A Long Term, Randomised, Double Blind, Placebo-controlled Study to Determine the Effect of Albiglutide, When Added to Standard Blood Glucose Lowering Therapies, on Major Cardiovascular Events in Patients With Type 2 Diabetes Mellitus
Phase: PHASE4
Conditions: Diabetes Mellitus
Sponsor: GlaxoSmithKline

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TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A long term, randomised, double-blind, placebo-controlled study 
to determine the effect of albiglutide, when added to standard 
blood glucose lowering therapies, on major cardiovascular 
events in patients with Type 2 diabetes mellitus.  Harmony 
Outcomes Trial
Compound Number:
GSK716155
Development Phase:
III/IV
Effective Date:
04-APR-2017
Protocol Amendment Number:  03
Author (s): The protocol was developed by the members of the Executive Committee in 
conjunction with Duke Clinical Research Institute and the Sponsor.
The following individuals provided substantial input during protocol development:
Non-sponsor:
 
(Executive Committee Co-Chair); 
 
(Executive Committee Co-Chair); 
Sponsor: 
 
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
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Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2014N193553_00
2014-SEP-25
Original
2014N193553_01
2014-NOV-24
Amendment No. 1
Clarification added regarding follow-up after discontinuation of investigational product.
Addition of safety assessment to dose adjustment visits.
Addition of Country Specific Requirements appendix.
Correction of typographical errors and inconsistent terminology.
2014N193553_02
2015-JUL-22
Amendment No. 2
Amendment to study phase for participating countries where albiglutide is not licensed.
Update list of Authors.
Update to Sponsor Information
Removal of discrepancy in level of pregnancy testing required for inclusion.
Reformatting of Time and Event table to improve clarity.
Addition of table of visits for subjects discontinuing investigational product (previously 
included in text) as an aid to investigators.
Addition of requirement of Mexican Ministry of Health to report events referred to 
Clinical Endpoint Committee from Mexican investigators as Serious Adverse Events.
Addition of requirement to record lipid results if they are available from subjects’ routine 
clinical care outside of the trial.
Clarify that TRIM-D should not be assessed at Baseline in subjects whose diabetes is 
treated by diet and exercise alone.
Simplification of description of safety analyses to properly reflect the planned reports.
Correction of typographical and process errors.
2014N193553_03
2017-APR-04
Amendment No. 3
Addition of requirement that the study achieve a median subject follow up of at least 1.5 
years as well as the sample size derived number of primary endpoints.
Specifying that to meet the primary objective of assessing the effect of albiglutide with 
respect to MACE, the primary analysis will be non-inferiority. If the pre-specified non-

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inferiority criterion is met then superiority testing will be performed with a closed testing 
procedure.  Previously, superiority testing of MACE was considered a secondary 
endpoint.
Removal of multiplicity testing strategy for selected secondary endpoints.
Revision of the data collection strategy for the exploratory electronic healthcare record 
ancillary study (Appendix 7) with improved clarity for the planned data flow and 
analytical approach.

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SPONSOR INFORMATION PAGE
Clinical Study Identifier: GLP116174
Sponsor Legal Registered Address:
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford, Middlesex, TW8 9GS, UK
Sponsor Contact Address
GlaxoSmithKline Research & Development Limited
Iron Bridge Road 
Stockley Park West, Uxbridge, Middlesex, UB11 1BU, UK
Telephone: 
GlaxoSmithKline Research & Development Limited
2301 Renaissance Boulevard
Building #510
Post Office Box 61540
King of Prussia, Pennsylvania 19406, USA
Telephone number:
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline affiliate 
company (or designee). Where applicable, the details of the Sponsor and contact person 
will be provided to the relevant regulatory authority as part of the clinical trial 
submission.
Sponsor Medical Monitor Contact Information: 
Dr
2301 Renaissance Boulevard
REN0410
King of Prussia, Pennsylvania 19406, USA
Email:
Telephone number: Office: 
                                Cell: 
 
                                Out of hours: 
Sponsor Serious Adverse Events (SAE) Contact Information:
Dr 
As above for Medical Monitor Contact
Regulatory Agency Identifying Number(s):
Investigational New Drug (IND) Number: IND65177
European Drug Regulatory Authorities Clinical Trials (EudraCT) No. 2014-001824-32.
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number GLP116174
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date

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TABLE OF CONTENTS
PAGE
LIST OF ABBREVIATIONS...........................................................................................10
PROTOCOL SUMMARY...............................................................................................12
1.
INTRODUCTION....................................................................................................15
1.1.
Background ................................................................................................15
1.2.
Rationale ....................................................................................................16
2.
OBJECTIVES AND ENDPOINTS...........................................................................17
3.
STUDY DESIGN ....................................................................................................18
3.1.
Overall Design ............................................................................................18
3.2.
Standard of Care ........................................................................................19
3.3.
Discussion of Design ..................................................................................20
3.4.
Benefit:Risk Assessment ............................................................................21
3.4.1.
Risk Assessment .........................................................................21
3.4.1.1.
Identified Risks...........................................................22
3.4.1.2.
Potential Risks............................................................23
3.4.2.
Benefit Assessment.....................................................................24
3.4.3.
Overall Benefit:Risk Conclusion...................................................25
4.
SUBJECT SELECTION AND WITHDRAWAL CRITERIA.......................................25
4.1.
Inclusion Criteria.........................................................................................25
4.2.
Exclusion Criteria........................................................................................27
4.3.
Screening/Baseline Failures .......................................................................28
4.4.
Criteria for Early Discontinuation of Investigational Product ........................28
4.4.1.
Early Discontinuation of Investigational Product...........................28
4.4.2.
Reasons for Discontinuation of Investigational Product................29
4.4.3.
Liver Chemistry Stopping Criteria ................................................30
4.4.4.
eGFR Stopping Criteria................................................................31
4.5.
Procedures for Subject Follow-up ...............................................................32
4.5.1.
Withdrawal of Consent for Contact...............................................32
4.5.2.
Subjects Deemed Lost to Follow-up.............................................33
5.
STUDY TREATMENTS..........................................................................................33
5.1.
Investigational Product and Other Study Treatment....................................33
5.2.
Treatment Assignment................................................................................34
5.3.
Blinding.......................................................................................................35
5.4.
Product Accountability ................................................................................35
5.5.
Treatment Compliance................................................................................35
5.6.
Concomitant Medications and Non-Drug Therapies....................................36
5.6.1.
Permitted Medications and Non-Drug Therapies..........................36
5.6.2.
Prohibited Medications and Non-Drug Therapies.........................36
5.7.
Treatment after the End of the Study ..........................................................37
5.8.
Treatment of Study Treatment Overdose....................................................37
6.
STUDY ASSESSMENTS AND PROCEDURES .....................................................37
6.1.
Critical Baseline Assessments....................................................................41
6.2.
Safety .........................................................................................................41
6.2.1.
Cardiovascular Events.................................................................41

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6.2.1.1.
Other CV Events ........................................................42
6.2.2.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........42
6.2.2.1.
Time period and Frequency for collecting AE 
and SAE information...................................................43
6.2.2.2.
Method of Detecting AEs and SAEs ...........................43
6.2.2.3.
Follow-up of AEs and SAEs........................................44
6.2.2.4.
Sentinel Events ..........................................................44
6.2.2.5.
Regulatory Reporting Requirements for SAEs............44
6.2.3.
Adverse Events of Special Interest ..............................................45
6.2.4.
Clinically Important Microvascular Events....................................46
6.2.5.
Pregnancy ...................................................................................46
6.2.6.
Clinical Laboratory Assessments .................................................47
6.2.6.1.
Estimated Glomerular Filtration Rate (eGFR) .............48
6.2.7.
Physical examination ...................................................................48
6.3.
Value Evidence and Outcomes...................................................................49
6.3.1.
Value Evidence and Outcomes Assessments..............................49
6.3.1.1.
Treatment Related Impact Measure – Diabetes 
(TRIM-D) ....................................................................49
6.3.1.2.
EQ-5D ........................................................................49
6.3.1.3.
Exploratory Diabetes Management Questions............50
6.3.1.4.
Healthcare Resource Utilisation..................................50
6.4.
Genetic Research.......................................................................................50
7.
DATA MANAGEMENT ...........................................................................................50
8.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS...................................51
8.1.
Hypotheses.................................................................................................51
8.2.
Study Design Considerations......................................................................51
8.2.1.
Sample Size Assumptions ...........................................................51
8.2.2.
Sample Size Sensitivity for MACE non-inferiority.........................52
8.2.3.
Sample Size Re-estimation..........................................................52
8.3.
Data Analysis Considerations .....................................................................52
8.3.1.
Analysis Populations....................................................................52
8.3.2.
Analysis Data Set ........................................................................53
8.3.3.
Treatment Comparisons ..............................................................53
8.3.3.1.
Primary Comparisons of Interest ................................53
8.3.3.2.
Other Comparisons of Interest....................................54
8.3.4.
Interim Analysis ...........................................................................54
8.3.5.
Multiplicity Controls......................................................................54
8.3.6.
Key Elements of Analysis Plan ....................................................55
8.3.6.1.
Primary Analysis.........................................................55
8.3.6.2.
Secondary Endpoint Analysis .....................................56
8.3.6.3.
Subgroup Analysis......................................................57
8.3.6.4.
Other Safety Analyses................................................57
8.3.6.5.
Value Evidence and Outcomes Analyses ...................57
9.
STUDY CONDUCT CONSIDERATIONS ...............................................................58
9.1.
Posting of Information on Publicly Available Clinical Trial Registers............58
9.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................58
9.3.
Quality Control (Study Monitoring) ..............................................................59
9.4.
Quality Assurance.......................................................................................59

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9.5.
Study and Site Closure ...............................................................................59
9.6.
Records Retention......................................................................................60
9.7.
Provision of Study Results to Investigators, Posting of Information 
on Publicly Available Clinical Trials Registers and Publication....................60
9.8.
Independent Data Monitoring Committee (IDMC) .......................................61
9.9.
Pancreatitis Adjudication Committee...........................................................61
10. REFERENCES.......................................................................................................62
11. APPENDICES........................................................................................................65
11.1.
Appendix 1: Genetic Research ...................................................................65
11.2.
Appendix 2: GSK Modified List of Highly Effective Methods for 
Avoiding Pregnancy in Females of Reproductive Potential (FRP)...............70
11.3.
Appendix 3: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................71
11.4.
Appendix 4: Liver Safety Drug Restart Guidelines ......................................75
11.5.
Appendix 5: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................77
11.5.1.
Definition of Adverse Events........................................................77
11.5.2.
Definition of Serious Adverse Events...........................................78
11.5.3.
Recording of AEs and SAEs ........................................................80
11.5.4.
Evaluating AEs and SAEs............................................................81
11.5.5.
Reporting of SAEs to GSK...........................................................82
11.6.
Appendix 6: Collection of Pregnancy Information........................................83
11.7.
Appendix 7: Electronic Health Record Ancillary Study ................................84
11.7.1.
Introduction..................................................................................84
11.7.1.1.
Background ................................................................84
11.7.1.2.
Literature Review .......................................................84
11.7.1.3.
Ancillary Study Rationale............................................85
11.7.2.
Ancillary Study OBJECTIVES......................................................86
11.7.2.1.
Primary Objectives .....................................................86
11.7.3.
Ancillary Study design..................................................................87
11.7.3.1.
Study Design..............................................................87
11.7.3.2.
Data Flow Strategies – Introduction............................87
11.7.3.3.
Site Selection .............................................................88
11.7.3.4.
Data Flows .................................................................89
11.7.4.
DATA ANALYSIS.........................................................................91
11.7.4.1.
Sample Size Expectations..........................................91
11.7.4.2.
General Analytic Approach.........................................91
11.8.
Appendix 8: Country Specific Requirements...............................................93
11.9.
Appendix 9: Protocol Amendment Changes................................................94
11.9.1.
Changes Resulting from Protocol Amendment 1..........................94
11.9.2.
Changes Resulting from Protocol Amendment 2..........................98
11.9.3.
Changes Resulting from Protocol Amendment 3........................111

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LIST OF ABBREVIATIONS
ACCF
American College of Cardiology Foundation
ADA
American Diabetes Association
AE
adverse event
AHA
American Heart Association
ALT (SGPT)
alanine aminotransferase (serum glutamic pyruvic 
transaminase)
ANCOVA
analysis of covariance
AST (SGOT)
aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase)
BI
baseline basal insulin population
BMI
body mass index
bpm
beats per minute
CABG
coronary artery bypass graft
CAD
coronary artery disease
CEC
Cardiovascular Endpoint Committee
CI
confidence interval
CPK
creatine phosphokinase 
CONSORT
Consolidated Standards of Reporting Trials
DCRI
Duke Clinical Research Institute
DNA
deoxyribonucleic acid
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
EHR
electronic health record
ESC
European Society of Cardiology
FDA
US Food and Drug Administration
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
HbA1c
glycated haemoglobin
hCG
human chorionic gonadotrophin
HDLc
high density lipoprotein cholesterol
HLA
human leukocyte antigen 
HRT
hormone replacement therapy
IB
Investigator’s Brochure
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
INR
international normal range
IRB
Institutional Review Board
ITT
intent-to-treat
IVRS
Interactive Voice Response System

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KM
Kaplan-Meier
LDH
lactate dehydrogenase
LFT
liver function test
LDLc
low density lipoprotein cholesterol
MACE
major adverse cardiovascular event
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MEN-2
multiple endocrine neoplasia type 2
MSDS
Material Safety Data Sheet
MTC
medullary thyroid cancer
NHLBI
National Heart, Lung and Blood Institute
NI
non-insulin population
PAD
peripheral arterial disease
PD
pharmacodynamics
PHI
Protected Health Information
PK
pharmacokinetics
PP
per protocol
RAP
Reporting Analysis Plan
RR
relative risk
s.c.
subcutaneous
SAE
serious adverse event
SRM
Study Reference Manual
SU
sulfonylureas
TC
total cholesterol
Tg
triglycerides
TIA
transient ischemic attack
TRIM-D
Treatment Related Impact Measures-D
ULN
upper limit of normal range
WHF
World Heart Federation
WHO
World Health Organization
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
EQ-5D
PopMedNet
SAS

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PROTOCOL SUMMARY
Rationale
Albiglutide is a novel analogue of glucagon-like peptide-1 (GLP-1) with a sufficiently 
long half-life to permit once a week injection. Albiglutide is licensed for the treatment of 
type 2 diabetes as an adjunct to diet and exercise, as monotherapy, or in combination with 
existing therapies, including basal insulin. The Food and Drug Administration (FDA) has 
issued guidance on evaluating cardiovascular risk in new anti-diabetic therapies to treat 
type 2 diabetes [FDA Guidance for Industry, 2008].  For a premarketing application that 
contains a meta-analysis of major adverse cardiovascular events (MACE) for which the 
upper bound of the 95 percent confidence interval for the relative risk is between 1.3 and 
1.8, a post-marketing trial generally will be necessary to definitively show that the upper 
bound of the two-sided 95 percent confidence interval for the estimated risk ratio is less 
than 1.3.  The MACE meta-analysis of the albiglutide Phase III program  (primary 
endpoint cardiovascular death, myocardial infarction, stroke and hospitalization for 
unstable angina), whilst ruling out an upper bound of the confidence interval for 
cardiovascular events of 1.8, was not able to rule out (due to a relatively small number of 
events) a relative risk (RR) upper bound of 1.3.  For this reason GlaxoSmithKline (GSK) 
will conduct this cardiovascular outcome study as a US post-marketing requirement, to 
evaluate the effect of albiglutide on cardiovascular events in subjects with type 2 
diabetes.
Objectives/Endpoints
Objectives
Endpoints
Primary
To assess the effect of 
albiglutide with respect to 
MACE when added to 
glycaemic standard of care 
versus standard of care 
alone
Time to first occurrence of MACE (cardiovascular death, 
myocardial infarction,  or stroke) 
The primary analysis will be non-inferiority. If the pre-
specified non-inferiority criterion is met then superiority 
testing will be performed 1 
Secondary
To supplement the primary 
objective by further 
characterization of the 
effects of albiglutide on 
cardiovascular outcomes 

Time to first occurrence of the following:

MACE or urgent revascularisation for unstable angina

The individual components of the primary endpoint

Cardiovascular death or hospitalization due to heart failure
To evaluate the effects of 
albiglutide on metabolic 
management of type 2 
diabetes

Time to initiation of insulin of more than 3 months duration for 
those subjects not treated with insulin at study start  

Time to initiation of prandial insulin in those subjects on basal 
insulin at study start

The proportion of subjects achieving glycaemic control 
(HbA1c ≤ 7.0% at final assessment) with no severe 
hypoglycaemic incidents and weight gain <5% of body weight  

The time to first occurrence of a clinically important 

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Objectives
Endpoints
microvascular event (see Section 6.2.4)

Change in glycated haemoglobin (HbA1c)

Change in body weight

Patient reported outcomes from Treatment Related Impact 
Measures-D (TRIM-D)/EQ5D
To evaluate the safety of 
albiglutide

All cause mortality

Non-fatal serious adverse events (SAEs)

Adverse events (AEs) leading to discontinuation of 
investigational product 

AE of special interest (see Section 6.2.3)

Change in estimated glomerular filtration rate (eGFR) 
calculated using Modification of Diet in Renal Disease 
(MDRD) formula

Change in blood pressure and heart rate
1. As part of a closed testing procedure and therefore no adjustment will be made to the significance level (see Section 
8.3.5)  
Overall Design
This is a randomised, double blind, parallel group, placebo-controlled study. 
Treatment Arms and Duration
All subjects will receive standard of care for their diabetes and cardiovascular health 
which can be adjusted by the healthcare professional responsible for the subject during 
the study according to clinical need and with close adherence to professional society 
treatment guidelines.  The study comparison is thus between albiglutide added to 
standard of care and standard of care alone.  Placebo injections will be used to ensure 
study assessments are performed without knowledge of treatment assignment.  Treatment 
with albiglutide or placebo will be randomly allocated in a 1:1 ratio.  The starting dose of 
albiglutide is 30 mg weekly which may be up-titrated to 50mg weekly if further 
improvement of glycaemic control is required. 
The study will continue until it is projected that at least 611 adjudicated MACE events 
will have occurred while requiring that the projected median duration of subject follow-
up be at least 1.5 years. The maximum duration of the study for an individual participant 
is dependent both on the time taken for recruitment and the MACE event rate. If 611 
events are reached before the estimated median duration of subject follow-up is projected 
to be at least 1.5 years, then the study will continue until it is predicted that the median 
subject follow-up time is at least 1.5 years. In that case more than 611 events would
likely be observed.
An Independent Data Monitoring Committee (IDMC) will have study oversight to ensure 
participant safety and scientific integrity of the data.
Type and Number of Subjects
A total of 9400 subjects with type 2 diabetes and a previous history of cardiovascular  
disease and who do not have optimal glycaemic control will be studied. 

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Analysis
The study’s primary question is whether albiglutide is non-inferior by a margin of 1.3
with respect to its effect on adjudicated MACE, when added to glycaemic standard of 
care, versus standard of care alone. If non-inferiority is achieved, then superiority will be 
tested. The primary analysis is an Intent-to-Treat (ITT) analysis of the time to the first 
occurrence of MACE using Cox’s Proportional Hazard regression.  

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1.
INTRODUCTION
1.1.
Background
Diabetes affects an estimated 347 million people worldwide, with type 2 diabetes 
accounting for more than 90% of cases [WHO, 2013]. The primary manifestation of this 
disease is chronic hyperglycaemia, resulting from resistance to insulin action at a cellular 
and molecular level and a relative inadequacy in the secretion of endogenous insulin 
[American Diabetes Association, 2014]. Chronic hyperglycaemia has been firmly 
established as a key factor in the development of microvascular complications 
(retinopathy, nephropathy, and neuropathy).  Individuals with type 2 diabetes are also at 
greatly elevated risk of cardiovascular disease.
The management of glycaemia in individuals with type 2 diabetes consists of diet, 
exercise, and weight reduction together with oral anti-diabetic drug, injectable agents 
such as GLP-1 receptor agonists or insulin therapy, to achieve near normoglycaemia as 
reflected by a target HbA1c level of 7%, where possible, without significant 
hypoglycaemia or other adverse effects of treatment. Despite the large number of 
available therapeutic agents, a high proportion of subjects fail to achieve or maintain 
target HbA1c levels [Khunti, 2013] owing to the inexorable decline in endogenous 
insulin production characteristic of the disease, and limitations in existing treatments. 
New agents with complementary mechanisms (permitting combination use) or more 
favourable safety profiles are needed to help more subjects achieve glycaemic targets. 
GLP-1 is secreted by intestinal L-cells in response to ingestion of food. In a healthy 
individual, it plays an important role regulating postprandial blood glucose by stimulating 
glucose-dependent insulin secretion by the pancreas. GLP-1 suppresses glucagon 
secretion, leading to reduced hepatic glucose output. It also delays gastric emptying time 
and slows small bowel motility, delaying food absorption and slowing the rate of glucose 
appearance in the blood. In patients with type 2 diabetes the postprandial rise in 
endogenous GLP-1 is absent or reduced [Vilsbøll, 2001]. 
GLP-1 receptor agonists have been developed as anti-hyperglycemic therapy for type 2 
diabetes to replace or supplement endogenous GLP-1 in order to increase meal-related 
insulin secretion, reduce inappropriate glucagon secretion, and slow GI motility. They 
have demonstrated substantial effectiveness in improving glycaemic control while 
mitigating the risk of hypoglycaemia and weight gain commonly associated with some of 
the other treatments for type 2 diabetes [Stonehouse, 2012].  
Albiglutide is a novel analogue of GLP-1 generated through a genetic fusion of 2 
modified recombinant human GLP-1 molecules linked in tandem to recombinant human 
albumin. Albiglutide is licensed for the treatment of type 2 diabetes as an adjunct to diet 
and exercise, as monotherapy, or in combination with existing therapies (oral anti-
diabetic therapies or basal insulin).  It has been granted marketing authorisation by the 
European Medicines Agency (EMA) (March 2014) and the FDA (April 2014).  Details of 
the clinical trial results can be found in the Investigator Brochure (IB).

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1.2.
Rationale
The FDA has issued guidance on evaluating cardiovascular risk in new anti-diabetic 
therapies to treat type 2 diabetes [FDA Guidance for Industry, 2008]. For a premarketing 
application that contains a meta-analysis of MACE, for which the upper bound of the 95 
percent confidence interval for the relative risk is between 1.3 and 1.8, a post-marketing 
trial may be necessary to definitively show that the upper bound of the two-sided 95 
percent confidence interval for the estimated risk ratio is less than 1.3.
The MACE + meta-analysis of the albiglutide Phase III program (primary endpoint 
cardiovascular death, myocardial infarction, stroke and hospitalization for unstable 
angina), whilst ruling out an upper bound of the confidence interval for cardiovascular 
events of 1.8, was not able to rule out (due to a relatively small number of events) a RR 
upper bound of 1.3. For this reason GSK will conduct this cardiovascular outcome study 
as a US post-marketing requirement, to evaluate the effect of albiglutide on 
cardiovascular events in subjects with type 2 diabetes. 
Preclinical studies have provided evidence that GLP-1 receptor stimulation favourably 
effects endothelial function, recovery from ischemic injury, and myocardial function in 
animals [reviewed in Okerson, 2012]. Albiglutide reduced infarct size assessed 24 hours
after 30 minutes temporary left anterior descending coronary artery occlusion in 
normoglycaemic rats [Bao, 2011]. GLP-1 infusion has been shown to improve 
endothelial function in subjects with stable coronary disease [Nystrom, 2004]. In subjects 
with ST-segment elevation myocardial infarction treated with primary percutaneous 
coronary intervention, the GLP-1 receptor agonist, exenatide, administered at the time of 
reperfusion has been reported to increase myocardial salvage [Lønborg, 2012].  In the 
Phase III studies, small mean increases in heart rate (1 to 2 bpm) and a higher incidence 
of atrial fibrillation/flutter events were observed with albiglutide.  It is difficult to predict 
whether these preclinical and clinical findings will translate into effect on major 
cardiovascular events.

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2.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
To assess the effect of 
albiglutide with respect to
MACE when added to 
glycaemic standard of care 
versus standard of care 
alone
Time to first occurrence of MACE (cardiovascular death, 
myocardial infarction,  or stroke) 
The primary analysis will be non-inferiority. If the pre-
specified non-inferiority criterion is met then superiority 
testing will be performed1
Secondary
To supplement the primary 
objective by further 
characterization of the 
effects of albiglutide on 
cardiovascular outcomes 

Time to first occurrence of the following:

MACE or urgent revascularisation for unstable angina

The individual components of the primary endpoint

Cardiovascular death or hospitalization due to heart failure
To evaluate the effects of 
albiglutide on metabolic 
management of type 2 
diabetes

Time to initiation of insulin of more than 3 months duration for 
those subjects not treated with insulin at study start 

Time to initiation of prandial insulin in those subjects on basal 
insulin at study start

The proportion of subjects achieving glycaemic control 
(HbA1c ≤ 7.0% at final assessment) with no severe 
hypoglycaemic incidents and weight gain <5% of body weight

The time to first occurrence of a clinically important 
microvascular event (see Section 6.2.4)

Change in HbA1c

Change in body weight

Patient reported outcomes from TRIM-D/EQ5D
To evaluate the safety of 
albiglutide

All cause mortality

Non-fatal SAEs

AEs leading to discontinuation of investigational product 

AE of special interest (see Section 6.2.3)

Change in eGFR calculated using MDRD formula

Change in blood pressure and heart rate
Exploratory
To evaluate patient reported 
experience of diabetes 
treatment

Patient reported outcomes from study specific questionnaire
To evaluate (at a subset of 
sites) barriers to using the 
electronic health record 
(EHR) to facilitate trial 
enrolment and the quality of 

Workflow impact of an EHR-generated list of subjects to 
facilitate trial enrolment. 

