eur 
Respir J Suppl 2002;37:47s-50s.
National Institutes of Health. National Heart, Lung, and Blood Institute (NHLBI). 
National Asthma Education and Prevention Program. Expert Panel Report 3: guidelines 
for the diagnosis and management of asthma. August 2007. NIH publication no. 07-4051 
Available at: http://www.nhlbi.nih.gov/guidelines/asthma/index.htm. Accessed 
November, 10, 2008.
Proceedings of the ATS workshop on refractory asthma: current understanding, 
recommendations, and unanswered questions. Am J Respir Crit Care Med
2000;162:2341-2351.
Robinson DS, Hamid Q, Ying S, Tsicopoulos A, Barkans J, Bentley AM, Corrigan C, 
Durham SR, Kay AB. Predominant TH2-like bronchoalveolar T-lymphocyte population 
in atopic asthma. N Engl J Med 1992;326:298-304.
 
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Robinson DS, Ying S, Bentley AM, Meng Q, North J, Durham SR, Kay AB, Hamid Q. 
Relationships among numbers of bronchoalveolar lavage cells expressing messenger 
ribonucleic acid for cytokines, asthma symptoms, and airway methacholine 
responsiveness in atopic asthma. J Allergy Clin Immunol 1993;92:397-403.
Sampson HA, Munoz-Furlong A, Campbell RL, et. al. Second symposium on the 
definition and management of anaphylaxis: summary report--Second National Institute of 
Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J 
Allergy Clin Immunol 2006;117:391-397.
Wang JM, Rambaldi A, Biondi A, Chen ZG, Sanderson CJ, Mantovani A. Recombinant 
human interleukin 5 is a selective eosinophil chemoattractant. Eur J Immunol
1989;19:701-705.
Wardlaw AJ, Brightling C, Green R, Woltmann G, Pavord I. Eosinophils in asthma and 
other allergic diseases. Br Med Bull 2000;56:985-1003.
 
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11.
APPENDICES
11.1.
Appendix 1: Country Specific Requirements
Country-Specific Requirements 
No country-specific requirements exist.
 
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11.2.
Appendix 2: Acceptable Birth Control
To be eligible for entry into the study, females of childbearing potential must commit to 
consistent and correct use of an acceptable method of birth control from the time of 
consent, for the duration of the trial, and for 4 months after the last study drug 
administration.

Male partner who is sterile prior to the female subject’s entry into the study and 
is the sole sexual partner for that female subject 

Abstinence from penile-vaginal intercourse

Implants of levonorgestrel  or etonogestrel 

Injectable progestogen

Oral contraceptive (either combined or progestogen alone)

Estrogenic vaginal ring

Percutaneous contraceptive patches

Any intrauterine device (IUD) with a documented failure rate of less than 1% 
per year.

Male condom combined with a vaginal spermicide (foam, gel, film, cream, or 
suppository)

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 analyzed to confirm childbearing potential.  
 
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Females on hormone replacement therapy (HRT) and whose menopausal status is in 
doubt will be required to use one of the contraception methods listed above for females of 
childbearing potential if they wish to continue their HRT during the study.  Otherwise, 
they must discontinue HRT to allow confirmation of post-menopausal status prior to 
study enrollment.  For most forms of HRT, at least 2-4 weeks should elapse between the 
cessation of therapy and the blood draw; this interval depends on the type and dosage of 
HRT.  Following confirmation of their post-menopausal status, they can resume use of 
HRT during the study without use of a contraceptive method.
Based on the absence of an identified reproductive hazard from preclinical studies, 
absence of a genotoxic potential, and very low levels of mepolizumab that might be 
present in semen, there is no recognized risk for mepolizumab to affect human sperm or 
the fetus if transferred to a female partner via semen. Therefore, the use of condoms or 
other methods of contraception in the male study subject is not required.
 
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11.3.
Appendix 3: Liver Chemistry Stopping and Followup Criteria
Phase III-IV Liver Safety Algorithms
ALT>3xULN
plus 
bilirubin >2x 
ULN (or
plus INR >1.5, 
if measured)*
No
Yes
Yes
•Instruct subject to stop investigational product (IP)
•Notify GSK + arrange clinical followup within 24-72h
•Perform liver chemistries and liver event follow up 
assessments (serology, PK sample etc as in protocol) 
•Complete liver event CRF, SAE data collection tool if 
appropriate, + liver imaging +/or biopsy CRFs if  tests 
performed.
•Obtain weekly liver chemistries [**as far as possible] 
until resolved, stabilised or returned to baseline 
•Withdraw subject from study after liver chemistry 
monitoring complete + do not re-challenge with IP
•Instruct subject to stop investigational product (IP)
•Notify GSK + arrange clinical followup within 24h
•Perform liver chemistries and liver event follow up 
assessments (serology, PK sample etc as in protocol) 
•Report as SAE (excl. hepatic impairment or cirrhosis 
studies)+ complete liver event CRF, SAE data collection 
tool, + liver imaging +/or biopsy CRFs if tests performed.
•Obtain twice weekly liver chemistries until resolved, 
stabilised or returned to baseline values
•Consultation with hepatologist/specialist recommended
•Withdraw subject from study after liver chemistry 
monitoring complete + do not re-challenge with IP
Hepatitis 
symptoms
or rash?
No
Able to 
monitor 
weekly for 
4 weeks?
Yes
No**
Yes
Continue IP
Obtain twice 
monthly liver 
chemistries until 
normalised or 
back to baseline 
values
Yes
Yes
ALT<3xULN 
+ bilirubin
<2xULN 
after ? 4 
wks?
Yes
ALT 
>5xULN 
but 
<8xULN
No
ALT 
>8xULN
Yes
ALT >5 
and 
<8xULN 
for > 2 
wks
Yes
No
ALT>3xULN 
but <5xULN 
+ bilirubin
<2xULN+no 
symptoms
No
Able to 
monitor 
weekly for 
> 2 wks?
No
No
Notify GSK within 24h 
to discuss subject 
safety
Continue IP
Check liver chemistry 
weekly for 4 weeks
Yes
No
*INR value not applicable to patients on anticoagulants
 
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11.4.
Appendix 4: Anaphylaxis Criteria
Joint NIAID/FAAN Second Symposium on Anaphylaxis [Sampson, 2006]. The criteria 
do not make a distinction based on underlying mechanism. These criteria are summarized 
as follows:
1.
Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, swollen lips-
tongue-uvula), and at least one of the following:

Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced 
PEF, hypoxemia) 

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):

Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, 
swollen lips-tongue-uvula)

Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced 
PEF, hypoxemia)

Reduced BP or associated symptoms (e.g., hypotonia [collapse], syncope, 
incontinence)

Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting)
3.
Reduced BP after exposure to known allergen for that patient (minutes to several 
hours):

Infants and children: low systolic BP (age specific) or greater than 30% decrease 
in systolic BP

Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from 
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11.5.
Appendix 5: Cardiovascular Screening Questions
At screening each subject should be asked the following:
Unrelated to the symptoms you experience with your asthma:
1. Do you have any pain or discomfort (such as pressure) in your chest? 
h. If yes, does this pain/discomfort/pressure go to other areas of your body such as 
neck, jaw, throat, or down your arms (including a numbness feeling in your arm) 
when it occurs?
2. When you walk at an ordinary pace on a level surface does this produce chest 
pain? If yes, respond to a and b:
a. Does this chest pain or discomfort occur when you are not doing any activities 
such as resting in bed or sitting in a chair?  
b. Has this chest pain/discomfort been more frequent or more intense or last longer 
or come on with less exertion lately?
3. When you walk uphill or hurry does this produce chest pain/discomfort?
4. Do you use or have you been previously prescribed nitroglycerine to relieve the 
discomfort?  

If yes, have you needed to increase the number of pills or frequency of using the 
pills recently?
i.
If the subject responds “yes” to any of the above questions a study physician 
should further assess for the presence of undiagnosed or unrecognized angina 
when evaluating Exclusion Criterion 4.  
Subject responses will be entered into the eCRF.
 
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11.6.
Appendix 6: New York Heart Association Functional 
Classification of Congestive Heart Failure
CLASS
PATIENT SYMPTOMS
I
Patients with cardiac disease but resulting in no limitation of physical activity. 
Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea or 
anginal pain.
II
Patients with cardiac disease resulting in slight limitation of physical activity. 
They are comfortable at rest. Ordinary physical activity results in fatigue, 
palpitation, dyspnea or anginal pain
III
Patients with cardiac disease resulting in marked limitation of physical activity. 
They are comfortable at rest. Less than ordinary activity causes fatigue, 
palpitation, dyspnea or anginal pain
IV
Patients with cardiac disease resulting in inability to carry on any physical activity 
without discomfort. Symptoms of heart failure or the anginal syndrome may be 
present even at rest. If any physical activity is undertaken, discomfort increases
Adapted from American Heart Association, 2012
 
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11.7.
Appendix 7: Protocol Changes
Scope
This amendment applies to all sites
Protocol changes specified in Amendment No. 1 are summarized below:

To clarify that the rationale and objective of the study includes long-term provision 
of mepolizumab therapy to subjects who have severe asthma and participated in 
MEA112997

To clarify that only monoclonal antibodies are excluded, rather than all biologics

To clarify reason for more frequent safety monitoring at the start of the study 

To correct Inclusion criterion 5 from Randomisation Visit to Visit 2

To add exclusion criterion for significant cardiovascular disease

To correct inconsistencies between protocol text and the Time and Events Table

To correct bilirubin exclusion criterion at visit 2

To expand on requirements for designating a subject as lost to follow-up

To add visit window for the follow-up visit

To move baseline spirometry from the screen visit to the baseline visit

To clarify that all subjects will have an immunogenicity test 12 weeks after last dose

To correct Section 8.3.5.2 wording “Efficacy” to “Safety”

To add reference to support Appendix 6 and remove 3 references which are not cited 
in the protocol.

To add Appendix 5 and Appendix 6 and amended Section 6.1 and Section 6.3.9. to 
support the determination of exclusion criteria 4
Protocol Changes Amendment 1:
Section RATIONALE
Additional Text:
This trial also provides subjects who participated in the MEA112997 study, and meet the 
current trial eligibility criteria, the option of receiving treatment with mepolizumab, as an 
add-on to their standard of care treatment for severe asthma. 
 
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Section OBJECTIVES 
Additional Text:
To provide long-term treatment with mepolizumab to subjects who participated in 
MEA112997
Section STUDY DESIGN
Original Text:
Subjects will remain on standard of care asthma therapy, which may be adjusted during 
the study, at the discretion of their physician. The use of Xolair (omalizumab) or any 
other biologic will not be permitted during the course of the study. 
Subjects will be monitored in the clinic approximately every 4 weeks to assess adverse 
events and asthma status.  The Asthma Control Questionnaire-5 (ACQ) will be used to 
assist the investigator in assessing the subject’s asthma status along with spirometry at 
regular intervals.  As some subjects may have previously received placebo while 
participating in the MEA112997 study and are naive to mepolizumab, safety lab 
monitoring will be more frequent at the start of the study.  Appropriate safety labs will be 
drawn prior to starting treatment and then at week 4, 8, 12, 24, 36 and 48.  Thereafter, 
these will be collected every 24 weeks.  Labs will also be obtained at 12 weeks after 
discontinuing mepolizumab.  Subjects discontinuing mepolizumab treatment should be 
monitored for exacerbation of their asthma.
Serum samples for anti-mepolizumab antibody measurements will be obtained from all 
subjects at screen, week 4, 24 and 48 of the initial year, week 24 and 48 for every 
additional year, as well as at the Follow-up Visit. Any anti-mepolizumab antibody 
positive sample will be tested for neutralization antibody.
Revised Text
Subjects will remain on standard of care asthma therapy, which may be adjusted during 
the study, at the discretion of their physician. The use of Xolair (omalizumab) or any 
other monoclonal antibody will not be permitted during the course of the study. 
Subjects will be monitored in the clinic approximately every 4 weeks to assess adverse 
events and asthma status.  The Asthma Control Questionnaire-5 (ACQ) will be used to 
assist the investigator in assessing the subject’s asthma status along with spirometry at 
regular intervals.  As some subjects may have previously received placebo while 
participating in the MEA112997 study and are naive to mepolizumab, safety lab 
monitoring will be more frequent at the start of the study.  Appropriate safety labs will be 
drawn prior to starting treatment and then at week 4, 8, 12, 24, 36 and 48.  Thereafter, 
these will be collected every 24 weeks.  Labs will also be obtained at 12 weeks after 
discontinuing mepolizumab.  Subjects discontinuing mepolizumab treatment should be 
monitored for exacerbation of their asthma.
 
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Serum samples for anti-mepolizumab antibody measurements will be obtained from all 
subjects at  Weeks 0,4, 24 and 48 of the initial year, week 24 and 48 for every additional 
year, as well as at the Follow-up Visit. Any anti-mepolizumab antibody positive sample 
will be tested for neutralization antibody.
Section 1.2 Rationale
Added text:
This trial also provides subjects who participated in the MEA112997 study, and meet the 
current trial eligibility criteria, the option of receiving treatment with mepolizumab, as an 
add-on to their standard of care treatment for severe asthma. 
Section 2 Objectives:
Added Text:

To provide long-term treatment with mepolizumab to subjects who participated in 
MEA112997
Section 3.1 Study Design:
Original Text:
Subjects will remain on standard of care asthma therapy, which may be adjusted during 
the study, at the discretion of their physician. The use of Xolair (omalizumab) or any 
other biologic will not be permitted during the course of the study.  
Revised Text:
Subjects will remain on standard of care asthma therapy, which may be adjusted during 
the study, at the discretion of their physician. The use of Xolair (omalizumab) or any 
other monoclonal antibody will not be permitted during the course of the study.  
Original Text:
At each clinic visit, adverse events will be assessed, and appropriate safety labs will be 
obtained as per the Time and Events schedule (see Table 2 and Table 3).  As laboratory 
results have not been characterized when subjects reinstitute treatment with 
mepolizumab, safety lab monitoring will be more frequent at the start of the study.  
Exacerbations will also be reviewed at each clinic visit.
Revised Text
At each clinic visit, adverse events will be assessed, and appropriate safety labs will be 
obtained as per the Time and Events schedule (see Table 2 and Table 3).  As some 
subjects will be naive to mepolizumab, safety lab monitoring will be more frequent at 
the start of the study.  Exacerbations will also be reviewed at each clinic visit.
 
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Section 4.2 Inclusion Criteria:
Original Text:
A serum pregnancy test is required of all females. at the initial Screening Visit 
(Visit 1).  In addition, a urine pregnancy test will be performed for all females prior 
to randomisation, during each scheduled study visit prior to the injection of 
investigational product, and during the Follow-up Visit. 
Revised Text:
A serum pregnancy test is required of all females. at the initial Screening Visit 
(Visit 1).  In addition, a urine pregnancy test will be performed for all females prior 
toVisit 2, during each scheduled study visit prior to the injection of investigational 
product, and during the Follow-up Visit. 
Section 4.3 Exclusion Criteria:
Added Text:
4. Cardiovascular: Subjects who have severe or clinically significant 
cardiovascular disease uncontrolled with standard treatment. Including but not 
limited to:
a.
known ejection fraction of <30% OR
b. severe heart failure meeting New York Heart Association Class IV (see 
Appendix 6  classification OR
c.
hospitalised in the 12 months prior to Visit 1 for severe heart failure 
meeting New York Heart Association Class III (see Appendix 6) OR
d. angina diagnosed less than 3 months prior to Visit 1 or at Visit 1 
Section 4.5 Withdrawal Criteria:
Original Text:
Subjects are free to discontinue participation in the study at anytime. Every effort should 
be made to have the subject return for a Follow-up visit 12 weeks post last mepolizumab 
injection.
Subjects may also be withdrawn from this study if mepolizumab becomes commercially 
available in the respective country, marketing of mepolizumab is no longer being sought 
in the respective country, or upon decision of the sponsor to discontinue further 
development of mepolizumab.
The primary reason for withdrawal will be recorded in the eCRF and any data collected 
up until the point of withdrawal will be used in the data analyses. For those subjects that 
are lost to follow-up, every effort will be made to contact the subject to assure their 
safety. These efforts should be documented in the clinic notes at the site.
 
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Revised Text:
Subjects are free to discontinue participation in the study at anytime. Every effort should 
be made to have the subject return for a Follow-up visit 12 weeks post last mepolizumab 
injection. In those instances where the subject specifies the reason for withdrawal of 
consent, this information will be captured in the eCRF.
A subject should only be designated as lost to follow-up if the site is unable to 
establish contact with the subject after 3 documented attempts via 2 different 
methods (phone, text, e-mail, certified letter, etc). These efforts should be 
documented in the clinic notes at the site.
Subjects may also be withdrawn from this study if mepolizumab becomes commercially 
available in the respective country, marketing of mepolizumab is no longer being sought 
in the respective country, or upon decision of the sponsor to discontinue further 
development of mepolizumab.
The primary reason for withdrawal will be recorded in the eCRF and any data collected 
up until the point of withdrawal will be used in the data analyses. 
Section 5.7.2 Prohibited Medications:
Original Text:
Medication
Washout Time
Prior to Screening Visit
Investigational drugs
1 month or 5 half-lives whichever is 
longer
Omalizumab [Xolair] 
130 days
Other biologicals
5 half-lives
Experimental anti-inflammatory drugs (non biologicals)
3 months
Revised Text:
Medication
Washout Time
Prior to Screening Visit
Investigational drugs
1 month or 5 half-lives whichever is 
longer
Omalizumab [Xolair] 
130 days
Other monoclonal antibodies
5 half-lives
Experimental anti-inflammatory drugs (non biologicals)
3 months
Section 6 Study Assessments and Procedures:
Added Footnote:
6.
Follow-up visit window is 2 weeks
Moved initial sprirometry from screen visit to Visit 2 (Baseline)
 
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Section 6.1 Critical Baseline Assessments:
Original Text:

Cardiovascular medical history/risk factors will be assessed at baseline.
Revised Text:

Cardiovascular medical history/risk factors will be assessed at screening. This 
assessment must include a review of the subject responses to the 
cardiovascular assessment questions (See Appendix 5) and height, weight, 
blood pressure, medical conditions, and family history of premature 
cardiovascular disease.
Section 6.3.5: Cardiovascular Events
Added Text:
Investigators will be required to fill out event specific pages in the eCRF 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 thrombosis

Deep Venous Thrombosis

Revascularization
Cardiovascular events information should be recorded on the corresponding eCRF pages 
within one week of when the AE/SAE(s) are first reported.  Please refer to Section 6.3.9 
for timelines for reporting AE/SAEs.
Section 6.3.6: Death Events
In addition, all deaths will require completion of a specific death data collection page in 
the eCRF.  The death data collection page in the eCRF includes questions regarding 
cardiovascular (including sudden cardiac death) and non-cardiovascular death.
Death information should be recorded on the death eCRF page within one week of when 
the death is first reported.
Please refer to Section 6.3.9 for timelines for reporting SAEs.
 
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Section 6.3.9 Prompt Reporting of Serious Adverse Events and Other Events to 
GSK
Original Text:
Initial Reports
Follow-up Information on a Previous 
Report
Type of Event
Time Frame
Documents
Time Frame
Documents
All SAEs
24 hours
“SAE” data 
collection tool
24 hours
Updated “SAE” data 
collection tool
Revised Text:
Initial Reports
Follow-up Information on a Previous 
Report
Type of Event
Time Frame
Documents
Time Frame
Documents
All SAEs
24 hours
“SAE” data 
collection tool
24 hours
Updated “SAE” 
data collection tool
“CV events” 
and/or “death” 
data collection 
tool(s) 
Section 6.4 Immunogenicity:
Original Text:
For subjects who prematurely withdraw from the study, immunogenicity testing will 
occur at 12 weeks after the last dose.
Revised Text:
For all who prematurely withdraw from the study subjects, immunogenicity testing will 
occur at 12 weeks after the last dose.
Section 8.3.5.2 Safety Analyses:
Original Text:
All efficacy endpoints will be summarised using descriptive statistics. Further details will 
be provided in the RAP.
Revised Text:
All safety endpoints will be summarised using descriptive statistics. Further details will 
be provided in the RAP.
 
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Section 10 References:
Added text:
American Heart Association.  Classes of Heart Failure.  Available at: 
http://www.heart.org/HEARTORG/Conditions/HeartFailure/AboutHeartFailure/Classes-
of-Heart-Failure_UCM_306328_Article.jsp.  Accessed 14 August 2012.
Deleted text:
Dolan P, Cookson R. A qualitative study of the extent to which health gain matters when 
choosing between groups of patients. Health Policy 2000;51:19-30.
Flood-Page P, Swenson C, Faiferman I, Matthews J, Williams M, Brannick L, Robinson 
D, Wenzel S, Busse W, Hansel T and Barnes N. A study to evaluate safety and efficacy 
of mepolizumab in patients with moderate persistent asthma. Am J Resp Crit Care 
2007;176:1062-1071.
Haldar P, Brightling CE, Hargadon B, Gupta S, Monteiro W, Sousa A, Marshall RP, 
Bradding P, Green RH, Wardlaw AJ, Pavord ID. Mepolizumab and exacerbations of 
refractory eosinophilic asthma. N Engl J Med 2009;360:973-984.
 
