An Open Label, Randomised, Three Arm, Single Dose, Multicentre, Parallel Group Study in Healthy Subjects to Compare the Pharmacokinetics of Subcutaneous Mepolizumab When Delivered as a Liquid Drug Product in a Safety Syringe or an Auto Injector With a Reconstituted Lyophilised Drug Product From a Vial
Phase: PHASE3
Conditions: Asthma
Sponsor: GlaxoSmithKline

2016N275057_03
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The GlaxoSmithKline group of companies
204958
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TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
An open label, randomised, three arm, single dose, multicentre,
parallel group study in healthy subjects to compare the
pharmacokinetics of subcutaneous mepolizumab when delivered
as a liquid drug product in a safety syringe or an auto injector
with a reconstituted lyophilised drug product from a vial
Compound Number:
SB240563
Development Phase:
III
Effective Date:
10-JUL-2017
Protocol Amendment Number:  03
Author (s):
 
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD

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Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2016N275057_00
2016-AUG-31
Original
2016N275057_01
2016-NOV-05
Amendment No. 1
Update to the content of the Device error forms to reflect consistency with other data 
captured in similar studies.  Updated withdrawal wording Section 5.4.1.   Removal of 
Cardiovascular and deaths events Section 7.3.1.4. 
2016N275057_02
2016-NOV-17
Amendment No. 2
Minor changes incorporated throughout the document as part of the QC step. 
2016N275057_03
2017-JUL-10
Amendment No.3
Section 7.3.1.4 Cardiovascular and Death Events section has been removed. Subsequent 
Section 7.3.1.5 “Regulatory reporting requirements for SAE’s” is assigned Section 
number 7.3.1.4 to maintain numerical sequence.

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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
Site Address
Primary 
Medical 
Monitor 
Telephone: 
Cell: 
GlaxoSmithKline
Upper Merion
709 Swedeland 
Road, King of 
Prussia, PA –
19406, USA
Secondary 
Medical 
Monitor
 
Telephone:
Cell: 
GlaxoSmithKline
5 Moore Drive, PO 
Box 13398, 
Research Triangle 
Park (RTP), NC 
27709-3398, USA
SAE 
contact  
information 
Medical 
monitor as 
above 
Telephone: 
Cell: 
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.
IND No: 006971,          EudraCT No: 2016-002405-19
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 204958
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 204958........................................................9
2.
INTRODUCTION....................................................................................................14
2.1.
Study Rationale ..........................................................................................14
2.2.
Brief Background ........................................................................................15
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................16
4.
STUDY DESIGN ....................................................................................................17
4.1.
Overall Design ............................................................................................17
4.2.
Treatment Arms and Duration.....................................................................18
4.3.
Type and Number of Subjects.....................................................................18
4.4.
Design Justification.....................................................................................19
4.5.
Dose Justification........................................................................................20
4.6.
Benefit:Risk Assessment ............................................................................20
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........................................................................................26
5.3.
Screening/Baseline/Run-in Failures............................................................28
5.4.
Withdrawal/Stopping Criteria.......................................................................28
5.4.1.
Withdrawal from the study ...........................................................28
5.4.2.
Liver Chemistry Stopping Criteria ................................................29
5.4.3.
QTc Stopping criteria...................................................................29
5.5.
Subject and Study Completion....................................................................29
6.
STUDY TREATMENT ............................................................................................30
6.1.
Investigational Product and Other Study Treatment....................................30
6.2.
Medical Devices..........................................................................................32
6.3.
Treatment Assignment................................................................................32
6.4.
Blinding.......................................................................................................32
6.5.
Packaging and Labeling..............................................................................32
6.6.
Preparation/Handling/Storage/Accountability..............................................32
6.7.
Training Session.........................................................................................33
6.8.
Compliance with Study Treatment Administration.......................................33
6.9.
Treatment of Study Treatment Overdose....................................................34
6.10.
Treatment after the End of the Study ..........................................................34
6.11.
Lifestyle and/or Dietary Restrictions............................................................34
6.11.1.
Caffeine, Alcohol, and Tobacco ...................................................34
6.11.2.
Activity .........................................................................................34
6.12.
Concomitant Medications and Non-Drug Therapies....................................35
6.12.1.
Permitted Medications and Non-Drug Therapies..........................35
6.12.2.
Prohibited Medications and Non-Drug Therapies.........................35
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................35

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7.1.
Time and Events Table...............................................................................37
7.2.
Screening and Critical Baseline Assessments ............................................41
7.2.1.
Critical procedures performed at Screening.................................41
7.2.2.
Critical procedures performed at first treatment visit ....................42
7.3.
Safety .........................................................................................................42
7.3.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........42
7.3.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................42
7.3.1.2.
Method of Detecting AEs and SAEs ...........................43
7.3.1.3.
Follow-up of AEs and SAEs........................................43
7.3.1.4.
Regulatory Reporting Requirements for SAEs............44
7.3.2.
Pregnancy ...................................................................................44
7.4.
Medical Device Incidents (Including Malfunctions)......................................44
7.4.1.
Time Period for Detecting Medical Device Incidents ....................44
7.4.2.
Follow-up of Medical Device Incidents.........................................45
7.4.3.
Prompt Reporting of Medical Device Incidents to GSK ................45
7.4.4.
Autoinjector and safety syringe functionality assessment.............45
7.4.5.
Returning defective Medical Devices to GSK...............................45
7.4.6.
Regulatory Reporting Requirements for Medical Device 
Incidents ......................................................................................45
7.5.
Physical Exams ..........................................................................................46
7.5.1.
Vital Signs....................................................................................46
7.5.2.
Electrocardiogram (ECG).............................................................46
7.5.3.
Clinical Safety Laboratory Assessments ......................................46
7.6.
Pharmacokinetics .......................................................................................48
7.6.1.
Blood Sample Collection..............................................................48
7.6.2.
Sample Analysis ..........................................................................48
7.7.
Pharmacodynamic Markers ........................................................................48
7.8.
Immunogenicity...........................................................................................48
8.
DATA MANAGEMENT ...........................................................................................48
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................49
9.1.
Hypotheses.................................................................................................49
9.2.
Sample Size Considerations.......................................................................49
9.3.
Data Analysis Considerations .....................................................................50
9.3.1.
Analysis Populations....................................................................50
9.3.1.1.
All Treated Subjects Population..................................50
9.3.1.2.
Pharmacokinetic Population .......................................50
9.3.2.
Interim Analysis ...........................................................................50
9.4.
Key Elements of Analysis Plan ...................................................................50
9.4.1.
Raw Plasma Concentrations........................................................50
9.4.2.
Derived Plasma Pharmacokinetic Parameters.............................50
9.5.
Primary Analyses........................................................................................51
9.6.
Secondary Analyses ...................................................................................51
9.6.1.
Exploratory Analyses ...................................................................52
10. STUDY GOVERNANCE CONSIDERATIONS........................................................52
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............52
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................52
10.3.
Quality Control (Study Monitoring) ..............................................................53

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10.4.
Quality Assurance.......................................................................................53
10.5.
Study and Site Closure ...............................................................................54
10.6.
Records Retention......................................................................................54
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................55
11. REFERENCES.......................................................................................................56
12. APPENDICES........................................................................................................59
12.1.
Appendix 1 – Abbreviations and Trademarks..............................................59
12.2.
Appendix 2 - Liver Safety Required Actions and Follow up
Assessments ..............................................................................................61
12.3.
Appendix 3 - Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events ............................63
12.4.
Appendix 4 - Definition of and Procedures for Documenting Medical 
Device Incidents .........................................................................................69
12.5.
Appendix 5 - Modified List of Highly Effective Methods for Avoiding 
Pregnancy in FRP and Collection of Pregnancy Information.......................71
12.6.
Appendix 6 - Anaphylaxis Criteria ...............................................................73
12.7.
Appendix 7- Inspection of the Autoinjector..................................................74
12.8.
Appendix 8 - Auto injector Error/Failure reporting form ...............................75
12.9.
Appendix 9 - Inspection of the Safety Syringe.............................................78
12.10. Appendix 10 - Safety Syringe Error/ Failure reporting form.........................79
12.11. Appendix 11 - Country Specific Requirements............................................82
12.12. Appendix 12 - Protocol Amendment Changes 01........................................83
12.13. Appendix 13 - Protocol Amendment Changes 02......................................103
12.14. Appendix 14 - Protocol Amendment Changes 03......................................112

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1.
PROTOCOL SYNOPSIS FOR STUDY 204958
Rationale
Mepolizumab (SB-240563) is a humanized 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 signaling. Neutralization of IL-
5 with mepolizumab reduces blood, sputum and tissue eosinophils, which results in a 
reduction in exacerbations/flares and in the maintenance dose of oral corticosteroids 
(OCS) in various eosinophilic-mediated diseases.
Mepolizumab has been investigated for the treatment of patients with severe eosinophilic 
asthma who have current blood eosinophil levels of 150 cells/μL or greater, or historical 
blood eosinophil levels (within 12 months) of 300 cells/μL or greater and history of 
exacerbations despite high dose inhaled  corticosteroid therapy and an additional 
controller.  It has been recently approved in a number of markets including the EU (03 
December 2015) and US (04 November 2015). Mepolizumab has also been evaluated in 
subjects with moderate asthma, FIP1L1/PDGFR-negative hypereosinophilic syndrome 
(HES), eosinophilic esophagitis (EoE) and eosinophilic granulomatosis with polyangiitis 
(EGPA) (i.e. Churg Strauss syndrome). 
Mepolizumab for Injection, a sterile, single-use, preservative-free, lyophilized drug 
product formulation (herein referred to as lyophilized drug product) was used in the 
clinical development programs and is the current marketed presentation for asthma 
(Nucala™).  Before use, each vial of lyophilized drug product must be reconstituted 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, has 
been developed. Administration of Mepolizumab Injection (herein referred to as liquid 
drug product in autoinjector or liquid drug product in safety syringe) will be more 
convenient and may allow the ultimate goal of patient self-administration. 
In vitro analytical data confirms that the liquid and lyophilised formulations of 
mepolizumab are comparable. Consequently the likelihood of clinically significant 
differences in the systemic exposure, efficacy or safety profile between the liquid drug 
product in the safety syringe or autoinjector and the lyophilised powder for reconstitution 
in the vial is considered to be low. However, in addition to demonstration of in vitro 
biochemical comparability, the change in formulation and the change in drug product 
presentation from a manually administered reconstituted lyophile to a liquid 
(administered from a safety syringe or autoinjector) requires demonstration clinically that 
the relative bioavailability of the treatments are similar  (ICHQ5E; biopharmaceutical 
comparability).
The aim of this study is to provide relative bioavailability data to support the transition 
from the currently marketed presentation of the lyophilised powder for reconstitution to a 
ready-to-use liquid in a pre-filled syringe assembled into either a safety syringe or an 
autoinjector.  The study is intended to demonstrate comparable mepolizumab 
pharmacokinetics following a single subcutaneous (SC) dose administration in healthy 
subjects. Safety (including immunogenicity) and tolerability will also be evaluated. Blood 
eosinophil count and device functionality will also be explored.

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Objective(s)/Endpoint(s)
Objectives
Endpoints
Primary

To compare the pharmacokinetics of 
subcutaneous mepolizumab following 
a single dose of the. liquid drug 
product in safety syringe with the 
lyophilized drug product

Mepolizumab PK parameters: 
Cmax, AUC(0-t) and AUC(0-∞).

To compare the pharmacokinetics of 
subcutaneous mepolizumab following 
a single dose of the liquid drug product 
in autoinjector with the lyophilized 
drug product.

Mepolizumab PK parameters: 
Cmax, AUC(0-t) and AUC(0-∞).
Secondary

To assess additional pharmacokinetic 
parameters following mepolizumab 
subcutaneous administration of the 
liquid drug product in autoinjector or 
the liquid drug product in safety 
syringe in comparison with the 
lyophilized drug product, as data
permit

tmax, CL/F, Vd/F, λz, t ½, tlast, 
%AUCex.

To assess the safety and tolerability of 
mepolizumab following a single SC 
dose of the liquid drug product in  
autoinjector or the liquid drug product 
in safety syringe in comparison with 
the lyophilised drug product

Adverse events (AEs), serious adverse 
events (SAEs), including systemic 
reactions and injection site reactions.

Haematology and Clinical Chemistry

Vital signs

12-lead ECG

To assess the immunogenicity of 
mepolizumab following a single SC 
dose of the liquid drug product in   
autoinjector or the liquid drug product 
in safety syringe in comparison with 
the lyophilised drug product

Frequency of positive anti-
mepolizumab binding antibodies and 
neutralizing antibodies

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Overall Design
This will be a randomised, open label, three arm, single dose, multicentre, parallel group 
study in healthy subjects.  Three different mepolizumab treatments will be administered: 

a liquid drug product in a safety syringe (test),

a liquid drug product in an autoinjector (test),

a reconstituted lyophilised drug product from a vial (reference).  
All treatments will be administered SC by a health care professional (HCP).  The study 
will compare the pharmacokinetics and safety of mepolizumab administered as a liquid 
drug product in two different devices with the reconstituted lyophilised drug product. 
Blood eosinophil count and device functionality will also be explored.  Subjects will 
receive 100 mg mepolizumab SC as a single injection. The randomisation will be 
stratified by body weight (<70kg, 70-<80kg and ≥80kg). The site of injection will be 
randomised 1:1:1 to the upper arm, abdomen or thigh.  
Each subject will receive a single SC dose of mepolizumab on Day 1 and will continue to 
be followed for 85 days after drug administration. On Day 1 Subjects will be observed for 
at least 8 hours after drug administration until they are sent home from the unit.