Concordance, sensitivity, specificity, and accuracy of baseline 
characteristics extracted from the EHR compared with those 
reported on the electronic case report form (eCRF)3

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Objectives
Endpoints
EHR data for use in 
populating baseline 
characteristics and 
identifying events of interest 
during trial follow-up.2

Concordance, sensitivity, specificity, and accuracy of EHR-
identified events compared with study events 3,4
1.
As part of a closed testing procedure and therefore no adjustment will be made to the significance level (see 
Section 8.3.5)  
2.
Details are provided in a separate EHR ancillary study protocol (Appendix 7).  Results from this exploratory 
investigation will be reported separately from the main clinical study report.
3.
Comparison of EHR identified events with study events will be conducted in the same data subset.
4.
Analyses to be undertaken after the main trial results are published.
3.
STUDY DESIGN
3.1.
Overall Design
This is a randomised, double blind, parallel-group, placebo-controlled, multicentre study.  
In countries where marketing authorization has been granted to albiglutide for the 
treatment of type 2 diabetes it is classified as a Phase IV study, elsewhere is should be 
considered to be a Phase III study. This study will recruit approximately 9400 subjects 
with type 2 diabetes and a previous history of cardiovascular disease who are failing to 
achieve optimal glycaemic control on their current anti-hyperglycaemic regimen. 
Subjects will be randomised in a 1:1 ratio to albiglutide or albiglutide matching placebo 
administered once weekly by subcutaneous (s.c.) injection.  
All subjects will receive standard of care which can be adjusted by their usual care 
provider(s) during the study according to clinical need (See Section 3.2). The study 
comparison is between albiglutide added to standard of care and standard of care alone.  
The starting dose of albiglutide will be 30 mg once weekly. If at any stage after 5 weeks 
of treatment the subject needs to have intensified therapy to improve glycaemic control, 
the dose of investigational product should be increased before altering the doses of or 
adding other glucose-lowering medication. This treatment decision will be the 
responsibility of the investigator. In this case the subject will called in for an unscheduled 
visit to increase the dose from 30 mg to 50mg. Subjects randomly assigned to albiglutide 
matching placebo will also go through the increased dose procedure to maintain study 
blind. If a subject experiences tolerability issues with the higher, 50mg dose then the 
investigator may decrease the dose back to 30 mg without the need for an unscheduled 
visit to supervise down titration. Use of GLP-1 receptor agonists will be prohibited but 
other glucose-lowering medications permitted, provided they are not contraindicated for 
the individual subject concerned.
This study is designed with minimal intervention above normal clinical care of subjects 
with type 2 diabetes, whilst allowing thorough evaluation of  cardiovascular and other 
events of special interest (Section 6.2.3), thus investigating the safety of albiglutide in the 
typical clinical situation.  Sites will employ pre-screening to assess potential subjects for 
study entry. Screening and randomisation can then occur at the same visit or in close 
proximity depending on scheduling.  Contact with subjects will be every four months 

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after the randomisation visit. HbA1c will be measured at 4 month clinic visits. Serum 
creatinine and liver function tests (LFTs) will be measured and a targeted physical 
assessment performed at 8 month clinic visits (Table 1). 
The study will continue until it is projected that at least 611 adjudicated MACE events 
will have occurred while requiring that the projected median duration of subject follow-
up be at least 1.5 years. The maximum duration of the study for an individual participant 
is dependent both on the time taken for recruitment and the MACE event rate, and was 
originally estimated to be between 3 and 5 years. If the observed rate for MACE is 2.0% 
or 3.0%, the mean follow-up will be 3.2 or 2.2 years, respectively. If the observed rate for 
MACE is sufficiently high such that the median subject follow-up would be less than 1.5 
years then the study will continue until it is projected that the median follow-up is at least 
1.5 years. In this scenario, the maximum duration of the study for an individual 
participant would be less than the 3 to 5 years originally estimated.
An Executive Committee will be the main decision-making body for the study, in 
collaboration with the Sponsor (GSK).  It is charged with the overall scientific, 
professional and operational conduct of the study.  Amongst other roles pre-specified in 
its Charter, the Executive Committee will ensure proper study conduct and conformance 
to the protocol, consider and agree  changes to the protocol based on emerging scientific 
and/or clinical advances (e.g., new emerging data with other GLP-1 receptor agonists), 
advise on the selection of study sites and assist in subject recruitment strategies.
An IDMC will have study oversight to ensure participant safety and scientific integrity of 
the data (Section 9.8), an independent Cardiovascular Endpoint Committee (CEC) 
blinded to treatment allocation will adjudicate cardiovascular outcome events (Section 
6.2.1) and a Pancreatitis Adjudication Committee will adjudicate potential events of 
pancreatitis.
Subject completion is defined as completion of all periods of the study up to and 
including any follow-up period.
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 (Table 1), are essential and required for study 
conduct. 
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Reference Manual (SRM). The SRM will provide 
the site personnel with administrative and detailed technical information that does not 
impact subject safety.
3.2.
Standard of Care
Anti-hyperglcaemic and cardiovascular medications will be used at the discretion of the 
usual care provider(s) (or investigator if also the usual care provider), who will be 
informed of the patient’s enrolment in the trial, the use of blinded trial medication, and 
that use of GLP-1 receptor agonists  (other than the use of  randomised albiglutide)  is 
contraindicated during the trial period. Usual care providers will be encouraged to follow 

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the most up to date guidelines for diabetes and cardiovascular care based upon local and 
institutional practice patterns and any relevant published practice guidelines (e.g., 
Inzucchi, 2012).  Treatment for type 2 diabetes will be captured by name and total daily 
dose at the time of study visits, while other relevant (cardiovascular) concomitant 
medications will be collected only as drug classes (see Section 5.6.1). 
During the study investigators are expected to monitor patients’ type 2 diabetes regimens 
and communicate with usual care providers, who will be responsible for adjusting their 
regimen in order to achieve locally-appropriate HbA1c goals.  The Executive Committee 
and National Country Leaders will encourage investigators to follow clinical care 
practice guidelines published by national and international societies regarding type 2 
diabetes over the course of the trial.  These practice guideline goals will be 
individualized, with the understanding that currently applicable glycaemic guidelines 
may vary among different geographic regions.  With adherence to local custom and laws 
(including privacy regulations such as the Health Insurance Portability and 
Accountability Act), types of communication may be informal e.g. email or telephone 
exchanges, to enhance frequency and ease of two-way communication.
Any agent, with the exception of GLP-1 receptor agonists, is acceptable for reaching 
HbA1c goals.  If HbA1c goals are not met following adjustment with oral medications in 
patients not receiving insulin, an insulin regimen may be initiated. Patients already 
receiving insulin therapy may up-titrate insulin during the trial if necessary. Patients 
should be reminded to keep taking their blinded trial medication throughout the course of 
the trial even in the case after initiation of insulin.
The Executive Committee and National Country Leaders will also monitor the standard 
of care of management of diabetes and cardiovascular disease. Similar to the 
management of type 2 diabetes, sites and investigators will be expected to adhere to local 
clinical practice guidelines.  Sites will be provided training on clinical management 
guidelines to re-enforce standard of care adherence. Information on medications 
important to management of cardiovascular risk will be captured during study visits.  The 
Executive Committee and National Country Leaders will review on a periodic basis the 
use of medications for cardiovascular risk prevention to ensure patients are receiving 
standard of care. If there are unusually low goal attainments for standard of care, site 
investigators will be advised accordingly.
3.3.
Discussion of Design
This study is a clinical outcomes trial required by FDA as a post-marketing requirement 
to evaluate cardiovascular safety.  It will provide important information regarding the 
cardiovascular safety and metabolic effects of albiglutide treatment of subjects with type 
2 diabetes.  Sufficient MACE events must be observed during the study to permit the 
assessment of cardiovascular safety.  Consequently, to enter the study subjects must have 
established cardiovascular disease as well as type 2 diabetes. The study is powered on a 
predefined number of clinical events, consequently the number of subjects required and 
study duration may vary from that stated in the protocol.

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This will be a double-blind, placebo-controlled study. All subjects will receive placebo or 
albiglutide in addition to usual standard of care for type 2 diabetes and cardiovascular 
disease, in order to assess the effect of albiglutide above that of currently available 
therapies alone.
The primary cardiovascular comparison will be to assess whether albiglutide is non-
inferior to placebo with respect to time to first MACE. If non-inferiority is established, 
the time to first MACE for albiglutide compared to placebo will be tested for superiority. 
Missing data may inappropriately bias comparison towards declaring non-inferiority. The 
longer the duration of a study, the more difficult it is to avoid loss to follow-up and other 
sources of missing data. The product of the projected duration of this study and the 
number of subjects to be studied is intended to minimize the risk of missing data whilst 
still permitting the assessment of the safety of albiglutide to be over an appreciable period
of time. Every effort will be made to keep subjects on their assigned study medication 
according to the protocol.  Subjects who stop study medication will be followed 
throughout the whole study duration.  More details about procedures for subject follow-
up are provided in Section 4.5.
Phase III studies confirmed the glycaemic 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 glycaemia for at least 2 years in many subjects with type 2 
diabetes, an increase in dose to 50 mg weekly offered additional benefit without 
significant safety issues (See IB for further details).  
3.4.
Benefit:Risk Assessment
Albiglutide has been evaluated in an international programme of studies involving 
approximately 9000 subject-years of overall exposure to date (including over 4000 
subject-years of exposure to albiglutide). The programme included 8 well-controlled 
Phase III studies (including one in subjects with concurrent renal impairment), ranging in 
duration from 32 weeks to 3 years, and using both 30 mg and 50 mg once weekly dosing.  
This has permitted a thorough assessment of efficacy, safety, and tolerability in a 
population of subjects with type 2 diabetes that spanned newly diagnosed individuals 
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 
albiglutide can be found in the IB and in the product labelling for those countries where 
marketing authorisation has been granted.  The following section outlines the risk 
assessment and mitigation strategy for this protocol:  
3.4.1.
Risk Assessment
The identified and potential risks associated with the use of albiglutide, or the GLP-1 
receptor agonist class, as well as the mitigation strategy for key risks of clinical 
significance are provided below. Please refer to the IB for a thorough summary of the 
nonclinical and clinical experience with albiglutide as well as the complete Guidance for 
the Investigator. The risks associated with study comparator, placebo, are also provided 

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below.  Subjects will have the AE profile of GLP-1 receptor agonists, and albiglutide in 
particular, explained to them by the investigator and via the informed consent form.
3.4.1.1.
Identified Risks
Pancreatitis. Acute pancreatitis has been reported in association with albiglutide and 
other GLP-1 receptor agonists in clinical trials and during  postmarketing experience. 
Albiglutide has not been studied in subjects with a history of pancreatitis to determine 
whether they are at increased risk for pancreatitis. Subjects with a history of pancreatitis 
or who are considered at significant risk of developing pancreatitis are excluded from 
entering the study. Subjects will be informed of the characteristic symptom of 
pancreatitis: persistent severe abdominal pain. If pancreatitis is suspected, investigational 
product should be promptly discontinued and if pancreatitis is confirmed, investigational 
product will not be restarted.
Gastrointestinal events. Albiglutide has not been studied in subjects with severe 
gastrointestinal (GI) disease, including severe gastroparesis. Subjects with severe 
gastroparesis will be excluded from the study. Use of albiglutide and other GLP-1 
receptor agonists can be associated with GI side effects such as diarrhoea, nausea, and 
vomiting; the frequency of these events increased as renal function decreased.  These 
types of GI reactions can be associated with dehydration and worsened renal function. 
(see below and see Section 4.4.4). Other GI related adverse reactions with albiglutide 
include dyspepsia, gastro-oesophageal reflux disease and constipation.
Hypoglycaemia. Albiglutide’s mechanism of action is associated with a low intrinsic risk 
of significant hypoglycaemia. However, when used in combination with insulin (or 
insulin secretagogues) the risk of hypoglycaemia is increased. Investigators will be 
reminded that it may be necessary to reduce the dose of insulin or insulin secretagogues 
when starting study medication to reduce the risk of hypoglycaemia. Routine standard of 
care for subjects treated with insulin secretagogues and insulin includes advice about 
avoidance of hypoglycaemia which will be reinforced.  All subjects are required to have a 
last indicator of glycaemic control of above HbA1c = 7% which is expected to reduce the 
risk of hypoglycaemia when starting albiglutide. 
Immunogenicity. Hypersensitivity reactions are of potential concern with any injected 
protein and were reported rarely in the Phase III programme. In the Phase III programme 
one subject (anti-albiglutide antibody negative) developed rash, itching and dyspnoea 
.Subjects with known allergy to any GLP-1 receptor agonist or excipients of albiglutide 
are excluded from the study.  Subjects will be informed of the symptoms of severe 
hypersensitivity or allergy and be advised to seek medical assistance immediately. In the 
Phase III programme approximately 5% of subjects developed anti-albiglutide antibodies.  
Subjects who tested positive for anti-albiglutide antibodies experienced a similar 
glycaemic response (HbA1c and fasting plasma glucose) to those who did not test 
positive for antibodies. Other than injection site reactions (see below), the overall safety 
profile appeared similar among the subset of subjects who did and those who did not test 
positive for anti-albiglutide antibodies.  Anti-albiglutide antibody formation is not 
expected to impact the overall safety of albiglutide treatment and therefore will not be 
measure routinely in this study. 

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Injection site reactions. Albiglutide injections may cause rash, erythema or itching 
and/or other reactions at the site of injection. . Subjects will be advised that when 
injecting in the same region, to use a different injection site each week. In the Phase III 
program, most subjects with injection site reactions did not test positive for anti-
albiglutide antibodies. However, injection site reactions were reported more frequently 
among those who did test positive for anti-albiglutide antibodies (41% of the antidrug 
antibody positive subjects reported one or more injection site reactions) than among those 
who were consistently antibody negative (14% of the antidrug antibody negative subjects 
reported one or more injection site reactions).  
Other adverse reactions (e.g. pneumonia, atrial fibrillation/flutter, and appendicitis). In 
the Phase III programme in type 2 diabetes, other possible albiglutide related adverse 
reactions were identified. These events occurred at a cumulative incidence <3% in studies 
up to 3 years in duration. These events were reported more frequently with albiglutide 
than comparators. 
3.4.1.2.
Potential Risks
Thyroid C-cell tumours. GLP-1 receptor agonists, including albiglutide increase serum 
calcitonin in rodents and other GLP-1 receptor agonists are associated with thyroid C-cell 
focal hyperplasia and C-cell tumours in rodents It is unknown whether GLP-1 receptor 
agonists are associated with thyroid C-cell tumours in humans, including medullary 
thyroid cancer (MTC). 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. Subjects with treatment emergent thyroid nodules should be referred to a specialist 
for evaluation in accordance with local treatment guidelines.  Routine monitoring of 
serum calcitonin is not recommended.  However, if serum calcitonin is found to be 
elevated the subject should be referred to a specialist for further evaluation. If MTC or 
other thyroid C-cell neoplasia is diagnosed, investigational product will be discontinued.
Other malignant neoplasms Concerns have been raised regarding use of incretin based 
therapies and other malignancies such as pancreatic cancer [Egan, 2014], malignancy 
when used in combination with insulin based on hypotheses of biological plausibility 
[European Public Assessment Report, 2014], and haematological malignancies [FDA 
Summary Basis of Approval, 2014].
Hepatotoxicity. Hepatotoxicity is an area of interest in drug development. Patients with 
type 2 diabetes are at increased risk for liver enzyme abnormalities and disease related 
liver conditions.  One subject treated with albiglutide in the Phase III clinical programme 
developed probable drug induced liver injury with an asymptomatic elevation in alanine 
amino transferase (ALT) and total bilirubin although the cases 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 4.4.3).
Subject population with severe renal impairment (eGFR <30 mL/min/1.73m2).
Experience in type 2 diabetes subjects with severe renal impairment is limited (in the 
Phase III programme a total of 19 subjects with eGFR <30 mL/min/1.73m2 received 
albiglutide). 

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In a Phase 3 study of patients with varying degrees of renal impairment, in the albiglutide 
group, on-therapy GI AEs occurred with a higher incidence and higher event rate in 
subjects with moderate and severe renal impairment compared to those with mild renal 
impairment. Because these GI events may lead to dehydration and worsen renal function, 
worsening renal function will be closely evaluated as an AE of special interest, serum 
creatinine will be measured every 8 months, and subjects will discontinue IP if eGFR 
falls below 15 mL/min/1.73m2. Subjects with known severe renal impairment are 
excluded from the study (see Section 4.4.4).
Drug Interactions.  Like other members of the class, albiglutide causes a delay in gastric 
emptying, and thereby has the potential to impact the absorption of concomitantly 
administered oral medications. During the development programme, drug interactions 
studies were conducted with digoxin, warfarin, oral contraceptives, and simvastatin 
which demonstrated no clinically relevant PK or PD effects. Investigators will be advised 
to take the effect of albiglutide on gastric emptying into account when prescribing 
concomitant medication.
Pregnancy and Lactation.  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.  
Placebo control. In subjects treated with placebo, symptoms and long-term risks of 
hyperglycaemia may not improve or may worsen. During the study, intensification of 
glucose-lowering treatments other than study drug will be allowed in both treatment arms 
with a treat-to-target approach. Albiglutide placebo injections may cause injection site 
reactions. Subjects will be advised when injecting into the same region to use a different 
injection site each week.
3.4.2.
Benefit Assessment
In subjects with type 2 diabetes albiglutide treatment resulted in clinically relevant 
lowering of HbA1c at both the 30 mg and 50 mg doses when given as monotherapy and 
in combination with metformin, sulfonylureas (SUs), thiazolidinedione or basal insulin.  
The durability of the effect on glycaemic control was shown over a study period of up to 
3 years. Consistent with its mechanism of action, albiglutide was not associated with 
clinically relevant hypoglycaemia except when used in combination with an SU or 
insulin, and incidence rates with the combination were less than those reported with SUs 
or insulin alone. Treatment with albiglutide generally produced a steady reduction in 
weight over time.
For subjects not yet on insulin at the start of the study, data from the Phase III programme 
suggest that the use of albiglutide once weekly in a pen device may have the potential to 
delay the need to start daily insulin injections.  This will be formally assessed within this 
trial.  Similarly, it is possible that for those already taking basal insulin, albiglutide may 

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delay the need to introduce short-acting prandial injections and for those taking 
basal/bolus or pre-mixed insulin, it may reduce the dosage of insulin and/or the number 
of daily injections needed to achieve good glycaemic control.  These will also be 
evaluated in the study.
Subjects in the placebo arm will also be receiving effective anti-hyperglycaemic 
medication which will be titrated up or down as required to improve or maintain 
glycaemic control, and therefore these subjects should also demonstrate reductions in
HbA1c, though weight gain (rather than weight loss) may occur depending upon the 
medication selected.   
Finally, as a result of participating in a clinical trial, each subject will receive more 
contact with the study site than would be performed as part of their usual standard of 
care.
3.4.3.
Overall Benefit:Risk Conclusion
Taking into account the measures taken to minimise risk to subjects participating in this 
study, the known and potential risks identified with albiglutide are justified by the 
benefits have been demonstrated in subjects with type 2 diabetes.
4.
SUBJECT SELECTION AND WITHDRAWAL CRITERIA
4.1.
Inclusion Criteria
Specific information regarding warnings, precautions, contraindications, AEs, and other 
pertinent information on the GSK investigational product or other study treatment that 
may impact subject eligibility is provided in the IB for albiglutide and in the product 
label for those countries where marketing authorisation has been granted.
Deviations from inclusion criteria are not allowed because they can potentially jeopardise 
the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential.   
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
1. Men or women at least 40 years old with a diagnosis of type 2 diabetes.
2. Established cardiovascular disease, including at least 1 of the following:
a. Coronary artery disease with EITHER of the following:
Documented history of spontaneous myocardial infarction, at least 30 days 
prior to Screening.
Documented coronary artery disease (CAD) ≥ 50% stenosis in 1 or more 
major epicardial coronary arteries, determined by invasive angiography, or 
history of surgical or percutaneous (balloon and/or stent) coronary 
revascularization procedure (at least 30 days prior to Screening for 

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percutaneous procedures and at least 5 years prior to Screening for coronary 
artery bypass graft (CABG)).
b. Cerebrovascular disease – ANY of the following:
Documented history of ischaemic stroke, at least 90 days prior to study entry.
Carotid arterial disease with 50% stenosis documented by carotid 
ultrasound, magnetic resonance imaging or angiography, with or without 
symptoms of neurologic deficit.
Carotid vascular procedure (e.g. stenting or surgical revascularisation), at 
least 30 days prior to Screening.
c. Peripheral arterial disease (PAD) with EITHER of the following: 
intermittent claudication and ankle:brachial index < 0.9 in at least one ankle 
prior non-traumatic amputation, or peripheral vascular procedure (e.g. 
stenting or surgical revascularisation), due to peripheral arterial ischaemia.
3. HbA1c >7.0% (53 mmol/mol) based on the most recent documented laboratory 
assessment measured no more than 6 months prior to randomization. Local 
laboratory HbA1c values taken as part of usual care are permitted.
4. Female: subject is eligible to participate if she is not pregnant (as confirmed by a 
negative urine 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 GSK 
Modified List of Highly Effective Methods for Avoiding Pregnancy in Females 
of Reproductive Potential (FRP) (e.g, combined oral contraceptive pill; see 
Appendix 2) 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.
This 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. 
Other situations in which contraception in FRP may not need to be mandated 
should be discussed with the Medical Monitor.
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 oestradiol 
<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 

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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.
5. Able and willing to provide informed consent.
4.2.
Exclusion Criteria
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardise the scientific integrity of the study, regulatory acceptability or subject safety. 
Therefore, adherence to the criteria as specified in the protocol is essential. 
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
1. eGFR calculated using MDRD formula <30mL/min/1.73m2 (based on the most 
recent documented serum creatinine laboratory assessment measured no more than 6 
months prior to randomization. Local laboratory creatinine values taken as part of 
usual care are permitted) or renal replacement therapy.
2. Use of a GLP-1 receptor agonist at Screening.
3. Severe gastroparesis requiring therapy within 6 months prior to Screening. 
4. History of pancreatitis or considered clinically at significant risk of developing 
pancreatitis during the course of the study (e.g. due to symptomatic gallstones, 
excess alcohol use).
5. Personal or family history of medullary carcinoma of the thyroid or subject with 
MEN-2. Personal history of pancreatic neuroendocrine tumours. In the opinion of the 
investigator, the subject has a medical history which might affect his / her ability to 
remain in the study for its entire duration, or which might limit management, such as 
life expectancy of <5 years (e.g. due to active malignancy).
6. Subject has a medical history which in the opinion of the investigator might limit the 
individual’s ability to take trial treatments for the duration of the study or to 
otherwise complete the study.
7. Breastfeeding, pregnancy, or planning a pregnancy during the course of the study. 
Pregnancy test will be required in women of child bearing potential. Women who 
have undergone a sterilisation procedure or who are clearly post-menopausal will not 
be required to undergo pregnancy testing.  Women who have developed spontaneous 
secondary amenorrhoea of 12 months or more where post-menopausal status is in 
doubt, a blood sample where FSH >40MU/ml and oestrodiol <40 pg/mL (<140 
pmol/L) are simultaneously measured will be considered confirmatory.
8. Known allergy to any GLP-1 receptor agonist or excipients of albiglutide.
9. Use of another investigational product within 30 days or according to local 
regulations, or currently enrolled in a study of an investigational device.

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10. Any other reason the investigator deems the subject to be unsuitable for the study.
4.3.
Screening/Baseline Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomised.  In order to ensure transparent reporting of screen 
failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements [Schulz, 2010], and respond to queries from regulatory 
authorities, a minimal set of screen failure information is required including 
Demography, Screen Failure details, Eligibility Criteria, and any SAEs.
Re-screening of subjects who did not meet the eligibility criteria for HbA1c or creatinine 
based on local laboratory values taken as part of usual care is permitted. If values were 
based on laboratory results as part of usual care then one re-test is permitted within the 
protocol at Screening. Any future re-screening will be based on laboratory results 
obtained as part of usual care.
4.4.
Criteria for Early Discontinuation of Investigational Product
The primary analysis will be conducted on an ITT analysis basis so it is important that 
every subject is followed for the duration of the study, regardless of whether the subject 
continues to take investigational product, unless consent for all follow up is actively 
withdrawn.
The requirements for handling early discontinuations from investigational product are 
described below. Details of the requirements for subject follow-up are provided in 
Section 4.5.
4.4.1.
Early Discontinuation of Investigational Product
If a subject chooses to discontinue investigational product between scheduled face-to-
face visits they should be encouraged to contact the investigator site by telephone.  
Subjects should first be counselled to consider temporary discontinuation of 
investigational product prior to choosing to discontinue investigational product 
permanently, unless the reason for discontinuation is one of those listed below (Reasons 
for Discontinuation of Investigational Product).  If the discontinuation is permanent, the 
subject should be asked to attend the clinic as soon as possible to complete the 
assessments as for the final study visit (see Table 1) and then continue in the study for 
follow-up. The procedures for follow-up for a subject who permanently discontinues 
treatment with investigational product prior to the study end are given in Section 4.5. 
In all cases, reasons for discontinuation of investigational product and the date of last 
dose will be recorded. 

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4.4.2.
Reasons for Discontinuation of Investigational Product
Any subject experiencing the following will be required to discontinue investigational 
product:
AE:
Pancreatitis, acute or chronic. 
Pancreatic cancer.
MTC or other thyroid C-cell neoplasia.  In subjects where a treatment emergent 
thyroid nodule is identified, if serum calcitonin is measured at the discretion of 
the Investigator (e.g., per local guidelines) and found to be >100 ng/L this 
should prompt further investigation for MTC and potential interruption or 
discontinuation of investigational product until diagnosis has been resolved.
Liver chemistry abnormalities exceeding the threshold criteria outlined in Section 
4.4.3
Severe allergic/hypersensitivity reactions that are considered by the investigator to 
be attributable to investigational product or without a likely alternative 
aetiology.
Other AE which, in the opinion of the investigator precludes continuation of dosing.
eGFR<15ml/min/1.73m2 (Section 4.4.4) or the need for renal replacement therapy.
Subject becomes pregnant during the study.
Need for chronic use of a prohibited concomitant medication (Section 5.6.2)
Decision by subject or proxy.
Sponsor terminated study.
Investigator site closed and subject was unable to transfer to another investigative site.
If investigational product is discontinued, the subject should continue in the study and be 
followed until the final study visit as detailed in Section 4.5.

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4.4.3.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event aetiology (in alignment with the FDA 
premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
Phase III-IV Liver Chemistry Stopping and Increased Monitoring Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus 
Bilirubin≥2x
ULN (>35% 
direct) or plus
INR>1.5, if 
measured*
Possible  
Hy’s Law
ALT≥3xULN
ALT
≥8xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
No
Yes
Yes
Yes
No
No
No
See algorithm 
for continued 
therapy with 
increased liver 
chemistry 
monitoring
Yes
*INR value not applicable to subjects on anticoagulants 
ALT 
≥3xULN 
but 
<8xULN
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*

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Liver safety required actions and follow up assessments section can be found in 
Appendix 3.
Phase III-IV 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*
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 3.
Drug re-challenge following drug induced liver injury is not allowed. 
Restart may be considered if GSK Medical Governance approval is granted (see 
Appendix 4 for details). Restart refers to resuming study treatment following liver 
stopping events in which there is a clear underlying cause (other than DILI) of the liver 
event (e.g. biliary obstruction, pancreatic events, hypotension, acute viral hepatitis). 
Furthermore, there should be no evidence of alcoholic hepatitis or hypersensitivity, and 
the study treatment should not be associated with human leukocyte antigen (HLA) 
markers of liver injury.
4.4.4.
eGFR Stopping Criteria
A baseline eGFR ≥ 30mL/min/1.73m2 is a requirement for entering the study. Subjects 
can continue to take investigational product if functioning well as long as eGFR is 
≥15mL/min/1.73m2. 
During this study, if a subject’s eGFR approaches 30mL/min/1.73m2 closer monitoring of 
renal function is considered prudent, according to standard clinical practice. Particular 

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care should be taken to monitor renal function in subjects with renal impairment 
reporting severe adverse GI events. If eGRF is <15mL/min//1.73m2 and considered 
irreversible based on consecutive measurements the investigational product should be 
discontinued, the subject continue in the study and be followed until the final study visit. 
If eGRF is <15mL/min/1.73m2 and the patient is considered to have temporary acute 
kidney injury that is potentially reversible, the investigational product should be 
temporarily discontinued until the eGRF is stable and ≥15mL/min//1.73m2. Events 
considered to reflect worsening renal function should be reported as SAE/AEs and 
targeted eCRFs completed for this AE of special interest (Section 6.2.3).
4.5.
Procedures for Subject Follow-up
As described in Section 4.4, subjects who permanently discontinue investigational 
product will be asked to attend the clinic as soon as possible.  They will continue in the 
study for follow-up. Five weeks (1 week) after discontinuation of investigational 
product, subjects will be contacted for a follow-up by telephone.  They will be asked to 
return to clinic according to the 8 monthly visit schedule and in addition be contacted by 
telephone at a time corresponding to the 4-monthly visit they would have otherwise made 
to replenish study medication supply. If instead of these interim telephone contacts the 
subject prefers to attend clinic every 4 months as originally scheduled that is an 
acceptable alternative.
If a subject permanently discontinues investigational product and is unable to attend visits 
in-person, he/she will be contacted by telephone or other methods to assess study 
outcomes and vital status, unless the subject has specifically withdrawn consent for all 
forms of contact. Follow-up of subjects who withdraw consent for contact is described 
below.
Every effort should be made to educate the subjects on the importance of remaining in 
the study and attending scheduled study visits including those required after early 
discontinuation of investigational product. 
Other subject follow-up options to collect study outcomes and vital status should be 
pursued according to local laws and regulations. If one of these alternate methods to 
collect study outcomes and vital status is acceptable to the subject, then the subject will 
be deemed not to have withdrawn consent for follow-up.
4.5.1.
Withdrawal of Consent for Contact
Subjects who no longer wish to attend study visits in-person will be asked to be contacted 
by telephone or other methods to assess study outcomes and vital status.  However, if a 
subject specifically withdraws consent to be contacted for additional information, no 
further study visits or study-related telephone contacts can be conducted. Information 
regarding study outcomes or vital status will continue to be collected from available 
sources including those in the public domain. Additionally, alternative permitted options 
to obtain study outcomes and vital status will be reviewed based on accepted local laws 
and regulations. For any subject who withdraws consent for contact, the study site will be 
asked to document the discussion with the subject regarding each of the contact options 
that were offered.