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Section 11.5 Appendix 5
Added text:
Appendix 5 Cardiovascular Screening Questions
At screening each subject should be asked the following:
Unrelated to the symptoms you experience with your asthma:
1. Do you have any pain or discomfort (such as pressure) in your chest? 
a.
If yes, does this pain/discomfort/pressure go to other areas of your body such as 
neck, jaw, throat, or down your arms (including a numbness feeling in your arm) 
when it occurs?
2. When you walk at an ordinary pace on a level surface does this produce chest 
pain? If yes, respond to a and b:
a.
Does this chest pain or discomfort occur when you are not doing any 
activities such as resting in bed or sitting in a chair?  
b. Has this chest pain/discomfort been more frequent or more intense or last 
longer or come on with less exertion lately?
3.
When you walk uphill or hurry does this produce chest pain/discomfort?
4. Do you use or have you been previously prescribed nitroglycerine to relieve the 
discomfort?  

If yes, have you needed to increase the number of pills or frequency of using the 
pills recently?
b.
If the subject responds “yes” to any of the above questions a study physician 
should further assess for the presence of undiagnosed or unrecognized angina 
when evaluating Exclusion Criterion 4.  
Subject responses will be entered into the eCRF.
 
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Section 11.6 Appendix 6
Added Text:
Appendix 6 New York Heart Association Functional Classification of Congestive Heart 
Failure 
CLASS
PATIENT SYMPTOMS
I
Patients with cardiac disease but resulting in no limitation of physical activity. 
Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea or 
anginal pain.
II
Patients with cardiac disease resulting in slight limitation of physical activity. 
They are comfortable at rest. Ordinary physical activity results in fatigue, 
palpitation, dyspnea or anginal pain
III
Patients with cardiac disease resulting in marked limitation of physical activity. 
They are comfortable at rest. Less than ordinary activity causes fatigue, 
palpitation, dyspnea or anginal pain
IV
Patients with cardiac disease resulting in inability to carry on any physical activity 
without discomfort. Symptoms of heart failure or the anginal syndrome may be 
present even at rest. If any physical activity is undertaken, discomfort increases
Adapted from American Heart Association, 2012.
Appendix 7
Original Text:
1. Liver Function: Liver Function Tests at screening that meet any of the following: 

ALT ≥2 x ULN (upper limit of normal) 

AST ≥2 x ULN 

Alk Phos ≥2 x ULN 

Bilirubin ≥2 x ULN (isolated bilirubin ≥2 x ULN is acceptable if bilirubin is 
fractionated and direct bilirubin is <35%   
Revised Text:
5.
Liver Function: Liver Function Tests at screening that meet any of the following: 

ALT ≥2 x ULN (upper limit of normal) 

AST ≥2 x ULN 

Alk Phos ≥2 x ULN 

Bilirubin >1.5 x ULN (isolated bilirubin >1.5x ULN is acceptable if bilirubin is 
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Protocol Amendment Number 02
Scope: This amendment applies to all sites.
Protocol Changes specified in Amendment No. 2 are summarised below:

To add two additional immunogenicity sample assessment time points when the 
100mg vial is introduced. 

To allow other syringe sizes for study drug administration

To allow for study drug administration in the upper thigh or the arm

To add the prohibited non-drug therapies to Section 5.7.2

To list Adverse Events and Serious Adverse Events on the same line in Table 3

To correct a formatting error for Section 4.6

To remove specific test name for confirming Hepatitis C positive sample

To delete redundant text in Section 6.3.3.1

To remove from Section 6.3.7 the requirement to report outcome of pregnancy in 
female partners of male subjects

To include analyses of immunogenicity data in Section 8.3 and to clarify when 
interim analyses will be performed
Study Design:
Added Text:
A maximum of two additional anti-mepolizumab antibody samples will be obtained; one 
immediately prior to the first dose and the other prior to the second dose with the 100mg 
mepolizumab vial. If the first or second dose coincides with a visit where an 
immunogenicity sample is already required, it is not necessary to obtain an additional 
sample. 
Added Text:
All subjects will be dosed with the 250mg vial up until such time that the 100mg vial is 
available at the site and all regulatory/ethics approvals have been received.  Once the 
100mg vial is available at the site, all subjects will switch to dosing with 100mg vial.  
Subjects will then be dosed with the 100mg vial for the duration of the study.  
Section 4.6
Corrected formatting to add the Section number.
 
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Section 5.2 Dosage and Administration:
Original Text
Once the mepolizumab vial is reconstituted, 100 mg of mepolizumab should be drawn 
into a 1ml polypropylene syringe, and administered right away.
Revised Text:
Once the mepolizumab vial is reconstituted, 100 mg of mepolizumab should be drawn 
into a polypropylene syringe, and administered right away.
Section 5.3 Treatment Assignment:
Original Text:
All subjects will receive 100 mg of mepolizumab administered subcutaneously into the 
upper arm approximately every 4 weeks.  
Revised Text:
All subjects will receive 100 mg of mepolizumab administered subcutaneously into the 
upper thigh or the back of the upper arm approximately every 4 weeks.  
Section 5.7.2 Prohibited Medications and Non-Drug Therapies
Added Text:
Additionally, Bronchial Thermoplasty and Radiotherapy are excluded for 12 months 
prior to Visit 1 and for the duration of the study.  Neither CPAP nor oxygen therapy may 
be initiated after Visit 1.
Time and Events For First Year Table 2:
Original Text:
Hepatitis B Surface Antigen and Hepatitis C antibody ( if Hepatitis C antibody positive, a hepatitis C RIBA should be 
automatically performed on the same sample to confirm the result)
Revised Text:
Hepatitis B Surface Antigen and Hepatitis C antibody ( if Hepatitis C antibody positive, a hepatitis C confirmatory test 
should be automatically performed to confirm the result)
Added Text:
* Take additional immunogenicity sample prior to first dose with 100mg vial and prior to the second dose with the 
100mg vial
 
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Table 3 Time and Events Table for Additional Years:
Original Text:
Adverse Events
Revised Text:
Adverse Events/SAEs
Added Text:
* Take additional immunogenicity sample prior to first dose with 100mg vial and prior to the second dose with the 
100mg vial. Maximum of 2 additional samples
Section 6.3.3.1 Definition of an AE
Deleted Text:
The signs and symptoms and/or clinical sequelae resulting from lack of efficacy will be 
reported if they fulfill the definition of an AE or SAE.  Also, “lack of efficacy” or 
“failure of expected pharmacological action” also constitutes an AE or SAE.
Deleted Text:
Section 6.3.7 Pregnancy:
In addition, the investigator must attempt to collect pregnancy information on any female 
partners of male study subjects who become pregnant while the subject is enrolled in the 
study.  Pregnancy information must be reported to GSK as described above.
Section 6.4 Immunogenicity
Added Text:
Two additional anti-mepolizumab antibody samples will be obtained;   One prior to the 
first dose and the other prior to the second dose with the 100mg mepolizumab vial. 
Original Text:
Section 8.3.4 Interim Analysis
Interim analysis will be performed on an annual basis and at other times as needed in 
order to provide open-label safety data to inform the risk-benefit assessment of 
mepolizumab in severe asthma.
Revised Text:
Interim analysis will be performed as needed in order to provide open-label safety data to 
inform the risk-benefit assessment of mepolizumab in severe asthma.
 
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Original Text:
Section 8.3.5.3 Health Outcome Analyses
No health outcomes endpoints are defined for this study.
Revised Text:
Section 8.3.5.3 Immunogenicity Analyses
All immunogenicity endpoints will be summarised using descriptive statistics. The 
number and percentage of subjects with positive neutralizing antibodies before and after 
the introduction of the 100mg mepolizumab vial will be tabulated. Further details will be 
provided in the RAP.
Deleted Text:
Section 8.3.5.4 Pharmacodynamic Analyses
No pharmacodynamic endpoints are defined for this study.
Appendix 7 Amendment 01
Added Text:
Appendix 7
Original Text:
2. Liver Function: Liver Function Tests at screening that meet any of the following: 

ALT ≥2 x ULN (upper limit of normal) 

AST ≥2 x ULN 

Alk Phos ≥2 x ULN 

Bilirubin ≥2 x ULN (isolated bilirubin ≥2 x ULN is acceptable if bilirubin is 
fractionated and direct bilirubin is <35%   
Revised Text:
2.
Liver Function: Liver Function Tests at screening that meet any of the following: 

ALT ≥2 x ULN (upper limit of normal) 

AST ≥2 x ULN 

Alk Phos ≥2 x ULN 

Bilirubin >1.5 x ULN (isolated bilirubin >1.5x ULN is acceptable if bilirubin is 
fractionated and direct bilirubin is <35%)
 
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Protocol Amendment Number 03 Changes
Scope: This amendment applies to all sites.
Protocol Changes specified in Amendment No. 3 are summarised below:
Change No. 1: To change the Follow-up visit from 12 weeks to 4 weeks post last dose of 
IP. This occurs in multiple sections of the protocol listed below.  The rationale is that the 
original reason for the Follow-up visit was to collect the final immunogenicity sample 12 
weeks after the last dose of IP.  The sensitivity of the immunogenicity test has since 
improved and the immunogenicity sample at the Exit visit is now sufficient.   
Study Design
Original text: 
Labs will also be obtained at 12 weeks after discontinuing mepolizumab.  
Changed to:
Labs will also be obtained at 4 weeks after discontinuing mepolizumab.  
Additional paragraph added to Study Design and to Section 3.1 Study Design:
The study closure process will begin, on a country by country basis, as mepolizumab 
becomes commercially available for prescription.  Please see the SPM for more details.
Section 4.5 Withdrawal Criteria
Original text:
Every effort should be made to have the subject return for a Follow-up visit 12 weeks 
post last mepolizumab injection.
Changed to:
Every effort should be made to have the subject return for a Follow-up visit 4 weeks post 
last mepolizumab injection.
Section 6 Table 2 Study Assessments and Procedures, column header
Original text:
Follow-up 12 weeks post last injection
Changed to:
Follow-up 4 weeks post last injection
 
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Section 6 Study Assessments and Procedures (Footnote No. 6)
Original text:
6.  Follow-up visit window is 2 weeks
Changed to:
6.  Follow-up visit window is 1 weeks
Section 6 Table 3 Study Assessments and Procedures, column header
Original text:
Follow-up 12 weeks post last injection
Changed to:
Follow-up 4 weeks post last injection
Section 6 Table 3 Study Assessments and Procedures (Footnote No. 4)
Original text:
4.  Follow-up visit window is 2 weeks
Changed to:
4.  Follow-up visit window is 1 weeks
Section 6.3.8 Time Period and Frequency of Detecting AEs and SAEs
Original text: 
AEs will be collected from the start of investigational product (Visit 2) and until the 
follow up visit (12 weeks after the last injection).
Changed to:
AEs will be collected from the start of investigational product (Visit 2) and until the 
follow up visit (4 weeks after the last injection).
Section 6.4 Immunogenicity
Original text: 
For all subjects, immunogenicity testing will occur at 12 weeks after the last dose.
Changed to:
For all subjects, immunogenicity testing will occur at 4 weeks after the last dose.
 
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Change No. 2: To update the time limit from reconstitution to administration of IP
Section 5.2 Dosage and Administration
Original text:
Once the mepolizumab vial is reconstituted, 100 mg of mepolizumab should be drawn 
into a polypropylene syringe, and administered right away.
Changed to:
Once the mepolizumab vial is reconstituted, 100 mg of mepolizumab should be drawn 
into a polypropylene syringe, and administered according to the instructions in the SPM.
 
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Division: World Wide Development
Retention Category: GRS019
Information Type: Reporting and Analysis Plan
Title:
Reporting and Analysis Plan for MEA115666: A multi-centre, 
open-label, long term safety study of mepolizumab in asthmatic 
subjects who participated in the MEA112997 trial.
Compound Number:
SB-240563
Effective Date:
06-APR-2017
Reporting and Analysis Plan Amendment Number: 01
Description: This study will provide long term safety and immunogenicity data when 
mepolizumab is administered subcutaneously (SC) to subjects with severe, refractory 
asthma with a history of eosinophilic inflammation. Additionally, this study will inform 
on the safety and immunogenicity profile when mepolizumab therapy is reinstituted in 
subjects following a cessation in drug therapy.
Safety will be assessed by adverse events, clinical laboratory samples, ECGs,
immunogenicity and vital signs. 
Additional assessments are included to evaluate the effects of mepolizumab on a range of 
clinical markers of asthma control.
Subject: Severe refractory asthma, mepolizumab, eosinophils, SB-240563, extension
study, safety
Author’s Name and Functional Area: 
03-APR-2017
Statistician, Clinical Statistics, Quantitative Sciences
Final Approval:
Approved via email by
Director, 
Clinical Statistics
06-APR-2017
Copyright 2017 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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Agreed by Core RAP team (via e-mail): 
Project Physician Lead, 
Respiratory Therapeutic Unit
Clinical Investigation Leader, 
Respiratory Therapeutic Unit
Director, 
Safety Evaluation & Risk Management
Manager, 
Clinical Programming
 
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TABLE OF CONTENTS
PAGE
ABBREVIATIONS ...........................................................................................................6
1.
INTRODUCTION......................................................................................................8
1.1.
Revision Chronology.....................................................................................8
2.
STUDY OBJECTIVE(S) AND ENDPOINT(S) ...........................................................8
2.1.
Study Objective(s) ........................................................................................8
2.1.1.
Primary Objective ..........................................................................8
2.1.2.
Secondary Objectives....................................................................9
2.2.
Study Endpoint(s) .........................................................................................9
2.2.1.
Primary Endpoint ...........................................................................9
2.2.2.
Secondary Endpoints.....................................................................9
2.3.
Statistical Hypotheses...................................................................................9
3.
STUDY DESIGN ......................................................................................................9
4.
PLANNED ANALYSES ..........................................................................................11
4.1.
Interim Analyses .........................................................................................11
4.1.1.
Independent Data Monitoring Committee.....................................11
5.
SAMPLE SIZE CONSIDERATIONS.......................................................................13
5.1.
Sample Size Assumptions ..........................................................................13
6.
ANALYSIS POPULATIONS ...................................................................................13
7.
TREATMENT COMPARISONS..............................................................................13
7.1.
Data Display Treatment and Other Sub-group Descriptors .........................14
8.
GENERAL CONSIDERATIONS FOR DATA ANALYSES.......................................15
8.1.
Multicentre Studies .....................................................................................15
8.2.
Other Strata and Covariates .......................................................................15
8.3.
Examination of Subgroups..........................................................................15
8.4.
Multiple Comparisons and Multiplicity .........................................................16
9.
DATA HANDLING CONVENTIONS .......................................................................16
9.1.
Withdrawal and Missing Data......................................................................16
9.1.1.
Screening and Enrollment............................................................16
9.1.2.
Missing Data................................................................................16
9.2.
Derived and Transformed Data...................................................................16
9.2.1.
Definition of Baseline and Change from Baseline ........................16
9.2.2.
Exacerbations within MEA115666 ...............................................17
9.2.3.
Annualised Rate of Exacerbations in the Interval Between 
Studies ........................................................................................17
9.2.4.
Percent Predicted FEV1 ...............................................................18
9.2.5.
12-Lead ECG...............................................................................18
9.2.6.
Log Transformed Data.................................................................18
9.3.
Assessment Windows.................................................................................18
9.3.1.
On-Treatment Exacerbations.......................................................18
9.3.2.
On-Treatment Phase ...................................................................19
 
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9.3.2.1.
Mepolizumab Drug Product 1 Period ..........................19
9.3.2.2.
Mepolizumab Drug Product 2 Period ..........................19
9.4.
Values of Potential Clinical Importance.......................................................20
9.5.
Adverse Events...........................................................................................20
9.5.1.
Exposure Adjusted Adverse Events.............................................20
10. STUDY POPULATION...........................................................................................20
10.1.
Disposition of Subjects................................................................................20
10.2.
Protocol Deviations.....................................................................................21
10.3.
Demographic and Baseline Characteristics.................................................21
10.3.1.
Demography and Race................................................................21
10.3.2.
Medical Conditions ......................................................................21
10.3.3.
Cardiovascular Assessment.........................................................21
10.3.4.
Since Completion of MEA112997 ................................................21
10.3.5.
Baseline Lung Function Tests......................................................22
10.4.
Treatment Compliance................................................................................22
10.5.
Concomitant Medications............................................................................22
11. EFFICACY ANALYSES..........................................................................................22
11.1.
Annualised Rate of Exacerbations ..............................................................23
11.2.
Time to First Exacerbation ..........................................................................23
11.3.
Asthma Control Questionnaire Score..........................................................23
11.4.
FEV1 Measured by Clinic Spirometry ..........................................................23
11.5.
Blood Eosinophils .......................................................................................23
12. SAFETY ANALYSES .............................................................................................24
12.1.
Extent of Exposure .....................................................................................24
12.2.
Adverse Events...........................................................................................24
12.3.
Adverse Events of Special Interest .............................................................25
12.4.
Deaths and Serious Adverse Events...........................................................27
12.5.
Adverse Events Leading to Discontinuation of Investigational 
Product and/or Withdrawal from the Study and Other Significant 
Adverse Events...........................................................................................28
12.6.
Cardiovascular Events of Interest ...............................................................28
12.7.
Pregnancies (as applicable)........................................................................29
12.8.
Clinical Laboratory Evaluations...................................................................29
12.9.
Liver Events................................................................................................29
12.10. Vital Signs...................................................................................................30
12.11. 12-lead ECG...............................................................................................30
12.12. Immunogenicity...........................................................................................30
13. HEALTH OUTCOMES ANALYSES........................................................................32
13.1.
Resource Utilisation Measures ...................................................................32
14. CLINICAL PHARMACOLOGY DATA ANALYSES..................................................32
15. BIOMARKER DATA ANALYSIS.............................................................................32
16. PHARMACOGENETIC DATA ANALYSES.............................................................32
17. REFERENCES.......................................................................................................33
18. ATTACHMENTS ....................................................................................................34
 
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18.1.
Table of Contents for Data Display Specifications.......................................34
18.1.1.
Study Population Tables..............................................................34
18.1.2.
Study Population Figures.............................................................35
18.1.3.
Study Population Listings.............................................................35
18.1.4.
Efficacy Tables ............................................................................36
18.1.5.
Efficacy Figures ...........................................................................36
18.1.6.
Efficacy Listings...........................................................................36
18.1.7.
Safety Tables...............................................................................36
18.1.8.
Safety Figures .............................................................................40
18.1.9.
Safety Listings .............................................................................40
18.1.10. Health Outcomes Tables .............................................................42
18.2.
Data Display Specifications ........................................................................42
18.3.
Laboratory Potential Clinical Concern Values .............................................43
 
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ABBREVIATIONS
ACQ
Asthma Control Questionnaire
ADA
Anti-drug antibody
AE
AESI
Adverse event
Adverse events of special interest
ALT
Alanine transaminase
ASE
All Subjects Enrolled
AT
As Treated
ATC
Anatomical Therapeutic Chemical
CEC
Clinical Endpoint Committee
CI
Confidence Interval
CS
Corticosteroid
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
ED
Emergency Department
FEV1
Forced expiratory volume in 1 second
FVC
Forced vital capacity
GSK
GlaxoSmithKline
IDMC
Independent Data Monitoring Committee
IgE
Immunoglobulin E
IM
Intramuscular
IV
Intravenous
LFT
Liver function test
LLQ
Lower Limit of Quantification
MDP1
Mepolizumab Drug Product 1
MDP2
Mepolizumab Drug Product 2
MedDRA
Medicinal dictionary for regulatory activities
mg
Milligram
mL
Millilitres
N
Number of subjects in the treatment group
n
Number of subjects with non-missing values
NAb
Neutralising antibody
NHANES
National Health and Nutrition Examination Survey
OCS
Oral corticosteroids
OLE
Open label extension (study)
PI
Principal Investigator
PT
Preferred Term
QTc(B)
QT interval corrected by Bazett's method
QTc(F)
QT interval corrected by Fridericia's method
RAP
Reporting and Analysis Plan
RUCAM
Roussel Uclaf Causality Assessment Method
SAE
Serious adverse event
SC
Subcutaneous
SD
Standard Deviation
SE
Standard Error
SDAC
Statistical Data Analysis Centre
SOC
System Organ Class
 
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Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
SAS
Xolair
 
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1.
INTRODUCTION
The purpose of the data analyses outlined in this Reporting and Analysis Plan (RAP) is to 
evaluate the safety, immunogenicity and effectiveness of treatment with 100mg
mepolizumab administered subcutaneously (SC) every 4 weeks in subjects with severe,
uncontrolled refractory asthma.
This RAP is based on Section 8 (Data Analysis and Statistical Considerations) of the 
MEA115666 study protocol issued 06-Mar-2013 (GlaxoSmithKline Document Number
2012N139436_02) and is intended for use by the Statistics & Programming Department.  
The data analyses produced will be used in a Clinical Study Report.
1.1.
Revision Chronology
RAP Section
Amendment Details
Original Reporting and Analysis Plan Effective date: 20-AUG-2013
Reporting and Analysis Plan Amendment 1 Effective date: 06-APR-2017
Amendments 

Inserted additional outputs to summarise the Adverse Events of Special Interests as agreed 
within the Program Safety Analysis Plan (PSAP)  

Inserted additional table of protocol deviations 

Clarified that the most frequent on-treatment AEs will be defined as AEs with frequency ≥3% 
and not ≥2%

Inserted additional tables and listings of subjects with emergent hepatobiliary laboratory 
abnormalities and an additional listing of all clinical chemistry results for subjects who meet the
liver event criteria

Removed a listing of urinanalysis results as no such data is collected in this study
2.
STUDY OBJECTIVE(S) AND ENDPOINT(S)
2.1.
Study Objective(s)
2.1.1.
Primary Objective
The primary objective of this study is to describe the long-term safety profile of 
mepolizumab.
 