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Treatment Arms and Duration
Subjects will be randomised to one of three treatment arms in a 1:1:1 ratio:

100 mg SC of the liquid drug product in safety syringe

100 mg SC of the liquid drug product in autoinjector

100 mg SC of the reconstituted lyophilised drug product 
Subjects will receive 100 mg mepolizumab SC as a single injection.  The randomisation 
will be stratified by body weight (<70kg, 70-<80kg and ≥80kg).  Subjects will also be 
randomised in a 1:1:1 ratio to one of three injection locations: upper arm, abdomen or 
thigh. The selection of administration into the right or left side will be based on the 
preference of the subject or if no preference is expressed, the preference of the 
investigator.  
Subjects will be screened within 30 days before dose administration.
For any given treatment arm subjects will be resident in the unit from the morning before 
Day 1 (Day –1) until at least 8 hours after drug administration on Day 1, after which 
subjects will be sent home if deemed appropriate at the discretion of the investigator. The 
study will include a further 15 outpatient visits at 24h (Day 2), 48h (Day 3) and on Days 
4, 5, 6, 7, 8, 9, 10, 15, 22, 29, 43, 57 and 85 for PK, PD and safety evaluations. A subject 
will be considered having completed the study if they complete the final visit on day 85. 
Each subject will participate in the study for up to approximately 16 weeks (85 days after 
drug administration), and will have a screening visit, a single dose treatment period, and a 
follow-up visit. 
Follow-up procedures will be performed on the day of discharge (Day 85) after the last 
blood sample is collected. 
Type and Number of Subjects
This study will be conducted in male and female healthy subjects aged ≥18 years old.  
Approximately 243 healthy subjects will be randomised resulting in at least 216 
completed subjects (approximately 72 for each mepolizumab treatment, 24 per injection 
site). At least 27 subjects will be randomised within each of three body weight strata 
(<70kg, 70-<80kg and ≥80kg), resulting in at least 9 subjects randomised to each 
mepolizumab treatment within each weight strata and 3 subjects within each 
mepolizumab treatment, weight strata and injection site. Additional subjects may be 
enrolled if deemed appropriate to ensure at least 216 completed subjects at the discretion 
of the Sponsor in consultation with the Investigator. (i.e. complete Day 85 visit). See 
Table 1.

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Table1
Study Design with treatment arms, body weight ranges and 
injection sites
Number of 
Subjects
Safety Syringe
Auto injector
Lyophilized 
Formulation
Upper 
Arm
Thigh
Abdomen
Upper 
Arm
Thigh
Abdomen
Upper 
Arm
Thigh
Abdomen
Body Weight
<70 
kg
≥3
≥3
≥3
≥3
≥3
≥3
≥3
≥3
≥3
≥27
70 –
<80 
kg
≥3
≥3
≥3
≥3
≥3
≥3
≥3
≥3
≥3
≥27
≥80 
kg
≥3
≥3
≥3
≥3
≥3
≥3
≥3
≥3
≥3
≥27
Total
≥27
≥27
≥27
243
Analysis
The primary analysis will compare AUC(0-t), AUC(0-∞) and Cmax for each test treatment 
(liquid drug product in autoinjector or liquid drug product in safety syringe) to the 
reference (reconstituted lyophilised drug product). The analysis for each treatment 
comparison will be conducted excluding the data from the test treatment that is not 
relevant for that comparison. The parameters AUC(0-t), AUC(0-∞) and Cmax will be loge
transformed and analysed separately using a fixed effects model, including treatment 
group and injection site (upper arm, abdomen, thigh) as categorical variables and baseline 
weight as a continuous covariate fitted on the loge scale. Point estimates and associated 
two-sided 90% confidence intervals (CI) will be constructed for the differences between 
the test and reference treatments on the loge scale; these will be back-transformed to 
provide point estimates and two-sided 90% CIs for the ratio of each of the test treatments 
to the reference treatment on the original scale.
Safety data will be presented in tabular and/or graphical format and summarised 
descriptively according to GSK’s Integrated Data Standards Library (IDSL) standards.  

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2.
INTRODUCTION
2.1.
Study Rationale
Mepolizumab (SB-240563) is a humanized 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. Neutralization of IL-
5 with mepolizumab reduces blood and sputum eosinophils, which results in a reduction 
in exacerbations/flares and in the maintenance dose of oral corticosteroids (OCS) in 
various eosinophilic-mediated diseases.
Mepolizumab has been investigated for the treatment of patients with severe eosinophilic 
asthma who have current blood eosinophil levels of 150 cells/μL or greater, or historical 
blood eosinophil levels (within 12 months) of 300 cells/μL or greater and history of 
exacerbations despite high dose inhaled corticosteroid therapy and an additional 
controller. It has been recently approved in a number of markets including the EU (03 
December 2015) and US (04 November 2015). Mepolizumab has also been evaluated in 
subjects with moderate asthma, FIP1L1/PDGFR-negative hypereosinophilic syndrome 
(HES), eosinophilic esophagitis (EoE) and eosinophilic granulomatosis with polyangiitis 
(EGPA) (i.e., Churg Strauss syndrome).  Clinical data for mepolizumab administered by 
the intravenous (IV), SC or IM routes in a variety of eosinophilic conditions is 
summarised in the Investigators’ Brochure (GlaxoSmithKline Document Number 
CM2003/00010/10).  The liquid drug product is described in the Investigators’ Brochure 
Supplement (GlaxoSmithKline Document Number 2016N290279_00).
Mepolizumab for Injection, a sterile, single-use, preservative-free, lyophilized drug 
product formulation (herein referred to as lyophilized drug product) was used in the 
clinical development program and is the current marketed presentation for asthma 
(Nucala™).  Before use each vial of lyophilized drug product must be reconstituted 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, has 
been developed. Administration of Mepolizumab Injection (herein referred to as liquid 
drug product in autoinjector or liquid drug product in safety syringe) will be more 
convenient and may allow the ultimate goal of patient self-administration.  Mepolizumab 
Injection has not been previously administered in man.
In vitro analytical data confirms that the liquid and lyophilised formulations of 
mepolizumab are comparable. Consequently the likelihood of clinically significant 
differences in the systemic exposure, efficacy or safety profile between the liquid drug 
product in safety syringe or auto injector and the lyophilised drug product is considered 
to be low. However, in addition to demonstration of in vitro biochemical comparability, 
the change in formulation and the change in drug product presentation from a manually 
administered reconstituted lyophile to a liquid drug product (administered from a safety 
syringe or autoinjector) requires demonstration clinically that the relative bioavailability 
of the treatments are similar (ICHQ5E; biopharmaceutical comparability). A full 
description of the liquid drug product (safety syringe and autoinjector) is given in the 

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Investigators’ Brochure Supplement (GlaxoSmithKline Document Number 
2016N290279_00).
The aim of this study is to provide relative bioavailability data to support the transition 
from the currently marketed presentation of the lyophilised drug product to the liquid 
drug product in autoinjector and the liquid drug product in safety syringe.  The study is 
intended to demonstrate comparable mepolizumab pharmacokinetics following a single 
subcutaneous (SC) dose administration in healthy subjects. Safety (including 
immunogenicity) and tolerability will also be evaluated. Blood eosinophil count and 
device functionality will also be explored.
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).
The randomized, multi-centre, placebo-controlled exacerbation studies MEA112997, 
MEA115588 (Pavord, 2012, Ortega, 2014) and Oral Corticosteroid (OCS) Reduction 
Study MEA115575 (Bel, 2014) have demonstrated the efficacy of mepolizumab and 
support the use of mepolizumab 100 mg 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 (Pavord, 2012) and MEA115588 
(Ortega, 2014).

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 (GlaxoSmithKline Document Number 2016N290279_00).

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3.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Primary

To compare the pharmacokinetics of 
subcutaneous mepolizumab following 
a single dose of the. liquid drug 
product in safety syringe with the 
lyophilized drug product

Mepolizumab PK parameters: 
Cmax, AUC(0-t) and AUC(0-∞).

To compare the pharmacokinetics of 
subcutaneous mepolizumab following 
a single dose of the liquid drug product 
in autoinjector with the lyophilized 
drug product.

Mepolizumab PK parameters: 
Cmax, AUC(0-t) and AUC(0-∞).
Secondary

To assess additional pharmacokinetic 
parameters following mepolizumab 
subcutaneous administration of the 
liquid drug product in autoinjector or 
the liquid drug product in safety 
syringe in comparison with the 
lyophilized drug product, as data 
permit

tmax, CL/F, Vd/F, λz, t ½, tlast, 
%AUCex.

To assess the safety and tolerability of 
mepolizumab following a single SC 
dose of the liquid drug product in  
autoinjector or the liquid drug product 
in safety syringe in comparison with 
the lyophilised drug product

Adverse events (AEs), serious adverse 
events (SAEs), including systemic 
reactions and injection site reactions.

Haematology and Clinical Chemistry

Vital signs

12-lead ECG

To assess the immunogenicity of 
mepolizumab following a single SC 
dose of the liquid drug product in   
autoinjector or the liquid drug product 
in safety syringe in comparison with 
the lyophilised drug product

Frequency of positive anti-
mepolizumab binding antibodies and 
neutralizing antibodies

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Objectives
Endpoints
Exploratory

To evaluate mepolizumab 
pharmacodynamic effects on blood 
eosinophil count following a single SC 
dose of the liquid drug product in  
safety syringe or the liquid drug 
product in autoinjector in comparison 
with the lyophilised drug product

Ratio to baseline in blood eosinophil 
count over time

To evaluate safety syringe and 
autoinjector use & functionality

User and device errors 
4.
STUDY DESIGN
4.1.
Overall Design
This will be a randomised, multi-centre, open-label, three arm, parallel-group, single-
dose study in healthy subjects.  Three different mepolizumab treatments will be 
administered:

a liquid drug product in a safety syringe (test),

a liquid drug product in an autoinjector (test),

a reconstituted lyophilised drug product from a vial (reference).  

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All treatments will be administered SC by a health care professional (HCP).  The study 
will compare the pharmacokinetics and safety of mepolizumab administered as a liquid 
drug product in two different devices with the reconstituted lyophilised drug product. 
Blood eosinophil count and device functionality will also be explored.
Subjects will receive 100 mg mepolizumab SC as a single injection. The randomisation
will be stratified by body weight (<70kg, 70-<80kg and ≥80kg). The site of injection will 
be randomised 1:1:1 to the upper arm, abdomen or thigh.  
Each subject will receive a single SC dose of mepolizumab on Day 1 and will be 
observed and blood samples collected for at least 8 hours post dose until they are sent 
home from the unit. Subjects will continue to be followed for 85 days after drug 
administration. 
4.2.
Treatment Arms and Duration
Subjects will be randomised to one of three treatment arms in a 1:1:1 ratio:

100 mg SC of the liquid drug product in safety syringe

100 mg SC of the liquid drug product in autoinjector

100 mg SC of the lyophilised drug product
Subjects will receive 100 mg mepolizumab SC as a single injection. The randomisation
will be stratified by body weight (<70kg, 70-<80kg and ≥80kg). The site of injection will 
be randomised 1:1:1 to the upper arm, abdomen or thigh.  The selection of administration 
into the right or left side will be based on the preference of the subject or if no preference 
is expressed, the preference of the investigator.  
Subjects will be screened within 30 days before dose administration.
For any given treatment arm subjects will be resident in the unit from the morning before 
Day 1 (Day –1) until at least 8 hours after drug administration on Day 1, after which 
subjects will be sent home if deemed appropriate at the discretion of the investigator. The 
study will include a further 15 outpatient visits at 24h (Day 2), 48h (Day 3) and on Days 
4, 5, 6, 7, 8, 9, 10, 15, 22, 29, 43, 57 and 85 for PK, PD and safety evaluations. A subject 
will be considered having completed the study if they complete the final visit on day 85. 
Each subject will participate in the study for up to approximately 16 weeks (up to 85 days 
after drug administration), and will have a screening visit, a single dose treatment period, 
and a follow-up visit. 
Follow-up procedures will be performed on the day of discharge (Day 85) after the last 
blood sample is collected. 
4.3.
Type and Number of Subjects
This study will be conducted in male and female healthy subjects aged ≥18 years old.  
Approximately 243 healthy subjects will be randomised resulting in at least 216 
completed subjects (approximately 72 for each mepolizumab treatment, 24 per injection 

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site). At least 27 subjects will be randomised within each of three body weight strata 
(<70kg, 70-<80kg and ≥80kg), resulting in at least 9 subjects randomised to each 
mepolizumab treatment within each weight strata and 3 subjects within each 
mepolizumab treatment, weight strata and injection site. Additional subjects may be 
enrolled if deemed appropriate to ensure at least 216 completed subjects at the discretion 
of the Sponsor in consultation with the Investigator. (i.e. complete Day 85 visit). See 
Table 1 below.
Table 1
Study Design with treatment arms, body weight ranges and injection 
sites.
Number of 
Subjects
Safety Syringe
Auto injector
Lyophilized 
Formulation
Upper 
Arm
Thigh
Abdomen
Upper 
Arm
Thigh
Abdomen
Upper 
Arm
Thigh
Abdomen
Body Weight
<70 
kg
≥3
≥3
≥3
≥3
≥3
≥3
≥3
≥3
≥3
≥27
70 –
<80 
kg
≥3
≥3
≥3
≥3
≥3
≥3
≥3
≥3
≥3
≥27
≥80 
kg
≥3
≥3
≥3
≥3
≥3
≥3
≥3
≥3
≥3
≥27
Total
≥27
≥27
≥27
243
4.4.
Design Justification
A healthy subject population is considered to be suitable for the evaluation of 
mepolizumab PK comparability among treatments as all treatments will be administered 
to the same population and any differences would therefore be detected appropriately.  
Healthy subjects are considered to be a suitable population for biopharmaceutical PK 
comparability studies and the data can be extrapolated to other populations (European 
Medicines Agency, (2010) Guideline on the investigation of bioequivalence.).
Mepolizumab has a prolonged half-life of approximately 3 weeks and a crossover design 
would require an extended washout period that would limit recruitment and likely lead to 
significant drop-outs and is therefore considered inappropriate.  A parallel group design 
in healthy subjects is the typical approach for such studies with monoclonal antibodies 
and has been successfully used for a number of similar products. 
To minimise the impact of potential confounding factors and variability, the study will be 
stratified by body weight as this is the main covariate of mepolizumab exposure, although 
the effect is not large enough to be clinically relevant. To investigate the effect of 

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injection site, mepolizumab will be administered by the health care provider at one of 
three injection sites (upper arm, abdomen or thigh). In order to prevent bias as well as 
maintain balance in treatment groups, the injection site will be randomised.  Collection of 
PK samples up to Day 85 will ensure that mepolizumab plasma concentration-time 
profile is well described with the extrapolated portion of AUC0-∞ well below 20%.  
4.5.
Dose Justification
A single mepolizumab dose of 100 mg administered SC is selected in this study as it is 
the approved therapeutic dose in severe asthma and the anticipated therapeutic dose in 
chronic obstructive pulmonary disease (COPD).
A higher SC dose of 300 mg is currently being investigated in EGPA and HES patients.  
However, this 300 mg SC dose is delivered as multiple injections (3x100 mg) of the same 
presentation as the reference product in this study (reconstituted lyophilised powder in a 
vial) and is anticipated to be delivered as 3x100 mg of the liquid formulation.  
Consequently the assessment of a 100 mg SC dose in this study is considered appropriate 
to also support the comparability of the liquid formulation delivered via a safety syringe 
or an auto injector to the lyophilised powder for reconstitution at a dose of 300 mg.
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 (IB). The following section outlines the key risks, risk assessment and 
mitigation strategy for this protocol based on mepolizumab lyophilised drug product.  
The safety profile of the mepolizumab liquid drug product is anticipated to be similar to 
the lyophilised drug product.  

