Clinical trial NCT02793154
Conditions: Diabetes Mellitus, Type 2
Keywords: gastric emptying albiglutide GMA exenatide type 2 diabetes mellitus
Sponsor: GlaxoSmithKline
Start date: 2016-09-26; Completion date: 2017-03-16
Enrollment: 4 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to compare the effect of albiglutide and exenatide on gastric myoelectrical activity (GMA), gastric emptying (GE) and nausea (as measured by visual analogue scale \[VAS\]) in subjects with type 2 diabetes mellitus (T2DM). The study is divided in two parts. Part A will characterize the GMA, GE and nausea response to exenatide and confirm exenatide as a positive control for Part B. Part B will compare the effects of albiglutide and exenatide on GMA, GE and nausea.

Part A is a single arm, open-label design and all subjects will receive 10 microgram (mcg) subcutaneous exenatide twice daily for 5 days. This part will comprise 3 study periods: a 3-week screening/wash-out, 5-day treatment, and follow-up (within 7 days after the last dose of exenatide). The total duration of a subject's participation in Part A will be approximately 5 weeks. Once Part A is complete, data will be reviewed and a decision to progress to Part B will be made.

In Part B, subjects will be randomized 1:1 to receive either albiglutide (starting dose of 30 milligrams \[mg\] once weekly for 4 weeks, followed by 50 mg once weekly for 4 weeks) or exenatide (starting dose of 5 mcg twice daily for 4 weeks, followed by 10 mcg twice daily for 4 weeks). The total duration of a subject's participation in the study will be approximately 15 weeks.

Detailed description:

Arms: arm 1: Part A is a single arm design and all subjects will receive 10 mcg subcutaneous injection (SC) of exenatide twice daily for 5 days arm 2: In Part B, half of the subjects will be randomized to receive albiglutide: On Day 1: Once weekly SC injection at 30 mg for 4 weeks From Week 5, Day 1: Dose will be increased to 50 mg once weekly SC injection for 4 weeks arm 3: In Part B, half of the subjects will be randomized to receive exenatide: On Day 1: Twice daily SC injection at 5 mcg for 4 weeks.

From Week 5, Day 1: Dose will be uptitrated to 10 mcg twice daily SC injection for 4 weeks
Interventions: intervention 1: Exenatide intervention 2: Albiglutide
Intervention descriptions: intervention 1: Supplied as SC injection containing 250 mcg/mL of exenatide, provided in the following dose regimens: Part A: 10 mcg taken twice daily for 5 days; Part B: 5 mcg twice daily taken for 4 weeks followed by uptitration to 10 mcg for 4 weeks In both parts, it will be administered within 60-minute period before morning and evening meals (or before 2 meals with approximate \>=6 hours apart) intervention 2: Part B: Albiglutide will be supplied as follows:30 mg SC injection pen containing 40.3 mg lyophilized albiglutide and 0.65 mL; 50 mg SC injection pen contains 67 mg lyophilized albiglutide and 0.65 mL water; Starting dose will be 30 mg weekly for 4 weeks and then uptitrated to 50 mg weekly for 4 weeks; Administered as a single SC injection once a week in the morning

Protocol documents:
Prot_000.pdf: 
2015N255772_01
CONFIDENTIAL
204879
The GlaxoSmithKline group of companies
1
TITLE PAGE
Division: Worldwide Development
Information Type: 
Protocol Amendment
A Randomized, Open-label, Active-Controlled, Parallel-Group, 
Exploratory Study on the Effects of Repeated Doses of 
Albiglutide compared to Exenatide on Gastric Myoelectrical 
Activity and Gastric Emptying in Subjects with Type 2 Diabetes 
Mellitus
Compound Number:
GSK716155
Development Phase:
IV
Effective Date:
23-JUN-2016
Protocol Amendment Number: 1
Author (s):
Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2015N255772_00
2016-MAR-04
Original
2015N255772_01
2016-JUN-23
Amendment No. 1
Changes reflected in Protocol Amendment No. 1 have been included to address the 
following:

Increase the number of sites participating in Part A.  

Clarify time period for scheduling of the EGG and GEBT procedures

Add exploratory GMA endpoint

Incorporate administrative changes
Copyright 2016 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
2017N325664_00
PPD


 
2017N325664_00
PPD
PPD


2015N255772_01
CONFIDENTIAL
204879
3
MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information: 
Role
Name
Day Time Phone Number 
and email address
After-hours 
Phone/Cell/
Pager 
Number
Fax 
Number
Site Address
Primary 
Medical 
Monitor 
None
GlaxoSmithKline
1250 S. 
Collegeville
Road
Collegeville, PA
19426
Secondary 
Medical 
Monitor
None
GlaxoSmithKline
1250 S. 
Collegeville 
Road
Collegeville, PA
19426
SAE contact  
information 
None
GlaxoSmithKline
1250 S. 
Collegeville 
Road
Collegeville, PA
19426
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
 
2017N325664_00
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


2015N255772_01
CONFIDENTIAL
204879
4
INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number : 2015N255772_01
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
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
5
TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 204879........................................................9
2.
INTRODUCTION....................................................................................................13
2.1.
Study Rationale ..........................................................................................13
2.2.
Brief Background ........................................................................................14
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................15
3.1.
Part A: Objectives and Endpoints ...............................................................15
3.2.
Part B: Objectives and Endpoints ...............................................................16
4.
STUDY DESIGN ....................................................................................................17
4.1.
Part A: Study Design ..................................................................................17
4.1.1.
Overall Design .............................................................................17
4.1.2.
Treatment Arms and Duration......................................................18
4.1.3.
Number of Subjects .....................................................................19
4.2.
Part A Data Review ....................................................................................19
4.3.
Part B: Study Design ..................................................................................19
4.3.1.
Overall Design .............................................................................19
4.3.2.
Treatment Arms and Duration......................................................20
4.3.3.
Number of Subjects .....................................................................21
4.4.
Design Justification.....................................................................................21
4.5.
Dose Justification........................................................................................21
4.6.
Benefit:Risk Assessment ............................................................................22
4.6.1.
Risk Assessment .........................................................................22
4.6.2.
Benefit Assessment.....................................................................23
4.6.3.
Overall Benefit:Risk Conclusion...................................................23
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............23
5.1.
Inclusion Criteria.........................................................................................24
5.2.
Exclusion Criteria........................................................................................25
5.3.
Additional Inclusion Criteria for Randomization...........................................27
5.4.
Screening/Randomization Failures .............................................................27
5.5.
Withdrawal/Stopping Criteria.......................................................................28
5.5.1.
Liver Chemistry Stopping Criteria ................................................29
5.5.1.1.
Study Treatment Restart or Rechallenge....................31
5.6.
Subject and Study Completion....................................................................31
6.
STUDY TREATMENT ............................................................................................31
6.1.
Investigational Product and Other Study Treatment....................................31
6.2.
Treatment Assignment................................................................................32
6.3.
Planned Dose Adjustments.........................................................................33
6.4.
Blinding.......................................................................................................33
6.5.
Packaging and Labeling..............................................................................33
6.6.
Preparation/Handling/Storage/Accountability..............................................34
6.7.
Compliance with Study Treatment Administration.......................................34
6.8.
Treatment of Study Treatment Overdose....................................................35
6.8.1.
Albiglutide....................................................................................35
6.8.2.
Exenatide.....................................................................................35
6.9.
Treatment after the End of the Study ..........................................................35
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
6
6.10.
Concomitant Medications and Non-Drug Therapies....................................36
6.10.1.
Permitted Medications and Non-Drug Therapies..........................36
6.10.2.
Prohibited Medications and Non-Drug Therapies.........................36
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................37
7.1.
Time and Events Table...............................................................................38
7.2.
Screening and Critical Baseline Assessments ............................................42
7.3.
EGG and GEBT Test ..................................................................................42
7.3.1.
EGG ............................................................................................42
7.3.2.
GEBT...........................................................................................43
7.4.
Safety .........................................................................................................43
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........43
7.4.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................44
7.4.1.2.
Method of Detecting AEs and SAEs ...........................44
7.4.1.3.
Follow-up of AEs and SAEs........................................44
7.4.1.4.
Cardiovascular and Death Events ..............................45
7.4.1.5.
AEs of Special Interest ...............................................45
7.4.1.6.
Regulatory Reporting Requirements for SAEs............46
7.4.2.
Pregnancy ...................................................................................47
7.4.3.
Physical Exams ...........................................................................47
7.4.4.
Vital Signs....................................................................................47
7.4.5.
Electrocardiogram (ECG).............................................................47
7.4.6.
Gastroparesis Cardinal Symptom Index Daily Dairy 
(GCSI-DD)...................................................................................48
7.4.7.
Clinical Safety Laboratory Assessments ......................................49
7.4.7.1.
FPG and HbA1c Central Laboratory ............................51
7.4.7.2.
Estimated Glomerular Filtration Rate (eGFR) .............51
7.4.8.
Diabetic Dietary Instruction and Exercise.....................................51
7.4.9.
Home Blood Glucose Monitoring .................................................51
7.4.9.1.
Fasting Capillary Blood Glucose at clinical 
visits ...........................................................................52
7.4.10.
Hyperglycemic Events .................................................................52
7.4.11.
Hypoglycemic Events...................................................................52
7.5.
Tracking of Albiglutide  and Exenatide Pen Injector Failures and 
User Errors .................................................................................................53
7.6.
Immunogenicity...........................................................................................53
7.7.
Genetics .....................................................................................................53
8.
DATA MANAGEMENT ...........................................................................................54
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................54
9.1.
Part A: Statistical Considerations and Data.................................................54
9.1.1.
Hypotheses..................................................................................54
9.1.2.
Sample Size Considerations........................................................54
9.1.2.1.
Sample Size Assumptions..........................................54
9.1.2.2.
Sample Size Re-estimation or Adjustment..................54
9.1.3.
Data Analysis Considerations ......................................................54
9.1.3.1.
Analysis Populations ..................................................55
9.1.4.
Key Elements of Analysis Plan ....................................................55
9.1.4.1.
Exploratory Analysis...................................................55
9.1.4.2.
Part A review..............................................................55
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
7
9.2.
Part B: Statistical Considerations and Data Analysis ..................................55
9.2.1.
Hypotheses..................................................................................55
9.2.2.
Sample Size Considerations........................................................55
9.2.2.1.
Sample Size Assumptions..........................................55
9.2.2.2.
Sample Size Re-estimation or Adjustment..................55
9.2.3.
Data Analysis Considerations ......................................................56
9.2.3.1.
Analysis Populations ..................................................56
9.2.3.2.
Interim Analysis..........................................................56
9.2.4.
Key Elements of Analysis Plan ....................................................56
9.2.4.1.
Primary Analysis.........................................................56
9.2.4.2.
Secondary analyses ...................................................57
9.2.4.3.
Exploratory analyses ..................................................57
10. STUDY GOVERNANCE CONSIDERATIONS........................................................57
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............57
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................57
10.3.
Quality Control (Study Monitoring) ..............................................................58
10.4.
Quality Assurance.......................................................................................59
10.5.
Study and Site Closure ...............................................................................59
10.6.
Records Retention......................................................................................59
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................60
10.8.
Review Committees....................................................................................60
10.8.1.
Pancreatitis Adjudication Committee............................................60
11. REFERENCES.......................................................................................................61
12. APPENDICES........................................................................................................65
12.1.
Appendix 1 – Abbreviations and Trademarks..............................................65
12.2.
Appendix 2: Risk Assessment for Albiglutide (GSK716155) and 
Exenatide (Byetta) ......................................................................................67
12.3.
Appendix 3: Assessment of Upper Gastrointestinal Symptom 
Severity Index (PAGI-SYM 2.0-S)...............................................................76
12.4.
Appendix 4: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP) and 
Collection of Pregnancy Information ...........................................................78
12.4.1.
Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP) ..............78
12.4.2.
Collection of Pregnancy Information ............................................78
12.5.
Appendix 5: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................80
12.6.
Appendix 6: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................83
12.6.1.
Definition of Adverse Events........................................................83
12.6.2.
Definition of Serious Adverse Events...........................................84
12.6.3.
Definition of Cardiovascular Events .............................................85
12.6.4.
Recording of AEs and SAEs ........................................................86
12.6.5.
Evaluating AEs and SAEs............................................................86
12.6.6.
Reporting of SAEs to GSK...........................................................88
12.7.
Appendix 7: Genetic Research ...................................................................89
12.8.
Appendix 8 - Country Specific Requirements..............................................92
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
8
12.9.
Appendix 9: Protocol Changes....................................................................93
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
9
1.
PROTOCOL SYNOPSIS FOR STUDY 204879
Rationale
To gain insight into a potential peripheral mechanism of nausea associated with 
glucagon-like peptide-1 receptor (GLP-1R) agonists; this study will compare the effect of 
albiglutide and exenatide on gastric myoelectrical activity (GMA), gastric emptying (GE) 
and nausea [as measured by visual analogue scale (VAS)] in subjects with type 2 diabetes 
mellitus (T2DM). The study is divided in two parts. Part A will characterize the GMA, 
GE and nausea response to exenatide and confirm exenatide as a positive control for Part 
B. Part B will compare the effects of albiglutide and exenatide on GMA, GE and nausea.
Objective(s)/Endpoint(s)
Part A is a pilot phase. Part B primary and secondary objectives are listed below:
Part B Objectives
Objectives
Endpoints
Primary
To evaluate the effect of albiglutide compared to 
exenatide on GMA.

Change from baseline in electrogastrogram 
(EGG) parameters at Weeks 2, 5, and 8 at each 
time interval (pre-and 10, 20 and 30 min after water 
load).

Distribution of average power by frequency 
region (as % of power).

Ratios of average power post-water load test 
(post-WLT)/pre water load test (pre-WLT) by 
frequency region.

Percentage (%) of time with the dominant 
EGG frequencies in the four frequency ranges 
(bradygastria, normal, tachygastria and 
duodenal).

Change from baseline in EGG parameters related 
to VAS of nausea at Week 2, 5, and 8  at each time 
interval (pre-and 10, 20 and 30 min after water 
load)
Secondary
To assess the effect of albiglutide on GE 
compared to exenatide

Change from baseline of time to half gastric 
emptying (GEt½) at Week 5 and 8

Change from baseline of profiles of 13C excreted in 
breath (kPCD1) at Weeks 5 and 8 at each time 
interval (45, 90, 120, 150, 180 and 240 min) 
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
10
Objectives
Endpoints
To assess the effect of albiglutide on the volume 
of water ingested during EGG compared to 
exenatide

Change from baseline of volume of water ingested 
during water load EGG test at Weeks 2, 5 and 8.
To evaluate the effect of albiglutide on stomach 
fullness, hunger, bloating and abdominal pain 
during EGG with water load test compared with 
exenatide
Change from baseline of VAS of stomach fullness, 
hunger, bloating and abdominal pain during the EGG 
water load test at each time interval (pre-and 10, 20 
and 30 min after water load) at Week 2, 5, and 8.
To evaluate safety and tolerability of albiglutide 
and exenatide

Vital signs, clinical laboratory tests, adverse events 
(AEs), and Gastroparesis Cardinal Symptom Index 
– Daily Diary (GCSI-DD).

Nausea AEs presenting outside the timing of the 
WLT and GCSI-DD.
Exploratory
To evaluate change in gastric rhythm status
(Data permitting)

At Weeks 2, 5, and 8; over 30 min and at each 
time interval (pre-and 10, 20 and 30 min after water 
load).
Number and % of subjects with a shift in 
gastric rhythm status.
Number and % of subjects by gastric rhythm 
status.
Mean and mean change from baseline in 
average dominant frequency
1.
Percent dose excreted of 13C *1000
Overall Design
Part A Overall Design

Part A is a single arm, open label pilot phase to evaluate the effect of 5-day repeated 
doses of exenatide (10 g twice daily) on GMA, GE and nausea in subjects with 
T2DM.

Part A will comprise 3 study periods: screening/wash-out (up to 3 weeks), treatment 
(5±1 days), and post-treatment follow-up (within 7 days after the last dose of 
exenatide). 

Part A will recruit subjects with T2DM (>6 months since diagnosis) with glycated 
hemoglobin (HbA1c) >6.5% and ≤9.0%, fasting plasma glucose (FPG) ˂210 mg/dL
(central lab) at screening and on a current regimen of diet and exercise or a stable 
dose of one oral anti-diabetic medication (OAM) (maintained for   2 months prior to 
screening).

Fasting capillary blood glucose will be confirmed to be 230 mg/dL at baseline.

Subjects receiving monotherapy with an OAM of metformin, sulfonylurea, sodium-
glucose co-transporter-2 (SGLT2) inhibitors, or meglitinide at screening will be 
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
11
washed out for 2 days for immediate release and 4 days for extended release OAM
prior to baseline. 

A subject’s nutritional plan will be optimized prior to baseline and maintained during 
the entire study.

All evaluations and assessments will be performed as outpatient visits.

Subjects will undergo 2 EGG and 2 gastric emptying breath tests (GEBT) 
assessments.

At the end of the Part A, subjects previously on an OAM will restart OAM at the 
discretion of the investigator after the last dose of exenatide. The half-life of 
exenatide (2-3 hours) should be taken into consideration.
Part A - Treatment Arms and Duration
Part A is a single arm. All subjects will receive 10 g subcutaneous exenatide twice daily 
for 5±1 days. The total duration of a subject’s participation will be approximately 5 
weeks.
Part A – Type and Number of Subjects

A sufficient number of subjects with T2DM will be screened and enrolled to achieve 
approximately 10 evaluable subjects.

If subjects prematurely discontinue the Part A, additional replacement subjects may 
be enrolled at the discretion of the Investigator in consultation with the Sponsor.
Part A Data Review
Once Part A is complete, data will be reviewed and a decision to progress or not to Part B 
will be made. A decision to progress to Part B will be made based on the confirmation
that change in GMA caused by the administration of exenatide is detectable by an EGG
with WLT. Confirmation of safety when adding the WTL on top of a GLP1 receptor 
agonist will be required to progress to Part B. Adjustments to the study design of Part B 
(e.g., endpoint evaluation and/or number of subjects) may be made prior to progression to 
Part B. Details will be described in the Reporting and Analysis Plan (RAP).
Part B: Overall Design

Part B is randomized, open-label, multicenter, active-controlled, parallel-group study 
of 8 weeks treatment duration to compare the effects of albiglutide on GMA, GE and 
nausea as measured by VAS with exenatide as a positive control. The central readers 
of EGG and GEBT tests will be blinded to assigned treatments. 

Part B will comprise 3 study periods: screening/wash-out (up to 3 weeks), treatment 
(8 weeks), and post-treatment follow-up (4 weeks). 

Part B will recruit subjects with T2DM (>6 months since diagnosis) with HbA1c
>6.5% and ≤9.0%, FPG ˂210 mg/dL (central lab) at screening and on a current 
regimen of diet and exercise or a stable dose of one OAM (maintained for 2 months 
prior to screening).
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
12

Fasting capillary blood glucose will be confirmed to be 230 mg/dL at baseline.

Subjects participating in Part A are not allowed to participate in Part B. 

Subjects receiving monotherapy with an OAM of metformin, sulfonylurea, SGLT2-
inhibitor, or meglitinide will be washed out for 2 days for immediate release and 4 
days for extended release OAM prior to randomization. 

A subject’s nutritional plan will be optimized prior to randomization and maintained 
during the entire study.

All evaluations and assessments will be performed as outpatient visits.

Subjects will undergo 4 EGG and 3 GEBT assessments.

At the end of the Part B subjects previously on an OAM will restart OAM at the 
discretion of the investigator after the last dose of study treatment. The half-life of 
albiglutide/exenatide should be taken into consideration.

At randomization, subjects will be stratified by screening HbA1c value (<7.5% and 
7.5%), and background use of OAM (OAM use versus no OAM use). Additional 
stratification may be added based on the results from Part A.
Treatment Arms and Duration 

Subjects will be randomized in a 1:1 ratio to either albiglutide or exenatide.
Medication
Albiglutide Group
Exenatide Group
Albiglutide or 
Exenatide
After Baseline EGG on Day 1: once weekly 
SC injection at 30 mg for 4 weeks.
From Week 5 Day 1: uptitrate to 50 mg once 
weekly SC injection for 4 weeks 
After Baseline EGG on Day 1: twice daily SC 
injection at 5 g for 4 weeks.
From Week 5 Day 1: uptitrate to 10 g twice 
daily SC injection for 4 weeks
SC = subcutaneous

Total duration of a subject’s participation will be approximately 15 weeks.

Down-titration (dose reduction) of albiglutide or exantide is NOT permitted.  If a 
subject experiences tolerability issues then the subject may be withdrawn from the 
study at the discretion of the investigator.
Type and Number of Subjects

Approximately 62 subjects with T2DM will be randomized. Assuming 20% of 
subjects will be withdrawn or lost to follow-up this will allow for 50 evaluable 
subjects (25 evaluable subjects per treatment group).
Analysis
The primary and secondary endpoints will be analyzed using a mixed-effect model with 
repeated measures (MMRM). The MMRM will be assessed to compare albiglutide to 
exenatide.
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
13
2.
INTRODUCTION
2.1.
Study Rationale
GLP-1R agonists (i.e., exenatide, liraglutide, albiglutide, lixisenatide, and dulaglutide) 
are medications for the treatment of T2DM. All have demonstrated reductions in HbA1c, 
FPG without body weight gain while having a low risk of hypoglycemia. 
Gastrointestinal (GI) adverse events are relevant for this therapeutic class, with increased 
incidence of nausea and vomiting [Leiter, 2014; Reusch, 2014; Rosenstock, 2009; 
Neumiller, 2009]. Various mechanisms have been proposed to explain the 
pathophysiology of nausea associated with GLP-1R agonists, including food 
accumulation in the stomach due to slowing gastric emptying, activation of peripheral 
GLP-1R and subsequent stimulation of the central nervous system (CNS) via vagal 
afferents and direct activation of CNS GLP-1R [Baggio, 2004]. The incidence of nausea 
varies among the members of this therapeutic class [Sun, 2012, Trujillo, 2015]. 
The dose- and time-dependent effects of albiglutide were evaluated in a Phase 2b dose 
ranging, open-label, active reference (exenatide) study.  The proportion of subjects with 
nausea and or vomiting was less than 10% at each week with albiglutide 30 mg weekly 
and declined over time, with no nausea or vomiting after 8 weeks. The incidence of 
nausea and/or vomiting with exenatide reached 20% by week 2, increased at week 5 to a 
peak incidence of 29% after uptitration and declined over time [Rosenstock, 2009]. 
Albiglutide 50 mg weekly dose was not included in this study. However 50 mg bi-weekly 
and monthly and 100 mg monthly were studied. Starting albiglutide at 50- or 100 mg was 
associated with a higher incidence of nausea/vomiting. 
In a head to head, 32-week, open-label clinical trial in patients with T2DM, in which non-
inferiority of albiglutide of a 95% confidence interval (CI) upper margin of 0·3% for 
HbA1c was not met, the incidence of nausea was 9.9% for albiglutide and 29.2% for 
liraglutide, and the incidence of vomiting 5.0% and 29.3% respectively [Pratley, 2014]. 
In a 26-week open-label, forced titration clinical trial, nausea was reported in 
approximately 25.5% and 28% of subjects treated with liraglutide and exenatide, 
respectively [Buse, 2009]. In exenatide Phase 3 program, nausea was reported in up to
44% of subjects receiving exenatide [Byetta, US Prescribing Information, 2015]. 
Dulaglutide, another once weekly GLP-1R agonist reported ~20% incidence of nausea at 
the highest approved dose in the results from pooled placebo-controlled trials [Trulicity, 
US Prescribing Information, 2015].
The reasons for the differences in incidence of nausea in clinical trials between
albiglutide and other GLP-1R agonists are not fully understood. Potential explanations 
include differences in the pharmacokinetic profiles (e.g., albiglutide Tmax 3 days, 
dulaglutide Tmax 2 days, exenatide Tmax 2.1 h, or liraglutide Tmax 13h). It is unknown 
if these differences result in compound specific patterns of receptor occupancy and 
pharmacodynamic response. Differences in molecular size and structure among GLP-1R 
agonists may also impact penetration through the blood brain barrier and activity in brain 
receptors. 
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
14
Electrogastrogram (EGG) is a noninvasive technique to assess GMA [Koch, 2001]. It is 
used in clinical practice to identify if patients with nausea and other upper GI symptoms 
without mechanical causes have disturbances in the myoelectrical gastric rhythm, and to 
confirm the diagnosis of gastroparesis. “EGG with water load test” is a standardized test 
to induce gastric distention and measure myoelectrical responses as well as collect VAS 
of upper gastrointestinal symptoms (stomach fullness, hunger, nausea, bloating and 
abdominal pain) under standardized conditions. The gastric distention produced by the 
water load induces nausea in a high proportion of patients, allowing the assessment of 
GMA during the episodes of nausea. Episodes of nausea are typically associated with 
disturbance in GMA called gastric dysrhythmias.
To gain insight into a potential peripheral mechanism of nausea associated with GLP-1R 
agonists; this study will compare the effect of albiglutide and exenatide on GMA, GE and 
VAS of nausea in T2DM subjects. Albiglutide will be administered weekly at the initial 
dose of 30 mg and uptitrated to 50 mg after 4 weeks. Exenatide will be administered 
twice daily at dose of 5g and uptitrated to 10 g twice daily after 4 weeks. The study is 
divided in two parts. Part A will characterize the GMA, GE response and nausea to 
exenatide and confirm exenatide as a positive control for Part B. Part B will compare the 
effects of albiglutide and exenatide on GMA, GE and nausea.
2.2.
Brief Background
Albiglutide is a recombinant fusion protein (molecular weight of ~73kDa) consisting of 
two copies of a 30-amino-acid sequence of modified human GLP-1 linked in tandem to 
human albumin [Matthews, 2008; Bush, 2009]. The GLP-1 sequence has been modified 
to confer resistance to DPP-4-mediated proteolysis. These modifications greatly extend 
the half-life (approximately 5 days), allowing once weekly dosing by subcutaneous 
injection and a steady state within 3-4 weeks. 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; Rosenstock, 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 that shares 53% sequence homology with human 
GLP-1 [Goke, 1993]. 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]. 
In normal subjects the GMA is generated by the pacemaker interstitial cells of Cajal, 
located in upper third of gastric body on the greater curvature, that discharge at a normal 
frequency of 3 cycles per minute (cpm) [Koh, 1998]. The shift of frequency from normal 
GMA to a slower (bradygastria) or faster (tachygastria) rhythm is termed as gastric 
dysrhythmia. These gastric dysrhythmias have been linked to nausea in clinical trials, and 
the use of GMA assessed in EGG with water load test has been suggested as a useful tool 
to evaluate and characterize nausea in a variety of clinical conditions [Koch, 2001]. 
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
15
A preclinical study in ferrets demonstrated that exenatide administered peripherally 
induced retching and resulted in gastric dysrhythmias detected using radiotelemetry [Lu, 
2014]. No studies to date have evaluated the effect of GLP-1R agonists on GMA in 
humans. 
GEBT is a recently FDA approved method to measure GE of solid food in adults. 
Performance characteristics of GEBT are comparable to those of the gold standard of 
gastric emptying scintigraphy. GEBT is a non-radioactive and non-invasive technology.
3.
OBJECTIVE(S) AND ENDPOINT(S)
3.1.
Part A: Objectives and Endpoints
Objectives
Endpoints
Exploratory
To evaluate the effect of exenatide on GMA 

