An Open-label, Single Arm, Repeat Dose, Multi-centre Study to Evaluate the Use of a Safety Syringe for the Subcutaneous Administration of Mepolizumab in Subjects With Severe Eosinophilic Asthma (Study 205667)
Phase: PHASE3
Conditions: Asthma
Sponsor: GlaxoSmithKline

2016N275349_02
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The GlaxoSmithKline group of companies
205667
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TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
An open-label, single arm, repeat dose, multi-centre study to 
evaluate the use of a safety syringe for the subcutaneous 
administration of mepolizumab in subjects with severe 
eosinophilic asthma (Study 205667)
Compound Number:
SB-240563
Development Phase:
IIIA
Effective Date:
06-OCT-2016
Protocol Amendment Number:  01
Author (s):
 
 
Copyright 2016 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD

2016N275349_02
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The GlaxoSmithKline group of companies
205667
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Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2016N275349_00
2016-AUG-12
Original
2016N275349_01
2016-AUG-18
Republishing
To add serious systemic reactions including anaphylaxis to the risk assessment section
To remove GCSP as a contributory author as per GUI_264305 (3.0)
To clarify the wording around assessing eosinophilia from blood counts collected 
following a Liver Stopping Event
2016N275349_02
2016-OCT-06
Amendment No. 1
To refine the criteria for a successful injection following a use-related risk review
To amend Exclusion Criterion 7 to allow either Fridericia’s or Bazett’s to be used as the 
correction formula for heart rate when measuring the QT interval
To remove Exclusion Criterion 15 as the exclusion of pregnant or lactating females is 
covered in Inclusion Criterion 9
To correct the EudraCT No.
To correct minor typographical errors

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MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information: 
Role
Name
Day Time Phone Number and 
email address
After-hours 
Phone/Cell/
Pager 
Number
Fax 
Number
Site Address
Primary 
Medical 
Monitor 
Telephone: 
Cell:
Fax: 
GlaxoSmithKline
Upper Merion
709 Swedeland 
Road, King of 
Prussia, PA –
19406
USA
Secondary 
Medical 
Monitor
 
Telephone: 
Cell:
Fax: 
GlaxoSmithKline
Upper Merion
709 Swedeland 
Road, King of 
Prussia, PA –
19406
USA
SAE 
contact  
information 
Telephone: 
Cell:
Fax: 
GlaxoSmithKline
Upper Merion
709 Swedeland 
Road, King of 
Prussia, PA –
19406
USA
Sponsor Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate 
Company (or designee). If applicable, the details of the alternative Sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application.   
Regulatory Agency Identifying Number(s): IND No 006971, EudraCT No: 2016-001831-
10
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 205667
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
1.
PROTOCOL SYNOPSIS FOR STUDY 205667........................................................9
2.
INTRODUCTION....................................................................................................12
2.1.
Study Rationale ..........................................................................................12
2.2.
Brief Background ........................................................................................12
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................13
4.
STUDY DESIGN ....................................................................................................15
4.1.
Overall Design ............................................................................................15
4.2.
Treatment Arms and Duration.....................................................................17
4.3.
Type and Number of Subjects.....................................................................19
4.4.
Design Justification.....................................................................................19
4.5.
Dose Justification........................................................................................19
4.6.
Benefit:Risk Assessment ............................................................................19
4.6.1.
Risk Assessment .........................................................................21
4.6.2.
Benefit Assessment.....................................................................24
4.6.3.
Overall Benefit:Risk Conclusion...................................................24
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............24
5.1.
Inclusion Criteria.........................................................................................25
5.2.
Exclusion Criteria........................................................................................27
5.3.
Continuation to Treatment Criteria ..............................................................28
5.4.
Pre-Screening/Screening Failures ..............................................................29
5.5.
Withdrawal/Stopping Criteria.......................................................................29
5.5.1.
Withdrawal from the Study...........................................................30
5.5.2.
Liver Chemistry Stopping Criteria ................................................31
5.5.2.1.
Study Treatment Restart or Rechallenge....................32
5.5.3.
QTc Stopping Criteria ..................................................................32
5.6.
Subject and Study Completion....................................................................33
6.
STUDY TREATMENT ............................................................................................33
6.1.
Investigational Product and Other Study Treatment....................................33
6.2.
Medical Devices..........................................................................................34
6.3.
Treatment Assignment................................................................................35
6.4.
Blinding.......................................................................................................35
6.5.
Packaging and Labeling..............................................................................35
6.6.
Preparation/Handling/Storage/Accountability..............................................35
6.7.
Training Session.........................................................................................36
6.8.
Compliance with Study Treatment Administration.......................................36
6.8.1.
Self-Administration at the Clinic ...................................................36
6.8.2.
Self-Administration Outside the Clinic..........................................37
6.9.
Treatment of Study Treatment Overdose....................................................37
6.10.
Treatment after the End of the Study ..........................................................37
6.11.
Concomitant Medications and Non-Drug Therapies....................................38
6.11.1.
Permitted Medications and Non-Drug Therapies..........................38
6.11.2.
Prohibited Medications and Non-Drug Therapies.........................38

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7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................39
7.1.
Time and Events Table...............................................................................40
7.2.
Screening and Critical Baseline Assessments ............................................43
7.2.1.
Critical procedures performed at Screening (Visit 1)....................43
7.2.2.
Critical procedures performed at first treatment Visit 
(Baseline Visit 2)..........................................................................44
7.3.
Assessment of Safety Syringe Use.............................................................44
7.4.
Pain Assessment........................................................................................45
7.5.
Device Usability/Functionality Question ......................................................45
7.6.
Exit Interviews ............................................................................................45
7.7.
Safety .........................................................................................................46
7.7.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........46
7.7.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................46
7.7.1.2.
Method of Detecting AEs and SAEs ...........................47
7.7.1.3.
Follow-up of AEs and SAEs........................................47
7.7.1.4.
Cardiovascular and Death Events ..............................47
7.7.1.4.1.
Cardiovascular events ............................47
7.7.1.4.2.
Deaths....................................................47
7.7.1.5.
Regulatory Reporting Requirements for SAEs............48
7.7.2.
Pregnancy ...................................................................................48
7.7.3.
Medical Device Incidents (Including Malfunctions).......................48
7.7.3.1.
Time Period for Detecting Medical Device 
Incidents.....................................................................48
7.7.3.2.
Follow-up of Medical Device Incidents........................49
7.7.3.3.
Prompt Reporting of Medical Device Incidents 
to GSK........................................................................49
7.7.3.4.
Regulatory Reporting Requirements for 
Medical Device Incidents............................................49
7.7.4.
Physical Exams ...........................................................................50
7.7.5.
Vital Signs....................................................................................50
7.7.6.
Electrocardiogram (ECG).............................................................50
7.7.7.
Clinical Safety Laboratory Assessments ......................................50
7.8.
Pharmacodynamic Markers ........................................................................52
7.9.
Pharmacokinetics .......................................................................................52
7.10.
Immunogenicity...........................................................................................52
7.11.
Genetics .....................................................................................................52
8.
DATA MANAGEMENT ...........................................................................................52
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................53
9.1.
Hypotheses.................................................................................................53
9.2.
Sample Size Considerations.......................................................................53
9.2.1.
Sample Size Assumptions ...........................................................53
9.2.2.
Sample Size Sensitivity................................................................53
9.3.
Data Analysis Considerations .....................................................................54
9.3.1.
Analysis Populations....................................................................54
9.3.2.
Treatment Comparisons ..............................................................54
9.3.3.
Interim Analysis ...........................................................................54
9.4.
Key Elements of Analysis Plan ...................................................................54
9.4.1.
Analyses to Evaluate Safety Syringe ...........................................54
9.4.2.
Safety Analyses...........................................................................55

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9.4.3.
Pharmacodynamic Analyses........................................................56
9.4.4.
Pharmacokinetic Analyses...........................................................56
10. STUDY GOVERNANCE CONSIDERATIONS........................................................56
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............56
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................56
10.3.
Quality Control (Study Monitoring) ..............................................................57
10.4.
Quality Assurance.......................................................................................57
10.5.
Study and Site Closure ...............................................................................58
10.6.
Records Retention......................................................................................58
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................59
11. REFERENCES.......................................................................................................60
12. APPENDICES........................................................................................................61
12.1.
Appendix 1: Abbreviations and Trademarks................................................61
12.2.
Appendix 2: Anaphylaxis Criteria ................................................................64
12.3.
Appendix 3: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in FRP and Collection of Pregnancy Information.......................65
12.3.1.
Definition of post menopausal female ..........................................65
12.3.2.
Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP) ..............65
12.3.3.
Collection of Pregnancy Information ............................................66
12.3.4.
References ..................................................................................67
12.4.
Appendix 4: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................68
12.4.1.
Liver chemistry stopping criteria and required follow up 
assessments................................................................................68
12.4.2.
Liver chemistry increased monitoring criteria with 
continued therapy ........................................................................70
12.5.
Appendix 5: Definition of and Procedures for Documenting Medical 
Device Incidents .........................................................................................71
12.5.1.
Definitions of a Medical Device Incident.......................................71
12.5.2.
Documenting Medical Device Incidents .......................................72
12.6.
Appendix 6: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................73
12.6.1.
Definition of Adverse Events........................................................73
12.6.2.
Definition of Serious Adverse Events...........................................74
12.6.3.
Definition of Cardiovascular Events .............................................76
12.6.4.
Recording of AEs and SAEs ........................................................76
12.6.5.
Evaluating AEs and SAEs............................................................77
12.6.6.
Reporting of SAEs to GSK...........................................................78
12.7.
Appendix 7: Genetic Research ...................................................................80
12.8.
Appendix 8: Country Specific Requirements...............................................83
12.9.
Appendix 9: Protocol Changes....................................................................84

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1.
PROTOCOL SYNOPSIS FOR STUDY 205667
Rationale
Mepolizumab (SB-240563) is a humanised monoclonal antibody (IgG1, kappa, mAb) 
that blocks human interleukin-5 (hIL-5) from binding to the IL-5 receptor complex 
expressed on the eosinophil cell surface and thus inhibits signalling; neutralisation of IL-
5 with mepolizumab reduces blood, sputum and tissue eosinophils.
Mepolizumab for Injection is supplied as a sterile, single-use, preservative-free, 
lyophilised powder formulation (herein referred to as lyophilised drug product). This is 
the form that was used in the clinical development programmes and is the current 
marketed presentation for asthma (NUCALA™). Before use, a healthcare provider must 
reconstitute each vial of lyophilised drug product with water for injection using aseptic 
techniques. As part of the life-cycle of mepolizumab, a liquid drug product provided as a 
ready-to-use pre-filled syringe assembled into either a safety syringe or an autoinjector, 
Mepolizumab Injection, has been developed.  Administration of Mepolizumab Injection 
(herein referred to as liquid drug product in safety syringe) will improve patient/physician 
convenience and enable home/self injection via caregivers and/or patients.
Objective(s)/Endpoint(s)
The aim of this study is to assess the correct real-world use of a safety syringe for the 
repeat self-administration of mepolizumab subcutaneously by determining the proportion 
of subjects with severe eosinophilic asthma who are successfully able to self-administer a 
dose of mepolizumab. For the purposes of this study, ‘self-administration’ is defined as 
either the administration of mepolizumab liquid drug product in safety syringe by the 
subject themselves or by their caregiver.
The primary and secondary objectives and associated endpoints are outlined below:
Objectives
Endpoints
Primary

To assess the use of the combination 
product, mepolizumab liquid drug 
product in safety syringe for the 
subcutaneous self-administration of 
mepolizumab by subjects with severe 
eosinophilic asthma

Proportion of subjects successfully able 
to self-administer their observed third 
dose at Week 8
Secondary

To assess the use of mepolizumab 
liquid drug product in safety syringe 
outside the clinic setting

Proportion of subjects successfully 
able to self-administer their 
unobserved second dose outside the 
clinic setting at Week 4

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Overall Design
This Phase III study will be an open-label, single-arm, repeat-dose, multi-centre study of 
mepolizumab liquid drug product in a safety syringe (100 mg) administered
subcutaneously (SC) every 4 weeks in subjects with severe eosinophilic asthma.  Subjects 
will receive 100 mg mepolizumab SC as a single injection that is self-administered in the 
thigh, abdomen or administered in the upper arm (caregiver only). The site of 
administration will be recorded.
Subjects (and/or their caregiver, if applicable) will self-administer mepolizumab liquid 
drug product in safety syringe for the first time immediately after being trained in its use 
at Visit 2 (i.e. the Start of Study Visit). The training is designed to be representative of 
the instruction and training materials that will be provided once the device is 
commercially available. 
Three doses of mepolizumab drug product in the safety syringe will be self-administered 
by the subject/caregiver at 4-weekly intervals; 2 doses will be administered under 
observation in the clinic (at Visits 2 and 4).  The second in clinic administration (Visit 4) 
will not include any onsite training or other support, other than the Instructions for Use 
(IFU), which could assist the subject.  One dose will be administered outside the clinic 
and without observation (within 24 hours after attending the clinic for Visit 3). Following 
each injection, subjects will complete a patient diary immediately following, 1- and 24-
hours after administration indicating the pain experienced and, for the unobserved dose 
administered at home following Visit 3, subjects/caregivers will complete a checklist of 
the steps required to successfully administer the injection. At the End of Study Visit 
(Visit 5), subjects will be asked about their overall experience with the liquid drug 
product in safety syringe, including device performance and ease of use. 
Treatment Arms and Duration
The study is single arm in which all subjects will receive mepolizumab 100 mg SC from 
the liquid drug product in safety syringe presentation.  Each subject will participate in the 
study for up to 18 weeks and will have a Pre-screening visit (Visit 0), a Screening visit 
(Visit 1) and a 12-week Treatment Period (Visits 2 through 4) which concludes with End 
of Study assessments (Visit 5) 4 weeks after the last dose of mepolizumab at Visit 4.
Type and Number of Subjects
Male or female subjects aged 12 years or older with severe eosinophilic asthma. Subjects 
must either have been receiving mepolizumab administered SC for the treatment of 
severe eosinophilic asthma every 4 weeks for at least 12 weeks prior to Visit 1 or, if not 
previously using mepolizumab, must be using high dose inhaled corticosteroids plus an 
additional controller with a history of 1 or more exacerbations requiring systemic 
corticosteroids in the 12 months prior to Visit 1.
Approximately 75 subjects will be screened to achieve 55 enrolled subjects with the aim 
of achieving 50 completed/evaluable subjects.

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Sample Size Calculations and Statistical Analyses
No formal sample size calculations were performed. Assuming a 30% dropout rate 
during screening, approximately 75 subjects will be screened in order to enrol 55 subjects 
(attempting at least one self-administration of mepolizumab). Assuming a dropout rate of 
up to 10% during the study, 55 enrolled subjects should provide at least 50 subjects with 
complete study data.
The number and percentage of subjects successfully able to self-administer their doses 
will be presented together with 95% confidence intervals.  No hypothesis testing will be 
performed.