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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 
SC 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 IV group

20/412 subjects or 5% in the placebo 
group. 
The most common symptoms reported with 
any systemic reaction included headache, 
Daily monitoring of serious adverse events 
(SAEs) by medical monitor; regular 
systematic review of AE/SAE data from 
ongoing studies by the GlaxoSmithKline
(GSK) study team and/or safety review 
team. 
Customized AE and SAE case report form 
(eDC) utilised for targeted collection of 
information for systemic reactions adverse 
events.
Use of Joint NIAID/FAAN 2nd Symposium 
on Anaphylaxis to collect data on reports of 
anaphylaxis (see Appendix 2).
Subjects remain in clinic for up to 8 hours 
following administration of  mepolizumab 
to complete all assessments.

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
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 
summarized in the 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’.
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 
Daily monitoring of serious adverse events 
(SAEs) by medical monitor; regular 
systematic review of AE/SAE data from 
ongoing studies by GSK study team and/or 
safety review team. 
Customized AE and SAE case report form 
(in the eDC)  utilized for targeted collection 
of information for local injection site 
reactions adverse events.

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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
the Investigator’.
Potential risk of Immunogenicity
Biopharmaceutical products may elicit anti-
drug antibody (ADA) and neutralizing 
antibody (Nab), which have the potential to 
modulate pharmacokinetic (PK), 
pharmacodynamic (PD) or produce adverse 
reactions. 
Mepolizumab has low immunogenic 
potential. Both incidence and titer data from 
completed 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’.
Blood samples will be collected for 
detection of both ADA and Nab.

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4.6.2.
Benefit Assessment
In this study, there are no anticipated benefit for the participating subjects since these 
subjects are healthy subjects. The autoinjector and safety syringe will however provide a 
more convenient mode of delivery from previous mepolizumab administration and 
potentially provide 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.  This study will be conducted in healthy subjects 
which are not expected to receive benefit from this treatment. The change in drug product 
presentation from a reconstituted lyophilised drug product in a vial to a liquid drug 
product in an autoinjector or a safety syringe is not anticipated to alter the overall safety 
profile of mepolizumab.
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 Investigator’s Brochure 
(number). 
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.

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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 are 
met:
AGE
1.
18 years of age and over at the time of signing the informed consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2.
Healthy as determined by the investigator or medically qualified designee based on a 
medical evaluation including medical history, physical examination, vital signs, 
laboratory tests, and cardiac monitoring.  A subject with a clinical abnormality or 
laboratory parameter(s) which is/are not specifically listed in the inclusion or 
exclusion criteria, outside the reference range for the population being studied may 
be included only if the investigator agrees and documents that the finding is unlikely 
to introduce additional risk factors and will not interfere with the study procedures or 
ability to interpret study results.
WEIGHT
3.
Body weight 50 kg and body mass index (BMI) within the range 19.0-30kg/m2
(inclusive)
SEX
4.
Male or Female.
5.
A female subject is eligible to participate if she is not pregnant (as confirmed by a 
negative human chorionic gonadotrophin (hCG) test), 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
Post- menopausal females- refer to Appendix 5 for definition 
b.
Subject is of reproductive potential and agrees to follow one of the options listed in 

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the Modified List of Highly Effective Methods for Avoiding Pregnancy in Females 
of Reproductive Potential (FRP) (Appendix 5) from 30 days prior to the first dose of 
study medication and until 16 weeks after the administration of the single dose of 
study medication.  
INFORMED CONSENT
6.
Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the consent form and in the protocol. The 
subject must be able to understand and communicate in the native language of the 
site, e.g. German in German sites.
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.
ALT  >1.5 xULN  
2.
Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%).
3.
Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones)
4.
QTcF >450 msec
5.
Any clinically relevant abnormality identified at the screening medical assessment 
(physical examination/medical history), clinical laboratory tests, or 12-lead ECG.
CONCOMITANT MEDICATIONS
6.
Use of prescription or non-prescription drugs, including vitamins, herbal and dietary 
supplements (including St John’s Wort) within 7 days (or 14 days if the drug is a 
potential enzyme inducer) or 5 half-lives (whichever is longer) before the first dose 
of study medication and until study completion, unless in the opinion of the 
investigator and GSK Medical Monitor the medication will not interfere with the 
study procedures or compromise subject safety.

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RELEVANT HABITS
7.
History of regular alcohol consumption within 6 months of the study defined as: 
8.
An average weekly intake of >14 units for females and >21 units for males.  One 
unit is equivalent to 8 g of alcohol: a half-pint (~240 ml) of beer, 1 glass (125 ml) of 
wine or 1 (25 ml) measure of spirits.
9.
Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or 
nicotine-containing products within 6 months prior to screening. Limit of 
>500 ng/mL.
10. Involved in any activities likely to result in any significant decrease or increase in
body weight during the study period (e.g. ‘crash’ dieting, bodybuilding).
CONTRAINDICATIONS 
11. History of sensitivity to any of the study medications, or components thereof or a 
history of drug or other allergy that, in the opinion of the investigator or Medical 
Monitor, contraindicates their participation.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
12. Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test 
result at screening or within 3 months prior to first dose of study treatment. 
13. A positive test for HIV antibody.
14. Subjects with known, pre-existing helminthes infestation within 6 months prior to 
Day 1.
15. Where participation in the study would result in donation of blood or blood products 
in excess of 500 mL within 3 months.
16. The subject has participated in a clinical trial and has received an investigational 
product within the following time period prior to the first dosing day in the current 
study: 30 days, 5 half-lives or twice the duration of the biological effect of the 
investigational product (whichever is longer).
17. Exposure to more than four new chemical entities within 12 months prior to the first 
dosing day.
18. A positive pre-study drug/alcohol screen.
19. A vulnerable subject. Defined as individuals whose willingness to volunteer in a 
clinical trial may be unduly influenced by the expectation, whether justified or not, 
of benefits associated with participation, or of a retaliatory response from senior 
members of a hierarchy in case of refusal to participate.
20. Subjects who work for the Sponsor, CRO, or one of the study centres.

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5.3.
Screening/Baseline/Run-in Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomized. 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 7.3).
Subjects can be re-screened if they fail screening following discussion with the GSK 
Medical monitor and Investigator.
5.4.
Withdrawal/Stopping Criteria
A subject may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioural or 
administrative reasons. If a subject withdraws from the study, he/she may request 
destruction of any samples taken, and the investigator must document this in the site 
study records. 
5.4.1.
Withdrawal from the study
If a subject withdraws from the study then the assessments in the time and events table 
under Section 7.1  Day 85 Withdraw (WD) column must be performed. A reason for the 
withdrawal from the study must be captured in the eDC.
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 criteria are met:

Laboratory parameters: Clinically important changes in laboratory parameters 
identified

Pregnancy: Positive pregnancy test (see Section 7.3.2). 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. 

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
In cases where the subject is deemed ‘lost to follow up’, the investigator or designee 
must make every effort to regain contact with the subject (where possible, 3 
telephone calls and if necessary a certified letter to the subject’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the subject’s medical record. 

Should the subject continue to be unreachable, only then will he/she be considered to 
have withdrawn from the study with a primary reason of “Lost to Follow-up”. 
5.4.2.
Liver Chemistry Stopping Criteria
Since this is a single dose study liver chemistry stopping criteria do not apply. 
However, in case of liver event following the single dose of study treatment all required 
follow up assessments must be completed. Refer to Appendix 2 for complete guidance.
Liver event is defined as:
ALT≥3xULN
If ALT≥3xULN AND bilirubin 2xULN (>35% direct bilirubin) or INR >1.5, 
Report as an SAE.
5.4.3.
QTc Stopping criteria
Since this is a single dose study QTc stopping criteria do not apply. 
However, the following guideline applies for the protocol-specified ECG and QTc 
evaluations.  

The same QT correction formula must be used for each individual subject to 
determine eligibility and for subsequent evaluations while on 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 QTcB, then QTcB must 
be used for subsequent evaluations while on the study.

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.
5.5.
Subject and Study Completion
A subject will be considered having completed the study if they complete the final visit 
on day 85.
The end of the study is defined as the last subject’s last visit.

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6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
Mepolizumab for Injection (also referred to as lyophilised drug product in this protocol) 
will be supplied by GSK in a 100 mg per vial strength.  Mepolizumab for Injection is a 
sterile, lyophilized drug product and is presented in 10 mL Type I glass, stoppered vials. 
The formulation contains sodium phosphate, sucrose and polysorbate 80.  The vial will 
be reconstituted with Sterile Water for Injection just prior to use.  Further details of dose 
preparation and administration can be found in the Clinical Investigator’s Brochure (CIB) 
and the Study Reference Manual (SRM).
Mepolizumab Injection (also referred to as liquid drug product in this protocol) will be 
supplied by GSK as a fixed-dose, fully disposable pre-filled Type I glass syringe with 
rubber stopper, which is assembled in an autoinjector or safety syringe. Mepolizumab 
Injection that is assembled into a safety syringe (also referred to as liquid drug product in 
safety syringe in this protocol) will have a back stop and plunger rod to enable manual 
delivery of the drug product.  Mepolizumab Injection that is assembled into an 
autoinjector (also referred to as liquid drug product in autoinjector in this protocol) will 
enable automated deliver of the drug product under the power of a spring mechanism.  
Both presentations of Mepolizumab Injection contain 100 mg of mepolizumab in a 1 mL 
volume.  The formulation contains sodium phosphate, citric acid, sucrose, EDTA and 
polysorbate 80.
Study Treatment: Lyophilized Drug 
Product
Study Treatment: Liquid Drug 
Product
Product name:
Mepolizumab (Nucala) (SB-240563)
Mepolizumab (Nucala) (SB-240563)
Description of 
Device:
N/A
Prefilled autoinjector
Prefilled Safety Syringe
Formulation 
description:
100 mg/mL mepolizumab following 
reconstitution with 1.2 mL sterile 
water for injection (WFI) with sodium 
phosphate, sucrose, and polysorbate 
80
100 mg/mL mepolizumab with sodium 
phosphate, citric acid, sucrose, EDTA 
and polysorbate 80
Dosage form:
Sterile, lyophilized powder for 
reconstitution
Sterile, liquid formulation
Unit dose 
strength(s)/
Dosage level(s):
100 mg/vial
100 mg/mL; 1.0 mL (deliverable)
Route of 
Administration 
SC injection
SC injection
Dosing 
instructions:
SC dose in upper arm, abodomen, or 
thigh following reconstitution with 1.2 
mL WFI
SC dose in upper arm, abdomen or 
thigh  

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Study Treatment: Lyophilized Drug 
Product
Study Treatment: Liquid Drug 
Product
Physical 
description: 
White, uniform, lyophilized cake.  
Clear to opalescent, colourless to 
pale yellow sterile solution after 
reconstitution.
Clear to opalescent, colourless to 
pale yellow sterile solution 
Physical 
description of 
device:
N/A
Autoinjector: Single use, disposable 
autoinjector assembled with the 
prefilled syringe containing the drug 
product. The autoinjector enables 
automatic delivery of the drug product 
under the power of a spring 
mechanism following activation of the 
device.  Start and end of injection 
clicks inform the user of correct use.  
A plastic needle cover shields the 
needle before and after injection to 
minimise the potential for needle stick 
injuries.
Safety syringe: Single use, 
disposable safety syringe. Needle
retracts into guard which locks.
Manufacturer/
source of 
procurement:
Lyophilized Drug product is 
manufactured at GSK, Parma, Italy
Prefilled syringe: Prefilled syringe 
components are procured from 
Becton Dickinson.  Prefilled syringe is 
filled with drug product and 
assembled at GSK, Barnard Castle, 
UK.
Autoinjector: The autoinjector 
components are manufactured by 
Ypsomed AG and assembled with the 
prefilled syringe at GSK, Barnard 
Castle, UK.
Safety syringe: supplied pre-filled 
with drug. Components are procured 
by Becton Dickinson.  Product 
assembled at GSK, Barnard Castle, 
UK.

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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 an autoinjector or a prefilled syringe 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 stopper are sourced from Becton Dickinson.  The prefilled syringe is filled 
and assembled at GSK Barnard Castle.  The prefilled syringe is assembled with safety 
syringe device components at GSK Barnard Castle. The safety syringe components are 
also sourced from Becton Dickinson.
The autoinjector components are manufactured by Ypsomed AG.  The auto injector 
components are assembled with the prefilled syringe at GSK Barnard Castle.
The instructions for use (IFU) of these injection devices are provided in the SRM. The 
instructions were developed and optimized as a result of formative human factors studies.
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 7.4.
6.3.
Treatment Assignment
Subjects will be assigned to one of the three treatments, reconstituted lyophilised powder 
from a vial, liquid formulation delivered by auto injector, liquid formulation delivered by 
safety syringe, in accordance with the randomization schedule generated by Clinical 
Statistics, prior to the start of the study, using validated internal software. Randomization 
numbers will be allocated centrally via interactive response technology (IRT).  The 
randomisation will be stratified by body weight (<70kg, 70-<80kg and ≥80kg) measured 
at day -1. The site of injection will also be randomised 1:1:1 to the upper arm, abdomen 
or thigh.
6.4.
Blinding
This will be an open-label single dose 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
Mepolizumab must be stored in a refrigerator or at a temperature of 2-8C and protected 
from light. 

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Under normal conditions of handling and administration, investigational product is not 
expected to pose significant safety risks to site staff. Take adequate precautions to avoid 
direct eye or skin contact and the generation of aerosols or mists. Notify the monitor of 
any unintentional occupational exposure. A Material Safety Data Sheet (MSDS)
/equivalent document describing the occupational hazards of mepolizumab and 
recommended handling precautions will be provided to site staff if required by local laws 
or will otherwise be available from GSK upon request.
A description of the methods and materials required for mepolizumab will be detailed in 
the SRM.