Change from baseline of EGG parameters at 
each recording time interval (pre-and 10, 20 and 
30 min after water load) compared to baseline: 

Distribution of average power by frequency 
region (as % of power)

Ratios of average power post- WLT/pre-
WLT by frequency region

Percentage (%) of time with the dominant 
EGG frequencies in the four frequency 
ranges (bradygastria, normal, tachygastria
and duodenal)

Change from baseline EGG parameters related 
to VAS of nausea at each recording time 
interval (pre-and 10, 20 and 30 min after water 
load) at Day 4:
To assess the effect of exenatide on GE

Change from baseline of time to half gastric 
emptying (GEt½) at Week 5 and 8

Change from baseline of profiles of 13C 
excreted in breath (kPCD1) at Day 5 and at 
each time interval (45, 90, 120, 150, 180 and 
240 min).
To assess the volume of water ingested during EGG 
Change from baseline of volume of water ingested 
during EGG with water load test at Day 4.
To evaluate the effect of exenatide on stomach 
fullness, hunger, bloating and abdominal pain during 
EGG with water load test
Change from baseline of VAS of stomach fullness, 
hunger, bloating and abdominal pain during the 
EGG water load test at each time interval (pre-and 
10, 20 and 30 min after water load) at Day 4
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
16
Objectives
Endpoints
Exploratory
To evaluate safety and tolerability of exenatide 
Vital signs, clinical laboratory tests, AEs, 
and GCSI-DD.
Nausea AEs presenting outside the timing 
of the WLT and GCSI-DD.
To evaluate change in gastric rhythm status (Data 
permitting)

At Weeks 2, 5, and 8; over 30 min and at each 
time interval (pre-and 10, 20 and 30 min after 
water load).
Number and % of subjects with a shift in 
gastric rhythm status.
Number and % of subjects by gastric 
rhythm status.
Mean and mean change from baseline in 
average dominant frequency
1.
Percent dose excreted of 13C *1000
3.2.
Part B: Objectives and Endpoints
Objectives
Endpoints
Primary
To evaluate the effect of albiglutide on GMA 
compared to exenatide

Change from baseline in EGG parameters at 
Weeks 2, 5, and 8 at each time interval (pre-and 
10, 20 and 30 min after water load) 

Distribution of average power by frequency 
region (as % of power)

Ratios of average power post-WLT/pre-WLT 
by frequency region

Percentage (%) of time with the dominant 
EGG frequencies in the four frequency ranges 
(bradygastria, normal, tachygastria and 
duodenal)

Change from baseline in EGG parameters related 
to VAS of nausea at Week 2, 5, and 8 at each time 
interval (pre-and 10, 20 and 30 min after water 
load)
Secondary
To assess the effect of albiglutide on GE 
compared to exenatide

Change from baseline of time to half gastric 
emptying (GEt½) at Weeks 5 and 8

Change from baseline of profiles of 13C excreted in 
breath (kPCD1) at Weeks 5 and 8 and at each time 
interval (45, 90, 120, 150, 180 and 240 min)
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
17
Objectives
Endpoints
To assess the effect of albiglutide on the volume 
of water ingested during EGG compared to 
exenatide
Change from baseline of volume of water ingested 
during water load EGG test at, Weeks 2, 5 and 8.
To evaluate the effect of albiglutide on stomach 
fullness, hunger, bloating and abdominal pain 
during EGG with water load test compared with 
exenatide
Change from baseline of VAS of stomach fullness, 
hunger, bloating and abdominal pain during the EGG 
water load test at each time interval (pre-and 10, 20 
and 30 min after water load) at Weeks 2, 5, and 8.
To evaluate safety and tolerability of albiglutide 
and exenatide

Vital signs, clinical laboratory tests, AEs, and GCSI-
DD.

Nausea AEs presenting outside the timing of the 
WLT and GCSI-DD.
Exploratory
To evaluate change in gastric rhythm status 
(Data permitting)

At Weeks 2, 5, and 8; over 30 min and at each 
time interval (pre-and 10, 20 and 30 min after water 
load).
Number and % of subjects with a shift in 
gastric rhythm status.
Number and % of subjects by gastric rhythm 
status.
Mean and mean change from baseline in 
average dominant frequency
1.
Percent dose excreted of 13C *1000
4.
STUDY DESIGN
The study will be conducted in two phases (Part A and Part B). The study results from 
Part A will be evaluated and a decision to progress to Part B will be made based on the 
confirmation that change in GMA caused by the administration of exenatide is detectable 
by an EGG with WLT.
4.1.
Part A: Study Design
4.1.1.
Overall Design

Part A is a single arm, open label pilot phase to evaluate the effect of 5-day 
repeated doses of exenatide (10 g twice daily) on GMA, GE and nausea in
subjects with T2DM.

Part A will comprise 3 study periods (Figure 1.): screening/wash-out (up to 
3 weeks), treatment (5±1 days), and post-treatment follow-up (within 7 days after 
the last dose of exenatide). 

Part A will recruit subjects with T2DM (>6 months since diagnosis) with HbA1c
>6.5% and ≤9.0%, FPG ˂210 mg/dL (central lab) at screening and on a current 
regimen of diet and exercise or a stable dose of one OAM (maintained for 2
months prior to screening).
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
18

Fasting capillary blood glucose will be confirmed to be 230 mg/dL at baseline
(see Section 5.3).

Subjects receiving monotherapy with an OAM of metformin, sulfonylurea, 
sodium-glucose co-transporter-2 (SGLT2) inhibitors, or meglitinide at screening 
will be washed out for 2 days for immediate release and 4 days for extended 
release OAM prior to baseline. 

A subject’s nutritional plan will be optimized following screening and maintained 
during the entire study.

All evaluations and assessments will be performed as outpatient visits.

Subjects will undergo 2 EGG and 2 GEBT assessments.

At the end of the Part A subjects previously on an OAM will restart OAM at the 
discretion of the investigator after the last dose of exenatide. The half-life of 
exenatide (2-3 hours) should be taken into consideration (see Section 6.9).

An overview of the study design for Part A is provided in Figure 1.
Figure 1
Study Schematic for Part A
FU-visit
Screening/washout
(0-3 weeks)
Treatment/Assessments
(5 days)
Follow-
up 
T2DM  
Diet/exercise 
or 
+1 OAM
HbA1c:
>6.5/≤9.0%
FPG:      
<210mg/dL
Pre-dose 
EGG
2-4 days OAM 
Wash-out
FCG 
≤ 230 mg/dL
at baseline  
(Day -1)
Exenatide
10 g  BID for 5 days 
(N=10)
1st dose Exenatide
(Day 1 after Pre-dose EGG)
Up to 3 weeks
Within 7 days 
Day 2
Day 3
Day 4
Day 5
Day  1
Day -1
Pre-dose 
GEBT
On-therapy 
EGG
On-therapy 
GEBT
Note: Two day washout for immediate release and 4 day washout for extended release OAMs.
FCG; fasting capillary blood glucose.
4.1.2.
Treatment Arms and Duration
Part A is a single arm design. All subjects will receive 10 g subcutaneous exenatide 
twice daily for 5±1 days. The total duration of a subject’s participation will be 
approximately 5 weeks.
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
19
4.1.3.
Number of Subjects

A sufficient number of subjects with T2DM will be screened and enrolled to achieve 
approximately 10 evaluable subjects.

If subjects prematurely discontinue the Part A, additional replacement subjects may
be enrolled at the discretion of the Investigator in consultation with the Sponsor.
4.2.
Part A Data Review
Once Part A is complete, data will be reviewed and a decision to progress to Part B will 
be made. Adjustments to the study design of Part B (e.g., endpoint evaluation and/or 
number of subjects) may be made prior to progression to Part B. A decision to progress to 
Part B will be made based on the confirmation that change in GMA caused by the 
administration of exenatide is detectable by an EGG with WLT. Confirmation of safety 
when adding the WTL on top of a GLP1 receptor agonist will be required to progress to 
Part B. Details will be described in the RAP.
Changes resulting from Part A review including refinement of endpoints and statistical 
assessment of the endpoints will be incorporated in the RAP and will not be considered 
an amendment to the Protocol.
4.3.
Part B: Study Design
4.3.1.
Overall Design

Part B is randomized, open-label, multicenter, active-controlled parallel group, 
study of 8 weeks treatment duration to compare the effects of albiglutide on 
GMA, GE and nausea as measured by VAS with exenatide as a positive control. 
The central readers of EGG and GEBT tests will be blinded to assigned 
treatments. 

Part B will comprise 3 study periods (Figure 2): screening/wash-out (up to 
3 weeks), treatment (8 weeks), and post-treatment follow-up (4 weeks). 

Part B will recruit subjects with T2DM (>6 months since diagnosis) with HbA1c
>6.5% and ≤9.0%, FPG ˂210 mg/dL (central lab) at screening and on a current 
regimen of diet and exercise or a stable dose of one OAM (maintained for 2
months prior to screening).

Fasting capillary blood glucose will be confirmed to be 230 mg/dL at baseline 
(see Section 5.3).

Subjects participating in Part A are not allowed to participate in Part B. 

Subjects receiving monotherapy with an OAM of metformin, SGLT2-inhibitor, 
sulfonylurea or meglitinide will be washed out for 2 days for immediate release 
and 4 days for extended release OAM prior to randomization. 

A subject’s nutritional plan will be optimized following screening and maintained 
during the entire study.

All evaluations and assessments will be performed as outpatient visits.
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
20

Subjects will undergo 4 EGG and 3 GEBT assessments.

At randomization, subjects will be stratified by screening HbA1c value (<7.5% 
and 7.5%), and background use of OAM (OAM use versus no OAM use). 
Additional stratification may be added based on the results from Part A.

At the end of the Part B subjects previously on an OAM will restart OAM at the 
discretion of the investigator after the last dose of study treatment. The half-life of 
albiglutide/exenatide should be taken into consideration (see Section 6.9).

An overview of the study design for Part B is provided in Figure 2.
Figure 2
Study Schematic for Part B
Follow-up
Screening/wash-out
(0-3 weeks)
Treatment/Assessments
(8 weeks)
Follow-up
(4 weeks)
T2DM  (N=62)
Diet/ exercise 
or 
+1 OAM
HbA1c:
>6.5/≤9.0%
FPG:
<210mg/dL
Albiglutide 
30mg weekly for 4 weeks
(N=31)
Up to 3 weeks
1.Pre-dose GEBT and EGG (x1): Day -1 and Day 1, respectively
2. Post-dose EGG (x3): Day 3 of Week, 2, 5 and  8
3. Post-dose GEBT (x2): Day 4 of Week 5 and 8
Albiglutide 
50mg weekly for 4 weeks
(N=31)
Exenatide
10 g  BID for 4 weeks
(N=31)
Uptitration
(Wk 5, Day 1)
1st Dose Albiglutide
(Day 1)
2-4 
days 
OAM 
Wash-
out
Exenatide
5 g BID for 4 weeks
(N=31)
Follow-up
1st Dose Exenatide
(Day 1)
Randomization  FCG: ≤230mg/dL
Uptitration
(Wk 5, Day 1)
Wk 1
Wks  9-12
Wk 2
Wk 3
Wk 4
Wk 5
Wk 6 
Wk 7
Wk 8
Note: Two day washout for immediate release and 4 day washout for extended release OAMs.
FCG; fasting capillary blood glucose
4.3.2.
Treatment Arms and Duration

Subjects will be randomized in a 1:1 ratio to either albiglutide or exenatide.
Medication
Albiglutide Group
Exenatide Group
Albiglutide or 
Exenatide
After Baseline EGG on Day 1: once weekly 
SC injection at 30 mg for 4 weeks.
From Week 5 Day 1: uptitrate to 50 mg once 
weekly SC injection for 4 weeks 
After Baseline EGG on Day 1: twice daily SC 
injection at 5 g for 4 weeks.
From Week 5 Day 1: uptitrate to 10 g  twice 
daily SC injection for 4 weeks
SC = subcutaneous

Total duration of a subject’s participation will be approximately 15 weeks
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
21

Down-titration (dose reduction) of albiglutide or exenatide is NOT permitted (see 
Section 6.3).  If a subject experiences tolerability issues then the subject may be 
withdrawn from the study at the discretion of the investigator.

During the study, any potential events of pancreatitis will be adjudicated by an 
independent pancreatitis adjudication committee (PAC) (Section 10.8).
4.3.3.
Number of Subjects

Approximately 62 subjects with T2DM will be randomized. Assuming 20% of 
subjects maybe withdrawn or lost to follow-up this will allow for 50 evaluable 
subjects (25 evaluable subjects per treatment group).
4.4.
Design Justification

This study is designed to gain insight into a potential peripheral 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. This study will compare the effect of albiglutide and exenatide on 
GMA, GE and VAS of nausea in T2DM subjects. 

The study population, indication and doses of albiglutide and exenatide used in this 
study are consistent with the approved prescribing information (PI) for albiglutide 
and exenatide, respectively.  

The treatment duration will allow the evaluation of GMA, GE and VAS of nausea at 
expected steady-state and over time for both medications.

EGG, GE and VAS of nausea will be assessed at the timing of expected Cmax.  

Exenatide, a short acting GLP-1R agonist is used as a positive control. In the 
exenatide Phase 3 program, nausea was reported in up to 44% of subjects receiving 
exenatide [Byetta, US Prescribing Information, 2015]. Clinical data comparing 
albiglutide with exenatide is available from the albiglutide Phase 2b study 
[Rosenstock, 2009].

The response of GMA to GLP-1R agonists has not been characterized in humans. 
Therefore, the study will be conducted in two phrases (Part A and Part B). Part A will 
characterize the effects of exenatide on GMA, GE, and nausea and confirm exenatide 
as a positive control for Part B. Part B will compare the effects of albiglutide to 
exenatide on GMA, GE and nausea.
4.5.
Dose Justification
The use of albiglutide and exenatide in the study starting with 30 mg and 5µg, 
respectively is consistent with the recommended starting doses according to PIs for 
albiglutide and exenatide, respectively.  Escalation to 50 mg and 10µg is also consistent 
with the maximal approved doses in clinical practice for both products.  This dosing 
approach will give the opportunity to assess and provide clinically meaningful data on 
nausea gastric mechanisms for the available regimens that clinicians prescribe to their 
patients. 
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
22
Albiglutide
Phase 3 studies confirmed the glycemic efficacy of both 30 mg and 50 mg doses of 
albiglutide, and both were generally well-tolerated. Although the 30 mg dose was 
effective at controlling glycemia for at least 2 years in many subjects with T2DM, an 
increase in dose to 50 mg weekly offered additional benefit without additional significant 
safety issues [See Investigator Brochure (IB) for further details].
Exenatide
Exenatide is approved to be initiated at 5 g administered twice daily at any time within 
the 60-min period before the morning and evening meals. Based on clinical responses in 
clinical practice, the dose of exenatide can be increase to 10 g bid.
4.6.
Benefit:Risk Assessment
Albiglutide has been evaluated in a comprehensive global program of studies involving 
over 4000 subject-years of exposure to albiglutide. The program included 8 well-
controlled Phase 3 studies, ranging in duration from 32 weeks to 3 years 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 that has included 
newly diagnosed subjects treated with diet and exercise alone through to subjects on 
background oral monotherapy, oral dual therapy, oral triple therapy, and basal insulin.
Summaries of findings from both clinical and non-clinical studies conducted with the 
albiglutide (GSK716155) can be found in the IB and in the US PI [Tanzeum, US 
Prescribing Information, 2015].
Summaries of findings from both clinical and nonclinical studies conducted with 
exenatide can be found in the PI [Byetta, US Prescribing Information, 2015].
The following sections outline the risk assessment and mitigation strategy for this 
protocol.
4.6.1.
Risk Assessment
Key identified and potential risks associated with the administration of albiglutide or 
exenatide, study participation or study procedures, and the mitigation strategies for key 
risks of clinical significance are summarized in Appendix 2. 
For albiglutide, please also refer to the IB and any IB supplements as well as the 
complete Guidance for the Investigator and the US PI [Tanzeum, US Prescribing 
Information, 2015]. For exenatide refer to the US PI [Byetta, US Prescribing Information, 
2015].
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
23
4.6.2.
Benefit Assessment
Both albiglutide and exenatide have been approved in the US as an adjunct to diet and 
exercise to improve glycemic control in adults with T2DM. The clinical data from the 
albiglutide Phase 3 development program showed that once-weekly albiglutide treatment 
(both with the 30 mg and 50 mg doses) resulted in clinically relevant lowering of HbA1c
and FPG in subjects with T2DM. The clinical data from the exenatide Phase 3 
development program indicated that 5 g bid for a month followed by 10 g bid resulted 
in clinically relevant lowering of HbA1c and FPG in subjects with T2DM [Byetta, US 
Prescribing Information, 2015].
In Part A, eligible subjects will only receive exenatide for 5±1 days; the benefit in 
glycemic control is expected to be minimal due to this short period of treatment. 
In Part B, subjects receiving study treatment (albiglutide or exenatide) as an adjunct to 
diet and exercise are expected to show beneficial reductions in HbA1c and FPG.
All subjects will receive diet and exercise advice reinforced at each visit, and medical 
examination at screening and follow up visits at no cost.
4.6.3.
Overall Benefit:Risk Conclusion
Measures to minimize risks provide protection to the subjects.  The relatively short 
duration of both Part A and Part B of the study may not allow the subjects to experience 
the full benefit of treatment in glycemic control typically observed in clinical practice on 
treatment with albiglutide or exenatide. Data from this study will contribute to the overall 
knowledge of the benefit-to-risk profile of albiglutide and exenatide. The results may 
help physicians to better understand T2DM, treatment for T2DM and the mechanism of 
GI tolerability (nausea) with study medications.
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, AEs, and other 
pertinent information on the GlaxoSmithKline (GSK) investigational product or other 
study treatment that may impact subject eligibility is provided in the IB/IB supplement(s) 
and US PI [Tanzeum, US Prescribing Information, 2015] for albiglutide and the US PI 
for exenatide [Byetta, US Prescribing Information, 2015].
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
24
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 60 years of age at the time of signing the informed consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY 
2.
T2DM diagnosed at least 6 months prior to screening.
3.
Subjects treated with diet and exercise alone or stable dose of single OAM of 
metformin, sulfonylurea (except chlorpropamide), SGLT2-inhibitor, or meglitinide 
for at least 2 months prior to screening.
4.
HbA1c >6.5% and ≤9.0% at screening. If the first HbA1c value does not meet 
eligibility criterion, the HbA1c may be rechecked once during screening.  If the 
average of these determinations meets the criterion, the subject is eligible.
5.
FPG 210 mg/dL (central lab) at screening. If the first FPG value does not meet 
eligibility criterion, the FPG may be rechecked once during screening.
6.
Patient assessment of upper gastrointestinal symptom severity index (PAGI-SYM 
2.0-S, Appendix 3) at screening:

Overall score 20 (if score is 21 and 25, subjects can be re-evaluated 2 weeks 
later)

Total score of items 1-9 is 9

Score from any of single item 2
WEIGHT
7.
Body mass index (BMI) >20 kg/m2 and <35 kg/m2 and a stable weight (no more than 
5% reported change within 3 months prior to screening).
SEX
8. Male or female.
9. Female: subject is eligible to participate if she is not pregnant (as confirmed by a 
negative serum human chorionic gonadotrophin (hCG) test for females of 
reproductive potential only), not breastfeeding, and at least one of the following 
conditions applies:
a) Reproductive potential and agrees to follow one of the options listed in the 
Modified List of Highly Effective Methods for Avoiding Pregnancy in Females 
of Reproductive Potential (FRP) (eg., combined oral contraceptive pill; see 
Appendix 4) from 30 days prior to the first dose of study medication and until 
after the last dose of study medication and completion of the follow-up visit.
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
25
b) Non-reproductive potential defined as either:

Pre-menopausal with one of the following: (i) documented tubal ligation; (ii) 
documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion; (iii) hysterectomy; or (iv) documented 
bilateral oophorectomy, or; 

Postmenopausal defined as 12 months of spontaneous amenorrhea and age 
appropriate (i.e., >50 years). In questionable cases, a blood sample with 
simultaneous follicle stimulating hormone (FSH) >40 mIU/mL and estradiol 
<40 pg/mL (<140 pmol/L) is confirmatory, depending on local laboratory 
ranges.  Females on hormone replacement therapy (HRT) and whose 
menopausal status is in doubt will be required to use one of the highly effective 
contraception methods if they wish to continue their HRT during the study.  
Otherwise, they must discontinue HRT to allow confirmation of post-
menopausal status prior to study enrolment.
REGULAR AND OTHER MEDICATIONS
10.
For the regular use of other medications (does not include medications excluded 
by the protocol), subjects must be on a stable dose for at least 4 weeks before screening. 
INFORMED CONSENT
11. 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.
Type 1 diabetes mellitus
2.
T2DM treated with more than one OAM or with chronic use of insulin within 3 
months prior to screening
3.
Hemoglobin <11 g/dL (<110 g/L) for male subjects and <10 g/dL (<100 g/L) for 
female subjects at screening
4.
Fasting triglyceride level >500 mg/dL at screening
5.
Hemoglobinopathy that may affect proper interpretation of HbA1c
6.
History of cancer that has not been in full remission for at least 3 years before 
screening. (A history of squamous cell or basal cell carcinoma of the skin or treated 
cervical intra-epithelial neoplasia I or II is allowed). 
7.
Personal or family history of medullary thyroid carcinoma (MTC) or multiple 
endocrine neoplasia type 2 (MEN-2).
8.
History of acute or chronic pancreatitis.
9.
History or current severe lactose intolerance
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
26
10. History of thyroid dysfunction or an abnormal (i.e., outside the normal reference 
range) thyroid function test assessed by thyroid stimulating hormone (TSH) at 
screening.
11. Alanine aminotransferase (ALT) >2.5x upper limit of normal (ULN).
12. Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%).
13. Current active liver or biliary disease (with the exception of Gilbert’s syndrome or 
asymptomatic gallstones or otherwise stable chronic liver disease per investigator 
assessment). 
NOTES: 

Stable chronic liver disease should generally be defined by the absence of 
ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or 
gastric varices, or persistent jaundice, or cirrhosis.
14. Clinical diagnosis of gastroparesis.
15. History of significant gastrointestinal medical conditions such as chronic 
esophagitis, peptic ulcer diseases, celiac disease, inflammatory bowel disease, 
unexplained abdominal pain or irritable bowel syndrome and/or history of surgery 
that in the opinion of the investigator is likely to significantly affect upper 
gastrointestinal or pancreatic function (e.g., gastric bypass, gastric banding, 
antrectomy, Roux-en-Y bypass, gastric vagotomy, small bowel resection, or 
surgeries thought to significantly affect upper GI function).
16. History of hypoglycemia unawareness (i.e., the absence of autonomic warning 
symptoms before the development of neuroglycopenic symptoms such as blurred 
vision, difficulty speaking, feeling faint, difficulty thinking, and confusion).
17. Diabetic complications (e.g., active proliferative retinopathy or severe diabetic 
neuropathy) or any other clinically significant abnormality (including a psychiatric 
disorder) that, in the opinion of the investigator, may pose additional risk in 
administering the investigational product or may influence data interpretation. 
18. Clinically significant cardiovascular (CV) and/or cerebrovascular disease at any 
time, such as prior MI, unstable angina, stroke, transient ischemic attack or 
documented heart failure, before screening.
19. Estimated glomerular filtration rate (eGFR) eGFR ≤75 mL/min/1.73 m2 [calculated 
using the Modification of Diet in Renal Disease (MDRD) formula] at screening.
20. Lung diseases associated with pulmonary dysfunction (e.g. chronic obstructive 
pulmonary disease).
21. 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 should be excluded unless 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.  
CONCOMITANT MEDICATIONS
22. Unable to refrain from medications that might modify GMA or gastrointestinal 
motility, such as prokinetics (e.g., erythromycin), anti-emetics (e.g., 
metoclopromide), narcotics (e.g., morphine), anticholinergics (e.g.,domperidone), 
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
27
anti-acids (e.g., proton pump inhibitors, H2 blockers) and laxatives, received within 7 
days prior to screening or high likelihood of a requirement during the study.
23. Use of oral or systemically injected glucocorticoids within the 3 months prior to 
randomization or high likelihood of a requirement for prolonged treatment (>1 week) 
in the 4months following randomization. However, short courses of oral steroids 
(single dose or multiple doses for up to 7 days) may be permitted provided these 
cases are discussed with the Medical Monitor. Inhaled, intra-articular, epidural, and 
topical corticosteroids are allowed.
CONTRAINDICATIONS 
24. Known allergy to albiglutide, exenatide or any product components (including yeast 
and human albumin), any other GLP-1 analogue, or other study treatment excipients 
OR other contraindications (per the PI) for the use of potential study treatment.
25. Intolerance or allergy to any component of gastric emptying test meal
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
26.
Received any GLP-1R agonist at any time
27.
Receipt of any investigational drug within the 30 days or 5 half-lives, whichever is 
longer, before screening, a history of receipt of an investigational antidiabetic drug 
within the 3 months before randomization.
28.
Exposure to more than 4 investigational medicinal products within 12 months prior 
to the first dosing day.
5.3.
Additional Inclusion Criteria for Randomization
Subjects must have fasting capillary blood glucose 230 mg/dL on Day -1 (baseline) or 
randomization. If fasting capillary blood glucose is >230mg/dL, the test should be 
repeated immediately on the same day. If the average of the 2 values of fasting capillary 
blood glucose is 230mg/dL, the subject can enter the study. If the average of the 2 
values of fasting capillary blood glucose is >230mg/dL, then subject can be re-tested
once as described above on a different day within the screening period.  
5.4.
Screening/Randomization Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomized. In order to ensure transparent reporting of screen 
failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and respond to queries from Regulatory authorities, a minimal 
set of screen failure information is required including Demography, Screen Failure 
details, Eligibility Criteria, and Serious Adverse Events (see Section 7.4.1.6).
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
28
5.5.
Withdrawal/Stopping Criteria
Every effort should be made to keep subjects in the study. The reason for a subject not 
completing the study will be recorded in the subject’s electronic case report form (eCRF). 
Any subject experiencing the following will be required to discontinue study treatment
and will be withdrawn from the study:

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, acute or chronic (see Section 7.4.1.5).