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4.5.2.
Subjects Deemed Lost to Follow-up
Finally, investigators should make every effort to contact subjects who are deemed lost to 
follow-up and who have not withdrawn consent to follow-up contacts, including pursuing 
any alternative contact methods permitted by local regulations. Where permitted, a third 
party may be used to locate alternative subject contact information that will be provided 
to the investigator. All attempts to contact subjects will be documented in the subject’s 
eCRF and source notes. 
Should a subject fail to attend the clinic for a required study visit, the site should attempt 
to contact the subject and re-schedule the missed visit as soon as possible. The site should 
also counsel the subject on the importance of maintaining the assigned visit schedule. In 
cases where the subject does not return for the rescheduled visit or cannot be reached to 
reschedule the missed visit, the site should make every effort to regain contact with the 
subject. Should the subject continue to be unreachable, then and only then will he/she be 
considered “Lost to Follow-up”. Nonetheless, efforts to attempt to locate and contact the 
subject will continue until the study end. 
5.
STUDY TREATMENTS
5.1.
Investigational Product and Other Study Treatment
Albiglutide (and albiglutide matching placebo) will be provided as a fixed-dose, fully 
disposable pen injector system for delivery of the investigational product (albiglutide or
albiglutide matching placebo) from a prefilled dual chamber glass cartridge that is an 
integral part of the pen. The pen is intended for single use by the subject. It is designed 
for manual reconstitution of the dose, priming and insertion of the pen needle, and 
manual injection by the subject. 
Albiglutide (or albiglutide matching placebo) is intended for self-administration as a 
subcutaneous injection in the abdomen, thigh or upper arm region.  Rotation of use of 
injection sites is recommended. Albiglutide and insulin may be injected in the same body 
region but the injections should not be adjacent to each other.  The albiglutide pen 
includes a mechanical locking system that prevents the user from manipulating the dose 
button before the cartridge has been fully reconstituted. Reconstitution is performed 
through rotation of the pen housing parts. The pen is designed to work with standard pen 
needles.
When the injector pen product is reconstituted by the subject, a neutral, isotonic solution 
is produced. Separate pens are required to deliver either 30 mg of albiglutide, 50 mg of 
albiglutide, or matching placebo in a 0.5-mL injection volume.
The contents of the label will be in accordance with all applicable regulatory 
requirements.
Under normal conditions of handling and administration, investigational product is not 
expected to pose significant safety risks to site staff.  Take adequate precautions to avoid 
direct eye or skin contact and the generation of aerosols or mists. Notify the monitor of 
any unintentional occupational exposure.  A Material Safety Data Sheet (MSDS) 

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describing the occupational hazards and recommended handling precautions will be 
provided to site staff if required by local laws or will otherwise be available from GSK 
upon request.
The investigational product (albiglutide and albiglutide matching placebo) must be stored 
in a secure area at 2°C to 8°C and protected from freezing. Each site must maintain a 
temperature log.  Access to and administration of the investigational product will be 
limited to the investigator and authorised site staff (investigator or designee).  
Investigational product must be dispensed or administered only to subjects enrolled in the 
study and in accordance with the protocol.
Procedures for the disposal of unused study treatment will be provided in the SRM.
Investigational product (albiglutide or albiglutide matching placebo) will be administered 
once weekly by subcutaneous injection. The first dose is to be administered at the clinic. 
The starting dose of albiglutide will be 30 mg once weekly.  If at any stage after 5 weeks 
of treatment in the opinion of the investigator the subject needs to have intensified 
therapy to improve glycaemic control, the dose of investigational product should be 
increased before altering the doses of other glucose-lowering medication. In this case the 
subject will called in for an unscheduled visit to supervise an increase in dose from 30 mg 
to 50 mg.  Subjects randomly assigned to albiglutide matching placebo will also go 
through the increased dose procedure to maintain study blind. If a subject experiences 
tolerability issues with the higher, 50mg dose then the investigator may decrease the dose 
back to 30 mg without the need for an unscheduled visit to supervise down titration, other 
than for the subject to collect pens of the correct dose.
Albiglutide (or albiglutide matching placebo) may be administered at any time of day 
without regard to meals. Preferably, it should be administered once a week on the same 
day each week. The day of weekly administration can be changed if necessary as long as 
the last dose was administered 4 or more days previously. If a dose is missed, it should be 
administered as soon as possible within 3 days after the missed dose. Thereafter, subjects 
can resume dosing on their usual day of administration. If it is more than 3 days after the 
missed dose, subjects should wait and administer their next regularly scheduled weekly 
dose.  
If a subject misses 4 or more consecutive doses, the investigator should contact the
medical monitor to discuss options for helping assure better compliance.
5.2.
Treatment Assignment
Subjects will be assigned to study treatment in accordance with the randomisation 
schedule.
Randomised treatment assignment will be done via the Interactive Voice Response 
System (IVRS), and randomisation will be implemented based on a sequestered fixed 
randomisation schedule. Study centre personnel will call the IVRS once a subject has met 
all prerequisites for randomization; the IVRS will assign treatment.

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Blinded study centre personnel will receive a randomisation notification indicating the 
unique subject identifier (randomisation number) and the date and time of randomisation. 
Each randomisation number will be a unique identifier. Once a randomisation number 
has been assigned, the number will not be reused even if the subject withdraws before 
receiving any investigational product. Details of the treatment assignment process are 
contained in the SRM.
5.3.
Blinding
This is a double-blind study, neither the subject nor the study physician will know which 
of the two treatments (albiglutide or placebo) the subject is receiving.
The investigator or treating physician may unblind a subject’s treatment assignment only 
in the case of an emergency or in the event of a serious medical condition, when 
knowledge of the study treatment is essential for the appropriate clinical 
management or welfare of the subject, as judged by the investigator.  Investigators 
have direct access to the subject’s individual study treatment.  It is preferred (but not 
mandatory) that the investigator first contacts the GSK Medical Monitor or appropriate 
GSK study personnel to discuss options before unblinding the subject’s treatment 
assignment.  If GSK study personnel are not contacted before the unblinding, the 
investigator must notify GSK as soon as possible after unblinding, but without revealing 
the treatment assignment of the unblinded subject, unless that information is important 
for the safety of subjects currently in the study.  The date and reason for the unblinding 
must be fully documented in the appropriate data collection tool.
If a subject is unblinded by the investigator or treating physician then discontinuation of 
investigational product treatment for that subject will be at the discretion of the 
investigator. However, the subject should continue to be followed in the study (see 
Section 4.5).
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any subject with an SAE.  If the SAE requires that an expedited 
regulatory report be sent to one or more regulatory agencies, a copy of the report, 
identifying the subject’s treatment assignment, may be sent to clinical investigators in 
accordance with local regulations and/or GSK policy.
5.4.
Product Accountability
In accordance with local regulatory requirements, the investigator, designated site staff, 
or head of the medical institution (where applicable) must document the amount of 
investigational product dispensed and/or administered to study subjects, the amount 
returned unused by study subjects, and the amount received from and returned to GSK, 
when applicable.  Product accountability records must be maintained throughout the 
course of the study.
5.5.
Treatment Compliance
Subjects will be instructed to return all unused and used injector pens at the visits 
specified in the Time and Events Table (Table 1) in order to perform drug accountability 

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and determine compliance. Subjects will be provided with a sharps container for the 
disposal of used pens.  To comply with health and safety considerations there will be no 
count made of used pens; only returned unused pens will be counted. In addition, subjects 
will be provided with a pre-printed card at each dispensing visit to record the date of each 
dose. The card is to be returned at the next dispensing visit with the unused pens.
5.6.
Concomitant Medications and Non-Drug Therapies
5.6.1.
Permitted Medications and Non-Drug Therapies
The usual care provider will manage the subjects according to standard of care, following 
local prescribing information. Close adherence to professional society guidelines for 
standard of care therapies in type 2 diabetes and cardiovascular disease will be 
emphasized during study conduct. Standard of care is described in greater detail in 
Section 3.2.
Unless specified as a prohibited medication in Section 5.6.2, all concomitant medications 
should be considered permitted provided they are not contraindicated for the individual 
subject concerned.
Like other members of the class, albiglutide causes a delay in gastric emptying, and 
thereby has the potential to impact the absorption of concomitantly administered oral 
medications.  This should be taken into account by investigators when prescribing 
concomitant medication.
It may be necessary to reduce the dose of concomitantly administered insulin 
secretagogues (such as SUs) or insulin to reduce the risk of hypoglycaemia when starting 
albiglutide.
All concomitant anti-hyperglycaemic medications (name of agent, total daily dose, start 
and stop dates) will be recorded in the eCRF at each visit. Concomitant cardiovascular 
medications taken during the study will also be recorded at each visit by class of agent.
Additionally, all medications used within the 30 days prior to the onset and throughout 
the duration of an SAE, AE of special interest (Section 6.2.3), or an AE leading to 
discontinuation of investigational product will be recorded as individual agents, reason 
for use, together with start dates (and stop dates if applicable) and any changes since any 
previous AE.
5.6.2.
Prohibited Medications and Non-Drug Therapies
Subjects may not take a GLP-1 receptor agonist (other than blinded investigational 
product), nor any investigational drug, during the study (and any follow-up period after 
discontinuing investigational product).
If a subject receives a prohibited medication, a protocol deviation will be recorded.

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5.7.
Treatment after the End of the Study
Following the final study visit subjects will be contacted by telephone 5 1 weeks after 
last dose of study medication to assess any AEs ongoing since the last visit or newly 
emergent. 
Subjects will be treated as deemed appropriate by the investigator following the end of 
the study. Investigational product will not be provided to subjects by GSK after the end 
of the study.
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 investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition whether or not GSK is providing specific 
post study treatment.
5.8.
Treatment of Study Treatment Overdose
No data are available with regard to albiglutide overdose in humans. The highest 
recommended dose of albiglutide is 50 mg once weekly.
During clinical studies of subjects with type 2 diabetes, the highest dose of albiglutide 
administered was 100 mg subcutaneously every four weeks for 12 weeks. This dose was 
associated with an increased frequency of nausea, vomiting, and headache. 
There is no specific antidote for overdose with albiglutide. In the event of a suspected 
overdose, the appropriate supportive clinical care should be instituted, as dictated by the 
subject’s clinical status. Anticipated symptoms of an overdose may be severe nausea, 
vomiting or headache.  A prolonged period of observation and treatment for these 
symptoms may be necessary, taking into account the half-life of albiglutide (5 days).
6.
STUDY ASSESSMENTS AND PROCEDURES
The schedule of study assessments is shown in Table 1 and Table 2. Detailed procedures 
for each assessment are provided in the SRM.

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Table 1
Time and Events Table
Procedures1,2
Screening3
Randomization3
/Baseline 
(can be same day as 
Screening Visit)
Study Drug 
Check Phone 
Call
(4-6 wks post 
rand.)
Clinic Visit Month 4 
18 days then 
every  4 months 
18 days throughout 
the study
Unscheduled 
dose 
adjustment visit
(if warranted)
Final study 
clinic 
visit4 (or early 
withdrawal)
Follow up Phone 
Call
5 1 weeks after 
last IP dose
Written informed consent  
X
Review of Inc/excl criteria
X
X
Demography & directed medical history
X
Assessment of MACE  and micro-vascular events
X
X
HbA1c
X5
X
X
Serum creatinine (eGFR)
X5
X (alternate visits) 2
X
Liver Function Tests (LFTs)6
X
X (alternate visits) 2
X
Record available information on most recent lipid 
assessment 7
X
X (annually)
X
Genetic sampling8
X
Patient reported outcomes questionnaires9
X10
X (alternate visits) 2
X
Key concomitant non-diabetes medication
X
X
X
X
Diabetes medication
X
X
X
X
Study drug reminder
X
X
X
Physical examination11
X
X (alternate visits) 2
X
SAEs, AEs of special interest, AEs leading to IP 
discontinuation 
X
X
X
X
X
X
Pregnancy test12
X
X
Study drug dispense/compliance13
X
X
X
X
1. Subjects who discontinue investigational product should be handled as described in Section 4.4 and Section 4.5 and in Table 2.
2. Assessments at month 8, 16, 24 etc. will include patient reported outcomes questionnaires, serum creatinine (eGFR), LFTs and physical examination. Those at months 4, 12, 20 
etc do not. .
3. Screening and Randomisation can occur at the same visit if all eligibility information is available. If Screening and Randomisation occur at the same visit assessments should not 
be duplicated.
4. Once it is projected that the target number of MACE events will have been collected and that the projected median duration of subject follow-up is at least 1.5 years, a 3 month 
window will be defined for conducting the final, face to face visit.
5. HbA1c and creatinine assessed using local laboratories at Screening visit and measured no more than 6 months prior to randomisation. If HbA1c or creatinine have not been 
assessed in the previous 6 months assessments to be performed via a central laboratory and results available prior to randomization. The investigator has the discretion to repeat 

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screening HbA1c, and/or creatinine, based on clinical rationale even if previously available local results meet the eligibility criteria to allow the investigator to accommodate the 
possibility of change between screening and randomisation.
6. Liver function tests: ALT, AST, alkaline phosphatase, bilirubin, GGT. Blood samples for LFTs at randomization must be collected prior to the first dose of investigational product.
7. Lipid values (TC, LDLc, HDLc, Tg) to be recorded as available from routine clinical care at baseline and annually thereafter. If results are unavailable, lipids tests are not to be 
performed for the study.
8. Informed consent for genetic research must be obtained before collecting a sample.  This can be collected at any time after genetic consent has been obtained and randomisation 
has occurred.
9. TRIM-D, EQ-5D and study specific questionnaire (details in Section 6.3).
10. TRIM-D is not required for subjects whose diabetes is treated by diet and exercise alone at Baseline.
11. See Section 6.2.7.  
12. Only applies to women of child bearing potential. At screening perform urine pregnancy test.  If positive, send serum sample to the central laboratory for confirmation. At 
Randomisation perform a urine pregnancy test. If result is positive do not randomize the subject. If the urine pregnancy test is negative then the subject can be randomised. If 
Screening and Randomisation are to take place at the same visit then follow the instructions for Screening. See Section 6.2.6.
13. Study drug dispensing not performed at final visit, compliance check not performed at Randomisation.

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Table 2
Time and Events Table for Subjects Who Permanently Discontinue IP Prior to the End of the Study
Procedures
Clinic visit as soon 
after permanent 
discontinuation of IP 
as possible
Phone Call
5 1 week after 
last IP dose
Continue contact schedule 
established at randomisation 
4 monthly 1 month. 
Telephone 1,2
Continue contact schedule 
established at randomisation 
4 monthly 1 month. 
Clinic visit 1,3
Final study clinic 
visit 4
Assessment of MACE  and micro-vascular events
X
X
X
X
HbA1c
X
X
X
Serum creatinine (eGFR)
X
X
X
Liver Function Tests (LFTs)5
X
X
X
Record available information on most recent lipid 
assessment6
X
X (annually)
X (annually)
X
Patient reported outcomes questionnaire7
X
Key concomitant non-diabetes medication
X
X
X
X
X
Diabetes medication
X
X
X
X
X
Physical examination8
X
X
X
AEs leading to IP discontinuation
X
SAEs, AEs of special interest, 
X
X
X
X
X
Study drug compliance
X
1. After subjects permanently discontinue IP, follow-up should continue on the 4-monthly schedule established at randomisation.
2. Where a subject would have been scheduled to attend clinic at months 4, 12, 20, 28 etc after randomisation, a telephone contact will be performed instead (with assessments as 
shown above).
3. Where a subject would have been scheduled to attend clinic at months 8, 16, 24, 32 etc after randomisation, a clinic visit will be performed (with assessments as shown above).
If a subject who has permanently discontinued IP is unable to attend clinic then they will be contacted by telephone instead and the telephone contact assessments will be 
performed.
4. Once it is projected that the target number of MACE events will have been collected and that the projected median duration of subject follow-up is at least 1.5 years, a 3 month 
window will be defined for conducting the final, face to face visit.
5. Liver function tests: ALT, AST, alkaline phosphatase, bilirubin, GGT.
6. Lipid values (TC, LDLc, HDLc, Tg) to be recorded as available from routine clinical care annually. If results are unavailable, lipids tests are not to be performed for the study.
7. TRIM-D, EQ-5D and study specific questionnaire (details in Section 6.3).
8. See Section 6.2.7.  

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6.1.
Critical Baseline Assessments
Disease, and therapy history, including cardiovascular medical history/risk factors will be 
assessed at Baseline. Investigators are encouraged to implement lifestyle modifications 
and adjust or initiate the appropriate pharmacotherapy throughout the study as 
recommended by current locally followed therapeutic cardiovascular and diabetes 
guidelines for participants in the study.  Screening and randomisation can occur at the 
same visit depending on availability of information to determine eligibility of the subject 
to enter the study.
6.2.
Safety
The following sections provide further detail on the safety assessments.  Planned time 
points for all safety assessments are listed in the Time and Events Table (Table 1).  
Unscheduled visits will occur as medically necessary. Detailed procedures for obtaining 
each assessment are provided in the SRM.
Safety endpoints are described in Section 2 and will include monitoring of cardiovascular 
events (Section 6.2.1), deaths, AEs of special interest (Section 6.2.3), clinically 
significant microvascular events (Section 6.2.4), SAEs and AEs leading to 
discontinuation of investigational product.
Liver chemistry stopping and follow-up criteria and AEs are described in Section 4.4.3
and Appendix 3.
6.2.1.
Cardiovascular Events
Events referred to the CEC by the investigator as potential endpoints or transient 
ischemic attacks (TIAs) will not be collected or reported as SAEs, regardless of the 
adjudication outcome (Section 6.2.2)1. These events will be reviewed by an Independent 
Data Monitoring Committee (Section 9.8).
The CEC will review and adjudicate the following clinical events:
Myocardial infarction
Stroke
Unstable angina requiring hospitalization
Hospitalization for heart failure
Sudden cardiac death
TIA
                                                
1 There is one exception to this statement. Per requirement of the Mexican Ministry of Health, all events 
referred to the CEC by Mexican investigators will also be submitted as SAEs to the Mexican Ministry 
of Health.

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In addition, all clinical events submitted for adjudication and all other SAEs with a fatal 
outcome will be reviewed and adjudicated to classify the cause of death as cardiovascular 
or non-cardiovascular.
When the local investigator reported event and the CEC decision on the nature of the 
event differ, the CEC’s decision will be considered final. The detailed descriptions of the 
endpoint (and TIA) definitions necessary for adjudication are contained within the CEC 
Charter (available on request). The guiding principle will be the “2014 ACC/AHA Key 
Data Elements and Definitions for Cardiovascular and Stroke End Point Events for 
Clinical Trials” [ACC/AHA, 2014] and the “Third Universal Definition of Myocardial 
Infarction” endorsed by the European Society of Cardiology (ESC), the American 
College of Cardiology Foundation (ACCF), the American Heart Association (AHA), and 
the World Heart Federation (WHF) [Thygesen, 2012].
Source documentation required to support the adjudication of the events is described in 
the SRM.  Recording of potential endpoint and TIA events in the eCRF and submission 
of source documentation will be required for clinical events meeting reporting criteria 
whether or not an endpoint event is suspected by the investigator.
6.2.1.1.
Other CV Events
GSK has identified other CV events of special interest for all clinical studies. 
Investigators will be required to fill out event specific data collection tools for the 
following cardiovascular events which meet SAEs criteria or are non-serious events that 
result in discontinuation of investigational product:  
Arrhythmias (other than atrial fibrillation/flutter, see Section 6.2.3) 
Valvulopathy
Pulmonary hypertension
Peripheral arterial thromboembolism
Deep venous thrombosis/pulmonary embolism
Revascularisation (other than urgent revascularisation for unstable angina, a component 
of a secondary endpoint)
This information should be recorded in the specific cardiovascular eCRF within one 
week. 
6.2.2.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 5.
The investigator or site staff will be responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE.  
For this study events of myocardial infarction, stroke, unstable angina requiring urgent 
revascularization, hospitalization for heart failure, TIA and sudden cardiac death will not 
be collected or reported as AEs or SAEs. These events will be collected separately, 

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subjected to blinded adjudication by an independent CEC using prespecified diagnostic 
criteria, and reported separately (Section 6.2.1.1). All other events that meet serious 
criteria as defined in Appendix 5 should be reported as SAEs.
All events with an outcome of death will be adjudicated to classify the cause of death as 
specifically cardiovascular or non-cardiovascular. Any event resulting in death should be 
reported as a SAE unless the event is myocardial infartion, stroke, unstable angina w/ 
urgent revascularization, Heart failure, TIA or sudden cardiac death which the protocol 
specifies are not to be collected as adverse events. 
The study will not collect all non-serious AEs. Non-serious AEs leading to 
discontinuation of investigational product and non-serious AEs of special interest (see 
Section 6.2.3) will be collected. 
Any events not specifically addressed above should be reported as an AE or SAE 
according to the definitions in Appendix 5. 
6.2.2.1.
Time period and Frequency for collecting AE and SAE information
AEs and SAEs will be collected from the start of Study Treatment until the follow-up 
contact (see Section 6.2.2.3), at the timepoints specified in the Time and Events Table 
(Table 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.
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. 
All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Appendix 5.
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 5.
6.2.2.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting SAEs. Open-ended and non-
leading verbal questioning of the subject is the preferred method to inquire about SAE 
occurrence.  Appropriate questions include:
“How are you feeling?” 

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“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?” 
Additionally subjects will be asked specific questions about the occurrence of AEs of 
special interest (Section 6.2.3).
6.2.2.3.
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 6.2.3) 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 4.5). Further information on follow-up procedures is given in 
Appendix 5.
6.2.2.4.
Sentinel Events
A Sentinel Event is a GSK-defined SAE that is not necessarily drug-related but has been 
associated historically with adverse reactions for other drugs and is therefore worthy of 
heightened pharmacovigilance. Medical monitor review of all SAEs for possible Sentinel 
Events is mandated at GSK.  The GSK medical monitor may request additional clinical 
information on an urgent basis if a possible Sentinel Event is identified on SAE review. 
The current GSK-defined Sentinel Events are listed below:
Acquired Long QT Syndrome
Agranulocytosis/severe neutropenia 
Anaphylaxis and anaphylactoid reactions (see also Section 6.2.3)
Hepatotoxicity (see also Section 6.2.3)
Acute renal failure
Seizure
Stevens Johnson syndrome/toxic epidermal necrosis
6.2.2.5.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK or designee of SAEs and non-serious AEs 
related to study treatment (even for non- interventional post-marketing studies) is 
essential so that legal obligations and ethical responsibilities towards the safety of 
subjects and the safety of a product under clinical investigation are met. 
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators.

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Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
6.2.3.
Adverse Events of Special Interest
The investigator or site staff will be responsible for detecting, documenting and reporting 
events the following AEs of special interest:
Development of thyroid cancer 
Haematologic malignancy
Pancreatic cancer 
Pancreatitis 
Injection site reactions
Immunological reactions (e.g., drug hypersensitivity reactions involving 
anaphylaxis/anaphylactoid reactions, acute bronchoconstriction, angioedema, and/or 
acute urticaria) 
Severe hypoglycaemia events (which includes all events meeting the definition of SAEs 
Appendix 5)
Hepatic events
Hepatic enzyme elevations (including GGT)
Serious GI events
Appendicitis
Atrial fibrillation/flutter
Pneumonia
Worsening renal function
Diabetic retinopathy
The results of any investigation should be recorded in the relevant sections of the 
subjects’ eCRFs. In addition, for thyroid, pancreas or haematological malignancies 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. In subjects where a treatment 
emergent thyroid nodule is identified, if serum calcitonin is measured at the discretion of 
the Investigator (e.g., per local guidelines) and found to be >100 ng/L this should prompt 
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investigational product until diagnosis has been resolved. If MTC or other thyroid C-cell 
neoplasia is diagnosed, albiglutide will be discontinued.
A Pancreatitis Adjudication Committee composed of independent specialists in 
gastroenterology will review all cases of possible pancreatitis. 
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 in the SRM.  These 
events should be reported as AEs or SAEs based on the clinical evaluation of the subject. 
The reactions should be followed to completion as typical for any AE or SAE.  Subjects 
with allergic or drug hypersensitivity reactions that are considered by the investigator to 
be attributable to investigational product or without a likely alternative aetiology should 
have investigational product withdrawn and not re-introduced.
Episodes of severe hypoglycaemia will be recorded according to subject report.  Severe 
hypoglycaemic incidents will be defined as those episodes of hypoglycaemic symptoms 
for which the subject required assistance from another person and from which the subject 
recovered promptly after oral carbohydrate, intravenous glucose, glucagon administration 
or other resuscitative actions (definition per ADA Workgroup on Hypoglycaemia 
[Seaquist, 2013]).  Additionally, all episodes of hypoglycaemic symptoms which in the 
investigator’s opinion meet the definition of a SAE (defined in Appendix 5) will be 
included as severe hypoglycaemic episodes. During this study, if a subject’s eGFR 
approaches 30mL/min/1.73m2 closer monitoring of renal function is considered prudent, 
according to standard clinical practice. If eGRF is <15mL/min//1.73m2 follow the 
procedure set out in Section 4.4.4.
6.2.4.
Clinically Important Microvascular Events
Clinically important microvascular events are defined as the following: need for renal 
transplant or dialysis, new diabetes-related blindness, and procedures (laser 
photocoagulation or anti-vascular endothelial growth factor treatment or vitrectomy for 
diabetic retinopathy/eye disease).  Clinically important microvascular events will be 
reported as recorded in the eCRF by the investigator without adjudication.
The AEs associated with the above outcomes or treatments should be reported separately 
as an AE or SAE according to the definitions in Appendix 5.
6.2.5.
Pregnancy
If a subject becomes pregnant during the study they should discontinue Investigational 
Product.
Details of all pregnancies in female subjects will be collected after the start of dosing and 
until the end of the Post-treatment Follow-up Period.
If a pregnancy is reported then the investigator should inform GSK within 2 weeks of 
learning of the pregnancy and should follow the procedures outlined in Appendix 6.