Only subjects enrolled in the study may receive study treatment and only authorized 
site staff may supply or administer study treatment. 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 authorized site staff. 

The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation and final disposition records).

Further guidance and information for final disposition of unused study treatment are 
provided in the SRM. 
Mepolizumab lyophile will be provided as a lyophilised drug product in sterile vials for 
individual use and should be stored in a refrigerator at 2-8°C with protection from light. 
The vial will be reconstituted with Sterile Water for Injection, just prior to use.  Each vial 
will contain 100 mg mepolizumab as a single 1.0 mL injection (100 mg/mL).
Maintenance of a temperature log at the clinical dispensing sites (manual or automated) is 
required.
Mepolizumab liquid will be supplied in a single use safety syringe and prefilled syringe 
contained within an autoinjector and both should be stored in a refrigerator at 2-8°C with 
protection from light. Each injection device will contain 100 mg mepolizumab as a single 
1.0 mL injection of the liquid formulation (100 mg/mL). Maintenance of a temperature 
log at the clinical dispensing sites (manual or automated) is required.
6.7.
Training Session
Training of qualified site personnel in study treatment handling and administration 
techniques at each study site will be provided by GSK prior to the first subject 
administration at a given site. Further details of the training will be provided in the SRM.
6.8.
Compliance with Study Treatment Administration
Subjects will receive study treatment directly from the investigator or designee, under 
medical supervision.  The date and time of each dose administered in the clinic and site 
of administration (thigh, abdomen or upper arm) will be recorded in the source 
documents.  The study treatment, dose and study subject identification will be confirmed 

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at the time of dosing by a member of the study site staff other than the person 
administering the study treatment.  
In the event of an acute severe reaction (e.g., anaphylaxis) following administration of 
mepolizumab, there are personnel/staff onsite at the treatment facility who are 
appropriately trained in basic life support to manage the subject including administration 
of medications (e.g., epinephrine), and have access to a system that can promptly 
transport the subject to another facility for additional care if appropriate.
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
Subjects will not receive any additional treatment from GSK after completion of the 
study because only healthy subjects are eligible to participate in the study.
6.11.
Lifestyle and/or Dietary Restrictions
6.11.1.
Caffeine, Alcohol, and Tobacco

During the dosing session, subjects will abstain from ingesting caffeine- or xanthine-
containing products (e.g., coffee, tea, cola drinks and chocolate) for 12 hours prior to 
the start of dosing until collection of the final pharmacokinetic and/or PD sample of 
the session and prior to all out-patient visits. 

During the dosing session, subjects will abstain from alcohol for 24 hours prior to the 
start of dosing until collection of the final pharmacokinetic and/or PD sample of the 
session and prior to all out-patient visits. 

Use of tobacco products is not allowed from 6 months prior to screening until after 
the final follow-up visit.
6.11.2.
Activity
Subjects will abstain from strenuous exercise for 48 hours prior to each blood collection 
for clinical laboratory tests.  Subjects may participate in light recreational activities 
during the study (e.g. read).
Subjects should abstain from any activities likely to result in any significant decrease or 
increase in body weight during the study period (e.g. ‘crash’ dieting, bodybuilding).

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6.12.
Concomitant Medications and Non-Drug Therapies
6.12.1.
Permitted Medications and Non-Drug Therapies
Concomitant medications are not allowed during this study as outlined in Section 5.2
(exclusion criteria). 
Paracetamol (acetaminophen) 2g/day as a mild analgesic is allowed throughout the 
study. Other concomitant medication may be considered on a case by case basis by the 
investigator in consultation with the Medical Monitor if required.
6.12.2.
Prohibited Medications and Non-Drug Therapies
Subjects must refrain from the use of prescription or non-prescription drugs, including 
vitamins, herbal and dietary supplements (including St John’s Wort) within 7 days (or 14 
days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior 
to the first dose of study medication until completion of the follow-up visit, unless in the 
opinion of the Investigator and GSK Medical Monitor the medication will not interfere 
with the study procedures or compromise subject safety.
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 (Section 7.1), 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
The following points must be noted: 

If assessments are scheduled for the same nominal time, THEN the assessments 
should occur in the following order:
1. 12-lead ECG
2. vital signs
3. blood draws.  
Note: The timing of the assessments should allow the blood draw to occur at the 
nominal time as stated in the SRM.

The timing and number of planned study assessments, including safety, 
pharmacokinetic, PD/biomarker assessments may be altered during the course of 
the study based on newly available data (e.g., to obtain data closer to the time of 
peak plasma concentrations) to ensure appropriate monitoring. 

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
The change in timing or addition of time points for any planned study 
assessments must be documented in a Note to File which is approved by the 
relevant GSK study team member and then archived in the study sponsor and 
site study files, but this will not constitute a protocol amendment. 

The IRB/IEC will be informed of any safety issues that require alteration of the 
safety monitoring scheme or amendment of the Informed Consent Form. 

No more than 500 mL of blood will be collected over the duration of the study, 
including any extra assessments that may be required.

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7.1.
Time and Events Table
Procedure
Screening 
(up to 30 
days prior 
to Day 1)
Treatment Period 1 [Days]
Notes: 
Permitted Time 
windows will be 
defined in the GSK 
approved Windows 
Allowance 
Agreement used by 
each site
Day -1
1
2
3
4
5
6
7
8
9
10
15
22
29
43
57
85
(FUP/EW)
Informed consent
X
Inclusion and 
exclusion criteria
X
X
Demography
X
Full physical exam 
including height1
and weight2
X
X
X
1Height only at 
screening 
2Weight collected 
only at day -1
Medical history 
(includes 
substance usage) 
Including 
Cardiovascular 
medical 
history/risk factors
X
Alcohol test 
X
X
Alcohol measured in 
Serum
Drug Screen
X
X
Serum or Urine drug 
screen
Urine Cotinine test
X
X
Tobacco 

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Procedure
Screening 
(up to 30 
days prior 
to Day 1)
Treatment Period 1 [Days]
Notes: 
Permitted Time 
windows will be 
defined in the GSK 
approved Windows 
Allowance 
Agreement used by 
each site
Day -1
1
2
3
4
5
6
7
8
9
10
15
22
29
43
57
85
(FUP/EW)
Past and current 
medical conditions  
X
Pregnancy test 
X
X
X
X
All  pregnancy tests 
will be  performed in 
urine. 
Laboratory 
assessments 
including 
haematology, 
chemistry and 
urinanalysis
X
X
X
X
Includes Liver 
chemistry
HIV, Hep B and 
Hep C screen
X
If test otherwise 
performed within 3 
months prior to first 
dose of study 
treatment, testing at 
screening is not 
required
Immunogenicity
X
X3
X
X
X
3Day 1 Predose. 
Including ADA and 
Nab
12-lead ECG
X
X
X
Day 1 – Predose

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Procedure
Screening 
(up to 30 
days prior 
to Day 1)
Treatment Period 1 [Days]
Notes: 
Permitted Time 
windows will be 
defined in the GSK 
approved Windows 
Allowance 
Agreement used by 
each site
Day -1
1
2
3
4
5
6
7
8
9
10
15
22
29
43
57
85
(FUP/EW)
Vital signs
X
X
X4
X
X
X
X
X
X
X
X
4Day 1 – Predose
Parasite screening
X5
5Only required in high 
risk countries or for 
subjects who have 
visited high risk 
countries in the past 
six months.  Sites 
should use local 
laboratories
Randomisation 
X
Study Treatment
X
Complete either the 
autoinjector or the 
safety syringe 
functionality 
assessment (see 
Section 7.4.4) when 
applicable
AE review
X
==========================================================================
Including local 
injection site 
reactions and 
systemic reactions
Collected from day -1 
to Day 85

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Procedure
Screening 
(up to 30 
days prior 
to Day 1)
Treatment Period 1 [Days]
Notes: 
Permitted Time 
windows will be 
defined in the GSK 
approved Windows 
Allowance 
Agreement used by 
each site
Day -1
1
2
3
4
5
6
7
8
9
10
15
22
29
43
57
85
(FUP/EW)
SAE review
X
X
==========================================================================
Including local 
injection site 
reactions and 
systemic reactions
Collected from 
screening to Day 85
Concomitant 
medication review
X
X
==========================================================================
Collected from 
screening to Day 85
Blood Samples for 
PK 
X6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
6Day 1 – Predose, 2h 
& 8h Postdose
Blood samples for 
PD (blood 
eosinophils)
X7
X
X
X
X
X
X
7Day 1 – Predose
Autoinjector and 
safety syringe 
user/device error 
assessment
X
HCP reported. See 
Section 7.4.4. 
Follow up (FUP)
X

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7.2.
Screening and Critical Baseline Assessments
A subject number will be assigned at the time the informed consent form (ICF) is signed.  
During the screening Visit, study designated personnel must provide informed consent to 
study participants.
Once the informed consent document has been signed, screening assessments can be 
conducted. The following demographic parameters will be captured: year of birth, sex, 
race and ethnicity. From the screening visit onwards concomitant medications and SAEs 
(considered as related to study participation) must be reported.
7.2.1.
Critical procedures performed at Screening

Medical history including smoking status, current treatment 

Cardiovascular medical history/risk factors (as detailed in the eDC system). 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 

Vital signs

12-lead ECG

Laboratory tests. This should include:

Chemistry

Haematology with differential count

Urinalysis

Pregnancy test (serum) 

FSH 

Parasitic screening (only in countries with a high-risk or in subjects who have 
visited a high-risk country)

HIV, Hep B, Hep C screen

Blood for Immunogenicity 

Review of Inclusion/Exclusion criteria

Review of SAEs

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7.2.2.
Critical procedures performed at first treatment visit

Vital signs 

Blood for PK assessment

Blood for PD assessment (pre-dose sample)

Blood for Immunogenicity (pre-dose sample)

12 lead ECG

Study treatment

Device functionality questions

Review concomitant medications, AEs, SAEs
7.3.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1).  
7.3.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 3. 

The following adverse events of special interest will have additional information (i.e. 
corresponding symptoms) collected via AE and SAE pages in the eDC:

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 
6 will be collected on the AE and SAE eDC pages.
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 
7.3.1.1.
Time period and Frequency for collecting AE and SAE information

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK product 
will be recorded from the time a subject consents to participate in the study up to and 
including any follow-up contact. 

AEs will be collected from the start of Study Treatment until the follow-up contact 
on Day 85 (see Section 7.3.1.3), 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 eDC.

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
All SAEs will be recorded and reported to GSK within 24 hours, as indicated in the 
Time and Events Table Section 7.1.

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.
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 3.
7.3.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:

“How are you feeling?” 

“Have you had any (other) medical problems since your last visit/contact?” 

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?” 
7.3.1.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the 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 5.4). Further information on follow-up procedures is given in 
Appendix 3.

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7.3.1.4.
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.
7.3.2.
Pregnancy

Details of all pregnancies in female subjects will be collected after the start of dosing 
and until 16 weeks after 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 
5.
7.4.
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 4.
NOTE: Incidents fulfilling the definition of an AE/SAE will also follow the processes 
outlined in Section 7.3.1 and Appendix 3 of the Protocol. 
7.4.1.
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. 

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.

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NOTE: The method of documenting Medical Device Incidents is provided in Appendix 
4.
7.4.2.
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). 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.
7.4.3.
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. 
7.4.4.
Autoinjector and safety syringe functionality assessment
During administration of the autoinjector and safety syringe the HCP will be asked to 
inspect the medical device and complete the inspection questions in Appendix 7 and 
Appendix 9 respectively.
If there is an error with the medical device then refer to the Autoinjector or safety syringe 
Error / Failure Reporting Form in Appendix 8 or Appendix 10 respectively. 
7.4.5.
Returning defective Medical Devices to GSK
All defective devices will be returned to GSK

Please refer to the SRM for all details 
7.4.6.
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.

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
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.
7.5.
Physical Exams
Consider further specification (e.g. for height and weight measurements, the subject is 
allowed to wear indoor, daytime clothing with no shoes) if appropriate to the study.
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.
7.5.1.
Vital Signs

Vital signs will be measured in supine position after 5 minutes rest and will include 
temperature, systolic and diastolic blood pressure, pulse rate and respiratory rate. 
7.5.2.
Electrocardiogram (ECG)

Single 12-lead ECGs will be obtained at each timepoint 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. 
Refer to Section 5.4.3 for 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 before the vital signs assessments and 
followed by other study procedures. 
7.5.3.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in Section 7.1, 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 SRM. 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 eDC.
Refer to the SRM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws.

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Haematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed in Table 2.
Table 2
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
CK
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood and ketones by dipstick

Microscopic examination (if blood or protein is abnormal) 

Urine microscopic examination : RBC, WBC, Epithelial cells, Casts 
(hyaline, granular, cellular)
Other 
Screening 
Tests

HIV

Hepatitis B (HBsAg)

Hepatitis C (Hep C antibody)

FSH and estradiol (as needed in women of non-child bearing 
potential only)

Alcohol and drug screen (to include at minimum: cotinine, 
amphetamines, barbiturates, cocaine, opiates, cannabinoids and 
benzodiazepines)

Pregnancy-  All  tests will be performed in urine. 

Immunogenicity – Nab, ADA

Parasitic screening – for subjects who have travelled to countries 
with a high-risk 
NOTES :
1. Details of Required Actions and Follow-Up Assessments after liver event are 
given in Section 5.4.2 and Appendix 2.
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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7.6.
Pharmacokinetics
7.6.1.
Blood Sample Collection
Blood samples for determination of mepolizumab plasma concentration will be collected 
at the time points indicated in Section 7.1, Time and Events Table.  The actual date and 
time of each blood sample collection will be recorded.  The timing of PK samples may be 
altered and/or PK samples may be obtained at additional time points to ensure thorough 
PK monitoring.   Further details will be specified in the Study Reference Manual (SRM).
7.6.2.
Sample Analysis
Plasma analysis will be performed under the control of PTS, GSK, the details of which 
will be included in the Study Reference Manual (SRM). Concentrations of mepolizumab 
will be determined in plasma samples using the currently approved bioanalytical 
methodology. Raw data will be archived at the bioanalytical site (detailed in the SRM).
Once the plasma has been analyzed for mepolizumab any remaining plasma may be 
analyzed for other compound-related material and the results reported under a separate 
PTS, GSK protocol.
7.7.
Pharmacodynamic Markers
Blood eosinophil counts will be recorded at the visits specified in the Time and Events 
Schedule (Section 7.1).  
7.8.
Immunogenicity
Blood samples will be collected for the determination of anti-mepolizumab antibodies, 
prior to dosing and as detailed in the Time and Events Schedule (Section 7.1)
Details for sample collection and processing may be found in the SRM.
8.
DATA MANAGEMENT

For this study subject data will be entered into a GSK approved database and 
combined with data provided from other sources in a validated data system. The data 
will be transmitted electronically to GSK.  