Pancreatic cancer.

Confirmed MTC or other thyroid C-cell neoplasia.  

Liver chemistry abnormalities exceeding the threshold criteria outlined in 
Section 5.5.1

Severe allergic/hypersensitivity reactions that are considered by the 
investigator to be attributable to investigational product or that are not 
reasonably attributable to another cause (see Section 7.4.1.5). 

Recurrent hypoglycemia during the treatment period posing a potential risk to 
the subject, as judged by the investigator. 

Fasting capillary blood glucose 270 mg/dL after randomization on 3 consecutive 
days confirmed by central laboratory FPG (to be done within 1 week of the home 
glucose monitoring). 

eGFR <60mL/min/1.73 m2 (calculated using the MDRD formula).

Subject becomes pregnant or intends to become pregnant during the study.

Need for chronic use of a prohibited concomitant medication (Section 6.10.2)

Major protocol deviation (the investigator should discuss the protocol deviation with 
the Medical Monitor before withdrawing study medication).

Non compliance with study treatment. If a subject misses one dose of albiglutide or 
14 doses of exenatide, the investigator should contact the Medical Monitor, who will 
make a decision (on a case by case basis) on whether the subject should be withdrawn 
from the study for non compliance.

Subject decision (reason to be documented in the eCRF, if specified by the subject)

Investigator discretion 

Study closed/terminated or investigator site closed (where subject transfer to another 
site is not possible).
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
29
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 for next day. 

The site must counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in 
the study. 

In cases where the subject is deemed ‘lost to follow up’, the investigator or designee 
must make every effort to regain contact with the subject (where possible, 3 telephone 
calls and if necessary a certified letter to the subject’s last known mailing address or 
local equivalent methods). These contact attempts should be documented in the 
subject’s medical record. 

Should the subject continue to be unreachable, only then will he/she be considered to 
have withdrawn from the study with a primary reason of “Lost to Follow-up”. 
Subjects who are withdrawn or discontinue active participation in the study will no 
longer receive the randomized study treatment. Immediately upon discontinuation from 
active participation in this study, these subjects should complete the early withdrawal 
assessments and return for follow-up assessments (within 7 days for Part A and 4 weeks 
for Part B; Time and Events Table Section 7.1). If the subjects are unable or unwilling to 
return for the follow-up assessments, GSK will make every effort to follow-up with the 
subjects or their physician or caregiver.
A subject may withdraw from study treatment at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioral or 
administrative reasons. If a subject withdraws from the study, he/she may request 
destruction of any samples taken, and the investigator must document this in the site 
study records. 
Early withdrawn subjects previously on an OAM will restart OAM at the discretion of the 
investigator. The half-life of albiglutide/exenatide should be taken into consideration (see 
Section 6.9).
Study medication withdrawal will require withdrawal from the study. Withdrawn subjects 
may be replaced in study Part A; replacement subjects will be enrolled at the discretion of 
the Investigator in consultation with the Sponsor. Withdrawn subjects will not be 
replaced in Part B.
5.5.1.
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 US Food 
and Drug Administration (FDA) premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
30
Phase 3-4 Liver Chemistry Stopping and Increased Monitoring Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus 
Bilirubin≥2x
ULN (>35% 
direct) or plus
INR>1.5, if 
measured*
Possible  
Hy’s Law
ALT≥3xULN
ALT
≥8xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
No
Yes
Yes
Yes
No
No
No
See algorithm 
for continued 
therapy with 
increased liver 
chemistry 
monitoring
Yes
*INR value not applicable to subjects on anticoagulants 
ALT 
≥3xULN 
but 
<8xULN
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 5
Phase 3-4 Liver Chemistry Increased Monitoring Algorithm with Continued 
Therapy for ALT 3xULN but <8xULN
Continue Study Treatment   and   Monitor Liver Chemistry
Discontinue Study Treatment 
ALT≥5xULN 
but <8xULN
+ bili <2xULN +
no symptoms
No
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Yes
ALT ≥3xULN 
but <5xULN
+ bili <2xULN  +
no symptoms
Able to 
monitor  
weekly 
for  ≥2 
weeks
Persists for 
≥2 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
No
No
Able to 
monitor  
weekly 
for  ≥4 
weeks
Persists for 
≥4 weeks  
or other 
stopping 
criteria  
met
No
Yes
Yes
Yes
Yes
ALT ≥5xULN 
ALT <5xULN 
Yes
Yes
*INR value not applicable to subjects on anticoagulants 
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
31
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 5
5.5.1.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any subject participating in this study is not allowed.
5.6.
Subject and Study Completion
A completer for Part A is one who has completed all phases of the study described for 
Part A including the follow-up visit.  A completer for Part B is one who has completed all 
phases of the study described for Part B including the follow-up visit.
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.
A description of the study treatments is provided in Table 1
Table 1
Study Treatment
Study Treatment
Product name:
Albiglutide (Tanzeum in US)
Exenatide (Byetta)
Formulation/Dosage 
form/Delivery system:
Lyophilized albiglutide is provided 
as a fixed-dose, fully disposable 
pen injector system for delivery of 
the study treatment from a prefilled 
dual chamber cartridge (DCC) that 
is an integral part of the injector 
pen. It is designed for manual 
reconstitution of the dose, priming 
and insertion of the pen needle 
(29G), and manual injection.
The DCC contains lyophilized 
albiglutide (30 mg or 50 mg). 
When the injector pen product is 
reconstituted a neutral, isotonic 
solution is produced. The pen 
delivers albiglutide in an injection 
volume of 0.5 mL.
Byetta (exenatide) is a marketed 
product of AstraZeneca 
Pharmaceuticals LP. 
Exenatide is supplied as sterile 
solution for injection containing 
250 g /mL exenatdide.
The following dose packages are 
available:

5 g dose, 60 doses, 1.2 mL 
prefilled pen

10 g dose, 60 doses, 2.4 mL 
prefilled pen
Inactive ingredients include: 
metacresol, mannitol, glacial acetic 
acid, and sodium acetate trihydrate 
in water
Refer to the current PI for further 
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
32
Study Treatment
Product name:
Albiglutide (Tanzeum in US)
Exenatide (Byetta)
30 mg pen for injection contains 
40.3 mg lyophilized albiglutide and 
0.65 mL 
50 mg pen for injection contains 
67 mg lyophilized albiglutide and 
0.65 mL water 
Inactive ingredients include:153 mM 
mannital, 0.01% (W/W) polysobate 
80, 10mM sodium phosphate, and 
117 mM trehalose dehydrate in water
details.
Unit dose 
strength(s)/Dosage 
level(s):
30 mg  or 50 mg 
5g  or 10 g per dose 
Route of Administration
SC injection in the abdomen, thigh 
or upper arm region.
Rotation of injection sites is 
recommended.
SC injection in the abdomen, 
thigh or upper arm region.
Dosing instructions:
Study Part A: not applicable
Study Part B:30 mg, weekly for 4 
weeks, then uptitrated to 50 mg, 
weekly for 4 weeks
Administered as a single SC 
injection once a week on the same 
day each week.
Administered in the morning.
Study Part A: 10 g twice daily for 
5±1 days
Study Part B: 5 g twice daily for 4
weeks, then uptitrate to 10 g for 4 
weeks
Administered as a SC injection 
within the 60-minute period before 
the morning and evening meals (or 
before the two main meals of the 
day approximately 6 hours or more 
apart). 
Exenatide should not be 
administered after a meal
6.2.
Treatment Assignment
Part A:
All subjects in Part A of the study will receive 10 g exenatide twice daily for 5±1 days.
Part B:
Randomized treatment assignment will be done via a web-based interactive response 
(IRT) system (RAMOS NG). Randomization will be centralized and will be implemented 
based on a randomization schedule generated by Clinical Statistics using RAMOS. Study 
center personnel will access the IRT to execute each randomization once a subject has 
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
33
met all prerequisites for randomization and has completed all scheduled screening 
assessments.
Subjects will be assigned to study treatment in accordance with the randomization 
schedule. Eligible subjects will be stratified by screening HbA1c value (<7.5% and 
7.5%), and background use of OAM (OAM use versus no OAM use). Additional 
stratification may be added based on the results from Part A.
Subjects will be randomized in a 1:1 ratio to either open label albiglutide or exenatide.
Study centre personnel will receive a randomization notification indicating only the
unique subject identifier, the treatment assignment, 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 study treatment. 
6.3.
Planned Dose Adjustments
Part A:
There is no dose titration for Part A of this study. 
Part B:
Subjects will receive 30 mg of albiglutide once weekly during Weeks 1-4 and will then 
be up-titrated to 50 mg albiglutide once weekly at Week 5 for the remainder of the study.
Subjects will receive 5 g of exenatide twice daily during Weeks 1-4 and will then be up-
titrated to 10 g exenatide twice daily at Week 5 for the remainder of the study.  
Down-titration (dose reduction) of albiglutide and exenatide is NOT permitted.  If a 
subject experiences tolerability issues with the higher doses then the subject may be 
withdrawn from the study at the discretion of the investigator.
6.4.
Blinding
This will be a treatment open-label study. 
The reviewers/readers of EGG and individuals who perform sample testing and data 
production for GEBT will be blinded to randomized treatments.  The study team will 
remain blinded to the treatment assigned group for the assessment of safety aggregate 
data.  If an interim analysis is conducted (see Section 9.2.3.2.), the study team may be 
unblinded to the aggregate data.
6.5.
Packaging and Labeling
Exenatide and albiglutide are marketed products. Exenatide will be sourced locally. 
Clinical image albiglutide pens will be provided. The contents of the label will be in 
accordance with all applicable regulatory requirements. 
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
34
6.6.
Preparation/Handling/Storage/Accountability
No special preparation of study treatment is required other than that described in Section 
6.1
Only subjects enrolled in the study may receive study treatment and only authorized site 
staff may supply or administer study treatment.  All study treatments must be stored in a 
secure environmentally controlled and monitored (manual or automated) area in 
accordance with the labelled storage conditions with access limited to the investigator 
and authorized site staff. 
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance 
(i.e. receipt, reconciliation and final disposition records).  
Further guidance and information for final disposition of unused study treatment are 
provided in the 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.
6.7.
Compliance with Study Treatment Administration
Accountability will be done for the investigational product (albiglutide) and other study 
treatments (exenatide) at the time points specified in the Time and Events Table (Section 
7.1) Subjects will be instructed to return all unused investigational product and used 
injector pens in order to perform drug accountability and determine compliance.
Acceptable overall compliance for IP (albiglutide) and other study treatments (exenatide)
in this study will be 80%. Site personnel should confirm that subjects are taking their 
doses of albiglutide or exenatide, if appropriate, as prescribed by their physician. 
Adherence will be monitored for the duration of the study. 
When subjects are dosed at the site, they 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.  
When subjects self-administer study treatment(s) at home, subjects will be instructed to 
return all unused investigational product and used injector pens.  Compliance with 
albiglutide or exenatide will be assessed through a count of the returned injector pens and 
as reported by the subject. Compliance will be documented in the source documents and 
eCRF. Treatment start and stop dates, including dates for treatment delays will also be 
recorded in the eCRF.
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
35
6.8.
Treatment of Study Treatment Overdose
In the event of an overdose the investigator should:

Contact the Medical Monitor immediately.

Closely monitor the subject for AEs/serious adverse events (SAEs) that may be 
related to treatment overdose (see below). The appropriate supportive clinical care 
should be instituted, as dictated by the subject’s clinical signs and symptoms.

Document the quantity of the excess dose as well as the duration of the overdosing in 
the eCRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the subject.
6.8.1.
Albiglutide
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. 
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). 
There is no specific antidote for overdose with albiglutide. 
6.8.2.
Exenatide
In a clinical study of exenatide, three patients with T2DM each experienced a single 
overdose of 100 g 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. 
Refer to the exenatide US PI for further details.
6.9.
Treatment after the End of the Study
Investigational product will not be provided to subjects by GSK after the end of the 
study. In Part A, the last dose of exenatide will be in the morning before the GEBT on 
Day 5±1.  In Part B, the last dose of exenatide will be in the morning before the GEBT of 
Week 8 Day 41.  The last dose of albiglutide will be on Week 8 Day 1.
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s T2DM. After the last dose of albiglutide or exenatide, the 
investigator will provide subjects with instructions of how to continue to treat their 
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
36
T2DM after the end of the study.  The half-life of his/her study treatment 
(albiglutide/exenatide) should be taken into consideration.

The half-life of albiglutide is approximately 5 days, and significant therapeutic 
concentrations can persist for 3 to 4 weeks after discontinuation.  The choice of 
other medicinal products and dose selection should be considered accordingly, as 
adverse reactions may continue and efficacy may, at least partly, persist until 
albiglutide levels decline.

The half-life of exenatide is 2-3 hours.
6.10.
Concomitant Medications and Non-Drug Therapies
All medications taken at any time from 3 months prior to screening to the follow-up visit 
will be recorded in the eCRF. The minimum requirement is that drug name and the dates 
of administration are to be recorded.
Subjects on OAM at screening must discontinue OAM treatment as instructed in the 
protocol (see Section 4). After the last dose of albiglutide or exenatide, the investigator 
will provide subjects who were previously on an OAM with instructions of how and 
when to restart his/her OAM. The half-life of his/her study treatment 
(albiglutide/exenatide) should be taken into consideration (see Section 6.9).
6.10.1.
Permitted Medications and Non-Drug Therapies
Unless specified as a prohibited medication in Section 6.10.2, all concomitant 
prescription or over the counter medications should be considered permitted provided 
they are not contraindicated in the albiglutide or exenatide (depending on study 
treatment) PI or for the individual subject concerned. Although stable doses of all 
concomitant medications are preferable, changes in medications during the study to 
appropriately treat clinical conditions that might arise are allowed. 
Like other members of the class, albiglutide and exenatide cause a delay in gastric 
emptying, and thereby have the potential to impact the absorption of concomitantly 
administered oral medications. This should be taken into account by investigators when 
prescribing concomitant medication.
Investigators must adhere to the US FDA-approved PI for all permitted medications.
6.10.2.
Prohibited Medications and Non-Drug Therapies
Subjects must not use any of the following medications during the study (screening to 
end of treatment):
Any antidiabetic medications (e.g., GLP-1R agonist, DPP-4 inhibitors, metformin, 
meglitinide, sulphonylurea, thiazolidinedione, SGLT2 inhibitors or insulin) other 
than the randomly assigned study treatment. 
Any investigational drug other than the study treatment they have been randomly 
assigned to.
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
37
Oral or systemically injected corticosteroids (inhaled, intra-articular, epidural, and 
topical corticosteroids are allowed); short courses of oral steroids (single dose or 
multiple doses for up to 7 days) may be permitted provided these cases are 
discussed with the Medical Monitor.
Antiretroviral drugs.
Prescription and over-the-counter weight loss drugs. 
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., over the counter 
antacids, proton pump inhibitors, H2 blockers), laxatives and drugs affecting 
pancreatic or hepatobiliary systems.
If a subject receives a prohibited medication, the investigator should make the evaluation 
based on the reason (i.e., AE), duration of exposure and timings relative to the 
assessments in consultation with the Medical Monitor.
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.
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
38
7.1.
Time and Events Table
Table 2
Time and Events Table - Study Part A
Procedures
Screening/Wash-Out Period
(0-3 Weeks)
Treatment Period (exenatide)
(5 Days)
Un-
schedule
d
Early 
Withdrawal
Follow Up
Within 7 
Days
-21 to  
Day -4
Day -3 
to -5
Day -113
Day 1
Day 2
Day 3
Day 4
1 day13
Day 5
1 day13
Study Visit
1
2
3
4
5
6
Informed consent
X
Inclusion and exclusion criteria
X
X1
Demography, medical/disease history
X
Enrolment into Treatment Phase
X
OAM washout2
X
GEBT3
X
X12
EGG /water load / VAS3
X11
X12
ECG
X
Vital Signs
X
X
X
X
X
X
X
Height, Weight, BMI
X
Physical exam (F, Full; B, Brief)4
F
B
B
Concomitant medications review
X
X
X
X
X
X
X
AEs, SAEs, AEs of special interest review
X5
X5
X
X
X
X
X
X
PAGI-SYM6
X
GCSI-DD
X
X
X
X
Chemistry, hematology, urinalysis, lipids7
X
X
X
HbA1c
X
FPG
X
X
X
X
X
X
X
X
Fasting capillary glucose at clinic8
X
X
X
X
Diet/Exercise/SMBG advice/reinforcement9
X
X
X
X
X
X
Estradiol  and FSH (females only: if 
required)
X
Serum/Urine pregnancy test (FRP only)
S
U
U
U
U
TSH, Amylase and lipase
X
Genetics sample10
X
RAMOS registration
X
X
X
 
 
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
39
Procedures
Screening/Wash-Out Period
(0-3 Weeks)
Treatment Period (exenatide)
(5 Days)
Un-
schedule
d
Early 
Withdrawal
Follow Up
Within 7 
Days
-21 to  
Day -4
Day -3 
to -5
Day -113
Day 1
Day 2
Day 3
Day 4
1 day13
Day 5
1 day13
Study Visit
1
2
3
4
5
6
Exenatide dosing,
X11
X
X
X12
X12
Study medication compliance
X
X
X
1.
Before baseline assessment (Day -1), the investigator must review all inclusion and exclusion criteria to confirm subject’s eligibility. If a subject no longer meets all of the 
eligibility criteria, do not administer the study treatment and contact the Medical Monitor to discuss how to proceed (e.g., to determine if repeat testing is warranted). 
2.
For subjects taking OAM at screening only. At a minimum, two day washout for immediate release and at minimum 4 day washout for extended release OAMs. See footnote 
13.  For information on restarting OAM refer to Section 6.9.
3.
A small meal will be provided 2 hrs prior to the EGG procedure (Section 7.3.1). A meal will also be provided post-procedure for both the EGG and GEBT.
4.
Details of full and brief physical examinations are provided in Section 7.4.3.
5.
SAEs related to study participation only.
6.
The GCSI-DD questionnaire will be completed after the standard AE questions have been answered.
7.
Clinical chemistry, hematology, urinalysis and lipid assessments are described in Section 7.4.6. Lipids will be assessed at screening only.
8.
Fasting capillary glucose will be measured prior to administration of exenatide. On GEBT (Day 5) or EGG (Day 1 and Day 4) assessment days, fasting capillary glucose will be 
measured prior to the GEBT or EGG procedure.
9.
Subjects will be provided with diet and exercise guidance (see Section 7.4.8) and instructed on self monitoring blood glucose at screening (See Section 7.4.9).  Subject will be 
instructed to bring in their glucometers at each visit for review.  Diet/exercise/SMBG reinforced at subsequent visits. 
10. Informed consent for optional genetic research should be obtained before collecting a sample.
11. On the morning of Day 1, subjects will receive instructions and training on exenatide self administration and will be monitored by medical staff at the clinic during administration 
of the first dose. The first dose of exenatide will be administered after the baseline EGG procedure and before the post-procedure meal.
12. On Day 4 and 5, the morning dose of exenatide will be administered at clinic 1 hr (15 min) before the EGG or GEBT procedure.
13. Every effort should be made to schedule the procedures on the nominal visit day identified. However, in order to meet scheduling needs, subjects taking OAM can schedule 
Day-1 up to 3 days prior to Day 1 and the OAM stopped at least the day before the GEBT .  For subjects treated with diet and exercise alone Day-1 can occur within 7 days 
prior to Day 1. The EGG and GEBT should not be scheduled on the same day
 
 
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
40
Table 3
Time and Events Table Study Part B
Procedures
Screening/Wash-
Out Period
(0-3 weeks)
Treatment Period (exenatide or albiglutide)
(8 weeks)
Un
scheduled
Early 
Withdrawal
Follow-Up
Study Week
-3 to -1
-116
1
216
3
4
516
6
7
816
12
Study Day
-21 to  
-4
-3 to 
-5
-1
1
10±1
-
-
29±1 31±1 32±1
-
-
52±1 53±1
78-84±3
Study Visits
1
2
3
4
5
6
7
8
9
10
Informed consent
X
Inclusion and exclusion criteria
X
X1
Demography, medical/disease history
X
RAMOS registration
X
X
X
X
OAM washout2
X
GEBT3
X
X5
X5
EGG /water load / VAS3
X4
X5
X5
X5
ECG
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
Height, Weight, BMI
X
X6
X6
Physical exam (F, Full; B, Brief)7
F
B
B
B
B
Concomitant medications review
X
X
X
X
X
X
X
X
X
X
X
X
AEs, SAEs, AEs of special interest review
X8
X8
X
X
X
X
X
X
X
X
X
X
PAGI-SYM
X
GCSI-DD9
X
X
X
X
X
X
X
Chemistry, hematology, urinalysis, lipids10
X
X11
X
X
HbA1c
X
X
X
X
X
FPG
X
X
X
X
X
X
X
X
X
X
Diet/Exercise/SMBG advice/reinforcement 12
X
X
X
X
X
X
X
X
X
capillary blood glucose at clinic
X
X
X
X
X
X
X
X
X
X
Estradiol  and FSH (females only: if required)
X
Serum/Urine pregnancy test (FRP only)
S
U
U
U
U
U
TSH, Amylase and lipase
X
Genetics sample13
X
Randomization
X
Dispense study medication
X
X
 
 
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
41
Procedures
Screening/Wash-
Out Period
(0-3 weeks)
Treatment Period (exenatide or albiglutide)
(8 weeks)
Un
scheduled
Early 
Withdrawal
Follow-Up
Study Week
-3 to -1
-116
1
216
3
4
516
6
7
816
12
Study Day
-21 to  
-4
-3 to 
-5
-1
1
10±1
-
-
29±1 31±1 32±1
-
-
52±1 53±1
78-84±3
Study Visits
1
2
3
4
5
6
7
8
9
10
Study treatment administration training, (1st
dose & 1st uptitration dose)
X14
X15
Study treatment administration
X
X
X
X
X
X
X
X
In clinic meal
X
X
X
X
X
X
X
X
Study medication compliance
X
X
X
X
X
X
X
1.
Before randomization, the investigator must review all inclusion and exclusion criteria to confirm subject’s eligibility. If a subject no longer meets all of the eligibility criteria, do 
not randomize the subject and contact the Medical Monitor to discuss how to proceed (e.g., to determine if repeat testing is warranted). 
2.
For subjects taking OAM at screening only. At a minimum, two day washout for immediate release and at a minimum 4 day washout for extended release OAMs.  See footnote 16.  
For information on restarting OAM refer to Section 6.9
3.
A small meal will be provided 2 hrs prior to the EGG procedure (Section 7.3.1). A meal will also be provided post-procedure for both the EGG and GEBT.
4.
The Day 1 (baseline) EGG is to be conducted before administration of study medication. 
5.
The EGG must be scheduled 31 days after the albiglutide dose.  The morning dose of exenatide will be administered at clinic 1 hr (15 min) before the EGG or GEBT procedure.
6.
Weight only
7.
Details of full and brief physical examinations are provided in Section 7.4.3.
8.
Only related to study participation SAEs
9.
The GCSI-DD questionnaire will be completed after the standard AE questions have been answered.
10. Clinical chemistry, hematology, urinalysis and lipid assessments are described in Section 7.4.6. Lipids will be assessed at screening only. 
11. Creatinine for eGFR only
12. Subjects will be provided with diet and exercise guidance (see Section 7.4.8) and instructed on self monitoring blood glucose at screening (See Section 7.4.9).  Subject will be 
instructed to bring in their glucometers at each visit for review.  Diet/exercise/SMBG reinforced at subsequent visits.
13. Informed consent for optional Genetic research should be obtained before collecting a sample.
14. On the morning of Day 1, after baseline EGG test, subjects will receive instructions and training on exenatide or albiglutide self administration and will be monitored by medical 
staff at the clinic during administration of the first dose. The first dose of will be administered after the baseline EGG procedure and before the post-procedure meal.
15. On Day 29 (1day), study treatment will be uptitrated to 10 g twice daily exenatide or 50 mg once weekly albiglutide (see Section 6.3). Subjects will receive instructions and 
training on exenatide or albiglutide self administration and will be monitored by medical staff at the clinic during administration of the first dose.
16. Every effort should be made to schedule the procedures on the nominal visit day identified. However, in order to meet scheduling needs, subjects taking OAM can schedule Day-1 
up to 3 days prior to Day 1 and the OAM stopped at least the day before the GEBT .  For subjects treated with diet and exercise alone Day-1 can occur within 7 days prior to 
Day 1. The EGG and GEBT should not be scheduled on the same day.
 