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2.1.2.
Secondary Objectives

To provide long-term treatment with mepolizumab to subjects who participated in
MEA112997.

To evaluate the effects of mepolizumab on a range of clinical markers of asthma
control.
2.2.
Study Endpoint(s)
2.2.1.
Primary Endpoint

Adverse Events (AEs) including both systemic (i.e. allergic/IgE-mediated and 
non-allergic) and local site reactions.
2.2.2.
Secondary Endpoints

Frequency of positive anti-mepolizumab binding antibodies and neutralising 
antibodies

Annualised rate of exacerbations

Asthma Control Questionnaire (ACQ) score

Forced expiratory volume in 1 second (FEV1) as measured by clinic spirometry

Number of withdrawals due to lack of efficacy

Number of withdrawals due to adverse events

Number of hospitalizations due to adverse events including asthma exacerbations

Frequency of both systemic (i.e., allergic/IgE-mediated and non-allergic) and 
local site reactions

12-Lead Electrocardiogram (ECG) to derive the following endpoints:
o
Mean change from baseline in the QTc(F) (QT interval corrected by 
Fridericia's method)
o
Mean change from baseline in QTc(B) (QT interval corrected by Bazett's 
method)
o
Maximum change from baseline for QTc(F) and QTc(B).

Vital signs

Clinical Laboratory Parameters
2.3.
Statistical Hypotheses
Because the study has a single treatment arm, statistical analyses of treatment effect will
not be performed. Therefore no hypotheses have been defined for this study.
3.
STUDY DESIGN
This is a multi-centre, open-label, long term, safety study of 100mg mepolizumab 
administered subcutaneously in addition to standard of care in subjects with severe, 
refractory asthma and a history of eosinophilic inflammation. Subjects who participated 
in the MEA112997 trial will be offered the opportunity to consent for this study. All 
subjects will have experienced a gap of at least 10 months since receiving their last 
double-blind study medication in MEA112997.
 
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At Visit 1 subjects will undergo an initial screening to assess their eligibility to 
participate in this study. This screening will include: informed consent, vital signs, update 
of medical history, immunogenicity status based on MEA112997 data, smoking status, 
prior monoclonal antibody use, and exacerbations post completion of MEA112997. 
Subjects meeting the Visit 1 eligibility criteria will enter the run-in period. The purpose 
of the run-in period is to allow for receipt and review of lab results and the ECG over-
read. Visit 2 will mark the end of the run-in period.
Those subjects meeting all the inclusion criteria and none of the exclusion criteria will
receive their first mepolizumab dose at Visit 2. Subjects will continue to receive
mepolizumab SC injections approximately every 4 weeks until either:

The risk/benefit profile for the subject is no longer positive in the opinion of the
investigator or

the subject’s physician withdraws the subject or

the subject withdraws consent or

the sponsor discontinues development of mepolizumab or

the sponsor discontinues the study in the relevant participating country or

mepolizumab becomes commercially available in the relevant participating
country
During the trial the vial strength used when dosing will be changed for most subjects, 
however this will depend on the timing of regulatory approval. The 100mg dose of 
mepolizumab will be reconstituted from a vial of 250mg/vial strength up until such time 
that the 100mg/vial strength is available at the site. Once the 100mg/vial strength is
available at the site, all subjects will be dosed with 100mg mepolizumab reconstituted 
from the 100mg/vial strength at their next treatment visit and for the remainder of the 
study. This change of vial strength will be when subjects are transitioned onto the new 
drug product. Hereafter, the 250mg/vial strength will be referred to as mepolizumab drug 
product 1 (MDP1) and the 100mg/vial strength (to which subjects will transition) will be 
referred to as mepolizumab drug product 2 (MDP2). In the case that MDP2 is not 
approved for use by ethics/regulatory at a local site/country subjects will continue to be 
dosed with MDP1.
Subjects will remain on standard of care asthma therapy, which may be adjusted during 
the study, at the discretion of their physician. The use of Xolair (omalizumab) or any 
other monoclonal antibody will not be permitted during the course of the study.
Subjects will be monitored in the clinic approximately every 4 weeks to assess adverse 
events and asthma status. The Asthma Control Questionnaire-5 (ACQ) will be used to 
assist the investigator in assessing the subject’s asthma status along with spirometry at 
regular intervals. Exacerbations will also be reviewed at each clinic visit. As some 
subjects may have previously received placebo while participating in the MEA112997 
trial and are naive to mepolizumab, safety lab monitoring will be more frequent at the 
start of the study. Appropriate safety labs will be drawn prior to starting treatment and 
then at week 4, 8, 12, 24, 36 and 48. Thereafter, these will be collected every 24 weeks. 
Labs will also be obtained at 12 weeks after discontinuing mepolizumab. Subjects 
 
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discontinuing mepolizumab treatment should be monitored for exacerbation of their 
asthma.
Serum samples for anti-mepolizumab antibody measurements will be obtained from all
subjects at Weeks 0, 4, 24 and 48 of the initial year, week 24 and 48 for every additional
year, as well as at the Follow-up Visit. Any anti-mepolizumab antibody positive sample
will be tested for neutralising antibody.
A maximum of two additional anti-mepolizumab antibody samples will be obtained; one
immediately prior to the first dose and the other prior to the second dose with MDP2. If
the first or second dose coincides with a visit where an immunogenicity sample is already 
required, it is not necessary to obtain an additional sample.
4.
PLANNED ANALYSES
4.1.
Interim Analyses
At a date agreed by the study team a data look will be performed on a subset of the data. 
The aim of the data look is solely to ensure that all of the required tables, figures and 
listings are being produced and formatted correctly, such that the output produced at the 
planned analysis date is correct and complete.
Interim analyses will be performed as needed in order to provide open-label safety data to 
inform the risk-benefit assessment of mepolizumab in severe asthma. Specifically, an 
interim analysis will be performed to support the initial regulatory filing of mepolizumab.
A second interim will also be performed to support any possible safety updates following 
these submissions.
At each interim a ‘cut’ will be made in the data, where any data collected beyond a pre-
specified cut-off date will not be included within the datasets to be reported. See Section 
10, Section 11, Section 12, Section 13 and Section 14 for details of all planned analyses 
at these interims.
This analysis will be performed by the study statistics and programming team and not by 
the SDAC described below who solely support the phase III programme IDMC.  The 
safety results from this interim analysis will be reviewed by the internal GSK 
mepolizumab safety review team. 
Access to the results from this interim analysis will not be confidential.  Specifically the 
results may be provided to the study team, GSK governance boards, external 
investigators and to regulatory authorities.
4.1.1.
Independent Data Monitoring Committee
An Independent Data Monitoring Committee (IDMC) will be utilised in this study to 
ensure external objective review of safety issues in order to protect the ethical and safety 
interests of subjects and to protect the scientific validity of the study. The IDMC will 
review cardiovascular adverse events and all cause mortality from the following studies 
 
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in the Mepolizumab Severe Asthma Phase III Program: MEA115575; MEA115588; 
MEA115666 (this study); MEA115661.
The unblinded statistical analyses will be performed by an independent Statistical Data 
Analysis Centre (SDAC) at Duke University, North Carolina. Unblinded results will not 
be made available to the study team: The SDAC will communicate directly with the 
IDMC, and IDMC recommendations will be made to a primary contact who is external to 
the mepolizumab study team(s) at GSK. See IDMC Charter (available on request).
Stopping guidelines will be based on comparing event rates between mepolizumab and 
placebo in the two double-blind trials MEA115588 and MEA115575.  The two open 
label studies do not include any comparator data and therefore are not part of the formal 
stopping guidelines.
Two event rates will be considered:
a)
SAEs (including deaths) adjudicated to be cardiovascular events in nature;
b)
all cause mortality.
Analysis will be performed based on a meta-analysis of the two studies. For the purposes
of the analysis, the two mepolizumab treatment arms (75mg IV and 100mg SC) in study 
MEA115588 will be combined to produce an overall event rate for mepolizumab in that 
study. Event rates will be compared between mepolizumab and placebo using the Peto 
odds ratio test. An estimate and 99% CI will be produced for the odds ratio for 
experiencing an event on mepolizumab compared to placebo.
Non-binding statistical stopping guidelines of p<0.01 two-sided will be used for a) the 
analysis of SAEs deemed cardiovascular in nature and b) analysis of all cause mortality. 
Occurrence of either of these flags would signal further examination of available data by 
the IDMC, with consideration of altering the conduct of either of the studies or 
terminating either of the studies.  
This statistical analysis will be conducted once 8 subjects in the two double blind studies 
have experienced SAEs adjudicated to be cardiovascular in nature. The timings of further 
statistical analyses after the first analysis will be determined by the IDMC.
There are no circumstances under which IDMC review of the data would lead to a 
recommendation to stop for efficacy of mepolizumab. Therefore no adjustment to the 
final alpha level for efficacy will be made based on the safety stopping guidelines.
For full details of the analyses to be provided to the IDMC by the SDAC see the IDMC 
statistical analysis plan (available on request).
 
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5.
SAMPLE SIZE CONSIDERATIONS
5.1.
Sample Size Assumptions
There is no sample size calculation for this study. The sample size will be determined by 
the number of available subjects who were randomised into the MEA112997 trial and are 
eligible for the current study based on inclusion and exclusion criteria.
6.
ANALYSIS POPULATIONS
The following analysis populations will be derived as required:
All Subjects Enrolled Population
The All Subjects Enrolled (ASE) population will comprise all subjects for whom a record 
exists on the study database. This population will be used for summarising pre-treatment 
SAEs, listing AEs and summarising reasons for screen and run-in failures.
As Treated Population
The As Treated (AT) population will consist of all subjects who received at least one 
dose of open label mepolizumab. This population will be the primary population for all
summaries of efficacy and safety measures.
7.
TREATMENT COMPARISONS
Due to this study having a single treatment arm, statistical analyses of treatment effect
will not be performed. However, there are two comparisons which are of interest:
1) Reintroduction of mepolizumab vs. first time exposure: Adverse events and 
immunogenicity data collected during the first 6 months of treatment within 
MEA115666 will be summarised by treatment assigned within MEA112997. This 
is to assess whether subjects present differing responses to treatment dependant 
on whether they are being reintroduced to mepolizumab or this is their first time 
exposed to the drug (See Figure 1 and Table 1).
 
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Figure 1
Presentation of Data According to Subject’s Former Treatment
2) Change in drug product: Adverse events, immunogenicity and blood eosinophil 
data will be compared before and after the change in drug product of 
mepolizumab to investigate whether there is a difference on the safety or efficacy 
profile following the transition to the new drug product (See Figure 2).
Figure 2
Presentation of Data by Drug Product
7.1.
Data Display Treatment and Other Sub-group Descriptors
In the data displays the treatment groups will be identified as described in Table 1. All 
subjects will be presented within the single treatment group of ‘Mepolizumab 100mg 
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Table 1
Treatment Group Identifiers
Treatment Group
Descriptor
Mepolizumab 100mg SC every 4 weeks
Mepolizumab 100mg SC
8.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
Programming will be performed in a HARP environment using SAS Version 9 or a later 
release.
Summary tables will include N, the number of subjects in the treatment group, and n, the 
number of subjects with non-missing values.
8.1.
Multicentre Studies
Centres will be grouped into regions. The following regions are defined:

USA

European Union (France, Germany, Poland, Romania, UK)

Europe Non-EU (Russia, Ukraine)

South America (Argentina, Chile)

Rest of World (Australia, Canada, Korea)
The variable CENTREID will be used to identify investigators.
8.2.
Other Strata and Covariates
A covariate for region as described above will be included in all model-based analyses. 
Terms for baseline disease severity (as baseline % predicted pre-bronchodilator FEV1), 
the annualised rate of exacerbations in the interval between the MEA112997 trial and the 
screening visit of this study (as an ordinal variable: 0.0-<1.0, 1.0-<2.0, 2.0-<3.0, 3.0-
<4.0, ≥4, See Section 9.2.3) and time on-treatment (as an offset variable) will also be 
included when estimating the annualised rate of exacerbations.
If there are insufficient subjects in each region or exacerbation rate category for the 
statistical procedures to converge satisfactorily, further combining of these covariates
will be considered.
8.3.
Examination of Subgroups
Tabulations of adverse events, immunogenicity and blood eosinophil data will also be 
reproduced by drug product administered in order to investigate whether there is a 
differential effect of the two drug products used within the trial (See Section 12 and 
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The annualised rate of exacerbations will also be estimated according to blood eosinophil 
level of ≥150/μL or <150/μL at baseline within MEA115666.
8.4.
Multiple Comparisons and Multiplicity
Not applicable.
9.
DATA HANDLING CONVENTIONS
Details of key definitions and data handling conventions are detailed below as 
appropriate.
9.1.
Withdrawal and Missing Data
9.1.1.
Screening and Enrollment
A subject is considered a Screen Failure if he/she has been assigned a subject identifier 
but does not continue in the study beyond Visit 1 (Screening). A subject is considered a 
Run-in Failure if he/she is not a Screen Failure and entered the run-in period, but was not 
dosed with mepolizumab.
9.1.2.
Missing Data
The primary reason for withdrawal will be recorded in the electronic case report form
(eCRF) and any data collected up until the point of withdrawal will be used in the data 
analyses. No imputation will be performed if a subject drops out of the study for any 
reason, or is lost to follow-up, and their response is unknown.
9.2.
Derived and Transformed Data
9.2.1.
Definition of Baseline and Change from Baseline
The baseline values for each assessment will be the Visit 2 pre-dose assessment. If a 
value is missing at Visit 2 then the value recorded at Visit 1 (Screening) will be used as 
the baseline.
For ECG, clinical chemistry and haematology assessments not scheduled for collection at 
Visit 2, the baseline value will be that recorded at Visit 1 (Screening).
Generally change from baseline will be defined as the difference between the value of the 
endpoint at the time point of interest and the baseline value. However, if stated below, a 
change from baseline analysis may be performed on the ratio scale and change from 
baseline will be the ratio: time point of interest value/baseline value.
 
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9.2.2.
Exacerbations within MEA115666
Exacerbations of asthma will be defined as worsening of asthma which requires use of 
systemic corticosteroids1 and/or hospitalisation and/or Emergency Department (ED) 
visits.
1For all subjects, IV or oral steroid (e.g., prednisone) for at least 3 days or a single IM 
CS dose is required. For subjects on maintenance systemic corticosteroids, at least 
double the existing maintenance dose for at least 3 days is required.
The on-treatment collection period for exacerbations will be defined as being from Visit 
2 until either the date of the data collection cut-off or the date of withdrawal inclusive 
(but no greater than 4 weeks post last study dose received), See Section 9.3.1. For 
consistency, exacerbations separated by less than 7 days will be treated as a continuation 
of the same exacerbation. 
It should be noted that exacerbations recorded in the eCRF will not be verified using 
eDiary data to confirm that the exacerbation was associated with changes in peak flow, 
rescue medication use, nocturnal awakening due to asthma symptoms requiring rescue 
medication use or symptoms. However, 96% of exacerbations captured within
MEA112997 met the protocol-defined exacerbation criteria, and only in 4% of the cases 
were the site/PI not able to provide any objective data to justify the use of corticosteroids.
9.2.3.
Annualised Rate of Exacerbations in the Interval Between
Studies
The annualised rate of exacerbations in the gap between the MEA112997 trial and the 
screening visit of this study will be calculated as:
For those subjects that completed the study: 
For those subjects that withdrew from the trial early:
This rate will be derived and then categorised as explained in Section 8.2. A value of 
365.25 represents the average number of days in a year.
It should be noted that the number of exacerbations reported between the completion of 
MEA112997 and screening of MEA115666 is self-reported and not subject to 
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9.2.4.
Percent Predicted FEV1
The predicted normal FEV1 is based on the NHANES III equations [Hankinson, 1999] 
and [Hankinson, 2010]. If a subject is recorded as having Hispanic or Latino ethnicity
then the Mexican-American equation will be used (irrespective of race). Otherwise, if a 
subject is recorded as being African-American/African Heritage race, then the African-
American equation will be used, similarly if a subject is recorded as being of Asian race, 
then the Asian equation will be used. Otherwise the Caucasian equation is used.
9.2.5.
12-Lead ECG
‘Maximum post-baseline’ QTc(F) and QTc(B) values will be derived as the maximum 
value recorded at any scheduled or unscheduled visit during the treatment period. 
9.2.6.
Log Transformed Data
Where log-transformed data are used, then summary statistics for these endpoints will 
include geometric mean, and a measure of spread (SD or SE) on the natural log scale. 
Values of zero will be imputed as 0.005 for that measure prior to the log transformation. 
9.3.
Assessment Windows
Clinic visits are scheduled to take place as specified in the protocol. Measurements 
outside visit windows will not be excluded from analyses on any population.
If a subject withdraws at a scheduled visit, and these data were scheduled to be collected 
at that visit, the data will be summarised and analysed (as appropriate) together with data 
from subjects who did not withdraw.
If a subject withdraws at a scheduled visit at which these data were not scheduled to be 
collected, or if a subject withdraws between scheduled visits, data will be slotted to the 
next visit.
9.3.1.
On-Treatment Exacerbations
In order to model the annualised rate of exacerbations, the reporting period for 
exacerbations will be as follows:
For subjects remaining in the study:
(Data collection cut-off date) – (Visit 2 date) + 1.
For early withdrawals: 
(Date of withdrawal) – (Visit 2 date) + 1.
The on-treatment collection period for exacerbations will be defined as being from Visit 
2 until either the date of the data collection cut-off or the date of withdrawal inclusive 
(but no greater than 4 weeks post last study dose received). 
 
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9.3.2.
On-Treatment Phase
The on-treatment phase for any purpose except the classification of exacerbations is 
defined as being from the day of the first administration to the day of the last 
administration of study treatment + another 28 days inclusive (but no greater than the data 
collection cut-off date).
i.e. time on-treatment will otherwise be defined as follows:
For all subjects: 
(Date of last administration) – (Date of first administration) + 29
but no greater than the data collection cut-off date.
This on-treatment phase will be divided into two periods partitioned at the date and time 
of receiving the new drug product. This transition will occur when a subject switches
from dosing with MDP1 to be dosed with MDP2 for the remainder of the study.
9.3.2.1.
Mepolizumab Drug Product 1 Period
For those subjects that have transitioned onto MDP2, the mepolizumab drug product 1
period starts on the first day of dosing with MDP1, and ends the minute prior to the first 
dose of MDP2.
For those subjects that have not transitioned onto MDP2, the mepolizumab drug product 
1 period is defined as being from the day of the first administration using MDP1 to the 
day of the last administration using MDP1 + another 28 days inclusive (but no greater 
than the data collection cut-off date).
i.e. time within the mepolizumab drug product 1 period will be defined as:
(Date of first MDP2 administration) – (Date of first MDP1 administration) + 1
for those subjects that have transitioned onto MDP2 or
(Date of last MDP1 administration) – (Date of first MDP1 administration) + 29
(but no greater than the data collection cut-off date) for those subjects that have not 
transitioned onto MDP2.
9.3.2.2.
Mepolizumab Drug Product 2 Period
The mepolizumab drug product 2 period is defined as being from the date and time of the 
first administration of MDP2 to the day of the last administration using MDP2 + another 
28 days (but no greater than the data collection cut-off date).
i.e. time within the mepolizumab drug product 2 period will be defined as:
(Date of last MDP2 administration) – (Date of first MDP2 administration) + 28
(but no greater than the data collection cut-off date)
 
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9.4.
Values of Potential Clinical Importance
Haematological and clinical chemistry data from subjects who have values outside the 
normal range and values of potential clinical concern will be listed. Graphical displays of 
liver function test results will be produced as described in Section 12.9 to identify any 
liver function tests results which may be of clinical concern. See attachment: Section 18.3
for reference values of potential clinical concern.
9.5.
Adverse Events
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) coding dictionary.  Classification of an AE as pre-, on- or post-treatment will 
be made with reference to the study treatment start and stop dates and the AE onset date.  
If the AE onset date is missing or partial then the AE will be considered on-treatment 
unless there is evidence to the contrary (e.g. the month of the onset date is present and is 
less than the month of the first dose of study medication).  AEs with onset up to 4 weeks 
after the last dose of treatment will be considered on-treatment.  AEs with onset after this 
period will be considered post-treatment but will be assigned to the treatment previously 
received. 
Any SAEs for screen failures or run-in failures will be classified as pre-treatment SAEs.
The most frequent on-treatment AEs will be defined as AEs with frequency ≥3% (prior to 
rounding).
When presenting summaries of adverse events by drug product, the onset date and time 
of each event will be used to deem in which drug product period the event occurred. For 
the definitions of the two drug product periods, see Section 9.3.2.1 and Section 9.3.2.2.
When presenting the data in this way, if the AE onset date or time is missing or partial 
then the most conservative approach possible will be taken.
9.5.1.
Exposure Adjusted Adverse Events
The number of events per 1000 subject-years of exposure will be calculated as:
10.
STUDY POPULATION
10.1.
Disposition of Subjects
A summary of the number of subjects included in each population will be produced. 
The proportion of screen failures, the proportion who reported each reason for screen 
failure, the proportion of run-in failures and the proportion who reported each reason for 
run-in failure will be presented for the ASE population.
 