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2.
INTRODUCTION
Mepolizumab (SB-240563) is a humanised monoclonal antibody (IgG1, kappa, mAb) 
that blocks human interleukin-5 (hIL-5) from binding to the IL-5 receptor complex 
expressed on the eosinophil cell surface and thus inhibits signalling; neutralisation of IL-
5 with mepolizumab reduces blood, sputum and eosinophils.
Mepolizumab has recently been approved in a number of markets including the United 
States (US), European Union (EU), Canada, Australia, Japan, South Korea, Switzerland 
and Taiwan for the treatment of severe eosinophilic asthma.  Mepolizumab is also under 
development for other indications, including the treatment of Chronic Obstructive 
Pulmonary Disease (COPD), FIP1L1/PDGFR-negative hypereosinophilic syndrome 
(HES) and eosinophilic granulomatosis with polyangiitis (EGPA) (i.e., Churg Strauss 
syndrome).
2.1.
Study Rationale
Mepolizumab for Injection is supplied as a sterile, single-use, preservative-free, 
lyophilised formulation (herein referred to as lyophilised drug product). This is the form 
that was used in the clinical development programmes and is the current marketed 
presentation for asthma (NUCALA™). Before use, a healthcare provider must 
reconstitute each vial of lyophilised drug product with water for injection (WFI) using 
aseptic techniques. As part of the life cycle of mepolizumab, a liquid drug product 
(provided as a ready-to-use pre-filled syringe assembled into either a safety syringe or an 
autoinjector), Mepolizumab Injection, is being developed.  Administration of 
Mepolizumab Injection (herein referred to as liquid drug product in safety syringe) is 
intended to improve patient/physician convenience and enable home/self injection via 
caregivers and/or patients.
The changes to the liquid drug product site of manufacture, processing and formulation 
have been minimised. The liquid drug product has been assessed against the lyophilised 
drug product, prior to clinical evaluation, using comprehensive biochemical/biophysical 
comparability evaluations with comparability between the two products being 
demonstrated. The likelihood of clinically significant differences in the systemic 
exposure, efficacy, safety and/or immunogenicity of the liquid drug product in 
autoinjector or safety syringe as compared with the reconstituted lyophilised drug product 
is considered to be low.  To provide further assurance of comparable exposure from the 
liquid drug products and the lyophilised drug product, a single-dose pharmacokinetic 
(PK) comparability study in healthy subjects will be performed in parallel with this trial 
(Study 204958).
2.2.
Brief Background
Mepolizumab binds with high affinity to human IL-5 and blocks its binding to and the 
activation of the IL-5 receptor (CD125).
Randomised, multi-centre, placebo-controlled exacerbation studies (MEA112997, 
MEA115588) and an Oral Corticosteroid (OCS) Reduction Study (MEA115575) have 

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demonstrated the efficacy of mepolizumab and support the use of mepolizumab 100 mg 
subcutaneous (SC) every 4 weeks as an add-on therapy for the treatment of severe 
eosinophilic asthma. Compared with placebo, mepolizumab has been shown to: 

Reduce the rate of clinically significant exacerbations by approximately 50%.  These 
results were replicated in studies MEA112997 and MEA115588.

Reduce the rate of exacerbations requiring hospitalisations and/or Emergency 
Department (ED) visits, with mean reductions ranging from 32% to 61%.

Produce statistically significant and/or clinically relevant improvements in lung 
function based on forced expiratory volume in one second (FEV1), asthma control 
based on Asthma Control Questionnaire (ACQ-5), quality of life based on St. 
George’s Respiratory Questionnaire (SGRQ) and clinician and subject-rated overall 
response to therapy in the target population.  

Produce consistent reductions in blood eosinophil levels detected at Week 4 which 
were sustained for the duration of treatment.
Additional details of the pharmacology, efficacy and safety can be found in the 
Investigator Brochure (IB) [GSK Document Number CM2003/00010/10].
3.
OBJECTIVE(S) AND ENDPOINT(S)
The aim of this study is to assess the correct real-world use of the mepolizumab liquid 
drug product in safety syringe for the repeat self-administration of mepolizumab 
subcutaneously by determining the proportion of subjects with severe eosinophilic 
asthma who are successfully able to self-administer a dose of mepolizumab. For the 
purposes of this study, ‘self-administration’ is defined as either the administration of 
mepolizumab liquid drug product in safety syringe by the subject themselves or by their 
caregiver.
The objectives and endpoints associated with these objectives are outlined below:
Objectives
Endpoints
Primary

To assess the use of the combination 
product, mepolizumab liquid drug 
product in safety syringe for the 
subcutaneous self-administration of 
mepolizumab by subjects with severe 
eosinophilic asthma

Proportion of subjects successfully able
to self-administer their observed third 
dose at Week 8
Secondary

To assess the use of mepolizumab 
liquid drug product in safety syringe 
outside the clinic setting

Proportion of subjects successfully 
able to self-administer their 
unobserved second dose outside the 
clinic setting at Week 4

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Objectives
Endpoints
Other

To assess the use of mepolizumab 
liquid drug product in safety syringe 
both inside and outside of the clinic 
setting

To evaluate safety syringe use & 
functionality

To evaluate any safety syringe injection
errors/failures related to use or device 
performance

To characterise the subject experience 
of using the mepolizumab liquid drug 
product in safety syringe

To assess mepolizumab plasma trough 
concentrations following the SC 
administration of mepolizumab liquid 
drug product in safety syringe

To assess the pharmacodynamic effect 
following the SC administration of 
mepolizumab liquid drug product in 
safety syringe

Proportion of subjects successfully able 
to self-administer their observed first 
dose at Week 0

Proportion of subjects successfully able 
to self-administer both their unobserved
second dose and observed third 
observed dose at Weeks 4 and 8

Proportion of subjects successfully able 
to self-administer all three doses at 
Weeks 0, 4 and 8

Device usability/functionality
questionnaire completed at the End of 
Study/Early Withdrawal Visit

Investigator evaluation of user/device 
errors

Root cause analysis of each 
unsuccessful injection

Subject Exit Interviews completed over 
the telephone after the End of 
Study/Early Withdrawal Visit

Mepolizumab plasma trough 
concentrations (Ctrough) at Weeks 4, 8 
and 12

Ratio to baseline of blood eosinophils 
at  Weeks 4, 8 and 12

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Objectives
Endpoints
Safety
To evaluate the safety and tolerability of 
mepolizumab liquid drug product in safety 
syringe

Incidence and frequency of Adverse 
Events / Serious Adverse Events 
including systemic reactions and 
injection site reactions

Incidence of asthma exacerbations

Clinically significant change in 
haematological and/or clinical 
chemistry parameters.

Vital signs

12-lead electrocardiogram (ECG)

Incidence of immunogenicity

Level of self-reported pain 
immediately following,1- and 24-hours 
following each injection (patient diary)
4.
STUDY DESIGN
4.1.
Overall Design
This Phase III study will be an open-label, single arm, repeat-dose, multi-centre study of 
mepolizumab liquid drug product in safety syringe (100 mg) administered SC every 4 
weeks in subjects with severe eosinophilic asthma. The study is designed to evaluate the 
use of the safety syringe liquid drug product presentation by severe eosinophilic asthma 
subjects (or their caregivers) for the SC administration of mepolizumab (Figure 1).

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Figure 1
Study Schematic
For the purposes of this study, ‘self-administration’ is defined as either the administration 
of mepolizumab liquid drug product in safety syringe by the subject themselves or by 
their caregiver. If applicable, only one caregiver per subject will be permitted.
Subjects will receive 100 mg mepolizumab SC as a single injection that is self-
administered in the thigh, abdomen or administered in the upper arm (caregiver only), 
using the liquid drug product in safety syringe presentation. The site of administration 
will be recorded.
Subjects (and/or their caregiver, if applicable) will self-administer mepolizumab liquid 
drug product in safety syringe for the first time immediately after being trained in its use 
at Visit 2 (i.e. the Start of Study Visit). The training is designed to be representative of 
the instruction and training materials, including the Instructions for Use (IFU) that will be 
provided once the device is commercially available. 
Three doses of mepolizumab liquid drug product in safety syringe will be self-
administered by the subject/caregiver at 4-weekly intervals; 2 doses will be administered 
under observation in the clinic (at Visits 2 and 4).  The second in clinic administration 
(Visit 4) will not include any onsite training or support, other than the IFU, which could 
assist the subject.  One dose will be administered outside the clinic and without 
observation (within 24 hours after attending the clinic for Visit 3). Following each 
injection, subjects will complete a patient diary, included in the Study Reference Manual 
(SRM), and report the pain experienced immediately following, 1- and 24-hours post 
injection. Observations about the injection will be recorded by the investigators for the 
doses administered in the clinic using an observer checklist. For the unobserved dose 
administered at home, a similar checklist detailing the steps required to successfully 
administer the injection will be completed by the subject/caregiver. All injections will be 
assessed by the investigator for success based on:

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
Direct observation of the self-administration using the investigator Observer 
Checklist if the mepolizumab dose was administered in the clinic, and inspection 
of the safety syringe

Subject/caregiver completed checklist and inspection by the investigator of the 
returned safety syringe if the mepolizumab dose was administered outside the 
clinic
A self-administered injection is considered successful if the following criteria are met: 

Use of a correct injection site (abdomen/thigh or upper arm [caregiver only])

Full dose administered: subject fully inserts the needle, slowly depresses the 
plunger until the stopper reaches the bottom of the syringe and activates the 
needle guard by moving the thumb up

No observations are made with respect to the safety syringe, following inspection 
by the investigator, which indicates the full dose has not been dispensed
If the above criteria are met, the investigator will confirm the injection was successfully 
delivered. 
Any unsuccessful injection will undergo a root-cause investigation, following a scripted 
approach, and evaluation to assess whether the unsuccessful injection was associated with 
the instructions / use of the device or whether it was associated with a device failure 
using the Safety Syringe Error/Failure Reporting Form, further details of which can be 
found in the SRM. All devices associated with an unsuccessful injection, will be 
evaluated by Device Engineering at GlaxoSmithKline (GSK), post-use, to assess overall 
performance and robustness of the device.
At the End of Study Visit, subjects will be asked to record their overall experience with 
the safety syringe including device performance.
In all subjects, blood samples for both PK, haematology assessment (which will include 
blood eosinophil count for the pharmacodynamic effect assessment) and clinical 
chemistry assessment will be collected at the time points indicated in the Time and 
Events Table (Section 7.1).
4.2.
Treatment Arms and Duration
This is a single arm study in which all subjects will receive mepolizumab 100 mg SC 
every 4 weeks, using the liquid drug product in safety syringe presentation, for 12 weeks. 
Each subject will participate in the study for up to 18 weeks (Visit 0 to the End of Study 
Visit (Visit 5) as described in Table 1.

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Table 1
Study Phases
Phase
Phase Title
Duration
Description
1
Pre-screening
0 to 2 weeks
At the Pre-screening Visit, details about 
the study and procedures will be explained 
through the informed consent process. The 
Pre-screening Visit (Visit 0) can occur on 
the same day as the Screening Visit (Visit 
1) but must be completed prior to 
initiating any Visit 1 procedures. 
2
Screening
1 to 4 weeks
Subjects will be assessed for eligibility at 
the Screening Visit (Visit 1). Blood draws 
will be taken for assessments of liver 
function and to determine blood 
eosinophil levels in subjects not 
previously using mepolizumab and who 
do not meet the historical blood eosinophil 
criterion. 
3
Treatment
12 weeks
At Visit 2 (Week 0) those subjects who 
continue to meet the eligibility criteria and 
the continuation to treatment criteria (see 
Section 5.3) will receive mepolizumab 
100 mg SC every 4 weeks for a total of 3 
doses. 
The treatment period will conclude with 
subjects completing End of Study Visit 
(Visit 5) assessments approximately 4 
weeks after the subject was administered 
their last dose of study treatment at Visit 
4. 
A subject who adheres to the study treatment and assessment schedule (as detailed in 
Time and Events Table, Section 7.1) will be considered to have completed the study if 
they complete all of the assessments at the End of Study visit (Visit 5). A subject who
permanently discontinues study treatment early will be withdrawn from the study after 
completing the Early Withdrawal visit (see Time and Events Table, Section 7.1).
Subjects receiving mepolizumab prior to the study will be advised to continue with their 
pre-study mepolizumab treatment following completion of the assessments at the End of 
Study/Early Withdrawal visit. Subjects not receiving mepolizumab prior to the start of 
the study will have mepolizumab treatment stopped at the End of Study/Early 
Withdrawal visit and will receive appropriate care and treatment as determined by their 
treating physician.

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4.3.
Type and Number of Subjects
Approximately 75 subjects with severe eosinophilic asthma will be screened in order to 
achieve 55 enrolled subjects (attempting at least one self-administration of mepolizumab) 
and 50 subjects with complete study data.
4.4.
Design Justification
An open-label, repeat-dose, single arm, multi-centre study design is deemed appropriate 
to evaluate self-administration of mepolizumab liquid drug product in safety syringe in 
subjects with severe eosinophilic asthma. A population of subjects with severe 
eosinophilic asthma either currently receiving or not currently receiving commercially 
available mepolizumab SC at study entry (Visit 1) was selected to reflect the intended 
population in “real world” conditions. Subjects not currently receiving mepolizumab will 
be required to have severe eosinophilic asthma and be using high dose inhaled 
corticosteroids (ICS) plus a second controller, with a history of ≥1 exacerbations 
requiring treatment with systemic corticosteroids in the previous 12 months. The 
standardised training provided in this study will be representative of the instruction and 
training materials that will be given once the device is commercially available for use. 
Subjects will be instructed to use the safety syringe at the clinic immediately after being 
trained in its use at Visit 2 (Week 0) and thereafter at 4-weekly intervals either at the 
clinic or outside of the clinic (Time and Events Table, Section 7.1). The primary endpoint 
of the study will be assessed under observation at Visit 4, 8 weeks after the subject 
received training in the use of the safety syringe.
With regards to the pharmacokinetic and pharmacodynamic assessments, it is 
acknowledged that mepolizumab exposure will not be at steady-state after the first and 
second SC doses (administered at Visits 2 and at home following Visit 3, respectively) in 
those subjects not previously receiving mepolizumab treatment at Visit 1; however, 
mepolizumab plasma concentration at the end of the dosing interval (Ctrough) 
measurements can be compared with historical data. Likewise data from the Phase III 
study MEA115588 showed that in subjects previously not treated with mepolizumab, the 
reduction in blood eosinophil count at the end of the dosing interval following the first 
SC dose of mepolizumab (i.e. pre-steady-state) was close to the reduction observed at the 
end of the dosing interval following the eighth SC dose of mepolizumab (i.e. at steady-
state). Therefore, in those subjects not receiving mepolizumab treatment at Visit 1, 
assessing the pharmacodynamic effect of mepolizumab is still of interest. 
4.5.
Dose Justification
The 100 mg dose of mepolizumab liquid drug product in safety syringe will match the 
dose of reconstituted lyophilised drug product (the currently marketed form).
4.6.
Benefit:Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
mepolizumab (SB-240563) lyophilised drug product can be found in the Investigator’s 
Brochure [GSK Document Number CM2003/00010/10].  The following section outlines 

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the key risks, risk assessment and mitigation strategy for this protocol based on 
mepolizumab lyophilised formulation.  The safety profile of the mepolizumab liquid 
formulation is anticipated to be similar to the lyophilized formulation.  