Management of clinical data will be performed in accordance with approved 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.  

Subject initials and full date of birth will not be collected or transmitted to GSK 
according to GSK policy.

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9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1.
Hypotheses
This study is designed to evaluate mepolizumab PK comparability following a single SC 
administration, i.e. the relative bioavailability, between 

The liquid drug product from the autoinjector (test) and the reconstituted 
lyophilised drug product from the vial (reference)

The liquid drug product from the safety syringe (test) and the reconstituted 
lyophilised drug product from the vial (reference)
For AUC(0-t), AUC(0-∞) and Cmax, point estimates and corresponding two-sided 90% 
confidence intervals (CI) will be constructed for the ratio of the geometric mean of each 
test treatment to the geometric mean of the reference treatment, μ(test)/μ(reference). No 
formal hypothesis will be tested. However, interpretation of the comparability of the 
autoinjector and safety syringe with the reconstituted lyophilised drug product will be 
guided by a two-sided 90% CI for μ(test)/μ(reference) in the range (0.80, 1.25) for 
AUC(0-t), AUC(0-∞) and Cmax.
9.2.
Sample Size Considerations
The primary objective of this study is to evaluate the PK comparability of the liquid drug 
product administered by both the autoinjector and safety syringe with the lyophilised 
drug product when reconstituted from the vial. The sample size for this study is based on 
the number of subjects needed to demonstrate a two-sided 90% CI for 
μ(test)/μ(reference) within the guide range of (0.80, 1.25) for AUC(0-∞), AUC(0-t) and 
Cmax.
Variability estimates for AUC(0-∞), AUC(0-τ) and Cmax for mepolizumab were considered 
from three studies; SB-240563/017, SB-240563/018 and MEA114092. Only data from 
treatment groups with SC administration of mepolizumab in the upper arm, abdomen or 
thigh, for doses of 125mg and 250mg across the 3 studies was considered. 
For AUC, estimates for the between subject standard deviation on the loge scale, after 
adjusting for body weight, ranged from 0.18 to 0.27, with a mean (weighted by degrees 
of freedom) estimate of 0.222. For Cmax, estimates for the between subject standard 
deviation on the loge scale, after adjusting for body weight, ranged from 0.20 to 0.32, 
with a mean (weighted by degrees of freedom) estimate of 0.252.
The joint power to demonstrate an observed 90% CI within the guide range (0.80, 1.25) 
for AUC(0-t), AUC(0-∞) and Cmax for both the autoinjector and safety syringe has been 
estimated using simulation. Assuming standard deviations on the log e scale of 0.222 for 
AUC(0-t), AUC(0-∞) and 0.252 for Cmax (i.e. the mean estimates given above), a true 
difference between the formulations of 5% and a within subject correlation between AUC 
and Cmax of 0.8, the estimated joint power with 72 subjects per treatment group is 98%. 
Assuming standard deviations on the log e scale of 0.27 for AUC(0-t), AUC(0-∞) and 0.32 

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for Cmax (i.e. the highest estimates given above), and with all other assumptions as 
above, the estimated joint power with 72 subjects per treatment group is 89%.
To allow for a dropout rate of up to 10%, approximately 243 subjects (81 per treatment 
group) will be enrolled in this study.
No sample size re-estimation will be performed.
9.3.
Data Analysis Considerations
Final analysis will be performed after the completion of the study and final data base 
freeze. Complete details of the planned analysis will be documented in the Reporting and 
Analysis Plan (RAP).
9.3.1.
Analysis Populations
9.3.1.1.
All Treated Subjects Population
The ‘All Treated Subjects’ population will comprise all subjects who receive 
mepolizumab. This population will be used for all safety and tolerability, study 
population and exploratory analyses.
9.3.1.2.
Pharmacokinetic Population
The pharmacokinetic population will comprise all subjects in the ‘All Treated Subjects’ 
population who have at least one PK sample obtained and analysed. This population will 
be used for all pharmacokinetic analyses, including the primary analysis.
9.3.2.
Interim Analysis
No interim analyses are planned.
9.4.
Key Elements of Analysis Plan
9.4.1.
Raw Plasma Concentrations
Blood sampling time will be related to the start of dosing. Linear and semi-logarithmic 
individual plasma concentration-time profiles and mean and median profiles will be 
plotted for each treatment. Plasma concentrations of mepolizumab will be listed and 
summarised by treatment group and within each treatment group by weight category 
(<70kg, 70-<80kg and ≥80kg) and by injection site; and nominal time.
9.4.2.
Derived Plasma Pharmacokinetic Parameters
Pharmacokinetic analysis will be the responsibility of the Clinical Pharmacology
Modeling and Simulation Department, QSci, GSK. Plasma concentration time data for
mepolizumab will be analyzed by non-compartmental methods according to 
GlaxoSmithKline guidance document, GUI_00000051487 and using WinNonlin.
Calculations will be based on the actual sampling times recorded during the study.
From the plasma concentration time data, the following pharmacokinetic parameters will

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be determined, as data permit, for each treatment and for each subject:
• maximum observed plasma concentration (Cmax)
• time to Cmax (tmax)
• area under the plasma concentration time curve [AUC(0-t), AUC(0-week4) and AUC
(0-∞)]
• %AUCextrapolated
• Last time point where the concentration is above the limit of quantification (tlast)
• Apparent clearance (CL/F)
• Apparent volume of distribution (Vd/F)
• terminal phase elimination rate constant (λz)
• the number of points used to determine λz
• the terminal phase half-life (t1/2).
Pharmacokinetic data will be presented in graphical and/or tabular form and will be listed 
and summarized descriptively by treatment group, and within each treatment group by 
weight category (<70kg, 70-<80kg and ≥80kg) and by injection site.  
All pharmacokinetic data will be stored in the Archives, GlaxoSmithKline 
Pharmaceuticals, R&D.
Statistical analyses of the pharmacokinetic parameter data will be the responsibility of
Clinical Statistics, GlaxoSmithKline.
9.5.
Primary Analyses
The primary analysis will compare AUC(0-t), AUC(0-∞) and Cmax for each test treatment 
(liquid formulation from the autoinjector or safety syringe) to the reference (reconstituted 
lyophilised powder from the vial). The analysis for each treatment comparison will be 
conducted excluding the data from the test treatment that is not relevant for that 
comparison. The parameters AUC(0-t), AUC(0-∞) and Cmax will be loge transformed and 
analysed separately using a fixed effects model, including treatment group and injection 
site (upper arm, abdomen, thigh) as categorical variables and baseline weight as a 
continuous covariate fitted on the loge scale. Point estimates and associated two-sided 
90% CIs will be constructed for the differences between the test and reference treatments 
on the loge scale; these will be back-transformed to provide point estimates and two-sided 
90% CIs for the ratio of each of the test treatments to the reference treatment on the 
original scale.
9.6.
Secondary Analyses
Safety data will be presented in tabular and/or graphical format and summarised 
descriptively according to GSK’s Integrated Data Standards Library (IDSL) standards. 
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). 

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All laboratory parameters for clinical chemistry and haematology will be summarized 
and tabulated.
Each ECG parameter at every assessed time point will be summarized. Summary 
statistics of QT interval corrected for heart rate according to Frederica’s formula (QTcF) 
and QT interval corrected for heart rate according to Bazett’s formula (QTcB) as well as 
change from baseline values will be presented by time point.
Summary statistics of pulse rate and systolic and diastolic blood pressure will be 
presented by time point.
Immunogenicity will be summarized using appropriate descriptive statistics.
9.6.1.
Exploratory Analyses
Ratio to baseline in blood eosinophil count will be log transformed and compared 
between treatments using a mixed model repeated measures analysis, adjusting for the 
covariates of baseline blood eosinophil count (log scale) and baseline weight (log scale). 
Time point and injection site (upper arm, abdomen, thigh) will be fitted as a categorical 
variables with the effect of treatment group and baseline blood eosinophil count varying 
at each timepoint (i.e. timepoint-by-baseline and timepoint-by-treatment interactions will 
be included in the model).
User and device errors will be summarized using appropriate descriptive statistics.
10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers 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 ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the 1996  
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

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
Obtaining signed informed consent

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol deviations 
to IRB/IEC)

GSK will provide full details of the above procedures, either verbally, in writing, or 
both.

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 eDC system 
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. 

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
In the event of an assessment, audit or inspection, the investigator (and institution) 
must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all 
relevant documents and to allocate their time and the time of their staff to discuss the 
conduct of the study, any findings/relevant issues and to implement any corrective 
and/or preventative actions to address any findings/issues identified.
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 

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re-generating a hard copy, if required.  Furthermore, the investigator must ensure 
there is an acceptable back-up of these reproductions and that an acceptable quality 
control process exists for making these reproductions.

GSK will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements.  The minimum retention time 
will meet the strictest standard applicable to that site for the study, as dictated by any 
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.
GSK will provide the investigator with the randomization codes for their site only after 
completion of the full statistical analysis.
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.
REFERENCES
Bel EH, Wenzel SE, Thompson PJ, Prazma CM, Keene ON, Yancey SW et al. Oral 
Glucocorticoid-Sparing Effect of Mepolizumab in Eosinophilic Asthma. N Engl J Med 
2014 September 8;371(13):1189-97.
Chioato A (2013).  Canakimumab bioequivalence: syringe vs dry powder.  Clin Drug 
Investig. 33; 801-808.
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]
European Medicines Agency / GUIDELINE ON THE INVESTIGATION OF 
BIOEQUIVALENCE/ 
ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/01/
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.
GlaxoSmithKline Document Number (2016N290279_00). Investigator’s Brochure for 
SB-240563. 01-AUG-2016.
GlaxoSmithKline Document Number (CM2003/00010/10). Investigator’s Brochure for 
SB-240563. 03-DEC-2015.
GlaxoSmithKline guidance document, GUI_00000051487. Non-Compartmental Analysis 
of Pharmacokinetic. 29-Oct-2014.
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.

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Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, et.al., editors. 
Contraceptive Technology. 20th edition. Atlanta, Georgia: Ardent Media, Inc., 2011: 50.
Table 3-2.
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.
Kronenberg HM, Melmed S, Polonsky KS, Larsen PR, editors. Williams Textbook of 
Endocrinology, 11th edition. Philadelphia: Saunders, 2008.
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 September 8;371(13):1198-207.
Pavord ID, Korn S, Howarth P, et al. Mepolizumab for severe eosinophilic asthma 
(DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet 2012;380:651–
59.
Pourvasei R (2013).  Denosumab biocomparability. AAPS 15(1); 70-77
Riviere GJ (2011).  Omalizumab bioequivalence injection solution vs dry powder. J 
Bioequiv Avalailab. 3(6) 144-150.
Sampson HA, Munoz-Furlong A, Campbell RL, et. Al. Second symposium on the 
definition and management of anaphylaxis: summary report—Second National Institute 
of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J 
Allergy Clin Immunol 2006;117:391-397.
Strauss JF, Barbieri RL, editors. Yen and Jaffe’s Reproductive Endocrinology. 5th 
edition, Philadelphia, Elsevier/Saunders, 2004.

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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
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.
Zenhua X (2015) Golimumab autoinjector PK bridging.  Clinical Therapeutics 37(2); 
427-438.

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12.
APPENDICES
12.1.
Appendix 1 – Abbreviations and Trademarks
Abbreviations
ACQ-5
Asthma Control Questionnaire
ADA
Anti Drug Antibody
AE
Adverse Event
AUC
Area Under the Concentration-Time Curve
AUC(0-week4)
Area Under the Concentration-Time Curve from Time Zero 
(pre-dose) to Week 4
AUC(0-t)
Area Under the Concentration-Time Curve from Time Zero 
(pre-dose) to Last Time of Quantifiable Concentration
AUC(0-∞)
Area Under the Concentration-Time Curve from Time Zero 
Extrapolated to Infinite Time
%AUCex
Percentage of AUC(0-∞) Obtained by Extrapolation
AE
Adverse Event
BMI
Body Mass Index
CI
Confidence Interval
CL/F
Apparent Clearance Following Subcutaneous Dosing
Cmax
Maximum Observed Concentration
CONSORT
Consolidated Standards of Reporting Trials
COPD
Chronic Obstructive Pulmonary Disease
eDC
Electronic data capture
EGPA
Eosinophilic granulomatosis with polyangiitis
EOE
Eosinophilic esophagitis
ECG
Electrocardiogram
FEV1
Forced Expiratory volume in 1 second
FRP
Females of Reproductive potential
GSK
GlaxoSmithKline
HBsAg
Hepatitis B surface antigen
HCP
Healthcare Provider
hCG
Human chorionic gonadotrophin
HES
Hypereosinophilic syndrome
IB
Investigator’s Brochure
IDSL
Integrated Data Standards Library
IL
Interleukin
IV
Intravenous
λz
Terminal Phase Elimination Rate Constant
Nab
Neutralising antibody
OCS
Oral corticosteroids
PK
Pharmacokinetic
PD
Pharmacodynamic
SAE
Serious Adverse Event 
SC
Subcutaneous

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SGRQ
St George’s Respiratory Questionnaire
SRM
Study reference manual
tlast
Time of Last Observed Concentration
tmax
Time to Cmax
t½
Terminal Phase Half-life
Vd/F
Apparent Volume of Distribution Following Subcutaneous 
Dosing
WCBP
Women of child bearing potential
WFI
Water For Injection
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NUCALA™
WinNonlin

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12.2.
Appendix 2 - Liver Safety Required Actions and Follow up 
Assessments
Liver chemistry stopping criteria for healthy volunteers and required follow 
up assessments
Liver chemistry stopping criteria have been designed to assure subject safety and to 
evaluate liver event etiology (in alignment with the FDA premarketing clinical liver 
safety guidance).
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Since this is a single dose study liver chemistry stopping criteria do not apply. However, 
in case of liver event following the single dose of study treatment (defined as liver 
stopping event in table below) all required follow up assessments must be completed.
Liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT-absolute
ALT≥3xULN
If  ALT≥3xULN  AND bilirubin1,2 2xULN (>35% direct bilirubin) or  INR >1.5, 
Report as an SAE.
See additional Actions and Follow Up Assessments listed below
Required Actions and Follow up Assessments following Liver Stopping Event
Actions
Follow Up Assessments
Report the event to GSK within 24 hours
Complete the liver event eDC, 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, stabilise, or return to within baseline 
(see MONITORING below)
MONITORING:
If ALT≥3xULN AND bilirubin 2xULN  or INR 
>1.5
Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform liver 
event follow up assessments within  24 hrs
Viral hepatitis serology3
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. 
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.