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6.2.6.
Clinical Laboratory Assessments
All protocol required laboratory assessments must be conducted in accordance with the 
Laboratory Manual, and Protocol Time and Events Schedule (Table 1).  Details for the 
preparation and shipment of samples will be provided by the laboratory and are detailed 
in the laboratory manual. Reference ranges for all central laboratory safety parameters 
will be provided to the site.
If additional non-protocol specified laboratory assessments result in a change in subject 
management or are considered clinically significant by the investigator (e.g., SAE or AE 
of special interest or dose modification) the results must be recorded in the CRF.
Refer to the SRM/laboratory manual for appropriate processing and handling of samples 
to avoid duplicate and/or additional blood draws.
The following laboratory assessments will be performed: serum creatinine, HbA1c, liver 
function tests [AST (SGOT), ALT (SGPT), alkaline phosphatase, bilirubin, GGT], and 
urine and serum hCG pregnancy test (for women of child bearing potential). All study-
required laboratory assessments will be performed by a central laboratory, with the 
exception of HbA1c and creatinine at Screening and urine pregnancy test at 
Screening/Randomization. 
Screening HbA1c and serum creatinine
Screening HbA1c and serum creatinine values should be based on the most recent local 
laboratory values taken as part of usual care within the previous 6 months and the values 
entered into the eCRF. These assessments must have been performed at an accredited 
laboratory.  HbA1c screening results must be either Diabetes Control and Complications 
Trial (DCCT) aligned or International Federation of Clinical Chemistry and Laboratory 
Medicine (IFCC) standardized.  HbA1c screening results from point of care equipment 
are acceptable provided that the equipment is maintained by an accredited laboratory.  If 
HbA1c or creatinine have not been assessed in the previous 6 months, laboratory 
assessments will be performed via the central laboratory to determine eligibility (if a 
local laboratory is used in error the results are acceptable for determining eligibility). The 
investigator has the discretion to repeat screening HbA1c, and/or creatinine, based on 
clinical rationale even if previously available local results meet the eligibility criteria to 
allow the investigator to accommodate the possibility of change between screening and 
randomisation.
Re-screening of subjects who did not meet the eligibility criteria for HbA1c or creatinine 
based on local laboratory values taken as part of usual care is permitted. If values were 
based on laboratory results as part of usual care then one re-test is permitted within the 
protocol at Screening. Any future re-screening will be based on laboratory results 
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Pregnancy testing (for women of childbearing potential)
At the screening visit perform a urine pregnancy test. If the urine pregnancy test is 
positive, send a serum blood sample to the central laboratory for confirmation of 
pregnancy. 
At the Randomisation visit perform a urine pregnancy test. If the result is positive do not 
randomize the subject. If the urine pregnancy test is negative then the subject can be 
randomised (provided all other eligibility criteria have been met).
If Screening and Randomisation are to take place at the same visit then follow the 
instructions for Screening. Do not randomise if the urine pregnancy test is positive; send 
a serum blood sample to the central laboratory for confirmation of pregnancy. If the urine 
pregnancy test is negative then the subject can be randomised at the same visit (provided 
all other eligibility criteria have been met).
Lipids
Where serum lipid tests have been performed as part of the subject’s routine clinical care 
(i.e. not as a study procedure) the most recent results should be recorded at baseline and 
annually thereafter.  The lipid parameters to be recorded are total cholesterol (TC), low 
density lipoprotein cholesterol (LDLc), high density lipoprotein (HDLc) and triglycerides 
(Tg).
If any or all of these results are not already available from the subject’s records then 
separate lipid tests should not be performed solely for the study.
6.2.6.1.
Estimated Glomerular Filtration Rate (eGFR)
Serum creatinine will be measured every 8 months by a central laboratory. 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).
6.2.7.
Physical examination
A general physical examination, including height and neck (thyroid), will be performed at 
randomization. A targeted physical examination will be performed at all other time points 
as specified in the Time and Events Table (Table 1). The targeted physical examination 
will evaluate the cardiovascular system and injection sites and will include measurement 
of blood pressure and heart rate taken with the subject either in a semi-recumbent or 
seated position after at least a 5-minute rest period.

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6.3.
Value Evidence and Outcomes
6.3.1.
Value Evidence and Outcomes Assessments
6.3.1.1.
Treatment Related Impact Measure – Diabetes (TRIM-D)
In order to evaluate satisfaction with treatment and to compare satisfaction across 
treatment groups, the TRIM-D questionnaire will be self administered by all subjects at 
baseline (except for subjects whose diabetes is treated by diet and exercise alone) and all 
subjects at each 8 month visit (and, to the extent possible, at the time of study completion 
or withdrawal from the study).
The TRIM-D, developed in 2009, is a 28-item treatment satisfaction measure scored to 
produce 5 sub-scale scores (Treatment Burden, Daily Life, Diabetes Management, 
Psychological Health, and Compliance) as well as a total score. It is available in a wide 
range of translations.
The TRIM-D development, in accordance with the principles of the Food and Drug 
Administration Patient Reported Outcome Guidance document, was based on findings 
from the published literature including content from already-existing treatment 
satisfaction measures as well as significant input from subjects with type 1 and with type 
2 diabetes and from expert diabetes clinicians.  The TRIM-D has been evaluated in a 
sample of 507 subjects (74% with type 2 diabetes) and has been shown to have 
acceptable reliability and validity [Brod, 2009a]. Its responsiveness was also evaluated in 
a sample of 242 subjects (71% with type 2 diabetes) and found to be acceptable [Brod, 
2009b].  Some preliminary work has been done on estimating its minimal important 
difference but this needs further exploration [Brod, 2009b].
6.3.1.2.
EQ-5D
The EQ-5D will be self-administered by subjects in order to measure generic health 
status. Combining the EQ-5D with the disease-specific TRIM-D, which is designed to 
have maximum sensitivity to relevant aspects of disease related treatment, will provide a 
more robust evaluation of the impact of treatments for type 2 diabetes and allow for 
clearer interpretation of study results.  TRIM-D results, if consistent with the general 
trends seen in the EQ-5D, will have enhanced credibility.
The EQ-5D is a standardized instrument used to evaluate generic health-related quality of 
life. It is applicable to a wide range of health conditions and treatments, and it provides a 
simple descriptive profile and a single index value for health status.  It is also used to 
provide utilities, or preference weights, for use in economic (cost effectiveness) 
evaluations.  It is available in 141 self complete official language versions.
The EQ-5D has been used extensively in studies to measure the impact of type 2 diabetes 
and treatments for the disease. A systematic review identified 54 publications reporting 
EQ-5D responses and 39 papers presenting evidence on the measurement properties of 
the EQ-5D in this population [Janssen, 2011].  This evidence supported the validity, 
reliability, and responsiveness of the EQ-5D for evaluating health-related quality of life 
in subjects with type 2 diabetes.  Other studies reported that index scores from the EQ-5D 

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have been shown to be an independent predictor of the risk of mortality, future vascular 
events, and other complications in people with type 2 diabetes [Clarke, 2009]. In 
addition, the SHIELD longitudinal study (1,741 respondents with type 2 diabetes and 
4,543 without diabetes) used the EQ-5D to assess the 5-year changes in health-related 
quality of life in type 2 diabetes [Grandy, 2012].
6.3.1.3.
Exploratory Diabetes Management Questions
In addition to the standardised instruments described above, patient experience in relation 
to the management of their diabetes will be evaluated in a subset of sites using a small 
number of self-administered diabetes management questions. These types of customized 
questions have been used successfully in asthma and in diabetes when patients are 
involved with goal-setting [Juniper, 1992; Anderson, 2010]. This tailored approach is an 
opportunity to capture data in the study that are not otherwise available from standard 
PRO measures such as the TRIM-D and the EQ-5D. As an exploratory endpoint, this set 
of questions (3 items at baseline, and at each 8 month follow-up visit) imposes very little 
patient or site burden, but can offer critical insight into the one area of the patient’s 
choosing that s/he finds most difficult to manage. In addition, this patient-centred 
endpoint has the potential to be sensitive to changes over time.
These questions have been developed by GSK based on factors identified as important to
subjects in the development of published, validated and reliable subject reported 
outcomes instruments in type 2 diabetes.
6.3.1.4.
Healthcare Resource Utilisation
Data will be collected on the following heathcare resource use:
All cause hospitalisations and related healthcare resource use.
Healthcare resource use data  will be collected in order to facilitate subsequent health-
economic analyses comparing costs between albiglutide added to standard of care and 
placebo added to standard of care (cost is not an end point in the study). 
Data on all-cause hospitalizations and related inpatient healthcare resource use will be 
collected.  This will include:
All-Cause hospitalisation including: Admission and discharge diagnoses 
(primary and secondary), length of stay, level/type of ward, and time spent in 
Intensive Therapy Unit (or equivalent).
6.4.
Genetic Research
Information regarding genetic research is included in Appendix 1.  
7.
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.

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Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., removing 
errors and inconsistencies in the data.
Adverse events and concomitant medications terms will be coded using MedDRA 
(Medical Dictionary for Regulatory Activities) and an internal validated medication 
dictionary, GSKDrug.  
CRFs (including queries and audit trails) will be retained by GSK, and copies will be sent 
to the investigator to maintain as the investigator copy.  Subject initials will not be 
collected or transmitted to GSK according to GSK policy.
8.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS
8.1.
Hypotheses
This trial will examine the following primary question:

Whether albiglutide is non inferior by a margin of 1.3 with respect to its effect on 
adjudicated MACE, when added to glycaemic standard of care, versus standard of 
care alone. Letting λ1 = hazard ratio for time to first MACE for albiglutide vs 
placebo, then:
Null hypothesis: log λ1 ≥ log(1.3)
Alternative hypothesis: log λ1 < log(1.3)

If non-inferiority is established, the effect on adjudicated MACE will be tested for 
superiority in a closed testing procedure.  Letting λ1 = hazard ratio for time to first 
MACE for albiglutide vs placebo, then:
Null hypothesis: log λ1 ≥ log(1.0)
Alternative hypothesis: log λ1 < log(1.0)
8.2.
Study Design Considerations
8.2.1.
Sample Size Assumptions
The primary outcome will be analyzed such that the overall Type 1 error is no greater 
than 5% (two-sided).  Specifically, the non-inferiority assessment of albiglutide 
compared to placebo will be conducted at 0.05 level, requiring one-sided significance at 
0.025.  
The power for MACE non-inferiority is calculated via the asymptotic variance and 
normality of the maximum likelihood estimator for the log-hazard ratio. Assuming a true 
hazard ratio of 1.0, 611 events will be needed to have 90% power to rule out non-
inferiority margin of 1.3 for the hazard ratio with type I error of 0.05.  A total of 9400 
subjects will be enrolled and followed until it is projected that approximately 611 
adjudicated MACE events will have occurred and the median duration of subject follow-

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up is estimated to be at least 1.5 years. If, for example, the observed rate for MACE is 
2.0% or 3.0%, the mean follow-up will be 3.2 or 2.2 years respectively, assuming that the 
number of subjects lost to follow-up accounts for 1% or less.  
8.2.2.
Sample Size Sensitivity for MACE non-inferiority
9400 subjects will be enrolled to cumulate the first MACE events experienced by 611 
unique subjects. The study duration may vary depending on actual MACE event rate and 
duration of enrolment period. If the estimated median duration of subject follow-up is 
less than 1.5 years at the time that 611 events have occurred then study will continue until 
it is estimated that the median duration of subject follow-up is at least 1.5 years.
Table 3
Indicative* Total Study Duration Sensitivity for Varying MACE Event 
Rate and Duration of Recruitment
Duration of recruitment
1.5 yrs
2.0 yrs
2.5 yrs
3.0 yrs
MACE rate (% pa)
2.0
4.1yrs
4.4yrs
4.6yrs
4.9yrs
2.5
3.4 yrs
3.7yrs
3.9yrs
4.2yrs
3.0
3.0yrs
3.2yrs
3.5yrs
3.8yrs
3.5
2.7yrs
2.9yrs
3.2yrs
3.4yrs
* Although indicative, other scenarios are possible
8.2.3.
Sample Size Re-estimation
The aggregate blinded event-rate data will be periodically reviewed by the Executive 
Committee and the sponsor. The study has an event-driven design and also requires that 
the projected median duration of subject follow up be at least 1.5 years. Should emerging 
data diverge significantly from protocol assumptions, the total sample size and/or follow 
up time may be adjusted, within the bounds of feasibility, to achieve the event target.
8.3.
Data Analysis Considerations
8.3.1.
Analysis Populations
The intent-to-treat (ITT) population will include all randomly assigned subjects. The ITT 
subjects will be analyzed according to randomised treatment. The inference for primary 
objectives in the study will be made from ITT population.
Per-protocol Population (PP) will exclude the subjects who have major protocol 
violations. Per-protocol analysis will include Per-protocol population only and their data 
upon to the time of discontinuation of investigational product plus 56 days.

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The non-insulin population (NI) will include all subjects in the ITT population who are 
not on insulin at baseline. Inference for the time to insulin endpoint will be made from 
the NI population. 
The baseline basal insulin user population (BI) will include all subjects in the ITT 
population who are on basal insulin, but not on other insulin at baseline. Inference for the 
time to prandial insulin endpoint will be made on BI population.
The safety population will include all enrolled subjects who receive at least 1 dose of 
study treatment. The safety population subjects will be analyzed according to the 
treatment received. The safety population will be used for analyses of safety objectives.
Other analysis populations will be defined in the RAP. 
8.3.2.
Analysis Data Set
For time to event data, censoring time for subjects who lost to follow-up is defined as 
following:
For primary analysis, subjects who are lost to follow-up will be censored at the date of 
last evidence of confirmatory status for MACE events. 
For on-treatment analysis, censoring date will be the last dose date. 
For on-therapy analysis (on-treatment+56 days), censoring date will be the last dose 
date+56 days.
For analysis of all cause of mortality, censoring date will be the latest date known alive.
8.3.3.
Treatment Comparisons
Demographic and baseline characteristics (e.g., gender, age, racial or ethnic origin, height 
and weight, body mass index (BMI), blood pressure and other characteristics) will be 
summarized for each treatment group.  In addition, smoking and alcohol habits, diabetic 
and cardiovascular medical history, baseline laboratory results, and prior medications will 
be summarized by treatment group.  Binary and ordinal characteristics will be 
summarized by counts and percentages, while continuous variables will be represented by 
mean and standard deviations or medians and percentiles, as appropriate.  Any variables 
with treatment imbalances may be considered as covariates for further analysis of an 
exploratory nature.  Such covariates will be identified on the basis of the clinical 
relevance of the observed treatment difference.
8.3.3.1.
Primary Comparisons of Interest
The primary endpoint will be the time to the first occurrence of MACE over the full 
duration of the study. A p-value for non-inferiority of the primary endpoint will be 
calculated from a Cox Proportional Hazards (PH) regression model with treatment group 
as the only covariate for the hypotheses described in Section 8.1. If non-inferiority is 
established, a p-value for superiority for the primary endpoint will be calculated from a 
Cox Proportional Hazards (PH) regression model with treatment group as the only 
covariate for the hypotheses described in Section 8.1.

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8.3.3.2.
Other Comparisons of Interest
For other analyses incidence rates will be presented for binary data and summary 
statistics (mean, median, standard deviation, minimum, and maximum) will be presented 
for continuous data.  Time to event endpoints will be evaluated via the p-value from a 
Cox PH regression model with treatment as the only covariate.  Furthermore, summary 
statistics of change from baseline for HbA1c will be presented along with percent of 
subjects within ranges of clinical interest (e.g., HbA1c < 7.0%).  Available lipid data will 
be summarized for descriptive purposes.
8.3.4.
Interim Analysis
An IDMC will monitor progress of the study and ensure that it meets the highest 
standards of ethics and subject safety.    All cardiovascular event data, together with other 
safety data, will be sent to the IDMC for review at approximately every 6 months after 
the first subject has been randomised to receive treatment.  This frequency may be 
adjusted, if deemed necessary by the IDMC, depending on the enrolment rates and the 
rate of safety events.  There are no plans to stop the study early for a non-inferiority or 
benefit claim, however should the IDMC identify in the course of its scheduled reviews 
overwhelming evidence of MACE benefit (e.g., p < 0.001), with directionally consistent 
findings on all-cause mortality, the IDMC might consider recommending early stopping.  
This approach essentially preserves the final alpha for the end-of-study analysis at 5% 
and hence there are no plans to adjust the final alpha on account on safety reviews 
conducted by the IDMC. The IDMC charter, reporting and procedures are outlined in 
separate documents.
8.3.5.
Multiplicity Controls
If non-inferiority is established for the primary endpoint, the data will be used to test for 
evidence of superiority. This approach is a closed testing procedure, and therefore, no 
adjustment for multiplicity is required [Hung, 2009].
Other Secondary Endpoints and Subgroup Analysis
The following secondary endpoints will provide supportive evidence for cardiovascular 
safety and metabolic efficacy and will not use any multiplicity adjustment procedure. 
Results will be presented with confidence interval and nominal p-values:
Components of primary endpoint (MACE = cardiovascular death, MI, stroke)
MACE + urgent revascularisation for unstable angina
Cardiovascular death or hospitalisation for heart failure
Time to initiation of insulin of more than 3 months duration for those subjects not treated 
with insulin at study start  
Time to initiation of prandial insulin in those subjects treated with basal insulin at study 
start.

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The proportion of subjects achieving glycaemic control (HbA1c ≤ 7.0% at final 
assessment) with no severe hypoglycaemic incidents and weight gain <5% of body 
weight  
Mean HbA1c  at scheduled visits and change from baseline
Mean body weight at scheduled visits and change from baseline
Mean eGFR at scheduled visits and change from baseline
Composite microvascular endpoint
To examine the degree of consistency of the overall treatment effect in terms of important 
prognostic factors, subgroup analyses of the primary outcomes will be performed based 
on subject demographics and baseline characteristics. These exploratory subgroup 
analyses will not be adjusted for multiple comparisons and will be interpreted 
descriptively.
8.3.6.
Key Elements of Analysis Plan
Any deviations from the original analysis planned in the protocol agreed upon prior to 
finalization of the RAP, will be described in that document. Any additional changes to 
the planned analysis in the RAP will be described in the final clinical study report.
8.3.6.1.
Primary Analysis
The primary analysis is an ITT analysis of the time to the first occurrence of MACE over 
the full duration of the study. Time to event analyses will be performed using Cox’s 
Proportional Hazard regression with SAS PHREG with treatment group as the only 
covariate.  Data for subjects without a primary event will be censored.
Treatment differences will be estimated via the hazard ratio and its 95% confidence 
interval (CI). 
The hypothesis of non-inferiority of albiglutide relative to placebo group with hazard 
ratio less than 1.3 with respect to cardiovascular risk will be tested at the end of the study.
If non-inferiority is established, the hypothesis of superiority of albiglutide relative to 
placebo will be tested.  
The absolute risk difference per 100 PY, with its associated 95% confidence interval, will 
also be presented.
The product-limit estimates of the probabilities (and their standard errors) of first MACE 
over time will be computed and displayed as Kaplan-Meier (KM) survival curves for  
albiglutide and placebo groups.  The KM curves will also be presented corresponding to 
the above comparisons.
The total number of all MACE or any of its components will be analyzed by Poisson 
regression model. The incidence rate per 100 person-years, relative risk and their 95% CI 
will be presented. Number of subjects who experienced at least one event, 2 or 3 or more 
MACE or its components will also be summarized by treatment group.

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As sensitivity analyses, the analyses described above will be repeated using events occur 
while on-treatment and events occur during the period of on-treatment plus 56 days post 
last dose.
8.3.6.2.
Secondary Endpoint Analysis
Endpoints that supplement the primary objective by further characterization of the effects 
of albiglutide on cardiovascular outcomes endpoints: 
Supportive endpoints including the time to first occurrence of adjudicated MACE or 
urgent revascularisation for unstable angina, time to first occurrence of individual 
components of MACE, time to first occurrence of cardiovascular death or hospitalisation 
for heart failure will be analyzed using a proportional Cox regression model similarly as 
the primary endpoint.
Endpoints that evaluate the effects of albiglutide on metabolic management of type 2 
diabetes: 
Among the subjects who are not on insulin at baseline (NI population), time to insulin 
will be analyzed using a proportional Cox regression model similar to the primary MACE 
analysis. The product-limit estimates of the probabilities (and their standard errors) of 
adding insulin over time will be computed and displayed as Kaplan-Meier (KM) survival 
curves for albiglutide and  placebo treatment groups. The KM curves will also be 
presented corresponding to the above comparisons.
The composite of the proportion of those achieving good control (HbA1c ≤ 7.0%) AND 
having no severe hypoglycaemic incidents AND weight gain <5% at the end of the study 
will be evaluated utilize nonparametric, covariance-adjusted, extended Mantel-Haenszel 
tests. Additional analysis will be provided for scheduled visits. Nominal p-values and 
95% CIs will be presented for these visits. Time to introduction of prandial insulin in 
those on basal insulin orals anti-hyperglycemic drugs at baseline will be analyzed using 
a Cox PH model and KM method similar to the primary endpoint.
Composite of microvascular events will be analyzed using a proportional Cox regression 
model and KM method similar to the primary endpoint.
HbA1c, body weight and eGFR will be analyzed using a repeated mixed effect model. 
The least square means, 95%CIs and nominal p-values will be presented.
Additional analysis will be performed to assess the incidence rate of recurrent severe 
hypoglycaemic events between treatment groups during the course of the study. A 
repeated Poisson regression model including treatment and visit as factors will be used to 
test treatment difference with offset for person years. An unstructured working 
correlation matrix will be used in the iterative estimation process. The model-adjusted 
least square incidence rate for each treatment as well as the treatment difference of the 
incidence rate will be reported. Events of severe hypoglycaemia will also be summarized 
descriptively by treatment group. Additional summary by baseline HbA1c, renal status 
and age subgroup will also be provided.
Further analysis details will be provided in the RAP.

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8.3.6.3.
Subgroup Analysis
Separate subgroup analyses of the primary outcomes will be performed based on subject 
demographics and baseline characteristics.  Subgroups may include sex, age group, BMI, 
whether subjects have history of a previous cardiovascular event, and baseline HbA1C, 
background of anti-hyperglycaemia treatment etc. The detail of subgroups will be pre-
specified in the RAP.  Consistency of treatment effects will be assessed using Cox 
regression, along with the 95% confidence intervals for the relative risk or hazard ratios 
for each subgroup a nominal alpha level for interaction of 0.10 will be used.  The effect 
of treatment interaction with subgroups will also explored; however as the number of 
these subgroup variables may be large, the probability of observing at least one 
statistically significant result may be high.  Thus these additional analyses will be 
considered exploratory regardless of the p-value associated with any interaction.
Further details will be provided in the RAP.
8.3.6.4.
Other Safety Analyses
Subject demographics, medical history, prior and concomitant medications, vital sign 
measurements, laboratory values, physical examination assessments, will be summarized 
by treatment group using descriptive statistics. 
For continuous variables, these summaries will include sample size, mean, median, 
standard deviation, minimum, and maximum. For categorical variables, the summaries 
will include frequencies and corresponding percentages. 
For SAEs, AEs leading to permanent IP withdrawal  and AEs of special interest, the 
number and percentage of subjects, total number of events and incidence density will be 
presented by treatment group and overall at the SOC and Preferred Term (PT) level. 
Relative Risk and its 95% CI may also be presented on a targeted basis. The time to first 
occurrence of specific events will be summarized.
All cause mortality will be summarized by treatment group and analyzed using a Cox PH 
model similarly as the-primary endpoint.
All events sent to CEC (including TIAs) will be summarized.
Pancreatitis events will be adjudicated by the independent Pancreatitis Adjudication 
Committee. The information for investigator reported pancreatitis events and its 
adjudication results will be summarized.
Further analysis details will be provided in the RAP.
8.3.6.5.
Value Evidence and Outcomes Analyses
TRIM-D total score and score for each domain will be summarized descriptively by 
treatment group and scheduled visit. Score changes from baseline will be compared 
between treatments for each visit by an ANCOVA model.

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For EQ-5D, subjects’ responses at each visit for the 5 domains will be summarized 
categorically by treatment group, together with the summary of utility score at each visit 
and change from baseline by treatment group. Change from baseline will be compared 
between treatment groups for each visit by an ANCOVA model. 
For study specific PRO questions, responses will be summarized descriptively by 
treatment group and scheduled visit. 
Healthcare resource use will be summarized by treatment group and visit. 
Further analysis details will be provided in the RAP.
9.
STUDY CONDUCT CONSIDERATIONS
9.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrolment of subjects begins.
9.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a site, GSK will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH E6 Good Clinical Practice 
(GCP), all applicable subject privacy requirements, and the guiding principles of the 
current version of the Declaration of Helsinki.  This includes, but is not limited to, the 
following:
IRB/IEC review and favourable opinion/approval of the study protocol and amendments 
as applicable
Signed informed consent to be obtained for each subject before participation in the study 
(and for amendments as applicable)
Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol deviations to 
IRB/IEC)
GSK will provide full details of the above procedures, either verbally, in writing, or both.
Signed informed consent must be obtained for each subject prior to participation in the 
study
The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.  Optional assessments 
(including those in a separate protocol and/or under separate informed consent) and the 

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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.
9.3.
Quality Control (Study Monitoring)
In accordance with applicable regulations including GCP, and GSK procedures, GSK 
monitors will contact the site prior to the start of the study to review with the site staff the 
protocol, study requirements, and their responsibilities to satisfy regulatory, ethical, and 
GSK requirements.  
When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the CRF will serve 
as the source document.
GSK will monitor the study to ensure that the:
Data are authentic, accurate, and complete.
Safety and rights of subjects are being protected.
Study is conducted in accordance with the currently approved protocol and any other 
study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents.
9.4.
Quality Assurance
To ensure compliance with GCP and all applicable regulatory requirements, GSK may 
conduct a quality assurance assessment and/or audit of the site records, and the regulatory 
agencies may conduct a regulatory inspection at any time during or after completion of 
the study. 
In the event of an assessment, audit or inspection, the investigator (and institution) must 
agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all relevant 
documents and to allocate their time and the time of their staff to discuss the conduct of 
the study, any findings/relevant issues and to implement any corrective and/or 
preventative actions to address any findings/issues identified.
9.5.
Study and Site Closure
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.  

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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.
9.6.
Records Retention
Following closure of the study, the investigator or the head of the medical institution 
(where applicable) must maintain all site study records (except for those required by local 
regulations to be maintained elsewhere), in a safe and secure location.  
The records must be maintained to allow easy and timely retrieval, when needed (e.g., for 
a GSK audit or regulatory inspection) and must be available for review in conjunction 
with assessment of the facility, supporting systems, and relevant site staff.  
Where permitted by local laws/regulations or institutional policy, some or all of these 
records can be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution needs to be exercised before such action is taken.  
The investigator must ensure that all reproductions are legible and are a true and accurate 
copy of the original and meet accessibility and retrieval standards, including re-
generating a hard copy, if required.  Furthermore, the investigator must ensure there is an 
acceptable back-up of these reproductions and that an acceptable quality control process 
exists for making these reproductions.
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.
9.7.
Provision of Study Results to Investigators, Posting of 
Information on Publicly Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 

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opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
GSK will provide the investigator with the randomisation codes for their site only after 
completion of the full statistical analysis.
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy.
9.8.
Independent Data Monitoring Committee (IDMC)
An IDMC will be utilized in this study to ensure external objective medical and/or 
statistical review of safety and/or efficacy issues in order to protect the ethical and safety 
interests of subjects and to protect the scientific validity of the study.  The schedule of 
any planned interim analysis and the analysis plan for IDMC review is described in the 
charter.
9.9.
Pancreatitis Adjudication Committee
Detailed information on suspected pancreatitis events will be collected on special pages 
of the eCRF. A Pancreatitis Adjudication Committee composed of independent 
specialists in gastroenterology will review cases of possible pancreatitis. Details of this 
committee and case adjudication are described in the committee’s charter available on 
request.

