Clinical trial NCT02802514
Conditions: Diabetes Mellitus
Keywords: Gastrointestinal Glucagon like peptide Nausea Magnetic resonance imaging
Sponsor: GlaxoSmithKline
Start date: 2016-09-20; Completion date: 2017-09-07
Enrollment: 5 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The drug effects will be studied after a single dose of 50 milligram (mg) albiglutide and a single dose of 10 microgram exenatide, to gain insight into the central mechanisms of nausea associated with Glucagon-like peptide-1 receptor (GLP-1R) agonists. This study will explore the potential differences at the expected time of maximum concentration (Cmax) between a long-acting (albiglutide) and short-acting (exenatide) GLP-1R agonist in brain activation of healthy volunteers assessed by magnetic resonance imaging (MRI). This is a phase IV, 2-part, 2-period crossover (session), single dose, randomized, single blind (blinded to both the subject and the imaging evaluators analysing the MRI data), placebo- and active-controlled study in adult healthy volunteers who are susceptible to motion sickness. Part A and Part B are the same in design, both consisting of a screening stage, a dosing/assessment stage, and a follow-up visit. Data from Part A will inform progression, methods, and analysis plan for Part B. Each sequence includes three scanning visits: albiglutide plus scan, exenatide plus scan and an off-therapy -natural history scan with a 6-9 week washout period between the dosing scans. A total of 24 to 28 subjects will be randomized in the study (Part A and Part B). The cross over design is divided into 2 sessions and schedule is as follow, on Day 1 (either Session 1 (S1) or Session 2 (S2) per, if randomized) subject will under go an off-therapy MRI scan, on Day 5 subject will receive a single dose of 50 mg albiglutide or albiglutide placebo, and Day 8 subject will receive a single dose of 10 microgram exenatide or saline placebo followed by a post-dose MRI scan. At each session subject will receive only one active drug (albiglutide or exenatide).

Detailed description:

Arms: arm 1: In session 1, eligible subject will undergo off-therapy MRI scan Subject will receive single dose each of 50 mg albiglutide on Day 5 and exenatide placebo on Day 8 followed by a post-dose MRI. In session 2, subject will receive single dose each of albiglutide placebo on Day 1 (Week 9) and 10 microgram exenatide on Day 4 followed by a post-dose MRI scan. There will be 6-9 week washout period between Session 1 and Session 2 arm 2: In session 1, eligible subject will receive single dose each of 50 mg albiglutide on Day 1 and exenatide placebo on Day 4 followed by a post-dose MRI scan. In session 2, Day 1 (Week 9) subject will undergo off-therapy MRI scan. Subject will receive single dose each of albiglutide placebo on Day 5 and 10 microgram of exenatide on Day 8 followed by a post-dose MRI scan. There will be 6-9 week washout period between Session 1 and Session 2 arm 3: In session 1, Day 1 subject will undergo off-therapy MRI scan Subject will receive single dose each of albiglutide placebo on Day 5 and 10 microgram of exenatide on Day 8 followed by a post-dose MRI scan In session 2, eligible subject will receive single dose each of 50 mg albiglutide on Day 1 (Week 9) and exenatide placebo Day 4 followed by a post-dose MRI scan. There will be 6-9 week washout period between Session 1 and Session 2 arm 4: In session 1, subject will receive single dose each of albiglutide placebo on Day 1 and 10 microgram exenatide on Day 4 followed by a post-dose MRI scan. In session 2, subject will undergo off-therapy MRI scan on Day 1 (Week 9). Subject will receive single dose each of 50 mg albiglutide on Day 5 and exenatide placebo on Day 8 followed by a post-dose MRI scan.. There will be 6-9 week washout period between Session 1 and Session 2
Interventions: intervention 1: Albiglutide 50mg intervention 2: Albiglutide matching placebo intervention 3: Exenatide 10microgram intervention 4: Exenatide placebo (saline)
Intervention descriptions: intervention 1: It is provided as a single use fixed dose disposable pen injector (0.5 mL) system for SC delivery. A 50 mg pen contains 67 mg lyophilized albiglutide and 0.65 mL diluents. It will be injected subcutaneously (SC) in the upper arm. intervention 2: It is provided as a single use fixed dose disposable pen injector (0.5 mL) system for SC delivery. It will be injected subcutaneously (SC) in the upper arm intervention 3: It is provided as a sterile solution containing 250 microgram/mL exenatide. One dose of 10 microgram is equivalent to 0.04 ml. It will be injected subcutaneously (SC) in the upper arm intervention 4: It is provided as a sterile saline. It will be injected subcutaneously (SC) in the upper arm

Protocol documents:
Prot_000.pdf: 
2015N250344_02
CONFIDENTIAL
The GlaxoSmithKline group of companies
201840
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
Study 201840: An Exploratory Randomized, 2-Part, Single-
blind, 2-Period Crossover Study Comparing the Effect of 
Albiglutide with Exenatide on Regional Brain Activity Related 
to Nausea in Healthy Volunteers
Compound Number:
GSK716155
Development Phase:
IV
Effective Date:
28-NOV-2016
Protocol Amendment Number: 1
Author (s):
Copyright 2016 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD


2015N250344_02
CONFIDENTIAL
The GlaxoSmithKline group of companies
201840
2
Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2015N250344_00
2015- MAR-28
Original
2015N250344_01
2016-MAR-30
Republished
2015N250344_02
2016-NOV-28
Amendment No. 1
Changes reflected in Protocol Amendment No. 1 have been included to address the 
following:

Correct inclusion criterion #4 to MSSQ-short and a score of >17 

Correct exclusion criterion #4 to allow MRI safe glasses

Update the exploratory endpoint GMA to adapt to the format delivered by the 
electrogastrographic output used during fMRI

Clarify time period for scheduling screening procedures

Include statement to allow rescreening with approval from Medical Monitor

Clarify time of prohibition of food and drink to align with IRB requirements

Incorporate administrative changes updating primary and secondary medical 
monitor roles


 
PPD
PPD


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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 
GlaxoSmithKline
1250 South 
Collegeville Road, 
Collegeville, PA 
19426,
United States
Secondary 
Medical 
Monitor
GlaxoSmithKline
1250 South 
Collegeville Road, 
Collegeville, PA 
19426,
United States
SAE contact  
information 
GlaxoSmithKline
1250 South 
Collegeville Road, 
Collegeville, PA 
19426,
United States
Sponsor Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate 
Company (or designee). If applicable, the details of the alternative Sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application.   
Regulatory Agency Identifying Number(s): 
IND Number: 065177
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


2015N250344_02
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 2015N250344_02
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


2015N250344_02
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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 201840........................................................9
2.
INTRODUCTION....................................................................................................12
2.1.
Study Rationale ..........................................................................................12
2.2.
Brief Background ........................................................................................14
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................15
4.
STUDY DESIGN ....................................................................................................15
4.1.
Overall Design ............................................................................................15
4.2.
Treatment Arms and Duration.....................................................................18
4.3.
Type and Number of Subjects.....................................................................18
4.4.
Design Justification.....................................................................................18
4.5.
Dose Justification........................................................................................19
4.6.
Benefit:Risk Assessment ............................................................................20
4.6.1.
Risk Assessment .........................................................................21
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............28
5.1.
Inclusion Criteria.........................................................................................28
5.2.
Exclusion Criteria........................................................................................30
5.3.
Screening/Baseline/Run-in Failures............................................................32
5.4.
Withdrawal/Stopping Criteria.......................................................................33
5.4.1.
Liver Chemistry Stopping Criteria ................................................34
5.4.2.
QTc Stopping Criteria ..................................................................34
5.4.3.
Withdrawal Procedures................................................................34
5.5.
Subject and Study Completion....................................................................35
6.
STUDY TREATMENT ............................................................................................35
6.1.
Investigational Product and Other Study Treatment....................................35
6.2.
Treatment Assignment................................................................................36
6.3.
Planned Dose Adjustments.........................................................................36
6.4.
Blinding.......................................................................................................36
6.5.
Packaging and Labeling..............................................................................36
6.6.
Preparation/Handling/Storage/Accountability..............................................36
6.7.
Compliance with Study Treatment Administration.......................................37
6.8.
Treatment of Study Treatment Overdose....................................................38
6.8.1.
Albiglutide....................................................................................38
6.8.2.
Exenatide (Byetta) .......................................................................38
6.9.
Treatment after the End of the Study ..........................................................38
6.10.
Lifestyle and/or Dietary Restrictions............................................................39
6.10.1.
Meals and Dietary Restrictions ....................................................39
6.10.2.
Caffeine, Alcohol, and Tobacco ...................................................39
6.11.
Concomitant Medications and Non-Drug Therapies....................................39
6.11.1.
Prohibited Medications and Non-Drug Therapies.........................39
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................40
7.1.
Time and Events Table...............................................................................41
7.1.1.
Part A and B WITH Off-therapy MRI in Session 1........................41


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7.1.2.
Part A and B WITHOUT Off-therapy MRI in Session 1.................44
7.2.
Screening and Critical Baseline Assessments ............................................47
7.2.1.
Motion Sickness Susceptibility Questionnaire Short 
(MSSQ-Short)..............................................................................47
7.2.2.
Edinburgh Handedness Inventory................................................47
7.2.3.
Mock fMRI ...................................................................................47
7.3.
Endpoints....................................................................................................48
7.3.1.
Magnetic Resonance Imaging......................................................48
7.3.2.
Autonomic Monitoring ..................................................................49
7.3.3.
Nausea severity psychophysics ...................................................49
7.3.4.
Subject assessment of nausea ....................................................50
7.3.5.
Electrogastrogram .......................................................................50
7.4.
Safety .........................................................................................................50
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........51
7.4.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................51
7.4.1.2.
Method of Detecting AEs and SAEs ...........................51
7.4.1.3.
Follow-up of AEs and SAEs........................................52
7.4.1.4.
Adverse Events (AE) of Special Interest.....................52
7.4.1.5.
Regulatory Reporting Requirements for SAEs............52
7.4.2.
Pregnancy ...................................................................................53
7.4.3.
Hypoglycemia ..............................................................................53
7.4.4.
Physical Exams ...........................................................................53
7.4.5.
Discharge ....................................................................................53
7.4.6.
Vital Signs....................................................................................53
7.4.7.
Electrocardiogram (ECG).............................................................54
7.4.8.
Clinical Safety Laboratory Assessments ......................................54
7.5.
Tracking of Albiglutide and Exenatide Pen Injector Failures and 
User Errors .................................................................................................55
8.
DATA MANAGEMENT ...........................................................................................56
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................56
9.1.
Hypotheses.................................................................................................56
9.2.
Sample Size Considerations.......................................................................56
9.2.1.
Sample Size Assumptions & Size Sensitivity ...............................57
9.2.2.
Sample Size Re-estimation or Adjustment...................................57
9.3.
Data Analysis Considerations .....................................................................57
9.3.1.
Analysis Populations....................................................................59
9.3.2.
Part A Data Review .....................................................................59
9.4.
Key Elements of Analysis Plan ...................................................................60
10. STUDY GOVERNANCE CONSIDERATIONS........................................................60
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............60
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................60
10.3.
Quality Control (Study Monitoring) ..............................................................61
10.4.
Quality Assurance.......................................................................................61
10.5.
Study and Site Closure ...............................................................................62
10.6.
Records Retention......................................................................................62
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................63


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8
10.8.
Review Committees....................................................................................63
11. REFERENCES.......................................................................................................64
12. APPENDICES........................................................................................................68
12.1.
Appendix 1 – Abbreviations and Trademarks..............................................68
12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................70
12.3.
Appendix 3: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................72
12.3.1.
Definition of Adverse Events........................................................72
12.3.2.
Definition of Serious Adverse Events...........................................73
12.3.3.
Definition of Cardiovascular Events .............................................74
12.3.4.
Recording of AEs and SAEs ........................................................75
12.3.5.
Evaluating AEs and SAEs............................................................76
12.3.6.
Reporting of SAEs to GSK...........................................................77
12.4.
Appendix 4: Collection of Pregnancy Information........................................79
12.5.
Appendix 5 Edinburgh Handedness Inventory ............................................80
12.6.
Appendix 6 Motion Sickness Susceptibility Questionnaire ..........................81
12.7.
Appendix 7 Visual Analog Scale .................................................................82
12.8.
Appendix 8 Motion Sickness Assessment Questionnaire (MSAQ) ..............83
12.9.
Appendix 9 Country Specific Requirements................................................84
12.10. Appendix 10 Protocol Changes...................................................................85


2015N250344_02
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1.
PROTOCOL SYNOPSIS FOR STUDY 201840
Rationale
Albiglutide is a long-acting glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonist 
(Tmax 3-5 days) that has been developed as a once weekly subcutaneous injection 
treatment of type 2 diabetes mellitus (T2DM) and approved by the US Food and Drug 
Administration (FDA), the European Medicines Agency (EMA) and other regulatory 
agencies.  In clinical trials, nausea is a common side effect of the currently marketed 
GLP-1R agonists.  It is not clear whether nausea associated with GLP-1R agonists is 
caused by stimulation of GLP-1R in the gastrointestinal system, by activation of the 
nausea centers at the central nervous system (CNS) via vagal afferent fibers, by direct 
activation of GLP-1R in the brain following blood–brain barrier penetration, or by 
combination of peripheral and central GLP-1R activation as the most likely mechanisms.  
Although the various GLP-1R agonists share the same receptor and basic mechanisms of 
action, differences in pharmacokinetic and pharmacodynamic characteristics may 
translate into differential clinical effects and tolerability profiles, with differences in the 
incidence of nausea in clinical trials. The dose- and time-dependent efficacy and safety 
effects of albiglutide were evaluated in a phase 2b dose ranging, open-label, active 
reference (exenatide) study.  The study included two albiglutide 50 mg dosing regimens 
(biweekly and monthly).  Exenatide 5 g bid was up-titrated to 10 g after 4 weeks 
consistent with the label to maximize tolerability.  The change in HbA1c after 16 weeks 
was -0.79% and -0.55% for the 50 mg albiglutide biweekly and monthly regimens, 
respectively, and -0.54% for exenatide.  The peak weekly incidence of nausea and/or 
vomiting for 50 mg albiglutide (without up-titration) was 25.7%.  Exenatide 5 g up-
titrated to 10 g resulted in a peak weekly incidence of nausea or vomiting of 29%.  The 
peak weekly incidence of nausea alone was 25.7% for the 50 mg albiglutide regimens 
(without up-titration) and 22.6% for exenatide (up-titrated) after 4 weeks 
[GlaxoSmithKline Document Number ZC2007/00001/00].
To gain insight into the physiologic pathways leading to nausea associated with GLP-1R 
agonists, this study will explore the regional differences in brain activity and connectivity 
in healthy volunteers receiving single doses of albiglutide or exenatide, a short acting 
GLP-1R agonist that has been shown to cross the blood brain barrier in mice after 
peripheral administration [Kastin, 2003].  There are no human data of blood brain barrier 
penetration with albiglutide although limited transfer has been suggested in a murine 
model [GlaxoSmithKline Document Number 2015N232567_00].  For both drugs, brain 
activity will be assessed at the expected time of Cmax using functional magnetic 
resonance imaging (fMRI) to assess changes in blood oxygen level dependent (BOLD) 
signal in the resting-state BOLD, arterial spin labeling (ASL), and magnetic resonance 
spectroscopy (MRS). fMRI will be assessed without drug while nausea is induced 
observing the rotation of vertical stripes in a rotating drum to create the illusion of self 
motion (vection).


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Objective(s)/Endpoint(s)
Objectives
Endpoints
Primary

To explore the effect of single dose 50 mg 
albiglutide compared to single dose 10 g 
exenatide on regional brain activity and 
connectivity associated with nausea in healthy 
volunteers

Resting-state BOLD signal (fMRI)

Regional cerebral blood flow (rCBF) (fMRI-ASL)

Glutamate concentration in nausea-associated 
brain regions (MRS)

GABA concentration in nausea-associated brain 
regions (MRS)
Secondary

To  evaluate autonomic effects of single dose 
50 mg albiglutide compared to single dose 10 
g exenatide

To assess safety and tolerability of single dose 
50 mg albiglutide and single dose 10 g 
exenatide

Heart rate, heart rate variability, respiratory rate, 
ECG intervals, blood pressure, skin 
conductance level

Vital signs, clinical laboratory tests, adverse 
events, Nausea ratings scale, GI-VAS and 
MSAQ
Exploratory

To evaluate gastric myoelectrical activity (GMA)
of single dose 50 mg albiglutide compared to 
single dose 10 g exenatide

GMA: description of frequency region(s)
(Bradygastria, Normal, Tachygastria) 
Overall Design
This is a phase IV, 2-part, 2-period crossover, single dose, randomized, single blind 
(blinded to both the subject and the imaging evaluators analysing the MRI data), placebo-
and active-controlled study in adult healthy volunteers susceptible to motion sickness. 
The study is designed to evaluate if albiglutide and exenatide modulate nausea-related 
brain activity and connectivity as assessed by MRI.  Placebo is used to enable albiglutide 
and exenatide to be dosed at different times relative to MRI due to differences in Tmax, 
while preserving single-blind.
The two parts of the study, Part A and Part B are the same in design, both consisting of a 
screening stage, a dosing/assessment stage, and a follow-up visit.  Part A will test the 
acquisition parameters and scanning paradigms for Part B.  Part A will initially 
randomize 4 subjects.  Based on data review from the initial 4 subjects, an additional 4 
subjects may be randomized for Part A.  Reasons to enroll a second cohort include the 
need to modify acquisition parameters and scanning paradigms.  If the modifications are 
substantial, a second cohort of 4 subjects will be added to Part A before progressing to 
Part B.  Part B will randomize 20 subjects. Data from the Part A will inform progression, 
methods, and analysis plan for Part B.  
After screening, eligible subjects will be randomized to one of the four crossover 
dosing/imaging sequences, shown in study design figure below, which include two 
dosing/imaging sessions and one washout period between them. Subjects will return for 
a follow-up visit post last dosing.


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Session 1 and Session 2 each consist of 2 or 3 single-day out-patient visits according to 
the randomization schedule. There will be a 6-9 week washout period between Session 1 
and Session 2.  

Day 1 (Session 1 or 2 per randomization) for an off-therapy MRI scan, consisting 
of resting-state fMRI, a nauseogenic task fMRI, ASL and MRS, and nausea 
associated assessments,

Day 5 for a single dose of 50 mg albiglutide or albiglutide placebo, and

Day 8 for a single dose of 10 g exenatide or saline injection (exenatide placebo)
followed by a post-dose MRI scan consisting of resting-state fMRI, ASL and 
MRS, and nausea associated assessments.
Note:  Off-therapy MRI and post-dose MRI both include MRS, ASL, and resting state BOLD.  In addition, the Off-
therapy MRI will include a visual nauseogenic task fMRI (See Time and Events tables for full list of assessments during 
scan). *Number of subjects can be increased in Part A based on imaging evaluators’ judgment in consultation with the 
Investigator and Sponsor after data review from 4 subjects
Treatment Arms and Duration
In either Part A or Part B, the total duration of a subject’s participation is approximately 
15-19 weeks, assuming up to 4 weeks for screening, 8 days each for Session 1 and 
Session 2, 6 to 9 weeks for washout, and a 4 weeks post last treatment follow-up.
Subjects will be randomized to one of the following treatment sequences:
Sequence 
Session 1a
Session 2a
1
Off-
therapy 
MRI
50 mg 
albiglutide
placeboc
(post-dose MRI)
placebob
10 g exenatide
(post-dose MRI)
2
50 mg 
albiglutide
placeboc
(post-dose MRI)
Off-therapy MRI
placebob
10 g exenatide
(post-dose MRI)
3
Off-
therapy 
MRI
placebob
10 g exenatide
(post-dose MRI)
50 mg 
albiglutide
placeboc
(post-dose MRI)
4
placebob
10 g exenatide
(post-dose fMRI)
Off-therapy MRI
50 mg 
albiglutide
placeboc
(post-dose MRI)
a.
All administration will be given at fixed dose once daily by subcutaneous injection.
b.
Placebo pen for albiglutide


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c.
Saline injection will be given as placebo for exenatide
All doses will be given in the morning.  Overnight fasting is always required prior to
MRI sessions (see details in Section 6.10.1).  It is recommended that the MRI scan be 
scheduled for early in the morning at the same time of day for each subject for all MRI
scanning sessions.
Type and Number of Subjects
Part A will initially randomize 4 subjects.  Based on data review from the initial 4 
subjects, an additional 4 subjects may be randomized for Part A.  Part B will randomize 
20 subjects.
Analysis
Data from Parts A and B will be pooled, as appropriate, for final analysis. For 
comparisons between albiglutide and exenatide, analysis of variance (ANOVA) will be 
used to analyze quantifiable endpoints with treatment and period as fixed effects, and 
subject as random effect.  Pearson’s and Spearman’s correlation coefficients will be used 
to review relationships between selected quantifiable end points.  A minimum of four 
subjects will be enrolled and analyzed in Part A (Cohort 1).  Based on the results, a 
decision to enroll 4 additional subjects could be taken (Cohort 2).  The criteria for this 
decision will be based on clinical (e.g., safety) and technical judgment after review of the 
neuroimaging data.  Changes in brain activity associated with exenatide or albiglutide in 
imaging modalities tested will inform progression, methods, and analysis plan to Part B.  
For each subject adverse events will be reviewed by the Medical Monitor in both Parts A 
and B prior to the next subject being studied.  Data analysis for Part A and Part B will be 
exploratory.  The analysis plan for Part B will be finalized based on Part A results.  
2.
INTRODUCTION
2.1.
Study Rationale
GLP-1R agonists (i.e., exenatide, liraglutide, albiglutide, and dulaglutide) are approved 
therapies for the treatment of T2DM.  These agents mimic the action of endogenous 
GLP-1 stimulating the release of insulin in a glucose dependent manner and reducing 
glucagon secretion, effectively lowering fasting plasma glucose and hemoglobin A1c.  
The most commonly reported adverse events associated with the GLP-1R agonist class 
are nausea, vomiting and diarrhea.  The rate of GI related events vary among the agents 
[Trujillo, 2015] and the mechanism is not fully understood.  It is not clear whether nausea 
is caused by stimulation of GLP-1R in the gastrointestinal system resulting in delayed 
gastric emptying, or activation of the nausea centers at the central nervous system (CNS)
via vagal afferent fibers, or directly via activation of GLP-1Rs in the brain following 
blood–brain barrier penetration, or a combination of these mechanisms.  GLP-1R 
agonists share the same receptor and basic mechanisms of action, but there are 
differences in their pharmacokinetic and pharmacodynamic characteristics that appear to 
translate into differential tolerability profiles.  This difference appears to be most 
noticeable between long acting and short acting GLP-1 receptor agonists [Østergaard, 
2016].