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4.6.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP)
Risk of Systemic Reactions including allergic 
reactions
Biopharmaceutical products administered 
subcutaneously may elicit systemic (e.g. 
hypersensitivity) and local site reactions.
In the placebo controlled severe asthma studies 
both acute and delayed systemic reactions 
including hypersensitivity have been reported 
following administration of mepolizumab with 
incidence rates similar between mepolizumab 
and placebo-treated subjects:

54/915 subjects or 6% in the mepolizumab 
[all doses combined] group 

7/263 subjects or 3% in the mepolizumab 
100 mg SC group

12/344 subjects or 3% in the mepolizumab  
75 mg intravenous (IV) group 

20/412 subjects or 5% in the placebo 
group. 
The most common symptoms reported with any 
systemic reaction included headache, rash, 
pruritus, fatigue, and dizziness. While rare, 
serious systemic reactions including anaphylaxis 
have been reported.
Systemic reactions reported to date across the 
mepolizumab programme are summarised in the 
Daily monitoring of serious adverse events 
(SAEs) by medical monitor; regular systematic 
review of adverse event (AE)/SAE data from 
ongoing studies by the GSK study team and/or 
safety review team. 
Customised AE and SAE case report form 
(CRF) utilised for targeted collection of 
information for systemic reaction adverse 
events.
Use of Joint National Institute of Allergy and 
Infectious Diseases (NIAID)/Food Allergy 
and Anaphylaxis Network (FAAN) 2nd 
Symposium on Anaphylaxis to collect data on 
reports of anaphylaxis (see Appendix 2).
Subjects are monitored in clinic for at least 1 
hour following self-administration of 
mepolizumab at the clinic. For administration at 
home, subjects will be instructed to call the 
investigator and/or go to an Emergency 
Department for any unusual symptoms (e.g. 
symptoms concerning for hypersensitivity 
include skin rash [hives] or redness, swelling of 
the face or mouth, becoming wheezy, coughing 
or having difficulty in breathing and/or feeling 

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
IB “Adverse events of special interest” section; 
see also ‘Special Warnings and Special 
Precautions for Use’ section located in Section 6 
titled ‘Summary of Data and Guidance for the 
Investigator’ [GSK Document Number 
CM2003/00010/10]
weak or light headed).
Injection site reactions
In the placebo controlled severe asthma (PCSA) 
studies the incidence of local site reactions with 
SC administration of mepolizumab was higher 
on mepolizumab 100 mg SC group (21/263 or 
8%) compared to mepolizumab 75mg IV 
(10/344 or 3%) or placebo (13/412 or 3%). 
Symptoms included pain, erythema, swelling, 
itching, and burning sensation. 
Local injection site reactions reported to date 
across the mepolizumab program are 
summarized in the IB “Adverse events of 
special interest” section; see also Section 6 titled 
‘Summary of Data and Guidance for the 
Investigator’ [GSK Document Number 
CM2003/00010/10].
Daily monitoring of serious adverse events 
(SAEs) by medical monitor; regular systematic 
review of adverse event (AE)/SAE data from 
ongoing studies by GSK study team and/or 
safety review team. 
Customised AE and SAE case report form 
(CRF) utilised for targeted collection of 
information for local injection site reaction 
adverse events.
Pain assessment will also be done utilizing 
visual analog scale, in the patient diary, 
immediately after injection, 1 hour after 
injection and 24 hours (4 hours) after injection.
Potential risk of immunogenicity
Biopharmaceutical products may elicit anti-drug 
antibody (ADA) and neutralising antibody 
(NAb), which have the potential to modulate 
pharmacokinetic (PK), pharmacodynamic (PD) 
or produce adverse reactions.
Mepolizumab has low immunogenic potential. 
Both incidence and titer data from completed 
Blood samples will be collected for detection of 
both ADA and NAb.

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
studies demonstrate a low risk for loss of 
efficacy associated with AEs and/or altered 
PK/PD. Immunogenicity data reported to date 
across the mepolizumab development program 
are summarized in the IB; See Section 5.4 
‘Clinical Immunogenicity’ and a summary of 
immunogenicity findings in Section 6 ‘Other 
Potentially Clinically Relevant Information for 
the Investigator’ [GSK Document Number 
CM2003/00010/10].
Study Procedures
Injuries due to accidental needle sticks
The safety syringe has been designed and 
verified to comply with ISO23908 ‘Sharps 
injury protection – Requirements and test 
methods – Sharps protection features for single-
use hypodermic needles, introducers for 
catheters and needles used for blood sampling’
The subject will be educated by the staff prior to 
self-administration and their first scheduled 
dose will be supervised in the clinic by the staff. 
Additionally, the IFU will instruct the subject on 
the safe use of the device.
A plastic / rubber needle shield protects the 
needle before injection to minimise the potential 
for needle stick injuries.
The needle automatically retracts into the 
syringe body after the injection.

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4.6.2.
Benefit Assessment
Data from earlier studies [Haldar, 2009; Nair, 2009; Pavord, 2012] attest to the clinical 
utility of mepolizumab in the treatment of severe eosinophilic asthma which was 
confirmed in the Phase III studies MEA115575 and MEA115588 [Bel, 2014; Ortega, 
2014].  The safety syringe provides a more convenient mode of delivery from previous 
mepolizumab administration and potentially provides patients an option to self-
administer mepolizumab at home.
4.6.3.
Overall Benefit:Risk Conclusion
Current data from mepolizumab preclinical and clinical development indicate the ability 
of mepolizumab to inhibit IL-5 leading to consistent reduction in blood eosinophils, with 
demonstration of clinical benefit in the treatment of conditions associated with 
eosinophilic inflammation, such as asthma. Data from the Phase III asthma programme 
with mepolizumab demonstrates, compared to placebo, a reduction in asthma 
exacerbations, improvements in asthma control and quality of life (as measured by the 
ACQ and SGRQ, respectively), improvements in lung function and a reduction in oral 
corticosteroid use in those subjects on chronic OCS treatment. To date, the safety profile 
of mepolizumab has been favourable and the benefit/risk profile remains positive in 
patients with severe asthma. The change in drug product presentation from a lyophilised 
drug product to a liquid drug product in an safety syringe is not anticipated to alter the 
overall benefit:risk. The ability of subjects to self-administer treatment will be closely 
observed in the clinic and subjects will be instructed to seek medical attention if they 
experience any abnormal symptoms following administration at home, away from the 
clinic. 
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the IB/IB supplement(s).
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardise the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.

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5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
AGE
1. Age: At least 12 years of age inclusive, at the time of signing the informed consent.
[For those countries where local regulations permit enrolment of adults only, subject 
recruitment will be restricted to those who are 18 years of age]
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. Asthma: A physician diagnosis of asthma for ≥2 years that meets the National Heart, 
Lung and Blood Institute guidelines [National heart, lung and blood institute (NIH), 
2007] or Global Initiative for Asthma (GINA) guidelines [GINA, 2015]
3. Mepolizumab treatment:
a.
Not receiving mepolizumab treatment at Visit 1
(NB: these subjects must also meet inclusion criteria 4, 5, 6 and 7).
OR
b. Receiving 100 mg SC mepolizumab administered for the treatment of 
severe eosinophilic asthma every 4 weeks for at least 12 weeks prior to 
Visit 1.
The following inclusion criteria are only applicable to those subjects NOT receiving 
mepolizumab treatment at Visit 1:
4. Eosinophilic asthma: A high likelihood of eosinophilic asthma as per the required 
‘Continuation to Treatment’ - Criterion 2.
5. Inhaled Corticosteroid: A well-documented requirement for regular treatment with 
high dose inhaled corticosteroid (ICS) in the 12 months prior to Visit 1 with or 
without maintenance oral corticosteroids (OCS).

For subjects 18 years old:

ICS dose must be ≥880 mcg/day fluticasone propionate (FP) (ex-
actuator) or equivalent daily.

For ICS/long-acting-beta-2-agonist (LABA) combination 
preparations, the highest approved maintenance dose in the local 
country will meet this ICS criterion.

For subjects 12 to 17 years old:

ICS dose must be ≥440 μg/day FP (ex-actuator) or equivalent daily.

For ICS/LABA combination preparations, the mid-strength approved 
maintenance dose in the local country will meet this ICS criterion.

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6. Controller Medication: Current treatment with an additional controller medication, 
besides ICS, for at least 3 months or a documented failure in the past 12 months of an 
additional controller medication [e.g., long-acting beta-2-agonist (LABA), 
leukotriene receptor antagonist (LTRA), or theophylline] for at least 3 successive 
months.  
7. Exacerbation history: Previously confirmed history of one or more exacerbations 
requiring treatment with systemic corticosteroid (CS) [intramuscular (IM), 
intravenous, or oral] in the 12 months prior to Visit 1, despite the use of high-dose 
ICS.  For subjects receiving maintenance CS, the CS treatment for an exacerbation 
must have been a two-fold dose increase or greater.
WEIGHT
8. Body weight: A minimum 40 kg at Visit 1
SEX
9. Gender: Male or Female
Females: 
A female subject is eligible to participate if she is not pregnant (as confirmed by a 
negative urine human chorionic gonadotrophin (hCG) test), planning to become pregnant 
during the time of study participation (and up to 16 weeks after the last dose), not 
lactating, and at least one of the following conditions applies:
a.
Non-reproductive potential defined as:
Pre-menopausal females with one of the following:
Documented tubal ligation
Documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion 
Hysterectomy
Documented Bilateral Oophorectomy
Postmenopausal female (see Appendix 3 for specific criteria).
b.
Reproductive potential and agrees to follow one of the options listed in the Modified 
List of Highly Effective Methods for Avoiding Pregnancy in Females of 
Reproductive Potential (FRP) (see Appendix 3) from 30 days prior to the first dose 
of study medication and until 16 weeks after the last dose of study medication and 
completion of the End of Study/Early Withdrawal visit.
The investigator is responsible for ensuring that subjects understand how to properly use 
these methods of contraception.

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INFORMED CONSENT
10. Informed Consent: Capable of giving signed informed consent which includes 
compliance with the requirements and restrictions listed in the consent form and in 
this protocol.
5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL) 
1. Concurrent Respiratory Disease: Presence of a known pre-existing, clinically 
important lung condition other than asthma.  This includes current infection, 
bronchiectasis, pulmonary fibrosis, bronchopulmonary aspergillosis, or diagnoses of 
emphysema or chronic bronchitis (chronic obstructive pulmonary disease other than 
asthma) or a history of lung cancer.
2. Eosinophilic Diseases: Subjects with other conditions that could lead to elevated 
eosinophils such as Hypereosinophilic Syndromes, including Churg-Strauss 
Syndrome, or Eosinophilic Esophagitis.  Subjects with a known, pre-existing parasitic 
infestation within 6 months prior to Visit 1 are also to be excluded.
3. 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). 
4. Immunodeficiency: A known immunodeficiency (e.g. human immunodeficiency 
virus – HIV), other than that explained by the use of corticosteroids taken as therapy 
for asthma.
5. Other Concurrent Medical Conditions: Subjects who have known, pre-existing, 
clinically significant cardiovascular, endocrine, autoimmune, metabolic, neurological, 
renal, gastrointestinal, hepatic, haematological or any other system abnormalities that 
are uncontrolled with standard treatment.
6. Liver Disease: Known, pre-existing, unstable liver disease (as defined by the 
presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, esophageal or 
gastric varices or persistent jaundice), cirrhosis, and known biliary abnormalities 
(with the exception of Gilbert’s syndrome or asymptomatic gallstones).
7. ECG Assessment: QT interval corrected for heart rate by either Fridericia’s or 
Bazett’s formula QTc(F)/QTc(B) ≥450msec or QTc(F)/QTc(B) ≥480 msec for 
subjects with Bundle Branch Block at Visit 1.
CONCOMITANT MEDICATIONS
8. Xolair: Subjects who have received omalizumab within 130 days of Visit 1.
9. Other Monoclonal Antibodies not including mepolizumab: Subjects who have 
received any monoclonal antibody (other than Xolair) to treat inflammatory disease 
within 5 half-lives of Visit 1.