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10.
REFERENCES
ACC/AHA Key Data Elements and Definitions for Cardiovascular and Stroke End Point 
Events for Clinical Trials, February 4 2014 (peer review draft version)
American Diabetes Association (ADA). Diagnosis and classification of diabetes mellitus. 
Diabetes Care, 2014; 37 (Suppl 1): S81-S90.
Anderson DR, Christison-Lagay J, and Procter-Gray E. Self-Management goal setting in 
a community health center: the impact of goal attainment on diabetes outcomes. Diabetes 
Spectrum 23.2 (2010): 97-105.
Bao W, Aravindhan K, Alsaid H et al. Albiglutide, a long-lasting glucagon-like peptide-1 
analog, protects the rat heart against ischemia/reperfusion injury: evidence for improving 
cardiac metabolic efficiency.  PLoS One 6: e23570. 2011
Brod, M., Christensen, T., Kongsø, J. H. & Bushnell, D. M. Examining and interpreting 
responsiveness of the Diabetes Medication Satisfaction measure. J. Med. Econ. 12, 309–
316 (2009b).
Brod, M., Hammer, M., Christensen, T., Lessard, S. & Bushnell, D. M. Understanding 
and assessing the impact of treatment in diabetes: the Treatment-Related Impact 
Measures for Diabetes and Devices (TRIM-Diabetes and TRIM-Diabetes Device). Health 
Qual. Life Outcomes 7, 83 (2009a).
Butler AE, Campbell-Thompson M, Gurlo T, et al. Marked expansion of exocrine and 
endocrine pancreas with incretin therapy in humans with increased exocrine pancreas 
dysplasia and the potential for glucagon-producing neuroendocrine tumors. Diabetes. 
2013;62(7):2595-604.
Clarke PM, Hayes AJ, Glasziou PG, et al. Using the EQ-5D index score as a predictor of 
outcomes in patients with type 2 diabetes. Med Care 2009; 47: 61-68.
Cooper DS, Doherty GM, Haugen BR et al. Management guidelines for patients with 
thyroid nodules and differentiated thyroid cancer. Thyroid. 2006;16(2):109-142. 
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. 
European Public Assessment Report (EPAR) for Eperzan. 2014.Available at: 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/00273
5/human_med_001735.jsp&mid=WC0b01ac058001d124
FDA Summary Basis of Approval. 2014. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/125431Orig1s000TOC.cfm
Fu AZ, Qiu Y, Radican L, Yin DD, Mavros P. Pre-existing cardiovascular diseases and 
glycemic control in patients with type 2 diabetes mellitus in Europe: a matched cohort 
study. Cardiovasc Diabetol. 2010; 9:15.

2014N193553_03
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63
Grandy S, Fox KM. Change in health status (EQ-5D) over 5 years among individuals 
with and without type 2 diabetes mellitus in the SHIELD longitudinal study. Health and 
Quality of Life Outcomes 2012;10:99.
Guidance for Industry. Diabetes Mellitus: Developing Drugs and Therapeutic Biologics 
for Treatment and Prevention. U.S. Department of Health and Human Services. Food and 
Drug Administration. Center for Drug Evaluation and Research (CDER). February 2008 
Clinical/Medical. Available at http://www.fda.gov/cder/guidance/index.htm.
Hung HMJ, Wang SJ.  Some Controversial Multiple Testing Problems in Regulatory 
Applications, Journal of Biopharmaceutical Statistics 2009; 19:1, 1-11,
Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauk M, Peters AL, 
Tsapas A, Wender R, Matthews DR. Management of Hyperglycemia in Type 2 Diabetes: 
A Patient-Centered Approach Position Statement of the American Diabetes Association 
(ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 
2012; 35: 1364-1379
Janssen MF, Lubetkin EI, Sekhobo JP, Pickard AS. The use of the EQ-5D preference-
based health status measure in adults with Type 2 diabetes mellitus. Diabet Med 2011; 
28(4):395-413.
Juniper EF, Guyatt GH, Epstein RS, Ferrie PJ, Jaeschke R, Hiller TK. Evaluation of 
impairment of health-related quality of life in asthma: development of a questionnaire for 
use in clinical trials. Thorax 1992; 47: 76-83.
Khunti K, Andersen M, Wolden ML, Davies MJ and Thorsted BL. Clinical Inertia in 
People With Type 2 Diabetes. Diabetes Care. 2013; 36:3411-3417
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. 
Levey AS, Stevens LA, Schmid CH et al. A new equation to estimate glomerular 
filtration rate.  Ann Intern Med. 2009; 150: 604-12.
Lønborg J, Vejlstrup N, Kelbaek H et al. Exenatide reduces reperfusion injury in patients 
with ST-segment elevation myocardial infarction.  Eur Heart J 2012; 33: 1491-9.
Nystrom T, Gutniak MK, Zhang Q et al. Effects of glucagon-like peptide-1 on 
endothelial function in type 2 diabetes patients with stable coronary disease. Am J 
Physiol Endocrinol Metab 2004; 287: E1209-15.
Okerson T and Chilton RJ. The cardiovascular effects of GLP-1 receptor agonists. 
Cardiovascular Therapeutics 2012; 30: e146-155.

2014N193553_03
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Pacini F, Schlumberger M, Dralle H et al. European consensus for the management of 
patients with differentiated thyroid carcinoma of the follicular epithelium. Eur J 
Endocrinol. 2006;154(6):787-803.
Schulz KF, Altman DG, Moher D for the CONSORT Group. CONSORT 2010 
Statement: updated guidelines for reporting parallel group randomised trials. Available 
at: http://www. consort-
statement.org/Media/Default/Downloads/CONSORT%202010%20Statement/CONSORT
%202010%20Statement%20(BMJ).pdf
Seaquist E, Anderson J, Childs B, et al. Hypoglycemia and diabetes: A report of a 
workgroup of the American Diabetes Association and the Endocrine Society. Diabetes 
Care. 2013;36:1384-1395.
Stonehouse AH, Darsow T, Maggs DG. Incretin-based therapies. J Diabetes 
2012;4(1):55-67.
Thygesen K, Alpert JS, Jaffe AS etal. Third universal definition of myocardial 
infarction. European Heart Journal. 2012; 33: 2551–2567
Vilsbøll T, Krarup T, Deacon CF, Madsbad S, Holst JJ. Reduced postprandial 
concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic 
patients. Diabetes. 2001; 50(3):609-13.
World Health Organization (WHO). Diabetes Fact Sheet. October 2013. Available at 
http://www.who.int/mediacentre/factsheets/fs312/en/ (Accessed Apr 3, 2014).

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11.
APPENDICES
11.1.
Appendix 1: Genetic Research
Background
Genetics is the study of variability in drug response due to hereditary factors in 
populations.  There is increasing evidence that an individual's genetic background (i.e., 
genotype) may impact the pharmacokinetics (absorption, distribution, metabolism, 
elimination), pharmacodynamics (relationship between concentrations and 
pharmacologic effects or the time course of pharmacologic effects) and/or clinical 
outcome (in terms of efficacy and/or safety and tolerability).  Some reported examples of 
genetic associations with safety/adverse events include:
Drug
Disease
Gene Variant
Outcome
Abacavir
HIV 
[Hetherington, 
2002; 
Mallal, 2002; 
Mallal, 2008]
HLA-B* 57:01 
(Human 
Leukocyte 
Antigen B)
Carriage of the HLA-B*57:01 variant has been 
shown to increase a patient's risk for 
experiencing hypersensitivity to abacavir.  
Prospective HLA-B*57:01 screening and 
exclusion of HLA-B*57:01 positive patients 
from abacavir treatment significantly 
decreased the incidence of abacavir 
hypersensitivity.  Treatment guidelines and 
abacavir product labelling in the United States 
and Europe now recommend (US) or require 
(EU) prospective HLA-B*57:01 screening prior 
to initiation of abacavir to reduce the incidence 
of abacavir hypersensitivity.  HLA-B*57:01
screening should supplement but must never 
replace clinical risk management strategies for 
abacavir hypersensitivity.
Carbamaze
pine
Seizure, Bipolar 
disorders & 
Analgesia 
[Chung, 2010; 
Ferrell, 2008]
HLA-B*15:02
Independent studies indicated that patients of 
East Asian ancestry who carry HLA-B*15:02
are at higher risk of Stevens-Johnson 
Syndrome and toxic epidermal necrolysis.  
Regulators, including the US FDA and the 
Taiwanese TFDA, have updated the 
carbamazepine drug label to indicate that 
patients with ancestry in genetically at risk 
populations should be screened for the 
presence of HLA-B*15:02 prior to initiating 
treatment with carbamazepine.

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Drug
Disease
Gene Variant
Outcome
Irinotecan
Cancer 
[Innocenti, 2004; 
Liu, 2008; 
Schulz, 2009]
UGT1A1*28
Variations in the UGT1A1 gene can influence 
a patient’s ability to break down irinotecan, 
which can lead to increased blood levels of the 
drug and a higher risk of side effects. A dose 
of irinotecan that is safe for one patient with a 
particular UGT1A1 gene variation might be too 
high for another patient without this variation, 
raising the risk of certain side-effects that 
include neutropenia following initiation of 
Irinotecan treatment.  The irinotecan drug 
label indicates that individuals who have two 
copies of the UGT1A1*28 variant are at 
increased risk of neutropenia.  A genetic blood 
test is available that can detect variations in 
the gene.    
A key component to successful genetic research is the collection of samples during the 
conduct of clinical studies.
Collection of whole blood samples, even when no a priori hypothesis has been identified, 
may enable genetic analysis to be conducted if at any time it appears that there is a 
potential unexpected or unexplained variation in response to albiglutide.
Genetic Research Objectives
The objective of genetic research (if there is a potential unexpected or unexplained 
variation) is to investigate a relationship between genetic factors and response to 
albiglutide.  If at any time it appears there is potential variability in response in this 
clinical study or in a series of clinical studies with albiglutide, the following objectives 
may be investigated – the relationship between genetic variants and study treatment with 
respect to:
Safety and/or tolerability 
Efficacy
Study Population
Any subject who is enrolled in the clinical study, can participate in genetic research.  Any 
subject who has received an allogeneic bone marrow transplant must be excluded from 
genetic research.
Subject participation in the genetic research is voluntary and refusal to participate will 
not indicate withdrawal from the clinical study or result in any penalty or loss of benefits 
to which the subject would otherwise be entitled.

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Study Assessments and Procedures
Blood samples can be taken for deoxyribonucleic acid (DNA) extraction and used in 
genetic assessments.
If taking blood samples: in addition to any blood samples taken for the clinical study, a 
whole blood sample (~6ml) will be collected for the genetic research using a tube 
containing EDTA.  It is recommended that the blood sample be taken at the first 
opportunity after a subject has been randomised and provided informed consent for 
geneticresearch, but may be taken at any time while the subject is participating in the 
clinical study.
The genetic sample is labelled (or “coded”) with a study specific number that 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).  The blood 
sample is taken on a single occasion unless a duplicate sample is required due to inability 
to utilise the original sample.  
The DNA extracted from the blood sample may be subjected to sample quality control 
analysis.  This analysis will involve the genotyping of several genetic markers to confirm 
the integrity of individual samples.  If inconsistencies are noted in the analysis, then those 
samples may be destroyed.
The need to conduct genetic analysis may be identified after a study (or a set of studies) 
of albiglutide has been completed and the clinical study data reviewed.  In some cases, 
the samples may not be studied. e.g., no questions are raised about how people respond to 
albiglutide.
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 use samples collected from the study for 
the purpose stated in this protocol and in the informed consent form.  
Subjects can request their sample to be destroyed at any time.
Subject Withdrawal from Study
If a subject who has consented to participate in geneticresearch 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 geneticsample, if already collected:
Continue to participate in genetic research with the geneticsample retained for analysis 
Withdraw from geneticresearch and destroy the geneticsample 
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. The investigator should forward the Pharmacogenetic Sample 
Destruction Request Form to GSK as directed on the form. This can be done at any time 

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when a subject wishes to withdraw from genetic research or have their sample destroyed 
whether during the study or during the retention period following close of the main study.
Screen and Baseline Failures
If a blood sample for genetic research has been collected and it is determined that the 
subject does not meet the entry criteria for participation in the clinical study, then the 
investigator should instruct the participant 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.
Analyses
1.
Specific genes may be studied that encode the drug targets, or drug mechanism of 
action pathways, drug metabolizing enzymes, drug transporters or which may 
underpin adverse events, disease risk or drug response. These candidate genes may 
include a common set of ADME (Absorption, Distribution, Metabolism and 
Excretion) genes that are studied to determine the relationship between gene variants 
or treatment response and/or tolerance. 
In addition, continuing research may identify other enzymes, transporters, proteins or 
receptors that may be involved in response to albiglutide.  The genes that may code for 
these proteins may also be studied.
2.
Genome-wide scans involving a large number of polymorphic markers (e.g., single 
nucleotide polymorphisms) at defined locations in the genome, often correlated with 
a candidate gene, may be studied to determine the relationship between genetic 
variants and treatment response or tolerance. This approach is often employed when 
a definitive candidate gene(s) does not exist and/or the potential genetic effects are 
not well understood. 
If applicable and genetic research is conducted, appropriate statistical analysis methods 
will be used to evaluate pharmacogenetic data in the context of the other clinical data. 
Results of genetic investigations will be reported either as part of the main clinical study 
report or as a separate report. Endpoints of interest from all comparisons will be 
descriptively and/or graphically summarised as appropriate to the data.  A detailed 
description of the analysis to be performed will be documented in the study reporting and 
analysis plan (RAP) or in a separate pharmacogenetics RAP, as appropriate.  
Informed Consent
Subjects who do not wish to participate in geneticresearch may still participate in the 
clinical study.  Genetic informed consent must be obtained prior to any blood being taken 
for genetic research.
Provision of Study Results and Confidentiality of Subject’s Genetic Data
GSK may summarise the genetic research results in the clinical study report, or 
separately, or may publish the results in scientific journals. 

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GSK does not inform the investigator, subject, or anyone else (e.g., family members, 
study investigators, primary care physicians, 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.
References
Chung WH, Hung SL, Chen YT. Genetic predisposition of life-threatening antiepileptic-
induced skin reactions.  Expert Opin. Drug Saf. 2010; 9: 15-21.
Ferrell PB, McLeod HL.  Carbamazepine, HLA-B*1502 and risk of Stevens-Johnson 
syndrome and toxic epidermal necrolysis: US FDA recommendations.  
Pharmacogenomics. 2008; 9: 1543-1546.
Hetherington S, Hughes AR, Mosteller M, Shortino D, Baker KL, Spreen W, Lai E, 
Davies K, Handley A, Dow DJ, Fling ME, Stocum M, Bowman C, Thurmond LM, Roses 
AD. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. 
Lancet. 2002; 359:1121-1122.
Innocenti F, Undevia SD, Iyer L, Chen PX, Das S, Kocherginsky M, Karrison T, Janisch 
L, Ramirez J, Rudin CM, Vokes EE, Ratain MJ.  Genetic variants in the UDP-
glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J 
Clin Oncol 2004; 22: 1382-1388.
Liu CY, Chen PM, Chiou TJ, Liu JH, Lin JK, Lin TC, Chen WS, Jiang JK, Wang HS, 
Wang WS.  UGT1A1*28 polymorphism predicts irinotecan-induced severe toxicities 
without affecting treatment outcome and survival in patients with metastatic colorectal 
carcinoma.  Cancer. 2008; 112: 1932-1940.
Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, Sayer D, Castley A, Mamotte 
C, Maxwell D, James I.  Association between presence of HLA-B*5701, HLA-DR7, and 
HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir.  
Lancet. 2002; 359:727-732.
Mallal S, Phillips E, Carosi G, Molina JM, Workman C, Tomazic J, Jägel-Guedes E, 
Rugina S, Kozyrev O, Cid JF, Hay P, Nolan D, Hughes S, Hughes A, Ryan S, Fitch N, 
Thorborn D, Benbow A; PREDICT-1 Study Team.  HLA-B*5701 screening for 
hypersensitivity to abacavir. N Engl J Med. 2008; 358; 568-579
Schulz C, Heinemann V, Schalhorn A, Moosmann N, Zwingers T, Boeck S, Giessen C, 
Stemmler HJ. UGT1A1 gene polymorphism: Impact on toxicity and efficacy of 
irinotecan-based regimens in metastatic colorectal cancer.  World J. Gastroenterol. 2009; 
15: 5058-5066.

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11.2.
Appendix 2: GSK Modified List of Highly Effective Methods 
for Avoiding Pregnancy in Females of Reproductive 
Potential (FRP)
1.
Contraceptive subdermal implant that meets effectiveness criteria including a <1% 
rate of failure per year, as stated in the product label.
2.
Intrauterine device or intrauterine system that meets effectiveness criteria including a 
<1% rate of failure per year, as stated in the product label [Trussell, 2011]
3.
Oral Contraceptive, either combined or progestogen alone [Trussell, 2011] 
4.
Injectable progestogen [Trussell, 2011]
5.
Contraceptive vaginal ring [Trussell, 2011]
6.
Percutaneous contraceptive patches [Trussell, 2011]
7.
Male partner sterilization prior to the female subject's entry into the study, and this 
male is the sole partner for that subject. The information on the male sterility can 
come from interview with the subject on her male partner’s medical history.
8.
Male condom combined with a female diaphragm, with or without a vaginal 
spermicide (foam, gel, film, cream, or suppository). In the UK it is a country-specific 
requirement of the regulatory authority (Medicines and Healthcare Products 
Regulatory Agency) that a vaginal spermicide be used.
These allowed methods of contraception have a failure rate of less than 1% per year but 
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.
References
Trussell J, Contraceptive Efficacy. In: Hatcher RA, Trussell J, Nelson AL, Cates W, 
Kowal D, and Policar M (editors). Contraceptive Technology: Twentieth Revised 
Edition. New York: Ardent Media, 2011.Table 26-1

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11.3.
Appendix 3: Liver Safety Required Actions and Follow up 
Assessments
Phase III-IV liver chemistry stopping and increased monitoring criteria have been 
designed to assure subject safety and evaluate liver event aetiology (in alignment with the 
FDA premarketing clinical liver safety guidance).  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
Phase III-IV liver chemistry stopping criteria and required follow up assessments 
Liver Chemistry Stopping Criteria - Liver Stopping Event
ALT-absolute
ALT 8xULN
ALT Increase
ALT 5xULN but <8xULN  persists for 2 weeks
ALT 3xULN but <5xULN  persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot 
Monitor
ALT 5xULN but <8xULN and cannot be monitored weekly for 2 weeks
ALT 3xULN but <5xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be 
related to  liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue  study treatment 

Report the event to GSK within 24 hours

Complete the liver event CRF and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries 
resolve , stabilize, or return to within baseline
(see MONITORING below)

Do not restart subject with study treatment 
unless allowed per protocol and GSK Medical 
Governance approval is granted (refer to  

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 3 half lives (15 
days)  of last dose6

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN.

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Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments
Appendix 5)

If restart is not granted, permanently 
discontinue study treatment and continue 
subject in the study for any protocol specified 
follow up assessments 

Re-challenge is not allowed.
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

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 high 
pressure liquid chromatography assay 
(quantifies potential acetaminophen 
contribution to liver injury in subjects with 
definite or likely acetaminophen use in the 
preceding week [James, 2009]). NOTE: 
not required in China

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to subjects receiving anticoagulants

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3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)   
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
5.
If hepatitis delta antibody assay cannot be performed,, it can be replaced with a PCR of hepatitis D RNA virus 
(where needed) [Le Gal, 2005].
6.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM.  
Phase III-IV 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-Protein 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 

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Different Patterns of Virological Response to Interferon Therapy in Chronically Infected 
Patients.  J Clin Microbiol. 2005;43(5):2363–2369. 

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11.4.
Appendix 4: Liver Safety Drug Restart Guidelines
If subject meets liver chemistry stopping criteria do not restart subject with study 
treatment unless:

GSK Medical Governance approval is granted (as described below),

Ethics and/or IRB approval is obtained, if required, and

Separate consent for treatment restart is signed by the subject
If GSK Medical Governance approval to restart the subject with study treatment is not
granted, then the subject must permanently discontinue study treatment and may 
continue in the study for protocol-specified follow up assessments.
Restart Following Transient Resolving Liver Stopping Events Not Related to Study 
Treatment
Restart refers to resuming study treatment following liver stopping events in which there 
is a clear underlying cause (other than DILI) of the liver event (e.g. biliary obstruction, 
pancreatic events, hypotension, acute viral hepatitis). Furthermore, there should be no 
evidence of alcoholic hepatitis or hypersensitivity, and the study treatment should not be 
associated with HLA markers of liver injury.
Approval by GSK for study treatment restart can be considered where:
Investigator  requests consideration for study treatment restart if liver chemistries have a 
clear underlying cause (e.g., biliary obstruction, hypotension and liver chemistries have 
improved to normal or are within 1.5 x baseline and ALT <3xULN).
Restart risk factors (e.g. fever, rash, eosinophilia, or hypersensitivity, alcoholic hepatitis, 
possible study treatment-induced liver injury) or study treatment has an HLA genetic 
marker associated with liver injury (e.g. lapatinib, abacavir, amoxicillin/clavulanate) are 
reviewed and excluded.
Ethics Committee or Institutional Review Board approval of study treatment restart must 
be obtained, as required.
If restart of study treatment is approved by GSK Medical Governance in writing, the 
subject must be provided with a clear description of the possible benefits and risks of 
study treatment administration, including the possibility of recurrent, more severe liver 
injury or death.  
The subject must also provide signed informed consent specifically for the study 
treatment restart.  Documentation of informed consent must be recorded in the study 
chart.  
Study treatment must be administered at the dose specified by GSK.
Subjects approved by GSK Medical Governance for restarting study treatment must 
return to the clinic once a week for liver chemistry tests until stable liver chemistries have 
been demonstrated and then laboratory monitoring may resume as per protocol. 

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If after study treatment re-start, subject meets protocol-defined liver chemistry stopping 
criteria, follow usual stopping criteria instructions.
GSK Medical Monitor, and the Ethics Committee or Institutional Review Board as 
required, must be informed of the subject’s outcome following study treatment restart. 
GSK to be notified of any adverse events, as per Section 6.2.2 and Appendix 5

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11.5.
Appendix 5: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
11.5.1.
Definition of Adverse Events
Adverse Event Definition:
An AE is any untoward medical occurrence in a subject 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 unfavourable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.
Events meeting AE definition include:
Any abnormal laboratory test results (haematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECGs, radiological scans, vital signs measurements), 
including those that worsen from baseline, and felt to be clinically significant in the 
medical and scientific judgement of the investigator.
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
New conditions detected or diagnosed after study treatment administration even though it 
may have been present prior to the start of the study.
Signs, symptoms, or the clinical sequelae of a suspected interaction.
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-harming 
intent.  This should be reported regardless of sequelae).
The signs and symptoms and/or clinical sequelae resulting from lack of efficacy will be 
reported if they fulfil the definition of an AE or SAE.  Also, "lack of efficacy" or "failure 
of expected pharmacological action" also constitutes an AE or SAE.

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Events NOT meeting definition of an AE include:
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition.
The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the subject’s 
condition.
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads 
to the procedure is an AE.
Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
11.5.2.
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 fulfils any other serious criteria, the event is serious.  When in 
doubt as to whether “hospitalization” occurred or was necessary, the AE should be 
considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.

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

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11.5.3.
Recording of AEs and SAEs
AEs and SAE Recording:
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) relative 
to the event.
The investigator will then record all relevant information regarding an AE/SAE in the 
CRF
It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to GSK in lieu of completion of the GSK, AE/SAE CRF page.
There may be instances when copies of medical records for certain cases are requested by 
GSK.  In this instance, all subject identifiers, with the exception of the subject number, 
will be blinded on the copies of the medical records prior to submission of to GSK.
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.
Subject-completed Value Evidence and Outcomes questionnaires and the collection of 
AE data are independent components of the study.
Responses to each question in the Value Evidence and Outcomes questionnaire will be 
treated in accordance with standard scoring and statistical procedures detailed by the 
scale’s developer.
The use of a single question from a multidimensional health survey to designate a cause-
effect relationship to an AE is inappropriate.

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11.5.4.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:
Mild:  An event that is easily tolerated by the subject, causing minimal discomfort and 
not interfering with everyday activities.
Moderate:  An event that is sufficiently discomforting to interfere with normal everyday 
activities
Severe:  An event that prevents normal everyday activities. - an AE that is assessed as 
severe will not be confused with an SAE. Severity is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe.
An event is defined as ‘serious’ when it meets at least one of the pre-defined outcomes as 
described in the definition of an SAE.
Assessment of Causality
The investigator is obligated to assess the relationship between study treatment and the 
occurrence of each AE/SAE.
A "reasonable possibility" is meant to convey that there are facts/evidence or arguments 
to suggest a causal relationship, rather than a relationship cannot be ruled out.
The investigator will use clinical judgment to determine the relationship.
Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.
The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of his/her assessment.
For each AE/SAE the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK.  However, it is very important that 
the investigator always make an assessment of causality for every event prior to the 
initial transmission of the SAE data to GSK.
The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.

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Follow-up of AEs and SAEs
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.
The investigator is obligated to assist.  This may include additional laboratory tests or 
investigations, histopathological examinations or consultation with other health care 
professionals.
If a subject dies during participation in the study or during a recognized follow-up period, 
the investigator will provide GSK with a copy of any post-mortem findings, including 
histopathology.
New or updated information will be recorded in the originally completed CRF.
The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
11.5.5.
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 safety designee as detailed in the Study 
Reference Manual
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.
Site will enter the SAE data into the electronic system as soon as it becomes available.
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 or the 
SAE coordinator by telephone.
Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.

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11.6.
Appendix 6: Collection of Pregnancy Information
Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study
Information will be recorded on the appropriate form and submitted to GSK within 2 
weeks of learning of a subject's pregnancy.
Subject will be followed to determine the outcome of the pregnancy. The investigator 
will collect follow up information on mother and infant, which will be forwarded to GSK.  
Generally, follow-up will not be required for longer than 6 to 8 weeks beyond the 
estimated delivery date. 
Any termination of pregnancy will be reported, regardless of foetal 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 5. 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

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11.7.
Appendix 7: Electronic Health Record Ancillary Study
11.7.1.
Introduction
11.7.1.1.
Background
Clinical researchers and policy makers want to move towards embedding clinical trials 
directly within health care delivery systems in order to increase the relevance, speed, and 
efficiency of clinical research [Richesson, 2013]. The assumption is that the capabilities 
offered by Electronic Health Records (EHRs), along with concurrent changes in health 
care organization and delivery, and the development of a learning health system will 
transform the way clinical research is conducted [Etheredge, 2007; Greene, 2012]. 
In 2011, the National Heart, Lung, and Blood Institute (NHLBI) convened the NHLBI 
Working Group on Electronic Health Records: Research Priorities to Improve 
Cardiopulmonary Health in Clinical Practice. As part of their mission, this working group 
identified key research, policy, and training priorities [Curtis, 2014]. A key research 
priority was to leverage EHR tools to facilitate the efficient implementation of 
randomized clinical trials. Specific areas highlighted for increased efficiency included 
efficient data collection and outcome surveillance and confirmation.
11.7.1.2.
Literature Review
Electronic Health Records were primarily designed to document patient care and 
facilitate billing and reimbursement. The large amount of electronic data that are captured 
may also facilitate clinical research and public health surveillance. EHR data are 
inherently complex, originate from various settings (e.g., outpatient practices, hospitals, 
and laboratories) and may be inconsistently captured across systems. Despite the 
complexity of EHR data, national networks have begun to use these data to improve 
public health and generate real-world evidence [Toh, 2012]. The Patient Centered 
Outcomes Research network (PCORnet) (pcornet.org) is a research network that is 
currently being designed to support observational comparative effectiveness research and 
clinical trials that are embedded in clinical care settings [Fleurence, 2014]. Similarly, the 
NIH Health Care Systems Research Collaboratory (nihcollaboratory.org) is creating 
infrastructure to improve the conduct of embedded clinical trials. One ongoing NIH 
Collaboratory trial is the Time to Reduce Mortality in End-Stage Renal Disease study 
(TiME) (clinicaltrials.gov identifier: NCT02019225). TiME will examine optimal 
hemodialysis session length using data from EHR systems through a partnership between 
academic investigators and two health care provider organizations with different 
electronic data systems. There are several other recent examples of clinical trials that 
were embedded in health care delivery systems [Gulliford, 2014; van Staa, 2014]. For 
instance, one recent study evaluated the use of an electronic decision support tool to 
improve risk factor control (i.e., blood pressure and cholesterol) following a 
cerebrovascular event with outcome data collected from the EHR [Dregan, 2014]. While 
the specific intervention was not shown to be efficacious, data acquisition via EHR 
sources was robust and implemented at a low cost.