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Albiglutide, a long-acting GLP-1R agonist, (Tmax ~3-5 days), is an analogue of GLP-1 
generated through genetic fusion of 2 tandem copies of modified human GLP-1 with 97% 
amino acid sequence homology to endogenous human GLP-1 fragment 7-36 linked to 
human albumin (molecular weight: 72,970 Daltons) [TANZEUM (albiglutide) for 
injection, 2015].  There are no human data of blood brain barrier penetration with 
albiglutide although limited drug transfer has been suggested in a murine model 
[GlaxoSmithKline Document Number 2015N232567_00].  Exenatide, a short acting 
GLP-1R agonist (Tmax ~2 h), is a synthetic 39 amino acid peptide amide that shares 53% 
sequence homology with human GLP-1 [Goke, 1993] and with a molecular weight or 
4186.6 Daltons [BYETTA for injection, AstraZeneca 2015].  It has been shown to cross 
the blood brain barrier after peripheral administration in mice [Kastin, 2003].  However, 
there are conflicting data regarding whether circulating exenatide is able to cross the 
blood-brain barrier in humans [Schloegl, 2013].  
The dose- and time-dependent effects on glycemic control and gastrointestinal (GI) 
tolerability of albiglutide were evaluated in a Phase IIb dose ranging, open-label study 
with exenatide as an active reference.  The study included two 50 mg albiglutide 
regimens, biweekly and monthly dosing without up-titration.   Exenatide 5 g bid was 
up- titrated to 10 g after 4 weeks consistent with the label to maximize tolerability.  The 
change in HbA1c after 16 weeks was -0.79% and -0.55% for the 50 mg albiglutide 
biweekly and monthly regimens, respectively, and -0.54% for exenatide.  The peak 
weekly incidence of nausea or vomiting for 50 mg albiglutide (biweekly or monthly 
dosing arms without up-titration) was 25.7%.  Exenatide 5 g up-titrated to 10 g 
reported a peak weekly incidence of nausea or vomiting of 29%.  The peak weekly 
incidence of nausea alone was 25.7% for the 50 mg albiglutide regimens (without up-
titration) and 22.6% for exenatide (up-titrated) after 4 weeks [GlaxoSmithKline 
Document Number ZC2007/00001/00].
There continues to be an interest in the mechanism underlying the GI side effects with 
GLP-1R agonists [Smits, 2015].  To gain insight into the central mechanisms of nausea 
associated with GLP-1R agonists, this study will explore the potential differences at the 
expected time of Cmax between a long-acting (albiglutide) and short-acting (exenatide) 
GLP-1R agonist in brain activation of healthy volunteers, with special interest on regions 
found in previous research to be associated with vection-induced nausea [Napadow, 
2013, Farmer, 2015].  Nausea central mechanisms are complex.  The brain regions 
associated with pharmacologic or vection-induced nausea have been studied and 
demonstrated some overlap in the activated regions as well as some divergences 
[Napadow, 2013; Miller, 1996].  
The drug effects will be studied after a single dose of 50 mg albiglutide and a single dose 
of 10 g exenatide using 1) functional magnetic resonance imaging (fMRI) to assess 
changes in resting-state blood oxygen level dependent (BOLD) signal, 2) arterial spin 
labeling (ASL), and 3) magnetic resonance spectroscopy (MRS).  The highest approved 
doses will be used to maximize the potential to observe nausea and the timing of the MRI 
will overlap with Cmax.  Due to the difference in expected time of Cmax (albiglutide 3-5 
days and exenatide 2 hrs), the timing of MRI and other key study assessments relative to 
dosing are scheduled to coincide with expected Cmax timing.  Placebo is used to 
maintain the single-blind. 


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Observing the rotation of vertical stripes in a rotating drum to create the illusion of self 
motion (vection) is a well characterized stimulus (task) that can serve as a map of the 
central response to nausea [Napadow, 2013; Farmer, 2015].  Each subject will be studied 
under this standardized condition without the study medication to identify the brain 
circuitry associated with motion sickness induced nausea (an established vection task).  
Group analyses will then compare brain outcomes (e.g. connectivity) for motion sickness 
induced nausea versus nausea induced by different drugs to allow the inference of GLP 
1R agonist effects in nausea related brain activation.  The group activation maps 
generated from the vection task scans will also be used to define ROIs to better 
interrogate the drug-induced alterations in other neuroimaging outcomes (i.e. ASL, 
MRS). Each subject will act as their own control in this crossover design.  The resting-
state BOLD and cerebral blood flow (rCBF-ASL) will both be used to provide insight 
into the connectivity of the central nausea response.
By examining BOLD signals at rest and during task, ASL-rCBF changes and assessing in 
vivo metabolic changes through MRS [glutamate and gamma-aminobutyric acid (GABA)
concentrations], the relationship between neurotransmitter concentration and brain 
activation/deactivation in specific brain regions will be explored. 
The information from this study is expected to be of benefit for patients in the future, as 
insights on the mechanisms of nausea associated with GLP 1 receptor agonists are needed 
to design new strategies to minimize the occurrence and impact of these AEs with drugs 
currently in use, and to design new drugs able to avoid these mechanisms.
2.2.
Brief Background
Albiglutide has been approved in the European Union (EU), the US, and other countries 
for the treatment of T2DM as an adjunct to diet and exercise, as monotherapy (EU), or in 
combination with existing therapies.  The efficacy and safety of albiglutide has 
undergone extensive testing both as monotherapy and in combination with oral anti-
diabetic agents [Home, 2015]; [Ahren, 2014],  [Weissman, 2014]; [Leiter, 2014]; [Nauck 
, 2015]. Reductions in HbA1c are typically 0.3-1.0% with 30-mg uptitrated to 50-mg.  In 
clinical trials, albiglutide demonstrated a GI side-effect profile similar to placebo [Ahren, 
2014].  
Exenatide is a 39 amino acid peptide.  Due to its short half-life, exenatide is administered 
twice daily. The incidence of GI effects was reported most frequently at initiation of 
therapy (0-8 weeks) and decreased over time, i.e., nausea may resolve within 6-8 weeks 
in most patients [Heine, 2005]; [Meretto, 2008]; [Buse, 2004; [DeFronzo, 2005]; 
[Kendall, 2005], [Zinman, 2007]; [Nauck, 2007]; [Barnett, 2007].  Exenatide has been 
approved in the US indicated as an adjunct to diet and exercise to improve glycemic 
control in adults with T2DM.


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3.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Primary

To explore the effect of single dose 50 mg 
albiglutide compared to single dose 10 g 
exenatide on regional brain activity and 
connectivity associated with nausea in healthy 
volunteers

Resting-state BOLD signal (fMRI)

Regional cerebral blood flow (rCBF) (fMRI-ASL)

Glutamate concentration in nausea-associated 
brain regions (MRS)

GABA concentration in nausea-associated brain 
regions (MRS)
Secondary

To  evaluate autonomic effects of single dose 
50 mg albiglutide compared to single dose 10 
g exenatide

To assess safety and tolerability of single dose 
50 mg albiglutide and single dose 10 g 
exenatide

Heart rate, heart rate variability, respiratory rate, 
ECG intervals, blood pressure, skin 
conductance level

Vital signs, clinical laboratory tests, adverse 
events, Nausea ratings scale, GI VAS, and 
MSAQ
Exploratory

To evaluate gastric myoelectrical activity (GMA)
of single dose 50 mg albiglutide compared to 
single dose10 g exenatide

GMA: description of frequency region(s)  
(Bradygastria, Normal, Tachygastria) 
4.
STUDY DESIGN
4.1.
Overall Design
This is a phase IV, 2-part, 2-period crossover, single dose, randomized, single blind 
(blinded to both the subject and the imaging evaluators analysing the MRI data), placebo-
and active-controlled study in adult healthy volunteers who are susceptible to motion 
sickness.  The study is designed to evaluate if albiglutide and exenatide modulate nausea-
related brain activity and connectivity as assessed by MRI.  
The two parts of the study, Part A and Part B are the same in design, both consisting of a 
screening stage, a dosing/assessment stage, and a follow-up visit.  Part A will test the 
acquisition parameters and scanning paradigms to agree the experimental process for Part 
B.  Data from Part A will inform progression, methods, and analysis plan for Part B.  
Placebo is used to enable albiglutide and exenatide to be dosed at different times relative 
to MRI due to differences in Tmax, while preserving single-blind.  Part A will initially 
randomize 4 subjects.  Based on data review from the initial 4 subjects, an additional 4 
subjects may be randomized for Part A.  Reasons to enroll a second cohort include the 
need to modify acquisition parameters and scanning paradigms.  If the modifications are 
substantial, a second cohort of 4 subjects will be added to Part A before progressing to 
Part B.  Part B will randomize 20 subjects.   
After screening, eligible subjects will be randomized to one of the four crossover 
dosing/imaging sequences. Each sequence includes three scanning visits: albiglutide plus 
scan, exenatide plus scan and an off-therapy –natural history scan with a 6-9 week 


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washout period between the dosing scans. Subjects will return for a follow-up visit post 
last dosing.  
Note:  Off-therapy MRI and post-dose MRI both include MRS, ASL, and resting state BOLD.  In addition, the Off-
therapy MRI will include a visual nauseogenic task fMRI (See Time and Events tables for full list of assessments during 
scan). *Number of subjects can be increased in Part A based on imaging evaluator judgment in consultation with the 
Investigator and the Sponsor after data review from 4 subjects.
In both Part A and Part B, subjects who meet the eligibility criteria will be randomized in 
a crossover fashion to one of 4 different sequences, each consisting of two 
dosing/imaging sessions (Session 1 and Session 2) separated by a 6-9-week washout 
period (Section 4.2 Table 1). Each subject will undergo a single off-therapy MRI during 
a separate Visit according to the randomization sequence to minimize the total number of 
scans per subject.  The timing or sequencing of the off-therapy MRI will be randomized 
(i.e. Session 1 or Session 2) to account for potential learning effects.  Each subject will 
undergo one off-therapy MRI, one post-dose albiglutide MRI and one post-dose 
exenatide MRI for a total of 3 MRI scans during the study. The visit schedule is set to 
allow the Off-therapy MRI scan visit to occur approximately 7 days prior to the post-dose 
scan within the Session as this is the minimal recommended time between scans.  The 
visit on Day 5 allows the dosing of albiglutide or albiglutide placebo to occur 41 days 
before the post-dose MRI i.e., at estimated Tmax (3-5 days).  Because of the short Tmax (2 
hrs) for exenatide, exenatide or saline placebo is given on the day of the MRI scan (Day 
8).  Therefore, MRI Session 1 and Session 2 each consist of 2 or 3 single-day out-patient 
visits according to the randomization schedule on the following days:

Day 1 (Either Session 1 or 2 per randomization) for an off-therapy MRI scan
consisting of resting-state fMRI, a nauseogenic task fMRI, ASL and MRS and 
nausea associated assessments,

Day 5 for a single dose of 50 mg albiglutide or albiglutide placebo, and

Day 8 for a single dose of 10 g exenatide or saline placebo followed by a post-
dose MRI scan consisting of resting-state fMRI, ASL and MRS, and nausea 
associated assessments.
Subjects will be blindfolded when receiving the study medication injection to maintain 
the single-blind.


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For all MRI sessions, subjects must fast overnight and will be instructed to refrain from 
eating and drinking anything but water starting at approximately 10 pm the night before 
or with in 8 hours of the start of their MRI appointment.
For the off-therapy session, MRI scan and nausea associated assessments will be 
conducted without prior injection (no drug, no placebo).
On post-dose scanning visits, subjects will be offered a meal after the procedure before 
leaving the unit, and capillary glycemia will be assessed.
The Investigator or medically qualified site staff will approve the release of the subject 
from the clinic or will provide treatment as per standard of care as required.
Subjects in either Part A or Part B will have a total of 8 planned visits: Screening, mock 
MRI, Session 1 or 2 off therapy MRI, Session 1 Day 5 dosing, Session 1 Day 8 dosing 
and post-dose MRI, Session 2 Day 5 dosing, Session 2 Day 8 dosing and post-dose MRI, 
and Follow-up (see Section 7.1 Time and Events table).
Part A data review
Safety data from each subject enrolled in Part A will be reviewed in stream by the study 
team, and imaging data will be pre-processed and assessed for quality in stream. Once the 
first 4 subjects enrolled in Part A have completed, data will be reviewed.  The evaluation 
will include safety of exenatide and albiglutide administration at stated doses during 
MRI, fidelity of imaging and physiological (e.g. EGG) measures taken during the 
different MRI scan sessions.  Outcome options may include modifying acquisition 
parameters and the scanning paradigm.  If the modifications are substantial a second 
cohort of 4 subjects may be added to Part A before progressing to Part B.  The decision to 
either modify the imaging paradigms, randomize 4 more subjects for Part A or progress 
to Part B will be made based on the imaging evaluator’s judgment in consultation with 
the PI and Sponsor. A second interim data review will occur only if a decision to 
randomize 4 more for Part A is made after initial review of results from the first 4 
subjects.  This second review, should it occur, will use all data from 8 subjects.  
Adjustments to the study design of Part B (e.g., endpoint evaluation) may be made prior 
to progression to Part B.  
Part A data review is part of the exploratory nature of this study and could result in 
refinement of endpoints and statistical analysis.  These changes will be documented in the 
RAP and will not be considered an amendment to the Protocol.


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4.2.
Treatment Arms and Duration
Table 1
Randomization Sequences for Part A and Part B
Sequence 
Session 1a
Session 2a
1
Off-therapy 
MRI
50 mg 
albiglutide
placeboc
(post-dose MRI
placebob
10 g exenatide
(post-dose MRI
2
50 mg 
albiglutide
placeboc
(post-dose MRI
Off-
therapy 
MRI
placebob
10 g exenatide
(post-dose MRI
3
Off-therapy 
MRI
placebob
10 g exenatide
(post-dose MRI
50 mg 
albiglutide
placeboc
(post-dose MRI
4
placebob
10 g exenatide
(post-dose MRI
Off-
therapy 
MRI
50 mg 
albiglutide
placeboc
(post-dose MRI
a.
All administration will be given at fixed dose once daily by subcutaneous injection.
b.
Placebo pen for albiglutide
c.
Saline injection will be given as placebo for exenatide
All doses will be given in the morning.  For all MRI sessions subjects must fast overnight 
and will be required to refrain from eating and drinking anything but water starting at 
approximately 10 pm the night before or with in 8 hours of the start of their MRI 
appointment (see Section 6.10.1).  It is recommended that the MRI scan be scheduled for 
early in the morning at the same time of day for each subject for all MRI Sessions.
4.3.
Type and Number of Subjects
This study will enrol both male and female healthy volunteers 18-50 years old who are 
right handed and sensitive to motion sickness.  Approximately 60 healthy adults will be 
screened to achieve a total (from Parts A and B) of 24 or 28 randomized subjects.
In Part A, approximately 10 healthy adults will be screened to achieve 4 randomized.  An 
additional 4 subjects (Cohort 2) may be randomized if changes to the acquisition 
parameters and scanning paradigm require confirmation before progressing to Part B.
If subjects prematurely discontinue the study or individual subject technical issues arise, 
subjects may be replaced at the discretion of the Investigator or imaging evaluators in 
consultation with the Sponsor.  Subjects will be assigned to the same treatment sequence 
in order to meet the target number of subjects.
4.4.
Design Justification
This exploratory study is designed to gain insight into a potential central mechanism of 
nausea associated with GLP-1R agonists and to determine if this mechanism can explain 
the clinically observed difference in GI tolerability between albiglutide and exenatide in 
clinical trials.  Healthy volunteers will be enrolled in this study to allow an evaluation 
without the interference of morbidity.  Single dose provides evidence of initial brain 
response to drug stimuli avoiding unnecessary exposure of healthy volunteers to the 
drugs being investigated.  The crossover design is preferred because it allows the subject 
to act as their own control in the assessment of nausea which has a very strong subjective 
component [Levine, 2005].  Including subjects susceptible to motion sickness may 


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improve baseline nauseogenic central response. The assessment of CNS regional 
activation to nauseogenic drugs using fMRI comparing with standardized nauseogenic 
stimulus based on motion sickness is untested.  Therefore, the study will be implemented 
in two parts.  Part A will attempt to characterize brain activation with drug in comparison 
with brain activation with task identifying magnitude of signals, noise, artefacts, 
tolerability and safety.  Data from Part A will be analyzed to identify adjustments needed 
to the imaging technique to progress to the main study, Part B.
fMRI is non-invasive and widely available modality to measure drug effects on brain 
function. [Wang, 2010; Duncan, 2014].  fMRI has been used to characterize nausea 
induced by perception of movement (motion sickness model).  This study will combine 
the knowledge of pharmacological intervention and standardized task to study nausea, 
aiming to provide insight on drug effect in known patterns of brain activation and 
connectivity associated with nausea.  Resting-state fMRI will measure BOLD signal to 
identify neuronal activity and relevant networks with and without study medication.  fMR 
imaging during visual nauseogenic task will assess the percent change in BOLD without 
study medication to identify the activation of brain regions associated with nausea.  In 
addition to the hemodynamic changes as measured by BOLD signal and ASL, the study 
will investigate the correlation of chemical changes in two neurotransmitters, GABA and 
glutamate via MRS.  
This exploratory study will include exenatide, a well-studied short-acting GLP-1 receptor 
agonist, as the active control.  Exenatide has been shown to induce nausea at an incidence 
of 61.7% after a single 10 g dose in healthy volunteers over 24 hrs post-dose [Ellero, 
2010].  Temporal changes in the fMRI BOLD signal were observed after a single 5 g 
dose of exenatide [McKie, 2013].  The timing of the MRI is chosen to coincide with 
albiglutide and active control expected Tmax.  Therefore, the MRI is planned in 3 days 
for albiglutide but conducted after 1 hr for exenatide.  The washout period between 
injections is 6-9 weeks due to the long half-life of albiglutide (T1/2= 5 days).  Six to nine 
weeks will allow the scheduling of the scan visits to be aligned with the same phase of 
the menstrual cycle, when possible, for women of reproductive age.  
This exploratory study includes placebo (albiglutide placebo or saline subcutaneous 
injection) to maintain the subject’s blind and account for potential central activation that 
may result from receiving an injection prior to the MRI scan.
4.5.
Dose Justification
To maximize an observed effect of nausea, the dose of albiglutide in this study is 50 mg, 
the highest approved clinical dose for treatment of adults with T2DM.  To date, single 
doses of up to 100 mg have been safely administered to healthy volunteers in clinical 
trials [IB].    
The highest approved clinical dose of 10 g exenatide will be used as the active control.  
This dose has been safely used in clinical trials in healthy volunteers.  A single 
subcutaneous dose (10 g) of exenatide was administered to 120 healthy subjects.  
Among all subjects, mild to moderate nausea was the most frequent adverse event after 
exenatide dosing. Vomiting was also observed. [Ellero, 2010].  


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4.6.
Benefit:Risk Assessment
Albiglutide has been evaluated in a comprehensive global program of studies.  Sixty-two  
healthy volunteers have been exposed to one or two doses of albiglutide and 190 healthy 
volunteers have been exposed to multiple doses of albiglutide.  In the Phase III program, 
approximately 9000 patient-years of overall exposure to date (including over 4000 
patient-years of exposure to albiglutide), with 8 well-controlled studies (including 1 study 
in subjects with concurrent renal impairment), ranging in duration from 32 weeks to 3 
years and using both 30 mg and 50 mg once-weekly dosing.  This has permitted a robust 
assessment of efficacy, safety, and tolerability in a representative T2DM population.  
Across all studies, albiglutide was generally safe and well-tolerated.
Summaries of findings from both clinical and nonclinical studies conducted with
albiglutide can be found in the Investigator’s Brochure (IB) [GlaxoSmithKline Document 
Number RM2006/00602/08; and Supplement 1 GlaxoSmithKline Document Number 
2015N256204_00] and the product label [TANZEUM (albiglutide) for injection, 2015]. 
The following section outlines the risk assessment and mitigation strategy for this 
protocol.  
There is no expected health benefit to individual healthy volunteers participating in the 
study.  Risks of study medications and procedures are communicated to participating 
subjects via the Informed Consent document.  Additionally investigators are informed 
about risks via the US Prescribing Information and the Investigator Brochure.  The 
information from this study is expected to be of benefit for patients in the future, as 
insights on the mechanisms of nausea associated with GLP 1 receptor agonists are needed 
to design new strategies to minimize the occurrence and impact of these AEs with GLP 1 
receptor agonist drugs currently in use, and to design new drugs able to avoid these 
mechanisms.  