 
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
42
7.2.
Screening and Critical Baseline Assessments
Before any study-specific procedure is performed, valid informed consent must be 
obtained.
Demography and medical history (including cardiovascular medical history/risk factors, 
T2DM history, history of other prior and concomitant medical conditions) will be 
assessed at screening (as detailed in the eCRF).
Critical baseline assessments will include: GEBT, EGG.
Full details of screening and baseline assessments are provided in the Time and Events 
Table Section 7.1.
7.3.
EGG and GEBT Test
GEBT and EGG measurements will be undertaken in the clinic and performed on 
separate days. Measurements for both Part A and Part B will be taken at the time points 
specified in the Time and Events Table in Section 7.1. Clinical visits for EGG and GEBT 
will have a visit window of 1 day and should be planned to avoid days of expected 
holidays, weekends and vacations.  

Albiglutide should be self-administered in the morning 31 days before the EGG 
procedure.  

Exenatide should be self-administered twice daily.  In the morning of each test 
day, subjects should be instructed NOT to self- administer exenatide at home. The 
morning dose of exenatide on the day of in-clinic test must be administered by the 
site staff.  The dose of exenatide should be administered 1 hr 15 min prior to the 
start of the EGG or GEBT procedure. Every effort should be made to administer 
at the same pre-procedure time at each visit for the same subject.
7.3.1.
EGG
Subjects should have nothing to eat or drink from midnight prior to the EGG. Two hours 
before the EGG subjects will be provided one piece of toast and 4 US fluid ounces 
(120 mL) of apple juice. This provides a small amount of calories so subjects are not 
“starving” and also provides a consistent EGG baseline before the water load. Subjects 
should not have anything further to eat or drink until after the EGG procedure.
EGG is recorded with ECG-type electrodes placed on the surface of the epigastrium. The 
EGG signals are recorded on a strip chart for visual analysis and digitized simultaneously 
for computer analysis. The EGG recordings include a 15-min baseline tracing after which 
the subjects ingest water for 5-min until they perceive their stomach is full. All subjects 
will rate symptoms experienced immediately before and 10, 20 and 30 min after ingestion 
of the water. 
A VAS (0-100 mm) will be used to assess the intensity of the following sensations: no 
nausea (0) to severe nausea (100), stomach empty (0) to stomach full (100), hunger (0) to 
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
43
satiety (100) and no bloating (0) to severe bloating (100). The recording channel with the 
clearest electrogastrographic signal will be chosen for visual and computer analysis. 
The details of test procedures for EGG with water load test are provided in the SRM.
7.3.2.
GEBT
The GEBT should be administered after an overnight fast. No solid food should be 
consumed or vigorous activity undertaken within 8 hours prior to the test. Alcohol should 
not be ingested within 8 hours prior to testing. The individual being tested may consume 
a small amount of water up to 1 hour before the test, but not more than 4 fluid ounces. 
Coffee may enhance gastric motility and should not be consumed within 8 hours prior to 
testing. Subjects should not smoke/use tobacco products (e.g. chewing tobacco, nicotine 
gum) before or during administration of GEBT.
The GEBT will be conducted over a four-hour period. After an overnight fast, duplicate 
pre-meal breath samples will be collected in capped glass tubes. Subjects will then 
consume a standard GEBT meal containing 13C-Spirulina. Breath samples will be 
collected periodically.  All breath samples pre- and post-meal will be returned to a central 
laboratory for analysis by Gas Isotope Ratio Mass Spectrometry (GIRMS) to determine 
the ratio of 13CO2/12CO2 in each sample. By measuring the change in this ratio over time 
as compared to the pre-meal value, the rate of 13CO2 excretion can be calculated and the 
individual’s gastric emptying rate determined. 
The details of GEBT administration instructions and breath sample collection procedures 
will be provided in the SRM.
7.4.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1). Unscheduled visits will occur as medically necessary. Detailed procedures 
for obtaining each assessment are provided in the SRM.
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 6.
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 
Events of nausea, hunger, stomach fullness, bloating, and abdominal pain resulting from 
the water load test will be captured and reported as an endpoint through the VAS  and 
will not be considered an AE.  Any of these 5 events reported outside of the timings of 
the VAS collection should be recorded as an AE/SAE if meets the definition as noted in 
Appendix 6.
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
44
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 (see Section 7.4.1.3), at the timepoints specified in the Time and Events 
Table (Section 7.1).

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the eCRF.

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Appendix 6.

Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the study treatment or study participation, the 
investigator must promptly notify GSK.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 6.
7.4.1.2.
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?” 

“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) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up 
(as defined in Section 5.5). Further information on follow-up procedures is given in 
Appendix 6.
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
45
7.4.1.4.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 6 and all deaths, whether or not they
are considered SAEs, specific CV and Death sections of the eCRF will be required to be 
completed. These sections include questions regarding cardiovascular (including sudden 
cardiac death) and non-cardiovascular death. 
The CV eCRFs are presented as queries in response to reporting of certain CV Medical 
Dictionary for Regulatory Activities (MedDRA) terms. The CV information should be 
recorded in the specific cardiovascular section of the eCRF within one week of receipt of
a CV Event data query prompting its completion. 
The Death eCRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
7.4.1.5.
AEs of Special Interest
In the Phase 3a 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 (see Section 7.4.9)

Liver events 

CV events (see Section 7.4.1.4)

Injection site reactions 

Potential systemic allergic reactions

Pancreatitis 

MTC

Diabetic retinopathy 

Pneumonia 

Atrial fibrillation/atrial flutter 
The following additional AEs of special interest will be captured in the AE eCRF pages:

GI events

Pancreatic cancer 

Malignant neoplasms

Appendicitis
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
46
Subjects with pancreatitis, MTC or any drug hypersensitivity reaction, that is not 
reasonably attributable to another cause, should be withdrawn from the study and should 
not be rechallenged with albiglutide or exenatide (see Section 5.5 for complete list of 
AEs of special interest requiring withdrawal).
If a histopathologic analysis related to events of special interest is performed, a copy of 
the histopathology report and a discharge summary if the subject was admitted, or any 
available case summary (e.g. clinic letter), is to be provided to the Sponsor, if available.  
Subjects with treatment emergent thyroid nodules should be referred to a specialist for 
evaluation in accordance with local treatment guidelines. 
Subjects will be provided information detailing the symptoms of pancreatitis and will be 
instructed to hold study medication and contact the investigator immediately if they 
experience any of these symptoms. All cases of suspected pancreatitis will be referred to 
the PAC (see Section 10.8.1).
Subjects should also be closely monitored for signs of potential allergic or drug 
hypersensitivity reactions including anaphylaxis, angioedema, generalized urticaria, and 
other potential manifestations of systemic allergic or drug hypersensitivity reactions. A 
serum sample should be taken as soon as possible after any such event in order to 
measure antibody to the drug. Instructions for sample processing are provided in Section
7.6.  These events should be reported as AEs or SAEs based on the clinical evaluation of 
the subject. 
7.4.1.6.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK of SAEs related to study treatment (even 
for non- interventional post-marketing studies) is essential so that legal obligations and 
ethical responsibilities towards the safety of subjects and the safety of a product under 
clinical investigation are met. 
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
47
7.4.2.
Pregnancy

If a subject becomes pregnant during the study they should discontinue 
Investigational Product.

Any pregnancy that occurs during study participation (i.e., from 
baseline/randomization through the end of the post-treatment follow-up period) 
must be reported using a clinical trial pregnancy form.

If a pregnancy is reported then the investigator should inform GSK or designee 
within 2 weeks of learning of the pregnancy and should follow the procedures 
outlined in Appendix 4.
7.4.3.
Physical Exams
A full or brief physical examination will be performed at the time points specified in the 
Time and Events Table Section 7.1.
A full physical examination will include, at a minimum, assessment of the skin 
(including injection site), head, eyes, ears, nose, throat, thyroid, respiratory system 
cardiovascular system, abdomen (liver and spleen), lymph nodes, central nervous 
system and extremities. 
Brief physical examination includes evaluation of skin (including injection site), 
respiratory system, cardiovascular system, abdomen (liver, spleen), and central 
nervous system 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses

Weight will be performed at the time points specified in the Time and Events 
Table Section 7.1. Height 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.
7.4.4.
Vital Signs
For vital signs (blood pressure and pulse rate), a single measurement will be taken at the 
time points specified in the Time and Events Table (Section 7.1)
During visits when ECGs are scheduled, vital sign measurements will be taken after the 
completion of the ECG sampling. Subjects may be either in a semi-recumbent or seated 
position. During visits when ECGs are not scheduled, vital sign measurements will be 
taken while subjects are in a seated position after at least a 5-minute rest period. During 
visits where a blood draw is required, vital sign measurements will be taken prior to 
sample collection.
7.4.5.
Electrocardiogram (ECG)
A single 12-lead ECG recording (with subject in semirecumbent position for 10 to 
15 minutes before obtaining the ECG) will be performed at screening only using an ECG 
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
48
machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc 
intervals.  
It is recommended that the ECGs be performed before measurement of vital signs and 
collection of blood samples for laboratory testing.
7.4.6.
Gastroparesis Cardinal Symptom Index Daily Dairy (GCSI-DD)
 
2017N325664_00
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.


2015N255772_01
CONFIDENTIAL
204879
49
7.4.7.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 4, 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 labeled 
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 laboratory manual. Reference ranges for all safety parameters will be provided to 
the site by the laboratory responsible for the assessments.
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the eCRF.
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 with 
the exception of the fasting capillary blood glucose as noted in the Time and Events 
Table.
Hematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed in Table 4. Prior to the collection of blood samples, subjects should be fasting [no 
food or drink (except water) for at least 8 hours before sample collection]. During visits 
where ECGs and vital sign measurements are scheduled, blood samples will be collected 
after the completion of these assessments.
 
2017N325664_00
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.


2015N255772_01
CONFIDENTIAL
204879
50
Table 4
Protocol Required Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology

Platelet count

WBC count with 
Differential

RBC count

Neutrophils

Hemoglobin

Lymphocytes

Hematocrit

Monocytes

Eosinophils

Basophils
Clinical 
Chemistry1

AST

Bilirubin (total and 
direct/indirect)

Phosphorous

ALT

Calcium

Chloride

GGT

Magnesium

Albumin

BUN

Potassium

Total protein

Creatinine 

eGRF (MDRD)

Sodium
Urinalysis

Specific gravity

pH

Glucose

Ketones

Blood 

Nitrates

Leukocyte esterase

Microscopic 
examination (if 
blood or protein is 
abnormal)

Microalbumin

Creatinine
Glycemic 
parameters

HbA1c

FPG

Fasting capillary glucose
Lipid 
parameters5

Total cholesterol

LDL-C (direct)

HDL-C

Triglycerides
Other 
laboratory 
tests

Serum pregnancy 
test2

FSH3

Estradiol3

Urine pregnancy 
test2

TSH4

Lipase6

Amylase6
AST, aspartate transaminase; GGT, -glutamyltransferase; LDL-C, low density lipoprotein-C; HDL-C, 
high density lipoprotein-C; TSH, thyroid stimulating hormone, WBC, white blood cells
1.
Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up Assessments after 
liver stopping or monitoring event are given in Section 5.5.1 and Appendix 5.
2.
For females of reproductive potential only.
3.
. As needed in postmenopausal women were their menopausal status is in doubt (see Inclusion Criteria 
Section 5.1).
4.
TSH screening only. If TSH is above the ULN, free T4 (reflex) will also be measured
5.
Screening only.
6.
Screening only.
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
51
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.
7.4.7.1.
FPG and HbA1c Central Laboratory
HbA1c and FPG will be measured at the time points specified in the Time and Events 
Table in Section 7.1. If subjects are scheduled to receive study treatment during an in-
clinic visit, blood samples for HbA1c and FPG should be collected before administration 
of study treatment.
7.4.7.2.
Estimated Glomerular Filtration Rate (eGFR)
In order to monitor kidney function, serum creatinine will be measured at the time points 
specified in Time and Events Schedule in Section 7.1 It will be used to calculate eGFR 
using the MDRD formula [Levey, 2009], namely:
eGFR (ml/min/1.73m2) = 175 x (serum creatinine)-1.154 x (Age)-0.203 x (0.742 if female) x 
(1.212 if African American).
7.4.8.
Diabetic Dietary Instruction and Exercise
Standard diabetic dietary and exercise guidance will be provided by the site at screening 
and reinforced at each study visit specified in the Time and Events Table in Section 7.1.
7.4.9.
Home Blood Glucose Monitoring
Home blood glucose monitoring advice as well as advice on the signs and symptoms of 
hypoglycemia will be provided by the site at screening and reinforced at each study site 
visit specified in the Time and Events Table in Section 7.1.
All subjects in the study will be recommended to measure and record/store blood glucose 
values using their glucose meter each morning before breakfast. At least one day per 
week, subjects should measure blood glucose values at the following times (except 
GEBT and EGG assessment days).

Before breakfast (at least 8 hours without food intake)

Before lunch

Before dinner

At bedtime
The investigator will review the glucose meter readings at each study visit and will 
decide the frequency of measurements based on the subject’s individual needs.
Subjects should monitor the blood glucose as per the instructions of the investigator and 
as appropriate for their medical management. The subjects should report promptly, as 
directed by the investigator, the occurrence of hyperglycemia (i.e. fasting capillary blood 
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
52
glucose >270 mg/dL) or hypoglycemia (particularly if symptomatic) to the investigator 
(or his or her designee). Assessment and action should then occur as deemed appropriate 
by the investigator
7.4.9.1.
Fasting Capillary Blood Glucose at clinical visits
Capillary blood glucose will be measured prior to the EGG and GEBT procedures and 
recorded in the eCRF at the time points specified in the Time and Events Schedule in 
Section 7.1.
7.4.10.
Hyperglycemic Events
Subjects will be asked to report any hyperglycemic events, including time between study 
visits. Subjects requiring rescue therapy due to fasting plasma glucose ≥270 mg/dL
confirmed by central lab will be withdrawn from the study.  At investigator discretion, a 
subject may be withdrawn for hyperglycemia at any time for safety considerations, not 
necessarily reaching the threshold of fasting plasma glucose ≥270 mg/dL
7.4.11.
Hypoglycemic Events
Specific criteria for monitoring hypoglycemic events have been designed to ensure 
subject safety and to closely monitor hypoglycemia. Hypoglycemic events are defined as 
follows [Seaquist, 2013]:
Severe Hypoglycemia

Severe hypoglycemia is an event requiring assistance of another person to actively 
administer carbohydrates, glucagon, or take other corrective actions. Plasma glucose 
concentrations may not be available during an event, but neurological recovery 
following the return of plasma glucose to normal is considered sufficient evidence 
that the event was induced by a low plasma glucose concentration. 
Documented Symptomatic Hypoglycemia

Documented symptomatic hypoglycemia is an event during which typical symptoms 
of hypoglycemia are accompanied by a measured plasma glucose concentration 
70 mg/dL (3.9 mmol/L). 
Asymptomatic Hypoglycemia

Asymptomatic hypoglycemia is an event not accompanied by typical symptoms of 
hypoglycemia but with a measured plasma glucose concentration 70 mg/dL 
(3.9 mmol/L). 
Probable Symptomatic Hypoglycemia

Probable symptomatic hypoglycemia is an event during which symptoms typical of 
hypoglycemia are not accompanied by a plasma glucose determination but that was 
presumably caused by a plasma glucose concentration 70 mg/dL (3.9 mmol/L). 
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
53
Pseudohypoglycemia

Pseudohypoglycemia is an event during which the person with diabetes reports any 
of the typical symptoms of hypoglycemia with a measured plasma glucose 
concentration >70 mg/dL (>3.9 mmol/L) but approaching that level. 
Any hypoglycemic event, regardless of intensity, that satisfies the definition of an SAE 
(Appendix 6) should be categorized as outlined in this section and reported appropriately
in the SAE eCRF page and the hypoglycemic events AE of special interest page.
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.
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
7.6.
Immunogenicity
In the case of severe systemic allergic reactions that include anaphylaxis, angioedema, or 
other severe potential hypersensitivity reactions in subjects that have received albiglutide, 
that cannot reasonably be attributed to another cause, three 1-mL serum samples should 
be obtained for immunogenicity testing (within 24 hours of the event if possible) and sent 
to the central laboratory (see details in the SRM) for immediate distribution to contracted 
testing facility for specific immunological testing (albiglutide-specific immunoglobulin E 
and other tests, as appropriate). A follow-up serum sample will be taken 8 weeks after 
final dose of study treatment in these subjects.
Subjects with drug hypersensitivity reactions that are not reasonably attributable to 
another cause should be withdrawn from the study and should not be rechallenged with 
albiglutide (see Section 5.5 and Section 7.4.1.5).
7.7.
Genetics
Information regarding genetic research is included in Appendix 7.
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
54
8.
DATA MANAGEMENT

For this study, subject data will be entered into GSK defined eCRFs, 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.

AEs and concomitant medications terms will be coded using MedDRA and an 
internal validated medication dictionary, GSKDrug.  

eCRFs (including queries and audit trails) will be sent at the end of the study in 
CD format to GSK to be retained. Each investigator will receive a copy of their 
site specific data in the same format to maintain as the investigator copy. Subject 
initials will not be collected or transmitted to GSK according to GSK policy.
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1.
Part A: Statistical Considerations and Data
9.1.1.
Hypotheses
No formal statistical hypotheses are being tested in Part A. Part A will be a pilot phase 
investigating the effect of repeated doses of exenatide on GMA, GE, and VAS of nausea.
9.1.2.
Sample Size Considerations
9.1.2.1.
Sample Size Assumptions
Sample size for Part A is not based on formal sample size calculations; it is based on the 
anticipated minimum number to better estimate the effect of repeated doses of exenatide 
on GMA. The pivotal assessment of the repeated doses on GMA will be provided by Part 
B of the study, with Part A providing an exploratory assessment to support progression to 
Part B.
Approximately 10 evaluable subjects with T2DM will be enrolled in Part A of the study. 
9.1.2.2.
Sample Size Re-estimation or Adjustment
If subjects prematurely discontinue the Part A of the study or if the central data reader 
reports that the data is not valid, additional replacement subjects maybe enrolled at the 
discretion of the Investigator in consultation with the Sponsor.
9.1.3.
Data Analysis Considerations
All protocol defined endpoints will be summarized using suitable displays.
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
55
9.1.3.1.
Analysis Populations
For this exploratory study, the analysis set will include subjects who have valid data.
Data will be assessed and reviewed by the central reader before it is considered valid. 
Additional details will be provided in the RAP.
9.1.4.
Key Elements of Analysis Plan
9.1.4.1.
Exploratory Analysis
No formal statistical analyses will be performed for the exploratory endpoints that are 
listed under Section 3.1. All exploratory endpoints will be assessed using descriptive 
statistics and graphical displays as appropriate.
9.1.4.2.
Part A review
Changes resulting from Part A review including refinement of endpoints and statistical 
assessment of the endpoints will be incorporated in the RAP and will not be considered 
an amendment to the Protocol
9.2.
Part B: Statistical Considerations and Data Analysis
9.2.1.
Hypotheses
Hypotheses testing in Part B will be performed for the parameters listed in Section 3.2 to 
compare albiglutide to exenatide in subjects with T2DM for a treatment period of 8 
weeks.
9.2.2.
Sample Size Considerations
9.2.2.1.
Sample Size Assumptions
Approximately 62 subjects (31 per arm) will be randomized in a 1:1 ratio to either 
albiglutide or exenatide. The study will target to have a total of approximately 50 
evaluable subjects (25 subject per treatment arm) taking into account the assumed 
withdrawal rate of approximately 20%.  The study is exploratory in nature and there is no 
similar published work available in the same indication and population to act as a guide.  
This sample size is based on feasibility and the sample size assumptions may be re-
evaluated once Part A results are available.
9.2.2.2.
Sample Size Re-estimation or Adjustment
Based on the results from Part A the total sample size for Part B may be adjusted, within 
the bounds of feasibility.
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
56
9.2.3.
Data Analysis Considerations
9.2.3.1.
Analysis Populations
For this exploratory study, the analysis set will include subjects who have valid data.
Data will be assessed and reviewed by the central reader before it is considered valid. 
Additional details will be provided in the RAP.
9.2.3.2.
Interim Analysis
This is an open-label exploratory study with sample-size based on feasibility 
considerations. To support monitoring of endpoint variability; data aggregated by 
treatment group may be reviewed by the Sponsor while the trial is ongoing.
9.2.4.
Key Elements of Analysis Plan
9.2.4.1.
Primary Analysis
The primary endpoint is change from baseline in EGG parameters at Week 2, 5, and 8 at 
each time interval (pre-and 10, 20 and 30 min after water load). The primary endpoint is 
change in GMA as assessed by EGG parameters: change from baseline of distribution of 
average power by frequency region (as % of power); change from baseline of ratios of 
average power post-water load test (post-WLT)/pre water load test (pre-WLT) by 
frequency region; and change from baseline of percentage (%) of time with the dominant 
EGG frequencies in the four frequency ranges (bradygastria, normal, tachygastria and 
duodenal).  The primary analyses of the primary EGG parameters will be conducted 
using mixed-effect model with repeated measures (MMRM).  The MMRM model will 
include the EGG parameter as the dependent variable; treatment group, time interval, 
visit week, and treatment-by-week interaction as fixed effects; the relevant parameter 
baseline as covariate; and subject as a random effect. 
The primary endpoint of change from baseline in EGG parameters related to VAS of 
nausea at Week 2, 5, and 8 at each time interval (pre-and 10, 20 and 30 min after water 
load) will be analyzed using the MMRM method as described above.  The MMRM 
model will include the EGG parameter as the dependent variable (the same EGG 
parameters as listed above); treatment group, time interval, visit week, and treatment-by-
week interaction as fixed effects; the relevant parameter baseline as covariate; VAS of 
nausea as time varying covariate; and subject as a random effect.
Treatment effects estimates (and associated 95% CI) of albiglutide will be evaluated 
within this MMRM model as least squares means contrasts relative to exenatide. An 
unstructured covariance matrix will be used for the MMRM analysis, unless the model 
does not converge, in which case the covariance matrix will be decided upon model 
convergence status and the Akaike information criterion. 
Part B analysis is further described in the RAP.  
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
57
9.2.4.2.
Secondary analyses
The relative effects of albiglutide compared to exenatide will also be assessed across a 
number of secondary endpoints.  The secondary endpoints are defined in Section 3.2 and 
include change from baseline in T1/2 at Week 5 and 8; change from baseline in kPCD of 
GE at Week 5 and 8 and at each time interval (45, 90, 120, 150, 180 and 240 min);
change from baseline volume of water ingested during water load EGG test Week 2, 5 
and 8; and change from baseline of VAS of stomach fullness, hunger, bloating and 
abdominal pain during the EGG water load test at Week 2, 5, and 8. The secondary 
endpoints will be analyzed analogous to the primary endpoint using MMRM. In addition, 
summary statistics (including number of subjects, mean, median, min, max, SD, SE) and 
graphical displays will be provided.
The overall general safety and tolerability of albiglutide versus exenatide will be 
evaluated in tabular and/or graphical format and summarized descriptively.
Vital signs, clinical laboratory tests, adverse events (AEs), Gastroparesis Cardinal 
Symptom Index – Daily Diary (GCSI-DD), and nausea AEs presenting outside the timing 
of the WLT and GCSI-DD will be assessed using descriptive statistics.
9.2.4.3.
Exploratory analyses
The exploratory endpoint number and % of subjects with a shift in gastric rhythm status 
will be summarized descriptively by treatment group.  In addition, the number and 
percentage of subjects by gastric rhythm status will be provided by time interval and visit
The mean and mean change from baseline in average dominate frequency will be 
summarized using descriptive statistics.
The details of any further planned analyses, including subgroup analysis, will be provided 
in the RAP.  Moreover, the relationship between EGG parameters and FPG and HbA1c 
will be examined.
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/designee will obtain favourable opinion/approval from 
the appropriate regulatory agency to conduct the study in accordance with ICH Good 
Clinical Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
58
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki 2008 (which is based on the initial version enacted 
in 1996). 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 for each subject prior to participation in the 
study.

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol 
deviations to IRB/IEC)

GSK/designee will provide full details of the above procedures, either verbally, in 
writing, or both.
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/designee 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/designee 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/designee 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
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
59
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.
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.  
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
60

Where permitted by local laws/regulations or institutional policy, some or all of 
these records can be maintained in a format other than hard copy (e.g., microfiche, 
scanned, electronic); however, caution needs to be exercised before such action is 
taken.  

The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, 
including re-generating a hard copy, if required.  Furthermore, the investigator 
must ensure there is an acceptable back-up of these reproductions and that an 
acceptable quality control process exists for making these reproductions.