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11.7.1.3.
Ancillary Study Rationale
Despite these earlier studies demonstrating the potential opportunities with EHR-based 
data acquisition, our understanding of how EHR-based platforms might increase the 
efficiency of data collection, outcome surveillance, and confirmation in an integrated 
manner is unknown. EHRs are inherently heterogeneous, with each implementation 
different from the next. The barriers to using EHR-generated lists of patients to facilitate 
trial enrolment, the fitness of EHR data for populating baseline characteristics in an 
electronic case report form (eCRF) and the use of EHR data to find events of interest 
during trial follow-up are not well characterized. 
EHR systems contain a wealth of clinical data about patients who are connected to the 
health care delivery system and may be eligible for enrollment in a clinical trial.  
Anecdotal reports suggest that identification of potential patients using the EHR increases 
the number of patients to be screened but may not consistently translate to an increased 
number of patients enrolled. Causes are likely multi-factorial and may include the 
translatability of inclusion and exclusion criteria to structured clinical data and the 
algorithm used to identify potential patients. There is a need to empirically assess the 
utility of using an EHR-generated list of patients to facilitate trial enrolment as well as 
understanding the barriers to use of an EHR system for enrolment. 
Structured data captured in the EHR may be similar to data elements specified in baseline 
patient characteristics in the eCRF, yet EHR data are collected primarily to support 
clinical care and reimbursement needs.  Their fitness for use as source data for selected 
data elements of the baseline patient characteristics in the eCRF has not been established. 
During routine trial follow-up, study coordinators typically gather information from 
various sources including direct patient contact and medical records (some of which 
resides in electronic format, i.e., an EHR) of the enrolling institution and outside facilities 
to document events for study participants.  There is a need to specifically assess the 
utility of EHR data acquisition for follow-up events across multiple health systems, and 
to address challenges to the future use of EHR as source data for global trials and 
observational studies.
In summary, the EHR is a rich source of clinical data that are increasingly used in 
pragmatic health research initiatives, but the assumption that EHR data are fit for use in 
high-quality clinical research has not been rigorously evaluated.  To provide evidence to 
address this knowledge gap, GlaxoSmithKline (GSK) and Duke Clinical Research 
Institute (DCRI) are committed to conducting an exploratory EHR Ancillary Study 
alongside a large pragmatic clinical trial. The overarching goal is to further our 
understanding of how EHR data can be organized into a query-able format to facilitate a 
more efficient, reliable, and cost-effective research process.  As a collaboration between 
an academic research institute and a pharmaceutical sponsor, this project provides a 
unique opportunity to compare electronic health record data with baseline characteristics 
and adjudicated events captured as part of a large, contemporary, outcomes-based trial.

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11.7.2.
Ancillary Study OBJECTIVES
11.7.2.1.
Primary Objectives
Objective 1: Understand how EHR data are used to facilitate trial recruitment and 
the barriers to that use..
Using site study coordinator surveys, workflow assessment, qualitative analysis of a site-
level enrollment measure, and quantitative comparisons of enrolled patients with 
potentially eligible patients, this objective will enhance understanding of how EHR data 
are used to facilitate clinical trial enrollment at global HARMONY sites with an EHR 
system and who express interest in participating. All global sites with an EHR will be 
invited to participate in the qualitative component – which will occur after main study 
enrollment is complete.  For select sites in the United States, a quantitative analysis will 
be conducted comparing the proportion of eligible patients identified by a computerized 
algorithm to the site’s list of enrolled patients.  Algorithms will be developed based on 
structured data that represent trial inclusion criteria and submitted as a query to a subset 
of select sites with EHR systems that meet certain criteria and have technical capabilities.
Objective 2:  Evaluate the fitness of EHR data for use in populating the baseline 
characteristics in the eCRF
For select sites, the level of agreement between data extracted from the EHR and data 
documented on the baseline eCRF (reference standard) will be evaluated and compared 
among consented participants. This will occur after study completion and within selected 
data areas (e.g., demographics, medical history, concomitant medications). Additionally 
the performance of algorithms developed to identify comorbidities and other clinical 
concepts will be assessed at the site level and aggregated, where appropriate.
Other partnerships in select countries will support comparisons between data extracted 
from existing national-level electronic health data (or administrative claims data) and 
data documented on the baseline eCRF.  
Objective 3:  Explore the use of EHR data to find events of interest during trial 
follow-up 
For select sites, case-finding algorithms will be developed for select specified endpoints 
(e.g., all-cause death, myocardial infarction, stroke, urgent revascularization for unstable 
angina, hospitalization for heart failure) and applied to EHR data. At the conclusion of 
the main HARMONY-Outcomes study, the performance of EHR algorithms will be 
compared with eCRF-reported and adjudicated eCRF-reported events (reference 
standard).
Other partnerships in select countries will support comparisons between data extracted 
from existing national-level electronic health data (or administrative claims data) and 
eCRF reported and adjudicated eCRF-reported events.

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11.7.3.
Ancillary Study design
11.7.3.1.
Study Design
The ancillary study will be conducted in conjunction with the HARMONY-Outcomes 
trial, a randomised, double blind, parallel-group, placebo-masked, controlled study to 
evaluate the effect of albiglutide on cardiovascular events in patients with Type 2 
diabetes. Albiglutide will be administered subcutaneously once weekly in a population of 
patients with Type 2 diabetes and a previous history of cardiovascular disease and who 
do not have optimal glycaemic control. The majority of research activities in the ancillary 
study will take place following the close of the HARMONY Outcomes Trial, with 
specified timelines laid out in objective-specific workplans. Data extracted from the EHR 
for the purpose of the ancillary study will cover the time period from randomization into 
the main HARMONY Outcomes Trial study through the end of that study. Objective 1 
will include a qualitative survey for which all global sites with an EHR who express 
interest in participating will be invited to participate. In select sites, Objective 1 will also 
include the application of a screening algorithm to support the quantitative aspect of the 
analysis. For Objectives 2 and 3, select U.S. sites with specific technical capabilities will 
participate, as well as select countries where relevant national-level electronic health data 
are available and accessible.
11.7.3.2.
Data Flow Strategies – Introduction
The HARMONY EHR ancillary study will utilize two data flows, termed the DataMart 
and National strategies, to gather and analyze data.  The DataMart strategy will support 
work done at select U.S. sites, in order to access electronic health record data from 
patients enrolled in the main HARMONY Outcomes trial at these sites.  This strategy 
encompasses the quantitative section of Objective 1, as well as the entirety of Objectives 
2 and 3.  The National Strategy will support work done with global national partners, in 
order to access national electronic health data for patients enrolled in the main 
HARMONY Outcomes trial.  This strategy will encompass only Objectives 2 and 3.  
More detailed information regarding these strategies can be found below in Section 
11.7.3.4.

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11.7.3.3.
Site Selection
Table 4
HARMONY Outcomes Site and Country Participation by Ancillary 
Study Objective
Objective
Sites
Select Countries
Selected U.S. 
Sites with 
Technical 
Capabilities* 
(DataMart 
Strategy)
Global Sites 
with an 
Implemented 
EHR System 
U.S. 
VA 
Sites
U.S.** and Global 
Partners*** (National 
Strategy)
1: 
Qualitative
X
X
1: 
Quantitative
X
X
2
X
X
X
3
X
X
X
*Technical capabilities include ability to extract data from the EHR and transform to a common data 
format
**The U.S. National Strategy will acquire Medicare Claims data for Medicare beneficiaries enrolled as 
participants in HARMONY Outcomes U.S. sites.  A U.S. site may participate in both the U.S. DataMart 
Strategy and/or the U.S. National Strategy.
***Country selection considerations (dataset): 1) common person-level identifier, or equivalent data that 
can be used to link consented trial participants with national-level data  2) coverage of ~100% of defined 
population, and 3) availability of EHR events of interest
Objective 1 – Qualitative Site Selection
All HARMONY Outcomes sites (global) with an EHR will be invited to participate in the 
qualitative survey of Objective 1 of the ancillary study.
Objectives 1 (Quantitative), 2, 3 – Technical Site Selection in the DataMart Strategy
As part of the overall site selection process for the HARMONY Outcomes Trial, potential 
U.S. sites completed a feasibility survey to gauge their interest and suitability for 
participation in the technical components of the EHR Ancillary Study (ability to extract 
data from the EHR and transform to a common data format). The surveys included 
questions regarding experience with long-term outcome trials in general and specific
features of the planned trial. 
Key criteria used for selection of participating US sites for the technical components of 
Objectives 1 (Quantitative), 2, and 3 of the EHR-Ancillary Study include: 
•
Existence of an EHR 
•
Types of information currently contained in EHR;

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•
Current capability to extract EHR-type data from a data warehouse;
•
Institutional processes and policies for using EHR-type data for clinical research; 
•
Institutional experience extracting, transforming, and loading warehouse data into
a research DataMart that conforms with standardized specifications; and
•
Access to an enterprise data warehouse or clinical data repository that stores 
structured data from the EHR and is updated at least weekly.
•
Engagement of health system IT and analytical personnel
Objectives 2 and 3 – Technical National Partner Selection in the National Strategy
In select countries (Denmark, U.K. (England and Scotland), Sweden, Norway, and the 
United States), national partners will be asked to access existing national-level data 
sources to address Objectives 2 and 3. Key criteria used for the selection of participating 
countries include: 
•
Existence of an electronic health data source that covers either all of the national 
population or a defined population;
•
Availability of a common person level identifier(s) or equivalent data that can be 
used to link consented trial participants with national-level data;
•
Timely availability of information that can define the EHR events of interest (e.g. 
inpatient encounters and diagnoses, death or transfer out of population);  
•
An academic collaborator who has access and experience with the ethical, 
regulatory and technical requirements of using the data source
11.7.3.4.
Data Flows
Qualitative Data Sources (Objective 1)
Objective 1 will survey study coordinators to obtain information on trial enrollment 
workflows, with a focus on how EHR systems are routinely used in the screening 
process, and what works best to facilitate this process. This objective will collect primary 
data through qualitative surveys and focus groups with study coordinators from 
participating sites to identify best practices and barriers to the use of EHR data for trial 
screening and enrolment. 
First, a topic guide will be developed and tested with a small number of study 
coordinators to identify major survey themes. After revising and finalizing the guide, 
Webex focus groups will be conducted with coordinators to identify other relevant 
content. A report of findings will be generated based on a systematic analysis of the focus 
groups. A qualitative survey will then be developed based on topic guide testing, focus 
group report and feedback from survey experts and GSK team. The survey will be 
administered to study coordinators at participating sites.  Survey data will then be 
analysed and a data report will be generated. 

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We will also conduct a qualitative assessment of enrollment “funnels” at the site level, 
where enrollment funnel is defined as the process by which the population of potentially 
eligible participants is narrowed to the final enrolled study population. This qualitative 
assessment will focus on reasons for non-enrollment among eligible patients at the site 
level. Each site will report the criteria used to generate the list of potentially eligible trial 
participants so that we can describe where the enrollment funnel begins and how it is 
narrowed down from potentially eligible subjects to those enrolled in the trial.
DataMart Strategy Data Flows (Objectives 1 [Quantitative], 2, and 3)
For the analyses based on technical components in Objectives 1, 2, and 3, select sites 
with technical capabilities participating in the EHR Ancillary Study will be required to 
convert relevant patient data from their EHR system into a Research DataMart, based on 
a common data model. A common data model standardizes the definition, content and 
format of data across sites to enable a single standardized view that can be used for 
querying. This is essential since EHR data are stored in different ways at different sites. 
The common data model for the ancillary study will be adapted from the PCORnet 
Common Data Model and may include the following data areas: demographics, 
encounters, diagnoses, procedures, and selected laboratory results. The study site’s EHR 
system will not be changed and will continue to operate as implemented. The Research 
DataMart includes Protected Health Information (PHI) and will remain behind 
institutional firewalls.
The methods for extracting useful information from the Research Datamart will require a 
partnership between study site teams (site principal investigator, site study coordinator, 
and site technical support), GSK, and the DCRI Data Management Team. The study will 
utilize secure mechanisms to distribute queries to participating sites and receive results.  
Many sites will use Aqueduct, a software application that enables the creation, operation, 
and governance of research networks.  It allows partners to maintain physical and 
operational control over their data while allowing authorized users to send queries to the 
data. 
The DCRI Data Management Team will distribute code that extracts and returns data for 
randomized participants from the Research DataMart. These data from randomized 
participants across all participating sites will make up a subset of the EHR Ancillary 
study dataset. 
Required data elements of interest regarding baseline demographics and outcome events 
from the main HARMONY trial dataset will be transferred from GSK to DCRI after the 
completion of the study. DCRI will merge these data elements with the datamart EHR 
Ancillary study dataset.
National Strategy Data Flows (Objective 2 and 3)
Similarly, Objectives 2 and 3, as applied on the national level, will compare baseline 
characteristics and outcomes ascertained from the main HARMONY trial dataset with 
data from national electronic health data. However, the methods to access, extract and 
transfer data will be adapted to each participating country and will be guided by the 
expertise of the academic collaborator. Country specific methods will be used to 1) 

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access national-level electronic health data (for example, Medicare data in the U.S.), 2) 
use patient level identifier(s) to link HARMONY trial participants, and 3) transfer de-
identified patient-level national electronic health data to DCRI to create the National 
Strategy EHR ancillary dataset and compare data elements of interest regarding baseline 
demographics and outcome events from the main HARMONY trial dataset.  The final 
analysis dataset will be constructed after the end of the main HARMONY Outcomes trial 
and the data latency period, which is defined as the delay from the initial generation of 
EHR data or claims files to the availability of an analysis-ready dataset.
11.7.4.
DATA ANALYSIS
11.7.4.1.
Sample Size Expectations
The objectives of this ancillary study are exploratory (not confirmatory) in nature and not 
intended to be sufficiently powered to confirm a pre-determined level of sensitivity and 
specificity.  The qualitative portion of Objective 1 will be open to participation from any 
interested Global site with an EHR. The technical components (datamarts) of Objectives 
1, 2, and 3 of the ancillary study will target recruitment of ~7 U.S. sites, each recruiting 
12-15 subjects, to support the study aims.  The DataMart strategy will also utilize 
approximately 8 U.S. VA sites. The datasets generated using country-specific data for 
Objectives 2 and 3 are intended to include all randomized participants across 
HARMONY sites in each participating country.
11.7.4.2.
General Analytic Approach
In Objective 1, the proportion of eligible patients identified by the computerized 
algorithm will be compared to the list of enrolled patients at participating sites. The goals 
of Objectives 2 and 3 involve evaluating the performance of algorithms that map EHR-
based data into concepts present in the clinical trial dataset.  Algorithms will be informed 
by general and therapeutic area-specific data standards, including the standards efforts of 
professional societies. Baseline characteristics and study endpoints in the ancillary study 
dataset will be defined using diagnosis codes and procedure codes.  Published algorithms 
will be used whenever possible and these algorithms will be updated as necessary to 
account for coding changes since publication. The actual measures recorded in the
clinical trial dataset will be considered the reference standard against which these 
measures based on technical components are compared. 
For Objective 2, the performance of algorithms used to identify baseline characteristics 
will be evaluated. For Objective 3, the performance of algorithms used to identify trial 
events will be evaluated. Performance metrics will be calculated by site as well as across 
all sites.  Within the national data used for Objectives 2 and 3, all performance metrics 
will be calculated by country as well as across all countries.

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References
Barry SJ, Dinnett E, Kean S, Gaw A, Ford I. Are routinely collected NHS administrative 
records suitable for endpoint identification in clinical trials? Evidence from the West of 
Scotland Coronary Prevention Study. PloS one. 2013; 8(9):e75379.
Curtis LH, Brown J, Platt R. Four Health Data Networks Illustrate The Potential For A 
Shared National Multipurpose Big-Data Network. Health Affairs. July 1, 2014; 
33(7):1178-1186.
Dregan A, van Staa TP, McDermott L, et al. Point-of-Care Cluster Randomized Trial in 
Stroke Secondary Prevention Using Electronic Health Records. Stroke. July 1, 2014; 
45(7):2066-2071.
Etheredge LM. A rapid-learning health system. Health affairs. Mar-Apr 2007; 
26(2):w107-118.
Fleurence RL, Beal AC, Sheridan SE, Johnson LB, Selby JV. Patient-Powered Research 
Networks Aim To Improve Patient Care And Health Research. Health Affairs. July 1, 
2014; 33(7):1212-1219.
Greene SM, Reid RJ, Larson EB. Implementing the learning health system: from concept 
to action. Annals of internal medicine. Aug 7 2012;157(3):207-210.
Gulliford MC, van Staa T, Dregan A, et al. Electronic Health Records for Intervention 
Research: A Cluster Randomized Trial to Reduce Antibiotic Prescribing in Primary Care 
(eCRT Study). The Annals of Family Medicine. July 1, 2014; 12(4):344-351.
NHLBI Working Group on Electronic Health Records: Research Priorities to Improve 
Cardiopulmonary Health in Clinical Practice. 2011. 
http://www.nhlbi.nih.gov/meetings/workshops/ehr.htm. Accessed Jan 28, 2013.
Richesson RL, Hammond WE, Nahm M, et al. Electronic health records based 
phenotyping in next-generation clinical trials: a perspective from the NIH Health Care 
Systems Collaboratory. Journal of the American Medical Informatics Association: 
JAMIA. Dec 2013; 20(e2):e226-231.
Toh S, Reichman ME, Houstoun M, et al. COmparative risk for angioedema associated 
with the use of drugs that target the renin-angiotensin-aldosterone system. Archives of 
Internal Medicine. 2012; 172(20):1582-1589.
van Staa T, Dyson L, McCann G, et al. The opportunities and challenges of pragmatic 
point-of-care randomised trials using routinely collected electronic records: evaluations 
of two exemplar trials. Health Technol Assess. 2014/07/11 2014; 18(43).

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11.8.
Appendix 8: Country Specific Requirements

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11.9.
Appendix 9: Protocol Amendment Changes
11.9.1.
Changes Resulting from Protocol Amendment 1
This amendment is applicable to all participating countries.
Summary of Changes
1. Correction of typographical error in Exclusion criterion 7.
2. Clarification wording added to the description of when subjects should have 
telephone follow-up after discontinuing investigational product (IP).  Subjects 
should have the telephone follow-up 5 1 weeks after their last dose of IP 
whether they had continued IP through to the Final study visit, or discontinued 
before the Final study visit.
3. Time and Event Table modified to add adverse event checking (SAE, AEs of 
special interest, AEs leading to IP discontinuation) to dose adjustment visits, and 
to correct footnote assignment/typographical errors.
4. Revision of terminology used to describe unstable angina events referred for CEC 
adjudication to correctly reflect review process to be adopted by CEC.
5. Addition of Country Specific Requirements appendix (Appendix 8).
List of Specific Changes
Section 4.2, Exclusion criteria; criterion 7, fourth sentence.
Original text:
Women who have developed spontaneous secondary amenorrhoea of 12 months or more 
where post-menopausal status is in doubt, a blood sample where FSH >40MU/ml and 
oestrodiol <40 pg/mL (<14 pmol/L) are simultaneously measured will be considered 
confirmatory.
Amended text:
Women who have developed spontaneous secondary amenorrhoea of 12 months or more 
where post-menopausal status is in doubt, a blood sample where FSH >40MU/ml and 
oestrodiol <40 pg/mL (<140 pmol/L) are simultaneously measured will be considered 
confirmatory.

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Section 4.5 Procedures for Subject Follow-up
Original text:
As described in Section 4.4, subjects who permanently discontinue investigational 
product will be asked to attend the clinic as soon as possible.  They will continue in the 
study for follow-up. They will be asked to return to clinic according to the 8 monthly 
visit schedule and in addition be contacted by telephone at a time corresponding to the 4-
monthly visit they would have otherwise made to replenish study medication supply.  If 
instead of these interim telephone contacts the subject prefers to attend clinic every 4 
months as originally scheduled that is an acceptable alternative.
Amended text:
As described in Section 4.4, subjects who permanently discontinue investigational 
product will be asked to attend the clinic as soon as possible.  They will continue in the 
study for follow-up. Five weeks (1 week) after discontinuation of investigational 
product, subjects will be contacted for a follow-up by telephone.  They will be asked to 
return to clinic according to the 8 monthly visit schedule and in addition be contacted by 
telephone at a time corresponding to the 4-monthly visit they would have otherwise made 
to replenish study medication supply.  If instead of these interim telephone contacts the 
subject prefers to attend clinic every 4 months as originally scheduled that is an 
acceptable alternative.

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Table 1 Time and Events Table
Original text:
Procedures1,2
Screening2
Randomization3
/Baseline 
(can be same day 
as Screening 
Visit)
Study Drug 
Check Phone 
Call
(4-6 wks post 
and.)
Clinic Visit Month 4 
18 days then 
every 8 months 
18 days throughout 
the study
Unscheduled 
dose 
adjustment 
visit
(if warranted)
Clinic Visit Month 8 
18 days then 
every 8 months 
18 days throughout 
the study
Final study 
clinic 
visit4 (or 
early 
withdrawal)
Post-Study Follow up 
Phone Call
5 1 weeks after last 
IP dose
SAEs, AEs of special interest, AEs
leading to IP discontinuation 
X
X
X
X
X
X
1.    Subjects who discontinue investigational product should be handled as described in Section 4.4.
11.  Study drug dispensing not performed at final visit, compliance check not performed at Screening.
Amended text:
Procedures1,2
Screening3
Randomization3
/Baseline 
(can be same day 
as Screening 
Visit)
Study Drug 
Check Phone 
Call
(4-6 wks post 
rand.)
Clinic Visit Month 4 
18 days then 
every 8 months 
18 days throughout 
the study
Unscheduled 
dose 
adjustment 
visit
(if warranted)
Clinic Visit Month 8 
18 days then 
every 8 months 
18 days throughout 
the study
Final study 
clinic 
visit4 (or 
early 
withdrawal)
Post-Study Follow up 
Phone Call
5 1 weeks after last 
IP dose
SAEs, AEs of special interest, AEs 
leading to IP discontinuation 
X
X
X
X
X
X
X
1.    Subjects who discontinue investigational product should be handled as described in Section 4.4 and Section 4.5.
11.  Study drug dispensing not performed at final visit, compliance check not performed at Randomisation.

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Section 6.2.1 Cardiovascular Events
Original text:
The CEC will review and adjudicate the following clinical events:
Myocardial infarction
Stroke
Unstable angina requiring revascularization
Hospitalization for heart failure
Sudden cardiac death
TIA
In addition, all clinical events submitted for adjudication and all other SAEs with a fatal 
outcome will be reviewed and adjudicated to classify the cause of death as cardiovascular 
or non-cardiovascular.
Amended text:
The CEC will review and adjudicate the following clinical events:
Myocardial infarction
Stroke
Unstable angina requiring hospitalization
Hospitalization for heart failure
Sudden cardiac death
TIA
In addition, all clinical events submitted for adjudication and all other SAEs with a fatal 
outcome will be reviewed and adjudicated to classify the cause of death as cardiovascular 
or non-cardiovascular.
Appendix 8 – Country Specific Requirements
Appendix 8 added (not in original text). This is a blank page headed “11.8.Appendix 8: 
Country Specific Requirements” to serve as a placeholder to be replaced by each 
participating GSK Country Medical Department with the appropriate text upon receipt of 
the protocol and before they distribute it further within their country.

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11.9.2.
Changes Resulting from Protocol Amendment 2
This amendment is applicable to all participating countries (with the exception of item 8 
below which is specific to Mexico).
Summary of Changes
1. Amendment to indicate that the study should be considered Phase III in countries 
where albiglutide has not been granted marketing authorisation and Phase IV in 
countries where it has been.
2.
Update to list of protocol authors.
3. Update to Sponsor Medical Monitor Contact Information.
4. Correction of terminology in Treatment Assignment section.
5. Removal of discrepancy between inclusion criterion 4 which wrongly indicates a 
negative serum pregnancy test is required to exclude pregnancy and the Time & 
Event table (Section 6), Section 6.2.6 Clinical Laboratory Assessments, the model 
consent form and the Study Reference Manual (which all correctly indicate that 
the requirement is for a negative urine test).
6. Time and Event Table 1 re-formatted as some investigators had found it 
confusing.
7. Addition of a Time and Event table of assessments to be performed for patients 
permanently discontinuing IP (Table 2).  The visits and telephone contact to be 
performed for patients discontinuing IP had been described in text previously but 
an additional tabular format was recommended to aid investigators.
8. Mexican Ministry of Health requirement to report events referred to CEC by 
Mexican investigators to also be reported to the Ministry as SAEs.
9. Addition of requirement to record lipid results if they are available from subjects’ 
routine clinical care outside of the trial.
10. Clarify that TRIM-D should not be assessed at Baseline in subjects whose 
diabetes is treated by diet and exercise alone.
11. Corrections to Data Analysis and Statistical Considerations Section to make it 
more terminologically correct.
12. Simplification of description of information in Section 8.3.6.4 Other Safety 
Analyses to properly reflect the planned reports.
13. Correction of typographical error in spelling of spermicide.
14. Correction of recipient of faxed SAE reports if the electronic CRF is unavailable. 

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List of Specific Changes
Title Page
Original text:
Development Phase: IV
Amended text:
Development Phase: III/IV
Original text:
Author (s): The protocol was developed by the members of the Executive Committee in 
conjunction with Duke Clinical Research Institute and the Sponsor.
The following individuals provided substantial input during protocol development:
Non-sponsor:
 (Executive Committee Co-Chair); 
 (Executive Committee Co-
Chair); 
Sponsor:
 
Amended text:
Author (s): The protocol was developed by the members of the Executive Committee in 
conjunction with Duke Clinical Research Institute and the Sponsor.
The following individuals provided substantial input during protocol development:
Non-sponsor:
 
(Executive Committee Co-Chair); 
 
(Executive Committee Co-Chair); 
Sponsor:
 
Sponsor Information Page, Sponsor Medical Monitor Contact Information
Original text:
Sponsor Medical Monitor Contact Information: 
Dr 
2301 Renaissance Boulevard
REN0410
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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King of Prussia, Pennsylvania 19406, USA
Email: 
 
Fax: 
Telephone number: Office: 
                                Cell: 
 
                                Out of hours: 
Amended text:
Sponsor Medical Monitor Contact Information: 
Dr 
2301 Renaissance Boulevard
REN0410
King of Prussia, Pennsylvania 19406, USA
Email: 
Fax: 
 
Telephone number: Office: 
                                Cell: 
 
                                Out of hours: 
List of Abbreviations
Original text:
Did not include the abbreviations added in amendment.
Amended text:
HDLc
high density lipoprotein cholesterol
LDLc
low density lipoprotein cholesterol
Tg
triglycerides
TC
total cholesterol
Section 3.1 Overall Design, first paragraph
Original text:
This is a Phase IV, randomised, double blind, parallel-group, placebo-controlled, 
multicentre study.
Amended text:
This is a Phase IV, randomised, double blind, parallel-group, placebo-controlled, 
multicentre study.  In countries where marketing authorization has been granted to 
albiglutide for the treatment of type 2 diabetes it is classified as a Phase IV study, 
elsewhere is should be considered to be a Phase III study.
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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Section 4.1 Inclusion Criteria; criterion 4, first sentence
Original text:
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:
Amended text:
Female: subject is eligible to participate if she is not pregnant (as confirmed by a negative 
serum urine human chorionic gonadotrophin (hCG) test for females of reproductive 
potential only), not breastfeeding, and at least one of the following conditions applies:
Section 5.2 Treatment Assignment; final paragraph
Original text:
Blinded study centre personnel will receive a randomisation notification indicating only 
the unique subject identifier and the date and time of randomisation. 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 investigational product. 
Details of the treatment assignment process are contained in the SRM.
Amended text:
Blinded study centre personnel will receive a randomisation notification indicating only
the unique subject identifier (randomisation number) and the date and time of 
randomisation. Each randomisation subject number will be a unique identifier. Once a 
randomisation subject number has been assigned, the number will not be reused even if 
the subject withdraws before receiving any investigational product. Details of the 
treatment assignment process are contained in the SRM.