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4.6.1.
Risk Assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product: (albiglutide (GSK716155) and exenatide (Byetta))
Identified Risks
Pancreatitis
Albiglutide:
In clinical trials, acute pancreatitis has been reported in association with albiglutide and other 
GLP-1R agonists (refer to Section 5.4. and Section 6 of the IB).
Albiglutide has not been studied in subjects with a history of pancreatitis to determine whether 
these subjects are at increased risk for pancreatitis.
Exenatide:
Based on post marketing data, exenatide has been associated with acute pancreatitis, including 
fatal and non-fatal hemorrhagic or necrotizing pancreatitis (Byetta, Prescribing Information, 
AstraZeneca Pharmaceuticals LP, 2015).
Exenatide has not been studied in subjects with a history of pancreatitis.
Specific eligibility and withdrawal criteria (see 
Section 5.2 and Section 5.4 )
Risk communication via guidance for 
investigators (albiglutide IB and Prescribing 
Information (PI) and exenatide PI) and 
informed consent form for subjects
Gastrointestinal (GI) events
Albiglutide:
Albiglutide has not been studied in subjects with severe GI disease, including severe 
gastroparesis. Use of albiglutide may be associated with GI AEs (e.g., diarrhea, nausea, and
vomiting) (refer to Section 5.4.and Section 6 of the IB).
Exenatide:
Exenatide has not been studied in patients with severe gastrointestinal disease, including 
gastroparesis. Because exenatide is commonly associated with gastrointestinal adverse 
reactions, including nausea, vomiting and diarrhea, the use of exenatide is not recommended in 
patients with severe gastrointestinal disease (Prescribing Information, AstraZeneca 
Pharmaceuticals LP, 2015)
Specific GI eligibility and withdrawal criteria 
(see Section 5.2 and Section 5.4 )
Risk communication via guidance for 
investigators (albiglutide IB and PI and 
exenatide PI) and informed consent form for 
subjects
Hypoglycemia
Albiglutide
Albiglutide’s mechanism of action is associated with a low intrinsic risk of significant 
hypoglycemia (refer to Section 5.4. and Section 6 of the IB).
Exenatide
The risk of hypoglycemia in this study is 
anticipated to be low as study medications will 
be single-dose and in healthy volunteers.
Subjects will receive a meal after the imaging 
session. Investigator or medically qualifies 


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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
The risk of hypoglycemia is increased when exenatide is used in combination with medications 
known to cause hypoglycemia (e.g., insulin and insulin secretagogue)   (Byetta, Prescribing 
Information, AstraZeneca Pharmaceuticals LP, 2015).
staff will approve the discharge of subjects 
after IP administration and/or imaging session.
Post-scan measure of capillary blood glucose 
and withdrawal criteria (see Section 5.4) 
Risk communication via guidance for 
investigators (albiglutide IB and PI and 
exenatide PI) and informed consent form for 
subjects
Immunogenicity (e.g., clinical 
sequelae of antidrug antibodies,)
Albiglutide 
In the Phase III program, approximately 5% of subjects developed anti-albiglutide antibodies, 
but based on available clinical data, anti-albiglutide antibody formation is not expected to impact 
the overall safety or efficacy of albiglutide treatment (refer to Section 5.6. of the IB).
Although most subjects with injection site reactions were antibody negative (approximately 
85%), injection site reactions were reported more frequently for antibody-positive subjects 
(approximately 41%) than antibody-negative subjects (approximately 14%).
Exenatide:
Patients may develop antibodies to exenatide following treatment   In 1-4% of the subjects 
measured for antibody formation in clinical trials, formation of antibodies was associated with 
attenuated glycemic control. (Byetta, Prescribing Information, AstraZeneca Pharmaceuticals LP, 
2015).
Specific eligibility and withdrawal criteria (see 
Section 5.2 and Section 5.4)
Risk communication via guidance for 
investigators (albiglutide IB and PI and 
exenatide PI) and informed consent form for 
subjects
Hypersensitivity reactions
Albiglutide:
Hypersensitivity reactions are of potential concern with any injected protein and were reported 
rarely in the Phase III program (refer to Section 5.4 and Section 6 of the IB).
Across 8 Phase III clinical trials, a serious hypersensitivity reaction with pruritus, rash, and 
dyspnea occurred in a patient treated with albiglutide.
Exenatide:
There have been postmarketing reports of serious hypersensitivity reactions (e.g. anaphylaxis 
Specific eligibility and withdrawal criteria (see 
Section 5.2 and Section 5.4)
Risk communication via guidance for 
investigators (albiglutide IB and PI and 
exenatide PI) and informed consent form for 
subjects


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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
and angioedema) in patients treated with exenatide (Byetta, Prescribing Information, 
AstraZeneca Pharmaceuticals, 2015).
Injection site reactions
Albiglutide:
Albiglutide is given as an SC injection in the abdomen, thigh, or upper arm and may cause rash, 
erythema, and/or itching at the injection site (IB Section 5.4).
Exenatide: 
Injection-site reactions have been reported during post approval use of exenatide (Byetta, 
Prescribing Information, AstraZeneca Pharmaceuticals LP, 2015).
Risk communication via guidance for 
investigators (albiglutide IB and PI and 
exenatide PI) and informed consent form for 
subjects
Other adverse reactions
Albiglutide: 
In the Phase III program, other adverse reactions (e.g., pneumonia, atrial fibrillation/atrial flutter, 
and appendicitis) were observed with a cumulative incidence of <3% in studies up to 3 years in 
duration (Refer to Section 5.4 and Section 6 of the IB).
Exenatide:
The following additional adverse reactions have been reported during post approval use of 
exenatide: dysgeusia; somnolence, and alopecia
Increases in international normalized ratio with concomitant use of warfarin sometimes 
associated with bleeding.
Renal impairment sometimes requiring hemodialysis and kidney transplant
(Byetta, Prescribing Information, AstraZeneca Pharmaceuticals LP, 2015).
Risk communication via guidance for 
investigators (albiglutide IB Section 6 and 
exenatide PI) and informed consent form for 
subjects
Thyroid C-cell tumors
Albiglutide:
This potential risk arises from nonclinical rodent studies where GLP-1R agonists have been 
associated with increases in serum calcitonin, thyroid C-cell focal hyperplasia, and C-cell 
tumors. The relevance of these observations to humans is uncertain. 
In Phase III studies of up to 3 years in duration, albiglutide was not associated with clinically 
relevant increases in serum calcitonin (refer to Section 5.4 and Section 6 of the IB).
Specific eligibility criteria (see Section 5.2).
Risk communication via guidance for 
investigators (albiglutide IB and PI and 
exenatide PI) and informed consent form for 
subjects.


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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Exenatide
A 104-week carcinogenicity study was conducted in male and female rats at doses of 18, 70 or 
250 mcg/kg/day administrated  by bolus SC injection, benign thyroid C-cell adenomas were 
observed in female rats at all exenatide doses.
Pancreatic cancer 
Theoretical concern for pancreatic cancer associated with GLP-1-based therapies (Dipeptidyl 
peptidase (DPP)-IV inhibitors and GLP-1R agonists) is under evaluation by regulatory 
authorities [Egan, 2014] and has thus far concluded that a causal relationship cannot be 
established currently, but they will continue to investigate as more data become available.
Eligibility and withdrawal criteria (see Section 
5.2 and Section 5.4)


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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Hepatotoxicity
Albiglutide:
One subject in the Phase III clinical program developed a probable drug-induced liver injury with 
an asymptomatic elevation in ALT and total bilirubin, although the case had some atypical 
features and complicating factors (refer to Section 5.4 of the IB).
Specific eligibility and withdrawal criteria (see 
Section 5.2 and Section 5.4)
Drug interactions
Albiglutide:
Albiglutide causes a delay in gastric emptying and thereby has the potential to impact the 
absorption of concomitantly administered oral medications (refer to Section 5.2 and Section 6 of 
the IB).
Drug interaction studies have been conducted with digoxin, warfarin, oral contraceptives, and 
simvastatin, which demonstrated no clinically relevant PK or PD effects.
Exenatide:
The effect of exenatide to slow gastric emptying can reduce the extent and rate of absorption of 
orally administered drugs. Exenatide should be used with caution in patients receiving oral 
medications that have narrow therapeutic index or require rapid gastrointestinal absorption. For 
oral medications that are dependent on threshold concentrations for efficacy, such as 
contraceptives and antibiotics, patients should be advised to take those drugs at least 1 hour 
before exenatide injectionif such drugs are to be administered with food, patients should be 
advised to take them with a meal or snack when exenatide is not administered.  
Drug interaction studies of exenatide have been conducted with acetaminophen, digoxin, 
lovastatin, lisinopril, oral contraceptives, warfarin (Byetta, Prescribing Information, AstraZeneca 
Pharmaceuticals LP, 2015).
This study is being conducted on HV and we 
do not expect they will be taking concomitant 
medications.
Risk communication via guidance for 
investigators (albiglutide IB and PI and 
exenatide PI).
Pregnancy and lactation
Albiglutide:
Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown 
(refer to Section 4.4 and Section 6 of the IB).
It is not known if albiglutide is secreted into human milk during lactation. Given that albiglutide is 
an albumin-based protein therapeutic, it is likely to be present in human milk.
Decreased body weight in offspring was observed in mice treated with albiglutide during 
gestation and lactation.
Specific eligibility and withdrawal criteria (see 
Section 5.2 and Section 5.4)
Only a single dose of albiglutide (50 mg) and 
single dose of exenatide (10 µg) will be
administered per subject.
Risk communication via guidance for 
investigators (albiglutide IB and PI and 
exenatide PI) and informed consent form for 


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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Exenatide:
There are no adequate and well-controlled of exenatide use in pregnant women. In animal 
studies, exenatide caused cleft palate, irregular skeletal ossification and an increased number of 
neonatal deaths.
It is not known whether exenatide is excreted in human milk. However, exenatide is present at 
low concentrations in the milk of lactating mice (Byetta, Prescribing Information, AstraZeneca 
Pharmaceuticals LP, 2015).
subjects
Study Procedures
Nausea and or vomiting during 
visual nauseogenic task
Vection has been found to be a reliable method to study nausea (associated with motion) in 
combination with functional neuroimaging [Farmer, 2015].  Vection induces nausea and can 
possibly induce vomit.
Risk communication via informed consent form 
for subjects.

Subjects will be fasting overnight prior to 
each scanning session. 

Training of subjects on reporting nausea 
during fMRI sessions and nausea rating 
in mock fMRI.  

Instructing subjects how to stop 
nauseogenic stimulation if the subject 
feels the urge to vomit during fMRI 
sessions, in order to avoid vomit

Medical care with trained site staff to treat 
nausea and or vomit and provide medical 
support for emergencies.
MRI
Magnetic resonance imaging (MRI) is a medical imaging procedure that uses strong magnetic 
fields and radio waves to produce cross-sectional images of organs and internal structures in 
the body.  Therefore ferromagnetic interactions with devices, implants or other metallic items 
may occur.  Patients with severe claustrophobia may not be able to tolerate an MRI scan 
Specific eligibility and withdrawal criteria (see 
Section 5.2 and Section 5.4)
Subjects will undergo a “MOCK fMRI’ session 
to evaluate tolerability of placement in scanner


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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Other (Albiglutide/exenatide matching placebos)
Albiglutide matching placebo 
injections
Albiglutide placebo s.c. injections were associated with a clinically relevant rate of injection site 
reactions (Refer to Section 5.4.5.6 of the IB).
Risk communication via informed consent form 
for subjects.
Only a single s.c. dose of placebo will be 
administered per subject.
Saline injections
Exenatide placebo (saline) risk of injection site reaction with saline is unknown, and thought to 
be low risk.  
Risk communication via informed consent form 
for subjects.
Only a single s.c. dose of placebo will be 
administered per subject.


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5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events,
and other pertinent information on the albiglutide or exenatide that may impact subject 
eligibility is provided in the albiglutide IB [GlaxoSmithKline Document Number 
GlaxoSmithKline Document Number RM2006/00602/08; Supplement 1 
GlaxoSmithKline Document Number 2015N256204_00] and the product label 
[TANZEUM (albiglutide) for injection, GlaxoSmithKline 2015] and in the BYETTA
(exenatide) product insert [BYETTA for injection, AstraZeneca 2015].
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential.
5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
AGE
1. Between 18 and 50 years of age inclusive, 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, laboratory tests 
and cardiac monitoring.
3. Pure right-handed based on Edinburgh Handedness Inventory (Appendix 5)
4. Motion Sickness Susceptibility Questionnaire (MSSQ-short) Screening score >17 and 
mock fMRI nausea rating ≥2(See Appendix 6)
5. 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 (in consultation 
with the Medical Monitor, if necessary) decides 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
6. Subject’s body mass index (BMI) is 19 kg/m2 and ≤30kg/m2.


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SEX
7. Male OR
8. Female:  eligible to participate if she is not pregnant (as confirmed by a negative 
human chorionic gonadotrophin (hCG) test at screening and at other timepoints), not 
lactating, and at least one of the following conditions applies:

Non-reproductive potential defined as:
Pre-menopausal females with one of the following:

Documented tubal ligation

Documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion 

Hysterectomy

Documented Bilateral Oophorectomy
Postmenopausal defined as 12 months of spontaneous amenorrhea [in 
questionable cases a blood sample with simultaneous follicle stimulating 
hormone (FSH) and estradiol levels consistent with menopause to confirm 
(refer to laboratory reference ranges for confirmatory levels)].  

Reproductive potential and agrees to follow one of the options listed below in the 
GSK Modified List of Highly Effective Methods for Avoiding Pregnancy in 
Females of Reproductive Potential (FRP) requirements from 30 days prior to the 
first dose of study medication and for the duration of study including the 
completion of the follow-up visit.
GSK Modified List of Highly Effective Methods for Avoiding Pregnancy in 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.

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 sterilisation 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 


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ensuring that subjects understand how to properly use these methods of contraception.
INFORMED CONSENT
9. Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the consent form and in this protocol.
5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL) 
1.
Severe nausea (with or without vomiting) in the last three months or any event of 
unexplained nausea (with or without vomiting) as reported by the subject in the last 
14 days before screening. 
2.
History of vestibular or balance disorders as determined by the Investigator.
3.
History of smoking cigarettes or using tobacco products or any nicotine-containing 
products (including nicotine patches) within 3 months of screening.
4.
Subjects requiring visual correction to participate in visual task that cannot be 
corrected with contact lenses or MRI safe glasses.
5.
ALT >1.5xULN
6.
Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%) 
7. Current or chronic history of liver disease, or known hepatic or biliary abnormalities
8. QTcF > 450 msec, where QTcF is the QT interval corrected for heart rate according 
to Fridericia’s formula
9. Systolic blood pressure is ≥140 mm Hg at Screening; repeat blood pressures should 
be taken if the subject’s systolic blood pressure is ≥140 mm Hg and if the results are 
consistently ≥140 mm Hg, then the subject should be excluded and advised to 
consult a physician
10. Diastolic blood pressure is ≥ 90 mm Hg at Screening; repeat blood pressures should 
be taken if the subject’s diastolic blood pressure is ≥ 90 mm Hg and if the results are 
consistently ≥ 90 mm Hg, then the subject should be excluded and advised to consult 
a physician
11. Mean resting heart rate is >100 beats/min out of 3 consecutive measures taken 10 
minutes apart at Screening
12. History of intestinal obstruction, ileus, gastrointestinal surgery or any other medical 
condition or procedure (e.g., gastrectomy, gastric bypass, lap-band) that may impair 
gastrointestinal motility


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13. History of significant cardiovascular or pulmonary dysfunction prior to screening
14. History of acute or chronic pancreatitis
15. History of severe gastrointestinal disease, including gastroparesis, inflammatory 
bowel disease, Crohn’s disease, or irritable bowel syndrome
16. History of any significant psychiatric illness (e.g., schizophrenia, bipolar affective 
disorder, bulimia or anorexia nervosa) that in the opinion of the Investigator would 
interfere with participation in the study.
17. History and/or evidence of any other CNS disorder that in the opinion of the 
Investigator would interfere with participation in the study (e.g., epilepsy, brain 
tumour, brain surgery). 
18. History of clinically significant CNS trauma (e.g. traumatic brain injury, cerebral 
contusion, spinal cord compression) or seizures.
CONCOMITANT MEDICATIONS
19. Unable to 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, unless in the opinion of the 
Investigator and GSK Medical Monitor the medication will not interfere with the 
study procedures or compromise subject safety.
20. Received within 7 days prior to screening or unable to refrain from taking for the 
duration of each part of study, medications that might 

modify gastric myoelectical activity or gastrointestinal motility as prokinetic 
(e.g., erythromycin), anti-emetic agents (e.g., metoclopromide), narcotic 
analgesics (e.g., morphine), anticholinergic drugs(e.g., domperidone), anti-
acid (e.g., pump inhibitors, H2 blockers) and laxative agents

stimulate or inhibit CNS (e.g., modafinil, dexamphetamine, methylphenidate, 
bromopheniramine, chlorpheniramine, clemastine, diphenhydramine, 
hyrdoxyzine)
RELEVANT HABITS
21. History of regular alcohol consumption within 6 months of the study defined as an 
average weekly intake of >14 drinks for males or >7 drinks for females.  One drink 
is equivalent to 12 g of alcohol: 12 ounces (360 mL) of beer, 5 ounces (150 mL) of 
wine or 1.5 ounces (45 mL) of 80 proof distilled spirits.
22. Is unwilling to abstain from alcohol for 24 hours before dosing and before each MRI
scanning visit
23. Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or 
nicotine-containing products within 3 months prior to screening.
24. Subject has a history of significant weight loss (>5% reported change within 3 
months prior to screening) or is currently attempting weight loss


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CONTRAINDICATIONS 
25. History of hypersensitivity to albiglutide, exenatide, or any product components
26. Personal or family history of multiple endocrine neoplasia type 2, or medullary 
carcinoma of the thyroid
27. Subject has any known condition(s) that may be contraindicated or interfere with the 
completion of MRI scanning such as implants (e.g., pacemaker, cochlear), a medical 
or electronic device (e.g., metallic joint prostheses, metal pins, screws, plates, stents 
or surgical staples), or claustrophobia.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
28. An abnormal (i.e., outside the normal reference range) thyroid function test assessed 
by thyroid stimulating hormone and Free T4 at screening.
29. An abnormal amylase or lipase test at screening
30. A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody 
result within 3 months of screening or at screening
31. A positive pre-study drug/alcohol screen
32. A positive test for human immunodeficiency virus (HIV) antibody
33. Where participation in the study would result in donation of blood or blood products 
in excess of 500 mL within 56-day period
34. Subject has previously received any GLP-1R agonist at any time (e.g., albiglutide, 
exenatide, liraglutide, lixisenatide, dulaglutide) 
35. Subject has previously received DPP-IV inhibitor (sitagliptin, saxagliptin, linagliptin, 
alogliptin) within 30 days from screening
36. 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).
37. Exposure to more than 4 new investigational products within 12 months prior to the 
first dosing day.
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.  Subjects can be rescreened once
if agreed after discussion with the Medical Monitor.  


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5.4.
Withdrawal/Stopping Criteria
A subject may withdraw from the study at any time at his or her own request, or may be 
withdrawn at any time at the discretion of the Investigator or the Sponsor for safety, 
behavioral, or administrative reasons.  Safety data will be reviewed by the Sponsor 
in-stream by single case and collectively.  If a safety concerns arises, a decision about 
continuation of the study will be made. 
Any subject presenting with nausea symptoms on the day of the off-therapy MRI or who 
had vomited within 12 hours prior to the scheduled off-therapy MRI session visit can be 
rescheduled for the visit or withdrawn at the Investigator’s discretion.  
Subjects who cannot complete any of the study procedures may be replaced at the 
discretion of the Investigator after consultation with the Sponsor. 
A subject MUST be withdrawn from the study for the reasons including, but not limited 
to:

Any AE, which, in the opinion of the Investigator precludes effective participation of 
the subject or poses a safety concern
The following AEs will require withdrawal:

Confirmed pancreatitis 

Pancreatic cancer.

Confirmed MTC or other thyroid C-cell neoplasia.  

Liver chemistry abnormalities exceeding the threshold criteria outlined in 
Appendix 2

Severe allergic/hypersensitivity reactions that are considered by the 
Investigator to be attributable to investigational product or without a likely 
alternative aetiology. 

QTc stopping criteria  (see Section 5.4.2)

AE, which, in the opinion of the Investigator, requires withdrawal 

Severe hypoglycemia, which, in the opinion of the Investigator or medical 
monitor, requires withdrawal

Consent withdrawn

Lost to follow-up

Termination of study by sponsor 

Pregnancy

Any untoward findings during the MRI scan that may jeopardize the imaging analysis 
or subject safety.  
A subject MAY be withdrawn from the study for the reasons including, but not limited 
to:


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•
Nausea or vomiting requiring the use of anti-emetics or other interventions
•
Protocol deviation (the Investigator should discuss the protocol deviation with the 
medical monitor before withdrawing a subject)
•
Noncompliance with study visit schedule, as determined by the Investigator in 
consultation with the sponsor
•
Other: the reason must be documented on the electronic Case Report Form 
(eCRF)
5.4.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 2.
5.4.2.
QTc Stopping Criteria
A subject that meets either bulleted criterion below will be withdrawn from the study.