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10. Investigational Medications: Subjects who have received treatment with an 
investigational drug, other than mepolizumab within the past 30 days or five terminal 
phase half-lives of the drug whichever is longer, prior to visit 1 (this also includes 
investigational formulations of marketed products) or experimental anti-inflammatory 
drugs (non biologicals) in the past 3 months.
11. Chemotherapy: Subjects who have received chemotherapy within 12 months prior to 
Visit 1.
RELEVANT HABITS
12. Alcohol/Substance Abuse: A history (or suspected history) of alcohol misuse or 
substance abuse within 2 years prior to Visit 1.
CONTRAINDICATIONS 
13. Hypersensitivity: Subjects with hypersensitivity to mepolizumab or to any of the 
excipients (sodium phosphate, citric acid, sucrose, EDTA, polysorbate 80).
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
14. Adherence: Subjects who have known evidence of lack of adherence to controller 
medications and/or ability to follow physician’s recommendations.
5.3.
Continuation to Treatment Criteria
At Visit 2, those subjects who continue to meet the inclusion/exclusion criteria and who 
meet the continuation to treatment criteria will commence the study treatment phase until 
the target of approximately 55 enrolled subjects is reached.  
In order to receive study treatment subjects must have fulfilled all inclusion and 
exclusion criteria described in Section 5.1 and Section 5.2. In addition to the following:
REQUIRED CRITERIA TO START TREATMENT
1. Liver Function: At Visit 2, ALL study subjects must fulfil the following additional 
criteria in order to be eligible for study treatment:

Liver Function Tests: obtained at Visit 1:
o
Alanine aminotransferase (ALT)≤2x ULN (upper limit of normal)
o
Bilirubin ≤1.5x ULN (isolated bilirubin >1.5x ULN is acceptable if 
bilirubin is fractionated and direct bilirubin <35%)
2. Eosinophilic Phenotype: At Visit 2, study subjects that were NOT receiving 
mepolizumab treatment at Visit 1 must fulfil the following additional criteria in order 
to be eligible for study treatment:

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
Airway inflammation characterised as eosinophilic in nature as indicated by 
one of the following:
a) A peripheral blood eosinophil count of 300 cells/L that is related to 
asthma demonstrated in the past 12 months prior to Visit 1.
OR
b) A peripheral blood eosinophil count of 150 cells/L at Visit 1 that is 
related to asthma.
5.4.
Pre-Screening/Screening Failures
A subject will be assigned a subject number at the time the informed consent is signed.
A subject who is assigned a subject number at Visit 0 but does not have any screening 
Visit 1 procedures will be considered a pre-screen failure.
Screen failures will be defined as those subjects who complete at least one Visit 1 
(Screening) procedure but do not attempt to self-administer a dose of mepolizumab.
The following information will be collected in the electronic case report form (eCRF) for 
subjects who are pre-screen and screen failures:

Date of Informed Consent Form (ICF) signature

Demographic information including race, age and gender

Child bearing status assessment for all female subjects of reproductive potential 

Subject number

Details of asthma medications within 3 months of the pre-screening Visit 0

Details of asthma exacerbations during the pre-screening period

Serious Adverse Event information only for any SAE considered as related to 
study participation (e.g. protocol mandated procedures, invasive tests or change 
in existing therapy) or related to a GSK concomitant medication

Investigator signature page
In order to ensure transparent reporting of screen failure subjects, meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements, and respond to 
queries from Regulatory authorities, a minimal set of screen failure information is 
required including Demography, Screen Failure details, Eligibility Criteria, and Serious 
Adverse Events (see Section 7.7.1).
5.5.
Withdrawal/Stopping Criteria
A subject may withdraw from study treatment at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioural, or 

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administrative reasons. If a subject withdraws from the study, he/she may request 
destruction of any samples taken, and the investigator must document this in the site 
study records. As the aim of this study is to evaluate the use of the mepolizumab liquid 
drug product, in safety syringe presentation, for delivery of mepolizumab, subjects who 
permanently withdraw from study treatment will also be withdrawn from the study (see 
Section 5.5.1). Reasons for premature discontinuation of study treatment will be captured 
in the CRF.
5.5.1.
Withdrawal from the Study
Subjects who have withdrawn from the study should complete assessments for the Early 
Withdrawal Visit, 4 weeks after the last dose of mepolizumab (see Time and Events 
Table, Section 7.1).
A reason for the withdrawal from the study must be captured in the eCRF.
A subject must be discontinued if any of the following criteria are met:

Withdrawal of consent

Lost to follow-up
A subject will also be withdrawn from the study, in consultation with the medical 
monitor and principal investigator, if any of the following stopping criteria are met:

Laboratory parameters: Clinically important changes in laboratory parameters 
identified.

ECG: Clinically significant abnormality identified during the study that meet the 
QTc stopping criteria described in Section 5.5.3.

Liver Chemistry: Meets any of the Liver chemistry stopping criteria (See Section 
5.5.2 and Appendix 4.

Pregnancy: Positive pregnancy test (see Appendix 3). Pregnancy and pregnancy 
outcomes of subjects exposed to mepolizumab will be followed.
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as 
soon as possible. 

The site must counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or should 
continue in the study. 

In cases where the subject is deemed ‘lost to follow up’, the investigator or 
designee must make every effort to regain contact with the subject (where 
possible, 3 telephone calls and if necessary a certified letter to the subject’s last 
known mailing address or local equivalent methods). These contact attempts 
should be documented in the subject’s medical record. 

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
Should the subject continue to be unreachable, only then will he/she be considered 
to have withdrawn from the study with a primary reason of “Lost to Follow-up”. 
5.5.2.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the Food and 
Drug Administration [FDA] premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
Liver Chemistry Stopping and Increased Monitoring Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus 
Bilirubin≥2x
ULN (>35% 
direct) or plus
INR>1.5, if 
measured*
Possible  
Hy’s Law
ALT≥3xULN
ALT
≥8xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
No
Yes
Yes
Yes
No
No
No
See algorithm 
for continued 
therapy with 
increased liver 
chemistry 
monitoring
Yes
*INR value not applicable to subjects on anticoagulants 
ALT 
≥3xULN 
but 
<8xULN
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*

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Liver Chemistry Increased Monitoring Algorithm with Continued Therapy for ALT 
3xULN but <8xULN
Continue Study Treatment   and   Monitor Liver Chemistry
Discontinue Study Treatment 
ALT≥5xULN 
but <8xULN
+ bili <2xULN +
no symptoms
No
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Yes
ALT ≥3xULN 
but <5xULN
+ bili <2xULN  +
no symptoms
Able to 
monitor  
weekly 
for  ≥2 
weeks
Persists for 
≥2 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
No
No
Able to 
monitor  
weekly 
for  ≥4 
weeks
Persists for 
≥4 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
Yes
ALT ≥5xULN 
ALT <5xULN 
Yes
Yes
*INR value not applicable to subjects on anticoagulants 
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Required actions and follow-up assessment for all subjects who meet liver chemistry 
stopping or monitoring criteria are defined in Appendix 4.
5.5.2.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met, by 
any subject participating in this study, is not allowed.
5.5.3.
QTc Stopping Criteria

The same QT correction formula must be used for each individual subject to 
determine eligibility for and discontinuation from the study.  This formula may 
not be changed or substituted once the subject has been enrolled.  For example, if 
a subject is eligible for the protocol based on QT interval corrected for heart rate 
by Bazett’s formula (QTcB), then QTcB must be used for discontinuation of this 
individual subject as well.

Once the QT correction formula has been chosen for a subject’s eligibility, the 
same formula must continue to be used for that subject for all QTc data being 
collected for data analysis.  Safety ECGs and other non-protocol specified ECGs 
are an exception.  

The QTc should be based on single or averaged QTc values of triplicate 
electrocardiograms obtained over a brief (e.g., 5-10 minute) recording period. For 
example if a routine ECG demonstrates a prolonged QT, obtain 2 more ECGs 

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over a brief period and then use the averaged QTc values of the 3 ECGs to 
determine whether patient should be withdrawn from the study.
A subject who meets either of the bulleted criteria below will be withdrawn from the 
study:

QTc >500 msec OR Uncorrected QT >600 msec

Change from baseline (Visit 2) of QTc >60 msec
For patients with underlying bundle branch block, follow the discontinuation criteria 
listed below:
Baseline (Visit 2) QTc with Bundle 
Branch Block
Discontinuation QTc with Bundle 
Branch Block
<450 msec
>500 msec
450 – 480 msec
≥530 msec
5.6.
Subject and Study Completion
A completed subject is one who has completed the End of Study (Week 12) visit.
The end of the study is defined as the last subject’s last visit.
6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe the mepolizumab 
drug product in safety syringe received by the subject as per the protocol design. 
Mepolizumab liquid drug product will be supplied by GSK in Type I glass syringes with 
staked needles (1/2 inch x 29 gauge thin wall), sealed with latex-free rubber plungers.  
These will be assembled in single use, disposable safety syringes to enable delivery of the 
drug product. Each device will deliver 100mg mepolizumab in 1.0mL.  The formulation 
contains sodium phosphate, citric acid, sucrose, EDTA and polysorbate 80.

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Study Treatment
Product name:
Mepolizumab (NUCALA) (SB240563)
Device:
Pre-filled syringe contained within a safety syringe
Formulation description:
100 mg/mL mepolizumab with sodium phosphate, citric acid, 
sucrose EDTA and polysorbate 80
Dosage form:
Sterile, liquid formulation
Unit dose 
strength(s)/Dosage level(s):
100 mg/mL; 1.0mL (deliverable)
Route of Administration
SC injection
Dosing instructions:
SC dose in thigh, abdomen or upper arm every 4 weeks
Physical description: 
mepolizumab
Clear to opalescent, colourless to pale yellow sterile solution for 
SC injection in a single-use, pre-filled syringe contained within  
safety syringe
Physical description of 
injection device:
Single use, disposable safety syringe assembled with the pre-
filled syringe containing the drug product. The safety syringe 
enables delivery of the drug product by the subject/caregiver. A 
plastic needle cover shields the needle after injection to minimise 
the potential for needle stick injuries.
Manufacturer/source of 
procurement:
Pre-filled syringe: Pre-filled syringe components are procured 
from Becton Dickinson.  Prefilled syringe is filled with drug 
product and assembled at GSK, Barnard Castle, UK.
Safety syringe: The safety syringe components are 
manufactured by Becton Dickinson and assembled with the 
prefilled syringe at GSK, Barnard Castle, UK.
6.2.
Medical Devices
The GSK manufactured medical devices (or devices manufactured for GSK by a third 
party) provided for use in this study are injection devices: a prefilled syringe contained 
within a safety syringe. The devices used in the study are representative of the devices 
planned to be marketed for the product.
The components that comprise the prefilled syringe, including glass barrel with prestaked 
needle and plunger are sourced from Becton Dickinson.  The prefilled syringe is filled 
and assembled at GSK, Barnard Castle.  
The safety syringe components are manufactured by Becton Dickinson.  The safety 
syringe components are assembled with the prefilled syringe at GSK, Barnard Castle.
The IFU of these injection devices are provided in the SRM. The instructions were 
developed and optimised as a result of formative human factors studies and are 
representative of those that are planned for the product.

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GSK medical device incidents, including those resulting from malfunctions of the device, 
must be detected, documented, and reported by the investigator throughout the study –
see Section 7.7.3.
6.3.
Treatment Assignment
All subjects will be assigned to the same treatment at Visit 2 (Week 0).
6.4.
Blinding
This will be an open-label, single arm study. 
6.5.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
6.6.
Preparation/Handling/Storage/Accountability
No special preparation of study treatment is required.
Study treatment must be dispensed or administered according to procedures described 
herein.  Only subjects enrolled in the study may receive study treatment.  Only authorised 
site staff may supply study treatment.  All study treatment must be stored in a secure area 
with access limited to the investigator and authorised site staff.  
Mepolizumab will be supplied in a single-use safety syringe and should be stored in a 
refrigerator at 2 to 8°C with protection from light. Each injection device will contain 
100 mg mepolizumab as a single 1.0 mL injection of the liquid drug product (100
mg/mL).  Maintenance of a temperature log at the clinical dispensing sites (manual or 
automated) is required.

The investigator or designee must confirm appropriate temperature conditions 
have been maintained during transit for all study treatment received and any 
discrepancies are reported and resolved before use of the study treatment.

Only the subject or previously identified caregiver may administer the study 
treatment.  Whilst on site, all study treatments must be stored in a secure 
environmentally controlled and monitored (manual or automated) area in 
accordance with the labelled storage conditions with access limited to the 
investigator and authorised site staff. 

The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (i.e. receipt, reconciliation and final disposition records).  

Further guidance and information for final disposition of unused study treatment 
are provided in the SRM. 

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.  

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
A Material Safety Data Sheet (MSDS)/equivalent document describing 
occupational hazards and recommended handling precautions either will be 
provided to the investigator, where this is required by local laws, or is available 
upon request from GSK.

Subjects will be provided a safety syringe for home use at Visit 3 and asked to 
follow the information on the IFU with regards to the storage and use of the 
device. Cool bags and cold packs will be provided to transport the safety syringe 
from site to home. Subjects will be asked to return the used safety syringe at Visit 
4. A record of the dispensing of the safety syringe given to the subject at Visit 3 
and collection of the safety syringe returned at Visit 4 will be maintained by the 
Investigator or designee. The Investigator or designee will also inspect the 
returned safety syringe to determine if the dose has been dispensed correctly.
6.7.
Training Session
Training of study treatment, handling and administration techniques by qualified study 
site personnel will be provided to the study participants at Visit 2 prior to self-
administration.  The training is designed to be representative of the instruction and 
training materials that will be used in the post-marketing setting.  The training will 
consist of a walk-through of the IFU for the injection devices by the site personnel.  
Finally, the first actual injection will then be supervised by site personnel including 
feedback to the subject as needed.
6.8.
Compliance with Study Treatment Administration
A record of the number of safety syringes dispensed and returned by each subject must be 
maintained and reconciled with study treatment and compliance records.
6.8.1.
Self-Administration at the Clinic
Following the training (see Section 6.7) at Visit 2 (Week 0), the subject (and/or caregiver, 
if applicable) will self-administer the first dose of study treatment by SC injection under 
medical supervision of the investigator or designee at the study site. The 
subject/caregiver will also administer the dose of study treatment at the clinic under 
medical supervision, but without further training, at Visit 4 (Week 8). Observations about 
the injection will be recorded by the investigator using a checklist for the doses 
administered in the clinic. Details of the Observer Checklist can be found in the SRM. 
The subject will complete a patient diary with a visual analogue scale (VAS) indicating 
the pain experience immediately following, 1- and 24-hours after the dose.
The date, time of the dose, person administering the dose (subject/caregiver) and site of 
administration (thigh, abdomen or upper arm [caregiver only]) of each dose administered 
in the clinic will be recorded on the Observer Checklist and in the source documents.  
Subjects will be monitored for 1 hour after mepolizumab self-administrations in the clinic 
at Visit 2 and Visit 4.  In the event of an acute severe reaction (e.g., anaphylaxis) 
following administration of study treatment, there are personnel/staff onsite at the 
treatment facility who are appropriately trained in basic life support to manage the 

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subject including administration of medications (e.g., epinephrine), and have access to a 
system that can promptly transport the patient to another facility for additional care if 
appropriate.
6.8.2.
Self-Administration Outside the Clinic
The subject (or caregiver) will self-administer the dose of study treatment outside the 
clinic and without observation during Week 4, up to 24 hours after attending clinic Visit 
3. The subject/caregiver will complete a checklist of the steps required to use the safety 
syringe, which will also include the date and time of dose, site of injection, person 
administering the dose (subject/caregiver) and the ease with which the subject/caregiver 
was able to complete each of the critical steps required to administer the dose from the 
safety syringe. In addition, the subject will complete the patient diary capturing the pain 
experienced by the subject immediately following, 1- and 24-hours after the dose. 
Subjects will be instructed to contact clinical study staff if they have concerns or 
questions regarding self-administration. They will have the option of returning to the 
clinical site for further training or assistance with self-administration.  Requirement for 
additional training will be documented.
Compliance with the safety syringe will be assessed through reviewing the subject 
completed checklist, inspection of the returned safety syringe and querying the subject 
during the next site visit (Visit 4) and documented in the source documents.  
For self-administration of mepolizumab outside of the clinic (at home), subjects should 
be instructed to call the investigator and/or go to an Emergency Department for any 
unusual symptoms (e.g. skin rash [hives] or redness, swelling of the face or mouth, 
becoming wheezy, coughing or having difficulty in breathing and/or feeling weak or light 
headed).
6.9.
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 judgment in treating the symptoms 
of a suspected overdose.
6.10.
Treatment after the End of the Study
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition, whether or not GSK is providing specific 
post-study treatment.
There are no plans to provide mepolizumab following study completion.