GSK will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements.  The minimum retention time 
will meet the strictest standard applicable to that site for the study, as dictated by 
any 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/designee site or other 
mutually-agreeable location.
GSK/designee will also provide the investigator with the full summary of the study 
results.  The investigator is encouraged to share the summary results with the study 
subjects, as appropriate.
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy.
10.8.
Review Committees
10.8.1.
Pancreatitis Adjudication Committee
A PAC 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.
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
61
11.
REFERENCES
Ahren B, Johnson SL, Stewart M, Cirkel DT, Yang F, Feinglos MN, et al. HARMONY 
3: 104-week randomized, double-blind, placebo- and active-controlled trial assessing the 
efficacy and safety of albiglutide compared with placebo, sitagliptin, and glimepiride in 
patients with type 2 diabetes taking metformin. Diabetes Care. 2014;37:2141-8. 
Baggio LL, Huand Q, Brown TJ and Drucker DJ. A Recombinant Human Glucagon-Like 
Peptide (GLP)-1–Albumin Protein (Albugon) Mimics Peptidergic Activation of GLP-1 
Receptor–Dependent Pathways Coupled With Satiety, Gastrointestinal Motility, and 
Glucose Homeostasis. Diabetes 2004; 54: 2492-2500.
Barnett A H, Burger J, Johns D, Brodows R, Kendall DM, Roberts A et al. Tolerability 
and Efficacy of Exenatide and Titrated Insulin Glargine in Adult Patients with Type 2 
Diabetes Previously Uncontrolled with Metformin or a Sulfonylurea: A Multinational, 
Randomized, Open-Label, Two-Period, Crossover Noninferiority Trial Clinical 
Therapeutics. 2007; 29(11): 2333-2348.
Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD. Effects of Exenatide 
(Exendin-4) on Glycemic Control Over 30 Weeks in Sulfonylurea-Treated Patients With 
Type 2 Diabetes. Diabetes Care. 2004; 27(11): 2628-2635.
Buse JB, Rosenstock J, Sesti G, Schmidt WE, Montanya E, Brett JH et al. Liraglutide 
once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, 
parallel-group, multinational, open-label trial (LEAD-6). Lancet. 2009; 374: 39–47.
Bush MA, Matthews JE, De Boever EH, Dobbins RL, Hodge RJ, Stewart MW et al. 
Safety, tolerability, pharmacodynamics and pharmacokinetics of albiglutide, a long-
acting glucagon-like peptide-1 mimetic, in healthy subjects. Diabetes Obes Metab. 
2009;11:498-505. 
Byetta US Prescribing Information, Astra Zeneca Pharmaceuticals, February 2015. 
Available from: http://www.azpicentral.com/byetta/pi_byetta.pdf#page=1
DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD. Effects of 
Exenatide (Exendin-4) on Glycemic Control and Weight Over 30 Weeks in Metformin-
Treated Patients With Type 2 Diabetes. Diabetes Care. 2005; 28(5): 1092-1100.
Goke R, Fehmann HC, Linn T, Schmidt H, Krause M, Eng J et al. Exendin-4 is a high 
potency agonist and truncated exendin-(9-39)-amide an antagonist at the glucagon-like 
peptide 1-(7-36)-amide receptor of insulin-secreting beta-cells. J Biol Chem. 1993;
268:19650–5.
Heine RD, Van Gaal LF, Johns D, Mihm MJ, Widel MH and Brodows RG. Exenatide 
versus Insulin Glargine in Patients with Suboptimally Controlled Type 2 Diabetes A 
Randomized Trial. Ann Intern Med. 2005; 143:559-569.
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
62
Home PD, Shamanna P, Stewart M, Yang F, MIller M, Carr C et al. Efficacy and 
tolerability of albiglutide versus placebo or pioglitazone over 1 year in people with type 2 
diabetes currently taking metformin and glimepiride: HARMONY 5. Diabetes Obes 
Metab. 2015; 17:179-87. 
Kendall DM, Riddle MC, Rosenstock J, Zhuang D, Kim DD, Fineman MS et al.. Effects 
of Exenatide (Exendin-4) on Glycemic Control Over 30 Weeks in Patients With Type 2 
Diabetes Treated With Metformin and a Sulfonylurea. Diabetes Care. 2005; 28(5): 1083-
1091
Koch K. Electrogastrography: Physiological Basis and Clinical Application in Diabetic 
Gastropathy Diabetes Technology and Therapeutics. 2001; 3(1): 51-62.
Koh SD, Sanders KM and Ward SM. Spontaneous electrical rhythmicity in cultured 
interstitial cells of Cajal from the murine small intestine. Journal of Physiology. 1998; 
513(1):203—213.
Leiter LA, Carr C, Stewart M, Jones-Leone A, Scott R, Handelsman Y et al. Efficacy 
and safety of the once-weekly GLP-1 receptor agonist albiglutide versus sitagliptin in 
patients with type 2 diabetes and renal impairment: a randomized phase III study. 
Diabetes Care. 2014;37:2723-30. 
Levey AS, Stevens LA, Schmid CH, Zhang Y, Castro AF, Feldman HI  et al. A new
equation to estimate glomerular filtration rate.  Ann Intern Med. 2009; 150: 604-12.
Lu Z, Percie Du Sert N, Chan SW, Yeung C, Lin G, Yew D et al., Differential 
hypoglycaemic, anorectic, autonomic and emetic effects of the glucagon-like peptide 
receptor agonist, exendin-4, in the conscious telemetered ferret. Journal of Translational 
Medicine 2014; 12:327-329
Matthews JE, Stewart MW, De Boever EH, Dobbins RL, Hodge RL, Bush MA et al. 
Pharmacodynamics, pharmacokinetics, safety, and tolerability of albiglutide, a long-
acting glucagon-like peptide-1 mimetic, in patients with type 2 diabetes. Clin Endocrinol 
Metab. 2008; 93:4841-7. 
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
Nauck MA, Duran S, Kim D, Johns D, Northrup J, Festa A et al., A comparison of twice-
daily exenatide and biphasic insulin aspart in patients with type 2 diabetes who were 
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 
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
63
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#
Neumiller JJ, Campbell RK. Liraglutide: a once-daily incretin mimetic for the treatment 
of type 2 diabetes mellitus. Ann Pharmacother. 2009;43:1433-44. 
Pratley RE, Nauck MA, Barnett AH, Feinglos MN, Ovalle F, Rosenstock J et al. Once-
weekly albiglutide versus once-daily liraglutide in patients with type 2 diabetes 
inadequately controlled on oral drugs (HARMONY 7): a randomised, open-label, 
multicentre, non-inferiority phase 3 study. Lancet Diabetes Endocrinol. 2014; 2:289-97. 
Reusch J, Stewart M, Perkins CM, Cirkel DT, Ye J, Bode BW et al. Efficacy and safety 
of once-weekly glucagon-like peptide 1 receptor agonist albiglutide (HARMONY 1 
trial): 52-week primary endpoint results from a randomized, double-blind, placebo-
controlled trial in patients with type 2 diabetes mellitus not controlled on pioglitazone, 
with or without metformin. Diabetes Obes Metab. 2014; 16:1257-64.
Revicki DA, Camilleri M, Kuo B, et al. Development and content validity of a 
gastroparesis cardinal symptom index daily diary. Aliment Pharmacol Ther 2009;30:670-
80.
Revicki DA, Camilleri M, Kuo B, et al. Evaluating symptom outcomes in gastroparesis 
clinical trials: validity and responsiveness of the Gastroparesis Cardinal Symptom Index-
Daily Diary (GCSI-DD). Neurogastroenterol Motil 2012; 24, 456–e216
Revicki DA, Rentz AM, Dubois D, et al. Development and validation of a patient-
assessed gastroparesis symptom severity measure: the Gastroparesis Cardinal Symptom 
Index. Aliment Pharmacol Ther 2003;18:141-50
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, Yang F, Stewart M; Albiglutide Study Group. Potential 
of albiglutide, a long-acting GLP-1 receptor agonist, in type 2 diabetes: a randomized 
controlled trial exploring weekly, biweekly, and monthly dosing. Diabetes Care. 2009;
32: 1880-6. 
Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, et al. Hypoglycemia 
and diabetes:  a report of a workgroup of the American Diabetes Association and the 
Endocrine Society. Diabetes Care. 2013; 36:1384-95.
Sun F, Yu K, Yang Z, Wu S, Zhang Y, Shi L et al. Impact of GLP-1 Receptor Agonists 
on Major Gastrointestinal Disorders for Type 2 Diabetes Mellitus: A Mixed Treatment 
Comparison Meta-Analysis. Experimental Diabetes Research. 2012 Article ID 230624
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
64
Tanzeum US Prescribing Information, GlaxoSmithKline. May 2015. Available at: 
https://www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_In
formation/Tanzeum/pdf/TANZEUM-PI-MG-IFU-COMBINED.PDF. 
Trujillo JM, Nuffer W and Ellis SL. GLP-1 receptor agonists: a review of head to- head 
clinical studies. Ther Adv Endocrinol Metab. 2015; 6(1):19–28
Trulicity US Prescribing Information, Eli Lilly and Company. March 2015. Available at: 
http://pi.lilly.com/us/trulicity-uspi.pdf.
Weissman PN, Carr MC, Ye J, Cirkel DT, Stewart M, Ratley R et al. HARMONY 4: 
randomised clinical trial comparing once-weekly albiglutide and insulin glargine in 
patients with type 2 diabetes inadequately controlled with metformin with or without 
sulfonylurea. Diabetologia. 2014;57: 2475-84. 
Zinman B,  Hoogwerf BJ Garcia SD, Milton DR, Giaconia JM, Kim DD, Trautmann ME 
et al. The Effect of Adding Exenatide to a Thiazolidinedione in Suboptimally Controlled 
Type 2 Diabetes: A Randomized Trial. Ann of Intern Med. 2007; 146:477-485.
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
65
12.
APPENDICES
12.1.
Appendix 1 – Abbreviations and Trademarks
Abbreviations
AE
adverse event
ALT (SGPT)
alanine aminotransferase (serum glutamic pyruvic 
transaminase)
AST (SGOT)
aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase)
BMI
body mass index
BUN
blood urea nitrogen
CI
confidence interval
CNS
central nervous system
CONSORT
Consolidated Standards of Reporting Trials
CPK
creatine phosphokinase
cpm
cycles per minute
CV
cardiovascular
DCC
dual cartridge chamber
DNA
deoxyribonucleic acid
DPP-4
dipeptidyl peptidase 4
ECG
electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
EGG
electrogastrogram
FDA
US Food and Drug Administration
FPG
fasting plasma glucose
FRP
females of reproductive potential
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
GE
gastric emptying 
GEBT
gastric emptying breath test
GGT
gamma glutamyl transferase
GI
gastrointestinal
GIRMS
Gas Isotope Ratio Mass Spectrometry
GLP-1
glucagon-like peptide-1
GLP-1R
glucagon-like peptide-1 receptor
GMA
gastric myoelectrical activity
GCSI-DD
Gastroparesis Cardinal Symptom Index – Daily Diary
GSK
GlaxoSmithKline
HbA1c
glycated hemoglobin
hCG
human chorionic gonadotrophin
HDL-c
high density lipoproteins cholesterol
HRT
hormone replacement therapy
IB
Investigator’s Brochure
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
66
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IND
Investigational New Drug Application
IRB
Institutional Review Board
IRT
web-based interactive response system
ITT
intent-to-treat
LDH
lactate dehydrogenase
LDL-c
low density lipoproteins cholesterol
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MEN-2
multiple endocrine neoplasia type 2
MI
myocardial infarction
MMRM
mixed-effect model with repeated measures
MSDS
Material Safety Data Sheet
MTC
medullary thyroid cancer
OAM
oral anti-diabetic medication
PAC
Pancreatitis Adjudication Committee
PAGI-SYM
patient assessment of upper gastrointestinal symptom 
severity index
PK
pharmacokinetics
Pre-WLT
pre water load test
Post-WLT
post water load test
PI
Prescribing Information
RAP
Reporting Analysis Plan
RBC
red blood cell
SC
subcutaneous
SAE
serious adverse event
SGLT2
sodium-glucose co-transporter-2
SmPC
Summary of Product Characteristics
SRM
Study Reference Manual
T1/2
Half-life
T2DM
type 2 diabetes mellitus
TSH
thyroid stimulating hormone
ULN
upper limit of normal range
VAS
Visual analogue scale
WBC
white blood cell
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
TANZEUM
Byetta
RAMOS
RAMOS-NG
Trulicity
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
67
12.2.
Appendix 2: Risk Assessment for Albiglutide (GSK716155) and Exenatide (Byetta)
Risk of Clinical 
Significance
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
Albiglutide has not been studied in subjects with a history of pancreatitis to 
determine whether these subjects are at increased risk for pancreatitis.
Subjects with a history of acute or 
chronic pancreatitis are excluded from 
entering the study (See Section 5.2)
Subjects will be informed of the 
characteristic symptom of pancreatitis: 
persistent severe abdominal pain. If 
pancreatitis is suspected, albiglutide or 
exenatide should be promptly 
discontinued and if pancreatitis is 
confirmed, study treatment will not be
restarted (see Section 5.5).
Risk communication via guidance for 
investigators (see albiglutide IB or 
exenatide PI) and informed consent 
form for subjects.
Exenatide: 
Exenatide has not been studied in subjects with a history of pancreatitis.
Based on postmarketing data, exenatide has been associated with acute 
pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. 
Gastrointestinal (GI) 
events
Albiglutide:
Albiglutide has not been studied in subjects with severe GI disease, including 
severe gastroparesis.
Use of albiglutide and other GLP-1R agonists may be associated with GI AEs 
(e.g., diarrhea, nausea, and vomiting) 
Subjects with Clinically diagnosed 
gastroparesis or a history of significant
gastrointestinal medical conditions are 
excluded from entering the study (See 
Section 5.2).
Risk communication via guidance for 
investigators (see albiglutide IB or 
exenatide PI) and informed consent 
form for subjects.
Exenatide:
Exenatide has not been study in patients with severe gastrointestinal disease, 
including gastroparesis. Because Exenatide is commonly associated with 
gastrointestinal adverse reactions, including nausea, vomiting and diarrhea, the 
 
 
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
68
Risk of Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
use of Exenatide is not recommended in patients with severe gastrointestinal 
disease.
Hypoglycemia
Albiglutide:
Albiglutide’s mechanism of action is associated with a low intrinsic risk of 
significant hypoglycemia; however, when used in combination with insulin 
secretagogues (such as sulphonylurea) or insulin, the risk of hypoglycemia is 
increased.
Self- monitoring of blood glucose for 
hypoglycemia and advice on treatment 
are included in the study. 
The risk of hypoglycemia in this study is 
anticipated to be low as study 
medications will be used as 
monotherapy.
Risk communication via guidance for 
investigators (see albiglutide IB or 
exenatide PI)) and informed consent 
form for subjects
Exenatide: 
The risk of hypoglycemia is increased when exenatide is used in combination with 
a insulin, sulphonylurea or other glucose-independent insulin secretagogues (e.g. 
meglitinides).
Immunogenicity (e.g., 
clinical sequelae of 
antidrug antibodies) 
Albiglutide: 
In the Phase 3 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.
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%).
In the case of systemic allergic 
reactions that include anaphylaxis, 
angioedema, or other severe potential 
hypersensitivity reactions in subjects 
that have received albiglutide, that 
cannot reasonably be attributed to 
another cause a serum sample will be 
obtained for immunogenicity testing 
(see Section 7.6).
Subjects with severe allergic reactions 
that are considered by the investigator 
to be attributable to investigational 
product or without a likely alternative 
aetiology will be withdrawn from the 
study
Risk communication via guidance for 
investigators (see albiglutide IB or 
Exenatide:
Patients may develop antibodies following treatment with exenatide. Antibody 
measured in 90% of subjects.  In 1-4% of these subjects, formation of antibody 
was associated with attenuated glycemic control.
 
 
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
69
Risk of Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
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 3 program.
Across 8 Phase 3 clinical trials, a serious hypersensitivity reaction with pruritus, 
rash, and dyspnea occurred in a patient treated with albiglutide. 
Subjects with known allergy to any 
GLP-1 receptor agonist or excipients of 
albiglutide or exenatide are excluded 
from the study (See Section 5.2).
Subjects with severe 
allergic/hypersensitivity reactions that 
are considered by the investigator to be 
attributable to investigational product or 
without a likely alternative aetiology will 
be withdrawn from the study
Risk communication via guidance for 
investigators (see albiglutide IB or 
exenatide PI) and informed consent 
form for subjects.
Exenatide:
There have been postmarketing reports of serious hypersensitivity reactions (e.g. 
anaphylaxis and angioedma) in patients treated with Exenatide.
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.
Subjects will be advised that when 
injecting in the same region, to use a 
different injection site with each dose.
Risk communication via guidance for 
investigators (see albiglutide IB or 
exenatide PI) and informed consent 
form for subjects.
Exenatide: 
Injection-site reactions have been reported during post approval use of Exenatide .
Other adverse 
reactions
Albiglutide: 
e.g. pneumonia, atrial fibrillation/atrial flutter, and appendicitis
In the Phase 3 program, other adverse reactions were observed with a cumulative 
incidence of <3% in studies up to 3 years in duration.
Risk communication via guidance for 
investigators (see albiglutide IB or 
exenatide PI) and informed consent 
form for subjects
 
 
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
70
Risk of Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
Exenatide:
The following additional adverse reactions have been reported during 
postapproval use of exenatide: neurologic: dysgeusia; somnolence and alopecia
Increases in international normalized ratio with concomitant use of warfarin 
sometimes associated with bleeding. And renal impairment sometimes requiring 
hemodialysis and kidney transplant.
Investigational Product: (albiglutide (GSK716155) and exenatide (Byetta))
Potential Risks
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 3 studies of up to 3 years in duration, albiglutide was not associated with 
clinically relevant increases in serum calcitonin.
Subjects with a personal or family 
history of MTC or subjects with Multiple 
Endocrine Neoplasia syndrome type 2 
(MEN-2) are excluded from the study 
(See Section 5.2).
Risk communication via guidance for 
investigators (see albiglutide IB or 
exenatide PI) and informed consent 
form for subjects
Exenatide:
A 104-week carcinogenicity study was conducted in male and female rats at doses 
of 18, 70 or 250 g/kg/day administrated  by bolus SC injection, benign thyroid C-
cell adenomas were observed in female rats at all exenatide doses.
Other malignant 
neoplasms
(e.g., pancreatic 
cancer or malignancy 
when used in 
combination with 
insulin)
Theoretical concern for pancreatic cancer associated with GLP-1–based therapies 
(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.
Theoretical concern raised by the European Union regulatory authorities is based 
Subjects on treatment with insulin are 
not eligible for the study and subjects 
requiring insulin will be withdrawn.
 
 
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
71
Risk of Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
on their concern for the biological plausibility of a tumor-promoting effect when a 
GLP-1 agonist is combined with insulin.
CV safety of 
antidiabetic therapy
Albiglutide: 
T2DM is associated with an elevated risk of CV disease. Global regulatory 
agencies require new antidiabetic therapies to demonstrate that the new therapy is 
not associated with an unacceptable increase in CV risk. 
In the Phase 3 registration program, an independent Clinical Endpoint Committee 
prospectively adjudicated blinded CV events. The final CV meta-analysis showed 
no increased CV risk (MACE+ composed of CV death, MI, stroke, and 
hospitalization for unstable angina) with albiglutide versus all comparators 
(MACE+ hazard ratio = 1.00; 95% CI: 0.68, 1.49).
Subjects with clinically significant CV 
and/or cerebrovascular disease at any 
time before screening will be excluded 
from the study. Further details are 
provided in Section 5.2.
See albiglutide IB or exenatide PI
Exenatide 
There have been no clinical studies establishing conclusive evidence of 
macrovascular risk reduction with exenatide.
Hepatotoxicity
Albiglutide:
One subject in the Phase 3 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. 
Routine liver safety laboratory 
evaluations will be conducted and 
specific withdrawal criteria for elevated 
liver function tests have been defined 
(See Section 5.5.1).
Risk communication via informed 
consent form for subjects
Exenatide: 
No pharmacokinetic study has been performed in patients with diagnosis of acute 
or chronic hepatic impairment. Because exenatide is cleared primarily by the 
kidney, hepatic dysfunction is not expected to affect blood concentrations of 
exenatide.
 
 
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
72
Risk of Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
Investigational Product: (albiglutide (GSK716155) and exenatide (Byetta))
Additional Considerations
Patient population with
severe renal 
impairment
(eGFR 
<30 mL/min/1.73 m2)
Albiglutide:
Experience in T2DM patients with severe renal impairment is very limited.
Subjects with severe renal (eGFR <30 mL/min/1.73 m2) impairment receiving 
albiglutide experienced a higher frequency of diarrhea, nausea, and vomiting 
compared with subjects with mild/moderate renal impairment.
Subjects with an eGFR ≤75mL/min/1.73 
m2 (calculated using the MDRD
formula) are excluded from the study 
(see Section 5.2).
Risk communication via guidance for 
investigators (see Section 6 of the IB) 
and informed consent form for subjects.  
Exenatide:
Exenatide should be not be used on patients with severe renal impairment (eGFR 
<30 mL/min/1.73 m2). There have been postmarketing reports of altered renal 
function, including increased serum creatinine, renal impairment, worsened 
chronic renal failure and acute renal failure, sometime requiring hemodialysis or 
kidney transplantation. 
 
 
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
73
Risk of Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
Drug interactions
Albiglutide:
Albiglutide causes a delay in gastric emptying and thereby has the potential to 
impact the absorption of concomitantly administered oral medications.
Drug interaction studies have been conducted with digoxin, warfarin, oral 
contraceptives, and simvastatin, which demonstrated no clinically relevant PK or 
PD effects. 
Risk communication via guidance for 
investigators (see albiglutide IB or 
exenatide PI) and informed consent 
form for subjects
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
injection. . if 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.
Pregnancy and 
lactation
Albiglutide:
Studies in animals have shown reproductive toxicity. The potential risk for humans 
is unknown.
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.
Subjects who are breastfeeding, 
pregnant or planning a pregnancy 
during the course of the study are 
excluded. Additionally, all females of 
child-bearing potential must be taking 
adequate contraception during the 
study and have a negative pregnancy 
test prior to entry.  See Section 5.1 for 
further details.
Risk communication via guidance for 
investigators (see albiglutide IB or 
 
 
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
74
Risk of Clinical 
Significance
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.
exenatide PI) and informed consent 
form for subjects
Fetal & neonatal 
developmental toxicity
[non-clinical]
Albiglutide
Administration during the major period of organogenesis in female mice resulted in 
embryofetal lethality, and bent/wavy ribs in the fetus at 50 mg/kg/day (refer to 
Section 4.4.6 of the IB). Albiglutide is likely to be transferred to breast milk and 
may increase neonatal – cell mass (refer to Section 4.2.1 and Section 4.3.3 of the 
IB).
Exenatide
Based on animal data exenatide may cause fetal harm [Byetta, Prescribing 
Information, AstraZeneca Pharmaceuticals LP, 2015]
Specific eligibility and withdrawal criteria 
(see Section 5.1).
Risk communication via guidance for 
investigators (albiglutide IB and 
exenatide PI) and informed consent 
form for subjects. 
 
 
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
75
Risk of Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
Study Design or Procedures
EGG with water test 
load provokes nausea. 
Theoretically, vomiting 
may occur associated 
with water test load.
There are no published data on the incidence of nausea and vomiting during EGG 
with water load teat requiring medical care.  Theoretically, there is a risk of nausea 
or vomiting during EGG with water load test which may require medical care in this 
trial.
Subjects will be monitored by clinical 
staff during EGG with water load test. 
The EGG water test load will be 
stopped at the discretion of the 
investigator if vomit or intense nausea 
or any associated AE are observed.
Medical care in place at the 
investigational site to ensure patient
access to any required medical 
treatment associated with nausea 
induced by test procedures
AE = adverse event; ALT = alanine aminotransferase; CI = confidence interval; CV = cardiovascular; DPP-IV = dipeptidyl peptidase-IV; eGFR = 
estimated glomerular filtration rate; GI = gastrointestinal; GLP-1R = glucagon-like peptide-1 receptor; GSK = GlaxoSmithKline; IB = investigator’s 
brochure; MACE = major adverse cardiovascular event; MI = myocardial infarction; MTC = medullary thyroid carcinoma; PD = pharmacodynamic; 
PK = pharmacokinetic; PPAR = peroxisome proliferator-activated receptor; SC = subcutaneous; T2DM = type 2 diabetes mellitus; 
EGG=electrogastrogram
References
Egan AG, Blind E, Dunder K, de Graeff PA, Hummer BT. Pancreatic Safety of Incretin-Based Drugs—FDA and EMA Assessment. 
N Engl J Med. 2014; 370(9):794-7. 
 
 
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
76
12.3.
Appendix 3: Assessment of Upper Gastrointestinal 
Symptom Severity Index (PAGI-SYM 2.0-S)
 
2017N325664_00
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.


2015N255772_01
CONFIDENTIAL
204879
78
12.4.
Appendix 4: Modified List of Highly Effective Methods for 
Avoiding Pregnancy in Females of Reproductive Potential 
(FRP) and Collection of Pregnancy Information
12.4.1.
Modified List of Highly Effective Methods for Avoiding Pregnancy 
in Females of Reproductive Potential (FRP)
This list does not apply to FRP with same sex partners, when this is their preferred and 
usual lifestyle or for subjects who are and will continue to be abstinent from penile-
vaginal intercourse on a long term and persistent basis. 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 sterilization with documentation of azoospermia prior to the female 
subject's entry into the study, and this male is the sole partner for that subject 
[Hatcher, 2011]. The documentation on male sterility can come from the site 
personnel’s: review of subject’s medical records, medical examination and/or 
semen analysis, or medical history interview provided by her or her partner.
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
The investigator is responsible for ensuring that subjects understand how to properly use 
these methods of contraception.
12.4.2.
Collection of Pregnancy Information

Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study

Information will be recorded on the appropriate form and submitted to GSK within 2 
weeks of learning of a subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on mother and infant, which will be 
forwarded to GSK.  Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date. 
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
79

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK 
as described in Appendix 6. While the investigator is not obligated to actively seek
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.
Any female subject who becomes pregnant while participating 

will discontinue study medication and be withdrawn from the study
References
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, Policar MS, 
editors. Contraceptive Technology. 20th edition. Atlanta, Georgia: Ardent Media, Inc., 
2011: 50. Table 3-2.
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
80
12.5.
Appendix 5: Liver Safety Required Actions and Follow up 
Assessments
Phase 3-4 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
Phase 3-4 liver chemistry stopping criteria and required follow up assessments 
Liver Chemistry Stopping Criteria - Liver Stopping Event
ALT-absolute
ALT 8xULN
ALT Increase
ALT 5xULN but <8xULN  persists for 2 weeks
ALT 3xULN but <5xULN  persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot 
Monitor
ALT 5xULN but <8xULN and cannot be monitored weekly for 2 weeks
ALT 3xULN but <5xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be 
related to  liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue  study treatment 

Report the event to GSK within 24 hours

Complete the liver event eCRF and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries 
resolve , stabilize, or return to within baseline 
(see MONITORING below)

Do not restart/rechallenge subject with 
study treatment.