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The proportion of subjects in the AT population who has withdrawn from the study, and 
reported each reason for withdrawal, will be presented. A Kaplan-Meier plot showing the 
percentage of subjects withdrawing from the study over time will be produced for the AT
Population. 
The proportion of subjects in the AT population at each centre and within each country 
and region will be presented. Subject number in MEA115666, treatment received in
MEA115666, subject number in MEA112997 and treatment assigned in MEA112997 and 
will be listed for each centre in the AT population.
10.2.
Protocol Deviations
The proportion of subjects in the AT population who failed each inclusion, exclusion or 
Visit 2 criterion will be presented. Protocol deviations will be summarised and listed for 
the AT Population. 
10.3.
Demographic and Baseline Characteristics
10.3.1.
Demography and Race
Demographic characteristics (age, sex, ethnicity, height, weight and body mass index) 
will be summarised and listed.
The proportion of subjects reporting each race and racial combination and each detailed 
race and racial combination will be presented.  Race will be listed.
10.3.2.
Medical Conditions
An update in each subject’s medical history since completing the medical history form in 
the MEA112997 trial will be collected at Visit 1 (Screening). If a subject reports no 
change in medical history, the respective subject’s medical history information will be 
copied over from the MEA112997 trial.
The proportion of subjects who report medical conditions in each medical condition class 
will be presented, for past and current conditions separately. Past and current medical 
conditions will be listed.
10.3.3.
Cardiovascular Assessment
A summary of the baseline cardiovascular assessment will be presented. The proportion 
of subjects who report a family history of medical conditions that may indicate 
predisposition towards cardiovascular conditions will be summarised.
10.3.4.
Since Completion of MEA112997
The number of days and number of exacerbations experienced between the completion of 
MEA112997 and Visit 1 (Screening) in MEA115666 will be summarised. The 
completion date of MEA112997 will be considered as the Visit 16 (Week 52) date for 
 
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those subjects who completed the study, and will be considered as the date of withdrawal 
for those subjects that withdrew from the trial prematurely.
10.3.5.
Baseline Lung Function Tests
The following Baseline (Visit 2) clinic lung function results will be summarised:  

Pre bronchodilator FEV1 (mL)

Pre bronchodilator percent predicted FEV1 (%)

Pre bronchodilator Forced Vital Capacity FVC (mL)

Pre bronchodilator FEV1/FVC
10.4.
Treatment Compliance
A summary of treatment compliance is not applicable to this study; however number of 
treatments received is summarised in the Extent of Exposure Section 12.1.
10.5.
Concomitant Medications
The proportion of subjects reporting each concomitant medication will be presented.  
Multi-ingredient medications will be presented according to their combination ATC 
classification rather than the classifications of the ingredients.  Summaries will be split 
into asthma and non-asthma concomitant medications, as well as into those taken pre-
treatment, during treatment and post-treatment (as described in Section 9.3).  Asthma 
medication outputs will not display the ATC grouping.
Classification of a medication as pre-, on- or post-treatment will be made with reference 
to the study treatment start and stop dates and the medication start date.  If the medication
start date is missing or partial then the medication will be considered on-treatment unless 
there is evidence to the contrary (e.g. the month of the start date is present and is less than 
the month of the first dose of study medication).  Medications with a start date of up to 4 
weeks after the last dose of treatment will be considered on-treatment.  Medications with 
a start date after this period will be considered post-treatment.
Pre- and on-treatment respiratory medications will be summarised separately.
A medication will be summarised in every period (pre/during/post) in which it was taken, 
so a medication that was started in the run-in and stopped during active treatment will 
appear in both the pre-treatment and the during treatment tables.
A listing of the relationship between ATC level 1, ingredient and verbatim term will be 
produced together with listings of all asthma and non-asthma concomitant medications.
11.
EFFICACY ANALYSES
Efficacy data will be summarised using appropriate measures (means/geometric means, 
standard deviations, medians and ranges for continuous variables and frequencies and 
 
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percentages for categorical variables). Unless otherwise stated, analyses will be 
conducted only for the AT Population.  
11.1.
Annualised Rate of Exacerbations
The frequency of exacerbations of asthma collected during the on-treatment phase (See 
Section 9.3.1) will be summarised for the AT population. For consistency, exacerbations 
separated by less than 7 days will be treated as a continuation of the same exacerbation
(See Section 9.2.2).
The annualised rate of exacerbations will be estimated using a negative binomial 
generalised linear model with a log link-function. The covariates listed in Section 8.2 will 
be used in the model. The estimated mean rate per year and 95% confidence interval will 
be presented. (The estimates of the mean rates should be presented using the observed 
marginals of the sample covariates). 
The annualised rate of exacerbations will also be estimated according to blood eosinophil 
level of ≥150/μL or <150/μL at baseline within MEA115666.
11.2.
Time to First Exacerbation
Summaries and graphs of the Kaplan-Meier estimates of the proportion of subjects with 
an exacerbation over time will be produced.
11.3.
Asthma Control Questionnaire Score
Asthma Control Questionnaire (ACQ) score (absolute value and changes from baseline) 
will be summarised by visit. 
11.4.
FEV1 Measured by Clinic Spirometry
Pre-bronchodilator FEV1 (absolute value and changes from baseline (mL)) will be 
summarised by visit.
11.5.
Blood Eosinophils
Blood eosinophil count and ratio to baseline will be summarised by visit. Blood 
eosinophil count and ratio to baseline will be also be summarised by drug product and 
visit in a separate table. For the definitions of the two drug product periods, see Section
9.3.2.1 and Section 9.3.2.2.
Blood eosinophil counts collected whilst receiving the two drug products will be further 
compared by summarising the last sample to be collected prior to the first dose of MDP2 
and the first sample collected following the first dose with MDP2. This particular table 
will only include those subjects that have a blood eosinophil sample collected from both 
drug product periods.
Values of zero cells will be imputed as 0.005 prior to log transformation. Blood 
eosinophil data will also be listed.
 
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12.
SAFETY ANALYSES
All safety summaries and listings will be produced for the AT population, with the 
exception of the table of pre-treatment SAEs and relationship between system organ 
class, preferred term and verbatim term which will be reported for the ASE population. 
Similarly, listings of subject numbers for individual AEs, all AEs, fatal AEs and non-fatal 
SAEs will be reported for the ASE population.
12.1.
Extent of Exposure
The number of treatments administered and the number of days on-treatment will be 
summarised and listed. The listing of exposure will also contain information of the drug 
product administered at each dosing visit. For definition of on-treatment, see Section
9.3.2.
The number of treatments administered and the number of days on-treatment will also be 
summarised by drug product. For the definitions of the two drug product periods, see
Section 9.3.2.1 and Section 9.3.2.2.
12.2.
Adverse Events
Adverse events will be summarised by preferred term. Numbers will be presented for the 
whole population. Additionally, events experienced during the first 6 months of treatment 
within MEA115666 will be presented by treatment assigned within MEA112997.
AEs occurring during pre-treatment, on-treatment and post-treatment phase will be 
summarised separately.  
The number and percentage of subjects experiencing at least one AE of any type, AEs 
within each body system and AEs within each preferred term will be summarised.
All AEs and SAEs will be summarised by drug product. For the definitions of the two 
drug product periods, see Section 9.3.2.1 and Section 9.3.2.2.
Exposure adjusted rates of AEs will be presented by drug product to account for any 
differences in the length of exposure to the two different drug products within the trial.
For the definition of exposure adjusted AEs, see Section 9.5.1.
The following summary tables will be produced: 

Overview of all Adverse Events

Summary of all Adverse Events (on-treatment and post-treatment)

Summary of drug related Adverse Events (on-treatment)

Relationship of all Adverse Event SOCs, PTs, and Verbatim Text

Summary of Most Frequent (≥ 3% Incidence prior to rounding) Adverse Events
(on-treatment)
 
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
Summary of Number of Subjects and Occurrences of Common On-Treatment 
Non-Serious Adverse Events by System Organ Class

Summary of all Adverse Events Experienced During the First 6 Months of 
Treatment by Treatment Assigned within MEA112997 (on-treatment)

Summary of all AEs by drug product (on-treatment)

Summary of Exposure Adjusted AEs by drug product

Summary of On-Treatment Adverse Events by Highest Anti Drug Antibody 
Result At Any Time Post Baseline (See Section 12.12 for further details about
Immunogenicity)
The following listings will be produced:

Listing of Subject Numbers for Individual Adverse Events

Listing of all Adverse Events
12.3.
Adverse Events of Special Interest
Adverse events of special interest (AESIs) are adverse events associated with the 
identified and potential risks of exposure to mepolizumab. Details regarding these risks 
and the methods by which each AESI will be identified are provided in the Program 
Safety Analysis Plan (PSAP).
AESIs of systemic reactions and local injection site reactions are collected via targeted 
eCRF within the study.  Events captured on the eCRF as systemic reactions will be 
further categorized as allergic/hypersensitivity reactions or non-allergic reactions.  Events 
with preferred terms such as injection related reaction or administration related reaction 
will be considered non-allergic reactions. All remaining events will be considered 
allergic/hypersensitivity reactions. Events considered by the investigator to represent 
systemic reactions will be required to be assessed against Sampson’s diagnostic criteria 
for anaphylaxis [Sampson, 2006].
AESIs of opportunistic infections, malignancies, serious CVT events and serious 
ischemic events will be identified from a list of relevant preferred terms maintained 
within a project level reference dataset created based on the MedDRA dictionary
available at the time of database freeze for this study, further details of how relevant 
preferred terms are identified are given in the PSAP.
Separate summary tables showing the number and percent of subjects with each type of 
AESI, broken down by preferred term will be created.  Information will be reported as 
part of the standard AE tables for AESIs of infections, serious infections, neoplasms, 
cardiac disorders and serious cardiac disorders.
For each type of AESI a profile summary table will be produced containing information 
which would include, but not be limited to, the number of occurrences of the event, event 
characteristics, time to onset, intensity, outcome and action taken.
 
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A listing of any subjects with systemic reactions identified by the investigators as 
meeting the criteria for anaphylaxis as outlined by the 2006 Joint National Institute of 
Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network Second 
Symposium on Anaphylaxis [Sampson, 2006] will be provided.  
Adverse events experienced on a day of dosing will be summarised and presented by 
SOC and preferred term.
A listing of all adverse events experienced by subjects who have had at least one 
investigator defined systemic/local site reaction will be provided.
The following summary tables will be produced: 

Summary of Adverse Events Of Special Interest: Events Meeting the Criteria for 
Anaphylaxis (On-Treatment)

Summary of Adverse Events Of Special Interest: Systemic 
(Allergic/Hypersensitivity and Non-Allergic) Reactions (On-Treatment)

Summary of Adverse Events Of Special Interest: Systemic 
(Allergic/Hypersensitivity) Reactions (On-Treatment)

Summary of Adverse Events Of Special Interest: Systemic (Non-Allergic) 
Reactions (On-Treatment)

Summary of adverse events Experienced on Day of Dosing

Summary of Adverse Events Of Special Interest: Local Injection Site Reactions 
(On-Treatment)

Summary of Adverse Events Of Special Interest: Opportunistic Infections (On-
Treatment)

Summary of Adverse Events Of Special Interest: Malignancies (On-Treatment)

Summary of Adverse Events Of Special Interest: Serious Cardiac, Vascular and 
Thromboembolic Events (On-Treatment)

Summary of Adverse Events Of Special Interest: Serious Ischemic Events (On-
Treatment)
The following summary profile tables will be produced: 

Summary Profile of Adverse Events Of Special Interest: Events Meeting the 
Criteria for Anaphylaxis (On-Treatment)

Summary Profile of Adverse Events Of Special Interest: Systemic 
(Allergic/Hypersensitivity and non-Allergic) Reactions (On-Treatment)

Summary Profile of Adverse Events Of Special Interest: Systemic 
(Allergic/Hypersensitivity) Reactions (On-Treatment)

Summary Profile of Adverse Events Of Special Interest: Systemic (Non-Allergic) 
Reactions (On-Treatment)
 
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
Summary Profile of Adverse Events Of Special Interest: Local Injection Site 
Reactions (On-Treatment)

Summary Profile of Adverse Events Of Special Interest: Opportunistic Infections 
(On-Treatment)

Summary Profile of Adverse Events Of Special Interest: Malignancies (On-
Treatment)

Summary Profile of Adverse Events Of Special Interest: Serious Cardiac, 
Vascular and Thromboembolic Events (On-Treatment)

(This summary will report the events falling into the cardiac disorders and 
vascular disorders SOCs, plus additional thromboembolic events from other SOCs 
[e.g., stroke is categorized under the Nervous System SOC] identified by the 
Safety Review Team)

Summary Profile of Adverse Events Of Special Interest: Serious Ischemic Events 
(On-Treatment)
The following listings will be produced: 

Listing of Adverse Events Of Special Interest: Events Meeting the Criteria for 
Anaphylaxis

Listing of Adverse Events Of Special Interest: Systemic 
(Allergic/Hypersensitivity) Reactions

Listing of Adverse Events Of Special Interest: Systemic (Non-Allergic) Reactions

Listing of Adverse Events Experienced on Day of Dosing

Listing of Adverse Events Experienced by Subjects With Investigator Reported 
Systemic (Allergic/Hypersensitivity and Non-Allergic) Reactions

Listing of Adverse Events Of Special Interest: Local Injection Site Reactions

Listing of Adverse Events Experienced by Subjects With Local Injection Site 
Reactions

Listing of Adverse Events Of Special Interest: Opportunistic Infections

Listing of Adverse Events Of Special Interest: Malignancies

Listing of Adverse Events Of Special Interest: Serious Cardiac, Vascular and 
Thromboembolic Events

Listing of Adverse Events Of Special Interest: Serious Ischemic Events
12.4.
Deaths and Serious Adverse Events
The following summary tables will be produced: 

Summary of Serious Adverse Events (pre-treatment, on-treatment and post-
treatment)

Summary of Number of Subjects and Occurrences of Serious Adverse Events by 
System Organ Class and Preferred Term
 
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
Summary of Serious Adverse Events by drug product (on-treatment)

Summary of Exposure Adjusted Serious Adverse Events by drug product

Summary of Fatal Events (any period)

Summary of all Non-Fatal Serious Adverse Events (on-treatment and post-
treatment)
The following listings will be produced:

Listing of Fatal Adverse Events

Listing of all Non-Fatal Serious Adverse Events
12.5.
Adverse Events Leading to Discontinuation of 
Investigational Product and/or Withdrawal from the Study 
and Other Significant Adverse Events
The following summary tables will be produced: 

Summary of Adverse Events Leading to Permanent Discontinuation of Study 
Drug or Withdrawal from Study (pre-treatment and on/post-treatment)

Summary of Adverse Events Leading to Interruption of Study Drug (on-
treatment)
The following listings will be produced:

Listing of Adverse Events Leading to Permanent Discontinuation of Study Drug 
and/or Withdrawal from the Study
12.6.
Cardiovascular Events of Interest
The event specific pages in the eCRF will be summarised. Summaries of events which 
were reported and confirmed (or not) as cardiovascular following adjudication by the trial 
Clinical Endpoint Committee (CEC) will be summarised.
The following cardiovascular event listings will be produced for both CEC adjudicated 
events and all investigator reported events. Arrhythmias, pulmonary hypertension, 
revascularisation and valvulopathy events will not be adjudicated by the CEC so these 
event listings will only be produced for investigator reported events. Adjudicated 
investigator reported events that are not considered by the CEC to be cardiovascular in 
nature will be identified with a footnote in the relevant investigator reported event 
listings/summaries. 

Arrhythmias (Investigator reported only)

Congestive Heart Failure

Cerebrovascular Events/Strokes

Deep venous Thrombosis/ Pulmonary Embolism

Myocardial Infarction /Unstable Angina

Peripheral Arterial Thrombosis Embolism
 
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
Pulmonary Hypertension (Investigator reported only)

Revascularisation (Investigator reported only)

Valvulopathy (Investigator reported only)

Deaths (all cause)
12.7.
Pregnancies (as applicable)
Any pregnancy complication or elective termination of a pregnancy for medical reasons 
will be recorded as an AE or SAE and included in summaries and listings of AEs/SAEs 
as described above in Section 12.2.
12.8.
Clinical Laboratory Evaluations
The actual values and change from baseline values for clinical chemistry and 
haematology will be summarised, in separate tables. Summaries of the data outside the 
normal range and the changes from baseline relative to the normal range will also be 
produced, including ‘any time post-baseline’, which will include laboratory assessments 
taken at scheduled, unscheduled and Early Withdrawal visits and will report the most 
extreme value(s). Data from subjects who have values outside the normal range will be 
listed. The normal ranges will also be included in this listing.  Summaries of values of 
potential clinical concern will be produced.  Data from subjects who have values of 
potential clinical concern will be listed and the ranges of potential clinical concern will be 
included in this listing.
A trellis display of maximum post-dose liver function test (LFT) versus baseline LFT and 
a box plot of maximum LFTs will be produced.
12.9.
Liver Events
Subjects with emergent hepatobiliary laboratory abnormalities (for example ALT>=3x 
Upper Limit of Normal) will be summarised and listed. 
Liver event information will be summarised and listed for all subjects who report a liver 
event, to include:

The information captured on the Liver Event Assessment Form which is used to 
calculate the Roussel Uclaf Causality Assessment Method (RUCAM) score.  

The size of the biopsy and the recorded outcomes for the liver biopsy. 

The recorded outcomes for the liver imaging assessment.

All clinical chemistry results for subjects with Liver Event Criteria
Information on alcohol use for subjects who report a liver event will be included in the 
listing of substance use. Medical conditions reported at the time of the liver event will be 
included in the listing of medical conditions (see Section 10.3.2).
 
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12.10.
Vital Signs
Pre-dose systolic blood pressure, diastolic blood pressure and pulse rate including change 
from baseline on all visits will be summarised and listed.
12.11.
12-lead ECG
Actual and change from baseline (for post-baseline timepoints) values for QTc(F), 
QTc(B) and heart rate will be summarised by visit.  ECG results will also be listed. 
Abnormal findings and interpretations will be listed separately.
Individual maximum QTc(F) and QTc(B) values will also be summarised to show the 
number of subjects with maximum values (msec) in the following categories:

≤450

450 < to ≤480

480 < to ≤500

> 500 
Additionally, individual maximum changes from baseline in QTc(F) and QTc(B) values 
will be summarised to show the number of subjects with maximum changes (msec) in the 
following categories: 

< -60

≥ -60 to < -30

≥ -30 to < 0

≥  0 to < 30

≥  30 to < 60

≥ 60. 
12.12.
Immunogenicity
Two types of antibody assay will be performed, i.e. an immunogenicity status anti-drug 
antibody (ADA) assay and neutralising antibody (NAb) assay. For the ADA assay, a 
screening assessment will be performed which produces a result of positive or negative. 
For samples with a positive screening result, a confirmation assay will be carried out, 
which also produces a result of positive or negative. For samples with a positive 
confirmation result, a titre value will also be obtained to quantify the degree of binding. 
Subjects will be viewed as positive for the ADA assay if the confirmation assay is
positive.
For subjects who have a positive confirmation result for the ADA assay, a neutralising 
assay will be performed, which again produces a result of positive or negative. 
 
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A table will be produced summarising results for the ADA assay in the AT Population by
visit. The table will include the number and proportion of subjects in each results 
category (see below) for each visit. ADA confirmatory assay results will be categorised 
as follows:
1. Negative
2. Positive 
with the table also summarising the minimum, maximum and median titre values 
collected for subjects with positive ADA confirmatory assays.
Additionally, results for the ADA assay for the AT Population during the first 6 months 
of treatment within MEA115666 will be summarised by treatment assigned within 
MEA112997 and visit.
These two tables will also summarise the highest ADA assay confirmatory result 
obtained for each subject. If a subject had both Negative and Positive confirmatory
results, they will be included in the Positive category.
A table will also be produced summarising results for the ADA assay in the AT 
Population by drug product and visit. For the definitions of the two drug product periods, 
see Section 9.3.2.1 and Section 9.3.2.2. This table will also summarise the highest ADA 
assay confirmatory result obtained for each subject whilst receiving each drug product. If 
a subject had both Negative and Positive confirmatory results, they will be included in 
the Positive category.
A table will also be produced summarising results for the NAb assay in the AT
Population by visit. Neutralising assay results will be categorised as follows:
1. Negative
2. Positive 
Additionally, results for the NAb assay for the AT Population during the first 6 months of 
treatment within MEA115666 will be summarised by treatment assigned within 
MEA112997 and visit.
These two tables will also summarise the highest neutralising assay confirmatory result 
obtained for each subject. If a subject had both Negative and Positive results, they will be 
included in the Positive category.
A table will also be produced summarising results for the NAb assay in the AT 
Population by drug product and visit. For the definitions of the two drug product periods, 
see Section 9.3.2.1 and Section 9.3.2.2. This table will also summarise the highest 
neutralising assay confirmatory result obtained for each subject whilst receiving each 
drug product. If a subject had both Negative and Positive results, they will be included in 
the Positive category.
All immunogenicity results (i.e. ADA screening and confirmatory assay results, titre 
values, NAb results) will be listed.
 