QTcF >500 msec,

Change from baseline: QTcF >60 msec 
5.4.3.
Withdrawal Procedures
Subjects who withdraw from the study before completion of all procedures and 
assessments must complete all assessments for the follow-up visit (see Time and Events 
Table, Section 7.1).
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as 
soon as possible. 

The site must counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or should 
continue in the study. 

In cases where the subject is deemed ‘lost to follow up’, the Investigator or 
designee must make every effort to regain contact with the subject (where 
possible, 3 telephone calls and if necessary a certified letter to the subject’s last 
known mailing address or local equivalent methods). These contact attempts 
should be documented in the subject’s medical record. 


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
Should the subject continue to be unreachable, only then will he/she be considered 
to have withdrawn from the study with a primary reason of “Lost to Follow-up”. 
5.5.
Subject and Study Completion
A completed subject is one who has completed all scheduled visits including follow-up. 
Study Completion is defined as the last subject’s last visit.
6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design. Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments.
Study Treatment
Product name: 
Albiglutide 
(GSK716155)
Matching 
albiglutide 
placebo
Exenatide 
(Byetta)
Exenatide 
placebo (saline)
Formulation 
description:
Single-use fixed
dose, fully 
disposable pen 
injector system 
for SC delivery
Single-use fixed
dose, fully 
disposable pen 
injector system 
for SC delivery
A sterile solution 
containing 250 
g /mL exenatide
Sterile saline
Dosage form:
50 mg pen: 
Contains 67 mg 
lyophilised 
albiglutide and 
0.65 mL diluent 
designed to 
deliver a dose of 
50 mg in a 
volume of 0.5 mL 
after 
reconstitution.
NA
10 g per dose 
in 2.4 mL prefilled 
pen.  One dose 
will be used.
NA
Unit dose 
strength(s)/Dosage 
level(s):
50 mg in 0.5 mL 
injector volume
0.5 mL injector 
volume
10 g per dose in 
2.4 mL prefilled 
pen
0.04 mL
Route of 
Administration
SC
SC
SC
SC


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Study Treatment
Dosing instructions: 
To be 
reconstituted as 
directed in the 
SRM. Inject SC in 
the upper arm.
To be 
reconstituted as 
directed in the 
SRM. Inject SC in 
the upper arm.
Follow new pen 
set-up in 
prescribing 
information. Inject 
SC in the upper 
arm.
Inject SC in the 
upper arm.
6.2.
Treatment Assignment
Randomized treatment assignment will be done via web-based interactive response (IRT) 
system (RAMOS NG).
Subjects will be randomized to one of the 4 crossover dosing/imaging sequences in either 
Part A or Part B.  Once the required number of subjects have been randomized e.g. 
Cohort 1 in Part A, randomization of additional subjects will be put on hold.  
Randomization will resume after decision to either enroll a second Cohort in Part A or 
progress to Part B has been made.
Site personnel will receive a randomization notification indicating the unique subject 
identifier, the treatment sequence, and the date and time of randomization.  Each subject 
number will be a unique identifier.  Once a subject number has been assigned, the 
number will not be reused even if the subject withdraws before receiving any randomized 
study medication.
6.3.
Planned Dose Adjustments
There are no planned dose adjustments in this study.
6.4.
Blinding
This will be a single blind (GSK and site staff are unblinded but subjects and imaging 
evaluators of MRI are blinded) study and the following will apply. Evaluators in this 
study are staff who analyze neuroimaging data.  Every attempt will be made to maintain 
the single-blind.  Exenatide placebo is not available for this study.  An injection of saline 
using the same needle size will be given to the subjects who will be blind-folded at the 
time they receive the injection.
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

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 


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(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 Study Reference Manual (SRM). 

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.  Take adequate precautions to 
avoid direct eye or skin contact and the generation of aerosols or mists. In the case 
of unintentional occupational exposure notify the monitor, Medical Monitor 
and/or GSK study contact.

A Material Safety Data Sheet (MSDS)/equivalent document describing 
occupational hazards and recommended handling precautions either will be 
provided to the Investigator, where this is required by local laws, or is available 
upon request from GSK.
Albiglutide and matching albiglutide placebo
Albiglutide will be reconstituted as directed in the SRM. Albiglutide (and matching 
albiglutide placebo) is provided as a fixed-dose, fully disposable pen injector system for 
delivery of the investigational product (albiglutide or matching albiglutide placebo) from 
a prefilled dual chamber glass cartridge that is an integral part of the pen. It is intended 
for single use. The pen is designed for manual reconstitution of the dose, priming and 
insertion of the pen needle.  Albiglutide s.c. injection or placebo of albiglutide s.c 
injection will be administered by the site staff.
Exenatide and placebo (saline)
A description of the methods and materials required for dosing of exenatide is provided 
in the SRM.
Sterile saline s.c. as the exenatide placebo will be administered and will be detailed in the 
SRM.
Exenatide s.c. injection or placebo of exenatide s.c injection will be administered by the 
site staff.
6.7.
Compliance with Study Treatment Administration
Subjects are dosed at the site, and will receive study treatment directly from the 
Investigator or designee, under medical supervision.  The date and time of each dose 
administered in the clinic will be recorded in the source documents.  The dose of study 
treatment and study subject identification will be confirmed at the time of dosing by a 
member of the study site staff other than the person administering the study treatment.


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6.8.
Treatment of Study Treatment Overdose
In the event of an overdose the Investigator should:
1. contact the Medical Monitor immediately
2. closely monitor the subject for adverse events (AEs)/serious adverse events (SAEs) 
and laboratory abnormalities until albiglutide or exenatide can no longer be detected 
systemically (at least 25 days for albiglutide or 24 hrs for exenatide).
3. document the quantity of the excess dose as well as the duration of the overdosing in 
the eCRF.
6.8.1.
Albiglutide
For this study, once the 50 mg dose of albiglutide is administered, any dose of albiglutide
administered after that will be considered an overdose.
No data are available with regard to albiglutide overdose in humans. The highest
recommended dose of albiglutide is 50 mg once weekly. During clinical studies of
subjects with T2DM, the highest dose of albiglutide administered was 100 mg
subcutaneously every 4 weeks for 12 weeks. This dose was associated with an increased
frequency of nausea, vomiting, and headache. There is no specific antidote for overdose
with albiglutide. In the event of a suspected overdose, the appropriate supportive clinical
care should be instituted, as dictated by the subject’s clinical status. Anticipated
symptoms of an overdose may be severe nausea, vomiting, or headache. A prolonged
period of observation and treatment for these symptoms may be necessary, taking into
account the half-life of albiglutide (5 days).
6.8.2.
Exenatide (Byetta)
Overdosage of exenatide is described in the latest Byetta product insert [BYETTA for 
injection, AstraZeneca 2015] as follows:
“In a clinical study of Byetta, three patients with type 2 diabetes each experienced a 
single overdose of 100 mcg SC (10 times the maximum recommended dose). Effects of 
the overdoses included severe nausea, severe vomiting, and rapidly declining blood 
glucose concentrations. One of the three patients experienced severe hypoglycemia 
requiring parenteral glucose administration. The three patients recovered without 
complication. In the event of overdose, appropriate supportive treatment should be 
initiated according to the patient’s clinical signs and symptoms.”
6.9.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study because only healthy volunteers are eligible for study participation.


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6.10.
Lifestyle and/or Dietary Restrictions
6.10.1.
Meals and Dietary Restrictions
Subjects must refrain from eating and drinking anything but water starting at 
approximately 10 pm the night before or with in 8 hours of the start of their MRI 
appointment until completion of all study assessments on imaging day.  Subjects can 
drink water, but no more than 8 oz at a time and not within 2 hours of the appointment.  
The subjects will be offered a small meal prior to leaving the site after each post-dose 
scanning session visit.
6.10.2.
Caffeine, Alcohol, and Tobacco

Subjects will abstain from ingesting caffeine- or xanthine-containing products (e.g., 
coffee, tea, cola drinks and chocolate) after 10 pm the evening prior to each MRI
session day until completion of all study assessments on imaging day during each 
session. 

Subjects will abstain from alcohol for 24 hours prior to each dosing and each MRI
session day until completion of all study assessments on imaging day during each 
session.

Use of tobacco products is not allowed from 3 months prior to screening until after 
the final follow-up visit.
6.11.
Concomitant Medications and Non-Drug Therapies
6.11.1.
Prohibited Medications and Non-Drug Therapies
Subjects must abstain from taking prescription (excluding oral contraception) or non-
prescription drugs (including vitamins and dietary or herbal supplements) during the 
study, unless in the opinion of the Investigator and Medical Monitor, the medication will 
not interfere with the study.
Any subject requiring medications that 

may produce or reduce nausea or significantly affect gastrointestinal motility such 
as prokinetics (e.g., erythromycin), anti-emetics (e.g., metoclopromide), narcotic 
analgesics (e.g., morphine), anticholinergics (e.g.,domperidone), anti-acids (e.g., 
pump inhibitors, H2 blockers), laxatives and drugs affecting pancreatic or 
hepatobiliary systems, or

may stimulate or inhibit CNS (e.g., modafinil, dexamphetamine, methylphenidate,  
bromopheniramine, chlorpheniramine, clemastine, diphenhydramine, 
hyrdoxyzine)
may be withdrawn from the study at the discretion of the Investigator based on the 
reason (i.e., AE), duration of exposure and relative to the timing of the scans in 
consultation with the Medical Monitor.


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


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7.1.
Time and Events Table
7.1.1.
Part A and B WITH Off-therapy MRI in Session 1
Screen-
ing
Session 1
Wash 
out
Session 2
F/
U
Procedure
Week -4 to -1
Day 1 
Day 51m
Day 81m
Day 41m
Week 13
Pre-MRI
MRI
Post 
MRI
-2 h
-0.5 h
0 h
0.5 h
1 h
Post 
MRI
6-9 weeks
Day 1
-2 h
-0.5 h
0 h
0.5 h
1 h
Post 
MRI
0.5 h
1 h
0.5 h
1 h
0.5 h
1 h
Visit (all out-patient)
1
2
3
4
5
6
7
8
Informed Consent
X
Demographics
X
Medical historya
X
Prior/Concomitant medicationb
X
X
X
X
X
X
X
X
Complete physical
X
Brief physical
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine Drug, Breath Alcohol/Cotinine
X
X
X
X
X
X
X
12-lead ECGe
X
Pregnancy test (WCBP)c
X
X
X
X
HIV, Hep B and Hep C screend
X
Clinical laboratory testse
X
X
TSH, free T4, triglycerides, amylase 
and lipase 
X
Edinburgh Handedness Inventory
X
MSSQ-short
X
Mock fMRIf
X


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Screen-
ing
Session 1
Wash 
out
Session 2
F/
U
Procedure
Week -4 to -1
Day 1 
Day 51m
Day 81m
Day 41m
Week 13
Pre-MRI
MRI
Post 
MRI
-2 h
-0.5 h
0 h
0.5 h
1 h
Post 
MRI
6-9 weeks
Day 1
-2 h
-0.5 h
0 h
0.5 h
1 h
Post 
MRI
0.5 h
1 h
0.5 h
1 h
0.5 h
1 h
Randomization
X
Dosing albiglutide or placebog
X
X
Dosing exenatide or placebog
X
X
MRIh
X
X
X
Autonomic monitoring
X
X
X
Electrogastrogram
X
X
X
VAS
X
X
X
X
X
X
MSAQi
X
X
X
Capillary blood glucose
X
X
Fasting Plasma Glucose
X
X
Snackj
X
X
X
AE assessmentk
<============>
<=======================>
<=========================>
X
Dischargel
X
X
X
a.
Medical history includes alcohol/tobacco/caffeine usage.
b.
Prior-Medications are defined as prescription or over-the counter medications taken within 30 days of Screening.  Record concomitant medications and or changes.
c.
WCBP is women of child-bearing potential. Serum pregnancy test at Screening. Urine pregnancy at other specified time points.
d.
If test otherwise performed within 1 month prior to first dose of study treatment, testing at screening is not required.
e.
See Table 2 for list of laboratory parameters. Unscheduled Safety Labs and ECGs can be done at any time if the Investigator considers the assessments appropriate for 
subject safety.  .
f.
Mock fMRI is performed on a separate day during the screening period.  Scheduling should allow at least 1 week between the Mock fMRI and the next MRI scan.
g.
Albiglutide, exenatide or placebo is administered according to randomization sequence.
h.
All MRI include resting-state fMRI, ASL and MRS. Off-therapy MRI scan includes visual nauseogenic task fMRI and can be initiated once -assessments are completed.  The 
on-therapy scan should be initiated 1 hr ±15min  post the exenatide or exenatide placebo dose.  Pre-scan procedure timings are suggested times to allow completion of 
activities.  Post MRI procedure should be completed at the noted times ±15 min.


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i.
MSAQ is given following the VAS.
j.
Subjects will be offered a snack prior to leaving the site.
k.
Only events related to the Study Procedures meeting the SAE criteria are reported after screening and before dose on Session 1 Day 5.
l.
Subjects should remain at the site for at least 1 hr after completion of MRI.  All procedures and assessments must be complete prior to discharge. The Investigator will 
approve the release of the subject from the clinic, or will provide treatment for the standard of care as required.
m.
The Post-dose MRI MUST be scheduled 41 days after the albiglutide or albiglutide placebo dose. The day of dosing albiglutide is counted as the first day.


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7.1.2.
Part A and B WITHOUT Off-therapy MRI in Session 1
Screen-
ing
Session 1
Wash
out
Session 2
F/U
Procedure
Week -4 to -1
Day 1
Day 41m
6-9 weeks
Day 1 
Day 51m
Day 81m
Week 13
-2 h
-0.5 h
0 h
0.5 h
1 h
Post 
MRI
Pre-MRI
MRI
Post 
MRI
-2 h
-0.5 h
0 h
0.5 h
1 h
Post 
MRI
0.5 h
1 h
0.5 h
1 h
0.5 h
1 h
Visit (all out-patient)
1
2
3
4
5
6
7
8
Informed Consent
X
Demographics
X
Medical historya
X
Prior/Concomitant medicationb
X
X
X
X
X
X
X
X
Complete physical
X
Brief physical
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine Drug, Breath Alcohol/Cotinine 
X
X
X
X
X
X
X
12-lead ECGe
X
Serum or urine pregnancy test (WCBPc)
X
X
X
X
HIV, Hep B and Hep C screend
X
Clinical laboratory testse
X
X
TSH, triglycerides, amylase and lipase 
X
Edinburgh Handedness Inventory
X
MSSQ-short
X
Mock fMRIf
X
Randomization
X


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Screen-
ing
Session 1
Wash
out
Session 2
F/U
Procedure
Week -4 to -1
Day 1
Day 41m
6-9 weeks
Day 1 
Day 51m
Day 81m
Week 13
-2 h
-0.5 h
0 h
0.5 h
1 h
Post 
MRI
Pre-MRI
MRI
Post 
MRI
-2 h
-0.5 h
0 h
0.5 h
1 h
Post 
MRI
0.5 h
1 h
0.5 h
1 h
0.5 h
1 h
Visit (all out-patient)
1
2
3
4
5
6
7
8
Dosing albiglutide or placebog
X
X
Dosing exenatide or placebog
X
X
MRIh
X
X
X
Autonomic monitoring
X
X
X
Electrogastogram
X
X
X
VAS
X
X
X
X
X
X
MSAQii
X
X
X
Capillary blood glucose
X
X
Fasting Plasma Glucose
X
X
Snackj
X
X
X
AE assessmentk
X
<==================>
<==========>
X
<=====================>
X
Dischargel
X
X
X
a.
Medical history includes alcohol/tobacco/caffeine usage.
b.
Prior-Medications are defined as prescription or over-the counter medications taken within 30 days of Screening.  Record concomitant medications and or changes
c.
WCBP is women of child-bearing potential. Serum pregnancy test at Screening.  Urine pregnancy at other specified time points
d.
If test otherwise performed within 1 month prior to first dose of study treatment, testing at screening is not required
e.
See Table 2 for list of laboratory parameters.  Unscheduled Safety Labs and ECGs can be done at any time if the Investigator considers the assessments appropriate for 
subject safety. The blood sample Session 2 Day 5 must be collected prior to dosing.
f.
Mock fMRI session is performed on a separate day during the screening period.  Scheduling should allow at least 1 week between the Mock fMRI and the next MRI scan.
g.
Albiglutide, exenatide or placebo is administered according to randomization sequence.


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h.
All MRI include resting-state fMRI, ASL and MRS. Off-therapy MRI scan includes visual nauseogenic task fMRI and can be initiated once -assessments are completed.  The 
on-therapy scan should be initiated 1 hr ±15min post the exenatide or exenatide placebo dose.  Pre-scan procedure timings are suggested times to allow completion of 
activities.  Post MRI procedure should be completed at the noted times ±15 min.
i.
MSAQ is given following the VAS.
j.
Subjects will be offered a snack prior to leaving the site.
k.
Only events related to the Study Procedures meeting the SAE criteria are to be reported after screening and before dose on Session 1 Day 1.
l.
Subjects should remain at the site for at least 1 hr after completion of MRI.  All procedures and assessments must be complete prior to discharge. The Investigator will 
approve the release of the subject from the clinic, or will provide treatment for the standard of care as required.
m.
The Post-dose MRI MUST be scheduled 41 days after the albiglutide or albiglutide placebo dose. The day of dosing albiglutide is counted as the first day.


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7.2.
Screening and Critical Baseline Assessments
The following demographic parameters will be captured: year of birth, gender, race and 
ethnicity.
Medical/medication/family history will be assessed as related to the inclusion/exclusion 
criteria listed in Section 5.  
7.2.1.
Motion Sickness Susceptibility Questionnaire Short (MSSQ-
Short)
The MSSQ-Short will be completed by each potential subject at the screening visit.  The 
questionnaire collects brief background information and consists of two sections 
[Appendix 6].  Section A collects the subject’s childhood experience (before age 12) with 
travel and motion sickness.  Section B collects the subjects experience of travel and 
motion sickness over the last 10 years [Golding, 2006].
7.2.2.
Edinburgh Handedness Inventory
The Edinburgh Handedness Inventory consists of 10 items summarized as follows: (1) 
writing, (2) drawing, (3) throwing, (4) scissors, (5) toothbrush, (6) knife, without fork, (7) 
spoon, (8) broom (upper hand), (9) striking a match (match), and (10) opening box (lid).
Respondents are required to indicate their hand preference and strength of preference
[Appendix 5].
7.2.3.
Mock fMRI
Subjects will be oriented to the visual motion sickness stimulus, while inside of a mock 
fMRI scanner (a plywood constructed replica). The subject will practice rating nausea 
severity and get comfortable with the scale, as well as their own limits with respect to 
severe nausea on the verge of vomiting.  This will improve safety when they are then 
experiencing similar sensations inside the fMRI magnet. 
The visual motion stimulation will be projected onto a screen with a field-of-view 
approximately 150°.  This large unimpeded field of view is critical for inducing motion 
sickness with visual stimuli.  A concave screen will be positioned 10 cm in front of their 
eyes, onto which visual stimuli will be projected, from behind.  The nauseogenic stimulus 
will be a standardized visual presentation of alternating black (1.2 cm, 6.9° viewing 
angle) and white (1.85 cm, 10.6° viewing angle) stripes with left-to-right motion at 
~62.5°/s.  This left-to-right horizontal translation induces a vection sensation wherein 
subjects experience a false sensation of translating to the left.  Such images simulate the 
visual input provided by a rotating optokinetic drum, commonly used to induce vection 
(illusory self- motion) and nausea.  Symptoms severity will be rated as described below. 
Following the procedure, study personnel will debrief the subjects to ensure that they 
understand the rating levels and procedure.
0= no nausea, 1= minimal nausea, 2= mild nausea, 3= moderate nausea, 4= severe nausea


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7.3.
Endpoints
7.3.1.
Magnetic Resonance Imaging
All MRI assessments will be acquired on a Siemens 3T system located at the Martinos 
Center for Biomedical Imaging.  All Martinos scanners undergo quality assurance (QA) 
assessments every morning to ensure that fMRI signal drifts and variances are within 
limits and that signal spiking is not occurring.
Imaging scans will be reviewed by trained technologists and abnormal findings will be 
consulted with a radiologist.  Subjects will be advised to seek consultation based on the 
radiologist’s opinion.
Structural MRI:
Structural MRI data will be collected prior to all fMRI and MRS data collection using a 
T1-weighted magnetization-prepared rapid gradient-echo (MP-RAGE) pulse sequence.  
These data will be used to help align functional data to the MNI space, while exploratory 
analysis of gray matter volume and cortical thickness can be related to functional brain 
response and symptom severity.
Functional MRI
All fMRI analyses will use a combination of tools, previously validated, and used in the 
Napadow Lab for the analysis of similar data.  Tool packages will include: FSL (FMRIB 
Software Library; http://www.fsl.fmrib.ox.ac.uk/fsl/), AFNI (Analysis of Functional 
NeuroImages; http://afni.nimh.nih.gov/afni), and FreeSurfer 
(http://surfer.nmr.mgh.harvard.edu/).
BOLD fMRI Resting
Resting functional connectivity will be assessed using data acquired in the first 6 minutes 
of the vection task scan run , i.e. when the subject is resting, before any motion sickness 
provocation during the Off-therapy scan.  For on-drug MRI visits, a separate 6-minute 
BOLD fMRI resting state scan will be performed, and subjects will verbally rate (0-100 
NRS) their nausea intensity before and after this scan. Data will be analysed using 
validated independent component analysis (ICA) methods and seed voxel connectivity 
methods using functional localizer seeds obtained from the results of the motion sickness 
fMRI analyses.
BOLD fMRI Visual Nauseogenic Task 
The 3T MRI will include a specially configured, open-design multichannel head coil.  
For the visual nauseogenic task BOLD fMRI scan run, subjects will lay supine inside the 
MRI scanner while visual stimuli are projected onto a screen encompassing their entire 
field of view.  Subjects will be instructed to remain as still as possible, focus directly on 
the stimulus, and maintain as constant a rate of breathing as possible (i.e. not perform any 
respiratory maneuvers to decrease nausea).  Subjects will be instructed to keep their eyes 
open and just let the nausea sensation evolve.  The fMRI scan run will consist of a visual 