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Table 1 Time and Events Table
Original text:
Procedures1,2
Screening3 Randomization3
/Baseline 
(can be same day 
as Screening 
Visit)
Study Drug 
Check Phone 
Call
(4-6 wks post 
rand.)
Clinic Visit Month 4 
18 days then 
every 8 months 
18 days throughout 
the study
Unscheduled 
dose 
adjustment 
visit
(if warranted)
Clinic Visit Month 8 
18 days then 
every 8 months 
18 days throughout 
the study
Final study 
clinic 
visit4 (or 
early 
withdrawal)
Follow up Phone Call
5 1 weeks after last 
IP dose
Written informed consent  
X
Review of Inc/excl criteria
X
X
Demography & directed medical history
X
Assessment of MACE  and micro-vascular 
events
X
X
X
HbA1c
X5
X
X
X
Serum creatinine (eGFR)
X5
X
X
Liver Function Tests6
X
X
X
Genetic sampling7
X
Patient reported outcomes questionnaires8
X
X
X
Key concomitant non-diabetes medication
X
X
X
X
X
Diabetes medication
X
X
X
X
X
Study drug reminder
X
X
X
X
Physical examination9
X
X
X
SAEs, AEs of special interest, AEs leading 
to IP discontinuation 
X
X
X
X
X
X
X
Pregnancy test10
X
X
Study drug dispense/compliance11
X
X
X
X
X
1.
Subjects who discontinue investigational product should be handled as described in Section 4.4 and Section 4.5. 
2.
Assessments per the Month 4 visit will alternate with those per the Month 8 visit throughout the study i.e., assessments at months 4, 12, 20 etc will be per Month 4; those at month 
8, 16, 24 etc..will be per Month 8.
3.
Screening and Randomisation can occur at the same visit if all eligibility information is available. If Screening and Randomisation occur at the same visit assessments should not 
be duplicated.
4.
Once it is projected that the target number of MACE events will have been collected, a 3 month window will be defined for conducting the final, face to face visit.
5.
HbA1c and creatinine assessed using local laboratories at Screening visit and measured no more than 6 months prior to randomisation. If HbA1c or creatinine have not been 
assessed in the previous 6 months assessments to be performed via a central laboratory and results available prior to randomization. The investigator has the discretion to repeat 

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screening HbA1c, and/or creatinine, based on clinical rationale even if previously available local results meet the eligibility criteria to allow the investigator to accommodate the 
possibility of change between screening and randomisation.
6.
Liver function tests: ALT, AST, alkaline phosphatase, bilirubin, GGT. Blood samples for LFTs at randomization must be collected prior to the first dose of investigational product.
7.
Informed consent for genetic research must be obtained before collecting a sample.  Genetics sample can be collected at any time after genetic consent has been obtained and 
the subject has beenr randomised.
8.
TRIM-D, EQ-5D and study specific questionnaire (details in Section 6.3).
9.
See Section 6.2.7.  
10. Only applies to women of child bearing potential. At screening perform urine pregnancy test.  If positive, send serum sample to the central laboratory for confirmation. At 
Randomisation perform a urine pregnancy test. If result is positive do not randomize the subject. If the urine pregnancy test is negative then the subject can be randomised. If 
Screening and Randomisation are to take place at the same visit then follow the instructions for Screening. See Section 6.2.6.
11. Study drug dispensing not performed at final visit, compliance check not performed at Randomisation
Amended text:
Procedures1,2
Screening3
Randomization3
/Baseline 
(can be same day as 
Screening Visit)
Study Drug 
Check 
Phone Call
(4-6 wks post 
rand.)
Clinic Visit Month 4 
18 days then 
every 8 4 months 
18 days 
throughout the 
study
Unscheduled 
dose 
adjustment visit
(if warranted)
Clinic Visit 
Month 8 18 
days then every 
8 months 18 
days throughout 
the study
Final study 
clinic 
visit4 (or early 
withdrawal)
Follow up 
Phone Call
5 1 weeks 
after last IP 
dose
Written informed consent  
X
Review of Inc/excl criteria
X
X
Demography & directed medical history
X
Assessment of MACE  and micro-vascular 
events
X
X
X
HbA1c
X5
X
X
X
Serum creatinine (eGFR)
X5
X (alternate visits) 
2
X
X
Liver Function Tests (LFTs)6
X
X (alternate visits) 
2
X
X
Record available information on most 
recent lipid assessment7
X
X (annually)
X
Genetic sampling78
X
Patient reported outcomes questionnaires89
X10
X (alternate visits) 
2
X
X
Key concomitant non-diabetes medication
X
X
X
X
X

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Procedures1,2
Screening3
Randomization3
/Baseline 
(can be same day as 
Screening Visit)
Study Drug 
Check 
Phone Call
(4-6 wks post 
rand.)
Clinic Visit Month 4 
18 days then 
every 8 4 months 
18 days 
throughout the 
study
Unscheduled 
dose 
adjustment visit
(if warranted)
Clinic Visit 
Month 8 18 
days then every 
8 months 18 
days throughout 
the study
Final study 
clinic 
visit4 (or early 
withdrawal)
Follow up 
Phone Call
5 1 weeks 
after last IP 
dose
Diabetes medication
X
X
X
X
X
Study drug reminder
X
X
X
X
Physical examination911
X
X (alternate visits) 
2
X
X
SAEs, AEs of special interest, AEs leading to 
IP discontinuation 
X
X
X
X
X
X
X
Pregnancy test1012
X
X
Study drug dispense/compliance1113
X
X
X
X
X
1.
Subjects who discontinue investigational product should be handled as described in Section 4.4 and Section 4.5 and in Table 2. 
2.
Assessments per the Month 4 visit will alternate with those per the Month 8 visit throughout the study i.e., assessments at months 4, 12, 20 etc will be per Month 4; those at month 
8, 16, 24 etc..will be per Month 8.Assessments at month 8, 16, 24 etc. will include patient reported outcomes questionnaires, serum creatinine (eGFR), liver function 
tests and physical examination. Those at months 4, 12, 20 etc do not.
3.
Screening and Randomisation can occur at the same visit if all eligibility information is available. If Screening and Randomisation occur at the same visit assessments should not 
be duplicated.
4.
Once it is projected that the target number of MACE events will have been collected, a 3 month window will be defined for conducting the final, face to face visit.
5.
HbA1c and creatinine assessed using local laboratories at Screening visit and measured no more than 6 months prior to randomisation. If HbA1c or creatinine have not been 
assessed in the previous 6 months assessments to be performed via a central laboratory and results available prior to randomization. The investigator has the discretion to repeat 
screening HbA1c, and/or creatinine, based on clinical rationale even if previously available local results meet the eligibility criteria to allow the investigator to accommodate the 
possibility of change between screening and randomisation.
6.
Liver function tests: ALT, AST, alkaline phosphatase, bilirubin, GGT. Blood samples for LFTs at randomization must be collected prior to the first dose of investigational product.
7.
Lipid values (TC, LDLc, HDLc, Tg) to be recorded as available from routine clinical care at baseline and annually thereafter. If results are unavailable, lipid tests are 
not to be performed for the study.
8.
Informed consent for genetic research must be obtained before collecting a sample.  Genetics sampleThis can be collected at any time after genetic consent has been obtained 
and the subject has been randomisdrandomisation has occurred.
9.
TRIM-D, EQ-5D and study specific questionnaire (details in Section 6.3).
10. TRIM-D is not required for subjects whose diabetes is treated by diet and exercise alone at Baseline.
11. See Section 6.2.7.  
12. Only applies to women of child bearing potential. At screening perform urine pregnancy test.  If positive, send serum sample to the central laboratory for confirmation. At 
Randomisation perform a urine pregnancy test. If result is positive do not randomize the subject. If the urine pregnancy test is negative then the subject can be randomised. If 
Screening and Randomisation are to take place at the same visit then follow the instructions for Screening. See Section 6.2.6.
13. Study drug dispensing not performed at final visit, compliance check not performed at Randomisation

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Section 6 Study Assessments and Procedures; insertion of the following table after Table 1
Table 2
Time and Events Table for Subjects Who Permanently Discontinue IP Prior to the End of the Study
Procedures
Clinic visit as soon 
after permanent 
discontinuation of IP 
as possible
Phone Call
5 1 week after 
last IP dose
Continue contact schedule 
established at randomisation 
4 monthly 1 month. 
Telephone 1,2
Continue contact schedule 
established at randomisation 
4 monthly 1 month. 
Clinic visit 1,3
Final study clinic 
visit 4
Assessment of MACE  and micro-vascular events
X
X
X
X
HbA1c
X
X
X
Serum creatinine (eGFR)
X
X
X
Liver Function Tests (LFTs)5
X
X
X
Record available information on most recent lipid 
assessment6
X
X (annually)
X (annually)
X
Patient reported outcomes questionnaire7
X
Key concomitant non-diabetes medication
X
X
X
X
X
Diabetes medication
X
X
X
X
X
Physical examination8
X
X
X
AEs leading to IP discontinuation
X
SAEs, AEs of special interest, 
X
X
X
X
X
Study drug compliance
X
1. After subjects permanently discontinue IP, follow-up should continue on the 4-monthly schedule established at randomisation.
2. Where a subject would have been scheduled to attend clinic at months 4, 12, 20, 28 etc after randomisation, a telephone contact will be performed instead (with assessments as 
shown above).
3. Where a subject would have been scheduled to attend clinic at months 8, 16, 24, 32 etc after randomisation, a clinic visit will be performed (with assessments as shown above).
If a subject who has permanently discontinued IP is unable to attend clinic then they will be contacted by telephone instead and the telephone contact assessments will be 
performed.
4. Once it is projected that the target number of MACE events will have been collected, a 3 month window will be defined for conducting the final, face to face visit.
5. Liver function tests: ALT, AST, alkaline phosphatase, bilirubin, GGT.
6. Lipid values (TC, LDLc, HDLc, Tg) to be recorded as available from routine clinical care annually. If results are unavailable, lipids tests are not to be performed for the study.
7. TRIM-D, EQ-5D and study specific questionnaire (details in Section 6.3).
8. See Section 6.2.7.  

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Section 6.2.1 Cardiovascular Events; footnote added to end of first sentence.
Original text:
Events referred to the CEC by the investigator as potential endpoints or transient 
ischemic attacks (TIAs) will not be collected or reported as SAEs, regardless of the 
adjudication outcome (Section 6.2.2).
Amended text:
Events referred to the CEC by the investigator as potential endpoints or transient 
ischemic attacks (TIAs) will not be collected or reported as SAEs, regardless of the 
adjudication outcome (Section 6.2.2).1
Footnote:
1 There is one exception to this statement. Per requirement of the Mexican Ministry of 
Health, all events referred to the CEC by Mexican investigators will also be submitted 
as SAEs to the Mexican Ministry of Health.
Section 6.2.6 Clinical Laboratory Assessments; text to be inserted at end of sub-section
Lipids
Where serum lipid tests have been performed as part of the subject’s routine clinical 
care (i.e. not as a study procedure) the most recent results should be recorded at 
baseline and annually thereafter.  The lipid parameters to be recorded are total 
cholesterol (TC), low density lipoprotein cholesterol (LDLc), high density lipoprotein 
(HDLc) and triglycerides (Tg).
If any or all of these results are not already available from the subject’s records then 
separate lipid tests should not be performed solely for the study.
Section 6.3.1.1. Treatment Related Impact Measure – Diabetes (TRIM-D)
Original Text:
In order to evaluate satisfaction with treatment and to compare satisfaction across 
treatment groups, the TRIM-D questionnaire will be self administered by all subjects at 
baseline and at each 8 month visit (and, to the extent possible, at the time of study 
completion or withdrawal from the study).
Amended Text:
In order to evaluate satisfaction with treatment and to compare satisfaction across 
treatment groups, the TRIM-D questionnaire will be self administered by all subjects at 
baseline (except for subjects whose diabetes is treated by diet and exercise alone) and all 
subjects at each 8 month visit (and, to the extent possible, at the time of study completion 
or withdrawal from the study).

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Section 8.3.3.1 Primary Comparisons of Interest, second sentence
Original text:
The primary endpoint will be the time to the first occurrence of MACE over the full 
duration of the study. A p-value for the primary endpoint will be calculated from a Cox 
regression model with treatment group as the only covariate for the hypotheses described 
in Section 8.1.
Amended text:
The primary endpoint will be the time to the first occurrence of MACE over the full 
duration of the study. A p-value for the primary endpoint will be calculated from a Cox 
Proportional Hazards (PH) regression model with treatment group as the only covariate 
for the hypotheses described in Section 8.1.
Section 8.3.3.2. Other Comparisons of Interest, insertion of two new sentences:
Original text:
For other analyses incidence rates will be presented for binary data and summary 
statistics (mean, median, standard deviation, minimum, and maximum) will be presented 
for continuous data.  Furthermore, summary statistics of change from baseline for HbA1c 
will be presented along with percent of subjects within ranges of clinical interest (e.g., 
HbA1c < 7.0%).
Amended text:
For other analyses incidence rates will be presented for binary data and summary 
statistics (mean, median, standard deviation, minimum, and maximum) will be presented 
for continuous data.  Time to event endpoints will be evaluated via the p-value from a 
Cox PH regression model with treatment as the only covariate.  Furthermore, summary 
statistics of change from baseline for HbA1c will be presented along with percent of 
subjects within ranges of clinical interest (e.g., HbA1c < 7.0%).  Available lipid data will 
be summarized for descriptive purposes.
Section 8.3.6.2. Secondary Endpoint Analysis
Original text:
Composite of the proportion of those achieving good control (HbA1c ≤ 7.0%) AND no 
severe hypoglycaemic incidents AND weight gain <5% at the end of the study would be 
evaluated utilize nonparametric, covariance-adjusted, extended Mantel-Haenszel tests. 
Additional analysis will be provided for scheduled visits. Nominal p-values and 95% CIs 
will be presented for these visits. Time to introduction of prandial insulin in those on 
basal insulin orals anti-hyperglycemic drugs at baseline will be analyzed using PH 
model / log-rank test and KM method similar to the primary endpoint.
Composite of microvascular events will be analyzed using a proportional Cox regression 
model / log-rank test and KM method similar to the primary endpoint.

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Amended text:
Composite of the proportion of those achieving good control (HbA1c ≤ 7.0%) AND no 
severe hypoglycaemic incidents AND weight gain <5% at the end of the study would be 
evaluated utilize nonparametric, covariance-adjusted, extended Mantel-Haenszel tests. 
Additional analysis will be provided for scheduled visits. Nominal p-values and 95% CIs 
will be presented for these visits. Time to introduction of prandial insulin in those on 
basal insulin orals anti-hyperglycemic drugs at baseline will be analyzed using a Cox 
PH model / log-rank test and KM method similar to the primary endpoint.
Composite of microvascular events will be analyzed using a proportional Cox regression 
model / log-rank test and KM method similar to the primary endpoint.
Section 8.3.6.4. Other Safety Analyses, paragraphs 3, 4 and 5.
Original text:
For SAEs, AEs leading to withdrawal  and AEs of special interest occurring after 
discontinuation of investigational product, the number and percentage of subjects , total 
number of events, incidence density and event rate will be presented by treatment group 
and overall at the SOC, High Level Term and Preferred Term (PT) level. Relative Risk 
for each event and its 95% CI will also be presented. The time to first occurrence of the 
specific events and the time of the event with respect to the preceding dose of study 
medication will be summarized.
All cause mortality will be summarized by treatment group and analyzed using PH model 
similarly as the-primary endpoint.
All events sent to CEC (including TIAs) will be grouped by type based on the standard 
MedDRA queries that correspond to cardiovascular and cerebrovascular events. 
Adjudication results will be summarized by event type and treatment group. A by subject 
listing of these events will be generated.  The listing will include seriousness, severity, 
whether event is a reason for early study drug discontinuation or study withdrawal, and 
adjudication results.
Pancreatitis events will be adjudicated by the independent Pancreatitis Adjudication 
Committee. The information for investigator reported pancreatitis events and its 
adjudication results will be provided.
Amended text:
For SAEs, AEs leading to permanent IP withdrawal  and AEs of special interest 
occurring after discontinuation of investigational product, the number and percentage of 
subjects, total number of events, and incidence density and event rate will be presented 
by treatment group and overall at the SOC, High Level Term and Preferred Term (PT) 
level. Relative Risk for each event and its 95% CI willmay also be presented on a 
targeted basis. The time to first occurrence of the specific events and the time of the 
event with respect to the preceding dose of study medication will be summarized.

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All cause mortality will be summarized by treatment group and analyzed using a Cox PH 
model similarly as the primary endpoint.
All events sent to CEC (including TIAs) will be summarized. grouped by type based on 
the standard MedDRA queries that correspond to cardiovascular and cerebrovascular 
events. Adjudication results will be summarized by event type and treatment group. A by 
subject listing of these events will be generated.  The listing will include seriousness, 
severity, whether event is a reason for early study drug discontinuation or study 
withdrawal, and adjudication results.
Pancreatitis events will be adjudicated by the independent Pancreatitis Adjudication 
Committee. The information for investigator reported pancreatitis events and its 
adjudication results will be summarizedprovided.
Section 8.3.6.5 Value Evidence and Outcomes Analyses
Original Text:
TRIM-D total score and score for each domain will be summarized descriptively by 
treatment group and scheduled visit. Score changes from baseline will be compared 
between treatments for each visit by ANCOVA an model.
Amended Text:
TRIM-D total score and score for each domain will be summarized descriptively by 
treatment group and scheduled visit. Score changes from baseline will be compared 
between treatments for each visit by an ANCOVA an model.
Section 11.2  Appendix 2: GSK Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP), final listed item
Original text:
8.
Male condom combined with a female diaphragm, with or without a vaginal 
spermicide (foam, gel, film, cream, or suppository). In the UK it is a country-specific 
requirement of the regulatory authority (Medicines and Healthcare Products 
Regulatory Agency) that a vaginal spermcide be used.
Amended text:
8.
Male condom combined with a female diaphragm, with or without a vaginal 
spermicide (foam, gel, film, cream, or suppository). In the UK it is a country-specific 
requirement of the regulatory authority (Medicines and Healthcare Products 
Regulatory Agency) that a vaginal spermcidespermicide be used.

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Section 11.5.5 Reporting of SAEs to GSK, edit to second bullet, insertion of new third 
bullet
Original text:
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 or the SAE coordinator
Amended text:
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 or the SAE coordinatorsafety 
designee as detailed in the Study Reference Manual
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.

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11.9.3.
Changes Resulting from Protocol Amendment 3
This amendment is applicable to all participating countries (with the exception of item 4
below which includes components specific to the countries listed).
Summary of Changes
1. Addition of requirement that the study achieve a median subject follow up of at least 
1.5 years as well as the sample size derived number of primary endpoints.
2. Specifying that to meet the primary objective of assessing the effect of albiglutide 
with respect to MACE, the primary analysis will be non-inferiority. If the pre-
specified non-inferiority criterion is met then superiority testing will be performed 
with a closed testing procedure.  Previously, superiority testing of MACE was 
considered a secondary endpoint.
3. Removal of multiplicity testing strategy for selected secondary endpoints.
4. Revision of the data collection strategy for the exploratory electronic healthcare 
record ancillary study (Appendix 7) with improved clarity for the planned data flow 
and analytical approach.To be completed.

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List of Specific Changes
Protocol Summary – Objectives/Endpoints
Original text:
Objectives
Endpoints
Primary
To determine whether 
albiglutide is non-inferior 
with respect to MACE 
when added to glycaemic 
standard of care versus 
standard of care alone

Time to first occurrence of MACE (cardiovascular death, 
myocardial infarction,  or stroke) [Non-inferiority]
Secondary
To supplement the primary 
objective by further 
characterization of the 
effects of albiglutide on 
cardiovascular outcomes 

Time to first occurrence of MACE [Superiority](1 see footnote)

Time to first occurrence of the following:

MACE or urgent revascularisation for unstable angina

The individual components of the primary endpoint

Cardiovascular death or hospitalization due to heart failure
To evaluate the effects of 
albiglutide on metabolic 
management of type 2 
diabetes

Time to initiation of insulin of more than 3 months 
duration for those subjects not treated with insulin at 
study start (1 see footnote)

Time to initiation of prandial insulin in those subjects on basal 
insulin at study start

The proportion of subjects achieving glycaemic control 
(HbA1c ≤ 7.0% at final assessment) with no severe 
hypoglycaemic incidents and weight gain <5% of body 
weight (1 see footnote)

The time to first occurrence of a clinically important 
microvascular event (see Section 6.2.4)

Change in glycated haemoglobin (HbA1c)

Change in body weight

Patient reported outcomes from Treatment Related Impact 
Measures-D (TRIM-D)/EQ5D
To evaluate the safety of 
albiglutide

All cause mortality

Non-fatal serious adverse events (SAEs)

Adverse events (AEs) leading to discontinuation of 
investigational product 

AE of special interest (see Section 6.2.3)

Change in estimated glomerular filtration rate (eGFR) 
calculated using Modification of Diet in Renal Disease 
(MDRD) formula

Change in blood pressure and heart rate

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1. If the primary endpoint meets the criteria for non-inferiority, a multiple comparisons adjustment strategy will be 
performed for these 3 secondary endpoints as specified in the Section 8.3.5.
Amended text:
Objectives
Endpoints
Primary
To assess the effect of 
albiglutide with respect to 
MACE when added to 
glycaemic standard of 
care versus standard of 
care alone
Time to first occurrence of MACE (cardiovascular death, 
myocardial infarction,  or stroke) 
The primary analysis will be non-inferiority. If the pre-
specified non-inferiority criterion is met then superiority 
testing will be performed 1 
Secondary
To supplement the primary 
objective by further 
characterization of the 
effects of albiglutide on 
cardiovascular outcomes 

Time to first occurrence of the following:

MACE or urgent revascularisation for unstable angina

The individual components of the primary endpoint

Cardiovascular death or hospitalization due to heart 
failure
To evaluate the effects of 
albiglutide on metabolic 
management of type 2 
diabetes

Time to initiation of insulin of more than 3 months duration 
for those subjects not treated with insulin at study start  

Time to initiation of prandial insulin in those subjects on 
basal insulin at study start

The proportion of subjects achieving glycaemic control 
(HbA1c ≤ 7.0% at final assessment) with no severe 
hypoglycaemic incidents and weight gain <5% of body 
weight  

The time to first occurrence of a clinically important 
microvascular event (see Section 6.2.4)

Change in glycated haemoglobin (HbA1c)

Change in body weight

Patient reported outcomes from Treatment Related Impact 
Measures-D (TRIM-D)/EQ5D
To evaluate the safety of 
albiglutide

All cause mortality

Non-fatal serious adverse events (SAEs)

Adverse events (AEs) leading to discontinuation of 
investigational product 

AE of special interest (see Section 6.2.3)

Change in estimated glomerular filtration rate (eGFR) 
calculated using Modification of Diet in Renal Disease 
(MDRD) formula

Change in blood pressure and heart rate
1. As part of a closed testing procedure and therefore no adjustment will be made to the significance level (see Section 
8.3.5)  

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Protocol Summary – Treatment Arms and Duration
Original text:
The study will be event driven, i.e. follow up will continue until it is projected that 
approximately 611 adjudicated MACE events will have occurred. Consequently, the 
maximum duration of the study for an individual participant is dependent both on the 
time taken for recruitment and the MACE event rate, and is estimated to be between 3 
and 5 years.
Amended text:
The study will continue until it is projected that at least 611 adjudicated MACE events 
will have occurred while requiring that the projected median duration of subject follow-
up be at least 1.5 years. The maximum duration of the study for an individual participant 
is dependent both on the time taken for recruitment and the MACE event rate. If 611 
events are reached before the estimated median duration of subject follow-up is projected 
to be at least 1.5 years, then the study will continue until it is predicted that the median 
subject follow-up time is at least 1.5 years. In that case more than 611 events would 
likely be observed.
Protocol Summary – Analysis
Original text:
The study’s primary question is whether albiglutide is non-inferior by a margin of 1.3 
with respect to its effect on adjudicated MACE, when added to glycaemic standard of 
care, versus standard of care alone. The primary analysis is an Intent-to-Treat (ITT) 
analysis of the time to the first occurrence of MACE using Cox’s Proportional Hazard 
regression.
Amended text:
The study’s primary question is whether albiglutide is non-inferior by a margin of 1.3 
with respect to its effect on adjudicated MACE, when added to glycaemic standard of 
care, versus standard of care alone. If non-inferiority is achieved, then superiority will be 
tested. The primary analysis is an Intent-to-Treat (ITT) analysis of the time to the first 
occurrence of MACE using Cox’s Proportional Hazard regression.

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Section 2. Objectives and Endpoints
Original text:
Objectives
Endpoints
Primary
To determine whether 
albiglutide is non-inferior 
with respect to MACE 
when added to glycaemic 
standard of care versus 
standard of care alone

Time to first occurrence of MACE (cardiovascular death, 
myocardial infarction,  or stroke) [Non-inferiority]
Secondary
To supplement the primary 
objective by further 
characterization of the 
effects of albiglutide on 
cardiovascular outcomes 

Time to first occurrence of MACE [Superiority](1 see footnote)

Time to first occurrence of the following:

MACE or urgent revascularisation for unstable angina

The individual components of the primary endpoint

Cardiovascular death or hospitalization due to heart failure
To evaluate the effects of 
albiglutide on metabolic 
management of type 2 
diabetes

Time to initiation of insulin of more than 3 months 
duration for those subjects not treated with insulin at 
study start (1 see footnote)

Time to initiation of prandial insulin in those subjects on basal 
insulin at study start

The proportion of subjects achieving glycaemic control 
(HbA1c ≤ 7.0% at final assessment) with no severe 
hypoglycaemic incidents and weight gain <5% of body 
weight (1 see footnote)

The time to first occurrence of a clinically important 
microvascular event (see Section 6.2.4)

Change in HbA1c

Change in body weight

Patient reported outcomes from TRIM-D/EQ5D
To evaluate the safety of 
albiglutide

All cause mortality

Non-fatal SAEs

AEs leading to discontinuation of investigational product 

AE of special interest (see Section 6.2.3)

Change in eGFR calculated using MDRD formula

Change in blood pressure and heart rate
Exploratory
To evaluate patient reported 
experience of diabetes 
treatment

Patient reported outcomes from study specific questionnaire
To evaluate (at a subset of 
sites) barriers to using the 

Workflow impact of an EHR-generated list of subjects to 

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Objectives
Endpoints
electronic health record 
(EHR) to facilitate trial 
enrolment and the quality of 
EHR data for use in 
populating baseline 
characteristics and 
identifying events of interest 
during trial follow-up.2
facilitate trial enrolment. 