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13.
HEALTH OUTCOMES ANALYSES
13.1.
Resource Utilisation Measures
Healthcare resource use due to an exacerbation will be summarised for the AT 
population.
14.
CLINICAL PHARMACOLOGY DATA ANALYSES
Not applicable to this study.
15.
BIOMARKER DATA ANALYSIS
Not applicable to this study.
16.
PHARMACOGENETIC DATA ANALYSES
Not applicable to this study.
 
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17.
REFERENCES
GlaxoSmithKline Document Number 2012N139436_02 Study ID MEA115666. A multi-
centre, open-label, long term safety study of mepolizumab in asthmatic subjects who 
participated in the MEA112997 trial. Report Date 06-MAR-2013. 
Hankinson JL, Kawut SM, Shahar E, Smith LJ, Stukovsky KH, Barr RG. Performance of 
American Thoracic Society-Recommended Spirometry Reference Values in a 
Multiethnic Sample of Adults. Chest. 2010;137/1:138-145.
Hankinson JL, Odencrantz JR, Fedan KB. Spirometric Reference Values from a Sample 
of the General US Population. American Journal of Respiratory and Critical Care. 
1999;159:179-187. 
Sampson HA, Munoz-Furlong A, Campbell RL et al. Second Symposium on the
definition and management of anaphylaxis: Summary Report.Second National Institute of
Allergy and Infectious Disease / Food Allergy and Anaphylaxis Network Symposium.
Journal of Allergy and Clinical Immunology. 2006;117:391-397
 
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18.
ATTACHMENTS
18.1.
Table of Contents for Data Display Specifications
18.1.1.
Study Population Tables
Number
Title
Pop
5.01
Summary of Subject Populations
ASE
5.02
Summary of Reasons for Screen Failure 
ASE
5.03
Summary of Reasons for Run-in Failure 
ASE
5.04
Summary of Failed Inclusion/Exclusion/Visit 2 Criteria for 
Screen or Run-in Failures
ASE
5.05
Summary of Inclusion/Exclusion/Visit 2 Criteria Deviations for 
As Treated Subjects
AT
5.06
Summary of Subject Disposition
AT
5.07
Summary of Attendance at Each Clinic Visit
AT
5.08
Summary of Attendance at Each Clinic Visit by Drug Product
AT
5.09
Summary of Visit Where Drug Product Switched
AT
5.10
Summary of Number of Subjects by Region, Country and Centre
AT
5.11
Summary of Protocol Deviations
AT
5.12
Summary of Age Ranges
ASE
5.13
Summary of Demographic Characteristics 
AT
5.14
Summary of Race and Racial Combinations
AT
5.15
Summary of Race and Racial Combination Details
AT
5.16
Summary of Past Medical Conditions
AT
5.17
Summary of Current Medical Conditions
AT
5.18
Summary of Cardiovascular Assessments – Screening Questions
AT
5.19
Summary of Cardiovascular Assessments – Family History 
AT
5.20
Summary of Exacerbations Since Completion of MEA112997
AT
5.21
Summary of Time Since Completion of MEA112997
AT
5.22
Annualised Rate of Exacerbations Since Completion of 
MEA112997 
AT
5.23
Summary of History of Xolair Use
AT
5.24
Summary of Baseline Lung Function Results
AT
5.25
Summary of Asthma Concomitant Medications Taken Before the 
Run-In
AT
5.26
Summary of Asthma Concomitant Medications Taken During the 
Run-In
AT
5.27
Summary of Asthma Concomitant Medications Taken During 
Treatment
AT
 
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Number
Title
Pop
5.28
Summary of Asthma Concomitant Medications Started During 
Treatment
AT
5.29
Summary of Asthma Concomitant Medications Taken Post-
Treatment
AT
5.30
Summary of Asthma Concomitant Medications Taken Before the 
Run-In by Respiratory Medication Class
AT
5.31
Summary of Asthma Concomitant Medications Taken During 
Treatment by Respiratory Medication Class
AT
5.32
Summary of Asthma Concomitant Medications Started During 
Treatment by Respiratory Medication Class
AT
5.33
Summary of Asthma Concomitant Medications Taken Post-
Treatment by Respiratory Medication Class
AT
5.34
Summary of Non-Asthma Concomitant Medications Taken 
During Treatment
AT
18.1.2.
Study Population Figures
Number
Title
Pop
5.01
Time to End of Study 
AT
18.1.3.
Study Population Listings
Number
Title
Pop
5.01
Listing of Reasons for Withdrawal by Reason of Withdrawal
AT
5.02
Listing of Current and Previous Treatment
AT
5.03
Listing of Reasons for Screen Failure and Run-in Failure
ASE
5.04
Listing of Subjects with Inclusion, Exclusion and Visit 2 Criteria 
Deviations
ASE
5.05
Listing of Protocol Deviations
AT
5.06
Listing of Demographic Characteristics
AT
5.07
Listing of Race
AT
5.08
Listing of Medical Conditions
AT
5.09
Listing of Cardiovascular Assessment – Screening Questions
AT
5.10
Listing of Cardiovascular Assessment – Family History
AT
5.11
Listing of Relationship Between ATC Level 1, Ingredient and 
Verbatim Text
AT
5.12
Listing of Asthma Concomitant Medications
AT
5.13
Listing of non-Asthma Concomitant Medication
AT
 
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18.1.4.
Efficacy Tables
Number
Title
Pop
6.01
Overview of All Exacerbations
AT
6.02
Summary of Frequency of All Exacerbations
AT
6.03
Annualised Rate of Exacerbations
AT
6.04
Annualised Rate of Exacerbations by Baseline Blood Eosinophils
AT
6.05
Analysis of Time to First Exacerbation
AT
6.06
Summary of Asthma Control Questionnaire (ACQ) score
AT
6.07
Summary of Clinic Pre-Bronchodilator FEV1 (mL)
AT
6.08
Summary of Blood Eosinophils (GI/L)
AT
6.09
Summary of Blood Eosinophils (GI/L) by Drug Product
AT
6.10
Summary of Blood Eosinophils (GI/L) Pre and Post-Change in 
Drug Product
AT
18.1.5.
Efficacy Figures
Number
Title
Pop
6.01
Kaplan-Meier Cumulative Incidence Curve for Time to First 
Exacerbation
AT
18.1.6.
Efficacy Listings
Number
Title
Pop
6.01
Listing of Exacerbations
AT
6.02
Listing of Lung Function Data
AT
6.03
Listing of Blood Eosinophil Data
AT
18.1.7.
Safety Tables
Number
Title
Pop
7.01
Summary of Number of Treatments Administered
AT
7.02
Summary of Number of Treatments Administered by Drug 
Product
AT
7.03
Overview of All Adverse Events
AT
7.04
Summary of On-Treatment Adverse Events
AT
 
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Number
Title
Pop
7.05
Summary of Post-Treatment Adverse Events
AT
7.06
Summary of Drug-Related Adverse Events (On-Treatment)
AT
7.07
Relationship of All Adverse Event System Organ Class, 
Preferred Term and Verbatim Text
ASE
7.08
Summary of Most Frequent On-Treatment Adverse Events
AT
7.09
Summary of Serious Pre-Treatment Adverse Events
ASE
7.10
Summary of Serious On-Treatment Adverse Events
AT
7.11
Summary of Serious Post-Treatment Adverse Events
AT
7.12
Summary of Fatal Events
AT
7.13
Summary of Non-Fatal Serious Adverse Events (On-Treatment)
AT
7.14
Summary of Non-Fatal Serious Adverse Events (Post-
Treatment)
AT
7.15
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Drug or Withdrawal from Study (Pre-
Treatment)
ASE
7.16
Summary of On-Treatment Adverse Events Leading to 
Permanent Discontinuation of Study Drug or Withdrawal from 
Study (On and Post-Treatment)
AT
7.17
Summary of Adverse Events Leading to Interruption of Study 
Drug (On-Treatment)
AT
7.18
Summary of Number of Subjects and Occurrences of Common 
On-Treatment Non-Serious Adverse Events by System Organ 
Class
AT
7.19
Summary of Number of Subjects and Occurrences of Serious 
Adverse Events by System Organ Class and Preferred Term
AT
7.20
Summary of All Cause Deaths and Reported Cardiovascular 
Events by the Investigator
AT
7.21
Summary of CEC Adjudicated All Cause Deaths and 
Cardiovascular Events of Interest
AT
7.22
Summary of all Adverse Events Experienced During First 6 
Months of Treatment by Treatment Assigned within 
MEA112997
AT
7.23
Summary of all AEs by Drug Product (On-Treatment)
AT
7.24
Summary of Exposure Adjusted AEs by Drug Product (On-
Treatment)
AT
7.25
Summary of Serious Adverse Events by Drug Product (On-
Treatment)
AT
7.26
Summary of Exposure Adjusted Serious Adverse Events by 
Drug Product (On-Treatment)
AT
7.27
Summary of Chemistry Data
AT
7.28
Summary of Change From Baseline in Chemistry Data
AT
7.29
Summary of Chemistry Data Outside the Normal Range
AT
 
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Number
Title
Pop
7.30
Summary of Chemistry Changes from Baseline Relative to the 
Normal Range
AT
7.31
Summary of Chemistry Data Outside the Reference Range 
(Potential Clinical Concern)
AT
7.32
Summary of Chemistry Changes from Baseline Relative to the 
Reference Range (Potential Clinical Concern)
AT
7.33
Summary of Haematology Data
AT
7.34
Summary of Change From Baseline in Haematology Data
AT
7.35
Summary of Haematology Data Outside the Normal Range
AT
7.36
Summary of Haematology Changes from Baseline Relative to 
the Normal Range
AT
7.37
Summary of Haematology Data Outside the Reference Range 
(Potential Clinical Concern)
AT
7.38
Summary of Haematology Changes from Baseline Relative to 
the Reference Range (Potential Clinical Concern)
AT
7.39
Summary of Subjects Meeting Emergent Hepatobiliary
Laboratory Abnormality Criteria
AT
7.40
Summary of  Liver Events Assessment
AT
7.41
Summary of Current Medical Conditions at Onset of Liver 
Event
AT
7.42
Summary of Past Medical Conditions at Onset of Liver Event
AT
7.43
Summary of Vital Signs
AT
7.44
Summary of Change from Baseline in Vital Signs
AT
7.45
Summary of ECG findings
AT
7.46
Summary of ECG Values
AT
7.47
Summary of Change From Baseline in ECG Values
AT
7.48
Frequency of Maximum QTc(F) Interval (msec)
AT
7.49
Frequency of Maximum QTc(B) Interval (msec)
AT
7.50
Summary of ADA Assay Results
AT
7.51
Summary of NAb Assay Results
AT
7.52
Summary of ADA Assay Results During First 6 Months of 
Treatment by Treatment Assigned within MEA112997
AT
7.53
Summary of NAb Assay Results During First 6 Months of 
Treatment by Treatment Assigned within MEA112997
AT
7.54
Summary of ADA Assay Results by Drug Product
AT
7.55
Summary of NAb Assay Results by Drug Product
AT
7.56
Summary of ADA Assay Results Pre and Post-Change in Drug 
Product
AT
7.57
Summary of NAb Assay Results Pre and Post-Change in Drug 
Product
AT
7.58
Summary of Adverse Events Of Special Interest: Events Meeting the 
Criteria for Anaphylaxis (On-Treatment)
AT
 
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Number
Title
Pop
7.59
Summary of Adverse Events Of Special Interest: Systemic 
(Allergic/Hypersensitivity and Non-Allergic) Reactions (On-
Treatment)
AT
7.60
Summary of Adverse Events Of Special Interest: Systemic 
(Allergic/Hypersensitivity) Reactions (On-Treatment)
AT
7.61
Summary of Adverse Events Of Special Interest: Systemic (Non-
Allergic) Reactions (On-Treatment)
AT
7.62
Summary of adverse events Experienced on Day of Dosing
AT
7.63
Summary of Adverse Events Of Special Interest: Local Injection Site 
Reactions (On-Treatment)
AT
7.64
Summary of Adverse Events Of Special Interest: Opportunistic 
Infections (On-Treatment)
AT
7.65
Summary of Adverse Events Of Special Interest: Malignancies (On-
Treatment)
AT
7.66
Summary of Adverse Events Of Special Interest: Serious Cardiac, 
Vascular and Thromboembolic Events (On-Treatment)
AT
7.67
Summary of Adverse Events Of Special Interest: Serious Ischemic 
Events (On-Treatment)
AT
7.68
Summary Profile of Adverse Events Of Special Interest: Events 
Meeting the Criteria for Anaphylaxis (On-Treatment)
AT
7.69
Summary Profile of Adverse Events Of Special Interest: Systemic 
(Allergic/Hypersensitivity and non-Allergic) Reactions (On-
Treatment)
AT
7.70
Summary Profile of Adverse Events Of Special Interest: Systemic 
(Allergic/Hypersensitivity) Reactions (On-Treatment)
AT
7.71
Summary Profile of Adverse Events Of Special Interest: Systemic 
(Non-Allergic) Reactions (On-Treatment)
AT
7.72
Summary Profile of Adverse Events Of Special Interest: Local 
Injection Site Reactions (On-Treatment)
AT
7.73
Summary Profile of Adverse Events Of Special Interest: 
Opportunistic Infections (On-Treatment)
AT
7.74
Summary Profile of Adverse Events Of Special Interest: 
Malignancies (On-Treatment)
AT
7.75
Summary Profile of Adverse Events Of Special Interest: Serious 
AT
 
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Number
Title
Pop
Cardiac, Vascular and Thromboembolic Events (On-Treatment)
7.76
Summary Profile of Adverse Events Of Special Interest: Serious 
Ischemic Events (On-Treatment)
AT
7.77
Summary of Serious AEs and AEs of Special Interest
AT
7.78
Summary of On-Treatment Adverse Events by Highest Anti Drug 
Antibody Result At Any Time Post Baseline
AT
18.1.8.
Safety Figures
Number
Title
Pop
7.01
Trellis Display of Maximum Post-Baseline LFT Values Versus 
Baseline LFT Values
AT
7.02
Box Plot of Maximum Post-Baseline Liver Function Tests
AT
18.1.9.
Safety Listings
Number
Title
Pop
7.01
Listing of Exposure Data
AT
7.02
Listing of Subject Numbers for Individual Adverse Events
ASE
7.03
Listing of All Adverse Events
ASE
7.04
Listing of Fatal Adverse Events
ASE
7.05
Listing of Non-Fatal Serious Adverse Events
ASE
7.06
Listing of Adverse Events Leading to Permanent Discontinuation 
of Study Drug or Withdrawal from the Study
AT
7.07
Listing of Investigator Reported Cardiovascular Events: 
Arrhythmias
AT
7.08
Listing of Investigator Reported Cardiovascular Events: 
Congestive Heart Failure
AT
7.09
Listing of Investigator Reported Cardiovascular Events: 
Cerebrovascular Events/Stroke
AT
7.10
Listing of Investigator Reported Cardiovascular Events: Deep 
venous Thrombosis/ Pulmonary Embolism
AT
7.11
Listing of Investigator Reported Cardiovascular Events: 
Myocardial Infarction /Unstable Angina
AT
 
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Number
Title
Pop
7.12
Listing of Investigator Reported Cardiovascular Events: 
Peripheral Arterial Thrombosis Embolism
AT
7.13
Listing of Investigator Reported Cardiovascular Events: 
Pulmonary Hypertension
AT
7.14
Listing of Investigator Reported Cardiovascular Events: 
Revascularisation
AT
7.15
Listing of Investigator Reported Cardiovascular Events: 
Valvulopathy
AT
7.16
Listing of Investigator Reported Events: All Cause Deaths
AT
7.17
Listing of CEC Adjudicated Cardiovascular Events: Congestive 
Heart Failure
AT
7.18
Listing of CEC Adjudicated Cardiovascular Events: 
Cerebrovascular Events/Stroke
AT
7.19
Listing of CEC Adjudicated Cardiovascular Events: Deep 
venous Thrombosis/ Pulmonary Embolism
AT
7.20
Listing of CEC Adjudicated Cardiovascular Events: Myocardial 
Infarction /Unstable Angina
AT
7.21
Listing of CEC Adjudicated Cardiovascular Events: Peripheral 
Arterial Thrombosis Embolism
AT
7.22
Listing of CEC Adjudicated Events: All Cause Deaths
AT
7.23
Listing of Chemistry Data for Subjects with at Least One Value 
Outside the Normal Range
AT
7.24
Listing of Haematology Data for Subjects with at Least One 
Value Outside the Normal Range
AT
7.25
Listing of Subjects Meeting Hepatobiliary Laboratory Criteria
Post-Baseline
AT
7.26
Chemistry Results for Subjects Meeting Liver
Event Criteria
AT
7.27
Listing of Liver Event Information for RUCAM Score
AT
7.28
Listing of Liver Biopsy Details
AT
7.29
Listing of Liver Imaging Details
AT
7.30
Listing of Alcohol Intake at Onset of Liver Event
AT
7.31
Listing of Vital Signs
AT
7.32
Listing of ECG Values
AT
7.33
Listing of ECG Findings for Abnormal Interpretations
AT
7.34
Listing of Immunogenicity Results
AT
 
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Number
Title
Pop
7.35
Listing of Adverse Events Of Special Interest: Events Meeting the 
Criteria for Anaphylaxis
AT
7.36
Listing of Adverse Events Of Special Interest: Systemic 
(Allergic/Hypersensitivity) Reactions
AT
7.37
Listing of Adverse Events Of Special Interest: Systemic (Non-
Allergic) Reactions
AT
7.38
Listing of Adverse Events Experienced on Day of Dosing
AT
7.39
Listing of Adverse Events Experienced by Subjects With Investigator 
Reported Systemic (Allergic/Hypersensitivity and Non-Allergic) 
Reactions
AT
7.40
Listing of Adverse Events Of Special Interest: Local Injection Site 
Reactions
AT
7.41
Listing of Adverse Events Experienced by Subjects With Local 
Injection Site Reactions
AT
7.42
Listing of Adverse Events Of Special Interest: Opportunistic Infections
AT
7.43
Listing of Adverse Events Of Special Interest: Malignancies
AT
7.44
Listing of Adverse Events Of Special Interest: Serious Cardiac, 
Vascular and Thromboembolic Events
AT
7.45
Listing of Adverse Events Of Special Interest: Serious Ischemic Events
AT
18.1.10.
Health Outcomes Tables
Number
Title
Pop
8.01
Summary of Unscheduled Healthcare Resource Use Associated 
with an Exacerbation
AT
18.2.
Data Display Specifications
The data display shells are contained in separate documents which are available on 
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18.3.
Laboratory Potential Clinical Concern Values
Table 2
Chemistry Values of Potential Clinical Concern
ANALYTE
Age
Sex
SI Units
F3 low
F3 high
SODIUM
0+
Both
MMOL/L
120
160
POTASSIUM
3+
Both
MMOL/L
2.8
6.5
CALCIUM
3+
Both
MMOL/L
1.50
3.24
PHOSPHORUS, 
INORG
3+
Both
MMOL/L
0.32
GLUCOSE
1+
Both
MMOL/L
2.2
27.8
ALT (SGPT)
3-12
Both
U/L
>143 (and 
Total Bilirubin 
> 43)
ALT (SGPT)
13+
Both
U/L
>239 (and 
Total Bilirubin 
> 43)
Table 3
Haematology Values of Potential Clinical Concern
ANALYTE
Age
Sex
SI Units
F3 low
F3 high
HAEMOGLOBIN
12+
Both
G/L
71
199
HAEMATOCRIT
12+
Both
1
0.201
0.599
PLATELET 
COUNT
1+
Both
GI/L
31
1499
WHITE CELL 
COUNT
12+
Both
GI/L
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The GlaxoSmithKline group of companies
MEA115666
1
Division: World Wide Development
Retention Category: GRS019
Information Type: Reporting and Analysis Plan
Title:
Reporting and Analysis Plan for MEA115666: A multi-centre, 
open-label, long term safety study of mepolizumab in asthmatic 
subjects who participated in the MEA112997 trial.
Compound Number:
SB-240563
Effective Date:
20-AUG-2013
Description: This study will provide long term safety and immunogenicity data when 
mepolizumab is administered subcutaneously (SC) to subjects with severe, refractory 
asthma with a history of eosinophilic inflammation. Additionally, this study will inform 
on the safety and immunogenicity profile when mepolizumab therapy is reinstituted in 
subjects following a cessation in drug therapy.
Safety will be assessed by adverse events, clinical laboratory samples, ECGs,
immunogenicity and vital signs. 
Additional assessments are included to evaluate the effects of mepolizumab on a range of 
clinical markers of asthma control.
Subject: Severe refractory asthma, mepolizumab, eosinophils, SB-240563, extension
study, safety
Author’s Name, Title and Functional Area:
 Statistician, Clinical 
Statistics, Quantitative Sciences.
Copyright 2013 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited
 
 
 