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Liver Chemistry Stopping Criteria – Liver Stopping Event
Monitor subjects twice weekly until liver 
chemistries resolve, stabilise or return to within 
baseline
A specialist or hepatology consultation is 
recommended
If ALT≥3xULN AND bilirubin < 2xULN  and INR 
≤1.5:
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 alcohol use on the liver event alcohol 
intake case report form
If ALT≥3xULN AND bilirubin 2xULN  or INR 
>1.5:
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 
eDC 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.
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 
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, et.al..
Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose 
and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.

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12.3.
Appendix 3 - Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
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 (haematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae).

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE.  However, the signs and symptoms and/or clinical 
sequelae resulting from lack of efficacy will be reported if they fulfil the definition 
of an AE or SAE.

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.

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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.

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.
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.

Refer to Appendix 2 for the required liver chemistry follow-up instructions

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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 eDC

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 eDC 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.

Subject-completed Value Evidence and Outcomes questionnaires and the collection 
of AE data are independent components of the study.

Responses to each question in the Value Evidence and Outcomes questionnaire will 
be treated in accordance with standard scoring and statistical procedures detailed by 
the scale’s developer.

The use of a single question from a multidimensional health survey to designate a 
cause-effect relationship to an AE is inappropriate.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort
and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. - an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.

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

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Reporting of SAEs to GSK
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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12.4.
Appendix 4 - Definition of and Procedures for Documenting 
Medical Device Incidents
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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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  form will be completed as described in Appendix 3.

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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12.5.
Appendix 5 - Modified List of Highly Effective Methods for 
Avoiding Pregnancy in FRP and Collection of Pregnancy 
Information
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.
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.

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
Contraceptive subdermal implant

Intrauterine device or intrauterine system

Combined estrogen and progestogen oral contraceptive [Hatcher, 2011]

Injectable progestogen [Hatcher, 2011]

Contraceptive vaginal ring [Hatcher, 2011]

Percutaneous contraceptive patches [Hatcher, 2011]

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.
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 3. 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.

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12.6.
Appendix 6 - Anaphylaxis Criteria
Hypersensitivity reactions will be monitored using the diagnostic criteria for anaphylaxis 
as outlined by the Joint NIAID/FAAN Second Symposium on Anaphylaxis [Sampson, 
2006].  The criteria do not make a distinction based on underlying mechanism. These 
criteria are summarized as follows:

Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, swollen lips-
tongue-uvula), and at least one of the following:

Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow [PEF], hypoxemia)

Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction (e.g., 
hypotonia [collapse], syncope, incontinence)
Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours):

Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, swollen 
lips-tongue-uvula)

Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia)

Reduced BP or associated symptoms (e.g., hypotonia [collapse], syncope, 
incontinence)

Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting)
Reduced BP after exposure to known allergen for that patient (minutes to several hours):

Infants and children: low systolic BP (age specific) or greater than 30% decrease in 
systolic BP

Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that 
person’s baseline.

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12.7.
Appendix 7- Inspection of the Autoinjector
Injection Assessment - Autoinjector
Was the full dose successfully 
administered?
Yes, injection successful
                No, injection not successful (please complete the questions below 1)
No, injection not attempted
Were there any observations with respect to the user tasks that indicate that the 
full dose has not been administered? Check all that apply.
-
Incorrect injection site selected, record location below
        ________________________________________
-
Pen was not pushed all the way down and held
-
Pen pulled away before end of injection (i.e., before the second click, 
or before the plunger stops moving and the yellow indicator fills the 
window, or before holding for a total of 15seconds)
-
Evidence of liquid leaking from injection site (i.e. potentially indicating 
a premature lift or a wet injection) 
-
Other (please specify below)
         ________________________________________
Were there any observations with respect to the device that indicate that the full 
dose has not been dispensed? Check all that apply.
-
Pen leaking
-
Components broken / cracked
-
Cannot push the needle guard down to activate (i.e., force required is 
too high)
-
Pen does not activate (after pressing needle guard down)
-
Delivery stops before end of injection (yellow indicator stopped before 
reaching bottom of inspection window)
-
Other (please specify below)
         ________________________________________
Footnote 1 refers to the Autoinjector Error / Failure Reporting Form, Appendix 8.
Failure in either of these two events requires the appropriate form to be completed.
HCP should review the user tasks in completing the injection, the device and the 
packaging and complete Appendix 8 to capture any issues.

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12.8.
Appendix 8 - Auto injector Error/Failure reporting form
AUTOINJECTOR ERROR / FAILURE REPORTING FORM
Please write clearly using BLOCK CAPITAL LETTERS.
Please complete form within 24 hours of autoinjector failure/user error at site and submit 
to GSK
Primary Investigator:
Protocol #:
204958
Site Contact for IP Accountability:
Site #:
Contact Phone (print clearly):
Subject #:
E-mail (print clearly):
Autoinjector Kit #:
Site Address:
Date Dispensed:
Date Returned:
Has the autoinjector been used by the HCP?       ___ No             ___ Yes
(Considered a 
biohazard.)  
Was there an AE or SAE associated with this failure/error?      ___ No             ___ Yes 
If yes, please enter the eDC AE sequence number:______________________
Description of user error:
Which of the following user errors apply? Tick all that apply:
__   Did not check Expiration Date
__   Incorrect preparation or incorrect choice of injection site
__   Did not check product solution
__   Clear cap not removed from autoinjector

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__   Autoinjector not properly activated on injection site (e.g., needle guard  not flush 
with skin)
__   Autoinjector used upside down
__   Autoinjector pulled away before end of injection (i.e., before yellow indicator 
stopped moving)
__   Did not check inspection window for yellow indicator
__   Other (please specify below).
Description of failure:
Reason for Autoinjector Failure. Tick all that apply:
__   Autoinjector leaking
__   Components  broken/cracked/missing
__   Inspection window not clear
__   Cannot remove clear cap
__   Bent needle
__   Liquid is cloudy, discoloured or contains large particles
__   Cannot push the needle guard down to activate (i.e., force is too high)
__   Autoinjector does not activate (after pressing needle guard down)
__   Delivery stops before end of injection (yellow indicator stopped before reaching 
bottom of inspection window)
__   Other (please specify below)
Description of failure:

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Packaging Failure. Tick all that apply:
__   Device damaged
__   Packaging damaged or can’t read label
__   Security seal was broken
__   Autoinjector missing from kit
__   Other (please specify below)
Failure Outcome (check one):
    Subject received no dose
   Subject received a partial dose
       (ensure date used is captured above)
Resolution (check one) :
    Replacement autoinjector 
provided
    Dose omitted
    Subject Withdrawn
Replacement Autoinjector Dispensed Date:
Kit # of Replacement Autoinjector:
Instructions for further processing: Please fax or email completed Form to The GSK 
Pen Failure Processing Team at 
 or email address.  Please contact 
your study monitor with any questions or for troubleshooting.  Maintain the Form and in 
the patients’ records. You may be contacted further concerning the malfunctioned 
autoinjector.
PPD

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12.9.
Appendix 9 - Inspection of the Safety Syringe
Injection Assessment – Safety Syringe
Was the full dose successfully 
administered?
Yes, injection successful
                No, injection not successful (please complete the questions below 1)
No, injection not attempted
Were there any observations with respect to the user tasks that indicate that 
the full dose has not been administered? Check all that apply.
-
Incorrect injection site selected, record location below
        ________________________________________
-
Needle not fully inserted into site
-
Plunger not slowly pushed down
-
Plunger not pushed all the way down until the stopper reaches the 
bottom of the syringe
-
Thumb not moved up, plunger not risen and needle guard not 
activated
-
Evidence of liquid leaking from injection site (i.e. potentially indicating 
a premature lift or a wet injection)
-
Other (please specify below)
        ________________________________________
Were there any observations with respect to the device that indicate that the 
full dose has not been dispensed? Check all that apply.
-
Syringe leaking
-
Components broken / cracked
-
Cannot push the plunger rod down (i.e., required force is too high)
-
Other (please specify below)
         ________________________________________
Footnote 1 refers to the Safety Syringe Error / Failure Reporting Form, Appendix 10.
Failure in either of these two events requires the appropriate form to be completed. 
HCP should review the user tasks in completing the injection, the device and the 
packaging and complete Appendix 10 to capture any issues.

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12.10.
Appendix 10 - Safety Syringe Error/ Failure reporting form
SAFTEY SYRINGE ERROR / FAILURE REPORTING FORM
Please write clearly using BLOCK CAPITAL LETTERS.
Please complete form within 24 hours of safety syringe failure/user error at site and 
submit to GSK
Primary Investigator:
Protocol #:
204958
Site Contact for IP Accountability:
Site #:
Contact Phone (print clearly):
Subject #:
E-mail (print clearly):
Safety Syringe Number:
Site Address:
Date Dispensed:
Date Returned:
Has the safety syringe been used by the HCP?       ___ No             ___ Yes
(Considered a biohazard.)  
Was there an AE or SAE associated with this failure/error?      ___ No             ___ Yes 
If yes, please enter the eDC AE sequence number:______________________
Description of user error:
Which of the following user errors apply? Tick all that apply:
__   Did not check Expiration Date
__   Incorrect preparation or incorrect choice of injection site
__   Did not check product solution

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__   Needle shield not removed from safety syringe
__   Safety syringe pulled away before end of injection (i.e., before the plunger all the 
way down)
__   Did not check inspection window for white plunger
__   Other (please specify below).
Description of failure:
Reason for Safety Syringe Failure. Tick all that apply:
__   Safety Syringe leaking
__   Components  broken/cracked
__   Inspection window not clear
__   Cannot remove needle shield 
__   Bent needle
__   Liquid is cloudy, discoloured or contains large particles
__   Cannot push the plunger rod down (i.e., force is too high)
__   Other (please specify below)
Description of failure:
Packaging Failure. Tick all that apply:

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__   Device damaged
__   Packaging damaged or can’t read label
__   Security seal was broken
__   Other (please specify below)
Failure Outcome (check one):
    Subject received no dose
   Subject received a partial dose
       (ensure date used is captured above)
Resolution (check one) :
    Replacement safety syringe 
provided
    Dose omitted
    Subject Withdrawn
Replacement Safety Syringe Dispensed Date:
Replacement Safety Syringe 
Number:
Instructions for further processing: Please fax or email completed Form to The GSK 
Pen Failure Processing Team at 
 or email address.  Please contact 
your study monitor with any questions or for troubleshooting.  Maintain the Form and in 
the subjects’ records. You may be contacted further concerning the malfunctioned safety 
syringe.
PPD

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12.11.
Appendix 11 - Country Specific Requirements
No country-specific requirements exist.

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12.12.
Appendix 12 - Protocol Amendment Changes 01
Where this amendment Applies
This amendment applies across any site that will be used in the study.
Summary of Amendment Changes with Rationale
Change in medical monitor sponsor page. Removal of Cardiovascular and deaths events 
Section 7.3.1.4.
Update to the content of the error/failure reporting forms to reflect consistency with other 
data captured in similar studies.
List of Specific Changes
Title: Medical Monitor Page
PREVIOUS TEXT
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
Site Address
Primary 
Medical 
Monitor 
Telephone: 
Cell: 
GlaxoSmithKline
Upper Merion
709 Swedeland Road, 
King of Prussia, PA –
19406, USA
Secondary 
Medical 
Monitor
 
Telephone:
Cell: 
GlaxoSmithKline
5 Moore Drive, PO Box 
13398, Research 
Triangle Park (RTP), 
NC 27709-3398, USA
SAE contact  
information 
Medical 
monitor as 
above 
Telephone:
Cell: 
GlaxoSmithKline
5 Moore Drive, PO Box 
13398, Research 
Triangle Park (RTP), 
NC 27709-3398, USA 
PPD
PPD
PPD
PPD
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REVISED TEXT
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
Site Address
Primary 
Medical 
Monitor 
Telephone: 
Cell: 
GlaxoSmithKline
Upper Merion
709 Swedeland Road, 
King of Prussia, PA –
19406, USA
Secondary 
Medical 
Monitor
 
Telephone:
Cell: 
GlaxoSmithKline
5 Moore Drive, PO Box 
13398, Research 
Triangle Park (RTP), 
NC 27709-3398, USA
SAE contact  
information 
Medical 
monitor as 
above 
Telephone: 
Cell: 
GlaxoSmithKline
Upper Merion
709 Swedeland Road, 
King of Prussia, PA –
19406, USA
Title: Updated Exploratory endpoints in Section 3 Objectives and Endpoints
PREVIOUS TEXT
Exploratory

To evaluate mepolizumab 
pharmacodynamic effects on blood 
eosinophil count following a single SC 
dose of the liquid drug product in  
safety syringe or the liquid drug 
product in autoinjector in comparison 
with the lyophilised drug product

Ratio to baseline in blood eosinophil 
count over time

To evaluate safety syringe and 
autoinjector use & functionality

Device functionality questions 
PPD
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REVISED TEXT
Exploratory

To evaluate mepolizumab 
pharmacodynamic effects on blood 
eosinophil count following a single SC 
dose of the liquid drug product in  
safety syringe or the liquid drug 
product in autoinjector in comparison 
with the lyophilised drug product

Ratio to baseline in blood eosinophil 
count over time

To evaluate safety syringe and 
autoinjector use & functionality

User and device errors 
Title:  Updated Section 5.4.1 Withdrawal from the study 
PREVIOUS TEXT
5.4.1
Withdrawal from the study
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 criteria are met:

Laboratory parameters: Clinically important changes in laboratory parameters 
identified

Pregnancy: Positive pregnancy test (see Section 7.3.2). 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”. 
If a subject withdraws from the study then the assessments in the time and events 
table under Section 7.1  Day 85 Withdraw (WD) column must be performed. A 
reason for the withdrawal from the study must be captured in the eDC.
REVISED TEXT
Section 5.4.1
If a subject withdraws from the study then the assessments in the time and events 
table under Section 7.1  Day 85 Withdraw (WD) column must be performed. A 
reason for the withdrawal from the study must be captured in the eDC.
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 criteria are met:

Laboratory parameters: Clinically important changes in laboratory parameters 
identified

Pregnancy: Positive pregnancy test (see Section 7.3.2). 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. 