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6.11.
Concomitant Medications and Non-Drug Therapies
6.11.1.
Permitted Medications and Non-Drug Therapies
Throughout the study, subjects are to be maintained on their baseline standard of care 
asthma treatment.
For subjects previously receiving mepolizumab, additional asthma medications such as 
theophyllines or anti-leukotrienes will be permitted provided that they have been taken 
regularly in the 3 months prior to first dose of mepolizumab treatment (Visit 2, Week 0).
For subjects who have not previously received mepolizumab, subjects must have a
well-documented requirement for regular treatment with high dose inhaled corticosteroid 
(ICS) in the 12 months prior to Visit 1 with or without maintenance oral corticosteroids 
(OCS).

Subjects 18 years old:

ICS dose must be ≥880 mcg/day fluticasone propionate (FP) (ex-
actuator) or equivalent daily.

For ICS/LABA combination preparations, the highest approved 
maintenance dose in the local country will meet this ICS criterion.

Subjects 12 to 17 years old:

ICS dose must be ≥440 μg/day FP (ex-actuator) or equivalent daily.

For ICS/LABA combination preparations, the mid-strength approved 
maintenance dose in the local country will meet this ICS criterion.
Subject not previously receiving mepolizumab must also be receiving current 
treatment with an additional controller medication, besides ICS, for at least 3 months 
or a documented failure in the past 12 months of an additional controller medication 
[e.g., LABA, LTRA, or theophylline] for at least 3 successive months.  
All concomitant medications taken during the study will be recorded in the eCRF. In 
addition, all medications taken by the patient for the treatment of asthma including 
asthma exacerbations in the 12 months prior to Visit 1 must also be recorded in the 
eCRF. The minimum requirement is that the drug name and the dates of administration 
are recorded.
6.11.2.
Prohibited Medications and Non-Drug Therapies
The following medications (Table 2) are not allowed prior to screening (Visit 1) 
according to the following schedule, or during the study:

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Table 2
Medications not allowed prior to the Screening Visit 1 and 
throughout the study
Medication
Washout Time
Prior to Screening Visit 1
Omalizumab (Xolair)
Within 130 days
Other monoclonal antibodies (other than Xolair or 
mepolizumab) to treat inflammatory disease
5 half-lives
Investigational drugs (excluding mepolizumab)
30 days or 5 half-lives whichever is 
longer
Chemotherapy
12 months
Recreational drug use is not allowed during the study.
7.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct.
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Table Section 7.1

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7.1.
Time and Events Table
Pre-screening
Week -6 to Week -
5a
Screening
Week -4 to Week -
1
Week 0 (Day 
1)
Week 4 
(7 days)
Week 8
(7 days)
Week 12
(7 days)
End of Study/
Early Withdrawalb
Procedures                                          Visit number
V0
V1
V2
V3
V4
V5
Informed consent
X
Demography/child bearing status assessment
X
Medical history
X
Asthma and Exacerbation history
X
Asthma Therapy history
X
Smoking history
X
Parasitic screeningc
X
Prior needle use / self-administration assessment
X
Inclusion/Exclusion criteria
X
Training session 
Xd
Safety syringe self-administration in clinic
X
X
Safety syringe self-administration outside of clinic
Xe, f
Laboratory:
Urine pregnancy test
X
Xd
Xd
Xd
X
Hematology (including eosinophils)g / Clinical Chemistry
X
Xd
Xd
Xd
Xd
Urinalysis
X
Immunogenicity
Xd
Xd
PK
Xd
Xd
Xd
Xd
Pharmacogeneticsh
X
Physical/Clinical:
Vital signsi
X
Xd
Xd
Xd
X
12-lead ECG
X
X
Physical examination
X
X
Weight
X
Concomitant Medication
X
X
X
X
X
X
Serious Adverse Eventsj,k,l
X
X
X
X
X
X
Adverse Eventsj,k,l
X
X
X
X

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Pre-screening
Week -6 to Week -
5
Screening
Week -4 to Week -
1
Week 0 (Day 
1)
Week 4
(7 days)
Week 8
(7 days)
Week 12
(7 days)
End of Study/
Early Withdrawalb
Procedures                                           Visit number
V0
V1
V2
V3
V4
V5
Dispense patient diary
Xm
X
X
Return/review patient diary
X
X
Xn
Dispense safety syringe for self-administration outside of 
clinic
X
Return/ inspect safety syringe following self-administration 
outside of clinic
X
Xn,o
Subject completed pain assessment diary (0, 1- and 24-
hours post dose)
X
Xf
X
Safety syringe observer assessment checklist
X
X
Subject/caregiver completed safety syringe checklist
Xf
Assessment of injection success
X
Xp
Device usability/functionality questionnaire
X
Exit InterviewQ
(X)
a.
Pre-screening Visit can occur on the same day as the Screening Visit but must be completed prior to initiating any Visit 1 procedures; The Pre-screening Visit can be conducted 
up to a maximum of 2 weeks prior to the Screening Visit.
b.
The Early Withdrawal Visit will occur 4 weeks (7 days) after last dose of mepolizumab for any subject who withdraws prior to Week 12
c.
Parasitic screening is only required in countries with high-risk or for subjects who have visited high-risk countries in the past 6 months. Sites should use local laboratories.
d.
Perform prior to mepolizumab administration during the study and prior to restarting pre-study mepolizumab treatment on study completion/early withdrawal.
e.
Subjects will be instructed to contact clinical study staff at any time if they have concerns or questions regarding self-administration.  They will have the option of returning to the 
clinical site for further training or assistance with self-administration.  Requirement for additional training or assistance will be documented.
f.
Self-administration of mepolizumab using the safety syringe should occur within 24 hours following the clinic visit.
g.
Includes measurement of eosinophil levels for pharmacodynamic analysis at Visits 2, 3, 4 and 5
h.
Pharmacogenetic sample may be drawn any time after the respective informed consent form is signed and the subject is enrolled.
i.
Vital signs include temperature, sitting blood pressure, respiratory rate and pulse.
j.
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 other AEs/SAEs are recorded 
from the start of study treatment until the End of Study / Early Withdrawal visit.
k.
Injection site reactions (e.g., induration, erythema, edema, rash, pruritus, pain) are to be recorded on both AE and SAE CRF forms.
l.
Information on systemic reactions and events that meet the anaphylaxis criteria is collected on both AE and SAE CRF forms.
m.
Patient diary should be dispensed prior to administration of injection

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n.
For any subject who withdraws prior to Week 12, patient diary and study drug for self-administration outside of clinic will be returned at the Early Withdrawal visit (if applicable).
o.
Assessment to be completed at the Early Withdrawal visit only if the dose of mepolizumab immediately prior to withdrawal was administered outside of the clinic.
p.
Includes both the injection outside the clinic from Week 4 and the injection in clinic at Week 8
q.
In a subset of subjects only. Completed over the telephone after the End of Study/Early Withdrawal Visit

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7.2.
Screening and Critical Baseline Assessments
Subjects can perform the Pre-screening Visit (Visit 0) up to 2 weeks prior to or on the 
same day as the Screening Visit (Visit 1).  A subject number will be assigned at the time 
the informed consent form (ICF) is signed.  During the Pre-screening Visit, study 
designated personnel must provide informed consent (including informed consent for the 
optional pharmacogenetics part of the study, as applicable) to study participants.
Once the informed consent document has been signed, pre-screening assessments can be 
conducted. The following demographic parameters will be captured: year of birth, sex, 
race and ethnicity. In addition, Asthma Therapy, Asthma and Exacerbation history and 
concomitant medications will be assessed. From the pre-screening visit onwards 
concomitant medications, exacerbations and SAEs (considered as related to study 
participation) must be reported.
7.2.1.
Critical procedures performed at Screening (Visit 1)

Medical history including smoking status, history of sinusitis, nasal polyposis, 
aspirin sensitivity, current treatment, duration of asthma, courses of rescue 
corticosteroids in the past 12 months, history of previous intubations, asthma 
exacerbation history in the previous 12 months, asthma triggers and smoking history

Prior experience of needle use including any history of self-administration using an 
safety syringe device

Therapy history, including use of mepolizumab, omalizumab or previous biologics in 
the past 12 months (see Section 6.11.2). For subjects currently receiving 
mepolizumab, data will be collected on whether mepolizumab treatment was 
initiated based on an eosinophil count within 6 weeks of starting treatment or a 
historical measurement collected in the 12 months prior to initiating mepolizumab. 
The blood eosinophil count closest to the initiation of mepolizumab treatment, if 
available, should be recorded.

Cardiovascular medical history/risk factors (as detailed in the eCRF). This 
assessment must include a review of the subject responses to the cardiovascular 
assessment questions and height, weight, blood pressure, smoking history, medical 
conditions, and family history of premature cardiovascular disease

Physical exam (see Section 7.7.4)

Vital signs (see Section 7.7.5)

Resting 12-lead ECG (see Section 7.7.6)

Laboratory tests (see Section 7.7.7). This should include:

Chemistry

Haematology with differential count

Urinalysis

Urine pregnancy test- for all women of child bearing potential

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
Follicle stimulating hormone (FSH) will be assessed to confirm child-bearing 
status (if applicable)

Parasitic screening (only in countries with a high-risk or in subjects who have 
visited a high-risk country)

Review of Inclusion/Exclusion criteria

Review of exacerbations, SAEs
Procedures conducted as part of the subject’s routine clinical management [e.g. blood 
eosinophil counts] and obtained prior to signing of informed consent may be utilised for 
Screening or baseline purposes provided the procedure meets the protocol-defined criteria 
and has been performed within the timeframe defined in the Time and Events Schedule.
7.2.2.
Critical procedures performed at first treatment Visit (Baseline 
Visit 2)

Vital signs (see Section 7.7.5)

Laboratory tests (see Section 7.7.7). This should include

Clinical Chemistry

Haematology with differential

Blood for baseline immunogenicity

Blood for PK assessment

Urine pregnancy test for all females of childbearing potential

Review of exacerbations, concomitant medications, AEs, SAEs

Review of Continuation to Treatment criteria (see Section 5.3).

Training of the subject or caregiver as to the correct use of the safety syringe
7.3.
Assessment of Safety Syringe Use
At Visit 2 (Week 0), and at Visit 4 (Week 8), the investigator or designee will observe, 
using a checklist based on the safety syringe IFU, the ability of the subject/caregiver to 
(self)-administer the injection. The Observer Checklist (see SRM) will be used to 
determine if each step, according to the IFU, was completed easily, with some difficulty 
or not completed/intervention required. Failure to perform one of the critical steps, i.e., 
correct choice of injection site and a full dose administered (determined by the subject 
fully inserting the needle, slowly depressing the plunger until the stopper reaches the 
bottom of the syringe and activating the needle guard by moving the thumb up) will be 
deemed to be a failure to successfully administer the injection. In addition, the 
investigator will be asked to inspect the safety syringe, following each injection, to 
confirm that the white plunger has been pushed all the way down and the needle has 
retracted up into the syringe body, as well as noting any additional observations which 
indicate the full dose has not been dispensed.

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Any user errors or device malfunctions will be recorded and reported using the Safety 
Syringe Error/Failure Reporting Form (see SRM).  Malfunction or failure of the safety 
syringe meeting the definition of a Medical Device Incident (see Appendix 5), will also 
require a Medical Device Incident form to be completed and must be reported as 
described in Section 7.7.3.
Subjects will complete a patient diary at Week 0, 4 and 8 recording the pain experienced 
immediately following, 1- and 24-hour after the injection (see SRM). At Week 4, when 
self-administration is performed outside the clinic (within 24-hours of attending the Visit 
3 clinic visit), the subject/caregiver will also record the date and time of injection, site of 
injection, who administered the injection (subject or caregiver) and complete a checklist 
similar to the Observer Checklist outlining the various steps in the IFU and whether each 
step was completed easily, with some difficulty, or not completed (see SRM). The 
responses on the checklist will be checked by the Investigator or designee at the next 
clinic visit (Visit 4). Failure to perform one of the critical steps will deemed to be a 
failure to successfully administer the injection.
All devices utilised as part of the study will be returned to the clinic where they will be 
assessed to confirm that the device has been successfully actuated.  Any unsuccessful 
injection will undergo a root-cause investigation, following a scripted approach, and 
evaluation to assess whether the unsuccessful injection was associated with the 
instructions / use of the device or whether it was associated with a device failure using 
the Safety Syringe Error/Failure Reporting Form, further details of which can be found in 
the SRM. All devices associated with an unsuccessful injection, will be evaluated by 
Device Engineering, post-use, to assess overall performance and robustness of the device.
7.4.
Pain Assessment
Following each injection, any pain at the injection site will be assessed by the subject 
using a visual analog scale, in the patient diary, immediately after injection, 1 hour after 
injection and 24 hours (4 hours) after injection. The results will be recorded in the 
patient diary. All measurement timings are detailed in the Time and Events Table 
(Section 7.1) and further details regarding the pain assessment are found in the SRM.
7.5.
Device Usability/Functionality Question
A short survey will be administered to all subjects at the End of Study/Early Withdrawal 
Visit. This survey (see SRM) will collect quantitative data on patient views of treatment 
and the use of the safety syringe. 
7.6.
Exit Interviews
Exit interviews will be conducted after the End of Study/Early Withdrawal Visit over the 
telephone, in a subset of subjects only, to explore subjects’ experience with study 
treatment and device usage. Exit interviews are qualitative interviews conducted with 
study subjects to capture subject experiences in drug development on completion of 
participation in a clinical study. Interview questions are designed to fully assess a 
subject’s experience with a study medication and safety syringe and are administered in a 

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semi-structured format over the telephone by a trained interviewer. Subject feedback will 
be captured in a data collection sheet as well as being audio-taped for subsequent 
transcription and qualitative analysis. The Exit interview technique and questions will be 
described in the SRM.
7.7.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1).  
7.7.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 6.
The following adverse events of special interest will have customized AE and SAE pages 
in the eCRF:

Local injection site reactions

Systemic reactions
In addition, the information whether an event met the diagnostic criteria for anaphylaxis 
as outlined by the Second Symposium on Anaphylaxis [Sampson, 2006] and in Appendix 
2 will be collected on the AE and SAE CRF pages.
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 
7.7.1.1.
Time period and Frequency for collecting AE and SAE information

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK 
product will be recorded from the time a subject consents to participate in the 
study up to and including any follow-up contact. 

AEs will be collected from the start of Study Treatment (Visit 2) until the End of 
Study/Early Withdrawal Visit at the timepoints specified in the Time and Events 
Table (Section 7.1).

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the CRF.

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Appendix 6.

Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the study treatment or study participation, the 
investigator must promptly notify GSK.

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NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 6.
7.7.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:

“How are you feeling?” 

“Have you had any (other) medical problems since your last visit/contact?” 