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The GlaxoSmithKline group of companies
MEA115666
2
Approved by: 
Director Biostatistics and Programming
Clinical Statistics, Quantitative Sciences
Date:13-AUG-2013
Dr 
Project Physician Lead
Respiratory Therapeutic Unit  R&D
Date:20-AUG-2013
Director Safety Evaluation & Risk Management
Office of the Chief Medical Officer
Date:12-AUG-2013
Manager, Global Health Outcomes
Global Health Outcomes
Date:13-AUG-2013
Clinical Immunology Manager
Clinical Immunology
Date:16-AUG-2013
Clinical Investigation Leader, 
Respiratory Therapeutic Unit
Date:08-AUG-2013
 
 
 
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TABLE OF CONTENTS
PAGE
ABBREVIATIONS ...........................................................................................................6
1.
INTRODUCTION......................................................................................................8
2.
STUDY OBJECTIVE(S) AND ENDPOINT(S) ...........................................................8
2.1.
Study Objective(s) ........................................................................................8
2.1.1.
Primary Objective ..........................................................................8
2.1.2.
Secondary Objectives....................................................................8
2.2.
Study Endpoint(s) .........................................................................................8
2.2.1.
Primary Endpoint ...........................................................................8
2.2.2.
Secondary Endpoints.....................................................................8
2.3.
Statistical Hypotheses...................................................................................9
3.
STUDY DESIGN ......................................................................................................9
4.
PLANNED ANALYSES ..........................................................................................10
4.1.
Interim Analyses .........................................................................................10
4.1.1.
Independent Data Monitoring Committee.....................................11
5.
SAMPLE SIZE CONSIDERATIONS.......................................................................12
5.1.
Sample Size Assumptions ..........................................................................12
6.
ANALYSIS POPULATIONS ...................................................................................12
7.
TREATMENT COMPARISONS..............................................................................12
7.1.
Data Display Treatment and Other Sub-group Descriptors .........................14
8.
GENERAL CONSIDERATIONS FOR DATA ANALYSES.......................................14
8.1.
Multicentre Studies .....................................................................................14
8.2.
Other Strata and Covariates .......................................................................14
8.3.
Examination of Subgroups..........................................................................15
8.4.
Multiple Comparisons and Multiplicity .........................................................15
9.
DATA HANDLING CONVENTIONS .......................................................................15
9.1.
Withdrawal and Missing Data......................................................................15
9.1.1.
Screening and Enrollment............................................................15
9.1.2.
Missing Data................................................................................15
9.2.
Derived and Transformed Data...................................................................15
9.2.1.
Definition of Baseline and Change from Baseline ........................15
9.2.2.
Exacerbations within MEA115666 ...............................................16
9.2.3.
Annualised Rate of Exacerbations in the Interval Between 
Studies ........................................................................................16
9.2.4.
Percent Predicted FEV1 ...............................................................17
9.2.5.
12-Lead ECG...............................................................................17
9.2.6.
Log Transformed Data.................................................................17
9.3.
Assessment Windows.................................................................................17
9.3.1.
On-Treatment Exacerbations.......................................................17
9.3.2.
On-Treatment Phase ...................................................................18
9.3.2.1.
Mepolizumab Drug Product 1 Period ..........................18
 
 
 
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9.3.2.2.
Mepolizumab Drug Product 2 Period ..........................18
9.4.
Values of Potential Clinical Importance.......................................................19
9.5.
Adverse Events...........................................................................................19
9.5.1.
Exposure Adjusted Adverse Events.............................................19
10. STUDY POPULATION...........................................................................................20
10.1.
Disposition of Subjects................................................................................20
10.2.
Protocol Deviations.....................................................................................20
10.3.
Demographic and Baseline Characteristics.................................................20
10.3.1.
Demography and Race................................................................20
10.3.2.
Medical Conditions ......................................................................20
10.3.3.
Cardiovascular Assessment.........................................................21
10.3.4.
Since Completion of MEA112997 ................................................21
10.3.5.
Baseline Lung Function Tests......................................................21
10.4.
Treatment Compliance................................................................................21
10.5.
Concomitant Medications............................................................................21
11. EFFICACY ANALYSES..........................................................................................22
11.1.
Annualised Rate of Exacerbations ..............................................................22
11.2.
Time to First Exacerbation ..........................................................................22
11.3.
Hospitalisations Due to Exacerbations or Adverse Events..........................22
11.4.
Asthma Control Questionnaire Score..........................................................22
11.5.
FEV1 Measured by Clinic Spirometry ..........................................................23
11.6.
Blood Eosinophils .......................................................................................23
12. SAFETY ANALYSES .............................................................................................23
12.1.
Extent of Exposure .....................................................................................23
12.2.
Adverse Events...........................................................................................23
12.3.
Deaths and Serious Adverse Events...........................................................24
12.4.
Adverse Events Leading to Discontinuation of Investigational 
Product and/or Withdrawal from the Study and Other Significant 
Adverse Events...........................................................................................26
12.5.
Cardiovascular Events of Interest ...............................................................27
12.6.
Pregnancies (as applicable)........................................................................27
12.7.
Clinical Laboratory Evaluations...................................................................27
12.8.
Liver Events................................................................................................28
12.9.
Vital Signs...................................................................................................28
12.10. 12-lead ECG...............................................................................................28
12.11. Immunogenicity...........................................................................................29
13. HEALTH OUTCOMES ANALYSES........................................................................30
13.1.
Resource Utilisation Measures ...................................................................30
14. CLINICAL PHARMACOLOGY DATA ANALYSES..................................................30
15. BIOMARKER DATA ANALYSIS.............................................................................30
16. PHARMACOGENETIC DATA ANALYSES.............................................................30
17. REFERENCES.......................................................................................................31
18. ATTACHMENTS ....................................................................................................32
18.1.
Table of Contents for Data Display Specifications.......................................32
 
 
 
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18.1.1.
Study Population Tables..............................................................32
18.1.2.
Study Population Figures.............................................................33
18.1.3.
Study Population Listings.............................................................33
18.1.4.
Efficacy Tables ............................................................................34
18.1.5.
Efficacy Figures ...........................................................................34
18.1.6.
Efficacy Listings...........................................................................35
18.1.7.
Safety Tables...............................................................................35
18.1.8.
Safety Figures .............................................................................37
18.1.9.
Safety Listings .............................................................................37
18.1.10. Health Outcomes Tables .............................................................39
18.2.
Data Display Specifications ........................................................................39
18.3.
Laboratory Potential Clinical Concern Values .............................................40
 
 
 
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ABBREVIATIONS
ACQ
Asthma Control Questionnaire
ADA
Anti-drug antibody
AE
Adverse event
ALT
Alanine transaminase
ASE
All Subjects Enrolled
AT
As Treated
ATC
Anatomical Therapeutic Chemical
CEC
Clinical Endpoint Committee
CI
Confidence Interval
CS
Corticosteroid
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
ED
Emergency Department
FEV1
Forced expiratory volume in 1 second
FVC
Forced vital capacity
GSK
GlaxoSmithKline
IDMC
Independent Data Monitoring Committee
IgE
Immunoglobulin E
IM
Intramuscular
IV
Intravenous
LFT
Liver function test
LLQ
Lower Limit of Quantification
MDP1
Mepolizumab Drug Product 1
MDP2
Mepolizumab Drug Product 2
MedDRA
Medicinal dictionary for regulatory activities
mg
Milligram
mL
Millilitres
N
Number of subjects in the treatment group
n
Number of subjects with non-missing values
NAb
Neutralising antibody
NHANES
National Health and Nutrition Examination Survey
OCS
Oral corticosteroids
OLE
Open label extension (study)
PI
Principal Investigator
PT
Preferred Term
QTc(B)
QT interval corrected by Bazett's method
QTc(F)
QT interval corrected by Fridericia's method
RAP
Reporting and Analysis Plan
RUCAM
Roussel Uclaf Causality Assessment Method
SAE
Serious adverse event
SC
Subcutaneous
SD
Standard Deviation
SE
Standard Error
SDAC
Statistical Data Analysis Centre
SOC
System Organ Class
 
 
 
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7
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
SAS
Xolair
 
 
 
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1.
INTRODUCTION
The purpose of the data analyses outlined in this Reporting and Analysis Plan (RAP) is to 
evaluate the safety, immunogenicity and effectiveness of treatment with 100mg
mepolizumab administered subcutaneously (SC) every 4 weeks in subjects with severe,
uncontrolled refractory asthma.
This RAP is based on Section 8 (Data Analysis and Statistical Considerations) of the 
MEA115666 study protocol issued 06-Mar-2013 (GlaxoSmithKline Document Number
2012N139436_02) and is intended for use by the Statistics & Programming Department.  
The data analyses produced will be used in a Clinical Study Report.
2.
STUDY OBJECTIVE(S) AND ENDPOINT(S)
2.1.
Study Objective(s)
2.1.1.
Primary Objective
The primary objective of this study is to describe the long-term safety profile of 
mepolizumab.
2.1.2.
Secondary Objectives

To provide long-term treatment with mepolizumab to subjects who participated in
MEA112997.

To evaluate the effects of mepolizumab on a range of clinical markers of asthma
control.
2.2.
Study Endpoint(s)
2.2.1.
Primary Endpoint

Adverse Events (AEs) including both systemic (i.e. allergic/IgE-mediated and 
non-allergic) and local site reactions.
2.2.2.
Secondary Endpoints

Frequency of positive anti-mepolizumab binding antibodies and neutralising 
antibodies

Annualised rate of exacerbations

Asthma Control Questionnaire (ACQ) score

Forced expiratory volume in 1 second (FEV1) as measured by clinic spirometry

Number of withdrawals due to lack of efficacy

Number of withdrawals due to adverse events

Number of hospitalizations due to adverse events including asthma exacerbations

Frequency of both systemic (i.e., allergic/IgE-mediated and non-allergic) and 
local site reactions

12-Lead Electrocardiogram (ECG) to derive the following endpoints:
 
 
 
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o Mean change from baseline in the QTc(F) (QT interval corrected by 
Fridericia's method)
o Mean change from baseline in QTc(B) (QT interval corrected by Bazett's 
method)
o Maximum change from baseline for QTc(F) and QTc(B).

Vital signs

Clinical Laboratory Parameters
2.3.
Statistical Hypotheses
Because the study has a single treatment arm, statistical analyses of treatment effect will
not be performed. Therefore no hypotheses have been defined for this study.
3.
STUDY DESIGN
This is a multi-centre, open-label, long term, safety study of 100mg mepolizumab 
administered subcutaneously in addition to standard of care in subjects with severe, 
refractory asthma and a history of eosinophilic inflammation. Subjects who participated 
in the MEA112997 trial will be offered the opportunity to consent for this study. All 
subjects will have experienced a gap of at least 10 months since receiving their last 
double-blind study medication in MEA112997.
At Visit 1 subjects will undergo an initial screening to assess their eligibility to 
participate in this study. This screening will include: informed consent, vital signs, update 
of medical history, immunogenicity status based on MEA112997 data, smoking status, 
prior monoclonal antibody use, and exacerbations post completion of MEA112997. 
Subjects meeting the Visit 1 eligibility criteria will enter the run-in period. The purpose 
of the run-in period is to allow for receipt and review of lab results and the ECG over-
read. Visit 2 will mark the end of the run-in period.
Those subjects meeting all the inclusion criteria and none of the exclusion criteria will
receive their first mepolizumab dose at Visit 2. Subjects will continue to receive
mepolizumab SC injections approximately every 4 weeks until either:

The risk/benefit profile for the subject is no longer positive in the opinion of the
investigator or

the subject’s physician withdraws the subject or

the subject withdraws consent or

the sponsor discontinues development of mepolizumab or

the sponsor discontinues the study in the relevant participating country or

mepolizumab becomes commercially available in the relevant participating
country
During the trail the vial strength used when dosing will be changed for most subjects, 
however this will depend on the timing of regulatory approval. The 100mg dose of 
mepolizumab will be reconstituted from a vial of 250mg/vial strength up until such time 
that the 100mg/vial strength is available at the site. Once the 100mg/vial strength is
 
 
 
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available at the site, all subjects will be dosed with 100mg mepolizumab reconstituted 
from the 100mg/vial strength at their next treatment visit and for the remainder of the 
study. This change of vial strength will be when subjects are transitioned onto the new 
drug product. Hereafter, the 250mg/vial strength will be referred to as mepolizumab drug 
product 1 (MDP1) and the 100mg/vial strength (to which subjects will transition) will be 
referred to as mepolizumab drug product 2 (MDP2). In the case that MDP2 is not 
approved for use by ethics/regulatory at a local site/country subjects will continue to be 
dosed with MDP1.
Subjects will remain on standard of care asthma therapy, which may be adjusted during 
the study, at the discretion of their physician. The use of Xolair (omalizumab) or any 
other monoclonal antibody will not be permitted during the course of the study.
Subjects will be monitored in the clinic approximately every 4 weeks to assess adverse 
events and asthma status. The Asthma Control Questionnaire-5 (ACQ) will be used to 
assist the investigator in assessing the subject’s asthma status along with spirometry at 
regular intervals. Exacerbations will also be reviewed at each clinic visit. As some 
subjects may have previously received placebo while participating in the MEA112997 
trial and are naive to mepolizumab, safety lab monitoring will be more frequent at the 
start of the study. Appropriate safety labs will be drawn prior to starting treatment and 
then at week 4, 8, 12, 24, 36 and 48. Thereafter, these will be collected every 24 weeks. 
Labs will also be obtained at 12 weeks after discontinuing mepolizumab. Subjects 
discontinuing mepolizumab treatment should be monitored for exacerbation of their 
asthma.
Serum samples for anti-mepolizumab antibody measurements will be obtained from all
subjects at Weeks 0, 4, 24 and 48 of the initial year, week 24 and 48 for every additional
year, as well as at the Follow-up Visit. Any anti-mepolizumab antibody positive sample
will be tested for neutralising antibody.
A maximum of two additional anti-mepolizumab antibody samples will be obtained; one
immediately prior to the first dose and the other prior to the second dose with MDP2. If
the first or second dose coincides with a visit where an immunogenicity sample is already 
required, it is not necessary to obtain an additional sample.
4.
PLANNED ANALYSES
4.1.
Interim Analyses
At a date agreed by the study team a data look will be performed on a subset of the data. 
The aim of the data look is solely to ensure that all of the required tables, figures and 
listings are being produced and formatted correctly, such that the output produced at the 
planned analysis date is correct and complete.
Interim analyses will be performed as needed in order to provide open-label safety data to 
inform the risk-benefit assessment of mepolizumab in severe asthma. Specifically, an 
interim analysis will be performed to support the initial regulatory filing of mepolizumab.
A second interim will also be performed to support any possible safety updates following 
these submissions.
 
 
 
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At each interim a ‘cut’ will be made in the data, where any data collected beyond a pre-
specified cut-off date will not be included within the datasets to be reported. See Section 
10, Section 11, Section 12, Section 13 and Section 14 for details of all planned analyses 
at these interims.
This analysis will be performed by the study statistics and programming team and not by 
the SDAC described below who solely support the phase III programme IDMC.  The 
safety results from this interim analysis will be reviewed by the internal GSK 
mepolizumab safety review team. 
Access to the results from this interim analysis will not be confidential.  Specifically the 
results may be provided to the study team, GSK governance boards, external 
investigators and to regulatory authorities.
4.1.1.
Independent Data Monitoring Committee
An Independent Data Monitoring Committee (IDMC) will be utilised in this study to 
ensure external objective review of safety issues in order to protect the ethical and safety 
interests of subjects and to protect the scientific validity of the study. The IDMC will 
review cardiovascular adverse events and all cause mortality from the following studies 
in the Mepolizumab Severe Asthma Phase III Program: MEA115575; MEA115588; 
MEA115666 (this study); MEA115661.
The unblinded statistical analyses will be performed by an independent Statistical Data 
Analysis Centre (SDAC) at Duke University, North Carolina. Unblinded results will not 
be made available to the study team: The SDAC will communicate directly with the 
IDMC, and IDMC recommendations will be made to a primary contact who is external to 
the mepolizumab study team(s) at GSK. See IDMC Charter (available on request).
Stopping guidelines will be based on comparing event rates between mepolizumab and 
placebo in the two double-blind trials MEA115588 and MEA115575.  The two open 
label studies do not include any comparator data and therefore are not part of the formal 
stopping guidelines.
Two event rates will be considered:
a)
SAEs (including deaths) adjudicated to be cardiovascular events in nature;
b)
all cause mortality.
Analysis will be performed based on a meta-analysis of the two studies. For the purposes 
of the analysis, the two mepolizumab treatment arms (75mg IV and 100mg SC) in study 
MEA115588 will be combined to produce an overall event rate for mepolizumab in that 
study. Event rates will be compared between mepolizumab and placebo using the Peto 
odds ratio test. An estimate and 99% CI will be produced for the odds ratio for 
experiencing an event on mepolizumab compared to placebo.
Non-binding statistical stopping guidelines of p<0.01 two-sided will be used for a) the 
analysis of SAEs deemed cardiovascular in nature and b) analysis of all cause mortality. 
 
 
 
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Occurrence of either of these flags would signal further examination of available data by 
the IDMC, with consideration of altering the conduct of either of the studies or 
terminating either of the studies.  
This statistical analysis will be conducted once 8 subjects in the two double blind studies 
have experienced SAEs adjudicated to be cardiovascular in nature. The timings of further 
statistical analyses after the first analysis will be determined by the IDMC.
There are no circumstances under which IDMC review of the data would lead to a 
recommendation to stop for efficacy of mepolizumab. Therefore no adjustment to the 
final alpha level for efficacy will be made based on the safety stopping guidelines. 
For full details of the analyses to be provided to the IDMC by the SDAC see the IDMC 
statistical analysis plan (available on request).
5.
SAMPLE SIZE CONSIDERATIONS
5.1.
Sample Size Assumptions
There is no sample size calculation for this study. The sample size will be determined by 
the number of available subjects who were randomised into the MEA112997 trial and are 
eligible for the current study based on inclusion and exclusion criteria.
6.
ANALYSIS POPULATIONS
The following analysis populations will be derived as required:
All Subjects Enrolled Population
The All Subjects Enrolled (ASE) population will comprise all subjects for whom a record 
exists on the study database. This population will be used for summarising pre-treatment 
SAEs, listing AEs and summarising reasons for screen and run-in failures.
As Treated Population
The As Treated (AT) population will consist of all subjects who received at least one 
dose of open label mepolizumab. This population will be the primary population for all
summaries of efficacy and safety measures.
7.
TREATMENT COMPARISONS
Due to this study having a single treatment arm, statistical analyses of treatment effect
will not be performed. However, there are two comparisons which are of interest:
1) Reintroduction of mepolizumab vs. first time exposure: Adverse events and 
immunogenicity data collected during the first 6 months of treatment within 
MEA115666 will be summarised by treatment assigned within MEA112997. This 
is to assess whether subjects present differing responses to treatment dependant 
 
 
 
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on whether they are being reintroduced to mepolizumab or this is their first time 
exposed to the drug (See Figure 1 and Table 1).
Figure 1
Presentation of Data According to Subject’s Former Treatment
2) Change in drug product: Adverse events, immunogenicity and blood eosinophil 
data will be compared before and after the change in drug product of 
mepolizumab to investigate whether there is a difference on the safety or efficacy 
profile following the transition to the new drug product (See Figure 2).
Figure 2
Presentation of Data by Drug Product
 
 
 
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7.1.
Data Display Treatment and Other Sub-group Descriptors
In the data displays the treatment groups will be identified as described in Table 1. All 
subjects will be presented within the single treatment group of ‘Mepolizumab 100mg 
SC’.
Table 1
Treatment Group Identifiers
Treatment Group
Descriptor
Mepolizumab 100mg SC every 4 weeks
Mepolizumab 100mg SC
8.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
Programming will be performed in a HARP environment using SAS Version 9 or a later 
release.
Summary tables will include N, the number of subjects in the treatment group, and n, the 
number of subjects with non-missing values.
8.1.
Multicentre Studies
Centres will be grouped into regions. The following regions are defined:

USA

European Union (France, Germany, Poland, Romania, UK)

Europe Non-EU (Russia, Ukraine)

South America (Argentina, Chile)

Rest of World (Australia, Canada, Korea)
The variable CENTREID will be used to identify investigators.
8.2.
Other Strata and Covariates
A covariate for region as described above will be included in all model-based analyses. 
Terms for baseline disease severity (as baseline % predicted pre-bronchodilator FEV1), 
the annualised rate of exacerbations in the interval between the MEA112997 trial and the 
screening visit of this study (as an ordinal variable: 0.0-<1.0, 1.0-<2.0, 2.0-<3.0, 3.0-
<4.0, ≥4, See Section 9.2.3) and time on-treatment (as an offset variable) will also be 
included when estimating the annualised rate of exacerbations.
If there are insufficient subjects in each region or exacerbation rate category for the 
statistical procedures to converge satisfactorily, further combining of these covariates
will be considered.
 