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fixation baseline for 6 min, followed by a visual presentation of alternating black/white 
stripes translating to the subjects’ right field of view (gray background).  Nausea 
produced by the visual vection signal will be rated using a button box.   Once subjects 
rate a nausea level 4 (severe nausea) or 20 mins has passed, the stripes stimulation will be 
terminated and subjects will cross-hair fixate again for 6 min.
Arterial spin labeling (ASL)
ASL will be used to assess resting regional Cerebral Blood Flow (rCBF).  The pseudo-
Continuous ASL (pCASL) method will be used, which allows for adequate signal with 
whole brain coverage.  rCBF maps will be contrasted, comparing flow maps under 
different drug conditions, and in comparison with a non-drug resting state (data collected 
during the off-therapy MRI visit, before the vection nausea task).  Serial tagged and un-
tagged image volumes will be subtracted, and the difference metric will be used in 
conjunction with an assumed T1 of gray matter tissue, partition coefficient, efficiency, 
and established equations for estimating rCBF. 
Magnetic Resonance Spectroscopy (MRS) (GABA and glutamate)
GABA and glutamate magnetic resonance spectroscopy will be measured at rest. It will 
be measured prior to the motion sickness fMRI task run during the off-therapy scan.  A 
newly developed motion-corrected 3D MRS sequence that reliably edits GABA and 
glutamate will be used for non-invasive brain mapping of neurotransmitter concentration.  
The field of view will cover key nausea processing areas such as insula, cingulate, and 
basal ganglia.  The study will use a newly developed motion-corrected 3D magnetic 
resonance spectroscopy imaging (MRSI) sequence that, reliably evaluates 
glutamate/glutamine (GLX) concentration (FOV = 200x200x200, matrix=10x10x10, 
voxel 8 cc).  Spectra will be fitted with LCModel and metabolic maps will be obtained 
from the fitted signals.  The neurochemical maps will be transformed from anatomical 
subject space to MNI 152 standard space using non-linear registration (FNIRT, FSL).  A 
novel group level analysis of spectroscopic data will be performed using a mixed effects 
model in the MNI152 standard space to detect significant regional changes of 
neurotransmitter levels under different drug and non-drug conditions.  
7.3.2.
Autonomic Monitoring
All peripheral autonomic physiological signals will be collected at 400 Hz using Chart 
Data Acquisition Software (ADInstruments) on a laptop equipped with a 16-channel 
Powerlab DAQ System (ADInstruments).  Skin conductance level will be measured with 
MRI-compatible bipolar Ag/AgCl finger electrodes (MLT117F, ADInstruments) placed 
on the palmar aspect of the second and fourth fingers of the nondominant (left) hand, 
prior to the MRI session. Subjects’ ECG signal will be collected with an MRI-compatible 
Patient Monitoring system (Biopac 150, Biopac Systems Inc.) through MRI-compatible 
electrodes (VerMed, Bellows Falls) placed on the chest.
7.3.3.
Nausea severity psychophysics
Nausea ratings will be collected during motion sickness provocation using a 0-4 
numerical rating scale (NRS).  One member of the team will instruct the subject on how 


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to use the button box to rate his/her nausea sensation.  For the mock scanner training, 
once every 15 seconds, a sensory cue will be applied, reminding the subject to rate their 
nausea severity.  During the actual fMRI experiment, subjects will rate nausea severity 
using the button box, as they experience it, and ratings increase events will be used to 
guide data analysis.  We will ask the subject to press buttons on a MRI compatible 
button-box to rate nausea using the following scale:

Press the thumb button if you do not feel any nausea;

Button 1 (index finger) if minimal nausea is experienced;

Button 2 (middle finger) if mild nausea is experienced; 

Button 3 (ring finger) if moderate nausea is experienced;

Button 4 (pinky finger) if severe nausea is experienced;
The subject will be instructed that, when button 4 is pressed, signifying that severe 
nausea is experienced, the nauseating stimulus (moving lines) will be stopped. If, due to 
any reason, the subject wants to stop the experiment before, he/she can squeeze the 
squeeze bulb, the experiment will stop and the subject will be taken out of the mock or 
real fMRI magnet. 
7.3.4.
Subject assessment of nausea
Motion Sickness Assessment Questionnaire (MSAQ)
Following the visual nauseogenic task, subjects will complete the Motion Sickness 
Assessment Questionnaire (MSAQ) (Appendix 8), which quantifies the severity of 
different dimensions of nausea induced by motion sickness [Gianaros, 2001]
Visual Analogue Scale (VAS)
Each subject will complete a VAS to record their perception of stomach fullness, hunger, 
nausea, bloating and abdominal pain.  The VAS (Appendix 7) will be represented by 
lines, 100mm in length, anchored with words describing the most negative rating on the 
left and the most positive rating on the right.  The site will be provided with paper copies 
of the scale to administer at each MRI session. Subjects will complete a VAS form 
approximately 30 min before and approximately 30 min after each imaging scan session.  
7.3.5.
Electrogastrogram
Electrogastrography (EGG) is a technique for recording gastric myoelectrical activity 
using cutaneous electrodes (non-invasively) by placing three EKG-type electrodes in the 
epigastrium in standard positions. Signals will be obtained with appropriate amplification 
and filtering during the MRI scans.   The EGG summates the ongoing gastric slow wave 
and plateau potential activity of the stomach.  Collection of EGG during the MRI is 
experimental and may not progress if deemed uninterpretable.
7.4.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1).  Additional time points for safety tests such as vital signs, physical exams 


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and laboratory safety tests may be added during the course of the study based on newly 
available data to ensure appropriate safety monitoring.
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 3 (Section 12.3).
The Investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 
Nausea during the visual nauseogenic task is expected and will not be considered an AE, 
and will be reported as an endpoint.  Any other untoward medical events occurring 
during the visual nauseogenic task should be reported as an AE/SAE if meets the 
definition as noted in Appendix 3 (Section 12.3). 
7.4.1.1.
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, at the timepoints specified in the Time and Events Table (Section 7.1).

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the CRF.

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Appendix 3. 

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.
7.4.1.2.
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?” 


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
“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?” 
7.4.1.3.
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 and Section 7.4.1.4), 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 (Section 12.3).
7.4.1.4.
Adverse Events (AE) of Special Interest
In the Phase IV clinical development program, AEs of special interest included several 
areas of safety related concern for the T2DM population, particularly for a GLP-1R 
agonist such as albiglutide.  Specific eCRF pages will be used to capture additional 
details for the following AEs of special interest: 

Hypoglycemic events 

Liver events 

CV events 

Injection site reactions 

Potential systemic allergic reactions 

Pancreatitis 

Medullary thyroid cancer 

Pneumonia 

Atrial fibrillation/atrial flutter
The following additional AEs of special interest will be captured in the AE eCRF pages:

GI events

Malignant neoplasms, including pancreatic cancers

Appendicitis
7.4.1.5.
Regulatory Reporting Requirements for SAEs
Prompt notification by the Investigator to GSK of SAEs related to study treatment (even 
for non- interventional post-marketing studies) is essential so that legal obligations and 
ethical responsibilities towards the safety of subjects and the safety of a product under 
clinical investigation are met. 
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and Investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.


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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.
7.4.2.
Pregnancy

Details of all pregnancies in female subjects will be collected after the start of 
dosing and until the follow-up visit.

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 4.
7.4.3.
Hypoglycemia
Although not anticipated in the healthy volunteer population, hypoglycemia is a risk with 
treatment of a GLP-1 receptor agonist.  Capillary blood glucose measures will be taken 
after each post dose MRI.  A capillary blood glucose measure should be taken any time a 
subjects present with signs and or symptoms of hypoglycaemia and the subject treated 
with dietary therapy (i.e. a small meal), a carbohydrate load (e.g., glucose tables or 
orange juice), or any other required treatment at the discretion of the Investigator.  
Subjects will be asked to eat a snack after the investigational drug administration 
sessions. 
7.4.4.
Physical Exams

A complete physical examination will include, at a minimum, assessment of the 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems and skin. 
Height and weight will also be measured and recorded. 

A brief physical examination will include, at a minimum assessments of the skin 
(including injection site), lungs, cardiovascular system, and abdomen (liver and 
spleen).

Height weight and body mass index will be measured and recorded at screening 
only. Height and weight should be measured with the subject in indoor daytime 
clothing with no shoes.
7.4.5.
Discharge
Subjects will remain at the clinic for at least 1.0 hours after the dose of medication or 
completion of scan whichever is later.  All procedures and assessments must be complete 
before the subject is released.  The Investigator or medically qualified site staff will 
approve the release of the subject from the clinic or will provide treatment as per standard 
of care as required.
7.4.6.
Vital Signs

Vital signs will be measured in semi-supine position after 5 minutes rest and will 
include systolic and diastolic blood pressure and pulse rate.


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
For all vital signs, single measurement will be performed at time points specified 
in Time and Events Tables (Section 7.1).

Vital sign measurements can be repeated once if clinically significant changes or 
machine error occur. Out of range blood pressure and heart rates will be repeated 
at the Investigator’s discretion. 
7.4.7.
Electrocardiogram (ECG)

Single 12-lead ECGs will be obtained at screening using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and QTc 
intervals.  Refer to Section 5.4.2 for QTc withdrawal criteria and additional QTc 
readings that may be necessary.
7.4.8.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 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 CRF.
Refer to the SRM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws.
All study-required laboratory assessments will be performed by a central laboratory,
entered into the eCRF and sent to GSK via lab data transfer.
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


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Laboratory 
Assessments
Parameters
Clinical 
Chemistry 1
BUN
Potassium
AST (SGOT)
Total and direct 
bilirubin
Creatinine

eGRF 
(MDRD)
Sodium
ALT (SGPT)
Total Protein
Glucose 
Calcium
Alkaline phosphatise
Albumin
Glycemic 
parameters
Capillary blood glucose (for patient safety only)
Fasting plasma glucose
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood and ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Other 
Screening 
Tests

TSH, free T4, triglycerides, amylase and lipase

HIV, Hepatitis B and C Screen

Alcohol/Cotinine and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines)

Serum  or urine hCG Pregnancy test (as needed for women of child bearing 
potential) 2

FSH and estradiol-for women< 60 yrs and  <12 months postmenarchal and do not 
agree to effective method of birth control
NOTES :
1.
Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up 
Assessments after liver stopping or monitoring event are given in Section 5.4.1 and 
Appendix 2.
2.
Local urine testing will be standard for the protocol unless serum testing is required 
by local regulation or ethics committee.
All laboratory tests with values that are considered clinically significantly abnormal 
during participation in the study or within 25 days after the last dose of study treatment 
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.
7.5.
Tracking of Albiglutide and Exenatide Pen Injector Failures 
and User Errors
All albiglutide pen injector failures and user errors must be detected, documented, and 
reported by the Investigator throughout the study. Detailed information on albiglutide pen 
injector failures and user errors will be collected on the Albiglutide Injector Pen and 
Reporting Form.


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For both, albiglutide and exenatide pen injector failures and user errors associated with or 
resulting in events fulfilling the definition of an AE or SAE will follow the processes 
outlined in Section 7.4.1.
8.
DATA MANAGEMENT
For this study, subject data will be entered into GSK defined electronic CRFs, transmitted 
electronically to GSK or designee, and combined with data provided from other sources 
in a validated data system.
Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., removing 
errors and inconsistencies in the data.
Adverse events terms and concomitant medications will be coded using MedDRA 
(Medical Dictionary for Regulatory Activities) and an internal validated medication 
dictionary, GSKDrug.
CRFs (including queries and audit trails) will be retained by GSK, and copies will be sent 
to the Investigator to maintain as the Investigator copy. Subject initials will not be 
collected or transmitted to GSK according to GSK policy.
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
The study has 2 parts – Part A and Part B.  After Part A, a review of safety data as well as
fidelity of imaging and physiological (e.g. EGG) measures taken during the different 
MRI scan sessions will be performed.  Part A data review is part of the exploratory nature 
of this study and could result in refinement of endpoints and statistical analysis.  A 
decision to enroll 4 additional subjects, and/or adjust Part B design (e.g., change in MRS 
pulse sequence), will be made based on imaging evaluators’ judgment in consultation 
with the PI and Sponsor.
9.1.
Hypotheses
No primary hypothesis will be pre-specified due to the exploratory nature of the study.  
9.2.
Sample Size Considerations
A total from Parts A and B of 24 or 28 randomized subjects with valid MRI data that 
could be pooled for analysis will be targeted for the entire study.  Part A will initially 
randomize 4 subjects.  Based on data review from the initial 4 subjects, additional 4 
subjects may be randomized for Part A.  The decision to enroll another Cohort of 4 
subjects in Part A will be based on imaging evaluators’ judgment in consultation with the 
PI and Sponsor.    
Part B will randomize 20 subjects.
Subjects will be randomized according to treatment sequences described in Section 4.2.  


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9.2.1.
Sample Size Assumptions & Size Sensitivity
Accurate prospective determination of experimental power and sample size is difficult for 
fMRI experiments because many idiosyncratic factors (e.g. scanner sequence, brain 
region under investigation, task paradigm) can have a large influence on the effective 
signal-to-noise.  In addition, there is little similar published work available to act as a 
guide.  A target sample size in the range 12 to 24 is recommended by Desmond and 
Glover [Desmond, 2002] for fMRI experiments; though it should be noted that advances 
in acquisition technology and analysis techniques in the last thirteen years have 
significantly increased signal-to-noise, meaning the upper bound of the estimate (N≈24) 
may now be somewhat inflated. Importantly, the sample size chosen for this study is 
consistent with the sample size previously published by the Martinos Center group in 
their nausea neuroimaging study [Napadow, 2013]. 
9.2.2.
Sample Size Re-estimation or Adjustment
If subjects prematurely discontinue the study or individual subject technical issues arise, 
subjects will be replaced at the discretion of the imaging evaluators’ judgment in 
consultation with the Investigator and Sponsor.  Subjects will be assigned to the same 
treatment sequence in order to meet the target number of subjects.  Within each phase or 
part, the randomization of subjects should first be completed before subjects are replaced.  
Data from subjects who are replaced will be used only for safety analysis.
Issues that may lead to exclusion of data from analysis could include excessive head-
motion by the subject during a scan, identifiable artifacts on the brain images arising 
from problems with the scanner, and issues with the simultaneous physiological 
recordings (poor signals due to interference, or sensors moving out of position during a 
scan).  Data quality will be iteratively assessed by technical imaging site staff throughout 
the study in a blinded manner.  If some subjects’ data is sub-standard and therefore needs 
to be excluded, additional recruiting and testing may be conducted.  Data quality findings 
will be documented.
9.3.
Data Analysis Considerations
There will be 4 fMRI and 3 MRS data points as shown in the table below:
Treatment Period a
Albiglutide
Exenatide
Day Relative to Period 
Start b
1
Off-
therapy 
1
Off-
therapy
8
At T-max
8
At T-max
Visual Nauseogenic Task
No
Yes
No
No
MRI Data Point (DP) 
DP1
DP2
DP3
DP4


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Treatment Period a
Albiglutide
Exenatide
Resting State BOLD 
fMRI



Nauseogenic task based 
BOLD fMRI

ASL



MRS



a The order of the treatment periods will be randomized.
b The day is relative to start of the Treatment Period.
For each subject, the Off-therapy Day 1 assessment(s) (DP1 and/or DP2 in table above) 
during the dosing/imaging sessions will serve as the baseline fMRI assessment.  
Nauseogenic task BOLD signal (DP2,), will be assessed only during the off-therapy 
fMRI session.  For the BOLD endpoint, the main contrasts of interest are the differences 
in the connectivity between albiglutide and off-therapy (DP3-DP2), between Exenatide 
and off-therapy (DP4-DP2), and between Albiglutide and Exenatide (DP3-DP4).
For resting state analysis rCBF ASL endpoints, the contrasts of interest are the 
differences DP3-DP1, DP4-DP1, and DP4-DP3.  Similarly, for GABA and Glutamate 
concentrations, the main contrasts of interest are the differences DP3-DP1, DP4-DP1, and 
DP4-DP3. 
The vection-induced nausea will provide a reference to regions of nausea associated brain 
activity. A group map will be calculated as in the previous Martinos Center study, and 
regions of interest (ROI) will be defined from the group map.  These ROIs will then be 
used to perform masked comparison analyses for rCBF and MRS (where possible) data 
between the albiglutide vs exanatide and drug vs no-drug conditions.  Such targeted 
analyses will allow for greater power than whole brain analyses which will need to be 
more stringently corrected for multiple comparisons.   
There will be no imputation for missing data. Subjects who only partially complete the 
study may be included in some of the analyses where appropriate, depending on which 
data are available and which are missing.
Summary statistics (including number of subjects, mean, median, min, max, SD, SE) will 
be reported for continuous variables.  The frequency and percentage will be used to 
summarize categorical variables.  
Functional MRI Data
Pre-processing steps will include motion correction carried out by sequentially aligning 
each time-point across the series with a single target scan, using a rigid-body registration 
algorithm.  Further pre-processing steps may also include slice timing corrections and 


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spatial smoothing.  To ensure each subject’s parameter estimate maps (e.g. following 
general linear modeling, see below) lie in a common anatomical space, an initial affine 
registration will be applied from the native low-resolution Echo Planar Imaging (EPI)
data to the respective high resolution T1-weighted scan or a mean image of EPI scans.  
These spatially normalized subject-specific statistics will then undergo a further 
alignment onto a common atlas space such as the Montreal Neurological Institute (MNI) 
coordinate system.
Following pre-processing, several sets of statistical analyses will then be conducted, with 
standard methods (e.g. application of the General Linear Model, Independent 
Components Analysis) with the addition of sophisticated noise-modeling methods, 
derived from the acquired physiological data (respiratory/cardiac).  Data will be 
examined at both a whole-brain and regions of interest (ROI) level, with ROIs defined by 
intersecting anatomical label masks (based on standard atlases such as the well known 
Harvard-Oxford Atlas) with clusters derived from the group data. Other exploratory 
methods, such as Multi-Voxel Pattern Analysis (MVPA) may also be employed, as 
appropriate.  Analyses will take advantage of individual subject nausea rating responses 
during stimulation, for both stimulus-based (distinct windows), and percept based 
(increasing nausea transitions) analyses, as in previous publications [Napadow, 2013].  
Results from the off-therapy motion sickness task fMRI scan will be used to define ROI’s 
of nausea-related brain circuitry in the same individuals who will also experience on-
therapy nausea MRI scanning.  These ROI’s will be used to guide analysis of the fMRI, 
ASL, and MRS data from both on-therapy and off-therapy scan sessions. Group analyses 
will include both the entire on-drug group and, in a separate analysis, the subgroup of 
subjects who were on-drug and perceived nausea during the scan. This will allow for an 
investigation of sub-threshold changes in brain physiology due to the drug as well as 
more specific analyses targeting nausea perception as a result of drug intake.   
Arterial spin labeling (ASL) data will be pre-processed similarly for motion correction, 
and tagged and un-tagged images will be subtracted and used to calculate regional 
cerebral blood flow (rCBF) using validated equations for pulsed continuous ASL 
(pCASL).  ASL data acquired while the subject was experiencing nausea will then be 
contrasted with nausea-free scans acquired at the beginning of the Off-therapy MRI 
session (i.e. before the vection nausea task), to evaluate brain rCBF response during drug-
induced nausea perception.   
9.3.1.
Analysis Populations
For this exploratory study, the analysis set will include subjects who have valid data.
9.3.2.
Part A Data Review
There are 2 potential interim data reviews during the study.  The first interim data review 
will be performed after all MRI assessments from 4 subjects have been collected and 
cleaned.  Based on results from interim review, a decision to randomize 4 more subjects 
for Part A, and/or adjust Part B design (e.g., change in MRS pulse sequence), will be 
made based on imaging evaluators’ judgment in consultation with the PI and Sponsor. 


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A second interim data review will occur only if a decision to randomize 4 more for Part 
A is made after initial review of results from the first 4 subjects.  This second review, 
should it occur, will use all data from 8 subjects.  Once the required number of subjects 
has been randomized for an upcoming data review, randomization of additional subjects 
will be put on hold.  Randomization will resume after a decision to continue the study is 
made.
9.4.
Key Elements of Analysis Plan
Data from Parts A and B, as appropriate, will be pooled for final analysis.  For 
comparisons between Albiglutide and exenatide, analysis of variance (ANOVA) will be 
used to analyze quantifiable endpoints with treatment and period as fixed effects, and 
subject as random effect.  The contrast of interest for BOLD, ASL and MRS endpoints 
described in Section 9.3 will be tested using this model. 
Pearson’s and Spearman’s correlation coefficients will be used to review relationships 
between selected quantifiable end points.
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 International 
Conference on Harmonisation (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 GCP, all applicable subject 
privacy requirements, and the guiding principles of the current version of the Declaration 
of Helsinki.  This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable

Obtaining signed informed consent

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol 
deviations to IRB/IEC)


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
GSK will provide full details of the above procedures, either verbally, in writing, 
or both.