If restart/rechallenge not allowed or not 

Viral hepatitis serology4

Only in those with underlying chronic 
hepatitis B at study entry (identified by 
positive hepatitis B surface antigen) 
quantitative hepatitis B DNA and hepatitis 
delta antibody5.

Blood sample for pharmacokinetic (PK) 
analysis, obtained within obtained within 3 
half-lives (15 days) after last dose6

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
81
granted, permanently discontinue study 
treatment and may continue subject in the 
study for any protocol specified follow up 
assessments.
MONITORING:
For bilirubin or INR criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24 
hrs

Monitor subjects twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

A specialist or hepatology consultation is 
recommended
For All other criteria:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24-
72 hrs 

Monitor subjects weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
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
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG or gamma 
globulins).

Serum acetaminophen adduct HPLC 
assay (quantifies potential acetaminophen 
contribution to liver injury in subjects with 
definite or likely acetaminophen use in the 
preceding week [James, 2009]). NOTE: 
not required in China

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy eCRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to subjects receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)   
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
82
5.
If hepatitis delta antibody assay cannot be performed,, it can be replaced with a PCR of hepatitis D RNA virus 
(where needed) [Le Gal, 2005].
6.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the eCRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM.  
Phase 3-4 liver chemistry increased monitoring criteria with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 5xULN and <8xULN and
bilirubin <2xULN without symptoms 
believed to be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 2 weeks.
OR
ALT 3xULN and <5xULN and
bilirubin <2xULN without symptoms 
believed to be related to liver injury or 
hypersensitivity, and who can be 
monitored weekly for 4 weeks.

Notify the GSK Medical Monitor within 24 hours
of learning of the abnormality to discuss subject 
safety. 

Subject can continue study treatment 

Subject must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline 

If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above

If ALT decreases from ALT 5xULN and <8xULN 
to ≥3xULN but <5xULN, continue to monitor liver 
chemistries weekly. 

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor subjects twice monthly 
until liver chemistries normalize or return to within 
baseline.
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P, Gault E.  Quantification 
of Hepatitis Delta Virus RNA in Serum by Consensus Real-Time PCR Indicates 
Different Patterns of Virological Response to Interferon Therapy in Chronically Infected 
Patients.  J Clin Microbiol. 2005;43(5):2363–2369. 
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
83
12.6.
Appendix 6: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.6.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a patient or clinical investigation 
subject, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae).

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE.  However, the signs and symptoms and/or clinical 
sequelae resulting from lack of efficacy will be reported if they fulfil the definition of 
an AE or SAE.
Events NOT meeting definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
84
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.
12.6.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c.
Requires hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting.  Complications that occur during hospitalization are AEs.  
If a complication prolongs hospitalization or fulfills any other serious criteria, the 
event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d.
Results in disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
85

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.
12.6.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the eCRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
86

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
12.6.4.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the eCRF

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 eCRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK.  In this instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to 
submission of to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.
12.6.5.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. - an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
87
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of his/her assessment.

For each AE/SAE the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK.  However, it is very important 
that the investigator always make an assessment of causality for every event 
prior to the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.

The investigator is obligated to assist.  This may include additional laboratory tests 
or investigations, histopathological examinations or consultation with other health 
care professionals.

If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide GSK with a copy of any post-mortem findings, 
including histopathology.

New or updated information will be recorded in the originally completed eCRF.

The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
88
12.6.6.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data collection 
tool

If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax it to the Medical Monitor. Site will enter the 
serious adverse event data into the electronic system as soon as it becomes available.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of 
the SAE.

After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) will be taken off-line to prevent the entry of new data or changes to 
existing data

If a site receives a report of a new SAE from a study subject or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, the site can report this information on a paper SAE form or to the Medical 
Monitor by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
89
12.7.
Appendix 7: Genetic Research
Genetics – Background
Naturally occurring genetic variation may contribute to inter-individual variability in 
response to medicines, as well as an individual's risk of developing specific diseases. 
Genetic factors associated with disease characteristics may also be associated with 
response to therapy, and could help to explain some clinical study outcomes. For 
example, genetic variants associated with age-related macular degeneration are reported 
to account for much of the risk for the condition [Gorin, 2012] with certain variants 
reported to influence treatment response [Chen, 2012]. Thus, knowledge of the genetic 
etiology of disease may better inform understanding of disease and the development of 
medicines. Additionally, genetic variability may impact the pharmacokinetics 
(absorption, distribution, metabolism, and elimination), or pharmacodynamics 
(relationship between concentration and pharmacologic effects or the time course of 
pharmacologic effects) of a specific medicine and/or clinical outcomes (efficacy and/or 
safety) observed in a clinical study.
Genetic Research Objectives and Analyses
The objectives of the genetic research are to investigate the relationship between genetic 
variants and: 

Response to medicine, including albiglutide and exenatide or any concomitant 
medicines;

T2DM mellitus susceptibility, severity, and progression and related conditions
Genetic data may be generated while the study is underway or following completion of 
the study.  Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses). Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above.  Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives.
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in a Reporting and Analysis Plan 
(RAP) prior to initiation of the analysis. Planned analyses and results of genetic 
investigations will be reported either as part of the clinical RAP and study report, or in a 
separate genetics RAP and report, as appropriate.
Study Population
Any subject who is enrolled in the study can participate in genetic research.  Any subject 
who has received an allogeneic bone marrow transplant must be excluded from the 
genetic research.
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
90
Study Assessments and Procedures
A key component of successful genetic research is the collection of samples during 
clinical studies. Collection of samples, even when no a priori hypothesis has been 
identified, may enable future genetic analyses to be conducted to help understand 
variability in disease and medicine response.  

A 6 mL blood sample will be taken for Deoxyribonucleic acid (DNA) extraction. 
A blood sample is collected at the baseline visit, after the subject has been 
randomized and provided informed consent for genetic research. Instructions for 
collection and shipping of the genetic sample are described in the laboratory 
manual. The DNA from the blood sample may undergo quality control analyses to 
confirm the integrity of the sample. If there are concerns regarding the quality of 
the sample, then the sample may be destroyed. The blood sample is taken on a 
single occasion unless a duplicate sample is required due to an inability to utilize 
the original sample.  
The genetic sample is labelled (or “coded”) with the same study specific number used to 
label other samples and data in the study.   This number can be traced or linked back to 
the subject by the investigator or site staff. Coded samples do not carry personal 
identifiers (such as name or social security number). 
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study, or GSK may destroy the samples sooner.  GSK or those working 
with GSK (for example, other researchers) will only use samples collected from the study 
for the purpose stated in this protocol and in the informed consent form.  Samples may be 
used as part of the development of a companion diagnostic to support the GSK medicinal 
product.
Subjects can request their sample to be destroyed at any time.
Informed Consent
Subjects who do not wish to participate in the genetic research may still participate in the 
study.  Genetic informed consent must be obtained prior to any blood being taken.
Subject Withdrawal from Study
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample, if already 
collected:

Continue to participate in the genetic research in which case the genetic DNA 
sample is retained

Discontinue participation in the genetic research and destroy the genetic DNA 
sample 
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
91
If a subject withdraws consent for genetic research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in 
the site study records. 
Genotype data may be generated during the study or after completion of the study and 
may be analyzed during the study or stored for future analysis. 

If a subject withdraws consent for genetic research and genotype data has not been 
analyzed, it will not be analyzed or used for future research.  

Genetic data that has been analyzed at the time of withdrawn consent will 
continue to be stored and used, as appropriate. 
Screen and Baseline Failures
If a sample for genetic research has been collected and it is determined that the subject 
does not meet the entry criteria for participation in the study, then the investigator should 
instruct the subject that their genetic sample will be destroyed. No forms are required to 
complete this process as it will be completed as part of the consent and sample 
reconciliation process.  In this instance a sample destruction form will not be available to 
include in the site files.
Provision of Study Results and Confidentiality of Subject’s Genetic Data
GSK may summarize the genetic research results in the clinical study report, or 
separately and may publish the results in scientific journals. 
GSK may share genetic research data with other scientists to further scientific 
understanding in alignment with the informed consent. GSK does not inform the subject, 
family members, insurers, or employers of individual genotyping results that are not 
known to be relevant to the subject’s medical care at the time of the study, unless 
required by law. This is due to the fact that the information generated from genetic 
studies is generally preliminary in nature, and therefore the significance and scientific 
validity of the results are undetermined.  Further, data generated in a research laboratory 
may not meet regulatory requirements for inclusion in clinical care.
References
Chen H, Yu KD, Xu GZ. Association between Variant Y402H in Age-Related Macular 
Degeneration (AMD) Susceptibility Gene CFH and Treatment Response of AMD: A 
Meta-Analysis. PloS ONE 2012; 7: e42464
Gorin MB,. Genetic insights into age-related macular degeneration: Controversies 
addressing risk, causality, and therapeutics. Mol. Asp. Med. 2012; 33: 467-486.
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
92
12.8.
Appendix 8 - Country Specific Requirements
No country-specific requirements exist.
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
93
12.9.
Appendix 9: Protocol Changes
Protocol Amendment Number 01
Protocol Amendment Number 01 is applicable to all clinical study centers participating in 
this study. Protocol changes specified in Amendment Number 01 are summarized as 
follows: 

Part A was amended to remove the restrictions of a single-center to expand the 
number of participating sites to facilitate enrolment.  

Average dominant frequency was added as an exploratory endpoint for full 
inclusion of all EGG generated data.

Clarification was added to the visit window for Day-1 and the options for 
scheduling the EGG and GEBT to allow more flexibility to assist with scheduling 
and therefore enrolment.  In addition the dosing duration for Part A was corrected 
to 5 days ±1 day to be consistent with the visit windows in the Time and Events 
Table.

Incorporated other administrative changes to update/remove duplicate terms, 
correct typographical errors and correct missing checks on Time and Events table.
Specific Changes in the Text: (new text is indicated by bold)
Title Page:
Author (s): 
 
Medical Monitor/Sponsor Information Page:
Role
Name
Day Time Phone Number and 
email address
Primary Medical 
Monitor 
 
2017N325664_00
PPD
PPD
PPD
PPD


2015N255772_01
CONFIDENTIAL
204879
94
Secondary Medical 
Monitor
SAE contact  
information 
PROTOCOL SYNOPSIS 
Objectives/Endpoints Part B Objectives
Exploratory
To evaluate change in gastric rhythm status 
(Data permitting)

At Weeks 2, 5, and 8; over 30 min and at each 
time interval (pre-and 10, 20 and 30 min after 
water load).
Number and % of subjects with a shift in 
gastric rhythm status.
Number and % of subjects by gastric rhythm 
status at each time interval.

Mean and mean change from baseline in 
average dominant frequency
Overall Design
Part A
Overall Design

Part A is a single-center single arm, open label pilot phase to evaluate the effect of 5-
day repeated doses of exenatide (10 g twice daily) on GMA, GE and nausea in 
subjects with T2DM.

Part A will comprise 3 study periods: screening/wash-out (up to 3 weeks), treatment 
(5±1 days), and post-treatment follow-up (within 7 days after the last dose of 
exenatide). 
Part A
Treatment Arms and Duration

Part A is a single arm. All subjects will receive 10 g subcutaneous exenatide twice 
daily for 5±1 days. The total duration of a subject’s participation will be 
approximately 5 weeks.
 
2017N325664_00
PPD
PPD
PPD
PPD
PPD
PPD


2015N255772_01
CONFIDENTIAL
204879
95
PROTOCOL
Section 3.1 
Part A: Objectives and Endpoints
Objectives
Endpoints
Exploratory
To evaluate change in gastric rhythm status 
(Data permitting)

At Weeks 2, 5, and 8; over 30 min and at each 
time interval (pre-and 10, 20 and 30 min after 
water load).
Number and % of subjects with a shift in 
gastric rhythm status.
Number and % of subjects by gastric rhythm 
status at each time interval.

Mean and mean change from baseline in 
average dominant frequency
Section 3.2 
Part B: Objectives and Endpoints
Objectives
Endpoints
Exploratory
To evaluate change in gastric rhythm status 
(Data permitting)

At Weeks 2, 5, and 8; over 30 min and at each 
time interval (pre-and 10, 20 and 30 min after 
water load).
Number and % of subjects with a shift in 
gastric rhythm status.
Number and % of subjects by gastric rhythm 
status at each time interval.
Mean and mean change from baseline in 
average dominant frequency
Section 4.1.1
Part A Overall Design

Part A is a single center single arm, open label pilot phase to evaluate the effect of 5-
day repeated doses of exenatide (10 g twice daily) on GMA, GE and nausea in 
subjects with T2DM

Part A will comprise 3 study periods (Figure 1.): screening/wash-out (up to 
3 weeks), treatment (5±1 days), and post-treatment follow-up (within 7 days after the 
last dose of exenatide). 
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
96
Section 4.1.2 Treatment Arms and Duration
Part A is a single arm design. All subjects will receive 10 g subcutaneous exenatide 
twice daily for 5±1 days. The total duration of a subject’s participation will be 
approximately 5 weeks.
Section 4.6.2
Benefit Assessment
In Part A, eligible subjects will only receive exenatide for 5±1 days; the benefit in 
glycemic control is expected to be minimal due to this short period of treatment. 
Section 6.1 
Investigational Product and Other Study Treatments Table 1 
Dosing Instructions.
Study Part A: 10 g twice daily for 5±1 days
Section 6.2 
Treatment Assignment
All subjects in Part A of the study will receive 10 g exenatide twice daily for 5±1 days.
Section 6.9
Treatment after the End of the Study
In Part A, the last dose of exenatide will be in the morning before the GEBT on Day 5±1.
Section 7.1
Time and Events Table
Time and Events Table
Study Part A
Procedures
Screening/Wash-Out Period
(0-3 Weeks)
Treatment Period (exenatide)
(5 Days)
Day -21 to 
-4
Day -3 to -5
Day -113
Day 1
Day 2
Day 3
Day 4
1 day13
Day 5
1 day13
2.
For subjects taking OAM at screening only. At a minimum, two day washout for immediate release and 
at minimum 4 day washout for extended release OAMs. See footnote 13.    For information on 
restarting OAM refer to Section 6.9
13 Every effort should be made to schedule the procedures on the nominal visit day identified. 
However, in order to meet scheduling needs, subjects taking OAM can schedule Day-1 up to 3 
days prior to Day 1 and the OAM stopped at least the day before the GEBT .  For subjects 
treated with diet and exercise alone Day-1 can occur within 7 days prior to Day 1. The EGG and 
GEBT should not be scheduled on the same day.
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
97
Table 3 Time and Events Table Study Part B (only amended rows are shown)
Procedures
Screening/Wash-
Out Period
(0-3 weeks)
Treatment Period (exenatide or albiglutide)
(8 weeks)
Un
scheduled
Early 
Withdrawal
Follow-Up
Study Week
-3 to -1
-116
1
216
3
4
516
6
7
816
12
Study Day
-21 to  
-4
-3 to 
-5
-1
1
10±1
-
-
29±1 31±1 32±1
-
-
52±1 53±1
78-84±3
Study Visits
1
2
3
4
5
6
7
8
9
10
OAM washout2
X
Height, Weight, BMI
X
X6
X56
FPG
X
X
X
X
X
X
X
X
X
X
capillary blood glucose at clinic
X
X
X
X
X
X
X
X
X
X
2.
For subjects taking OAM at screening only. At a minimum, two day washout for immediate release and at minimum 4 day washout for extended release OAMs. 
See footnote 16.    For information on restarting OAM refer to Section 6.9
16 Every effort should be made to schedule the procedures on the nominal visit day identified. However, in order to meet scheduling needs, subjects 
taking OAM can schedule Day-1 up to 3 days prior to Day 1 and the OAM stopped at least the day before the GEBT.  For subjects treated with diet and 
exercise alone Day-1 can occur within 7 days prior to Day 1. The EGG and GEBT should not be scheduled on the same day.
 
 
 
2017N325664_00


2015N255772_01
CONFIDENTIAL
204879
98
Section 7.3
EGG and GEBT
GEBT and EGG measurements will be undertaken in the clinic and performed on 
separate days. Measurements for both Part A and Part B will be taken at the time points 
specified in the Time and Events Table in Section 7.1. Clinical visits for EGG and GEBT 
will have a visit window of 1 day. At the Week 5 and 8 visits, the EGG must be 
performed the day before the GEBT and should be planned to avoid days of expected 
holidays, weekends and vacations.  
Section 7.4.10 
Hyperglycemic Events
Subjects will be asked to report any hyperglycemic events, including time between 
study visits that occur between study visits. Subjects requiring rescue therapy due to
fasting plasma glucose ≥270 mg/dL confirmed by central lab will be withdrawn from the 
study.  At investigator discretion, a subject may be withdrawn for hyperglycemia at any 
time for safety considerations, not necessarily reaching the threshold of fasting plasma 
glucose ≥270 mg/dL 
Section 9.2.4.3
Exploratory Analysis
The mean and mean change from baseline in average dominate frequency will be 
summarized using descriptive statistics.
Other administrative changes

The reference to the Study Procedures Manual (SPM) was amended to Study 
Reference Manual (SRM) in the following Sections:
Section 6.6 
Preparation/Handling/Storage/Accountability
Section 7.3.1 EGG
Section 7.3.2 GEBT
Section 7.4 
Safety
Section 7.4.6 Gastroparesis Cardinal Symptom Index Daily Diary(GCSI-DD)
Section 7.4.7 Clinical Safety Laboratory Assessments
Section 7.6 
Immunogenicity
Appendix 1 
Abbreviations and Trademaarks
Appendix 5
Liver Safety Required Actions and Follow-up Assessments

Section 7.4.1 Protocol Required Laboratory Assessments
Table 4: deletion of Urea (already captured as BUN)
 
2017N325664_00

SAP_001.pdf: 
2017N325664_00 
204879 
CONFIDENTIAL 
The GlaxoSmithKline group of companies 
1 
 
 
 
Division 
Worldwide Development 
Information Type 
Reporting and Analysis Plan (RAP) 
 
Title 
: Reporting and Analysis Plan for A Randomized, Open-label, 
Active-Controlled, Parallel-Group, Exploratory Study on the 
Effects of Repeated Doses of Albiglutide compared to 
Exenatide on Gastric Myoelectrical Activity and Gastric 
Emptying in Subjects with Type 2 Diabetes Mellitus 
Compound Number 
: GSK716155 
Effective Date 
: 17-Aug-2017 
Amendment 
: 01 
 
 
Description : 
• 
The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 204879. 
• 
This RAP is intended to describe the exploratory endpoints for the study Part A only. 
• 
This study is terminated early prior to completion of Part A with a limited number of 
subjects (N=4) enrolled. Therefore, a synoptic CSR is planned and a brief RAP 
document is prepared accordingly. 
• 
This RAP will be provided to the study team members to convey the content of the 
final Statistical Analysis Complete (SAC) Deliverable. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Copyright 2017 the GlaxoSmithKline group of companies. All rights reserved. 
Unauthorised copying or use of this information is prohibited. 


2017N325664_00 
204879 
CONFIDENTIAL 
The GlaxoSmithKline group of companies 
2 
 
 
 
Revision Chronology 
 
GlaxoSmithKline 
Document 
Date 
Version 
Reporting and Analysis Plan (RAP)204879_Final 
23-Jun-2017 
Original 
Reporting and Analysis Plan 
(RAP)204879_Amendment_Final_01 
17-Aug-2017 
Amendment No. 1 
Changes reflected in RAP Amendment No. 1 have been included to address the 
following: 
• 
Appendix 5 Section 9.5.1 Data Display Numbering is updated with the appropriate 
listing number. 
• Appendix 5 Section 9.53 added 5 listing below: 
Listing 15: Listing of Exposure Data 
Listing 17: Listing of Visual Analogue Scale (VAS) Scores (0-100mm scale) 
Listing 18: Listing of Gastric Emptying 13C Excreted in Breath (kPCD1) Over Time 
by Treatment and Visit 
Listing 19: Listing of Time to Half Gastric Emptying (GET1/2) by Visit 
Listing 20: Listing of Volume of Water Ingested during EGG with Water Load Test 
And Listing of all EGG Endpoints the listing number changed from 15 to 16 
 
 
Author’s Name and Functional Area: 
 
PPD 
17-Aug-2017 
Principle Statistician 
 
Approved electronically via email by: 
 
PPD 
17-Aug-2017 
Dir Statistics & Programming 


3 
2017N325664_00 
204879 
CONFIDENTIAL 
 
 
 
TABLE OF CONTENTS 
 
PAGE 
1. 
REPORTING & ANALYSIS PLAN SYNPOSIS ................................................................. 5 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION .......................................................... 7 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan .................................. 7 
2.2. 
Study Objective(s) and Endpoint(s) ....................................................................... 7 
2.3. 
Study Design ............................................................................................................. 9 
2.3.1. 
Overview of Study Design and Key Features ....................................... 9 
2.3.2. 
Study Design ............................................................................................ 9 
3. 
PLANNED ANALYSES....................................................................................................... 10 
3.1. 
Interim Analyses ..................................................................................................... 10 
3.2. 
Final Analyses......................................................................................................... 10 
4. 
ANALYSIS POPULATIONS ............................................................................................... 10 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS .................................................................................................................. 11 
5.1. 
Reporting Conventions .......................................................................................... 11 
6. 
STUDY POPULATION ANALYSES ...................................................................................... 13 
6.1. 
Overview of Planned Analyses ............................................................................. 13 
6.2. 
Demographic and Baseline Characteristics ........................................................ 13 
6.3. 
Exposure to Study Drug......................................................................................... 13 
6.4. 
Medications ............................................................................................................. 14 
6.5. 
Safety Analyses ...................................................................................................... 15 
6.5.1. 
Overview of Planned Analyses ............................................................ 15 
6.5.2. 
Adverse Events ...................................................................................... 15 
6.5.3. 
Clinical Laboratory Evaluations ........................................................... 15 
6.5.3.1. 
Chemistry, Hematology and Urinalysis 
15 
6.5.4. 
Vital Signs ............................................................................................... 16 
6.5.5. 
Gastroparesis Cardinal Symptom Index Daily Dairy 
(GCSI-DD) .............................................................................................. 16 
7. 
OTHER STATISTICAL ANALYSES (EXPLORATORY) ................................................ 17 
7.1. 
Overview of Planned Analyses ............................................................................. 17 
7.2. 
Exploratory Analyses ............................................................................................. 17 
8. 
REFERENCES .................................................................................................................... 18 
9. 
APPENDICES ...................................................................................................................... 19 
9.1. 
Appendix 1: Time & Events ................................................................................... 20 
9.1.1. 
Protocol Defined Time & Events Part A .............................................. 20 
9.2. 
Appendix 2: Assessment Windows ...................................................................... 21 
9.2.1. 
Definitions of Study Day ....................................................................... 21 
9.3. 
Appendix 3: Values of Potential Clinical Importance .......................................... 22 
9.3.1. 
Laboratory .............................................................................................. 22 
9.4. 
Appendix 4 – Abbreviations & Trade Marks ........................................................ 25 
9.5. 
Appendix 5: List of Data Displays ......................................................................... 28 
9.5.1. 
Data Display Numbering ....................................................................... 28 


4 
2017N325664_00 
204879 
CONFIDENTIAL 
 
 
9.5.2. 
Study Population Tables ....................................................................... 28 
9.5.3. 
Listings .................................................................................................... 29 


5 
2017N325664_00 
204879 
CONFIDENTIAL 
 
 
1. 
REPORTING & ANALYSIS PLAN SYNPOSIS 
 
Purpose 
To gain insight into a potential peripheral mechanism of nausea associated 
with glucagon-like peptide-1 receptor (GLP-1R) agonists; this study will 
compare the effect of albiglutide and exenatide on gastric myoelectrical 
activity (GMA), gastric emptying (GE) and nausea [as measured by visual 
analogue scale (VAS)] in subjects with type 2 diabetes mellitus (T2DM). 
The study is divided in two parts. Part A will characterize the GMA, GE and 
nausea response to exenatide and confirm exenatide as a positive control for 
Part B. At the time the RAP preparation, the study had terminated early with 
a limited number of subjects enrolled in Part A. 
Protocol 
• 
This RAP is based on the protocol amendment 1 [(Dated: 23/June/2016) 
of study GSK 204879 (GSK Document No. : 2015N255772_01) and 
eCRF Version 1. 
Primary 
Objective 
To evaluate the effect of exenatide on GMA (pilot phase). 
Primary 
Endpoint 
(All endpoints for Part A are exploratory) 
• Change from baseline of electrogastrogram (EGG) parameters at 
each recording time interval (pre-and 10, 20 and 30 min after water 
load) compared to baseline: 
o Distribution of average power by frequency region (as % of power) 
o Ratios of average power post- WLT/pre-WLT by frequency region 
o Percentage (%) of time with the dominant EGG frequencies in the 
four frequency ranges (bradygastria, normal, tachygastria and 
duodenal) 
• Change from baseline EGG parameters related to VAS of nausea at 
each recording time interval (pre-and 10, 20 and 30 min after water 
load) at Day 4 
Study 
Design 
• This is a single arm, open label pilot phase to evaluate the effect of 5-day 
repeated doses of exenatide (10 µg twice daily) on GMA, GE and nausea 
in subjects with T2DM. 
• The study will comprise 3 study periods: screening/wash-out (up to 3 
weeks), treatment (5 days), and post-treatment follow-up (within 7 days 
after the last dose of exenatide). 
• The study will recruit subjects with T2DM (>6 months since diagnosis) 
with glycated hemoglobin (HbA1c) >6.5% and ≤9.0%, fasting plasma 
glucose (FPG) ˂=210 mg/dL (central lab) at screening and on a current 
regimen of diet and exercise or a stable dose of one oral anti-diabetic 
medication (OAM) (maintained for >= 2 months prior to screening). 
• Fasting capillary blood glucose will be confirmed to be <=230 mg/dL at 
baseline. 
• Subjects receiving monotherapy with an OAM of metformin, 


6 
2017N325664_00 
204879 
CONFIDENTIAL 
 
 
 
sulfonylurea, sodium glucose co-transporter-2 (SGLT2) inhibitors, or 
meglitinide at screening will be washed out for 2 days for immediate 
release and 4 days for extended release OAM prior to baseline. 
• Subject’s nutritional plan will be optimized prior to baseline and 
maintained during the entire study. 
• All evaluations and assessments will be performed as outpatient visits. 
Subjects will undergo 2 EGG and 2 gastric emptying breath tests 
(GEBT) assessments. 
• At the end of the Part A, subjects previously on an OAM will restart 
OAM at the discretion of the investigator after the last dose of exenatide. 
The half-life of exenatide (2-3 hours) should be taken into consideration. 
• The total duration of a subject’s participation will be approximately 5 
weeks. 
Planned 
Analyses 
• 
Part A: Final Analysis: After at least 10 evaluable subjects defined as 
having at least  one valid pre-dose EGG and one valid post –dose EGG , 
the final analysis for the clinical study report will be performed. At this 
time, the database will be frozen. The study is terminated early with a 
limited number of subjects enrolled in Part A. 
Analysis 
Populations 
The analysis set will include subjects who have taken at least one dose of 
study medication and one valid EGG data. Data will be assessed and 
reviewed by the central reader before it is considered valid. 
Hypothesis 
No formal statistical hypotheses are being tested in Part A. Part A will be a 
pilot phase investigating the effect of repeated doses of exenatide on GMA, 
GE, and VAS of nausea. 
Primary 
Analyses 
No formal statistical analyses will be performed for the exploratory 
endpoints for Part A.  All exploratory endpoints will be assessed using 
descriptive statistics and graphical displays as appropriate. 