 
 
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8.3.
Examination of Subgroups
Tabulations of adverse events, immunogenicity and blood eosinophil data will also be 
reproduced by drug product administered in order to investigate whether there is a 
differential effect of the two drug products used within the trial (See Section 12 and 
Section 11.6).
The annualised rate of exacerbations will also be estimated according to blood eosinophil 
level of ≥150/μL or <150/μL at baseline within MEA115666.
8.4.
Multiple Comparisons and Multiplicity
Not applicable.
9.
DATA HANDLING CONVENTIONS
Details of key definitions and data handling conventions are detailed below as 
appropriate.
9.1.
Withdrawal and Missing Data
9.1.1.
Screening and Enrollment
A subject is considered a Screen Failure if he/she has been assigned a subject identifier 
but does not continue in the study beyond Visit 1 (Screening). A subject is considered a 
Run-in Failure if he/she is not a Screen Failure and entered the run-in period, but was not 
dosed with mepolizumab.
9.1.2.
Missing Data
The primary reason for withdrawal will be recorded in the electronic case report form
(eCRF) and any data collected up until the point of withdrawal will be used in the data 
analyses. No imputation will be performed if a subject drops out of the study for any 
reason, or is lost to follow-up, and their response is unknown.
9.2.
Derived and Transformed Data
9.2.1.
Definition of Baseline and Change from Baseline
The baseline values for each assessment will be the Visit 2 pre-dose assessment. If a 
value is missing at Visit 2 then the value recorded at Visit 1 (Screening) will be used as 
the baseline.
For ECG, clinical chemistry and haematology assessments not scheduled for collection at 
Visit 2, the baseline value will be that recorded at Visit 1 (Screening).
Generally change from baseline will be defined as the difference between the value of the 
endpoint at the time point of interest and the baseline value. However, if stated below, a 
 
 
 
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change from baseline analysis may be performed on the ratio scale and change from 
baseline will be the ratio: time point of interest value/baseline value.
9.2.2.
Exacerbations within MEA115666
Exacerbations of asthma will be defined as worsening of asthma which requires use of 
systemic corticosteroids1 and/or hospitalisation and/or Emergency Department (ED) 
visits.
1For all subjects, IV or oral steroid (e.g., prednisone) for at least 3 days or a single IM 
CS dose is required. For subjects on maintenance systemic corticosteroids, at least 
double the existing maintenance dose for at least 3 days is required.
The on-treatment collection period for exacerbations will be defined as being from Visit 
2 until either the date of the data collection cut-off or the date of withdrawal inclusive 
(but no greater than 4 weeks post last study dose received), See Section 9.3.1. For 
consistency, exacerbations separated by less than 7 days will be treated as a continuation 
of the same exacerbation.
It should be noted that exacerbations recorded in the eCRF will not be verified using 
eDiary data to confirm that the exacerbation was associated with changes in peak flow, 
rescue medication use, nocturnal awakening due to asthma symptoms requiring rescue 
medication use or symptoms. However, 96% of exacerbations captured within
MEA112997 met the protocol-defined exacerbation criteria, and only in 4% of the cases 
were the site/PI not able to provide any objective data to justify the use of corticosteroids.
9.2.3.
Annualised Rate of Exacerbations in the Interval Between
Studies
The annualised rate of exacerbations in the gap between the MEA112997 trial and the 
screening visit of this study will be calculated as:
For those subjects that completed the study: 
For those subjects that withdrew from the trial early:
This rate will be derived and then categorised as explained in Section 8.2. A value of 
365.25 represents the average number of days in a year.
 
 
 
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It should be noted that the number of exacerbations reported between the completion of 
MEA112997 and screening of MEA115666 is self-reported and not subject to 
verification.
9.2.4.
Percent Predicted FEV1
The predicted normal FEV1 is based on the NHANES III equations [Hankinson, 1999] 
and [Hankinson, 2010]. If a subject is recorded as having Hispanic or Latino ethnicity
then the Mexican-American equation will be used (irrespective of race). Otherwise, if a 
subject is recorded as being African-American/African Heritage race, then the African-
American equation will be used, similarly if a subject is recorded as being of Asian race, 
then the Asian equation will be used. Otherwise the Caucasian equation is used.
9.2.5.
12-Lead ECG
‘Maximum post-baseline’ QTc(F) and QTc(B) values will be derived as the maximum 
value recorded at any scheduled or unscheduled visit during the treatment period. 
9.2.6.
Log Transformed Data
Where log-transformed data are used, then summary statistics for these endpoints will 
include geometric mean, and a measure of spread (SD or SE) on the natural log scale. 
Values of zero will be imputed as half the lower limit of quantification for that measure 
(LLQ/2) prior to the log transformation. 
9.3.
Assessment Windows
Clinic visits are scheduled to take place as specified in the protocol. Measurements 
outside visit windows will not be excluded from analyses on any population.
If a subject withdraws at a scheduled visit, and these data were scheduled to be collected 
at that visit, the data will be summarised and analysed (as appropriate) together with data 
from subjects who did not withdraw.
If a subject withdraws at a scheduled visit at which these data were not scheduled to be 
collected, or if a subject withdraws between scheduled visits, data will be slotted to the 
next visit.
9.3.1.
On-Treatment Exacerbations
In order to model the annualised rate of exacerbations, the reporting period for 
exacerbations will be as follows:
For subjects remaining in the study:
(Data collection cut-off date) – (Visit 2 date) + 1.
For early withdrawals: 
(Date of withdrawal) – (Visit 2 date) + 1.
 
 
 
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The on-treatment collection period for exacerbations will be defined as being from Visit 
2 until either the date of the data collection cut-off or the date of withdrawal inclusive 
(but no greater than 4 weeks post last study dose received). 
9.3.2.
On-Treatment Phase
The on-treatment phase for any purpose except the classification of exacerbations is 
defined as being from the day of the first administration to the day of the last 
administration of study treatment + another 28 days inclusive (but no greater than the data 
collection cut-off date).
i.e. time on-treatment will otherwise be defined as follows:
For all subjects: 
(Date of last administration) – (Date of first administration) + 29
but no greater than the data collection cut-off date.
This on-treatment phase will be divided into two periods partitioned at the date and time 
of receiving the new drug product. This transition will occur when a subject switches
from dosing with MDP1 to be dosed with MDP2 for the remainder of the study.
9.3.2.1.
Mepolizumab Drug Product 1 Period
For those subjects that have transitioned onto MDP2, the mepolizumab drug product 1
period starts on the first day of dosing with MDP1, and ends the minute prior to the first 
dose of MDP2.
For those subjects that have not transitioned onto MDP2, the mepolizumab drug product 
1 period is defined as being from the day of the first administration using MDP1 to the 
day of the last administration using MDP1 + another 28 days inclusive (but no greater 
than the data collection cut-off date).
i.e. time within the mepolizumab drug product 1 period will be defined as:
(Date of first MDP2 administration) – (Date of first MDP1 administration) + 1
for those subjects that have transitioned onto MDP2 or
(Date of last MDP1 administration) – (Date of first MDP1 administration) + 29
(but no greater than the data collection cut-off date) for those subjects that have not 
transitioned onto MDP2.
9.3.2.2.
Mepolizumab Drug Product 2 Period
The mepolizumab drug product 2 period is defined as being from the date and time of the 
first administration of MDP2 to the day of the last administration using MDP2 + another 
28 days (but no greater than the data collection cut-off date).
i.e. time within the mepolizumab drug product 2 period will be defined as:
 
 
 
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(Date of last MDP2 administration) – (Date of first MDP2 administration) + 28
(but no greater than the data collection cut-off date)
9.4.
Values of Potential Clinical Importance
Haematological and clinical chemistry data from subjects who have values outside the 
normal range and values of potential clinical concern will be listed. Graphical displays of 
liver function test results will be produced as described in Section 12.8 to identify any 
liver function tests results which may be of clinical concern. See attachment: Section 18.3
for reference values of potential clinical concern.
9.5.
Adverse Events
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) coding dictionary.  Classification of an AE as pre-, on- or post-treatment will 
be made with reference to the study treatment start and stop dates and the AE onset date.  
If the AE onset date is missing or partial then the AE will be considered on-treatment 
unless there is evidence to the contrary (e.g. the month of the onset date is present and is 
less than the month of the first dose of study medication).  AEs with onset up to 4 weeks 
after the last dose of treatment will be considered on-treatment.  AEs with onset after this 
period will be considered post-treatment but will be assigned to the treatment previously 
received.
Any SAEs for screen failures or run-in failures will be classified as pre-treatment SAEs.
The most frequent on-treatment AEs will be defined as AEs with frequency ≥2%.
When presenting summaries of adverse events by drug product, the onset date and time 
of each event will be used to deem in which drug product period the event occurred. For 
the definitions of the two drug product periods, see Section 9.3.2.1 and Section 9.3.2.2.
When presenting the data in this way, if the AE onset date or time is missing or partial 
then the most conservative approach possible will be taken.
9.5.1.
Exposure Adjusted Adverse Events
The number of events per 1000 subject-years of exposure will be calculated as:
 
 
 
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10.
STUDY POPULATION
10.1.
Disposition of Subjects
A summary of the number of subjects included in each population will be produced. 
The proportion of screen failures, the proportion who reported each reason for screen 
failure, the proportion of run-in failures and the proportion who reported each reason for 
run-in failure will be presented for the ASE population.
The proportion of subjects in the AT population who has withdrawn from the study, and 
reported each reason for withdrawal, will be presented. A Kaplan-Meier plot showing the 
percentage of subjects withdrawing from the study over time will be produced for the AT
Population. 
Summaries and graphs of the Kaplan-Meier estimates of the proportion of subjects 
withdrawn due to lack of efficacy over time will be produced.
Summaries and graphs of the Kaplan-Meier estimates of the proportion of subjects 
withdrawn due to adverse events over time will be produced.
The proportion of subjects in the AT population at each centre and within each country 
and region will be presented. Subject number in MEA115666, treatment received in
MEA115666, subject number in MEA112997 and treatment assigned in MEA112997 and 
will be listed for each centre in the AT population.
10.2.
Protocol Deviations
The proportion of subjects in the AT population who failed each inclusion, exclusion or 
Visit 2 criterion will be presented. Protocol deviations will be listed for the AT
Population. 
10.3.
Demographic and Baseline Characteristics
10.3.1.
Demography and Race
Demographic characteristics (age, sex, ethnicity, height, weight and body mass index) 
will be summarised and listed.
The proportion of subjects reporting each race and racial combination and each detailed 
race and racial combination will be presented.  Race will be listed.
10.3.2.
Medical Conditions
An update in each subject’s medical history since completing the medical history form in 
the MEA112997 trial will be collected at Visit 1 (Screening). If a subject reports no 
change in medical history, the respective subject’s medical history information will be 
copied over from the MEA112997 trial.
 
 
 
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The proportion of subjects who report medical conditions in each medical condition class 
will be presented, for past and current conditions separately. Past and current medical 
conditions will be listed.
10.3.3.
Cardiovascular Assessment
A summary of the baseline cardiovascular assessment will be presented. The proportion 
of subjects who report a family history of medical conditions that may indicate 
predisposition towards cardiovascular conditions will be summarised.
10.3.4.
Since Completion of MEA112997
The number of days and number of exacerbations experienced between the completion of 
MEA112997 and Visit 1 (Screening) in MEA115666 will be summarised. The 
completion date of MEA112997 will be considered as the Visit 16 (Week 52) date for 
those subjects who completed the study, and will be considered as the date of withdrawal 
for those subjects that withdrew from the trial prematurely.
10.3.5.
Baseline Lung Function Tests
The following Baseline (Visit 2) clinic lung function results will be summarised:  

Pre bronchodilator FEV1 (mL)

Pre bronchodilator percent predicted FEV1 (%)

Pre bronchodilator Forced Vital Capacity FVC (mL)

Pre bronchodilator FEV1/FVC
10.4.
Treatment Compliance
A summary of treatment compliance is not applicable to this study; however number of 
treatments received is summarised in the Extent of Exposure Section 12.1.
10.5.
Concomitant Medications
The proportion of subjects reporting each concomitant medication will be presented.  
Multi-ingredient medications will be presented according to their combination ATC 
classification rather than the classifications of the ingredients.  Summaries will be split 
into asthma and non-asthma concomitant medications, as well as into those taken pre-
treatment, during treatment and post-treatment (as described in Section 9.3).  Asthma 
medication outputs will not display the ATC grouping.
Classification of a medication as pre-, on- or post-treatment will be made with reference 
to the study treatment start and stop dates and the medication start date.  If the medication
start date is missing or partial then the medication will be considered on-treatment unless 
there is evidence to the contrary (e.g. the month of the start date is present and is less than 
the month of the first dose of study medication).  Medications with a start date of up to 4 
weeks after the last dose of treatment will be considered on-treatment.  Medications with 
a start date after this period will be considered post-treatment.
 
 
 
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Pre- and on-treatment respiratory medications will be summarised separately.
A medication will be summarised in every period (pre/during/post) in which it was taken, 
so a medication that was started in the run-in and stopped during active treatment will 
appear in both the pre-treatment and the during treatment tables.
A listing of the relationship between ATC level 1, ingredient and verbatim term will be 
produced together with listings of all asthma and non-asthma concomitant medications.
11.
EFFICACY ANALYSES
Efficacy data will be summarised using appropriate measures (means/geometric means, 
standard deviations, medians and ranges for continuous variables and frequencies and 
percentages for categorical variables). Unless otherwise stated, analyses will be 
conducted only for the AT Population.  
11.1.
Annualised Rate of Exacerbations
The frequency of exacerbations of asthma collected during the on-treatment phase (See 
Section 9.3.1) will be summarised for the AT population. For consistency, exacerbations 
separated by less than 7 days will be treated as a continuation of the same exacerbation
(See Section 9.2.2).
The annualised rate of exacerbations will be estimated using a negative binomial 
generalised linear model with a log link-function. The covariates listed in Section 8.2 will 
be used in the model. The estimated mean rate per year and 95% confidence interval will 
be presented. (The estimates of the mean rates should be presented using the observed 
marginals of the sample covariates). 
The annualised rate of exacerbations will also be estimated according to blood eosinophil 
level of ≥150/μL or <150/μL at baseline within MEA115666.
11.2.
Time to First Exacerbation
Summaries and graphs of the Kaplan-Meier estimates of the proportion of subjects with 
an exacerbation over time will be produced.
11.3.
Hospitalisations Due to Exacerbations or Adverse Events
Within a single table, the number of hospitalizations due to exacerbations and the number 
of hospitalizations due to adverse events will be summarized.
11.4.
Asthma Control Questionnaire Score
Asthma Control Questionnaire (ACQ) score (absolute value and changes from baseline) 
will be summarised by visit (withdrawals will be presented as a separate category). 
 
 
 
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11.5.
FEV1 Measured by Clinic Spirometry
Pre-bronchodilator FEV1 (absolute value and changes from baseline (mL)) will be 
summarised by visit.
11.6.
Blood Eosinophils
Blood eosinophil count and ratio to baseline will be summarised by visit. Blood 
eosinophil count and ratio to baseline will be also be summarised by drug product and 
visit in a separate table. For the definitions of the two drug product periods, see Section
9.3.2.1 and Section 9.3.2.2.
Blood eosinophil counts collected whilst receiving the two drug products will be further 
compared by summarising the last sample to be collected prior to the first dose of MDP2 
and the first sample collected following the first dose with MDP2. This particular table 
will only include those subjects that have a blood eosinophil sample collected from both 
drug product periods.
Values below the lower limit of quantification will be imputed as half the lower limit of 
quantification prior to summarising. Data will be log-transformed prior to summarising. 
Blood eosinophil data will also be listed.
12.
SAFETY ANALYSES
All safety summaries and listings will be produced for the AT population, with the 
exception of the table of pre-treatment SAEs and relationship between system organ 
class, preferred term and verbatim term which will be reported for the ASE population. 
Similarly, listings of subject numbers for individual AEs, all AEs, fatal AEs and non-fatal 
SAEs will be reported for the ASE population.
12.1.
Extent of Exposure
The number of treatments administered and the number of days on-treatment will be 
summarised and listed. The listing of exposure will also contain information of the drug 
product administered at each dosing visit. For definition of on-treatment, see Section
9.3.2.
The number of treatments administered and the number of days on-treatment will also be 
summarised by drug product. For the definitions of the two drug product periods, see
Section 9.3.2.1 and Section 9.3.2.2.
12.2.
Adverse Events
Adverse events will be summarised by preferred term. Numbers will be presented for the 
whole population. Additionally, events experienced during the first 6 months of treatment 
within MEA115666 will be presented by treatment assigned within MEA112997.
AEs occurring during pre-treatment, on-treatment and post-treatment phase will be 
summarised separately.  
 
 
 
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The number and percentage of subjects experiencing at least one AE of any type, AEs 
within each body system and AEs within each preferred term will be summarised.
All AEs and SAEs will be summarised by drug product. For the definitions of the two 
drug product periods, see Section 9.3.2.1 and Section 9.3.2.2.
Exposure adjusted rates of AEs will be presented by drug product to account for any 
differences in the length of exposure to the two different drug products within the trial.
For the definition of exposure adjusted AEs, see Section 9.5.1.

Overview of all Adverse Events
The following summary tables will be produced: 

Summary of all Adverse Events (on-treatment and post-treatment)

Summary of drug related Adverse Events (on-treatment)

Relationship of all Adverse Event SOCs, PTs, and Verbatim Text

Summary of Most Frequent (≥ 2% Incidence) Adverse Events (on-treatment)

Summary of all Adverse Events Experienced During the First 6 Months of 
Treatment by Treatment Assigned within MEA112997 (on-treatment)

Summary of all AEs by drug product (on-treatment)

Summary of Exposure Adjusted AEs by drug product
The following listings will be produced:

Listing of Subject Numbers for Individual Adverse Events

Listing of all Adverse Events
12.3.
Deaths and Serious Adverse Events
The following summary tables will be produced: 

Summary of Serious Adverse Events (pre-treatment, on-treatment and post-
treatment)

Summary of Serious Adverse Events by drug product (on-treatment)

Summary of Exposure Adjusted Serious Adverse Events by drug product

Summary of Fatal Events (any period)
The following listings will be produced:
 
 
 
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
Listing of Fatal Adverse Events

Listing of all Non-Fatal Serious Adverse Events
 
 
 
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12.4.
Adverse Events Leading to Discontinuation of 
Investigational Product and/or Withdrawal from the Study 
and Other Significant Adverse Events
Systemic or local site injection reactions will be summarised.
The following summary tables will be produced: 

Summary of Adverse Events Leading to Permanent Discontinuation of Study 
Drug or Withdrawal from Study (pre-treatment and on-treatment)

Summary of Adverse Events Leading to Interruption of Study Drug (on-
treatment)

Summary of AEs defined by the investigator as being systemic (non-allergic or 
allergic/hypersensitivity) reactions (on-treatment)

Summary of AEs defined by the investigator as being local injection site reactions 
(on-treatment)

Summary of symptoms associated with AEs defined by the investigator as being 
systemic (non-allergic or allergic/hypersensitivity) reactions (on-treatment)

Summary of symptoms associated with AEs defined by the investigator as being 
local injection site reactions (on-treatment)

Summary of Serious Cardiac, Vascular and Thromboembolic Adverse Events (on-
treatment) (This summary will report the events falling into the cardiac disorders 
and vascular disorders SOCs, plus additional thromboembolic events from other 
SOCs [e.g., stroke is categorized under the Nervous System SOC] identified by 
the Safety Review Team).
The following listings will be produced:

Listing of Adverse Events Leading to Permanent Discontinuation of Study Drug 
and/or Withdrawal from the Study (pre-treatment and on-treatment)

Listing of Adverse Events (with symptoms) defined by the investigator as being 
systemic (non-allergic or allergic/hypersensitivity) reactions (on-treatment)

Listing of Adverse Events (with symptoms) defined by the investigator as being 
local injection site reactions (on-treatment)

Listing of All Anaphylaxis Reaction Events

Listing of Opportunistic Infections (as defined by the Safety Review Team)
 
 
 
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12.5.
Cardiovascular Events of Interest
The event specific pages in the eCRF will be summarised. Summaries of events which 
were reported and confirmed (or not) as cardiovascular following adjudication by the trial 
Clinical Endpoint Committee (CEC) will be summarised.
The following cardiovascular event listings will be produced for both CEC adjudicated 
events and all investigator reported events. Arrhythmias, pulmonary hypertension, 
revascularisation and valvulopathy events will not be adjudicated by the CEC so these 
event listings will only be produced for investigator reported events. Adjudicated 
investigator reported events that are not considered by the CEC to be cardiovascular in 
nature will be identified with a footnote in the relevant investigator reported event 
listings/summaries. 

Arrhythmias (Investigator reported only)

Congestive Heart Failure

Cerebrovascular Events/Strokes

Deep venous Thrombosis/ Pulmonary Embolism

Myocardial Infarction /Unstable Angina

Peripheral Arterial Thrombosis Embolism

Pulmonary Hypertension (Investigator reported only)

Revascularisation (Investigator reported only)

Valvulopathy (Investigator reported only)

Deaths (all cause)
12.6.
Pregnancies (as applicable)
Any pregnancy complication or elective termination of a pregnancy for medical reasons 
will be recorded as an AE or SAE and included in summaries and listings of AEs/SAEs 
as described above in Section 12.2.
12.7.
Clinical Laboratory Evaluations
The actual values and change from baseline values for clinical chemistry and 
haematology will be summarised, in separate tables. Summaries of the data outside the 
normal range and the changes from baseline relative to the normal range will also be 
produced, including ‘any time post-baseline’, which will include laboratory assessments 
taken at scheduled, unscheduled and Early Withdrawal visits and will report the most 
extreme value(s). Data from subjects who have values outside the normal range will be 
listed. The normal ranges will also be included in this listing.  Summaries of values of 
 
 
 
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potential clinical concern will be produced.  Data from subjects who have values of 
potential clinical concern will be listed and the ranges of potential clinical concern will be 
included in this listing.
A trellis display of maximum post-dose liver function test (LFT) versus baseline LFT and 
a box plot of maximum LFTs will be produced.
12.8.
Liver Events
Liver event information will be summarised and listed for all subjects who report a liver 
event, to include:

The information captured on the Liver Event Assessment Form which is used to 
calculate the Roussel Uclaf Causality Assessment Method (RUCAM) score.  