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?” 
7.7.1.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All SAEs, and non-serious AEs of special interest 
(as defined in Section 4.6.1) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up 
(as defined in Section 5.5). Further information on follow-up procedures is given in 
Appendix 6.
7.7.1.4.
Cardiovascular and Death Events
7.7.1.4.1.
Cardiovascular events
Cardiovascular-related AEs and SAEs that will require the investigator to complete event 
specific pages in the eCRF are listed in Section 12.6.3, Appendix 6.
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 Appendix 6
for timelines for reporting AE/SAEs.
7.7.1.4.2.
Deaths
In addition, all deaths will require completion of a specific death data collection page in 
the eCRF.  The death data collection page in the eCRF includes questions regarding 
cardiovascular (including sudden cardiac death) and non-cardiovascular death.
Death information should be recorded on the death eCRF page within one week of when 
the death is first reported.
Please refer to Section 12.6.6, Appendix 6 for timelines for reporting SAEs.

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7.7.1.5.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK of SAEs related to study treatment (even 
for non- interventional post-marketing studies) is essential so that legal obligations and 
ethical responsibilities towards the safety of subjects and the safety of a product under 
clinical investigation are met. 
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
7.7.2.
Pregnancy

Details of all pregnancies in female subjects will be collected after the start of 
dosing (Visit 2) and until 16 weeks post-last dose.

If a pregnancy is reported then the investigator should inform GSK within 2 
weeks of learning of the pregnancy and should follow the procedures outlined in 
Appendix 3.
7.7.3.
Medical Device Incidents (Including Malfunctions)
GSK medical devices are being provided for use in this study.  In order to fulfil 
regulatory reporting obligations worldwide, the investigator is responsible for the 
detection and documentation of events meeting the definitions of incident or malfunction 
that occur during the study with such devices. 
The definition of a Medical Device Incident can be found in Appendix 5. 
NOTE: Incidents fulfilling the definition of an AE/SAE will also follow the processes 
outlined in Section 12.6 and Appendix 6 of the Protocol. 
7.7.3.1.
Time Period for Detecting Medical Device Incidents

Medical device incidents or malfunctions of the device that result in an incident will 
be detected, documented and reported during all periods of the study in which the 
GSK medical devices are available for use. 

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
If the investigator learns of any incident at any time after a subject has been 
discharged from the study, and such incident is reasonably related to a GSK medical 
device provided for the study, the investigator will promptly notify GSK.
NOTE: The method of documenting Medical Device Incidents is provided in 
Appendix 5.
7.7.3.2.
Follow-up of Medical Device Incidents

All medical device incidents involving an AE, will be followed until resolution of
the event, until the condition stabilizes, until the condition is otherwise explained, or 
until the subject is lost to follow-up (as defined in Section 5.5).  This applies to all 
subjects, including those withdrawn prematurely. 

The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as may be indicated to elucidate as completely as practical the nature 
and/or causality of the incident.

New or updated information will be recorded on the originally completed form with 
all changes signed and dated by the investigator.
7.7.3.3.
Prompt Reporting of Medical Device Incidents to GSK

Medical device incidents will be reported to GSK within 24 hours once the 
investigator determines that the event meets the protocol definition of a medical 
device incident.

Facsimile transmission of the "Medical Device Incident Report Form" is the 
preferred method to transmit this information to the Medical Monitor.

The same individual will be the contact for receipt of medical device reports and 
SAEs.

In the absence of facsimile equipment, notification by telephone is acceptable for 
incidents, with a copy of the "Medical Device Incident Report Form" sent by 
overnight mail. 
7.7.3.4.
Regulatory Reporting Requirements for Medical Device Incidents

The investigator will promptly report all incidents occurring with any GSK medical 
device provided for use in the study in order for GSK to fulfil the legal responsibility 
to notify appropriate regulatory bodies and other entities about certain safety 
information relating to medical devices being used in clinical studies.

The investigator, or responsible person according to local requirements (e.g., the 
head of the medical institution in Japan), will comply with the applicable local 
regulatory requirements relating to the reporting of incidents to the IRB/IEC.

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7.7.4.
Physical Exams

A complete physical examination will include, at a minimum, assessment of the 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. Height
and weight will also be measured and recorded at Visit 1.

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
7.7.5.
Vital Signs

As detailed in the Time and Events Schedule Table (Section 7.1), vital signs will 
be measured in semi-supine position after 5 minutes rest and will include systolic 
and diastolic blood pressure and pulse rate.

Vital signs assessments will be taken before measurement of any ECGs at the 
specified time point.
7.7.6.
Electrocardiogram (ECG)

A single 12-lead ECG will be obtained at each timepoint specified in the Time 
and Events Schedule Table (Section 7.1) during the study using an ECG machine 
that automatically calculates the heart rate and measures PR, QRS, QT, and QTc 
intervals.  

If a routine single ECG demonstrates a prolonged QT interval, obtain two more 
ECGs over a brief period, and then use the averaged QTc values of the three 
ECGs to determine whether the patient should be discontinued from the study.  
Refer to Section 5.5.3 for QTc withdrawal criteria and additional QTc readings 
that may be necessary.

ECG measurements will be made after the subject has rested in the supine position 
for 5 minutes.  The ECG should be obtained after the vital signs assessments and 
followed by other study procedures. 
7.7.7.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 3, must be conducted in 
accordance with the Laboratory Manual, and Protocol Time and Events Schedule.
Laboratory requisition forms must be completed and samples must be clearly labelled 
with the subject number, protocol number, site/centre number, and visit date. Details for 
the preparation and shipment of samples will be provided by the laboratory and are 
detailed in the laboratory manual. Reference ranges for all safety parameters will be 
provided to the site by the laboratory responsible for the assessments.
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the CRF.

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Refer to the SRM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws.
Haematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed in Table 3. 
Table 3
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Platelet Count
RBC Indices:
WBC count with Differential:
RBC Count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes
Hematocrit
Monocytes
Eosinophils
Basophils
Clinical 
Chemistry 1
BUN
Potassium
AST (SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
ALT (SGPT)
Total Protein
Glucose 
Calcium
Alkaline phosphatase
Albumin
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood and ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Other 
Screening 
Tests

FSH and estradiol (as needed in women of non-child bearing 
potential only)

Urine hCG Pregnancy test (as needed for women of child bearing 
potential) 2

Parasitic screening (only required in countries with high-risk or for 
subjects who have visited high-risk countries in the past 6 months). 
Sites should use local laboratories.
NOTES :
1.
Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up 
Assessments after liver stopping or monitoring event are given in Section 5.5.2 and 
Appendix 4.
2.
Local urine testing will be standard for the protocol unless serum testing is required 
by local regulation or ethics committee.
RBC: Red blood cell; MCV: Mean corpuscular volume; MCH: Mean corpuscular haemoglobin;BUN: Blood urea 
nitrogen; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; FSH: Follicle stimulating hormone
All laboratory tests with values that are considered clinically significantly abnormal 
during participation in the study should be repeated until the values return to normal or 
baseline.  If such values do not return to normal within a period judged reasonable by the 
investigator, the etiology should be identified and the sponsor notified.

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7.8.
Pharmacodynamic Markers
Blood eosinophil counts will be recorded as part of the standard haematological 
assessments performed at the visits specified in the Time and Events Schedule (Section 
7.1).  
7.9.
Pharmacokinetics
Blood samples for analysis of mepolizumab plasma concentration will be obtained as per 
the Time and Events table (Section 7.1).  Samples obtained at Visits 2, 3, 4 and 5 should 
be drawn prior to dosing.  The date and exact time of collection for each sample will be 
documented in the eCRF.
Details for collection and processing of samples may be found in the SRM.
7.10.
Immunogenicity
Blood samples will be collected for the determination of anti-mepolizumab antibodies, 
prior to dosing, as detailed in the Time and Events Schedule (Section 7.1)
Details for sample collection and processing may be found in the SRM.
7.11.
Genetics
Information regarding genetic research is included in Appendix 7.  IEC/IRB and, where 
required, the applicable regulatory agency must approve the genetic assessments before 
these can be conducted at the site.  The approval(s) must be in writing and will clearly 
specify approval of the genetic assessments (i.e., approval of Appendix 7).  In some 
cases, approval of the genetic assessments can occur after approval is obtained for the 
rest of the study.  If so, then the written approval will clearly indicate approval of the 
genetic assessments is being deferred and the study, except for pharmacogenetics (PGx)
and genetic assessments, can be initiated.  When genetic assessments will not be 
approved, then the approval for the rest of the study will clearly indicate this and 
therefore, genetic assessments will not be conducted.
8.
DATA MANAGEMENT

For this study subject data will be entered into GSK defined CRFs, transmitted 
electronically to GSK or designee and combined with data provided from other 
sources in a validated data system.  

Management of clinical data will be performed in accordance with applicable 
GSK standards and data cleaning procedures to ensure the integrity of the data, 
e.g., removing errors and inconsistencies in the data.

Adverse events and concomitant medications terms will be coded using MedDRA 
(Medical Dictionary for Regulatory Activities) and an internal validated 
medication dictionary, GSKDrug.  

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
CRFs (including queries and audit trails) will be retained by GSK, and copies will 
be sent to the investigator to maintain as the investigator copy.  Subject initials 
will not be collected or transmitted to GSK according to GSK policy.
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1.
Hypotheses
The study is designed to descriptively evaluate the mepolizumab liquid drug product in 
safety syringe for self-administration by subjects with severe eosinophilic asthma. 
No formal statistical hypothesis testing is planned.  The number and percentage of 
subjects successfully able to self-administer their mepolizumab dose will be summarized 
together with 95% confidence intervals (CI).
9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
No formal sample size calculations were performed. Assuming a 30% dropout rate 
during screening, approximately 75 subjects will be screened in order to enrol 55 subjects 
(attempting at least one self-administration of mepolizumab). Assuming a dropout rate of 
up to 10% during the study, 55 enrolled subjects should provide at least 50 subjects with 
complete study data. 
No sample size re-assessment/adjustment is planned.
9.2.2.
Sample Size Sensitivity
The estimated precision for the proportion of subjects successfully able to self-administer 
their mepolizumab dose is presented below, assuming 50 completed subjects:-
Observed Proportion (%)
95% CI
(Exact Method)
70
55, 82
80
66, 90
82
69, 91
84
71, 93
86
73, 94
88
76, 95
90
78, 97
92
81, 98
94
83, 99
96
86, 100
98
89, 100

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9.3.
Data Analysis Considerations
Full details of all pre-specified analyses will be described in the Reporting and Analysis 
Plan (RAP).
9.3.1.
Analysis Populations
All Subjects Population
The ‘All Subjects’ population will comprise all enrolled subjects (i.e. attempting at least 
one self-administration of mepolizumab). This population will be used for the evaluation 
of the mepolizumab liquid drug product in safety syringe and for the summaries relating 
to the safety and tolerability of mepolizumab.
PK Population:
The PK population will be defined as all enrolled subjects for whom at least one PK 
sample was obtained and analyzed.  This will be the primary population for assessing PK.
PD Population:
The PD population is defined as all enrolled subjects who also have a baseline PD 
measurement and at least one post-treatment PD measurement. This will be the primary 
population for assessing PD.
9.3.2.
Treatment Comparisons
This is a single arm study. There are no treatment comparisons. All analyses will be 
descriptive.
9.3.3.
Interim Analysis
No interim analysis is planned.
9.4.
Key Elements of Analysis Plan
9.4.1.
Analyses to Evaluate Safety Syringe
Primary Endpoint
The number and percentage of subjects successfully able to self-administer their observed 
third dose at Week 8 will be summarized together with 95% confidence intervals. The 
denominator for the percentage calculation will be the number of subjects attempting an 
injection at Week 8.
Secondary Endpoints
The following will be summarized, including 95% CIs:-

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
The number and percentage of subjects successfully able to self-administer their 
unobserved second dose at Week 4. The denominator for the percentage 
calculation will be the number of subjects attempting an injection at Week 4.

The number and percentage of subjects successfully able to self-administer their 
observed first dose at Week 0. The denominator for the percentage calculation 
will be the number of subjects attempting an injection at Week 0.

The number and percentage of subjects successfully able to self-administer both 
their unobserved second dose at Week 4 and their observed third dose at Week 8. 
The denominator for the percentage calculation will be the number of subjects 
attempting an injection at both Week 4 and Week 8.

The number and percentage of subjects successfully able to self-administer all 
three doses at Week 0, 4 and 8. The denominator for the percentage calculation 
will be the number of subjects attempting all 3 doses at Week 0, 4 and 8.
Data collected on the Observation Checklist relating to the correct use of the safety 
syringe and any device related issues preventing the full dose being administered will be 
summarised at each visit. 
The root cause evaluation of each unsuccessful injection via the Safety Syringe 
Error/Failure Reporting Form, including any observations noted by GSK Device 
Engineering, will be summarized separately by GSK Device Engineering for inclusion 
into the study report.
Device usability/functionality assessed at the end of the study will be summarised. 
9.4.2.
Safety Analyses
AEs will be coded using the MedDRA coding dictionary and summarized by preferred 
term. Separate summaries will be provided for all AEs, IP-related AEs, SAEs, events of 
special interest (including systemic reactions and local injection site reactions) and for 
AEs leading to permanent discontinuation of study treatment.  All laboratory parameters 
for clinical chemistry and hematology will be summarized and tabulated.
Exacerbations will be summarized and listed.
Each ECG parameter at every assessed time point will be summarized using summary 
statistics.  Summary statistics of QT interval corrected for heart rate according to 
Fridericia’s formula (QTcF) and QT interval corrected for heart rate according to Bazett’s 
formula (QTcB) as well as change from baseline value will be presented by visit.
Summary statistics of pulse rate and systolic and diastolic blood pressure will be 
presented by visit.
Pain VAS scores and categorical pain assessments will be summarized by visit and time 
post injection (immediately following, 1- and 24-hours post injection).

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Immunogenicity will be summarized using appropriate descriptive statistics.
9.4.3.
Pharmacodynamic Analyses
Ratio to baseline (Visit 2) in blood eosinophil count will be summarized by visit, using 
summary statistics appropriate for log-normal data, overall, by previous mepolizumab use 
(i.e. not receiving mepolizumab treatment at Visit 1 or receiving 100 mg SC 
mepolizumab administered for the treatment of severe eosinophilic asthma every 4 weeks 
for at least 12 weeks prior to Visit 1) and by injection site. Values below the lower limit 
of quantification will be imputed as half the lower limit of quantification.
9.4.4.
Pharmacokinetic Analyses
Pharmacokinetic analysis will be the responsibility of the Clinical Pharmacology 
Modeling & Simulation department within GSK. 
PK concentrations will be presented in graphical and/or tabular form and will be 
summarized descriptively overall, by previous mepolizumab use (i.e. not receiving 
mepolizumab treatment at Visit 1 or receiving 100 mg SC mepolizumab administered for 
the treatment of severe eosinophilic asthma every 4 weeks for at least 12 weeks prior to 
Visit 1) and by injection site.
10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a site, GSK will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with International Conference on 
Harmonisation (ICH) Good Clinical Practice (GCP), all applicable subject privacy 
requirements, and the guiding principles of the current version of the Declaration of 
Helsinki.  This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable

Obtaining signed informed consent

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
Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol 
deviations to IRB/IEC)

GSK will provide full details of the above procedures, either verbally, in writing, 
or both.