7 
2017N325664_00 
204879 
CONFIDENTIAL 
 
 
 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
 
The study terminated early with a limited number of subjects enrolled in Part A. 
Therefore, only data listings will be produced for selected data. These are limited in 
scope compared to the originally planned statistical analysis specified in the protocol 
amendment 1 [(Dated: June 23, 2016)]. 
 
2.2. 
Study Objective(s) and Endpoint(s) 
 
Part A: 
 
Objectives 
Endpoints 
Exploratory Objectives 
Exploratory Endpoints 
To evaluate the effect of exenatide 
on GMA 
• Change from baseline of EGG parameters at 
each recording time interval (pre-and 10, 20 
and 30 min after water load) compared to 
baseline: 
o Distribution of average power by frequency 
region (as % of power) 
o Ratios of average power post- WLT/pre- 
WLT by frequency region 
o Percentage (%) of time with the dominant 
EGG frequencies in the four frequency 
ranges (bradygastria, normal, tachygastria 
and duodenal) 
• Change from baseline EGG parameters 
related to VAS of nausea at each recording 
time interval (pre-and 10, 20 and 30 min 
after water load) at Day 4 
To assess the effect of exenatide on 
GE 
• Change from baseline of time to half gastric 
emptying (GEt½) at Day 5 
• 
Change from baseline of profiles of 13C 
excreted in breath (kPCD1) at Day 5 and at 
each time interval (45, 90, 120, 150, 180 
and 240 min). 
To assess the volume of water 
ingested during EGG 
Change from baseline of volume of water ingested 
during EGG with water load test at Day 4. 
To evaluate the effect of exenatide 
on stomach fullness, hunger, 
bloating and abdominal pain during 
EGG with water load test 
Change from baseline of VAS of stomach fullness, 
hunger, bloating and abdominal pain during the 
EGG water load test at each time interval (pre-and 
10, 20 and 30 min after water load) at Day 4 
To evaluate safety and tolerability 
of exenatide 
• Vital signs, clinical laboratory tests, AEs, 
and GCSI-DD. 
• Nausea AEs presenting outside the timing 
of the WLT and GCSI-DD. 


8 
2017N325664_00 
204879 
CONFIDENTIAL 
 
 
 
Objectives 
Endpoints 
To evaluate change in gastric 
rhythm status (Data 
permitting) 
At Day 4; over 30 min and at each 
time interval (pre-and 10, 20 and 30 min after 
• water load). 
• Number and % of subjects with a shift in 
gastric rhythm status. 
• Number and % of subjects by gastric 
rhythm status at each time interval. 
• Mean and mean change from baseline in 
• average dominant frequency 
1 Percent dose excreted of 13C *1000 


9 
2017N325664_00 
204879 
CONFIDENTIAL 
 
 
 
 
2.3. 
Study Design 
 
2.3.1. 
Overview of Study Design and Key Features 
 
Overview of Study Design and Key Features Part A 
 
Design Features 
Part A is a single arm, open label pilot phase 5-days of 
treatment. 
Dosing 
All subjects will receive 10 g subcutaneous exenatide 
twice daily for 5 days. The total duration of a subject’s 
participation will be approximately 5 weeks. 
Interim Analysis 
No interim analysis is planned for this study. 
 
Due to early termination the entirety of the study conduct was not carried out. 
2.3.2. 
Study Design 
 
Part A is a single arm, open label pilot phase to evaluate the effect of 5-day repeated 
doses of exenatide (10 µg twice daily) on GMA, GE and nausea in subjects with T2DM. 
Part A will comprise 3 study periods screening/wash-out (up to 3 weeks), treatment (5±1 
days), and post-treatment follow-up (within 7 days after the last dose of exenatide). 
 
At the time the RAP is being prepared, the study is terminated early with a limited 
number of subjects enrolled in Part A. 


10 
2017N325664_00 
204879 
CONFIDENTIAL 
 
 
 
3. 
PLANNED ANALYSES 
3.1. 
Interim Analyses 
 
No interim analysis is planned for this study. 
 
3.2. 
Final Analyses 
 
The final planned primary analyses will be performed after the completion of the 
following sequential step: 
 
1. All required database cleaning activities have been completed and final database 
release and database freeze has been declared by Data Management. 
 
 
 
4. 
ANALYSIS POPULATIONS 
 
Part A: 
Pharmacodynami 
c 
Comprise of all subjects who have taken 
at least one dose of study medication and 
one valid EGG data Data will be assessed 
and reviewed by the central reader before 
it is considered valid. The central reader 
will provide the valid data that will be 
used for the analyses. 
Pharmacodynamic 
All Subjects 
All subjects with at least one dose of 
study medication. 
Safety 
Enrolled 
All enrolled subjects. 
Enrolled 
NOTES : 
• 
Please refer to Appendix 5: List of Data Displays which details the population to be used for each displays being 
generated. 


11 
2017N325664_00 
204879 
CONFIDENTIAL 
 
 
 
 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS 
5.1. 
Reporting Conventions 
 
• 
All data displays will be presented according to the Integrated Data Standards 
Library (IDSL) reporting standards, where applicable. 
• Analyses will be performed using the 9.1.3 version of the SAS System or higher 
(SAS is a registered trademark of the SAS Institute Inc., Cary, NC, USA). 
Programs will be imported into HARP and the final output will be produced by 
running drivers in HARP. 
 
• Data collected at unplanned (i.e. unscheduled) time points will not be included in 
the summaries by visit unless otherwise stated. Unscheduled or unplanned 
readings will be presented in the listings and they will be included when 
determining worst-case flagging for post-baseline summaries. 
 
• In all data displays, planned and actual relative times will be relative to the study 
drug dosing time of the relevant dosing session. 
 
 
• Refer to IDSL standards (when applicable) for decimal place conventions. Raw 
data will generally be presented to the same number of decimal places as it was 
collected. 
 
• All data will be reported according to the actual treatment the subject received. 
Any departures from the planned treatment according to the randomization 
schedule will be documented in the report. 
 
• All observations that occurred prior to dosing will be considered as part of the 
pre-dose period.  All observations that occur during dosing will be attributed to 
the subject’s treatment. 
 
Deviations from the analyses in the RAP will be identified in the final clinical study 
report. 
 
Table 1 provides an overview of appendices within the RAP for outlining general 
considerations for data analyses and data handling conventions. 


12 
2017N325664_00 
204879 
CONFIDENTIAL 
 
 
 
Table 1 
Overview of Appendices 
 
Section Component 
9.1 
Appendix 1: Time & Events 
9.2 
Appendix 2: Assessment Windows 
9.3 
Appendix 3: Values of Potential Clinical Importance 
9.4 
Appendix 4: Abbreviations and Trademarks 
9.5 
Appendix 5: List of Data Displays 


13 
2017N325664_00 
204879 
CONFIDENTIAL 
 
 
 
 
6. 
STUDY POPULATION ANALYSES 
6.1. 
Overview of Planned Analyses 
 
Table 2 provides an overview of the planned study population analyses, with full details 
of data displays being presented in Appendix 5: List of Data Displays. 
 
Table 2 
Overview of Planned Study Population Analyses 
 
Display Type 
Data Display’s Generated 
Figure 
Table 
Listing 
Subject Disposition 
Reasons for Withdrawal from Study 
Y 
Y 
Demography and Baseline Characteristics 
Demographics and Baseline Characteristics 
Y 
Y 
Race & Racial Combinations 
Y 
Y 
Number of subjects by Site ID 
Y 
Y 
Age Ranges 
Y 
Medical Condition & Concomitant Medications 
Concomitant Medication 
Y 
Exposure 
Exposure to Study Drug 
Y 
Note: additional tables, listings and figures will be provided in Appendix 5: List of Data Displays. 
• 
Y = Yes display generated. 
Following review of the data, additional analyses maybe conducted to further support the 
evaluation and interpretation of the data. 
 
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, 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, if 
appropriate. 
 
6.3. 
Exposure to Study Drug 
 
A by-subject listing of study drug administration will also be presented. Overall study 
drug administration and treatment compliance will be present with the exposure to study 
drug listing. 


14 
2017N325664_00 
204879 
CONFIDENTIAL 
 
 
 
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. 


15 
2017N325664_00 
204879 
CONFIDENTIAL 
 
 
 
6.5. 
Safety Analyses 
 
6.5.1. 
Overview of Planned Analyses 
 
The safety analyses will be based on all subjects’ population. 
 
Table 3 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 5: List of Data Displays. 
 
Table 3 
Overview of Planned Safety Analyses 
 
Endpoints 
Observed 
Change from Baseline 
Summary 
Individual 
Summary 
Individual 
T 
F 
F 
L 
T 
F 
F 
L 
Adverse Events 
Y 
Y 
Clinical Laboratory 
Y 
Vital Signs 
Y 
GCSI-DD 
Y 
NOTES : 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
• 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data. 
Following review of the data, additional analyses maybe conducted to further support the 
evaluation and interpretation of the data. 
 
 
6.5.2. 
Adverse Events 
 
All AEs will be coded using MedDRA which will be updated whenever available 
throughout the life of the study. 
 
All AEs will be listed in a subject data listing. 
 
6.5.3. 
Clinical Laboratory Evaluations 
 
6.5.3.1. 
Chemistry, Hematology and Urinalysis 
 
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 central lab for the study records. 
 
Hematology parameters include red blood count, hemoglobin, hematocrit white blood 
cell count with differential, and platelet count. Chemistry blood urea nitrogen (BUN), 
potassium, aspartate aminotransferase (AST), total and direct bilirubin, creatinine, 
sodium, ALT, total protein, calcium, magnesium, chloride, phosphorus albumin, gamma 
glutamyl transferase (GGT), estimated glomerular filtration rate (eGFR), and lipids 


16 
2017N325664_00 
204879 
CONFIDENTIAL 
 
 
 
(including total cholesterol, LDL-C, HDL C, triglycerides,). Urinalysis parameters 
include microalbumin and creatnine and specific gravity, pH, glucose, nitrates, 
leukocytes esterase, blood and ketones by dipstick and microscopic examination (if blood 
or protein is abnormal). 
 
All laboratory parameters as collected will be presented in by-subject listings at every 
scheduled assessment time point. All listings will be done for the safety population and 
all laboratory data will be listed including other laboratory tests, such as TSH, and urine 
pregnancy test results. 
 
Additionally, the number of subjects with laboratory values of potential clinical concern 
will be provided in a listing by treatment group and scheduled assessment time point for 
hematology and chemistry. The criteria for laboratory values of potential clinical concern 
are detailed in Appendix 3: Values of Potential Clinical Importance. 
 
A listing of laboratory values of potential clinical concern will be provided for liver 
function tests, including ALT, AST, and total bilirubin. The criteria for liver function 
tests of potential clinical concern are detailed in Appendix 3: Values of Potential Clinical 
Importance. 
 
6.5.4. 
Vital Signs 
 
The vital sign analysis will include systolic blood pressure (mmHg), diastolic blood 
pressure (mmHg), and heart rate (bpm). 
 
Each vital sign parameter at every scheduled assessment time point will be presented in 
by-subject listings. . 
 
All listings will be produced for all subjects population. 
 
6.5.5. 
Gastroparesis Cardinal Symptom Index Daily Dairy (GCSI-DD) 
 
The GCSI-DD consists of nine symptom severity items covering the following domains: 
nausea/vomiting; fullness/early satiety, and bloating. In addition, the GCSI-DD contains 
two symptom severity items upper abdominal pain and overall rating of gastroparesis 
symptoms. Patients rate each symptom on a 6-point scale from 0 – 5 with lower scores 
representing less symptom severity.  All questions addressed in the GCSI-DD and the 
overall severity question will be listed in a subject data listing and by time point. 


17 
2017N325664_00 
204879 
CONFIDENTIAL 
 
 
 
 
7. 
OTHER STATISTICAL ANALYSES (EXPLORATORY) 
7.1. 
Overview of Planned Analyses 
 
The study was terminated early and therefore no analysis will be performed but data 
listing will be generated for all exploratory endpoints as in Appendix 5. 
 
7.2. 
Exploratory Analyses 
 
Listing will be provided for all endpoints. 


18 
2017N325664_00 
204879 
CONFIDENTIAL 
 
 
 
 
8. 
REFERENCES 
None. 


19 
2017N325664_00 
204879 
CONFIDENTIAL 
 
 
 
9. 
APPENDICES 
 
Section 
Appendix 
RAP Section 5 : General Considerations for Data Analyses & Data Handling Conventions 
Section 9.1 
Appendix 1: Time and Events 
Section 9.2 
Appendix 2: Assessment Windows 
Section 9.3 
Appendix 3: Values of Potential Clinical Importance 
Section 9.4 
Appendix 4: Abbreviations & Trade Marks 
Section 9.5 
Appendix 5: List of Data Displays 


20 
2017N325664_00 
204879 
CONFIDENTIAL 
 
 
 
 
9.1. 
Appendix 1: Time & Events 
 
9.1.1. 
Protocol Defined Time & Events Part A 
 
 
Note: section noted in time and event table referring to the protocol. 


21 
2017N325664_00 
204879 
CONFIDENTIAL 
9.2. 
Appendix 2: Assessment Windows 
 
 
9.2.1. 
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). 


22 
2017N325664_00 
204879 
CONFIDENTIAL 
 
 
 
 
9.3. 
Appendix 3: Values of Potential Clinical Importance 
 
9.3.1. 
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 
Nitrogen 
mmol/L 
None 
>2 x ULN 
Calcitonin 
pmol/L 
None 
>100 
Calcium 
mmol/L 
None 
<1.8 mmol/L 
>3.0 mmol/L 


23 
2017N325664_00 
204879 
CONFIDENTIAL 
 
 
 
Chemistry 
Laboratory 
Test 
Units 
Change from Baseline of 
Potential Clinical Concern 
Potential Clinical Concern 
Value 
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 
Magnesium 
mmol/L 
None 
<1 mmol/L 
>4 mmol/L 
Phosphorus 
mmol/L 
None 
0.323 mmol/L above ULN or 
below LLN 
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 


24 
2017N325664_00 
204879 
CONFIDENTIAL 
 
 
 
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 


25 
2017N325664_00 
204879 
CONFIDENTIAL 
 
 
 
 
9.4. 
Appendix 4 – Abbreviations & Trade Marks 
 
Abbreviations 
 
ADA 
American Diabetes Association 
AE 
adverse event 
ALT (SGPT) 
alanine aminotransferase (serum glutamic pyruvic 
transaminase) 
AST (SGOT) 
aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase) 
BMI 
body mass index 
BUN 
blood urea nitrogen 
CI 
confidence interval 
CONSORT 
Consolidated Standards of Reporting Trials 
CPK 
creatine phosphokinase 
CV 
cardiovascular 
DCC 
dual chamber cartridge 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
EGG 
electrogastrogram 
ELISA 
enzyme-linked immunosorbent assay 
EMA 
European Medicines Agency 
FDA 
US Food and Drug Administration 
FFA 
free fatty acids 
FPG 
fasting plasma glucose 
FRP 
females of reproductive potential 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
GCSP 
Global Clinical Safety and Pharmacovigilance 
GGT 
gamma glutamyl transferase 
GI 
gastrointestinal 
GLP-1 
glucagon-like peptide-1 
GSK 
GlaxoSmithKline 
HA 
human albumin 
HbA1c 
glycated hemoglobin 
HBcAb 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
HIV 
human immunodeficiency virus 
hCG 
human chorionic gonadotrophin 
HDL-c 
high density lipoproteins 
HRP 
horseradish peroxidase 
HRT 
hormone replacement therapy 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 


26 
2017N325664_00 
204879 
CONFIDENTIAL 
 
 
 
IEC 
Independent Ethics Committee 
INR 
international normal range 
IP 
investigational product 
IRB 
Institutional Review Board 
ISRs 
injection site reactions 
ITT 
intent-to-treat 
IVRS 
Interactive Voice Response System 
LDH 
lactate dehydrogenase 
LDL-c 
low density lipoproteins; 
LMCF 
last mean carried forward 
K2EDTA 
di-potassium ethylenediaminetetraacetic acid 
MACE 
major adverse cardiovascular event 
MCH 
mean corpuscular hemoglobin 
MCV 
mean corpuscular volume 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEN-2 
multiple endocrine neoplasia type 2 
MI 
myocardial infarction 
MSDS 
Material Safety Data Sheet 
MTC 
medullary thyroid cancer 
OC RDC 
Oracle Clinical Remote Data Capture 
PAC 
Pancreatitis Adjudication Committee 
PD 
pharmacodynamics 
PK 
pharmacokinetics 
PP 
per protocol 
PTS-DPMK 
Platform Technologies and Science-Drug Metabolism and 
Pharmacokinetics 
RAP 
Reporting Analysis Plan 
RBC 
red blood cell 
RNA 
ribonucleic acid 
s.c. 
subcutaneous 
SAC 
Statistical Analysis Complete 
SAE 
serious adverse event 
SmPC 
Summary of Product Characteristics 
SRM 
Study Reference Manual 
SU 
sulfonylureas 
T2DM 
type 2 diabetes mellitus 
TSH 
thyroid stimulating hormone 
ULN 
upper limit of normal range 
WBC 
white blood cell 
WCBP 
women of child bearing potential 


27 
2017N325664_00 
204879 
CONFIDENTIAL 
 
 
 
Trademark Information 
 
Trademarks of the GlaxoSmithKline 
group of companies 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
NONE 
MedDRA 


28 
2017N325664_00 
204879 
CONFIDENTIAL 
 
 
 
 
9.5. 
Appendix 5: List of Data Displays 
 
 
9.5.1. 
Data Display Numbering 
 
The following numbering will be applied for RAP generated displays: 
 
Section 
Listings 
Tables 
Study Population 
1 to 5 
1.1 to 1.5 
Safety 
6 to 15 
1.6 to 1.7 
Exploratory Endpoints 
16 to 20 
 
 
9.5.2. 
Study Population Tables 
 
Study Population Tables 
No. Population 
IDSL / TST ID 
/ Example 
Shell 
Title 
Programming 
Notes 
Deliverable 
[Priority] 
[Disposition] 
1.1. All 
Subjects 
ES1/ES1A 
Summary of Subjects 
Disposition for the Subject 
Conclusion Record 
[Demographics and Baseline Characteristics] 
1.2. All 
Subjects 
DM1 
Summary of Demographic 
Characteristics 
1.3. All 
Subjects 
DM5 
Summary of Race & Racial 
Combinations 
1.4. Enrolled 
NS1 
Summary of Number of 
Subjects by Country and Site 
ID 
1.5. Enrolled 
DM11 
Summary of Age Ranges 
Safety Tables 
1.6. All 
Subjects 
AE15 
Summary of Common (>=2%) 
Non-serious AEs by System 
Organ Class and Preferred 
Term 
1.7. All 
Subjects 
AE16 
Summary of Serious AEs by 
System Organ Class and 
Preferred Term 


29 
2017N325664_00 
204879 
CONFIDENTIAL 
 
 
 
9.5.3. 
Listings 
 
Listings 
No. 
Populatio 
n 
IDSL / 
TST ID / 
Exampl 
e Shell 
Title 
Programming 
Notes 
Deliverable 
[Priority] 
1. 
All 
Subjects 
Listing of Subjects with 
Inclusion/Exclusion Criteria 
Deviations 
2. 
All 
Subjects 
Listing of Reasons for 
Withdrawal from Study 
3. 
All 
Subjects 
Listing of Demographics and 
Baseline Characteristics 
4. 
All 
Subjects 
Listing of Race 
5. 
All 
Subjects 
Listing of Subjects by Site ID 
6. 
All 
Subjects 
Listing of Concomitant Medication 
by Generic Term 
7. 
All 
Subjects 
Listing of All Adverse Events 
8. 
All 
Subjects 
Listing of Hematology Laboratory 
Data 
9. 
All 
Subjects 
Listing of Chemistry Laboratory 
Data 
10. 
All 
Subjects 
Listing of Urinalysis Laboratory 
Data 
11. 
All 
Subjects 
Listing of Laboratory Data for 
Subjects with Any Value of Potential 
Clinical Concern 
12. 
All 
Subjects 
Listing of Liver Functions with Any 
Value of Potential Clinical Concern 
13. 
All 
Subjects 
Listing of Vital Signs 
14. 
All 
Subjects 
Listing of GCSI-DD 
15. 
All 
Subjects 
Listing of Exposure Data 
16. 
Pharmaco 
dynamic 
Listing of all EGG endpoints. 
17. 
Pharmaco 
dynamic 
Listing of Visual Analogue Scale 
(VAS) Scores (0-100mm scale) 


30 
2017N325664_00 
204879 
CONFIDENTIAL 
 
 
Listings 
No. 
Populatio 
n 
IDSL / 
TST ID / 
Exampl 
e Shell 
Title 
Programming 
Notes 
Deliverable 
[Priority] 
18. 
Pharmaco 
dynamic 
Listing of Gastric Emptying 13C 
Excreted in Breath (kPCD1) Over 
Time by Treatment and Visit 
19. 
Pharmaco 
dynamic 
Listing of Time to Half Gastric 
Emptying (GET1/2) by Visit 
20. 
Pharmaco 
dynamic 
Listing of Volume of Water Ingested 
during EGG with Water Load Test 


31 
2017N325664_00 
 
 
 
 
 
CONFIDENTIAL 
The GlaxoSmithKline group of companies 
204879 
 
Division 
:   Worldwide Development 
Information Type 
:   Reporting and Analysis Plan (RAP) 
 
 
Title 
: Reporting and Analysis Plan for A Randomized, Open-label, 
Active-Controlled, Parallel-Group, Exploratory Study on the 
Effects of Repeated Doses of Albiglutide compared to 
Exenatide on Gastric Myoelectrical Activity and Gastric 
Emptying in Subjects with Type 2 Diabetes Mellitus 
Compound Number 
: GSK716155 
Effective Date 
: 23-June-2017 
 
Description: 
• 
The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 204879. 
• 
This RAP is intended to describe the exploratory endpoints for the study Part A only. 
• 
This study is terminated early prior to completion of Part A with a limited number of 
subjects (N=4) enrolled. Therefore, a synoptic CSR is planned and a brief RAP 
document is prepared accordingly. 
• 
This RAP will be provided to the study team members to convey the content of the 
final Statistical Analysis Complete (SAC) Deliverable. 
 
Author’s Name and Functional Area: 
 
PPD 
23-June-2017 
Principle Statistician 
 
Approved by: 
 
PPD 
23-June-2017 
Dir Statistics & Programming 
 
 
 
 
 
 
 
 
 
 
Copyright 2017 the GlaxoSmithKline group of companies. All rights reserved. 
Unauthorised copying or use of this information is prohibited. 
 