The time from the start of study treatment to the liver event and the time from the 
most recent study treatment to the liver event.

The size of the biopsy and the recorded outcomes for the liver biopsy. 

The recorded outcomes for the liver imaging assessment.
Information on alcohol use for subjects who report a liver event will be included in the 
listing of substance use. Medical conditions reported at the time of the liver event will be
included in the listing of medical conditions (see Section 10.3.2).
12.9.
Vital Signs
Pre-dose systolic blood pressure, diastolic blood pressure and pulse rate including change 
from baseline on all visits will be summarised and listed.
12.10.
12-lead ECG
Actual and change from baseline (for post-baseline timepoints) values for QTc(F), 
QTc(B) and heart rate will be summarised by visit.  ECG results will also be listed. 
Abnormal findings and interpretations will be listed separately.
Individual maximum QTc(F) and QTc(B) values will also be summarised to show the 
number of subjects with maximum values (msec) in the following categories:

≤450

450 < to ≤480

480 < to ≤500

> 500 
Additionally, individual maximum changes from baseline in QTc(F) and QTc(B) values 
will be summarised to show the number of subjects with maximum changes (msec) in the 
following categories: 
 
 
 
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
< -60

≥ -60 to < -30

≥ -30 to < 0

≥  0 to < 30

≥  30 to < 60

≥ 60. 
12.11.
Immunogenicity
Two types of antibody assay will be performed, i.e. an immunogenicity status anti-drug 
antibody (ADA) assay and neutralising antibody (NAb) assay. For the ADA assay, a 
screening assessment will be performed which produces a result of positive or negative. 
For samples with a positive screening result, a confirmation assay will be carried out, 
which also produces a result of positive or negative. For samples with a positive 
confirmation result, a titre value will also be obtained to quantify the degree of binding. 
Subjects will be viewed as positive for the ADA assay if the confirmation assay is
positive.
For subjects who have a positive confirmation result for the ADA assay, a neutralising 
assay will be performed, which again produces a result of positive or negative. 
A table will be produced summarising results for the ADA assay in the AT Population by
visit. The table will include the number and proportion of subjects in each results 
category (see below) for each visit. ADA confirmatory assay results will be categorised 
as follows:
1. Negative
2. Positive (any titre result)

Positive (titre result ≤Q1)

Positive (titre result > Q1 - ≤Q2)

Positive (titre result > Q2 - ≤Q3)

Positive (titre result > Q3)
where Q1 – Q4 represents quartiles of all titre values observed in the study.
Additionally, results for the ADA assay for the AT Population during the first 6 months 
of treatment within MEA115666 will be summarised by treatment assigned within 
MEA112997 and visit.
These two tables will also summarise the highest ADA assay confirmatory result 
obtained for each subject. If a subject had both Negative and Positive confirmatory
results, they will be included in the Positive category. If a subject had titre results that fall 
into multiple titre result categories, they will be included in the highest category.
A table will also be produced summarising results for the ADA assay in the AT 
Population by drug product and visit. For the definitions of the two drug product periods, 
 
 
 
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see Section 9.3.2.1 and Section 9.3.2.2. This table will also summarise the highest ADA 
assay confirmatory result obtained for each subject whilst receiving each drug product. If 
a subject had both Negative and Positive confirmatory results, they will be included in 
the Positive category. If a subject had titre results that fall into multiple titre result 
categories, they will be included in the highest category.
A table will also be produced summarising results for the NAb assay in the AT
Population by visit. Neutralising assay results will be categorised as follows:
1. Negative
2. Positive 
Additionally, results for the NAb assay for the AT Population during the first 6 months of 
treatment within MEA115666 will be summarised by treatment assigned within 
MEA112997 and visit.
These two tables will also summarise the highest neutralising assay confirmatory result 
obtained for each subject. If a subject had both Negative and Positive results, they will be 
included in the Positive category.
A table will also be produced summarising results for the NAb assay in the AT 
Population by drug product and visit. For the definitions of the two drug product periods, 
see Section 9.3.2.1 and Section 9.3.2.2. This table will also summarise the highest 
neutralising assay confirmatory result obtained for each subject whilst receiving each 
drug product. If a subject had both Negative and Positive results, they will be included in 
the Positive category.
All immunogenicity results (i.e. ADA screening and confirmatory assay results, titre 
values, NAb results) will be listed.
13.
HEALTH OUTCOMES ANALYSES
13.1.
Resource Utilisation Measures
Healthcare resource use due to an exacerbation will be summarised for the AT 
population.
14.
CLINICAL PHARMACOLOGY DATA ANALYSES
Not applicable to this study.
15.
BIOMARKER DATA ANALYSIS
Not applicable to this study.
16.
PHARMACOGENETIC DATA ANALYSES
Not applicable to this study.
 
 
 
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17.
REFERENCES
GlaxoSmithKline Document Number 2012N139436_02 Study ID MEA115666. A multi-
centre, open-label, long term safety study of mepolizumab in asthmatic subjects who 
participated in the MEA112997 trial. Report Date 06-MAR-2013. 
Hankinson JL, Kawut SM, Shahar E, Smith LJ, Stukovsky KH, Barr RG. Performance of 
American Thoracic Society-Recommended Spirometry Reference Values in a 
Multiethnic Sample of Adults. Chest. 2010;137/1:138-145.
Hankinson JL, Odencrantz JR, Fedan KB. Spirometric Reference Values from a Sample 
of the General US Population. American Journal of Respiratory and Critical Care. 
1999;159:179-187. 
 
 
 
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18.
ATTACHMENTS
18.1.
Table of Contents for Data Display Specifications
18.1.1.
Study Population Tables
Number
Title
Pop
5.01
Summary of Subject Populations
ASE
5.02
Summary of Reasons for Screen Failure 
ASE
5.03
Summary of Reasons for Run-in Failure 
ASE
5.04
Summary of Attendance at Each Clinic Visit
AT
5.05
Summary of Attendance at Each Clinic Visit by Drug 
Product
AT
5.06
Summary of Visit Where Drug Product Switched
AT
5.07
Summary of Subject Disposition
AT
5.08
Analysis of Time to Withdrawal Due to Lack of 
Efficacy
AT
5.09
Analysis of Time to Withdrawal Due to Adverse Events
AT
5.10
Summary of Number of Subjects by Region, Country 
and Centre
AT
5.11
Summary of Failed Inclusion/Exclusion/Visit 2 Criteria 
for Screen or Run-in Failures
ASE
5.12
Summary of Inclusion/Exclusion/Visit 2 Criteria 
Deviations
AT
5.13
Summary of Demographic Characteristics 
AT
5.14
Summary of Race and Racial Combinations
AT
5.15
Summary of Race and Racial Combination Details
AT
5.16
Summary of Past Medical Conditions
AT
5.17
Summary of Current Medical Conditions
AT
5.18
Summary of Cardiovascular Assessments – Screening 
Questions
AT
5.19
Summary of Cardiovascular Assessments – Family 
History 
AT
5.20
Summary of Exacerbations Since Completion of 
MEA112997
AT
5.21
Summary of Time Since Completion of MEA112997
AT
5.22
Summary of History of Xolair Use
AT
5.23
Summary of Baseline Lung Function Results
AT
5.24
Summary of Asthma Concomitant Medications Taken 
Before the Run-In
AT
5.25
Summary of Asthma Concomitant Medications Taken 
During the Run-In
AT
 
 
 
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Number
Title
Pop
5.26
Summary of Asthma Concomitant Medications Taken 
During Treatment
AT
5.27
Summary of Asthma Concomitant Medications Started 
During Treatment
AT
5.28
Summary of Asthma Concomitant Medications Taken 
Post-Treatment
AT
5.29
Summary of Asthma Concomitant Medications Taken 
Before the Run-In by Respiratory Medication Class
AT
5.30
Summary of Asthma Concomitant Medications Taken 
During Treatment by Respiratory Medication Class
AT
5.31
Summary of Asthma Concomitant Medications Started 
During Treatment by Respiratory Medication Class
AT
5.32
Summary of Asthma Concomitant Medications Taken 
Post-Treatment by Respiratory Medication Class
AT
5.33
Summary of Non-Asthma Concomitant Medications 
Taken During Treatment
AT
18.1.2.
Study Population Figures
Number
Title
Pop
5.01
Time to Withdrawal
AT
5.02
Kaplan-Meier Cumulative Incidence Curve for Time to 
Withdrawal due to Lack of Efficacy
AT
5.03
Kaplan-Meier Cumulative Incidence Curve for Time to 
Withdrawal due to Adverse Events
AT
18.1.3.
Study Population Listings
Number
Title
Pop
5.01
Listing of Reasons for Screen Failure and Run-in 
Failure
ASE
5.02
Listing of Reasons for Withdrawal
AT
5.03
Listing of Current and Previous Treatment
AT
5.04
Listing of Subjects with Inclusion, Exclusion and Visit 
2 Criteria Deviations
AT
5.05
Listing of Protocol Deviations
AT
5.06
Listing of Demographic Characteristics
AT
5.07
Listing of Race
AT
 
 
 
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Number
Title
Pop
5.08
Listing of Medical Conditions
AT
5.09
Listing of Cardiovascular Assessment
AT
5.10
Listing of Relationship Between ATC Level 1, 
Ingredient and Verbatim Text
AT
5.11
Listing of Asthma Concomitant Medications
AT
5.12
Listing of non-Asthma Concomitant Medication
AT
18.1.4.
Efficacy Tables
Number
Title
Pop
6.01
Overview of All Exacerbations
AT
6.02
Overview of Exacerbations Requiring Hospitalisation 
and SAEs
AT
6.03
Summary of Frequency of Exacerbations
AT
6.04
Annualised Rate of Exacerbations
AT
6.05
Annualised Rate of Exacerbations by Baseline Blood 
Eosinophils
AT
6.06
Analysis of Time to First Exacerbation
AT
6.07
Summary of Hospitalisations due to Exacerbations and 
Adverse Events 
AT
6.08
Summary of Asthma Control Questionnaire (ACQ) 
score
AT
6.09
Summary of Clinic Pre-Bronchodilator FEV1
AT
6.10
Summary of Blood Eosinophils
AT
6.11
Summary of Blood Eosinophils by Drug Product
AT
6.12
Summary of Blood Eosinophils Pre and Post-Change in 
Drug Product
AT
18.1.5.
Efficacy Figures
Number
Title
Pop
6.01
Kaplan-Meier Cumulative Incidence Curve for Time to 
First Exacerbation
AT
 
 
 
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18.1.6.
Efficacy Listings
Number
Title
Pop
6.01
Listing of Exacerbations
AT
6.02
Listing of Lung Function Data
AT
6.03
Listing of Blood Eosinophil Data
AT
18.1.7.
Safety Tables
Number
Title
Pop
7.01
Summary of Number of Treatments Administered
AT
7.02
Summary of Number of Treatments Administered by 
Drug Product
AT
7.03
Overview of All Adverse Events
ASE
7.04
Summary of On-Treatment Adverse Events
AT
7.05
Summary of Post-Treatment Adverse Events
AT
7.06
Summary of Drug-Related Adverse Events (On-
Treatment)
AT
7.07
Relationship of All Adverse Event System Organ 
Class, Preferred Term and Verbatim Text
ASE
7.08
Summary of Most Frequent On-Treatment Adverse 
Events
AT
7.09
Summary of Serious Pre-Treatment Adverse Events
ASE
7.10
Summary of Serious On-Treatment Adverse Events
AT
7.11
Summary of Serious Post-Treatment Adverse Events
AT
7.12
Summary of Fatal Events
AT
7.13
Summary of Pre-Treatment Adverse Events Leading to 
Permanent Discontinuation of Study Drug or 
Withdrawal from Study 
ASE
7.14
Summary of On-Treatment Adverse Events Leading to 
Permanent Discontinuation of Study Drug or 
Withdrawal from Study
AT
7.15
Summary of Adverse Events Leading to Interruption of 
Study Drug (On-Treatment)
AT
7.16
Summary of AEs Defined by the Investigator as being 
Systemic (ie, Allergic/IgE-mediated and Non-allergic) 
Reactions (On-Treatment)
AT
7.17
Summary of AEs Defined by the Investigator as being 
Local Injection Site Reactions (On-Treatment)
AT
7.18
Summary of Symptoms Associated with AEs Defined 
by the Investigator as being Systemic (ie, Allergic/IgE-
AT
 
 
 
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Number
Title
Pop
mediated and Non-allergic) Reactions (On-Treatment)
7.19
Summary of Symptoms Associated with AEs Defined 
by the Investigator as being Local Injection Site 
Reactions (On-Treatment)
AT
7.20
Listing of Anaphylaxis Criteria
AT
7.21
Summary of Serious Cardiac, Vascular and 
Thromboembolic Adverse Events (On-Treatment)
AT
7.22
Summary of All Reported Cardiovascular Adverse 
Events of Interest
AT
7.23
Summary of All Reported and CEC Adjudicated 
Cardiovascular Adverse Events of Interest
AT
7.24
Summary of all Adverse Events Experienced During 
First 6 Months of Treatment by Treatment Assigned 
within MEA112997
AT
7.25
Summary of all AEs by Drug Product (On-Treatment)
AT
7.26
Summary of Exposure Adjusted AEs by Drug Product
AT
7.27
Summary of Serious Adverse Events by Drug Product 
(On-Treatment)
AT
7.28
Summary of Exposure Adjusted Serious Adverse 
Events by Drug Product
AT
7.29
Summary of Chemistry Data
AT
7.30
Summary of Change From Baseline in Chemistry Data
AT
7.31
Summary of Chemistry Data Outside the Normal 
Range
AT
7.32
Summary of Chemistry Changes from Baseline 
Relative to the Normal Range
AT
7.33
Summary of Chemistry Data Outside the Reference 
Range (Potential Clinical Concern)
AT
7.34
Summary of Chemistry Changes from Baseline 
Relative to the Reference Range (Potential Clinical 
Concern)
AT
7.35
Summary of Haematology Data
AT
7.36
Summary of Change From Baseline in Haematology 
Data
AT
7.37
Summary of Haematology Data Outside the Normal 
Range
AT
7.38
Summary of Haematology Changes from Baseline 
Relative to the Normal Range
AT
7.39
Summary of Haematology Data Outside the Reference 
Range (Potential Clinical Concern)
AT
7.40
Summary of Haematology Changes from Baseline 
Relative to the Reference Range (Potential Clinical 
Concern)
AT
7.41
Summary of  Liver Events Assessment
AT
 
 
 
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Number
Title
Pop
7.42
Summary of Time On-Treatment Before Liver Event
AT
7.43
Summary of Vital Signs
AT
7.44
Summary of Change from Baseline in Vital Signs
AT
7.45
Summary of ECG findings
AT
7.46
Summary of ECG Values
AT
7.47
Summary of Change From Baseline in ECG Values
AT
7.48
Frequency of Maximum QTc(F) Interval (msec)
AT
7.49
Frequency of Maximum QTc(B) Interval (msec)
AT
7.50
Summary of ADA Assay Results
AT
7.51
Summary of NAb Assay Results
AT
7.52
Summary of ADA Assay Results During First 6 
Months of Treatment by Treatment Assigned within 
MEA112997
AT
7.53
Summary of NAb Assay Results During First 6 Months 
of Treatment by Treatment Assigned within 
MEA112997
AT
7.54
Summary of ADA Assay Results by Drug Product
AT
7.55
Summary of NAb Assay Results by Drug Product
AT
18.1.8.
Safety Figures
Number
Title
Pop
7.01
Display of AE Incidence Rates
AT
7.02
Trellis Display of Maximum Post-Baseline LFT Values 
Versus Baseline LFT Values
AT
7.03
Box Plot of Maximum Post-Baseline Liver Function 
Tests
AT
18.1.9.
Safety Listings
Number
Title
Pop
7.01
Listing of Exposure Data
AT
7.02
Listing of Subject Numbers for Individual Adverse 
Events
ASE
7.03
Listing of All Adverse Events
ASE
7.04
Listing of Fatal Adverse Events
ASE
7.05
Listing of Non-Fatal Serious Adverse Events
ASE
 
 
 
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Number
Title
Pop
7.06
Listing of Adverse Events Leading to Permanent 
Discontinuation of Study Drug or Withdrawal from the 
Study
AT
7.07
Listing of Adverse Events Defined by the Investigator 
as a Systemic (ie, Allergic/IgE-mediated and Non-
allergic) Reaction
AT
7.08
Listing of Adverse Events Defined by the Investigator 
as a Local Injection Site Reaction
AT
7.09
Listing of Opportunistic Infections
AT
7.10
Listing of Investigator Reported Cardiovascular 
Events: Arrhythmias
AT
7.11
Listing of Investigator Reported Cardiovascular 
Events: Congestive Heart Failure
AT
7.12
Listing of Investigator Reported Cardiovascular 
Events: Cerebrovascular Events/Stroke
AT
7.13
Listing of Investigator Reported Cardiovascular 
Events: Deep venous Thrombosis/ Pulmonary 
Embolism
AT
7.14
Listing of Investigator Reported Cardiovascular 
Events: Myocardial Infarction /Unstable Angina
AT
7.15
Listing of Investigator Reported Cardiovascular 
Events: Peripheral Arterial Thrombosis Embolism
AT
7.16
Listing of Investigator Reported Cardiovascular 
Events: Pulmonary Hypertension
AT
7.17
Listing of Investigator Reported Cardiovascular 
Events: Revascularisation
AT
7.18
Listing of Investigator Reported Cardiovascular 
Events: Valvulopathy
AT
7.19
Listing of Investigator Reported Events: All Cause 
Deaths
AT
7.20
Listing of CEC Adjudicated Cardiovascular Events: 
Congestive Heart Failure
AT
7.21
Listing of CEC Adjudicated Cardiovascular Events: 
Cerebrovascular Events/Stroke
AT
7.22
Listing of CEC Adjudicated Cardiovascular Events: 
Deep venous Thrombosis/ Pulmonary Embolism
AT
7.23
Listing of CEC Adjudicated Cardiovascular Events: 
Myocardial Infarction /Unstable Angina
AT
7.24
Listing of CEC Adjudicated Cardiovascular Events: 
Peripheral Arterial Thrombosis Embolism
AT
7.25
Listing of CEC Adjudicated Events: All Cause Deaths
AT
7.26
Listing of Chemistry Data for Subjects with at Least 
One Value Outside the Normal Range
AT
 
 
 
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Number
Title
Pop
7.27
Listing of Haematology Data for Subjects with at 
Least One Value Outside the Normal Range
AT
7.28
Listing of Urinalysis Data
AT
7.29
Listing of Liver Event Information for RUCAM Score
AT
7.30
Listing of Liver Event Results and Time of Event 
Relative to Treatment
AT
7.31
Listing of Liver Biopsy Details
AT
7.32
Listing of Liver Imaging Details
AT
7.33
Listing of Alcohol Intake at Onset of Liver Event
AT
7.34
Listing of Vital Signs
AT
7.35
Listing of ECG Values
AT
7.36
Listing of ECG Findings for Abnormal Interpretations
AT
7.37
Listing of Immunogenicity Results
AT
18.1.10.
Health Outcomes Tables
Number
Title
Pop
8.01
Summary of Unscheduled Healthcare Resource Use 
Associated with an Exacerbation
AT
18.2.
Data Display Specifications
The data display shells are contained in separate documents which are available on 
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18.3.
Laboratory Potential Clinical Concern Values
Table 2
Chemistry Values of Potential Clinical Concern
ANALYTE
Age
Sex
SI Units
F3 low
F3 high
SODIUM
0+
Both
MMOL/L
120
160
POTASSIUM
3+
Both
MMOL/L
2.8
6.5
CALCIUM
3+
Both
MMOL/L
1.50
3.24
PHOSPHORUS, 
INORG
3+
Both
MMOL/L
0.32
GLUCOSE
1+
Both
MMOL/L
2.2
27.8
ALT (SGPT)
3-12
Both
U/L
>143 (and 
Total Bilirubin 
> 43)
ALT (SGPT)
13+
Both
U/L
>239 (and 
Total Bilirubin
> 43)
Table 3
Haematology Values of Potential Clinical Concern
ANALYTE
Age
Sex
SI Units
F3 low
F3 high
HAEMOGLOBIN
12+
Both
G/L
71
199
HAEMATOCRIT
12+
Both
1
0.201
0.599
PLATELET 
COUNT
1+
Both
GI/L
31
1499
WHITE CELL 
COUNT
12+
Both
GI/L
1.1
 
 
 
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