Signed informed consent must be obtained for each subject prior to participation 
in the study

The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.  

Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.  

Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities.  In this situation, 
written approval of the clinical protocol should state that approval of optional 
assessments is being deferred and the study, with the exception of the optional 
assessments, can be initiated.
10.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK monitors will contact the site prior to the start of the study to review with the 
site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and GSK requirements.  

When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the eCRF
will serve as the source document.
GSK will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any 
other study agreements, GCP, and all applicable regulatory requirements.
The Investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents
10.4.
Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK 
may conduct a quality assurance assessment and/or audit of the site records, and 
the regulatory agencies may conduct a regulatory inspection at any time during or 
after completion of the study. 

In the event of an assessment, audit or inspection, the Investigator (and institution) 
must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all 
relevant documents and to allocate their time and the time of their staff to discuss 
the conduct of the study, any findings/relevant issues and to implement any 
corrective and/or preventative actions to address any findings/issues identified.


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


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
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.
10.8.
Review Committees
A Pancreatitis Adjudication Committee composed of independent specialists in 
gastroenterology will review cases of possible pancreatitis. Details of this committee and 
case adjudication will be described in a separate charter.


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Meretto TJ, Milton DR, Ridge TD, MacConell LA, Okerson T, Wolka AM et al. Efficacy 
and Tolerability of Exenatide Monotherapy Over 24 Weeks in Antidiabetic Drug-Naive 
Patients with Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group Study. Clinical Therapeutics. 2008; 30 (8): 1448-1460
Miller AD, Rowley HA, Roberts TP, Kucharczyk J. Human cortical activity during 
vestibular- and drug-induced nausea detected using MSI. Ann N Y Acad Sci. 1996, 
781:670--672.
Napadow V, Sheehen J, Kim J, et al. The Brain Circuitry Underlying the Temporal 
Evolution of Nausea in Humans. Cerebral Cortex 2013; 24(4):806-813.
Nauck MA, Duran S, Kim D, Johns D, Northrup J, Festa A et al., A comparison of twice-
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suboptimally controlled with sulfonylurea and metformin: a non-inferiority study 
Diabetologia. 2007; 50:259–267
Nauck MA, Stewart MW, Perkins C, Jones-Leone A, Yang F, Perry C et al. Efficacy and 
safety of once-weekly GLP-1 receptor agonist albiglutide (HARMONY 2): 52 week 
primary endpoint results from a randomised, placebo-controlled trial in patients with type 
2 diabetes mellitus inadequately controlled with diet and exercise. Diabetologia. 
Published online 17 November 2015 available at: 
http://rd.springer.com/article/10.1007%2Fs00125-015-3795-1#
Østergaard L, Frandsen C, Madsbad S. Treatment Potential of the GLP-1 receptor 
agonists in Type 2 Diabetes Mellitus: a review. Expert Rev Clin Pharmacol 2016; 9 
(2):241–265.
Rosenstock J, Fonseca VA, Gross JL, Ratner RE, Ahren B, Leiter LA et al. Advancing 
basal insulin replacement in type 2 diabetes inadequately controlled with insulin glargine 
plus oral agents: a comparison of adding albiglutide, a weekly GLP-1 receptor agonist, 
versus thrice-daily prandial insulin lispro. Diabetes Care. 2014; 37:2317-25.
Rosenstock J, Reusch J, Bush M, et al. Potential of Albiglutide, a Long-Acting GLP-1 
Receptor Agonist, in Type 2 Diabetes. Diabetes Care, 2009 ; 32:(10), 2009.
Schloegl H, Percik R, Horstmann A, et al. Peptide hormones regulating appetite –focus 
on neuroimaging studies in humans. Diabetes Metab Res Rev 2011; 27: 104–112.


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Smits M, van Raalte  D, Tonneijck L, et al. Recent advances in clinical practice: GLP-1 
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12.
APPENDICES
12.1.
Appendix 1 : Abbreviations and Trademarks
Abbreviations
AE
Adverse event
AFNI
Analysis of Functional NeuroImages
ALT
Alanine aminotransferase
ASL
Arterial spin labeling
BMI
Body mass index
BOLD
Blood oxygen level dependent
CI
Confidence interval
Cmax
Maximum observed concentration
CNS
Central nervous system
CONSORT
Consolidated Standards of Reporting Trials
CV
Cardiovascular
DF
Dominant frequency
DP
Dominant power
DPP-IV
Dipeptidyl peptidase-IV
ECG
Electrocardiogram
eCRF
Electronic case report form
eGFR
Estimated glomerular filtration rate
EGG
Electrogastrography
EMA
European Medicines Agency
EPI
Echo Planar Imaging
EU
European Union
FDA
Food and Drug Administration
fMRI
Functional magnetic resonance imaging
FRP
Females of reproductive potential
FSH
Follicle stimulating hormone
FSL
FMRIB Software Library
GABA
Gamma-aminobutyric acid
GCP
Good Clinical Practice
GI
Gstrointestinal
GI
Gastrointestinal
GLP-1
Glucagon-like peptide-1
GLP-1R
Glucagon-like peptide-1 receptor
GMA
Gastric myoelectrical activity
GSK
GlaxoSmithKline
h
Hour
hCG
Human chorionic gonadotrophin
HIV
Human immunodeficiency virus
HV
Healthy volunteers
IB
Investigator brochure
ICA
Independent component analysis
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee


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IRB
Institutional Review Board
IVRS
Interactive voice response system
MACE
Major adverse cardiovascular event
MI
Myocardial infarction
MNI
Montreal Neurological Institute
MP-RAGE
Magnetization-prepared rapid gradient-echo
MRI
Magnetic resonance imaging
MRS
Magnetic resonance spectroscopy
MRSI
Magnetic resonance spectroscopy imaging
MSAQ
Motion Sickness Assessment Questionnaire
MSDS
Material Safety Data Sheet
MSSQ
Motion Sickness Susceptibility Questionnaire
MTC
Medullary thyroid carcinoma
MVPA
Multi-Voxel Pattern Analysis
NRS
Numerical rating scale
PCASL
Pseudo-Continuous ASL
PD
Pharmacodynamic
PI
Prescribing information
PK
Pharmacokinetic
PPAR
Peroxisome proliferator-activated receptor
QA
Quality assurance
rCBF
Regional cerebral blood flow
ROI
Regions of interest
SAE
Serious adverse event
SC
Subcutaneous
SD
Single dose
SOP
Standard operating procedure
SRM
Study reference manual
SU
Sulfonylurea
T&E
Time and Events
T1/2
Terminal phase half-life
T2DM
type 2 diabetes mellitus
Tmax
Time of occurrence of Cmax
ULN
Upper limit of normal
VAS
Visual analogue scale
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
Chiron RIBA
SAS
WinNonlin


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12.2.
Appendix 2 : Liver Safety Required Actions and Follow up 
Assessments
Phase I 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.
Phase I 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 CRF, and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries 
resolve, 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

Monitor subjects twice weekly until liver 
chemistries resolve, stabilise or return to 
within baseline

A specialist or hepatology consultation is 
recommended

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

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on 
the concomitant medications report form 
including acetaminophen, herbal remedies, 
other over the counter medications.

Record alcohol use on the liver event 
alcohol intake case report form
If ALT≥3xULN AND bilirubin 2xULN  or 
INR >1.5:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 


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Liver Chemistry Stopping Criteria – Liver Stopping Event
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
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG or gamma 
globulins).

Serum acetaminophen adduct HPLC assay 
(quantifies potential acetaminophen 
contribution to liver injury in subjects with 
definite or likely acetaminophen use in the 
preceding week [James, 2009]. NOTE: not 
required in China.

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured, which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to subjects receiving anticoagulants
3. 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, Davern TJ, Lee 
WM. 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
12.3.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a patient or clinical investigation 
subject, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgment 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.
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 


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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.
12.3.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c.
Requires hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting.  Complications that occur during hospitalization are 
AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.


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d.
Results in disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday 
life functions but do not constitute a substantial disruption
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition.  These should also be considered 
serious.

Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse
g.
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** > 1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick.  If fractionation is unavailable and ALT 3xULN 
and total bilirubin 2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.
12.3.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure


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
Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
12.3.4.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The Investigator will then record all relevant information regarding an AE/SAE in 
the CRF

It is not acceptable for the Investigator to send photocopies of the subject’s medical 
records to GSK in lieu of completion of the GSK, AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK.  In this instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to 
submission of to GSK.

The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.

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.


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12.3.5.
Evaluating AEs and SAEs
Assessment of Intensity
The Investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. - an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
Assessment of Causality

The Investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
out.

The Investigator will use clinical judgment to determine the relationship.

Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The Investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of his/her assessment.

For each AE/SAE the Investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations when an SAE has occurred and the Investigator has minimal 
information to include in the initial report to GSK.  However, it is very important 
that the Investigator always make an assessment of causality for every event 
prior to the initial transmission of the SAE data to GSK.

The Investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.


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Follow-up of AEs and SAEs

The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.

The Investigator is obligated to assist.  This may include additional laboratory tests 
or investigations, histopathological examinations or consultation with other health 
care professionals.

If a subject dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide GSK with a copy of any post-mortem findings, 
including histopathology.

New or updated information will be recorded in the originally completed CRF.

The Investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
12.3.6.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data collection 
tool

If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax it to the Medical Monitor

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

The Investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of 
the SAE.

After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) will be taken off-line to prevent the entry of new data or changes to 
existing data

If a site receives a report of a new SAE from a study subject or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, the site can report this information on a paper SAE form or to the Medical 
Monitor by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.


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SAE reporting to GSK via paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the Medical Monitor.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable, with a copy of the SAE data collection tool sent by 
overnight mail

Initial notification via the telephone does not replace the need for the Investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE receipt can be found at this beginning of the protocol on the 
Sponsor/Medical Monitor Contact Information page.
SAE reporting to GSK via PIMS

Facsimile transmission of the following PIMS listings for the corresponding subject 
is the preferred method to transmit SAE information to the Medical Monitor:
SAE listing
Demographic listing
Study treatment listing

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable, with a copy of all required information sent by overnight 
mail.

If the PIMS system is unavailable when the SAE occurs, the site will use the paper 
SAE form and fax that to the Medical Monitor. The site will enter the SAE data into 
PIMS as soon as the system becomes available.


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12.4.
Appendix 4: Collection of Pregnancy Information
For female subjects of reproductive potential:

Any female subjects who become pregnant while participating will be withdrawn 
from the study.

The 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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12.5.
Appendix 5 : Edinburgh Handedness Inventory
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third 
party copyright laws and therefore have been excluded.


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12.6.
Appendix 6 : Motion Sickness Susceptibility Questionnaire
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by 
third party copyright laws and therefore have been excluded.


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12.7.
Appendix 7 : Visual Analog Scale


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12.8.
Appendix 8 : Motion Sickness Assessment Questionnaire 
(MSAQ)
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third 
party copyright laws and therefore have been excluded.


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12.9.
Appendix 9 : Country Specific Requirements
No country-specific requirements exist.


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12.10.
Appendix 10 : Protocol Changes
Protocol Amendment Number 1
Protocol Amendment Number 1 is applicable to all clinical study centers participating in 
this study. This is a single center study.  Protocol changes specified in Amendment 
Number 1 are summarized as follows: 

Inclusion criterion #4 was updated to reflect the nausea susceptibility score of >17 
when using the MSSQ short form as described in the protocol.  The prior criterion 
erroneously reflected the nausea susceptibility score when using the MSSQ long 
form. 

Exclusion criterion #4 was expanded to allow the use of MRI safe glasses for 
subjects requiring vision correction.

A statement was added to allow rescreening with approval from Medical Monitor

Exploratory endpoint for GMA was updated to reflect output of EGG instrument.  
Flexibility was added to remove EGG as an endpoint if not able to collect during
MRI

The Time and Events Table was updated:
o
The Screening Period was updated to allow more flexibility in the 
scheduling of the screening procedures. 
o
Clarification of the timings of the Mock MRI and windows for the pre and 
post MRI procedures was added.
o
The statement that safety labs must be done in the fasting state was 
removed as measurements requiring fasting are described in Section 7.4.8 
Clinical Laboratory Assessments
o
Safety labs for Session 2 (Part A and B WITHOUT Off-therapy MRI in 
Session 1) were changed to be collected on Day 5 prior to dosing
o
Missing rows to indicate EGG in Table 7.1.2 and Randomization in both 
tables were added

The time period to stop food and drink except water was updated to align with 
IRB requirements

Administrative changes including updating the medical monitor roles and email 
addressed as well as minor typographical errors were corrected.
Specific Changes in the Text: (new text is indicated by bold; deleted text is indicated 
by strikethrough)


2015N250344_02
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86
Medical Monitor/Sponsor Information Page:
Role
Name
Day Time Phone Number and email 
address
Primary Medical 
Monitor
Secondary Medical 
Monitor
SAE contact  
information 
PROTOCOL SYNOPSIS 
Objectives/Endpoints 
Objectives
Endpoints
Primary

To explore the effect of single dose 50 mg 
albiglutide compared to single dose 10 g 
exenatide on regional brain activity and 
connectivity associated with nausea in healthy 
volunteers

Resting-state BOLD signal (fMRI)

Regional cerebral blood flow (rCBF) (fMRI-ASL)

Glutamate concentration in nausea-associated 
brain regions (MRS)

GABA concentration in nausea-associated brain 
regions (MRS)
Secondary

To  evaluate autonomic effects of single dose 
50 mg albiglutide compared to single dose 10 
g exenatide

To assess safety and tolerability of single dose 
50 mg albiglutide and single dose 10 g 
exenatide

Heart rate, heart rate variability, respiratory rate, 
ECG intervals, blood pressure, skin 
conductance level

Vital signs, clinical laboratory tests, adverse 
events, Nausea ratings scale, GI-VAS and 
MSAQ
Exploratory

To evaluate gastric myoelectrical activity (GMA)
of single dose 50 mg albiglutide compared to 
single dose 10 g exenatide

GMA: Dominant power (DP), Dominant 
frequency (DF), % time spent in 3 frequency 
bands (Bradygastria, Normal, Tachygastria) and 
Ratio of power in post-task versus pre-task

GMA: description of frequency region  
(Bradygastria, Normal, Tachygastria)
Study Design (diagram)
Screening
Week -4 
to -3
Week -2
Week -4 to -1
PPD
PPD


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Treatment arms and Duration
In either Part A or Part B, the total duration of a subject’s participation is approximately 
15 – 19 weeks, assuming 3- up to 4 weeks for screening, 8 days each for Session 1 and 
Session 2, 6 to 9 weeks for washout, and a 4 weeks post last treatment follow-up.
PROTOCOL
Section 3 Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary

To explore the effect of single dose 50 mg 
albiglutide compared to single dose 10 g 
exenatide on regional brain activity and 
connectivity associated with nausea in healthy 
volunteers

Resting-state BOLD signal (fMRI)

Regional cerebral blood flow (rCBF) (fMRI-ASL)

Glutamate concentration in nausea-associated 
brain regions (MRS)

GABA concentration in nausea-associated brain 
regions (MRS)
Secondary

To  evaluate autonomic effects of single dose 
50 mg albiglutide compared to single dose 10 
g exenatide

To assess safety and tolerability of single dose 
50 mg albiglutide and single dose 10 g 
exenatide

Heart rate, heart rate variability, respiratory rate, 
ECG intervals, blood pressure, skin 
conductance level

Vital signs, clinical laboratory tests, adverse 
events, Nausea ratings scale, GI VAS, and 
MSAQ
Exploratory

To evaluate gastric myoelectrical activity (GMA)
of single dose 50 mg albiglutide compared to 
single dose10 g exenatide

GMA: Dominant power (DP), Dominant 
frequency (DF), % time spent in 3 frequency 
bands (Bradygastria, Normal, Tachygastria) 
and Ratio of power in post-task versus pre-task

GMA: description of frequency region  
(Bradygastria, Normal, Tachygastria)
Section 4.1 Overall Design
(Diagram)
Screening
Week -4 
to -3
Week -2
Week -4 to -1
For all MRI sessions, subjects must fast overnight and will be instructed to refrain from 
eating and drinking after 9 pm of the evening before each session anything but water 


2015N250344_02
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starting at approximately 10 pm the night before or with in 8 hours of the start of 
their MRI appointment
Section 4.2 Treatment Arms and Duration
All doses will be given in the morning.  For all MRI sessions subjects must fast overnight 
and will be required to refrain from eating and drinking anything but water starting at 
approximately 10 pm the night before or with in 8 hours of the start of their MRI 
appointment after 9 pm of the evening prior to each MRI scan visit (see Section 6.10.1).  
Section 5.1 Inclusion Criteria
4.
Motion Sickness Susceptibility Questionnaire (MSSQ-short) Screening score >60 
17 and mock fMRI nausea rating ≥2(See Appendix 6)
Section 5.2 Exclusion Criteria
4. Use of eyeglasses during fMRI.  Subjects requiring visual correction to participate in 
visual task that cannot be corrected with contact lenses or MRI safe glasses.
Section 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.  Subjects can be rescreened
once if agreed after discussion with the Medical Monitor.
Section 6.10.1 Meals and Dietary Restrictions
Subjects must refrain from eating and drinking anything but water starting at 
approximately 10 pm the night before or with in 8 hours of the start of their MRI 
appointment after 9 pm of the evening prior to each MRI session day until completion of 
all study assessments on imaging day.  Subjects can drink water, but no more than 8 oz at 
a time and not within 2 hours of the appointment.  
Section 6.10.2 Caffeine, Alcohol, and Tobacco

Subjects will abstain from ingesting caffeine- or xanthine-containing products (e.g., 
coffee, tea, cola drinks and chocolate) after 9:00 10 pm the evening prior to each 
MRI session day until completion of all study assessments on imaging day during 
each session. 


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Section 7.1 Time and Events Table
Section 7.1.1 Part A and B WITH Off-therapy MRI in Session 1
Screen-
ing
Session 1
Wash 
out
Session 2
F/
U
Procedure
Week -4 to -1
Week -4 to -3
Week -1
Day 1 
Day 51m
Day 810
Day 410
Week 13
Pre-MRI
MRI
Post 
MRI
-2 h
-0.5 h
0 h
0.5 h
1 h
Post 
MRI
6-9 weeks
Day 1
-2 h
-0.5 h
0 h
0.5 h
1 h
Post 
MRI
0.5 h
1 h
0.5 h
1 h
0.5 h
1 h
Visit (all out-patient)
1
2
3
4
5
6
7
8
Informed Consent
X
Demographics
X
Medical historya
X
Prior/Concomitant medicationb
X
X
X
X
X
X
X
X
Complete physical
X
Brief physical
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine Drug, Breath Alcohol/Cotinine
X
X
X
X
X
X
X
12-lead ECG0
X
Pregnancy test (WCBP)0
X
X
X
X
HIV, Hep B and Hep C screen0
X
Clinical laboratory tests0
X
X
TSH, free T4, triglycerides, amylase 
and lipase 
X
Edinburgh Handedness Inventory
X
MSSQ-short
X
Mock fMRI0
X


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Screen-
ing
Session 1
Wash 
out
Session 2
F/
U
Procedure
Week -4 to -1
Week -4 to -3
Week -1
Day 1 
Day 51m
Day 810
Day 410
Week 13
Pre-MRI
MRI
Post 
MRI
-2 h
-0.5 h
0 h
0.5 h
1 h
Post 
MRI
6-9 weeks
Day 1
-2 h
-0.5 h
0 h
0.5 h
1 h
Post 
MRI
0.5 h
1 h
0.5 h
1 h
0.5 h
1 h
Randomization
X
Dosing albiglutide or placebo0
X
X
Dosing exenatide or placebo0
X
X
MRI0
X
X
X
Autonomic monitoring
X
X
X
Electrogastrogram
X
X
X
VAS
X
X
X
X
X
X
MSAQ0
X
X
X
Capillary blood glucose
X
X
Fasting Plasma Glucose
X
X
Snack0
X
X
X
AE assessment0
<============>
<=======================>
<=========================>
X
Discharge0
X
X
X
a.
Medical history includes alcohol/tobacco/caffeine usage.
b.
Prior-Medications are defined as prescription or over-the counter medications taken within 30 days of Screening.  Record concomitant medications and or changes.
c.
WCBP is women of child-bearing potential. Serum pregnancy test at Screening. Urine pregnancy at other specified time points.
d.
If test otherwise performed within 1 month prior to first dose of study treatment, testing at screening is not required.
e.
See Table 2 for list of laboratory parameters. Unscheduled Safety Labs and ECGs can be done at any time if the Investigator considers the assessments appropriate for 
subject safety.  Safety labs must be done in fasting state.
f.
Mock fMRI is performed on a separate day during the screening period.  Scheduling should allow at least 1 week between the Mock fMRI and the next MRI scan.
g.
Albiglutide, exenatide or placebo is administered according to randomization sequence.
h.
All MRI include resting-state fMRI, ASL and MRS. Off-therapy MRI scan includes visual nauseogenic task fMRI and can be initiated once -assessments are completed.  The 
on-therapy scan should be initiated 1 hr ±15min  post the exenatide or exenatide placebo dose.  Pre-scan procedure timings are suggested times to allow 
completion of activities.  Post MRI procedure should be completed at the noted times ±15 min.