 
 
1 


32 
2017N325664_00 
 
 
 
 
 
CONFIDENTIAL 
 
 
204879 
 
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 
2.3.1. 
Overview of Study Design and Key Features ........................................... 7 
2.3.2. 
Study Design .............................................................................................. 8 
3. 
PLANNED ANALYSES ........................................................................................................... 9 
3.1. 
Interim Analyses ......................................................................................................... 9 
3.2. 
Final Analyses ............................................................................................................. 9 
4. 
ANALYSIS POPULATIONS ................................................................................................... 9 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS ....................................................................................................................... 9 
5.1. 
Reporting Conventions ............................................................................................... 9 
6. 
STUDY POPULATION ANALYSES .................................................................................... 10 
6.1. 
Overview of Planned Analyses ................................................................................ 10 
6.2. 
Demographic and Baseline Characteristics ........................................................... 11 
6.3. 
Exposure to Study Drug ........................................................................................... 11 
6.4. 
Medications ............................................................................................................... 11 
6.5. 
Safety Analyses ........................................................................................................ 12 
6.5.1. 
Overview of Planned Analyses ............................................................... 12 
6.5.2. 
Adverse Events ........................................................................................ 12 
6.5.3. 
Clinical Laboratory Evaluations .............................................................. 12 
6.5.3.1. 
Chemistry, Hematology and Urinalysis 12 
6.5.4. 
Vital Signs ................................................................................................. 13 
6.5.5. 
Gastroparesis Cardinal Symptom Index Daily Dairy 
(GCSI-DD) ................................................................................................ 13 
7. 
OTHER STATISTICAL ANALYSES (EXPLORATORY) .................................................... 13 
7.1. 
Overview of Planned Analyses ................................................................................ 13 
7.2. 
Exploratory Analyses ................................................................................................ 13 
8. 
REFERENCES ....................................................................................................................... 14 
9. 
APPENDICES ........................................................................................................................ 15 
9.1. 
Appendix 1 Time & Events ....................................................................................... 16 
9.1.1. 
Protocol Defined Time & Events Part A .................................................. 16 
9.2. 
Appendix 2 Assessment Windows .............................................................................. 17 
9.2.1. 
Definitions of Study Day .......................................................................... 17 
9.3. 
Appendix 3 Values of Potential Clinical Importance ............................................... 18 
9.3.1. 
Laboratory ................................................................................................ 18 
9.4. 
Appendix 4 – Abbreviations & Trade Marks ............................................................ 21 
9.5. 
Appendix 5 List of Data Displays ............................................................................. 24 
9.5.1. 
Data Display Numbering ......................................................................... 24 
2 


33 
2017N325664_00 
 
 
CONFIDENTIAL 
204879 
9.5.2. 
Study Population Tables ......................................................................... 24 
9.5.3. 
Listings ...................................................................................................... 25 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3 


34 
2017N325664_00 
 
 
 
 
 
CONFIDENTIAL 
 
 
204879 
 
1. 
REPORTING & ANALYSIS PLAN SYNPOSIS 
 
Purpose 
To gain insight into a potential peripheral mechanism of nausea associated 
with glucagon-like peptide-1 receptor (GLP-1R) agonists; this study will 
compare the effect of albiglutide and exenatide on gastric myoelectrical 
activity (GMA), gastric emptying (GE) and nausea [as measured by visual 
analogue scale (VAS)] in subjects with type 2 diabetes mellitus (T2DM). 
The study is divided in two parts. Part A will characterize the GMA, GE and 
nausea response to exenatide and confirm exenatide as a positive control for 
Part B. At the time the RAP preparation, the study had terminated early with 
a limited number of subjects enrolled in Part A. 
Protocol 
• 
This RAP is based on the protocol amendment 1 [(Dated: 23/June/2016) 
of study GSK 204879 (GSK Document No. : 2015N255772_01) and 
eCRF Version 1. 
Primary 
Objective 
To evaluate the effect of exenatide on GMA (pilot phase). 
Primary 
Endpoint 
(All endpoints for Part A are exploratory) 
• Change from baseline of electrogastrogram (EGG) parameters at 
each recording time interval (pre-and 10, 20 and 30 min after water 
load) compared to baseline: 
o Distribution of average power by frequency region (as % of power) 
o Ratios of average power post- WLT/pre-WLT by frequency region 
o Percentage (%) of time with the dominant EGG frequencies in the 
four frequency ranges (bradygastria, normal, tachygastria and 
duodenal) 
• Change from baseline EGG parameters related to VAS of nausea at 
each recording time interval (pre-and 10, 20 and 30 min after water 
load) at Day 4 
Study 
Design 
• This is a single arm, open label pilot phase to evaluate the effect of 5-day 
repeated doses of exenatide (10 µg twice daily) on GMA, GE and nausea 
in subjects with T2DM. 
• The study will comprise 3 study periods: screening/wash-out (up to 3 
weeks), treatment (5 days), and post-treatment follow-up (within 7 days 
after the last dose of exenatide). 
• The study will recruit subjects with T2DM (>6 months since diagnosis) 
with glycated hemoglobin (HbA1c) >6.5% and ≤9.0%, fasting plasma 
glucose (FPG) ˂=210 mg/dL (central lab) at screening and on a current 
regimen of diet and exercise or a stable dose of one oral anti-diabetic 
medication (OAM) (maintained for >= 2 months prior to screening). 
• Fasting capillary blood glucose will be confirmed to be <=230 mg/dL at 
baseline. 
• Subjects receiving monotherapy with an OAM of metformin, 
sulfonylurea, sodium glucose co-transporter-2 (SGLT2) inhibitors, or 
meglitinide at screening will be washed out for 2 days for immediate 
release and 4 days for extended release OAM prior to baseline. 
• Subject’s nutritional plan will be optimized prior to baseline and 
 
4 


35 
2017N325664_00 
 
 
 
 
 
CONFIDENTIAL 
 
 
204879 
 
maintained during the entire study. 
• All evaluations and assessments will be performed as outpatient visits. 
Subjects will undergo 2 EGG and 2 gastric emptying breath tests 
(GEBT) assessments. 
• At the end of the Part A, subjects previously on an OAM will restart 
OAM at the discretion of the investigator after the last dose of exenatide. 
The half-life of exenatide (2-3 hours) should be taken into consideration. 
• The total duration of a subject’s participation will be approximately 5 
weeks. 
Planned 
Analyses 
• 
Part A: Final Analysis: After at least 10 evaluable subjects defined as 
having at least one valid pre-dose EGG and one valid post –dose EGG, 
the final analysis for the clinical study report will be performed. At this 
time, the database will be frozen.  The study is terminated early with a 
limited number of subjects enrolled in Part A. 
Analysis 
Populations 
The analysis set will include subjects who have taken at least one dose of 
study medication and one valid EGG data. Data will be assessed and 
reviewed by the central reader before it is considered valid. 
Hypothesis 
No formal statistical hypotheses are being tested in Part A. Part A will be a 
pilot phase investigating the effect of repeated doses of exenatide on GMA, 
GE, and VAS of nausea. 
Primary 
Analyses 
No formal statistical analyses will be performed for the exploratory 
endpoints for Part A.  All exploratory endpoints will be assessed using 
descriptive statistics and graphical displays as appropriate. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5 


36 
2017N325664_00 
 
 
 
 
 
CONFIDENTIAL 
 
 
204879 
 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
 
The study terminated early with a limited number of subjects enrolled in Part A. 
Therefore, only data listings will be produced for selected data. These are limited in 
scope compared to the originally planned statistical analysis specified in the protocol 
amendment 1 [(Dated: June 23, 2016)]. 
 
2.2. 
Study Objective(s) and Endpoint(s) 
 
Part A: 
 
Objectives 
Endpoints 
Exploratory Objectives 
Exploratory Endpoints 
To evaluate the effect of exenatide 
on GMA 
• Change from baseline of EGG parameters at 
each recording time interval (pre-and 10, 20 
and 30 min after water load) compared to 
baseline: 
o Distribution of average power by frequency 
region (as % of power) 
o Ratios of average power post- WLT/pre- 
WLT by frequency region 
o Percentage (%) of time with the dominant 
EGG frequencies in the four frequency 
ranges (bradygastria, normal, tachygastria 
and duodenal) 
• Change from baseline EGG parameters 
related to VAS of nausea at each recording 
time interval (pre-and 10, 20 and 30 min 
after water load) at Day 4 
To assess the effect of exenatide on 
GE 
• Change from baseline of time to half gastric 
emptying (GEt½) at Day 5 
• 
Change from baseline of profiles of 13C 
excreted in breath (kPCD1) at Day 5 and at 
each time interval (45, 90, 120, 150, 180 
and 240 min). 
To assess the volume of water 
ingested during EGG 
Change from baseline of volume of water ingested 
during EGG with water load test at Day 4. 
To evaluate the effect of exenatide 
on stomach fullness, hunger, 
bloating and abdominal pain during 
EGG with water load test 
Change from baseline of VAS of stomach fullness, 
hunger, bloating and abdominal pain during the 
EGG water load test at each time interval (pre-and 
10, 20 and 30 min after water load) at Day 4 
To evaluate safety and tolerability 
of exenatide 
• Vital signs, clinical laboratory tests, AEs, 
and GCSI-DD. 
• Nausea AEs presenting outside the timing 
of the WLT and GCSI-DD. 
 
 
6 


37 
2017N325664_00 
 
 
 
 
 
CONFIDENTIAL 
 
 
204879 
 
Objectives 
Endpoints 
To evaluate change in gastric 
rhythm status (Data 
permitting) 
At Day 4; over 30 min and at each 
time interval (pre-and 10, 20 and 30 min after 
• water load). 
• Number and % of subjects with a shift in 
gastric rhythm status. 
• Number and % of subjects by gastric 
rhythm status at each time interval. 
• Mean and mean change from baseline in 
• average dominant frequency 
1 Percent dose excreted of 13C *1000 
2.3. 
Study Design 
 
2.3.1. 
Overview of Study Design and Key Features 
 
Overview of Study Design and Key Features Part A 
 
Design Features 
Part A is a single arm, open label pilot phase 5-days of 
treatment. 
Dosing 
All subjects will receive 10 g subcutaneous exenatide 
twice daily for 5 days. The total duration of a subject’s 
participation will be approximately 5 weeks. 
Interim Analysis 
No interim analysis is planned for this study. 
 
Due to early termination, the entirety of the study conduct was not carried out. 
 
 
 
 
 
7 


38 
2017N325664_00 
 
 
 
 
 
CONFIDENTIAL 
 
 
204879 
 
2.3.2. 
Study Design 
 
Part A is a single arm, open label pilot phase to evaluate the effect of 5-day repeated 
doses of exenatide (10 µg twice daily) on GMA, GE and nausea in subjects with T2DM. 
Part A will comprise 3 study periods screening/wash-out (up to 3 weeks), treatment (5±1 
days), and post-treatment follow-up (within 7 days after the last dose of exenatide). 
 
At the time the RAP is being prepared, the study is terminated early with a limited 
number of subjects enrolled in Part A. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8 


39 
2017N325664_00 
 
 
 
 
 
CONFIDENTIAL 
 
 
204879 
 
3. 
PLANNED ANALYSES 
3.1. 
Interim Analyses 
 
No interim analysis is planned for this study.Final Analyses 
 
The final planned primary analyses will be performed after the completion of the 
following sequential step: 
 
All required database cleaning activities have been completed and final database release 
and database freeze has been declared by Data Management. 
 
4. 
ANALYSIS  POPULATIONS 
 
Part A: 
Pharmacodynami 
c 
Comprise of all subjects who have taken 
at least one dose of study medication and 
one valid EGG data Data will be assessed 
and reviewed by the central reader before 
it is considered valid. The central reader 
will provide the valid data that will be 
used for the analyses. 
Pharmacodynamic 
All Subjects 
All subjects with at least one dose of 
study medication. 
Safety 
Enrolled 
All enrolled subjects. 
Enrolled 
NOTES : 
• 
Please refer to Appendix 5: List of Data Displays which details the population to be used for each displays being 
generated. 
 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING  CONVENTIONS 
5.1. 
Reporting Conventions 
 
• 
All data displays will be presented according to the Integrated Data Standards 
Library (IDSL) reporting standards, where applicable. 
• 
Analyses will be performed using the 9.1.3 version of the SAS System or higher 
(SAS is a registered trademark of the SAS Institute Inc., Cary, NC, USA). 
Programs will be imported into HARP and the final output will be produced by 
running drivers in HARP. 
• 
Data collected at unplanned (i.e. unscheduled) time points will not be included 
in the summaries by visit unless otherwise stated. Unscheduled or unplanned 
readings will be presented in the listings and they will be included when 
determining worst-case flagging for post-baseline summaries. 
• 
In all data displays, planned and actual relative times will be relative to the study 
drug dosing time of the relevant dosing session. 
 
 
 
 
9 


2017N325664_00 
40 
 
 
 
 
 
CONFIDENTIAL 
 
 
204879 
 
• 
Refer to IDSL standards (when applicable) for decimal place conventions. Raw 
data will generally be presented to the same number of decimal places as it was 
collected. 
• 
All data will be reported according to the actual treatment the subject received. 
Any departures from the planned treatment according to the randomization 
schedule will be documented in the report. 
• 
All observations that occurred prior to dosing will be considered as part of the 
pre-dose period.  All observations that occur during dosing will be attributed to 
the subject’s treatment. 
Deviations from the analyses in the RAP will be identified in the final clinical study 
report. 
 
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 
9.1 
Appendix 1: Time & Events 
9.2 
Appendix 2: Assessment Windows 
9.3 
Appendix 3: Values of Potential Clinical Importance 
9.4 
Appendix 4: Abbreviations and Trademarks 
9.5 
Appendix 5: List of Data Displays 
 
6. 
STUDY POPULATION ANALYSES 
6.1. 
Overview of Planned Analyses 
 
Table 2 provides an overview of the planned study population analyses, with full details 
of data displays being presented in Appendix 5: List of Data Displays. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10 


2017N325664_00 
41 
 
 
 
 
 
CONFIDENTIAL 
 
 
204879 
 
Table 2 
Overview of Planned Study Population Analyses 
 
Display Type 
Data Display’s Generated 
Figure 
Table 
Listing 
Subject Disposition 
Reasons for Withdrawal from Study 
Y 
Y 
Demography and Baseline Characteristics 
Demographics and Baseline Characteristics 
Y 
Y 
Race & Racial Combinations 
Y 
Y 
Number of subjects by Site ID 
Y 
Y 
Age Ranges 
Y 
Medical Condition & Concomitant  Medications 
Concomitant Medication 
Y 
Exposure 
Exposure to Study Drug 
Y 
Note: additional tables, listings and figures will be provided in Appendix 5: List of Data Displays. 
• 
Y = Yes display generated. 
Following review of the data, additional analyses maybe conducted to further support the 
evaluation and interpretation of the data. 
 
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, 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, if 
appropriate. 
 
6.3. 
Exposure to Study Drug 
 
A by-subject listing of study drug administration will also be presented. Overall study 
drug administration and treatment compliance will be present with the exposure to study 
drug listing. 
 
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. 
 
 
 
11 


2017N325664_00 
42 
 
 
 
 
 
CONFIDENTIAL 
 
 
204879 
 
All medications will be listed. 
 
6.5. 
Safety Analyses 
 
6.5.1. 
Overview of Planned Analyses 
 
The safety analyses will be based on all subjects population. 
Table 3 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 5: List of Data Displays. 
 
Table 3 
Overview of Planned Safety Analyses 
 
Endpoints 
Observed 
Change from Baseline 
Summary 
Individual 
Summary 
Individual 
T 
F 
F 
L 
T 
F 
F 
L 
Adverse Events 
Y 
Y 
Clinical Laboratory 
Y 
Vital Signs 
Y 
GCSI-DD 
Y 
NOTES : 
• 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
• 
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted. 
• 
Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data. 
• 
Individual = Represents FL related to any displays of individual subject observed raw data. 
Following review of the data, additional analyses maybe conducted to further support the 
evaluation and interpretation of the data. 
 
6.5.2. 
Adverse Events 
 
All AEs will be coded using MedDRA which will be updated whenever available 
throughout the life of the study. 
 
All AEs will be listed in a subject data listing. 
 
6.5.3. 
Clinical Laboratory Evaluations 
 
6.5.3.1. 
Chemistry, Hematology and Urinalysis 
 
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 central lab for the study records. 
 
Hematology parameters include red blood count, hemoglobin, hematocrit white blood 
cell count with differential, and platelet count. Chemistry blood urea nitrogen (BUN), 
potassium, aspartate aminotransferase (AST), total and direct bilirubin, creatinine, 
sodium, ALT, total protein, calcium, magnesium, chloride, phosphorus albumin, , gamma 
glutamyl transferase (GGT), estimated glomerular filtration rate (eGFR), and lipids 
 
 
12 


2017N325664_00 
43 
 
 
 
 
 
CONFIDENTIAL 
 
 
204879 
 
(including total cholesterol, LDL-C, HDL C, triglycerides,). Urinalysis parameters 
include microalbumin and creatnine and specific gravity, pH, glucose, nitrates, 
leukocytes esterase, blood and ketones by dipstick and microscopic examination (if blood 
or protein is abnormal). 
 
All laboratory parameters as collected will be presented in by-subject listings at every 
scheduled assessment time point. All listings will be done for the safety population and 
all laboratory data will be listed including other laboratory tests, such as TSH, and urine 
pregnancy test results. 
 
Additionally, the number of subjects with laboratory values of potential clinical concern 
will be provided in a listing by treatment group and scheduled assessment time point for 
hematology and chemistry. The criteria for laboratory values of potential clinical concern 
are detailed in Appendix 3: Values of Potential Clinical Importance. 
 
A listing of laboratory values of potential clinical concern will be provided for liver 
function tests, including ALT, AST, and total bilirubin. The criteria for liver function 
tests of potential clinical concern are detailed in Appendix 3: Values of Potential Clinical 
Importance. 
 
6.5.4. 
Vital Signs 
 
The vital sign analysis will include systolic blood pressure (mmHg), diastolic blood 
pressure (mmHg), and heart rate (bpm). 
 
Each vital sign parameter at every scheduled assessment time point will be presented in 
by-subject listings. . 
 
All listings will be produced for all subjects population. 
 
6.5.5. 
Gastroparesis Cardinal Symptom Index Daily Dairy (GCSI-DD) 
 
The GCSI-DD consists of nine symptom severity items covering the following domains: 
nausea/vomiting; fullness/early satiety, and bloating. In addition, the GCSI-DD contains 
two symptom severity items upper abdominal pain and overall rating of gastroparesis 
symptoms. Patients rate each symptom on a 6-point scale from 0 – 5 with lower scores 
representing less symptom severity.  All questions addressed in the GCSI-DD and the 
overall severity question will be listed in a subject data listing and by time point. 
 
7. 
OTHER STATISTICAL ANALYSES (EXPLORATORY) 
7.1. 
Overview of Planned Analyses 
 
The study was terminated early and therefore no analysis will be performed but data 
listing will be generated for all exploratory endpoint as in Appendix 5. 
 
7.2. 
Exploratory Analyses 
 
Listing will be provided for all endpoints. 
 
 
13 


2017N325664_00 
44 
 
 
 
 
 
CONFIDENTIAL 
 
 
204879 
 
8. 
REFERENCES 
None. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
14 


2017N325664_00 
45 
 
 
 
 
 
CONFIDENTIAL 
 
 
204879 
 
9. 
APPENDICES 
 
Section 
Appendix 
RAP Section 5 : General Considerations for Data Analyses & Data Handling Conventions 
Section 9.1 
Appendix 1: Time and Events 
Section 9.2 
Appendix 2: Assessment Windows 
Section 9.3 
Appendix 3: Values of Potential Clinical Importance 
Section 9.4 
Appendix 4: Abbreviations & Trade Marks 
Section 9.5 
Appendix 5: List of Data Displays 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
15 


2017N325664_00 
46 
 
 
 
 
 
CONFIDENTIAL 
 
 
204879 
 
9.1. 
Appendix 1 Time & Events 
 
 
9.1.1. 
Protocol Defined Time & Events Part A 
 
 
Note: section noted in time and event table referring to the protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
16 


47 
2017N325664_00 
CONFIDENTIAL 
204879 
9.2. 
Appendix 2 Assessment Windows 
 
 
 
9.2.1. 
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). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
17 


48 
2017N325664_00 
 
 
 
 
 
CONFIDENTIAL 
 
 
204879 
 
9.3. 
Appendix 3 Values of Potential Clinical Importance 
 
9.3.1. 
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 
Nitrogen 
mmol/L 
None 
>2 x ULN 
Calcitonin 
pmol/L 
None 
>100 
Calcium 
mmol/L 
None 
<1.8 mmol/L 
>3.0 mmol/L 
 
18 


49 
2017N325664_00 
 
 
 
 
 
CONFIDENTIAL 
 
 
204879 
 
Chemistry 
Laboratory 
Test 
Units 
Change from Baseline of 
Potential Clinical Concern 
Potential Clinical Concern 
Value 
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 
Magnesium 
mmol/L 
None 
<1 mmol/L 
>4 mmol/L 
Phosphorus 
mmol/L 
None 
0.323 mmol/L above ULN or 
below LLN 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
19 


2017N325664_00 
50 
 
 
 
 
 
CONFIDENTIAL 
 
 
204879 
 
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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
20 


2017N325664_00 
51 
 
 
 
 
 
CONFIDENTIAL 
 
 
204879 
 
9.4. 
Appendix 4 – Abbreviations & Trade Marks 
 
 
 
Abbreviations 
 
ADA 
American Diabetes Association 
AE 
adverse event 
ALT (SGPT) 
alanine aminotransferase (serum glutamic pyruvic 
transaminase) 
AST (SGOT) 
aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase) 
BMI 
body mass index 
BUN 
blood urea nitrogen 
CI 
confidence interval 
CONSORT 
Consolidated Standards of Reporting Trials 
CPK 
creatine phosphokinase 
CV 
cardiovascular 
DCC 
dual chamber cartridge 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
EGG 
electrogastrogram 
ELISA 
enzyme-linked immunosorbent assay 
EMA 
European Medicines Agency 
FDA 
US Food and Drug Administration 
FFA 
free fatty acids 
FPG 
fasting plasma glucose 
FRP 
females of reproductive potential 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
GCSP 
Global Clinical Safety and Pharmacovigilance 
GGT 
gamma glutamyl transferase 
GI 
gastrointestinal 
GLP-1 
glucagon-like peptide-1 
GSK 
GlaxoSmithKline 
HA 
human albumin 
HbA1c 
glycated hemoglobin 
HBcAb 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
HIV 
human immunodeficiency virus 
hCG 
human chorionic gonadotrophin 
HDL-c 
high density lipoproteins 
HRP 
horseradish peroxidase 
HRT 
hormone replacement therapy 
 
 
21 


2017N325664_00 
52 
 
 
 
 
 
CONFIDENTIAL 
 
 
204879 
 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
INR 
international normal range 
IP 
investigational product 
IRB 
Institutional Review Board 
ISRs 
injection site reactions 
ITT 
intent-to-treat 
IVRS 
Interactive Voice Response System 
LDH 
lactate dehydrogenase 
LDL-c 
low density lipoproteins; 
LMCF 
last mean carried forward 
K2EDTA 
di-potassium ethylenediaminetetraacetic acid 
MACE 
major adverse cardiovascular event 
MCH 
mean corpuscular hemoglobin 
MCV 
mean corpuscular volume 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEN-2 
multiple endocrine neoplasia type 2 
MI 
myocardial infarction 
MSDS 
Material Safety Data Sheet 
MTC 
medullary thyroid cancer 
OC RDC 
Oracle Clinical Remote Data Capture 
PAC 
Pancreatitis Adjudication Committee 
PD 
pharmacodynamics 
PK 
pharmacokinetics 
PP 
per protocol 
PTS-DPMK 
Platform Technologies and Science-Drug Metabolism and 
Pharmacokinetics 
RAP 
Reporting Analysis Plan 
RBC 
red blood cell 
RNA 
ribonucleic acid 
s.c. 
subcutaneous 
SAC 
Statistical Analysis Complete 
SAE 
serious adverse event 
SmPC 
Summary of Product Characteristics 
SRM 
Study Reference Manual 
SU 
sulfonylureas 
T2DM 
type 2 diabetes mellitus 
TSH 
thyroid stimulating hormone 
ULN 
upper limit of normal range 
WBC 
white blood cell 
WCBP 
women of child bearing potential 
 
 
 
 
 
22 


2017N325664_00 
53 
 
 
 
 
 
CONFIDENTIAL 
 
 
204879 
 
Trademark Information 
 
Trademarks of the GlaxoSmithKline 
group of companies 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
NONE 
MedDRA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
23 


2017N325664_00 
54 
 
 
 
 
 
CONFIDENTIAL 
 
 
204879 
 
9.5. 
Appendix 5 List of Data Displays 
 
9.5.1. 
Data Display Numbering 
 
The following numbering will be applied for RAP generated displays: 
 
Section 
Listings 
Tables 
Study Population 
1 to 5 
1.1 to 1.5 
Safety 
6 to 14 
1.6 to 1.7 
Exploratory Endpoints 
15 
 
9.5.2. 
Study Population Tables 
 
Study Population Tables 
No 
. 
Popula 
tion 
IDSL / 
TST ID / 
Exampl 
e Shell 
Title 
Programming Notes 
Delivera 
ble 
[Priority] 
[Disposition] 
1.1. 
All 
Subject 
s 
ES1/ES 
1A 
Summary of Subjects Disposition for 
the Subject Conclusion Record 
[Demographics and Baseline Characteristics] 
1.2. 
All 
Subject 
s 
DM1 
Summary of Demographic 
Characteristics 
1.3. 
All 
Subject 
s 
DM5 
Summary of Race & Racial 
Combinations 
1.4. Enrolle 
d 
NS1 
Summary of Number of Subjects by 
Country and Site ID 
1.5. Enrolle 
d 
DM11 
Summary of Age Ranges 
Safety Tables 
1.6. 
All 
Subject 
s 
AE15 
Summary of Common (>=2%) Non- 
serious AEs by System Organ Class 
and Preferred Term 
1.7. 
All 
Subject 
s 
AE16 
Summary of Serious AEs by System 
Organ Class and Preferred Term 
 
 
 
 
 
 
 
24 


2017N325664_00 
55 
 
 
 
 
 
CONFIDENTIAL 
 
 
204879 
 
9.5.3. 
Listings 
 
Listings 
No. 
Population 
IDSL / 
TST ID / 
Example 
Shell 
Title 
Programming 
Notes 
Deliverable 
[Priority] 
1. 
All Subjects 
Listing of Subjects with 
Inclusion/Exclusion Criteria 
Deviations 
2. 
All Subjects 
Listing of Reasons for 
Withdrawal from Study 
3. 
All Subjects 
Listing of Demographics and 
Baseline Characteristics 
4. 
All Subjects 
Listing of Race 
5. 
All Subjects 
Listing of Subjects by Site 
ID 
6. 
All Subjects 
Listing of Concomitant 
Medication by Generic Term 
7. 
All Subjects 
Listing of All Adverse Events 
8. 
All Subjects 
Listing of Hematology 
Laboratory Data 
9. 
All Subjects 
Listing of Chemistry 
Laboratory Data 
10. 
All Subjects 
Listing of Urinalysis Laboratory 
Data 
11. 
All Subjects 
Listing of Laboratory Data for 
Subjects with Any Value of 
Potential Clinical Concern 
12. 
All Subjects 
Listing of Liver Functions with 
Any Value of Potential Clinical 
Concern 
13. 
All Subjects 
Listing of Vital Signs 
14. 
All Subjects 
Listing of GCSI-DD 
15. 
Pharmacodynamic 
Listing of all EGG endpoints. 
 
 
 
 
 
 
 
 
 
 
 
 
 
25