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”. 
Title: Update to title of procedure name in Section 7.1 Time and events table

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PREVIOUS TEXT:
Autoinjector 
and safety 
syringe 
functionality 
assessment
X
HCP reported. 
See Section 
7.4.4. 
REVISED TEXT:
Autoinjector 
and safety 
syringe 
user/device 
error 
assessment
X
HCP reported. 
See Section 
7.4.4. 
Title: Removal of Cardiovascular and death events section
PREVIOUS TEXT
7.3.1.4 
Cardiovascular and Death Events
7.3.1.4.1
Cardiovascular events
Cardiovascular-related AEs and SAEs that will require the investigator to complete event 
specific pages in the eDC system are listed in Section 12.3, Appendix 3.
Cardiovascular events information should be recorded on the corresponding eDC pages 
within one week of when the AE/SAE(s) are first reported.  Please refer to Appendix 3 
for timelines for reporting AE/SAEs.
7.3.1.4.2
Deaths
In addition, all deaths will require completion of a specific death data collection page in 
the eDC system.  The death data collection page in the eDC system includes questions 
regarding cardiovascular (including sudden cardiac death) and non-cardiovascular death.
Death information should be recorded on the death eDC system page within one week of 
when the death is first reported.
Please refer to Section 12.3, Appendix 3 for timelines for reporting SAEs.

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REVISED TEXT
7.3.1.4 
Cardiovascular and Death Events
No cardiovascular or death events will be captured in this study as this is a healthy 
volunteer study.
Title: Section 9.6.1 Update to the name of the device error
PREVIOUS TEXT
9.6.1
Exploratory Analyses
Ratio to baseline in blood eosinophil count will be log transformed and compared 
between treatments using a mixed model repeated measures analysis, adjusting for the 
covariates of baseline blood eosinophil count (log scale) and baseline weight (log scale). 
Time point and injection site (upper arm, abdomen, thigh) will be fitted as a categorical 
variables with the effect of treatment group and baseline blood eosinophil count varying 
at each timepoint (i.e. timepoint-by-baseline and timepoint-by-treatment interactions will 
be included in the model).
Device functionality questionnaire will be summarized using appropriate descriptive 
statistics.
REVISED TEXT
9.6.1
Exploratory Analyses
Ratio to baseline in blood eosinophil count will be log transformed and compared 
between treatments using a mixed model repeated measures analysis, adjusting for the 
covariates of baseline blood eosinophil count (log scale) and baseline weight (log scale). 
Time point and injection site (upper arm, abdomen, thigh) will be fitted as a categorical 
variables with the effect of treatment group and baseline blood eosinophil count varying 
at each timepoint (i.e. timepoint-by-baseline and timepoint-by-treatment interactions will 
be included in the model).
User and device errors will be summarized using appropriate descriptive statistics.
Title: Removal of Definition of Cardiovascular Events 
PREVIOUS TEXT
Appendix 3- Definition of and Procedures for Recording, Evaluating, Follow-Up 
and Reporting of Adverse Events

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Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the eDC 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
REVISED TEXT
This section has been removed from Appendix 3. 
Title: Update to Appendix 7 Inspection of the autoinjector
PREVIOUS TEXT
Appendix 7- Inspection of the Autoinjector
Footnote 1 refers to the Autoinjector Error / Failure Reporting Form, Appendix 8.
Failure in either of these two events requires the appropriate form to be completed. 

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Appendix 7- Inspection of the Autoinjector
Injection Assessment - Autoinjector
Was the full dose successfully 
administered?
Yes, injection successful
                No, injection not successful (please complete the questions below 1)
No, injection not attempted
Were there any observations with respect to the user tasks that indicate that the 
full dose has not been administered? Check all that apply.
-
Incorrect injection site selected, record location below
        ________________________________________
-
Pen was not pushed all the way down and held
-
Pen pulled away before end of injection (i.e., before the second click, 
or before the plunger stops moving and the yellow indicator fills the 
window, or before holding for a total of 15seconds)
-
Evidence of liquid leaking from injection site (i.e. potentially indicating 
a premature lift or a wet injection) 
-
Other (please specify below)
         ________________________________________
Were there any observations with respect to the device that indicate that the full 
dose has not been dispensed? Check all that apply.
-
Pen leaking
-
Components broken / cracked
-
Cannot push the needle guard down to activate (i.e., force required is 
too high)
-
Pen does not activate (after pressing needle guard down)
-
Delivery stops before end of injection (yellow indicator stopped before 
reaching bottom of inspection window)
-
Other (please specify below)
         ________________________________________
Footnote 1 refers to the Autoinjector Error / Failure Reporting Form, Appendix 8.
Failure in either of these two events requires the appropriate form to be completed. 

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HCP should review the user tasks in completing the injection, the device and the 
packaging and complete Appendix 8 to capture any issues.
Title: Update to Appendix 8 Auto injector Error/Failure reporting form 
PREVIOUS TEXT
AUTOINJECTOR ERROR / FAILURE REPORTING FORM
Please write clearly using BLOCK CAPITAL LETTERS.
Please complete form within 24 hours of autoinjector failure/user error at site and submit 
to GSK
Primary Investigator:
Protocol #:
204958
Site Contact for IP Accountability:
Site #:
Contact Phone (print clearly):
Subject #:
E-mail (print clearly):
Autoinjector Kit #:
Site Address:
Date Dispensed:
Date Returned:
Has the autoinjector been used by the HCP?       ___ No             ___ Yes
(Considered a 
biohazard.)  
Was there an AE or SAE associated with this failure/error?      ___ No             ___ Yes 
If yes, please enter the eDC AE sequence number:______________________
Description of user error:
Which of the following user errors apply? Tick all that apply:
__   Did not check Expiration Date

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__   Incorrect preparation or incorrect choice of injection site
__   Did not check product solution
__   Clear cap not removed from autoinjector
__   Autoinjector not properly activated on injection site (e.g., needle guard  not flush 
with skin)
__   Autoinjector used upside down
__   Autoinjector pulled away before end of injection (i.e., before yellow indicator 
stopped moving)
__   Did not check inspection window for yellow indicator
__   Other (please specify below).
Description of failure:
Reason for Autoinjector Failure. Tick all that apply:
__   Autoinjector leaking
__   Components  broken/cracked/missing
__   Inspection window not clear
__   Cannot remove clear cap
__   Bent needle
__   Liquid is cloudy, discoloured or contains large particles
__   Cannot push the needle guard down to activate (i.e., force is too high)
__   Autoinjector does not activate (after pressing needle guard down)
__   Delivery stops before end of injection (yellow indicator stopped before reaching 
bottom of inspection window)
__   Other (please specify below)
Description of failure:

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Packaging Failure. Tick all that apply:
__   Device damaged
__   Packaging damaged or can’t read label
__   Security seal was broken
__   Autoinjector missing from kit
__   Other (please specify below)
Failure Outcome (check one):
    Subject received no dose
   Subject received a partial dose
       (ensure date used is captured above)
Resolution (check one) :
    Replacement autoinjector 
provided
    Dose omitted
    Subject Withdrawn
Replacement Autoinjector Dispensed Date:
Kit # of Replacement Autoinjector:
Instructions for further processing: Please fax or email completed Form to The GSK Pen 
Failure Processing Team at 
 or email address.  Please contact your 
study monitor with any questions or for troubleshooting.  Maintain the Form and in the 
patients’ records. You may be contacted further concerning the malfunctioned 
autoinjector.
REVISED TEXT
AUTOINJECTOR (PEN) ERROR / FAILURE REPORTING FORM
Please write clearly using BLOCK CAPITAL LETTERS.
Please complete form within 24 hours of pen failure/user error at site and 
submit to GSK
via email to 
Primary Investigator:
Protocol #:
204958
Site Contact for IP Accountability:
Site #:
Contact Phone (print clearly):
Subject #:
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E-mail (print clearly):
Site Address:
Date Dispensed:
Date Returned:
Has the pen been used by the patient?       ___ No             ___ Yes
(Considered a 
biohazard.)  
Was there an AE or SAE associated with this failure/error?      ___ No             ___ Yes 
If yes, please enter the eCRF AE sequence number:______________________
Please provide overall description of user/pen/packaging error/failure:
Which of the following user errors apply? Tick all that apply:
__   Did not check expiration date
__   Did not check product solution
__   Incorrect choice of injection site
__   Clear needle cap not removed from autoinjector
__   Took longer than 5 minutes before carrying out the injection
__   Pen not properly activated on injection site (e.g., needle guard  not flush with skin)
__   Pen used upside down
__   Pen not pressed and held down
__   Pen pulled away before end of injection (i.e., before the second click, or before the yellow indicator
stopped moving, or 
        before holding for a total of 15seconds)
__   Evidence of liquid leaking from injection site (i.e. potentially indicating a premature lift or a 
wet injection)

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__   Other (please specify below).
Description of other user error:
Reason for pen failure. Tick all that apply:
__  Pen leaking
__  Components broken / cracked
__   Liquid is cloudy, discoloured or contains large particles
__   Cannot remove clear needle cap
__   Bent needle
__   Cannot push the needle guard down to activate (i.e., force required is too high)
__   Pen does not activate (after pressing needle guard down)
__   Delivery stops before end of injection (yellow indicator stopped before reaching bottom of 
inspection window)
__   Other (please specify below)
Description of other pen failure:
Packaging failure. Tick all that apply:
__  Device damaged
__  Packaging damaged or can’t read label
__   Security seal was broken
__   Pen missing from kit
__   Other (please specify below)

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Description of other packaging failure:
Error/failure outcome (check one):
   Subject received no dose
   Subject received a partial dose
       (ensure date used is captured above)
Resolution (check one) :
    Replacement pen provided
    Dose omitted
    Subject withdrawn
Replacement Pen Dispensed Date:
Instructions for further processing: Please email completed Form to The GSK 
Pen Failure Processing Team at 
  Please 
contact your study monitor with any questions or for troubleshooting.  Maintain 
the Form and in the subjects’ records. You may be contacted further concerning 
the malfunctioned pen.
Title: Appendix 9: Inspection of the safety syringe
PREVIOUS TEXT
Appendix 9 - Inspection of the Safety Syringe
Footnote 1 refers to the Safety Syringe Error / Failure Reporting Form, Appendix 10.
Failure in either of these two events requires the appropriate form to be completed. 
PPD

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REVISED TEXT
Appendix 9 - Inspection of the Safety Syringe
Injection Assessment – Syringe
Was the full dose successfully 
administered?
Yes, injection successful
                No, injection not successful (please complete the questions below 1)
No, injection not attempted
Were there any observations with respect to the user tasks that indicate that the 
full dose has not been administered? Check all that apply.
-
Incorrect injection site selected, record location below
        ________________________________________
-
Needle not fully inserted into site
-
Plunger not slowly pushed down
-
Plunger not pushed all the way down until the stopper reaches the 
bottom of the syringe
-
Thumb not moved up, plunger not risen and needle guard not 
activated
-
Evidence of liquid leaking from injection site (i.e. potentially indicating 
a premature lift or a wet injection)
-
Other (please specify below)
        ________________________________________
Were there any observations with respect to the device that indicate that the full 
dose has not been dispensed? Check all that apply.
-
Syringe leaking
-
Components broken / cracked
-
Cannot push the plunger rod down (i.e., required force is too high)
-
Other (please specify below)
         ________________________________________
Footnote 1 refers to the Safety Syringe Error / Failure Reporting Form, Appendix 10.
Failure in either of these two events requires the appropriate form to be completed. 
HCP should review the user tasks in completing the injection, the device and the 
packaging and complete Appendix 10 to capture any issues.

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Title: Update to Appendix 10 Safety Syringe Error/Failure reporting form
PREVIOUS TEXT
SAFTEY SYRINGE ERROR / FAILURE REPORTING FORM
Please write clearly using BLOCK CAPITAL LETTERS.
Please complete form within 24 hours of safety syringe failure/user error at site and 
submit to GSK
Primary Investigator:
Protocol #:
204958
Site Contact for IP Accountability:
Site #:
Contact Phone (print clearly):
Subject #:
E-mail (print clearly):
Safety Syringe Number:
Site Address:
Date Dispensed:
Date Returned:
Has the safety syringe been used by the HCP?       ___ No             ___ Yes
(Considered a biohazard.)  
Was there an AE or SAE associated with this failure/error?      ___ No             ___ Yes 
If yes, please enter the eDC AE sequence number:______________________
Description of user error:
Which of the following user errors apply? Tick all that apply:
__   Did not check Expiration Date
__   Incorrect preparation or incorrect choice of injection site
__   Did not check product solution
__   Needle shield not removed from safety syringe
__  Safety syringe pulled away before end of injection (i.e., before the plunger all the way down)

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__   Did not check inspection window for white plunger
__   Other (please specify below).
Description of failure:
Reason for Safety Syringe Failure. Tick all that apply:
__   Safety Syringe leaking
__   Components  broken/cracked
__   Inspection window not clear
__   Cannot remove needle shield 
__   Bent needle
__   Liquid is cloudy, discoloured or contains large particles
__   Cannot push the plunger rod down (i.e., force is too high)
__   Other (please specify below)
Description of failure:
Packaging Failure. Tick all that apply:
__   Device damaged
__   Packaging damaged or can’t read label
__   Security seal was broken
__   Other (please specify below)
Failure Outcome (check one):
    Subject received no dose
   Subject received a partial dose
       (ensure date used is captured above)
Resolution (check one) :
    Replacement safety syringe provided
    Dose omitted
    Subject Withdrawn