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Section 7.1.2 Part A and B WITHOUT Off-therapy MRI in Session 1
Screen-
ing
Session 1
Wash
out
Session 2
F/U
Procedure
Week -4 to -1
Week -4 to -3
Week -1
Day 1
Day 41m
6-9 weeks
Day 1 
Day 51m
Day 81m
Week 13
-2 h
-0.5 h
0 h
0.5 h
1 h
Post 
MRI
Pre-MRI
MRI
Post 
MRI
-2 h
-0.5 h
0 h
0.5 h
1 h
Post 
MRI
0.5 h
1 h
0.5 h
1 h
0.5 h
1 h
Visit (all out-patient)
1
2
3
4
5
6
7
8
Informed Consent
X
Demographics
X
Medical historya
X
Prior/Concomitant medicationb
X
X
X
X
X
X
X
X
Complete physical
X
Brief physical
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine Drug, Breath Alcohol/Cotinine 
X
X
X
X
X
X
X
12-lead ECGe
X
Serum or urine pregnancy test (WCBPc)
X
X
X
X
HIV, Hep B and Hep C screend
X
Clinical laboratory testse
X
X
X
TSH, triglycerides, amylase and lipase 
X
Edinburgh Handedness Inventory
X
MSSQ-short
X
Mock fMRIf
X
Randomization
X


2015N250344_02
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Screen-
ing
Session 1
Wash
out
Session 2
F/U
Procedure
Week -4 to -1
Week -4 to -3
Week -1
Day 1
Day 41m
6-9 weeks
Day 1 
Day 51m
Day 81m
Week 13
-2 h
-0.5 h
0 h
0.5 h
1 h
Post 
MRI
Pre-MRI
MRI
Post 
MRI
-2 h
-0.5 h
0 h
0.5 h
1 h
Post 
MRI
0.5 h
1 h
0.5 h
1 h
0.5 h
1 h
Visit (all out-patient)
1
2
3
4
5
6
7
8
Dosing albiglutide or placebog
X
X
Dosing exenatide or placebog
X
X
MRIh
X
X
X
Autonomic monitoring
X
X
X
Electrogastogram
X
X
X
VAS
X
X
X
X
X
X
MSAQi
X
X
X
Capillary blood glucose
X
X
Fasting Plasma Glucose
X
X
Snackj
X
X
X
AE assessmentk
X
<==================>
<==========>
X
<=====================>
X
Dischargel
X
X
X
a.
Medical history includes alcohol/tobacco/caffeine usage.
b.
Prior-Medications are defined as prescription or over-the counter medications taken within 30 days of Screening.  Record concomitant medications and or changes
c.
WCBP is women of child-bearing potential. Serum pregnancy test at Screening.  Urine pregnancy at other specified time points
d.
If test otherwise performed within 1 month prior to first dose of study treatment, testing at screening is not required
e.
See Table 2 for list of laboratory parameters.  Unscheduled Safety Labs and ECGs can be done at any time if the Investigator considers the assessments appropriate for 
subject safety. The blood sample Session 2 Day 5 must be collected prior to dosing. Safety labs must be done in fasting state
f.
Mock fMRI session and MSSQ task are is performed on a separate day.  Scheduling should allow at least 1 week between the Mock fMRI and the next MRI scan.once 
all other entry criteria met.
g.
Albiglutide, exenatide or placebo is administered according to randomization sequence.


2015N250344_02
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93
h.
All MRI include resting-state fMRI, ASL and MRS. Off-therapy MRI scan includes visual nauseogenic task fMRI and can be initiated once -assessments are completed.  The 
on-therapy scan should be initiated 1 hr ±15min  post the exenatide or exenatide placebo dose.  Pre-scan procedure timings are suggested times to allow 
completion of activities.  Post MRI procedure should be completed at the noted times ±15 min.
i.
MSAQ is given following the VAS.
j.
Subjects will be offered a snack prior to leaving the site.
k.
Only events related to the Study Procedures meeting the SAE criteria are to be reported after screening and before dose on Session 1 Day 1.
l.
Subjects should remain at the site for at least 1 hr after completion of MRI.  All procedures and assessments must be complete prior to discharge. The Investigator will approve 
the release of the subject from the clinic, or will provide treatment for the standard of care as required.
m.
The Post-dose MRI MUST be scheduled 41 days after the albiglutide or albiglutide placebo dose. The day of dosing albiglutide is counted as the first day.
Section 7.4.7 Electrogastrogram
Collection of EGG during the MRI is experimental and may not progress if deemed uninterpretable.

SAP_001.pdf: 
CONFIDENTIAL 
The GlaxoSmithKline group of companies 
 
201840 
 
 
1 
 
Division 
: Worldwide Development 
Information Type 
: Reporting and Analysis Plan (RAP) 
 
Title 
: Reporting and Analysis Plan for Study 201840: An 
Exploratory Randomized, 2-Part, Single-blind, 2-Period 
Crossover Study Comparing the Effect of Albiglutide with 
Exenatide on Regional Brain Activity Related to Nausea in 
Healthy Volunteers 
Compound Number  
: GSK716155 
Effective Date  
: [20-Nov-2017] 
 
Description: 
• 
The purpose of this RAP is to describe the planned analyses and outputs that will be 
reported by GSK Clinical Statistics & Programming Department. 
• 
This RAP is to describe Part A only since the study was terminated early and Part B 
was cancelled prior to the completion of Part A; however, Part A was completed as 
planned. 
• 
Analyses that will be performed by Massachusetts General Hospital (MGH)/Health 
Science & Technology (HST) Athinoula A. Martinos Center for Biomedical Imaging 
[Martinos] are described separately and are provide in Attachment 11. 
 
Author’s Name and Functional Area:  
 
20-Nov-2017 
Principle Statistician (Clinical Statistics) 
 
Approved by:  
 
30-Nov-2017 
Director (Clinical Statistics) 
 
Copyright 2017 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited. 
 
PPD
PPD


 
CONFIDENTIAL 
 
 
 
201840 
 
2 
 
TABLE OF CONTENTS 
PAGE 
1. 
REPORTING & ANALYSIS PLAN SYNPOSIS ......................................................... 4 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION .................................................. 6 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan ............................ 6 
2.2. 
Study Objective(s) and Endpoint(s)............................................................... 6 
2.3. 
Study Design ................................................................................................ 7 
2.4. 
Statistical Hypotheses................................................................................... 7 
3. 
PLANNED ANALYSES ............................................................................................ 8 
3.1. 
Interim Analyses ........................................................................................... 8 
3.2. 
Final Analyses .............................................................................................. 8 
4. 
ANALYSIS POPULATIONS ..................................................................................... 8 
4.1. 
Protocol Deviations ....................................................................................... 9 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS ..................................................................................................... 10 
6. 
STUDY POPULATION ANALYSES ....................................................................... 11 
6.1. 
Overview of Planned Analyses ................................................................... 11 
6.2. 
Demographic and Baseline Characteristics ................................................. 11 
6.3. 
Exposure to Study Drug .............................................................................. 11 
6.4. 
Medications ................................................................................................ 12 
7. 
PRIMARY STATISTICAL ANALYSES .................................................................... 13 
7.1. 
Efficacy Analyses ........................................................................................ 13 
7.1.1. 
Overview of Planned Efficacy Analyses ....................................... 13 
8. 
SECONDARY STATISTICAL ANALYSES ............................................................. 14 
8.1. 
Secondary Efficacy Analyses ...................................................................... 14 
8.2. 
Safety & Tolerability Analyses ..................................................................... 15 
8.2.1. 
Overview of Planned Analyses .................................................... 15 
8.2.2. 
Vital Signs .................................................................................... 15 
8.2.3. 
Clinical Laboratory Evaluations .................................................... 15 
8.2.4. 
Adverse Events............................................................................ 16 
8.2.5. 
Most Common Adverse Events .................................................... 16 
8.2.6. 
Deaths and Serious Adverse Events ............................................ 16 
8.2.7. 
Nausea Rating Scale ................................................................... 16 
8.2.8. 
GI VAS ........................................................................................ 16 
8.2.9. 
MSAQ .......................................................................................... 16 
8.2.10. 
Pregnancies ................................................................................. 16 
9. 
REFERENCES ....................................................................................................... 17 
10. APPENDICES ........................................................................................................ 18 
10.1. 
Appendix 1: Protocol Deviation Management and Definitions for 
Per-Protocol Population .............................................................................. 19 
10.2. 
Appendix 2: Time & Events ......................................................................... 20 
10.2.1. 
Protocol Defined Time & Events .................................................. 20 


 
CONFIDENTIAL 
 
 
 
201840 
 
3 
 
10.3. 
Appendix 3: Assessment Windows ............................................................. 21 
10.3.1. 
Definitions of Study Day ............................................................... 21 
10.4. 
Appendix 4: Values of Potential Clinical Importance ................................... 22 
10.4.1. 
Laboratory ................................................................................... 22 
10.4.2. 
Vital Signs .................................................................................... 24 
10.5. 
Appendix 5: Data Display Standards & Handling Conventions .................... 25 
10.5.1. 
Study Treatment Display Descriptors ........................................... 25 
10.6. 
Appendix 6 – Abbreviations & Trade Marks ................................................ 26 
10.6.1. 
Abbreviations ............................................................................... 26 
10.6.2. 
Trademarks ................................................................................. 27 
10.7. 
Appendix 7: List of Data Displays ............................................................... 28 
10.7.1. 
Data Display Numbering .............................................................. 28 
10.7.2. 
Study Population Tables .............................................................. 29 
10.7.3. 
Efficacy Tables ............................................................................ 29 
10.7.4. 
Safety Tables ............................................................................... 30 
10.7.5. 
ICH Listings ................................................................................. 30 
10.7.6. 
Non-ICH Listings .......................................................................... 31 
11. ATTACHMENTS [DOCUMENTATION FROM MARTINOS] ................................... 32 
11.1. 
Reporting & Analysis Plan for Imaging Data for Part A................................ 32 
11.1.1. 
Overview of Quality Control for Imaging Data .............................. 32 
 


 
CONFIDENTIAL 
 
 
 
201840 
 
4 
 
1. 
REPORTING & ANALYSIS PLAN SYNPOSIS 
Overview 
Key Elements of the RAP 
Purpose 
• 
The purpose of this RAP is to describe the planned analyses and outputs that 
will be reported by GSK Clinical Statistics & Programming Department. At the 
time of the RAP preparation, the study had terminated early and Part B was 
cancelled prior to the completion of Part A; however, Part A was completed as 
planned. This RAP is for Part A only. 
• 
Analysis that will be performed by Massachusetts General Hospital 
(MGH)/Health Science & Technology (HST) Athinoula A. Martinos Center for 
Biomedical Imaging [Martinos] is described in a separate document added as 
Attachment 11 to this RAP. 
Protocol 
• 
This RAP is based on protocol amendment 1 [(Dated: 28/Nov/2016) of study 
GSK 201840 (GSK Document No.: 2015N250344_02] and eCRF Version 5.1. 
Primary 
Objective  
• 
To explore the effect of single dose 50 mg albiglutide compared to single dose 
10 µg exenatide on regional brain activity and connectivity associated with 
nausea in healthy volunteers 
Primary 
Endpoints 
• 
Resting-state BOLD signal (fMRI) 
• 
Regional cerebral blood flow (rCBF) (fMRI-ASL) 
• 
Glutamate concentration in nausea-associated brain regions (MRS) 
• 
GABA concentration in nausea-associated brain regions (MRS) 
Study 
Design 
• 
This is a phase IV, 2-part, 2-period crossover, single dose, randomized, single 
blind (blinded to both the subject and the imaging evaluators analysing the MRI 
data), placebo and active-controlled study in adult healthy volunteers who are 
susceptible to motion sickness. 
Planned 
Analyses 
• 
Analysis of primary and some secondary endpoints for Part A will be performed 
by Martinos.  Details are described in Attachment 11. 
 
Analysis 
Populations 
• 
For this study, the analysis set will include subjects who have valid data as 
determined at the discretion by the imaging laboratory. 
Hypothesis 
• 
No primary hypothesis was pre-specified due to the exploratory nature of the 
study. 
Primary 
Analyses 
• 
The primary analyses will be exploratory in nature and will consist of summary 
outputs and listings and will cover the following primary endpoints: 
1. Resting-state BOLD signal (fMRI) 
2. Regional cerebral blood flow (rCBF) (fMRI-ASL) 
3. Glutamate concentration in nausea-associated brain regions (Magnetic 
resonance spectroscopy (MRS)) 


 
CONFIDENTIAL 
 
 
 
201840 
 
5 
 
Overview 
Key Elements of the RAP 
4. GABA concentration in nausea-associated brain regions (MRS) 
Secondary 
Analyses 
• 
Secondary analyses will also be exploratory in nature and will consist of 
summary statistics and listings for the following endpoints: 
1. Heart rate** 
2. heart rate variability**  
3. respiratory rate** 
4. ECG intervals** 
5. blood pressure**   
6. skin conductance level** 
• Secondary analyses consisting of summary statistics for continuous variables 
and frequency and percent for categorical variables will be performed for the 
following safety endpoints: 
1. Vital signs  
2. clinical laboratory tests*  
3. adverse events 
4. Nausea ratings scale ** 
5. Gastrointestinal-Visual analogue scale (GI VAS)  
6. Motion Sickness Assessment Questionnaire (MSAQ) 
 
             *Only listings will be provided.  
              ** Will be provided by Martinos 
 
 


 
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201840 
 
6 
 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
Since the study was terminated early; Part B was cancelled prior to the completion of Part 
A, 4 subjects completed Part A as planned and a decision was made to not complete 
group analysis of the 4 subjects. Therefore, no interim analyses will be performed as 
stated in the originally planned statistical analysis specified in the protocol / protocol 
amendment 1 [(Dated: 28/Nov/2016)]. 
2.2. 
Study Objective(s) and Endpoint(s) 
Objectives 
Endpoints 
Primary Objectives 
Primary Endpoints 
• 
To explore the effect of single dose 50 
mg albiglutide compared to single 
dose 10 g exenatide on regional brain 
activity and connectivity associated 
with nausea in healthy volunteers 
• 
Resting-state BOLD signal (fMRI) 
• 
Regional cerebral blood flow (rCBF) (fMRI-ASL) 
• 
Glutamate concentration in nausea-associated brain 
regions (MRS) 
• 
GABA concentration in nausea-associated brain regions 
(MRS) 
Secondary Objectives 
Secondary Endpoints 
• 
To evaluate autonomic effects of 
single dose 50 mg albiglutide 
compared to single dose 10 g 
exenatide 
• 
Heart rate, heart rate variability, respiratory rate, ECG 
intervals, blood pressure, skin conductance level 
• 
To assess safety and tolerability of 
single dose 50 mg albiglutide and 
single dose 10 g exenatide 
• 
Vital signs, clinical laboratory tests, adverse events, 
Nausea ratings scale, GI VAS, and MSAQ 
Exploratory Objectives 
Exploratory Endpoints 
• 
To evaluate gastric myoelectrical 
activity (GMA) of single dose 50 mg 
albiglutide compared to single dose10 
g exenatide 
• 
GMA: Dominant power (DP), Dominant frequency (DF), 
% time spent in 3 frequency bands (Bradygastria, Normal, 
Tachygastria) and Ratio of power in post-task versus pre-
task. (Martinos will provide analysis data if considered 
valid) 
 


 
CONFIDENTIAL 
 
 
 
201840 
 
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2.3. 
Study Design 
Overview of Study Design and Key Features 
 
Design 
Features 
• Phase IV, 2-part, 2-period crossover, single dose, randomized, single-blind 
(blinded to both the subject and the imaging evaluators analysing the MRI 
data), placebo and active-controlled study in adult healthy volunteers 
susceptible to motion sickness 
Treatment 
Assignment 
& Dosing 
• Subjects will be randomized to one of the following treatment sequences: 
Interim 
Analysis 
• Originally there were 2 potential interim data reviews during the study. 
However, since the study was terminated early no interim data review will be 
performed. 
 
Final 
Analysis 
• Final analysis will be performed after data from all randomized subjects in Part 
A have been cleaned and locked. 
 
2.4. 
Statistical Hypotheses 
No primary hypothesis was pre-specified due to the exploratory nature of the study. 


 
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3. 
PLANNED ANALYSES 
3.1. 
Interim Analyses 
No interim analyses will be performed since the study was terminated early and Part B 
cancelled prior to the completion of Part A; however, Part A was completed as planned. 
 
3.2. 
Final Analyses 
The final reporting will be performed after the completion of the following sequential 
steps: 
1. All subjects have completed Part A of the study as defined in the protocol. 
2. All required database cleaning activities have been completed and final database 
release and database freeze has been declared. 
The reporting and analysis of imaging data after completion of the study will be 
performed by Martinos.  Details are described in Attachment 11. 
 
4. 
ANALYSIS POPULATIONS 
Population 
Definition / Criteria 
Analyses Evaluated 
All Screened 
• All participants who were screened will be 
considered for this population. This population will 
be used for summarizing screening status 
• Screen failure 
Enrolled 
• All participants who were successfully screened 
and enrolled for the trial and for whom a record 
exists on the study database.  
• Study population 
Safety 
• Comprise of all subjects who receive at least one 
dose of study treatment. 
• This population will be based on the treatment the 
subject actually received. 
• This population will include subjects who were 
replaced due to imaging data being invalid or not 
evaluable but received study drug. 
• Safety 
Analysis Set 
(Randomised) 
• Comprise of all randomized subjects who receive 
treatment and with valid imaging data, that will be 
determined by Martinos. 
• Subjects who are replaced are excluded from this 
population. 
• Imaging (Mechanism 
of Action) 
NOTES :  
• 
Please refer to Appendix 7: List of Data Displays which details the population to be used for each display being 
generated. 
 


 
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4.1. 
Protocol Deviations 
• 
Protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
reviewed and tracked throughout the conduct of the study. However, there is no per-
protocol analysis that will be performed for this study. 
Only listings of the Protocol deviations will be provided if any. 


 
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5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS 
Table 1 provides an overview of appendices within the RAP for outlining general 
considerations for data analyses and data handling conventions.  
Table 1 
Overview of Appendices 
Section Component 
10.1 
Appendix 1: Protocol Deviation Management and Definitions for Imaging Analysis 
Population 
10.2 
Appendix 2: Time & Events 
10.3 
Appendix 3: Assessment Windows 
10.4 
Appendix 4: Values of Potential Clinical Importance 
Error! 
Referen
ce 
source 
not 
found. 
Error! Reference source not found.: Data Display Standards & Handling 
Conventions 
Error! 
Referen
ce 
source 
not 
found. 
Error! Reference source not found.: Abbreviations & Trade Marks 
Error! 
Referen
ce 
source 
not 
found. 
Error! Reference source not found.: List of Data Displays 
 


 
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6. 
STUDY POPULATION ANALYSES 
6.1. 
Overview of Planned Analyses 
The study population summary will be based on the Safety population, unless otherwise 
specified. 
Subject characteristics and safety data (captured in the eCRF) will be reported by GSK.  
GSK Statistics & Programming (S&P) will provide summary tables data listings of 
subject characteristics and safety data for Part A. 
Table 2 provides an overview of the planned study population summaries, with full 
details of data displays being presented in Appendix 7: List of Data Displays. 
Table 2 
Overview of Planned Study Population Summaries 
[Endpoint / Parameter / Display Type] 
Data Displays Generated 
Table 
Figure 
Listing 
Part A 
Reasons for Screening Failures 
Y 
 
Y 
Randomization 
 
 
Y 
Subject Disposition 
Y 
 
Y 
Summary of Number of Subjects by Site ID 
Y 
 
 
Demographics and Baseline Characteristics 
Y 
 
Y 
Race (& Racial Combinations) 
Y 
 
Y 
Age Ranges 
Y 
 
 
Medical Condition & Concomitant Medications 
Medical History 
 
 
Y 
Concomitant Medication 
 
 
Y 
Exposure 
Exposure to Study Drug 
 
 
Y 
NOTES : 
• 
Y = Yes display generated. 
 
6.2. 
Demographic and Baseline Characteristics 
Continuous variables such as age, body mass index, weight, and height will be 
summarized using descriptive statistics (n, mean, standard deviation, and median, 
minimum, maximum). Categorical variables including sex, race, ethnicity, tobacco use, 
alcohol intake, caffeine intake, and baseline weight category (<90 kg or ≥90 kg) will be 
summarized using numbers and percentages.  
Continuous variables such as age, body mass index, weight, and height will be presented 
in a by-subject listing. Listings will be presented using the safety population. 
 
 
6.3. 
Exposure to Study Drug 
 


 
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A by-subject listing of study drug administration will also be presented. 
 
 
6.4. 
Medications 
Any prior and concomitant medication used during the study will be recorded and coded 
using GSKDrug Dictionary (GSKDRUG), which will be updated whenever available 
throughout the life of the study.  
Any medication used during the study will be recorded, which will be updated whenever 
available throughout the life of the study.  
All medications will be listed. 
 


 
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7. 
PRIMARY STATISTICAL ANALYSES 
The imaging data will be reported by Martinos at the end of the study.  Details of the 
planned analyses are described in Attachment 11.  
7.1. 
Efficacy Analyses 
7.1.1. 
Overview of Planned Efficacy Analyses 
The primary efficacy analyses will be based on the all randomised population, unless 
otherwise specified. 
The efficacy analyses will be performed by Martinos, details of the planned analysed are 
described in Attachment 11. 