Signed informed consent must be obtained for each subject prior to participation 
in the study

The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.  

Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.  

Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities.  In this situation, 
written approval of the clinical protocol should state that approval of optional 
assessments is being deferred and the study, with the exception of the optional 
assessments, can be initiated.
10.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK monitors will contact the site prior to the start of the study to review with the 
site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and GSK requirements.  

When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the eCRF 
will serve as the source document.
GSK will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any 
other study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents.
10.4.
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 

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relevant documents and to allocate their time and the time of their staff to discuss 
the conduct of the study, any findings/relevant issues and to implement any 
corrective and/or preventative actions to address any findings/issues identified.
10.5.
Study and Site Closure

Upon completion or premature discontinuation of the study, the GSK monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and GSK Standard 
Operating Procedures.

GSK reserves the right to temporarily suspend or prematurely discontinue this 
study at any time for reasons including, but not limited to, safety or ethical issues 
or severe non-compliance. For multicenter studies, this can occur at one or more 
or at all sites.  

If GSK determines such action is needed, GSK will discuss the reasons for taking 
such action with the investigator or the head of the medical institution (where 
applicable).  When feasible, GSK will provide advance notification to the 
investigator or the head of the medical institution, where applicable, of the 
impending action.

If the study is suspended or prematurely discontinued for safety reasons, GSK will 
promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action.  

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation.
10.6.
Records Retention

Following closure of the study, the investigator or the head of the medical 
institution (where applicable) must maintain all site study records (except for 
those required by local regulations to be maintained elsewhere), in a safe and 
secure location.  

The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review 
in conjunction with assessment of the facility, supporting systems, and relevant 
site staff.  

Where permitted by local laws/regulations or institutional policy, some or all of 
these records can be maintained in a format other than hard copy (e.g., microfiche, 
scanned, electronic); however, caution needs to be exercised before such action is 
taken.  

The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, 
including re-generating a hard copy, if required.  Furthermore, the investigator 

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must ensure there is an acceptable back-up of these reproductions and that an 
acceptable quality control process exists for making these reproductions.

GSK will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements.  The minimum retention time 
will meet the strictest standard applicable to that site for the study, as dictated by 
any institutional requirements or local laws or regulations, GSK 
standards/procedures, and/or institutional requirements.  

The investigator must notify GSK of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of 
ownership of the records in the event the investigator is no longer associated with 
the site.
10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy.
A manuscript will be progressed for publication in the scientific literature if the results 
provide important scientific or medical knowledge.

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11.
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Glucocorticoid-Sparing Effect of Mepolizumab in Eosinophilic Asthma. N Engl J Med
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Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma 
(GINA) 2015. Available from: http://www.ginasthma.org/.
Haldar P, Brightling CE, Hargadon B, Gupta, S, Monteiro W, Sousa A et al. 
Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med. 
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Investigator Brochure (IB) GSK Document Number CM2003/00010/10, Date 03 DEC 
2015.
Nair P, Pizzichini MMM, Kjarsgaard M, Inman MD, Efthimiadis A, Pizzichini, E et al. 
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National heart, lung and blood institute (NIH) 2007. Expert panel report 3: Guidelines 
for the diagnosis and management of asthma. National asthma education and prevention 
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guidelines/full-report
Ortega HG, Liu MC, Pavord ID, Brusselle GG, FitzGerald JM, Chetta A et al. 
Mepolizumab Treatment in Patients with Severe Eosinophilic Asthma. N Engl J Med
2014;371(13):1198-1207.
Pavord ID, Korn S, Howarth P, Bleeker ER, Buhl R, Keene ON et al. Mepolizumab for 
severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled 
trial. Lancet 2012;380:651–659.
Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson Jr FN, Bock AS, Branum A 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.

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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
ACQ
Asthma Control Questionnaire
ADA
Anti-drug antibody
AE
Adverse Event
ALT
Alanine aminotransferase
AST
Aspartate aminotrasferase
BUN
Blood urea nitrogen
CI
Confidence Interval
CONSORT
Consolidated Standard of Reporting Trials
COPD
Chronic obstructive pulmonary disease
CRF
Case report form
CS
Corticosteroid
Ctrough
Trough concentration at the end of the dosing interval
CV
Cardiovascular
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
ED
Emergency Department
EGPA
Eosinophilic granulomatosis with polyangiitis
EMEA
European Medicines Agency
EU
European Union
FAAN
Food Allergy and Anaphylaxis Network
FDA
Food and Drug Administration
FEV1
Forced expiratory volume in 1 second
FP
Fluticasone Propionate
FRP
Females of Reproductive Potential
FSH
Follicle stimulating hormone
G
Gauge
g
gram
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GINA
Global Initiative for Asthma
GSK
GlaxoSmithKline
hCG
Human chorionic gonadotropin
HES
Hypereosinophilic Syndrome
hIL
Human interleukin
HIV
Human immunodeficiency virus
HRT
Hormone replacement therapy
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Conference on Harmonisation

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ICS
Inhaled corticosteroids
IEC
Independent Ethics Committee
IFU
Instructions for Use
IgG
Immunoglobulin
IL
Interleukin
IM
Intramuscular
IP
Investigational Product
IRB
Institutional Review Board
IV
Intravenous
kg
Kilogram
LABA
Lon-acting beta-2-agonist
LTRA
Leukotriene receptor antagonist
mAb
Monoclonal antibody
mcg
Microgram
MCH
Mean corpuscular hemoglobin
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
mL
Milliliter
mm Hg
Milliliter of mercury
MSDS
Material Safety Data Sheet
N/A
Not applicable
NAb
Neutralising antibody
NIAID
National Institute of Allergy and Infectious Disease
NIH
National Heart Lung and Blood Institute
OCS
Oral corticosteroids
PCSA
Placebo controlled severe asthma
PD
Pharmacodynamic
PEF
Peak expiratory flow
PGx
Pharmacogenetics
PK
Pharmacokinetic
QTc
QI interval corrected for heart rate
QTcB
QT interval corrected for heart rate by Bazett’s formula
QTcF
QT interval corrected for heart rate by Fridericia’s formula
R&D
Research & Development
RAP
Reporting and Analysis plan
RBC
Red blood cell
RNA
Ribonucleic acid
SAE
Serious Adverse Event
SC
Subcutaneous(ly)
SGRQ
St George’s Respiratory Questionnaire 
SRM
Study reference manual
UK
United Kingdom
ULN
Upper limit of normal
US
United States
V
Visit

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VAS
Visual Analogue Scale
WFI
Water for injection
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NUCALA
SAS
Xolair (omalizumab)

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

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12.3.
Appendix 3: Modified List of Highly Effective Methods for 
Avoiding Pregnancy in FRP and Collection of Pregnancy 
Information
12.3.1.
Definition of post menopausal female
Post menopausal female is defined as:

Females 60 years of age or older

Menopause is the phase associated with complete cessation of menstrual cycles and 
implies the loss of reproductive potential by ovarian failure. This typically occurs 
around 50 years of age, although it may occur earlier or later. A practical definition 
accepts menopause after 1 year without menses with an appropriate clinical profile, 
e.g., age appropriate, >45 years, in the absence of hormone replacement therapy 
(HRT) or medical suppression of the menstrual cycle (e.g., leuprolide treatment).

In questionable cases for women < 60 years of age, a blood sample with simultaneous 
follicle stimulating hormone and estradiol falling into the central laboratory’s 
postmenopausal reference range is confirmatory (these levels need to be adjusted for 
specific laboratories/assays) [Kronenberg, 2008; Strauss, 2004].

Females under 60 years of age, who are on HRT and wish to continue, and whose 
menopausal status is in doubt, are required to use a highly effective method to avoid 
pregnancy, as outlined in the protocol. Otherwise, they must discontinue HRT to 
allow confirmation of post-menopausal status prior to study enrolment. For most 
forms of HRT, at least 2 to 4 weeks will elapse between the cessation of therapy and 
the blood draw; this interval depends on the type and dosage of HRT. Following 
confirmation of their post-menopausal status, they can resume use of HRT during the 
study without use of a highly effective method to avoid pregnancy. If laboratory 
values for FSH and estradiol are drawn and the results do not confirm menopause on 
a potential subject that otherwise met the specifications for being post-menopausal 
defined above without question, the subject may still enrol in the study as a FNRP if 
approved by the GSK Medical Monitor and the safety physician.
12.3.2.
Modified List of Highly Effective Methods for Avoiding Pregnancy 
in Females of Reproductive Potential (FRP)
The list does not apply to FRP with same sex partners or for subjects who are and will 
continue to be abstinent from penile-vaginal intercourse on a long term and persistent 
basis, when this is their preferred and usual lifestyle. Periodic abstinence (e.g. calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.
1.
Contraceptive subdermal implant
2.
Intrauterine device or intrauterine system
3.
Combined estrogen and progestogen oral contraceptive [Hatcher, 2011]
4.
Injectable progestogen [Hatcher, 2011]

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5.
Contraceptive vaginal ring [Hatcher, 2011]
6.
Percutaneous contraceptive patches [Hatcher, 2011]
7.
Male partner sterilization with documentation of azoospermia prior to the female 
subject's entry into the study, and this male is the sole partner for that subject 
[Hatcher, 2011]. The documentation on male sterility can come from the site 
personnel’s: review of subject’s medical records, medical examination and/or semen 
analysis, or medical history interview provided by her or her partner.
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
12.3.3.
Collection of Pregnancy Information

Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study

Information will be recorded on the appropriate form and submitted to GSK within 2 
weeks of learning of a subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on mother and infant, which will be 
forwarded to GSK.  Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date. 

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK 
as described in Appendix 6. While the investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.
Any female subject who becomes pregnant while participating will be withdrawn 
from the study.

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12.3.4.
References
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, Policar MS, 
editors. Contraceptive Technology. 20th edition. Atlanta, Georgia: Ardent Media, Inc., 
2011: 50. Table 3-2.
Kronenberg HM, Melmed S, Polonsky KS, Larsen PR, editors. Williams Textbook of 
Endocrinology, 11th edition. Philadelphia: Saunders, 2008.
Strauss JF, Barbieri RL, editors. Yen and Jaffe’s Reproductive Endocrinology. 5th 
edition, Philadelphia, Elsevier/Saunders, 2004.

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12.4.
Appendix 4: Liver Safety Required Actions and Follow up 
Assessments
12.4.1.
Liver chemistry stopping criteria and required follow up 
assessments
Liver Chemistry Stopping Criteria - Liver Stopping Event
ALT-absolute
ALT 8xULN
ALT Increase
ALT 5xULN but <8xULN  persists for 2 weeks
ALT 3xULN but <5xULN  persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot 
Monitor
ALT 5xULN but <8xULN and cannot be monitored weekly for 2 weeks
ALT 3xULN but <5xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be 
related to  liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue study treatment 

Report the event to GSK within 24 hours

Complete the liver event CRF and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries 
resolve , stabilize, or return to within baseline 
(see MONITORING below)

Do not restart/rechallenge subject with 
study treatment.  Permanently discontinue 
study treatment and may continue subject in 
the study for any protocol specified follow up 
assessments

Viral hepatitis serology4

Only in those with underlying chronic 
hepatitis B at study entry (identified by 
positive hepatitis B surface antigen) 
quantitative hepatitis B DNA and hepatitis 
delta antibody5.

Blood sample for pharmacokinetic (PK) 
analysis, obtained within 4 weeks after last 
dose6

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia. Note: 
The mechanism of action of mepolizumab 
leads to lowering of eosinophils.

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Liver Chemistry Stopping Criteria - Liver Stopping Event
MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24 
hrs

Monitor subjects twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

A specialist or hepatology consultation is 
recommended
For All other criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24-
72 hrs 

Monitor subjects weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on 
the concomitant medications report form
including acetaminophen, herbal 
remedies, other over the counter 
medications.

Record alcohol use on the liver event 
alcohol intake case report form
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG or gamma 
globulins).

Serum acetaminophen adduct HPLC 
assay (quantifies potential acetaminophen 
contribution to liver injury in subjects with 
definite or likely acetaminophen use in the 
preceding week [James, 2009]). NOTE: 
not required in China

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to subjects receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)   
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
5.
If hepatitis delta antibody assay cannot be performed,, it can be replaced with a PCR of hepatitis D RNA virus 
(where needed) [Le Gal, 2005].

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6.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM.  
12.4.2.
Liver chemistry increased monitoring criteria with continued 
therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 5xULN and <8xULN and bilirubin 
<2xULN without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 2 weeks.
OR
ALT 3xULN and <5xULN and bilirubin 
<2xULN without symptoms believed to 
be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks.

Notify the GSK medical monitor within 24 hours of 
learning of the abnormality to discuss subject 
safety. 

Subject can continue study treatment  

Subject must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline 

If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above

If ALT decreases from ALT 5xULN and <8xULN to 
≥3xULN but <5xULN, continue to monitor liver 
chemistries weekly. 

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor subjects twice monthly 
until liver chemistries normalize or return to within 
baseline.
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P, Gault E.  Quantification 
of Hepatitis Delta Virus RNA in Serum by Consensus Real-Time PCR Indicates 
Different Patterns of Virological Response to Interferon Therapy in Chronically Infected 
Patients.  J Clin Microbiol. 2005;43(5):2363–2369. 

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12.5.
Appendix 5: Definition of and Procedures for Documenting 
Medical Device Incidents
12.5.1.
Definitions of a Medical Device Incident
The detection and documentation procedures described in this protocol apply to all GSK 
medical devices provided for use in the study (see Section 6.2 for the list of GSK medical 
devices).
Medical Device Incident Definition:

Incident – Any malfunction or deterioration in the characteristics and/or performance 
of a device, as well as any inadequacy in the labeling or the instructions for use 
which, directly or indirectly, might lead to or might have led to the death of a 
patient/user/other persons or to a serious deterioration in their state of health.

Not all incidents lead to death or serious deterioration in health.  The non-occurrence 
of such a result might have been due to other fortunate circumstances or to the 
intervention of health care personnel.
It is sufficient that:

an incident associated with a device happened and

the incident was such that, if it occurred again, might lead to death or a serious 
deterioration in health.
A serious deterioration in state of health can include:

life-threatening illness

permanent impairment of body function or permanent damage to a body 
structure

a condition necessitating medical or surgical intervention to prevent one of the 
above 

fetal distress, fetal death or any congenital abnormality or birth defects
Examples of incidents

a patient, user, care giver or professional is injured as a result of a medical device 
failure or its misuse

a patient’s treatment is interrupted or compromised by a medical device failure

misdiagnosis due to medical device failure leads to inappropriate treatment

a patient’s health deteriorates due to medical device failure

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12.5.2.
Documenting Medical Device Incidents
Medical Device Incident Documenting:

Any medical device incident occurring during the study will be documented in the 
subject’s medical records, in accordance with the investigator’s normal clinical 
practice, and on the appropriate form.