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Replacement Safety Syringe Dispensed Date:
Replacement Safety Syringe Number:
Instructions for further processing: Please fax or email completed Form to The GSK 
Pen Failure Processing Team at 
 or email address.  Please contact 
your study monitor with any questions or for troubleshooting.  Maintain the Form and in 
the subjects’ records. You may be contacted further concerning the malfunctioned safety 
syringe.
REVISED TEXT
SYRINGE ERROR / FAILURE REPORTING FORM
Please write clearly using BLOCK CAPITAL LETTERS.
Please complete form within 24 hours of safety syringe failure/user error at 
site and submit to GSK
via email to 
Primary Investigator:
Protocol #:
204958
Site Contact for IP Accountability:
Site #:
Contact Phone (print clearly):
Subject #:
E-mail (print clearly):
Site Address:
Date Dispensed:
Date Returned:
Has the safety syringe been used by the patient?       ___ No             ___ Yes
(Considered a biohazard.)  
Was there an AE or SAE associated with this failure/error?      ___ No             ___ Yes 
If yes, please enter the eCRF AE sequence number:______________________
Please provide overall description of user/pen/packaging error/failure:
PPD
PPD

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Which of the following user errors apply? Tick all that apply:
__   Did not check expiration date
__   Did not check product solution
__   Incorrect choice of injection site
__   Needle cap not removed from syringe
__   Took longer than 5 minutes before carrying out the injection
__   Did not pinch the skin around the injection site
__   Did not insert the entire needle into the pinched area at an angle
__   Syringe pulled away before end of injection (i.e., before the plunger is pushed all the way 
down)
__   Did not move thumb up to allow the plunger to rise and activate the needle guard
__   Evidence of liquid leaking from injection site (i.e. potentially indicating a premature lift or a 
wet injection)
__   Other (please specify below).
Description of other user error:
Syringe failure. Tick all that apply:
__  Syringe leaking
__   Components broken / cracked
__   Liquid is cloudy, discoloured or contains large particles
__   Cannot remove needle cap 
__  Bent needle
__   Cannot push the plunger rod down (i.e., required force is too high)

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__   Other (please specify below)
Description of other syringe failure:
Packaging failure. Tick all that apply:
__   Device damaged
__   Packaging damaged or can’t read label
__   Security seal was broken
__   Syringe missing from kit
__   Other (please specify below)
Description of other packaging failure:
Error/failure outcome (check one):
   Subject received no dose
   Subject received a partial dose
       (ensure date used is captured above)
Resolution (check one) :
    Replacement syringe provided
    Dose omitted
    Subject withdrawn
Replacement Syringe Dispensed Date:
Instructions for further processing: Please email completed Form to The GSK 
Safety Syringe Failure Processing Team at 
  Please contact your study monitor 
with any questions or for troubleshooting.  Maintain the Form and in the subjects’ 
records. You may be contacted further concerning the malfunctioned safety 
syringe.
PPD

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12.13.
Appendix 13 - Protocol Amendment Changes 02
Where this amendment Applies
This amendment applies across any site that will be used in the study.
Summary of Amendment Changes with Rationale
Minor changes overall to the document listing changes to abbreviations and text.
List of Specific Changes
Title: Cover page authors list
PREVIOUS TEXT
 
REVISED TEXT
Author (s):
 
Title: Investigator Protocol Agreement page
PREVIOUS TEXT
For protocol number 
REVISED TEXT
For protocol number 204958
Title: Abbreviations updated for Subcutaneous in Overall Design page 10 and 17
PREVIOUS TEXT
All treatments will be administered subcutaneous by a health care professional (HCP).  
The study will compare the pharmacokinetics and safety of mepolizumab administered as 
a liquid drug product in two different devices with the reconstituted lyophilised drug 
product. 
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REVISED TEXT
All treatments will be administered SC by a health care professional (HCP).  The study 
will compare the pharmacokinetics and safety of mepolizumab administered as a liquid 
drug product in two different devices with the reconstituted lyophilised drug product.
Title: Abbreviations updated for Confidence Interval in Analysis 
PREVIOUS TEXT
Analysis
Point estimates and associated two-sided 90% confidence intervals will be constructed 
for the differences between the test and reference treatments on the loge scale; these will 
be back-transformed to provide point estimates and two-sided 90% CIs for the ratio of 
each of the test treatments to the reference treatment on the original scale.
REVISED TEXT
Analysis
Point estimates and associated two-sided 90% confidence intervals (CI) will be 
constructed for the differences between the test and reference treatments on the loge
scale; these will be back-transformed to provide point estimates and two-sided 90% CIs 
for the ratio of each of the test treatments to the reference treatment on the original scale.
Title: Abbreviations updated for Confidence Interval in Analysis
PREVIOUS TEXT
Clinical data for mepolizumab administered by the IV, SC or IM routes in a variety of 
eosinophilic conditions is summarised in the Investigators’ Brochure (GlaxoSmithKline 
Document Number CM 2003/00010/10).
REVISED TEXT
Clinical data for mepolizumab administered by the intravenous (IV), SC or IM routes in 
a variety of eosinophilic conditions is summarised in the Investigators’ Brochure 
(GlaxoSmithKline Document Number CM 2003/00010/10).

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Title: Updated text in Section 4.3 Type and Number of subjects
PREVIOUS TEXT
Additional subjects may be enrolled if deemed appropriate to ensure at least 216 
completed subjects at the discretion of the Sponsor in consultation with the Investigator. 
(i.e. complete Day 85 visit). See Table 1
REVISED TEXT
Additional subjects may be enrolled if deemed appropriate to ensure at least 216 
completed subjects at the discretion of the Sponsor in consultation with the Investigator. 
(i.e. complete Day 85 visit). See Table 1 below.
Title: Section 4.5 Dose Justification
PREVIOUS TEXT
A single mepolizumab dose of 100 mg administered subcutaneous is selected in this 
study as it is the approved therapeutic dose in severe asthma and the anticipated 
therapeutic dose in COPD.
REVISED TEXT
A single mepolizumab dose of 100 mg administered SC is selected in this study as it is 
the approved therapeutic dose in severe asthma and the anticipated therapeutic dose in 
chronic obstructive pulmonary disease (COPD).
Title: Section 4.6 Benefit:Risk Assessment
PREVIOUS TEXT
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.
REVISED TEXT
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 (IB).

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Title: Section 4.6.1 Risk Assessment – Text that has changed is included in the table 
below.
PREVIOUS TEXT
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.
Daily monitoring of serious 
adverse events (SAEs) by 
medical monitor; regular 
systematic review of 
adverse events/SAE data 
from ongoing studies by the 
GSK study team and/or 
safety review team. 
Injection site reactions
Daily monitoring of serious 
adverse events (SAEs) by 
medical monitor; regular 
systematic review of 
adverse events/SAE data 
from ongoing studies by 
GSK study team and/or 
safety review team. 
REVISED TEXT
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 SC may elicit 
systemic (e.g. 
hypersensitivity) and local 
site reactions.
Daily monitoring of serious 
adverse events (SAEs) by 
medical monitor; regular 
systematic review of 
AE/SAE data from ongoing 
studies by the 
GlaxoSmithKline (GSK)

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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
study team and/or safety 
review team. 
Injection site reactions
Daily monitoring of serious 
adverse events (SAEs) by 
medical monitor; regular 
systematic review of 
AE/SAE data from ongoing 
studies by GSK study team 
and/or safety review team. 
Title: Section 6.2 Medical Devices
PREVIOUS TEXT
The instructions for use (IFU) of these injection devices are provided in the study 
reference manual (SRM). The instructions were developed and optimized as a result of 
formative human factors studies.
REVISED TEXT
The instructions for use (IFU) of these injection devices are provided in the SRM. The
instructions were developed and optimized as a result of formative human factors studies.
Title: Section 6.6 Preparation/Handling/Storage/Accountability
PREVIOUS TEXT
A description of the methods and materials required for mepolizumab will be detailed in 
the Study Reference Manual (SRM).
REVISED TEXT
A description of the methods and materials required for mepolizumab will be detailed in 
the SRM.

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Title: Section 6.11.1 Caffeine, Alcohol and Tobacco
PREVIOUS TEXT

During the dosing session, subjects will abstain from ingesting caffeine- or xanthine-
containing products (e.g., coffee, tea, cola drinks and chocolate) for 12 hours prior to 
the start of dosing until collection of the final pharmacokinetic and/or 
pharmacodynamic  sample of the session and prior to all out-patient visits. 

During the dosing session, subjects will abstain from alcohol for 24 hours prior to the 
start of dosing until collection of the final pharmacokinetic and/or 
pharmacodynamic sample of the session and prior to all out-patient visits. 
REVISED TEXT

During the dosing session, subjects will abstain from ingesting caffeine- or xanthine-
containing products (e.g., coffee, tea, cola drinks and chocolate) for 12 hours prior to 
the start of dosing until collection of the final pharmacokinetic and/or PD sample of 
the session and prior to all out-patient visits. 

During the dosing session, subjects will abstain from alcohol for 24 hours prior to the 
start of dosing until collection of the final pharmacokinetic and/or PD sample of the 
session and prior to all out-patient visits. 
Title: Section 7. Study Assessments and procedures
PREVIOUS TEXT

The timing and number of planned study assessments, including safety, 
pharmacokinetic, pharmacodynamic/biomarker assessments may be altered
during the course of the study based on newly available data (e.g., to obtain data 
closer to the time of peak plasma concentrations) to ensure appropriate 
monitoring. 
REVISED TEXT

The timing and number of planned study assessments, including safety, 
pharmacokinetic, PD/biomarker assessments may be altered during the course of 
the study based on newly available data (e.g., to obtain data closer to the time of 
peak plasma concentrations) to ensure appropriate monitoring. 

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Title: 7.6.2 Sample Analysis
PREVIOUS TEXT
Plasma analysis will be performed under the control of PTS, GlaxoSmithKline, the 
details of which will be included in the Study Reference Manual (SRM).
Once the plasma has been analyzed for mepolizumab any remaining plasma may be 
analyzed for other compound-related material and the results reported under a separate 
PTS, GlaxoSmithKline  protocol.
REVISED TEXT
Plasma analysis will be performed under the control of PTS, GSK, the details of which 
will be included in the Study Reference Manual (SRM). Concentrations of mepolizumab 
will be determined in plasma samples using the currently approved bioanalytical 
methodology. Raw data will be archived at the bioanalytical site (detailed in the SRM).
Once the plasma has been analyzed for mepolizumab any remaining plasma may be 
analyzed for other compound-related material and the results reported under a separate 
PTS, GSK protocol.
Title: Section 9.1 Hypotheses
PREVIOUS TEXT
For AUC(0-t), AUC(0-∞) and Cmax, point estimates and corresponding two-sided 90% 
confidence intervals will be constructed for the ratio of the geometric mean of each test 
treatment to the geometric mean of the reference treatment, μ(test)/μ(reference). No 
formal hypothesis will be tested. However, interpretation of the comparability of the 
autoinjector and safety syringe with the reconstituted lyophilised drug product will be 
guided by a two-sided 90% confidence interval for μ(test)/μ(reference) in the range 
(0.80, 1.25) for AUC(0-t), AUC(0-∞) and Cmax.
REVISED TEXT
For AUC(0-t), AUC(0-∞) and Cmax, point estimates and corresponding two-sided 90% 
confidence intervals (CI) will be constructed for the ratio of the geometric mean of each 
test treatment to the geometric mean of the reference treatment, μ(test)/μ(reference). No 
formal hypothesis will be tested. However, interpretation of the comparability of the 
autoinjector and safety syringe with the reconstituted lyophilised drug product will be 
guided by a two-sided 90% CI for μ(test)/μ(reference) in the range (0.80, 1.25) for 
AUC(0-t), AUC(0-∞) and Cmax.

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Title: Section 9.2 Sample Size considerations
PREVIOUS TEXT
Variability estimates for AUC(0-∞), AUC(0-τ) and Cmax for mepolizumab were considered 
from three studies; SB-240563/017, SB-240563/018 and MEA114092. Only data from 
treatment groups with subcutaneous administration of mepolizumab in the upper arm, 
abdomen or thigh, for doses of 125mg and 250mg across the 3 studies was considered. 
REVISED TEXT
Variability estimates for AUC(0-∞), AUC(0-τ) and Cmax for mepolizumab were considered 
from three studies; SB-240563/017, SB-240563/018 and MEA114092. Only data from 
treatment groups with SC administration of mepolizumab in the upper arm, abdomen or 
thigh, for doses of 125mg and 250mg across the 3 studies was considered. 
Title: 9.5 Primary Analyses
PREVIOUS TEXT
Point estimates and associated two-sided 90% confidence intervals will be constructed 
for the differences between the test and reference treatments on the loge scale; these will 
be back-transformed to provide point estimates and two-sided 90% CIs for the ratio of 
each of the test treatments to the reference treatment on the original scale.
REVISED TEXT
Point estimates and associated two-sided 90% CIs will be constructed for the differences 
between the test and reference treatments on the loge scale; these will be back-
transformed to provide point estimates and two-sided 90% CIs for the ratio of each of the 
test treatments to the reference treatment on the original scale.
Title: Section 11 References
PREVIOUS TEXT
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.
REVISED TEXT
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, et.al., editors. 
Contraceptive Technology. 20th edition. Atlanta, Georgia: Ardent Media, Inc., 2011: 50.
Table 3-2.

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Title: Section: 12.1 Appendix 1 – Abbreviations and Trademarks
The following abbreviations and trademarks have been removed from this version 
of the protocol.
AD
Atopic Dermatitis
CPAP
Continous Positive Airway Pressure
LABA
Long acting beta 2 agonist
LTRA
Leuketriene receptor anatagonist
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
ADVAIR™
Chiron RIBA
SAS

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12.14.
Appendix 14 - Protocol Amendment Changes 03
Where this amendment Applies
This amendment applies across any site that will be used in the study.
Specific Change
Title: Section 7.3.1.4. Cardiovascular and Death Events
PREVIOUS TEXT
No cardiovascular or death events will be captured in this study as this is a healthy 
volunteer study.
REVISED TEXT
Section has been deleted from the document
Specific Change
Title: Section 7.3.1.4. Cardiovascular and Death Events
PREVIOUS TEXT
Section 7.3.1.4. Cardiovascular and Death Events
No cardiovascular or death events will be captured in this study as this is a healthy 
volunteer study.
REVISED TEXT
*Upon deletion of Section 7.3.1.4 “Cardiovascular and Death Events” the subsequent 
Section 7.3.1.5 becomes 7.3.1.4, no change to body of text
Section 7.3.1.4. 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.

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Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.