 
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8. 
SECONDARY STATISTICAL ANALYSES 
8.1. 
Secondary Efficacy Analyses 
The secondary analysis to list autonomic effects of albiglutide compared to exenatide will 
be performed and reported by Martinos.  Details of the planned analyses are described in 
Attachment 11.  


 
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8.2. 
Safety & Tolerability Analyses 
8.2.1. 
Overview of Planned Analyses 
The safety analyses will be based on the Safety population, unless otherwise specified. 
Safety data (captured in the eCRF) will be reported by GSK.  GSK Statistics & 
Programming (S&P) will provide summary tables and data listings of safety data for Part 
A data. 
Table  provides an overview of the planned analyses, with further details of data displays 
being presented in Appendix 7: List of Data Displays. 
Table 3 
Overview of Planned Safety & Tolerability Analyses 
[Endpoint / Parameter/ Display 
Type] 
Data Displays Generated  
Summary 
Individual 
Table 
Figure 
Figure 
Listing 
Vital Signs 
Y 
 
 
Y 
Clinical Laboratory* 
 
 
 
Y 
Adverse Events 
Y 
 
 
Y 
12-lead ECG 
 
 
 
Y 
GI- VAS 
Y 
 
 
Y 
MSAQ 
Y 
 
 
Y 
MRI 
 
 
 
Y 
*Clinical Laboratory will include Fasting Plasma Glucose. 
 
8.2.2. 
Vital Signs 
The vital sign summary and analysis will include systolic blood pressure (mmHg), 
diastolic blood pressure (mmHg), and heart rate (bpm). 
For Part A, each vital sign parameter at every scheduled assessment time point will be 
summarized using descriptive statistics. Additionally, the number of subjects with vital 
signs of potential clinical concern will also be summarized. The criteria for vital signs of 
potential clinical concern are detailed in Appendix 7: Values of Potential Clinical 
Importance.  
 
All summaries will be done for the safety population and all vital sign data will be listed.  
8.2.3. 
Clinical Laboratory Evaluations 
Laboratory parameters include the following tests: hematology, chemistry and urinalysis.  
Established or generally acknowledged methods, normal ranges, and quality control 
procedures will be supplied by Quest Diagnostics Clinical Laboratory for the study 
records.  


 
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All laboratory parameters as collected will be presented in by-subject listings at every 
scheduled assessment time point for the safety population. 
Additionally, listing of the number of subjects with laboratory values of potential clinical 
concern will be provided and scheduled assessment time point for hematology and 
chemistry. The criteria for laboratory values of potential clinical concern are detailed in 
Appendix 7: Values of Potential Clinical Importance.  
Listings of clinical laboratory evaluations will be provided. 
 
8.2.4. 
Adverse Events 
All AEs will be coded using MedDRA which will be updated whenever available 
throughout the life of the study.  
For Part A safety review, adverse events will be summarized by treatment group. 
Summary of the number and percentage of subjects with any AE and the total number of 
AEs recorded will be provided. SAEs will be summarized.  
All AEs will be listed in a subject data listing. 
8.2.5. 
Most Common Adverse Events 
A summary of most common adverse events (>2% total incidence in any treatment arm) 
by treatment will be produced. 
8.2.6. 
Deaths and Serious Adverse Events 
Deaths and serious adverse events will be listed. 
8.2.7. 
Nausea Rating Scale 
Nausea rating scale will be provided by Martinos. 
8.2.8. 
GI VAS 
Summary statistics outputs and listings for GI VAS will be provided 
8.2.9. 
MSAQ 
Summary statistics outputs and listing for MSAQ will be provided. 
8.2.10. 
Pregnancies 
Listings for Pregnancies will be produced if any. 


 
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9. 
REFERENCES 
None. 


 
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10. 
APPENDICES 
Section 
Appendix 
Section 10.1 
Appendix 1: Protocol Deviation Management and Definitions for Per Protocol 
Population 
Section 10.2 
Appendix 2: Time and Events 
Section 10.3 
Appendix 3: Assessment Windows 
Section 10.4 
Appendix 4: Values of Potential Clinical Importance 
Section Error! 
Reference 
source not 
found. 
Error! Reference source not found.: Data Display Standards & Handling 
Conventions 
• Study Treatment & Sub-group Display Descriptors 
Section 10.6 
Appendix 6: Abbreviations & Trade Marks 
Section 10.7 
Appendix 7: List of Data Displays 
 


 
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10.1. 
Appendix 1: Protocol Deviation Management and Definitions 
for Per-Protocol Population 
 
 
The Protocol Deviation Management Plan (21/Feb/2017) will be used to identify the 
important protocol deviations. It is intended to categorize important protocol deviations 
that are anticipated to occur in a study and to document study-specific requirements for 
cross-functional team review of these protocol deviations and other deviations that may 
occur in the study. There is no pre-defined per protocol population criteria. 
 


 
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10.2. 
Appendix 2: Time & Events 
10.2.1. 
Protocol Defined Time & Events 
 
 
Note: reference to Table 2 in footnote e is in the protocol. 


 
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10.3. 
Appendix 3: Assessment Windows 
10.3.1. 
Definitions of Study Day 
When study day is used for display or in comparisons the following algorithm will be 
used: 
• Study day = date of assessment – date of first dose + 1, if day of assessment >= 
first dose date 
• Study day = date of assessment – date of first dose, if day of assessment < first 
dose date 
Note that the date of first dose is Day 1 and the day before the date of first dose is Day -1 
(there is no Day 0). 
 


 
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10.4. 
Appendix 4: Values of Potential Clinical Importance 
10.4.1. 
Laboratory 
 
Hematology 
Laboratory 
Test 
Units 
Change from Baseline of 
Potential Clinical Concern  
Potential Clinical Concern 
Value  
Basophils 
GI/L 
None 
None 
Eosinophils 
GI/L 
None 
None 
Hematocrit 
1 
>0.1 decrease 
>0.05 below LLN 
>0.04 above ULN 
Hemoglobin 
g/L 
>25 g/L decrease 
>20 g/L below LLN  
>10 g/L above ULN 
Lymphocytes 
GI/L 
None 
<0.5 x LLN 
Monocytes 
GI/L 
None 
None 
Neutrophils 
GI/L 
None 
<1 GI/L 
Neutrophil 
Bands 
GI/L 
None 
None 
Platelets 
GI/L 
None 
<80 GI/L 
>500 GI/L 
Red Blood Cell 
Count 
TI/L 
None 
None 
Segmented  
Neutrophils 
GI/L 
None 
<0.5 x LLN 
White Blood Cell 
Count 
GI/L 
None 
>1 GI/L below LLN  
>5 GI/L above ULN 
 
 
 
Chemistry 
Laboratory 
Test 
Units 
Change from Baseline of 
Potential Clinical Concern   
Potential Clinical Concern 
Value  
Albumin 
g/L 
None 
>5 g/L above ULN or below LLN 
Alkaline 
Phosphatase  
U/L 
None 
>3 x ULN 
ALT 
U/L 
None 
>3 x ULN 
AST 
U/L 
None 
>3 x ULN 
Bicarbonate 
(Carbon Dioxide 
Content) 
mmol/L 
None 
<16 mmol/L 
> 40 mmol/L 
Blood Urea 
mmol/L 
None 
>2 x ULN 


 
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Chemistry 
Laboratory 
Test 
Units 
Change from Baseline of 
Potential Clinical Concern   
Potential Clinical Concern 
Value  
Nitrogen 
Calcitonin 
pmol/L 
None 
>100 
Calcium 
mmol/L 
None 
<1.8 mmol/L 
>3.0 mmol/L 
Chloride 
mmol/L 
None 
None 
Creatinine  
umol/L 
 None 
>159 umol/L 
Direct Bilirubin 
umol/L 
None 
>1.35 x ULN 
Gamma 
Glutamyl 
Transferase 
U/L 
None 
>3 x ULN 
Glucose 
(fasting)  
mmol/L 
None 
<3 mmol/L 
>22 mmol/L 
Potassium 
mmol/L 
None 
>0.5 mmol/L below LLN  
>1.0 mmol/L above ULN 
Sodium 
mmol/L 
None 
>5 mmol/L above ULN or below 
LLN 
Total Bilirubin  
umol/L 
None 
>1.5 x ULN 
Total Protein 
g/L 
None 
>15 g/L above ULN or below 
LLN 
Uric acid 
umol/L 
None 
>654 umol/L 
Free Fatty Acids 
mmol/L 
None 
None 
HDL Cholesterol 
mmol/L 
None 
None 
LDL Cholesterol 
mmol/L 
None 
None 
Triglycerides 
mmol/L 
None 
> 9.04 mmol/L 
Total 
Cholesterol 
mmol/L 
None 
None 
 
 


 
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Liver Function Tests 
Laboratory Test 
Potential Clinical Concern Value      
ALT 
≥ 2 x ULN 
≥ 3 x ULN 
≥ 5 x ULN 
≥ 8 x ULN 
≥ 10 x ULN 
≥ 3 x ULN and Total Bilirubin ≥ 2 x ULN 
AST 
≥ 2 x ULN 
≥ 3 x ULN 
≥ 5 x ULN 
≥ 8 x ULN 
≥ 10 x ULN 
≥ 3 x ULN and Total Bilirubin ≥ 2 x ULN 
Total Bilirubin 
≥ 1.5 x ULN 
≥ 2 x ULN 
≥ 3 x ULN 
≥ 5 x ULN 
≥ 8 x ULN 
≥ 10 x ULN 
 
10.4.2. 
Vital Signs 
Parameter 
Units 
Potential Clinical Concern Value  
Systolic BP 
mmHg 
<100 mmHg 
>170 mmHg 
Diastolic BP 
mmHg 
<50 mmHg 
>110 mmHg  
Heart rate 
bpm 
<50 bpm 
> 120 bpm 
 


 
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10.5. 
Appendix 5: Data Display Standards & Handling 
Conventions 
 
10.5.1. 
Study Treatment Display Descriptors 
The study treatment descriptors are shown below. 
Treatment Descriptions 
RandAll NG  
Data Displays for Reporting  
Code 
Description 
Description 
Order [1] 
A 
Albiglutide 50mg 
Albiglutide 50mg 
1 
E 
Exenatide 10mcg 
Exenatide 10mcg 
2 
 
 


 
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10.6. 
Appendix 6 – Abbreviations & Trade Marks 
10.6.1. 
Abbreviations 
Abbreviation 
Description 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
AIC 
Akaike's Information Criteria 
A&R 
Analysis and Reporting  
BOLD 
Blood oxygen Level dependent 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence Interval 
CPMS 
Clinical Pharmacology Modelling & Simulation 
CS 
Clinical Statistics 
CSR 
Clinical Study Report 
CTR 
Clinical Trial Register 
CVb / CVw 
Coefficient of Variation (Between) / Coefficient of Variation (Within) 
DOB 
Date of Birth 
DP 
Decimal Places 
eCRF 
Electronic Case Record Form 
fMRI 
Functional magnetic resonance imaging 
GABA 
Gama-aminobutyric acid  
GI-VAS 
Gastrointestinal-Visual analogue scale 
IA 
Interim Analysis 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee  
IDSL 
Integrated Data Standards Library 
IMMS 
International Modules Management System 
IP 
Investigational Product 
ITT 
Intent-To-Treat 
GUI 
Guidance 
LOC 
Last Observation Carries Forward 
MMRM 
Mixed Model Repeated Measures 
MRS 
Magnetic resonance spectroscopy 
MSAQ 
Motion Sickness Assessment Questionnaire 
PCASL 
Pseudo-Continuous ASL 
PCI 
Potential Clinical Importance  
PD 
Pharmacodynamic 
PDMP 
Protocol Deviation Management Plan 
PK 
Pharmacokinetic 
PP 
Per Protocol 
QC 
Quality Control 
QTcF 
Frederica’s QT Interval Corrected for Heart Rate 
QTcB 
Bazett’s QT Interval Corrected for Heart Rate 
RAP 
Reporting & Analysis Plan 


 
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Abbreviation 
Description 
RAMOS 
Randomization & Medication Ordering System  
rCBF 
Regional cerebral blood flow 
SAC 
Statistical Analysis Complete 
SDTM 
Study Data Tabulation Model 
SOP 
Standard Operation Procedure 
TA 
Therapeutic Area 
TFL 
Tables, Figures & Listings  
GSK 
GlaxoSmithKline 
 
10.6.2. 
Trademarks 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
None 
 
MedDRA 
 
 
 
 
 
 
 


 
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10.7. 
Appendix 7: List of Data Displays 
10.7.1. 
Data Display Numbering 
 
The following numbering will be applied for RAP generated displays: 
Section 
Tables 
Figures 
Study Population 
1.1 to 1.8 
NA 
Efficacy* 
 
 
Safety 
3.1 to 3.5 
NA 
Section 
Listings 
ICH Listings 
1 to 21 
Other Listings 
22 to 24 
*Will be provided by Martinos  


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10.7.2. 
Study Population Tables 
Study Population: Tables 
No. 
Population 
IDSL / TST 
ID / 
Example 
Shell 
Title  
Programming 
Notes 
Deliverable 
[Priority] 
Subject Disposition 
1.1.  
Safety 
ES1A 
Summary of Subject Disposition for the Subject 
Conclusion Record 
 
SAC 
1.2.  
Screened 
ES6 
Summary of Screening Status and Reasons for 
Screen Failures 
 
SAC 
Demography 
1.3.  
Safety 
DM1 
Summary of Demographic Characteristics 
 
SAC 
1.4.  
Enrolled 
DM11 
Summary of Age Ranges 
 
SAC 
1.5.  
Safety 
DM5 
Summary of Race and Racial Combinations 
 
SAC 
1.6.  
Safety 
DM6 
Summary of Race and Racial Combination Details 
 
SAC 
1.7.  
Enrolled 
NS1 
Summary of Number of Subjects Enrolled by 
Country and Site ID 
 
SAC 
1.8.  
Enrolled 
SP1A 
Summary of Study Population 
 
SAC 
 
 
 
 
 
 
10.7.3. 
Efficacy Tables 
All Efficacy tables and listings will be provided by Martinos. 
 
 


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10.7.4. 
Safety Tables 
Safety: Tables 
No. 
Population 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming 
Notes 
Deliverable 
[Priority] 
3.1.  
Safety 
AE16 
Summary of Serious Adverse Events by System 
Organ Class and Preferred Term (Number of 
Subjects and Occurrences) 
 
SAC 
3.2.  
Safety 
AE15 
Summary of Common (>=2%) non-serious 
Adverse Events by System Organ Class and 
Preferred Term (Number of Subjects and 
Occurrences) 
 
SAC 
3.3.  
Safety 
 
Vital Signs of Clinical Concern by Visit 
 
SAC 
3.4.  
Safety 
 
Summary of GI- VAS 
 
SAC 
3.5.  
Safety 
 
Summary of MSAQ 
 
SAC 
 
 
10.7.5. 
ICH Listings 
 
ICH: Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title 
Programming 
Notes 
Deliverable 
[Priority] 
1 
Safety 
CP_TA1 
Listing of Randomised and Actual Treatments  
SAC 
2 
Safety 
ES3 
Listing of Reasons for Study Withdrawal 
 
SAC 
3 
All Screened 
ES7 
Listing of Reasons for Screening Failure 
 
SAC 
4 
Enrolled 
SA3a 
Listing of Subjects Excluded from Any 
Populations 
 
SAC 
5 
Safety 
DV2 
Listing of Important Protocol Deviations 
 
SAC 
6 
Safety 
IE3 
Listing of Subjects with Inclusion/Exclusion 
Criteria Deviations 
 
SAC 
7 
Safety 
DM2 
Listing of Demographic Characteristics 
 
SAC 
8 
Safety 
DM10 
Listing of Race 
 
SAC 
9 
Safety 
EX3 
Listing of Exposure 
 
SAC 


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ICH: Listings 
No. 
Population 
IDSL / TST ID / 
Example Shell 
Title 
Programming 
Notes 
Deliverable 
[Priority] 
10 
Safety 
AE7 
Listings of Subject Numbers for Individual 
Adverse Events 
 
SAC 
11 
Safety 
AE9 
Listing of All Adverse Events 
 
SAC 
12 
Safety 
AE9 
Listing of Serious Adverse Events 
 
SAC 
13 
 
Safety 
AE9 
Listing of Adverse Events Leading to 
Withdrawal from Study / Permanent 
Discontinuation of Study Treatment 
 
SAC 
14 
Safety 
AE7 
Listing of subjects who withdrew from study 
due to Adverse Event 
 
SAC 
15 
 
Safety 
LB5 
Listing of Clinical Chemistry Laboratory Data 
for Subjects Abnormalities of Potential 
Clinical Importance 
 
SAC 
16 
Safety 
LB5 
Listing of Haematology Data for Subjects with 
Abnormalities of Potential Clinical Importance 
 
SAC 
17 
Safety 
UR2b 
Listing of Urinalysis Data  
 
SAC 
18 
Safety 
EG3 
Listing of 12 lead ECG Values 
 
SAC 
19 
Safety 
CP_VS4 
Listing of Vital Signs for Subjects with 
Abnormalities of Potential Clinical Importance 
 
SAC 
20 
Safety 
LB5 
Listing of all Haematology Data 
 
SAC 
21 
Safety 
LB5 
Listing of all Chemistry Data 
 
SAC 
 
10.7.6. 
Non-ICH Listings 
Non-ICH: Listings 
No. 
Population 
IDSL / 
TST ID / 
Example 
Shell 
Title  
Programming 
Notes 
Deliverable 
[Priority] 
22 
Analysis 
 
Listing of GI- VAS 
 
SAC 
23 
Analysis 
 
Listing of MSAQ 
 
SAC 
24 
Analysis 
 
Listing of MRI 
 
SAC 


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11. 
ATTACHMENTS [DOCUMENTATION FROM MARTINOS] 
11.1. 
Reporting & Analysis Plan for Imaging Data for Part A 
11.1.1. 
Overview of Quality Control for Imaging Data 
Quality control procedures will include visual inspection of raw brain images for 
presence of various artifacts, including but not limited to, aliasing, excessive distortion, 
Nyquist N/2 ghosting, and signal inhomogeneities. We will also assess head motion 
correction parameters to ensure that subjects were not moving excessively during the 
functional MRI (BOLD fMRI and pCASL) scans. We will evaluate 1) total translation 
and rotation motion, 2) relative TR-to-TR motion, 3) number of relative translations (> 
0.1 mm). For pCASL data, we will calculate rCBF and ensure values within the gray 
matter are within normal bounds (40-60 mm/100 g tissue/min). For 1H-MRS data we will 
assess spectra to ensure adequate SNR (Cramer–Rao lower bounds values below 40%).  
 
We will perform single-subject level analyses and include data from (1) resting-state 
BOLD fMRI, (2) pseudo-continuous arterial spin labelling (pCASL), and (3) proton-
density weighted magnetic resonance spectroscopy (1H-MRS).  
 
Primary Outcomes/Endpoints:  
1. Resting-state functional connectivity (resting-state BOLD fMRI) 
2. Regional cerebral blood flow (rCBF) (pCASL) 
3. Glutamine/Glutamate (Glx) and GABA concentrations (1H-MRS) 
 
1.  Resting-state fMRI (rs-fMRI)   
Resting-state BOLD signal MRI data collected at off-therapy and exenatide post-dose 
MRI scan sessions will be analyzed using a whole-brain seed-to-voxel approach. The 
seed-to-voxel driven approach will include a priori seed ROIs placed in brain areas 
subserving nausea-related processing including regions identified from our prior study 
(Napadow et al. Cereb Ctx 2013). These regions will include: interoceptive/sensory 
(insula, dACC), emotional/affective (amygdala, pgACC), and cognitive/evaluative 
(dlPFC/OFC) brain areas, primary visual (V1) and extrastriate cortices (area MT+/V5). 
Group analyses will be performed using a paired t-test (off-therapy vs. exenatide) with 
FSL’s FLAME (FMRIB’s Local Analysis of Mixed Effects).  
2.  pCASL  
pCASL data will be analysed to assess regional cerebral blood flow (rCBF) within the 
brain during off-therapy relative to exenatide post-dose MRI scans. Quality control of 
imaging data will be performed by visual inspection with adequate data denoted by mean 
rCBF values over the gray matter within a previously defined normal range (i.e., 40-60 
mm/100 g tissue/min). In addition, all data will undergo motion and physiological noise 


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correction. These rCBF maps will be calculated for each subject and each scan at the 
single subject-level.  
 
 
3.  1H-MRS 
Magnetic resonance spectroscopy (1H-MRS) analysis will assess regional differences in 
glutamine/glutamate (Glx) and GABA concentrations, normalized as a ratio with 
creatine. MRS quantification of metabolites of interest will be based on frequency 
domain analysis using a Linear Combination of Model spectra (LCModel). Cramer–Rao 
lower bounds (CRLBs), as reported from the LCModel analysis, will be used to assess 
the reliability of the major metabolites and adequate SNR. CRLBs values less than 40% 
will be further analyzed. Metabolite maps for each subject, and each session will be 
calculated. 
 
Secondary outcomes/endpoints: 
Additional analyses will be conducted for secondary outcome measures including heart 
rate, heart rate variability, respiratory rate, ECG intervals, blood pressure, and skin 
conductance level. Electrogastrogram (EGG) data will also be analysed as a secondary 
exploratory outcome. We will provide clean, processed physiological data in the 
subject/scan directories when available (secondary ANS data will not be available from 
every scan due to MR-induced artifacts).