For incidents fulfilling the definition of an AE or an SAE, the appropriate AE/SAE 
CRF page will be completed as described in Appendix 6.

The form will be completed as thoroughly as possible and signed by the investigator 
before transmittal to GSK.

It is very important that the investigator provides his/her assessment of causality to 
the medical device provided by GSK at the time of the initial report, and describes 
any corrective or remedial actions taken to prevent recurrence of the incident.

A remedial action is any action other than routine maintenance or servicing of a 
device where such action is necessary to prevent recurrence of an incident. This 
includes any amendment to the design to prevent recurrence.

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12.6.
Appendix 6: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.6.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a patient or clinical investigation 
subject, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae).

The signs and symptoms and/or clinical sequelae resulting from lack of efficacy will 
be reported if they fulfil the definition of an AE or SAE.  Also, "lack of efficacy" or 
"failure of expected pharmacological action" also constitutes an AE or SAE.
Events NOT meeting definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 
condition.

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
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
12.6.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c.
Requires hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting.  Complications that occur during hospitalization are 
AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.

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d.
Results in disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday 
life functions but do not constitute a substantial disruption
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition.  These should also be considered 
serious.

Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse
g.
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** >1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick.  If fractionation is unavailable and ALT 3xULN 
and total bilirubin 2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.

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12.6.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
12.6.4.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the CRF

It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to GSK in lieu of completion of the GSK, AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK.  In this instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to 
submission of to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.

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12.6.5.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. - an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of his/her assessment.

For each AE/SAE the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK.  However, it is very important 
that the investigator always make an assessment of causality for every event 
prior to the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.

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Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.

The investigator is obligated to assist.  This may include additional laboratory tests 
or investigations, histopathological examinations or consultation with other health 
care professionals.

If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide GSK with a copy of any post-mortem findings, 
including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
12.6.6.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data collection 
tool

If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax it to the Medical Monitor

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of 
the SAE.

After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) will be taken off-line to prevent the entry of new data or changes to 
existing data

If a site receives a report of a new SAE from a study subject or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, the site can report this information on a paper SAE form or to the Medical 
Monitor by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.

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SAE reporting to GSK via paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the Medical Monitor

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable, with a copy of the SAE data collection tool sent by 
overnight mail

Initial notification via the telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE receipt can be found at this beginning of the protocol on the 
Sponsor/Medical Monitor Contact Information page.

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12.7.
Appendix 7: Genetic Research
Genetics – Background
Naturally occurring genetic variation may contribute to inter-individual variability in 
response to medicines, as well as an individual's risk of developing specific diseases. 
Genetic factors associated with disease characteristics may also be associated with 
response to therapy, and could help to explain some clinical study outcomes. For 
example, genetic variants associated with age-related macular degeneration (AMD) are 
reported to account for much of the risk for the condition [Gorin, 2012] with certain 
variants reported to influence treatment response [Chen, 2012]. Thus, knowledge of the 
genetic etiology of disease may better inform understanding of disease and the 
development of medicines. Additionally, genetic variability may impact the 
pharmacokinetics (absorption, distribution, metabolism, and elimination), or 
pharmacodynamics (relationship between concentration and pharmacologic effects or the 
time course of pharmacologic effects) of a specific medicine and/or clinical outcomes 
(efficacy and/or safety) observed in a clinical study.
Genetic Research Objectives and Analyses
The objectives of the genetic research are to investigate the relationship between genetic 
variants and: 

Response to medicine, including mepolizumab or any concomitant medicines;

Asthma susceptibility, severity, and progression and related conditions
Genetic data may be generated while the study is underway or following completion of 
the study.  Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses). Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above.  Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives.
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in a Reporting and Analysis Plan 
(RAP) prior to initiation of the analysis. Planned analyses and results of genetic 
investigations will be reported either as part of the clinical RAP and study report, or in a 
separate genetics RAP and report, as appropriate.
Study Population
Any subject who is enrolled in the study can participate in genetic research.  Any subject 
who has received an allogeneic bone marrow transplant must be excluded from the 
genetic research.
Study Assessments and Procedures
A key component of successful genetic research is the collection of samples during 
clinical studies. Collection of samples, even when no a priori hypothesis has been 

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identified, may enable future genetic analyses to be conducted to help understand 
variability in disease and medicine response.  

A 2 ml blood sample will be taken for Deoxyribonucleic acid (DNA) extraction. 
A blood sample is collected at the baseline visit, after the subject has been 
enrolled and provided informed consent for genetic research. Instructions for 
collection and shipping of the genetic sample are described in the laboratory 
manual. The DNA from the blood sample may undergo quality control analyses to 
confirm the integrity of the sample. If there are concerns regarding the quality of 
the sample, then the sample may be destroyed. The blood sample is taken on a 
single occasion unless a duplicate sample is required due to an inability to utilize 
the original sample.  
The genetic sample is labelled (or “coded”) with the same study specific number used to 
label other samples and data in the study.   This number can be traced or linked back to 
the subject by the investigator or site staff. Coded samples do not carry personal 
identifiers (such as name or social security number). 
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study, or GSK may destroy the samples sooner.  GSK or those working 
with GSK (for example, other researchers) will only use samples collected from the study 
for the purpose stated in this protocol and in the informed consent form.  Samples may be 
used as part of the development of a companion diagnostic to support the GSK medicinal 
product.
Subjects can request their sample to be destroyed at any time.
Informed Consent
Subjects who do not wish to participate in the genetic research may still participate in the 
study.  Genetic informed consent must be obtained prior to any blood being taken.
Subject Withdrawal from Study
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample, if already 
collected:

Continue to participate in the genetic research in which case the genetic DNA 
sample is retained

Discontinue participation in the genetic research and destroy the genetic DNA 
sample 
If a subject withdraws consent for genetic research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in 
the site study records. 

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Genotype data may be generated during the study or after completion of the study and 
may be analyzed during the study or stored for future analysis. 

If a subject withdraws consent for genetic research and genotype data has not been 
analyzed, it will not be analyzed or used for future research.  

Genetic data that has been analyzed at the time of withdrawn consent will 
continue to be stored and used, as appropriate. 
Screen Failures
If a sample for genetic research has been collected and it is determined that the subject 
does not meet the entry criteria for participation in the study, then the investigator should 
instruct the subject that their genetic sample will be destroyed. No forms are required to 
complete this process as it will be completed as part of the consent and sample 
reconciliation process.  In this instance a sample destruction form will not be available to 
include in the site files.
Provision of Study Results and Confidentiality of Subject’s Genetic Data
GSK may summarize the genetic research results in the clinical study report, or 
separately and may publish the results in scientific journals. 
GSK may share genetic research data with other scientists to further scientific 
understanding in alignment with the informed consent. GSK does not inform the subject, 
family members, insurers, or employers of individual genotyping results that are not 
known to be relevant to the subject’s medical care at the time of the study, unless 
required by law. This is due to the fact that the information generated from genetic 
studies is generally preliminary in nature, and therefore the significance and scientific 
validity of the results are undetermined.  Further, data generated in a research laboratory 
may not meet regulatory requirements for inclusion in clinical care.
References:
Chen H, Yu KD, Xu GZ. Association between Variant Y402H in Age-Related Macular 
Degeneration (AMD) Susceptibility Gene CFH and Treatment Response of AMD: A 
Meta-Analysis. PloS ONE 2012; 7: e42464
Gorin MB. Genetic insights into age-related macular degeneration: Controversies 
addressing risk, causality, and therapeutics. Mol. Asp. Med. 2012; 33: 467-486.

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12.8.
Appendix 8: Country Specific Requirements
No country-specific requirements exist.

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12.9.
Appendix 9: Protocol changes
Scope:
This amendment applies to all sites.
Protocol Changes specified in Amendment No.1 are summarised below.
Strike through text refers to deleted text and underlined refers to added text.
Protocol Changes
Sponsor Legal Registered Address
Rationale for change: EudraCT number different to the 204959 Autoinjector protocol
Regulatory Agency Identifying Number(s): IND No 006971, EudraCT No: 2016-001831-
10 001832-36
Section 1 Protocol Synopsis Objective(s)/Endpoints
Rationale for change: To present the primary endpoint in a tabular format and include 
the secondary endpoint, as per GSK protocol template standard.
Revised text:
The primary endpoint is the proportion of subjects successfully able to self-administer 
their observed third dose using the safety syringe at the clinic at Week 8.
The primary and secondary objectives and associated endpoints are outlined below:
Objectives
Endpoints
Primary

To assess the use of the combination 
product, mepolizumab liquid drug 
product in safety syringe for the 
subcutaneous self-administration of 
mepolizumab by subjects with severe 
eosinophilic asthma

Proportion of subjects successfully able 
to self-administer their observed third 
dose at Week 8
Secondary

To assess the use of mepolizumab 
liquid drug product in safety syringe 
outside the clinic setting

Proportion of subjects successfully 
able to self-administer their 
unobserved second dose outside the 
clinic setting at Week 4

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Section 4.1 Overall Design
Rationale for change: To refine the criteria for a successful injection following a use-
related risk review
Revised text: 

Safety syringe positioned with the entire needle inserted at an angle into skin that 
has been pinched and a full dose administered by slowly depressing the plunger 
until the stopper reaches the bottom of the syringe, thumb moved up allowing 
plunger to rise

Full dose administered: subject fully inserts the needle, slowly depresses the 
plunger until the stopper reaches the bottom of the syringe and activates the 
needle guard by moving the thumb up
Section 5.1 Inclusion Criterion No. 9/ Exclusion Criterion No. 15
Rationale for change: Included additional text to Inclusion Criterion 9 to allow 
Exclusion Criterion 15 to be removed:
Revised text:
9. Gender: Male or Female
Females: 
A female subject is eligible to participate if she is not pregnant (as confirmed by a 
negative urine human chorionic gonadotrophin (hCG) test), planning to become pregnant 
during the time of study participation (and up to 16 weeks after the last dose), not 
lactating, and at least one of the following conditions applies:
15.  Pregnancy: Subjects who are pregnant or breastfeeding. Patients should not be 
enrolled if they plan to become pregnant during the time of study participation (and up to 
16 weeks after the last dose).
Section 5.1 Exclusion Criterion No. 7
Rationale for change: To allow Bazett’s to be used as the correction formula for heart 
rate when measuring the QT interval consistent with text elsewhere in the protocol.
Revised Text:
7.  ECG Assessment: QT interval corrected for heart rate by either Fridericia’s or 
Bazett’s formula QTc(F)/QTc(B) ≥450msec or QTc(F)/QTc(B) ≥480 msec for subjects 
with Bundle Branch Block at Visit 1.

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Section 7.3 Assessment of Safety Syringe Use
Rational for change: To refine the criteria for a successful injection following a use-
related risk review
Revised text:
At Visit 2 (Week 0), and at Visit 4 (Week 8), the investigator or designee will observe, 
using a checklist based on the safety syringe IFU, the ability of the subject/caregiver to 
(self)-administer the injection. The Observer Checklist (see SRM) will be used to 
determine if each step, according to the IFU, was completed easily, with some difficulty 
or not completed/intervention required.
Failure to perform one of the critical steps (i.e., correct choice of injection site, safety
syringe positioned with the entire needle inserted at an angle into skin that has been 
pinched and a full dose administered (determined by the subject fully inserting the 
needle, by slowly depressing the plunger until the stopper reaches the bottom of the 
syringe, and activating the needle guard by moving the thumb up thumb moved up 
allowing plunger to rise) will be deemed to be a failure to successfully administer the 
injection.
Section 10.7 Provision of Study Results to Investigators
Rationale for change: Delete text related to randomization codes as study is open-label 
and randomization codes will not be used.
Revised text: 
GSK will provide the investigator with the randomization codes for their site only after 
completion of the full statistical analysis.
Section 11 References
Rationale for change: References not cited in the document.
Revised text:
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, editors. 
Contraceptive Technology. 19th edition. New York: Ardent Media, 2007(a): 24. Table 3-
2.
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, editors. 
Contraceptive Technology. 19th edition. New York: Ardent Media, 2007(b): 28.
Section 12.3.4 Appendix 3 
Rationale for change: References not cited in document

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Revised text:
CHMP, 2005 - EMA - Guideline on Adjuvants in Vaccines for Human Use, 
(CHMP/VEG/134716/2004), January 2005.
Cole LA, Khanlian SA, Sutton JM, Davies S, Rayburn WF. Accuracy of home pregnancy 
tests at the time of missed menses. Am J Ob Gyn 2004(190):100-5.
EMA/CHMP/ICH/449035/2009: General principles to address virus and vector shedding. 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/
WC500002680.pdf Accessed 28 Nov 2014.
EMEA/CHMP/GTWP/125459/2006: Guideline on the Nonclinical Studies Required 
Before First Clinical Use of Gene Therapy Medicinal Products [2008]
FDA CBER Guidance for industry, “Considerations for Developmental Toxicity Studies 
for Preventive and Therapeutic Vaccines for Infectious Disease Indications. U.S. FDA; 
Feb. 2006. 
FDA Medical Devices Safety Alerts and Notices, “Blood human chorionic gonadotropin 
(hCG) assays: What laboratorians should know about false-positive results”, 
http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/TipsandArticlesonDeviceS
afety/ucm109390.htm, accessed 17 Nov 2014.
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals For Human Use. ICH Harmonized Tripartite Guideline. Detection of 
Toxicity to Reproduction for Medicinal Products & Toxicity to Male Fertility. Parent 
Guideline dated 24 June 1993 (Addendum dated 9 November 2000 incorporated in 
November 2005. ICH S5 (R2)
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals For Human Use.  ICH Harmonized Tripartite Guideline. Nonclinical 
Evaluation for Anticancer Pharmaceuticals. ICH S9. 2009.
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals For Human Use. ICH Harmonized Tripartite Guideline. Nonclinical 
Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for 
Pharmaceuticals. ICH M3 (R2). 2009.
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals For Human Use. ICH Harmonized Tripartite Guideline. Preclinical 
Safety Evaluation of Biotechnology-Derived Pharmaceuticals. ICH S6 and Addendum 
ICH S6 (R1). 2011.
U.S. Dept of Health and Human Services, FDA, Center For Biologics Evaluation and 
Research: Guidance for Human Somatic Cell Therapy and Gene Therapy [1998]
WHO, 2013 - WHO - Guidelines on the Nonclinical Evaluation of Vaccine Adjuvants 
and Adjuvanted Vaccines, 2013

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World Health Organization. WHO/CONRAD Technical Consultation on Nonoxynol-9.
World Health Organization; Department of Reproductive Health and Research; Geneva; 
9-10 October 2001. Summary Report. 2001. WHO/RHR/03.8.