Concordance, sensitivity, specificity, and accuracy of baseline 
characteristics extracted from the EHR compared with those 
reported on the electronic case report form (eCRF)3

Concordance, sensitivity, specificity, and accuracy of EHR-
identified events compared with study events 3,4
1.
If the primary endpoint meets the criteria for non-inferiority, a multiple comparisons adjustment strategy will 
be performed for these 3 secondary endpoints as specified in the Section 8.3.5.
2.
Details are provided in a separate EHR ancillary study protocol (Appendix 7).  Results from this exploratory 
investigation will be reported separately from the main clinical study report.
3.
Comparison of EHR identified events with study events will be conducted in the same data subset.
4.
Analyses to be undertaken after the main trial results are published.
Amended text:
Objectives
Endpoints
Primary
To assess the effect of  
albiglutide with respect to 
MACE when added to 
glycaemic standard of care 
versus standard of care 
alone
Time to first occurrence of MACE (cardiovascular death, 
myocardial infarction,  or stroke) [Non-inferiority]
The primary analysis will be non-inferiority. If the pre-
specified non-inferiority criterion is met then superiority 
testing will be performed1
Secondary
To supplement the primary 
objective by further 
characterization of the 
effects of albiglutide on 
cardiovascular outcomes 

Time to first occurrence of the following:

MACE or urgent revascularisation for unstable angina

The individual components of the primary endpoint

Cardiovascular death or hospitalization due to heart failure
To evaluate the effects of 
albiglutide on metabolic 
management of type 2 
diabetes

Time to initiation of insulin of more than 3 months duration for 
those subjects not treated with insulin at study start 

Time to initiation of prandial insulin in those subjects on basal 
insulin at study start

The proportion of subjects achieving glycaemic control 
(HbA1c ≤ 7.0% at final assessment) with no severe 
hypoglycaemic incidents and weight gain <5% of body weight

The time to first occurrence of a clinically important 
microvascular event (see Section 6.2.4)

Change in HbA1c

Change in body weight

Patient reported outcomes from TRIM-D/EQ5D

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Objectives
Endpoints
To evaluate the safety of 
albiglutide

All cause mortality

Non-fatal SAEs

AEs leading to discontinuation of investigational product 

AE of special interest (see Section 6.2.3)

Change in eGFR calculated using MDRD formula

Change in blood pressure and heart rate
Exploratory
To evaluate patient reported 
experience of diabetes 
treatment

Patient reported outcomes from study specific questionnaire
To evaluate (at a subset of 
sites) barriers to using the 
electronic health record 
(EHR) to facilitate trial 
enrolment and the quality of 
EHR data for use in 
populating baseline 
characteristics and 
identifying events of interest 
during trial follow-up.2

Workflow impact of an EHR-generated list of subjects to 
facilitate trial enrolment. 

Concordance, sensitivity, specificity, and accuracy of baseline 
characteristics extracted from the EHR compared with those 
reported on the electronic case report form (eCRF)3

Concordance, sensitivity, specificity, and accuracy of EHR-
identified events compared with study events 3,4
1.
As part of a closed testing procedure and therefore no adjustment will be made to the significance level (see 
Section 8.3.5)  
2.
Details are provided in a separate EHR ancillary study protocol (Appendix 7).  Results from this exploratory 
investigation will be reported separately from the main clinical study report.
3.
Comparison of EHR identified events with study events will be conducted in the same data subset.
4.
Analyses to be undertaken after the main trial results are published.
Section 3.1. Overall Design (5th paragraph)
Original text:
The study will be event driven, i.e., follow up will continue until it is projected that 
approximately 611 adjudicated MACE events will have occurred. Consequently, the 
maximum duration of the study for an individual participant is dependent both on the 
time taken for recruitment and the MACE event rate, and is estimated to be between 3 
and 5 years. If the observed rate for MACE is 2.0% or 3.0%, the mean follow-up will be 
3.2 or 2.2 years, respectively.
Amended text:
The study will continue until it is projected that at least 611 adjudicated MACE events 
will have occurred while requiring that the projected median duration of subject follow-
up be at least 1.5 years. The maximum duration of the study for an individual participant 
is dependent both on the time taken for recruitment and the MACE event rate, and was 
originally estimated to be between 3 and 5 years. If the observed rate for MACE is 2.0% 

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or 3.0%, the mean follow-up will be 3.2 or 2.2 years, respectively. If the observed rate for 
MACE is sufficiently high such that the median subject follow-up would be less than 1.5 
years then the study will continue until it is projected that the median follow-up is at least 
1.5 years. In this scenario, the maximum duration of the study for an individual 
participant would be less than the 3 to 5 years originally estimated.
Section 3.3. Discussion of Design (3rd paragraph)
Original text:
The primary cardiovascular comparison will be to assess whether albiglutide is non-
inferior to placebo with respect to time to first MACE. 
Amended text:
The primary cardiovascular comparison will be to assess whether albiglutide is non-
inferior to placebo with respect to time to first MACE. If non-inferiority is established, 
the time to first MACE for albiglutide compared to placebo will be tested for superiority.
Section 6, Table 1, footnote 4
Original text:
4. Once it is projected that the target number of MACE events will have been collected, a 
3 month window will be defined for conducting the final, face to face visit.
Amended text:
4. Once it is projected that the target number of MACE events will have been collected 
and that the estimated projected median duration of subject follow-up is at least 1.5 years, 
a 3 month window will be defined for conducting the final, face to face visit.
Section 6, Table 2, footnote 4
Original text:
4. Once it is projected that the target number of MACE events will have been collected, a 
3 month window will be defined for conducting the final, face to face visit.
Amended text:
4. Once it is projected that the target number of MACE events will have been collected 
and that the estimated projected median duration of subject follow-up is at least 1.5 years, 
a 3 month window will be defined for conducting the final, face to face visit.

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Section 8.1 Hypotheses
Original text:
This trial will examine the following primary question:

Whether albiglutide is non inferior by a margin of 1.3 with respect to its effect on 
adjudicated MACE, when added to glycaemic standard of care, versus standard of 
care alone. Letting λ1 = hazard ratio for time to first MACE for albiglutide vs 
placebo, then:
Null hypothesis: log λ1 ≥ log(1.3)
Alternative hypothesis: log λ1 < log(1.3)
Amended text:
This trial will examine the following primary question:

Whether albiglutide is non inferior by a margin of 1.3 with respect to its effect on 
adjudicated MACE, when added to glycaemic standard of care, versus standard of 
care alone. Letting λ1 = hazard ratio for time to first MACE for albiglutide vs 
placebo, then:
Null hypothesis: log λ1 ≥ log(1.3)
Alternative hypothesis: log λ1 < log(1.3)

If non-inferiority is established, the effect on adjudicated MACE will be tested for 
superiority in a closed testing procedure.  Letting λ1 = hazard ratio for time to first 
MACE for albiglutide vs placebo, then:
Null hypothesis: log λ1 ≥ log(1.0)
Alternative hypothesis: log λ1 < log(1.0)
Section 8.2.1 Sample Size Assumptions (2nd paragraph)
Original text:
The power for MACE non-inferiority is calculated via the asymptotic variance and 
normality of the maximum likelihood estimator for the log-hazard ratio. Assuming a true 
hazard ratio of 1.0, 611 events will be needed to have 90% power to rule out non-
inferiority margin of 1.3 for the hazard ratio with type I error of 0.05.  The study duration 
will be event-driven.  A total of 9400 subjects will be enrolled and followed until it is 
projected that approximately 611 adjudicated MACE events will have occurred. If the 
observed rate for MACE is 2.0% or 3.0%, the mean follow-up will be 3.2 or 2.2 years 
respectively, assuming that the number of subjects lost to follow-up accounts for 1% or 
less.

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Amended text:
The power for MACE non-inferiority is calculated via the asymptotic variance and 
normality of the maximum likelihood estimator for the log-hazard ratio. Assuming a true 
hazard ratio of 1.0, 611 events will be needed to have 90% power to rule out non-
inferiority margin of 1.3 for the hazard ratio with type I error of 0.05.  A total of 9400 
subjects will be enrolled and followed until it is projected that approximately 611 
adjudicated MACE events will have occurred and the median duration of subject follow-
up is estimated to be at least 1.5 years. If, for example, the observed rate for MACE is 
2.0% or 3.0%, the mean follow-up will be 3.2 or 2.2 years respectively, assuming that the 
number of subjects lost to follow-up accounts for 1% or less.
Section 8.2.2 Sample Size Sensitivity for MACE non-inferiority
Original text:
9400 subjects will be enrolled to cumulate the first MACE events experienced by 611 
unique subjects. The study duration may vary depending on actual MACE event rate and 
duration of enrolment period.
Table 3
Total Study Duration Sensitivity for Varying MACE Event Rate and 
Duration of Recruitment
Duration of recruitment
1.5 yrs
2.0 yrs
2.5 yrs
3.0 yrs
MACE rate (% pa)
2.0
4.1yrs
4.4yrs
4.6yrs
4.9yrs
2.5
3.4 yrs
3.7yrs
3.9yrs
4.2yrs
3.0
3.0yrs
3.2yrs
3.5yrs
3.8yrs
3.5
2.7yrs
2.9yrs
3.2yrs
3.4yrs
Amended text:
9400 subjects will be enrolled to cumulate the first MACE events experienced by 611 
unique subjects. The study duration may vary depending on actual MACE event rate and 
duration of enrolment period. If the estimated median duration of subject follow-up is 
less than 1.5 years at the time that 611 events have occurred then study will continue until 
it is estimated that the median duration of subject follow-up is at least 1.5 years.

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Table 3
Indicative* Total Study Duration Sensitivity for Varying MACE Event 
Rate and Duration of Recruitment
Duration of recruitment
1.5 yrs
2.0 yrs
2.5 yrs
3.0 yrs
MACE rate (% pa)
2.0
4.1yrs
4.4yrs
4.6yrs
4.9yrs
2.5
3.4 yrs
3.7yrs
3.9yrs
4.2yrs
3.0
3.0yrs
3.2yrs
3.5yrs
3.8yrs
3.5
2.7yrs
2.9yrs
3.2yrs
3.4yrs
* Although indicative, other scenarios are possible
Section 8.2.3 Sample Size Re-estimation
Original text:
The aggregate blinded event-rate data will be periodically reviewed by the Executive 
Committee and the sponsor. The study has an event-driven design. Should emerging data 
diverge significantly from protocol assumptions, the total sample size and/or follow up 
time may be adjusted, within the bounds of feasibility, to achieve the event target.
Amended text:
The aggregate blinded event-rate data will be periodically reviewed by the Executive 
Committee and the sponsor. The study has an event-driven design and also requires that 
the projected median duration of subject follow up be at least 1.5 years. Should emerging 
data diverge significantly from protocol assumptions, the total sample size and/or follow 
up time may be adjusted, within the bounds of feasibility, to achieve the event target.
Section 8.3.3.1 Primary Comparisons of Interest
Original text:
The primary endpoint will be the time to the first occurrence of MACE over the full 
duration of the study. A p-value for the primary endpoint will be calculated from a Cox 
Proportional Hazards (PH) regression model with treatment group as the only covariate 
for the hypotheses described in Section 8.1.
The primary endpoint will be the time to the first occurrence of MACE over the full 
duration of the study. A p-value for non-inferiority of the primary endpoint will be 
calculated from a Cox Proportional Hazards (PH) regression model with treatment group 

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as the only covariate for the hypotheses described in Section 8.1. If non-inferiority is 
established, a p-value for superiority for the primary endpoint will be calculated from a 
Cox Proportional Hazards (PH) regression model with treatment group as the only 
covariate for the hypotheses described in Section 8.1.
Section 8.3.5 Multiplicity Controls
Original text from start of 8.3.5 to before “Other Secondary Endpoints and Subgroup 
Analysis”, including diagram deleted and replaced with:
Amended text:
If non-inferiority is established for the primary endpoint, the data will be used to test for 
evidence of superiority. This approach is a closed testing procedure, and therefore, no 
adjustment for multiplicity is required [Hung 2009].
Section 8.3.5 Multiplicity Controls (Other Secondary Endpoints and Subgroup Analysis)
Original text:
Other Secondary Endpoints and Subgroup Analysis
The following secondary endpoints will provide supportive evidence for cardiovascular 
safety and will not use any multiplicity adjustment procedure. 

Components of primary endpoint (MACE = cardiovascular death, MI, stroke)

MACE + urgent revascularisation for unstable angina

Cardiovascular death or hospitalisation for heart failure
Other secondary endpoints which do not qualify for formal statistical hypothesis testing 
will be analyzed and have results presented with confidence interval and nominal p-
values:

Mean HbA1c  at scheduled visits and change from baseline

Mean body weight at scheduled visits and change from baseline

Mean eGFR at scheduled visits and change from baseline

Time to initiation of prandial insulin

Composite microvascular endpoint
To examine the degree of consistency of the overall treatment effect in terms of important 
prognostic factors, subgroup analyses of the primary outcomes will be performed based 
on subject demographics and baseline characteristics. These exploratory subgroup 
analyses will not be adjusted for multiple comparisons and will be interpreted 
descriptively.

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Amended text:
Other Secondary Endpoints and Subgroup Analysis
The following secondary endpoints will provide supportive evidence for cardiovascular 
safety and metabolic efficacy and will not use any multiplicity adjustment procedure. 
Results will be presented with confidence interval and nominal p-values:
Components of primary endpoint (MACE = cardiovascular death, MI, stroke)
MACE + urgent revascularisation for unstable angina
Cardiovascular death or hospitalisation for heart failure
Time to initiation of insulin of more than 3 months duration for those subjects not treated 
with insulin at study start  
Time to initiation of prandial insulin in those subjects treated with basal insulin at study 
start.
The proportion of subjects achieving glycaemic control (HbA1c ≤ 7.0% at final 
assessment) with no severe hypoglycaemic incidents and weight gain <5% of body 
weight  
Mean HbA1c  at scheduled visits and change from baseline
Mean body weight at scheduled visits and change from baseline
Mean eGFR at scheduled visits and change from baseline
Composite microvascular endpoint
To examine the degree of consistency of the overall treatment effect in terms of important 
prognostic factors, subgroup analyses of the primary outcomes will be performed based 
on subject demographics and baseline characteristics. These exploratory subgroup 
analyses will not be adjusted for multiple comparisons and will be interpreted 
descriptively.
Section 8.3.6.1 Primary Analysis (3rd and 4th paragraphs)
Original text:
The hypothesis of non-inferiority of albiglutide relative to placebo group with hazard 
ratio less than 1.3 with respect to cardiovascular risk will be tested at the end of the study 
when ~611 first MACE events are cumulated. 
The strength of evidence for non-inferiority will be determined by testing the hypothesis 
that the observed hazard ratio is significantly different from the null margin of 1.3 (one-
sided p < 0.025 for such a test being equivalent to the upper 95% confidence limit after 
multiplicity adjustment for the hazard ratio being less than 1.3).  The absolute risk 
difference per 100 PY and superiority p-value for albiglutide vs. placebo will also be 
presented.

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Amended text:
The hypothesis of non-inferiority of albiglutide relative to placebo group with hazard 
ratio less than 1.3 with respect to cardiovascular risk will be tested at the end of the study. 
If non-inferiority is established, the hypothesis of superiority of albiglutide relative to 
placebo will be tested.  
The absolute risk difference per 100 PY, with its associated 95% confidence interval,  
will also be presented.
Section 8.3.6.2 Secondary Endpoint Analysis
Deletion of 1st bullet which originally read:
MACE superiority will be evaluated using the same Cox regression model as the primary 
analysis of MACE non-inferiority.
Section 10 References
Addition of following reference:
Hung HMJ, Wang SJ.  Some Controversial Multiple Testing Problems in Regulatory 
Applications, Journal of Biopharmaceutical Statistics 2009; 19:1, 1-11,
Appendix 7 Section 11.7.1.2 Literature Review
Original text:
Electronic Health Records were primarily designed to document patient care and 
facilitate billing and reimbursement. The large amount of electronic data that are captured 
may also facilitate clinical research and public health surveillance.5 Despite the 
complexity of EHR data, national networks have begun to use these data to improve 
public health and generate real-world evidence [Toh, 2012]. The Patient Centered 
Outcomes Research network (PCORnet) (pcornet.org) is a research network that is 
currently being designed to support observational comparative effectiveness research and 
clinical trials that are embedded in clinical care settings [Fleurence, 2014]. Similarly, the 
NIH Health Care Systems Research Collaboratory (nihcollaboratory.org) is creating 
infrastructure to improve the conduct of embedded clinical trials. One ongoing NIH 
Collaboratory trial is the Time to Reduce Mortality in End-Stage Renal Disease study 
(TiME) (clinicaltrials.gov identifier: NCT02019225). TiME is a large cluster-
randomized, pragmatic trial that will evaluate the effects of systematic implementation of 
hemodialysis sessions of at least four hours versus usual hemodialysis care. The trial 
involves data acquisition from EHR systems through a partnership between academic 
investigators and two health care provider organizations with different electronic data 
systems. There are several other recent examples of clinical trials that were embedded in 

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health care delivery systems [Gulliford, 2014; van Staa, 2014]. For instance, one recent 
study evaluated the use of an electronic decision support tool to improve risk factor 
control (i.e., blood pressure and cholesterol) following a cerebrovascular event with 
outcome data collected from the EHR [Dregan, 2014]. While the specific intervention 
was not shown to be efficacious, data acquisition via EHR sources was robust and 
implemented at a low cost.
Amended text:
Electronic Health Records were primarily designed to document patient care and 
facilitate billing and reimbursement. The large amount of electronic data that are captured 
may also facilitate clinical research and public health surveillance. EHR data are 
inherently complex, originate from various settings (e.g., outpatient practices, hospitals, 
and laboratories) and may be inconsistently captured across systems. Despite the 
complexity of EHR data, national networks have begun to use these data to improve 
public health and generate real-world evidence [Toh, 2012]. The Patient Centered 
Outcomes Research network (PCORnet) (pcornet.org) is a research network that is 
currently being designed to support observational comparative effectiveness research and 
clinical trials that are embedded in clinical care settings [Fleurence, 2014]. Similarly, the 
NIH Health Care Systems Research Collaboratory (nihcollaboratory.org) is creating 
infrastructure to improve the conduct of embedded clinical trials. One ongoing NIH 
Collaboratory trial is the Time to Reduce Mortality in End-Stage Renal Disease study 
(TiME) (clinicaltrials.gov identifier: NCT02019225). TiME will examine optimal 
hemodialysis session length using data from EHR systems through a partnership between 
academic investigators and two health care provider organizations with different 
electronic data systems. There are several other recent examples of clinical trials that 
were embedded in health care delivery systems [Gulliford, 2014; van Staa, 2014]. For 
instance, one recent study evaluated the use of an electronic decision support tool to 
improve risk factor control (i.e., blood pressure and cholesterol) following a 
cerebrovascular event with outcome data collected from the EHR [Dregan, 2014]. While 
the specific intervention was not shown to be efficacious, data acquisition via EHR 
sources was robust and implemented at a low cost.
Appendix 7 Section 11.7.1.3 Ancillary Study Rationale
Original text:
Despite these earlier studies demonstrating the potential opportunities with EHR-based 
data acquisition, our understanding of how EHR-based platforms might increase the 
efficiency of data collection, outcome surveillance, and confirmation in an integrated 
manner is unknown. EHRs are inherently heterogeneous, with each implementation 
different from the next. The barriers to using EHR-generated lists of patients to facilitate 
trial enrolment, the fitness of EHR data for populating baseline characteristics in an 
electronic case report form (eCRF) and the use of EHR data to find events of interest 
during trial follow-up are not well characterized. 

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EHR systems contain a wealth of clinical data about patients who are connected to the 
health care delivery system and may be eligible for enrollment in a clinical trial.  
Anecdotal reports suggest that identification of potential patients using the EHR increases 
the number of patients to be screened but may not consistently translate to an increased 
number of patients enrolled. Causes are likely multi-factorial and may include the 
translatability of inclusion and exclusion criteria to structured clinical data, the algorithm 
used to identify potential patients, institutional restrictions regarding unsolicited patient 
contact, and others. There is a need to empirically assess the barriers to using an EHR-
generated list of patients to facilitate trial enrollment. 
Structured data captured in the EHR may be similar to data elements specified in baseline 
patient characteristics in the eCRF, yet EHR data are collected primarily to support 
clinical care and reimbursement needs.  Their fitness for use as source data for selected 
data elements of the baseline patient characteristics in the eCRF has not been established.  
During routine trial follow-up, study coordinators typically gather information from 
various sources including direct patient contact and medical records of the enrolling 
institution and outside facilities to document events for study participants.  Evidence 
from the West of Scotland Coronary Prevention Study suggests that cardiovascular 
endpoints can be ascertained from routinely recorded EHR-type data, but classification 
was imperfect [Barry, 2013].There is a need to specifically assess the utility of EHR data 
acquisition for follow-up events across multiple health systems.
In summary, the EHR is a rich source of clinical data, but is designed specifically to 
support clinical care delivery and reimbursement needs. The assumption that EHR data 
are fit for use in high-quality clinical research has not been rigorously evaluated.  To 
provide evidence to address this knowledge gap, GlaxoSmithKline (GSK) and Duke 
Clinical Research Institute (DCRI) are committed to conducting an exploratory EHR 
Ancillary Study embedded within a large pragmatic clinical trial at selected study sites. 
The overarching goal is to further our understanding of how EHR data can be organized 
into a query-able format to facilitate a more efficient, reliable, and cost-effective research 
process.  The proposed empirical work is exploratory in nature and both qualitative and 
quantitative.
Amended text:
Despite these earlier studies demonstrating the potential opportunities with EHR-based 
data acquisition, our understanding of how EHR-based platforms might increase the 
efficiency of data collection, outcome surveillance, and confirmation in an integrated 
manner is unknown. EHRs are inherently heterogeneous, with each implementation 
different from the next. The barriers to using EHR-generated lists of patients to facilitate 
trial enrolment, the fitness of EHR data for populating baseline characteristics in an 
electronic case report form (eCRF) and the use of EHR data to find events of interest 
during trial follow-up are not well characterized. 
EHR systems contain a wealth of clinical data about patients who are connected to the 
health care delivery system and may be eligible for enrollment in a clinical trial.  
Anecdotal reports suggest that identification of potential patients using the EHR increases 
the number of patients to be screened but may not consistently translate to an increased 

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number of patients enrolled. Causes are likely multi-factorial and may include the 
translatability of inclusion and exclusion criteria to structured clinical data and the 
algorithm used to identify potential patients. There is a need to empirically assess the 
utility  of using an EHR-generated list of patients to facilitate trial enrolment as well as 
understanding the barriers to use of an EHR system for enrolment. 
Structured data captured in the EHR may be similar to data elements specified in baseline 
patient characteristics in the eCRF, yet EHR data are collected primarily to support 
clinical care and reimbursement needs.  Their fitness for use as source data for selected 
data elements of the baseline patient characteristics in the eCRF has not been established.  
During routine trial follow-up, study coordinators typically gather information from 
various sources including direct patient contact and medical records (some of which 
resides in electronic format, i.e., an EHR) of the enrolling institution and outside facilities 
to document events for study participants.  There is a need to specifically assess the 
utility of EHR data acquisition for follow-up events across multiple health systems, and 
to address challenges to the future use of EHR as source data for global trials and 
observational studies.
In summary, the EHR is a rich source of clinical data that are increasingly used in 
pragmatic health research initiatives, but the assumption that EHR data are fit for use in 
high-quality clinical research has not been rigorously evaluated.  To provide evidence to 
address this knowledge gap, GlaxoSmithKline (GSK) and Duke Clinical Research 
Institute (DCRI) are committed to conducting an exploratory EHR Ancillary Study 
alongside a large pragmatic clinical trial. The overarching goal is to further our
understanding of how EHR data can be organized into a query-able format to facilitate a 
more efficient, reliable, and cost-effective research process.  As a collaboration between 
an academic research institute and a pharmaceutical sponsor, this project provides a 
unique opportunity to compare electronic health record data with baseline characteristics 
and adjudicated events captured as part of a large, contemporary, outcomes-based trial.
Appendix 7 Section 11.7.2.1 Primary Objectives
Original text:
Objective 1: Assess the barriers to using an EHR-generated list of patients to 
facilitate trial enrollment.
Through site study coordinator surveys, workflow assessment, analysis of electronic 
screening logs, comparisons of enrolled patients with patients identified via algorithm, 
this retrospective objective will describe the screening “funnel” and identify factors 
responsible for narrowing the funnel from the pool of potentially eligible patients to those 
enrolled in the clinical trial.  Barriers for using EHR systems for this purpose will be 
assessed at the site level and common cross-site themes will be identified. 

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Objective 2:  Evaluate the fitness of EHR data for use in populating the baseline 
characteristics in the eCRF
After study completion and within selected data areas (e.g., demographics, medical 
history, concomitant medications), the level of agreement between data extracted from 
the EHR and data documented on the baseline eCRF (reference standard) will be 
evaluated. Additionally the performance of algorithms developed to identify 
comorbidities and other clinical concepts will be assessed at the site level and aggregated, 
where appropriate.  
Objective 3:  Explore the use of EHR data to find events of interest during trial 
follow-up 
Case-finding algorithms will be developed for select specified endpoints (i.e., myocardial 
infarction, stroke, unstable angina, heart failure as outlined in the main study protocol), 
run during the conduct of the trial, and used to identify potential cases for follow-up by 
the study coordinator. The site study coordinator will record the dispensation of each 
potential case so that reconciliation can occur between eCRF documented events and 
EHR-generated potential events. Safety event reporting will proceed as outlined in the 
main study protocol (Main Protocol Section 6.2). At the conclusion of the study, the yield 
of case-finding algorithms will be evaluated along with the performance of EHR-based 
algorithms with eCRF-reported as well as adjudicated eCRF-reported events (reference 
standard).
Amended text:
Objective 1: Understand how EHR data are used to facilitate trial recruitment and 
the barriers to that use..
Using site study coordinator surveys, workflow assessment, qualitative analysis of a site-
level enrollment measure, and quantitative comparisons of enrolled patients with 
potentially eligible patients, this objective will enhance understanding of how EHR data 
are used to facilitate clinical trial enrollment at global HARMONY sites with an EHR 
system and who express interest in participating. All global sites with an EHR will be 
invited to participate in the qualitative component – which will occur after main study 
enrollment is complete.  For select sites in the United States, a quantitative analysis will 
be conducted comparing the proportion of eligible patients identified by a computerized 
algorithm to the site’s list of enrolled patients.  Algorithms will be developed based on 
structured data that represent trial inclusion criteria and submitted as a query to a subset 
of select sites with EHR systems that meet certain criteria and have technical capabilities. 
Objective 2:  Evaluate the fitness of EHR data for use in populating the baseline 
characteristics in the eCRF
For select sites, the level of agreement between data extracted from the EHR and data 
documented on the baseline eCRF (reference standard) will be evaluated and compared 
among consented participants. This will occur after study completion and within selected 
data areas (e.g., demographics, medical history, concomitant medications). Additionally 

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the performance of algorithms developed to identify comorbidities and other clinical 
concepts will be assessed at the site level and aggregated, where appropriate.
Other partnerships in select countries will support comparisons between data extracted 
from existing national-level electronic health data (or administrative claims data) and 
data documented on the baseline eCRF.  
Objective 3:  Explore the use of EHR data to find events of interest during trial 
follow-up 
For select sites, case-finding algorithms will be developed for select specified endpoints 
(e.g., all-cause death, myocardial infarction, stroke, urgent revascularization for unstable 
angina, hospitalization for heart failure) and applied to EHR data. At the conclusion of 
the main HARMONY-Outcomes study, the performance of EHR algorithms will be 
compared with eCRF-reported and adjudicated eCRF-reported events (reference 
standard).
Other partnerships in select countries will support comparisons between data extracted 
from existing national-level electronic health data (or administrative claims data) and 
eCRF reported and adjudicated eCRF-reported events.
Appendix 7 Section 11.7.2.2 Secondary Objectives
Has been deleted.
Appendix 7 Section 11.7.3.1 Study Design
Original text:
The ancillary study will occur in the context of the HARMONY-Outcomes trial, a 
randomised, double blind, parallel-group, placebo-masked, controlled study to evaluate 
the effect of albiglutide on cardiovascular events in patients with Type 2 diabetes. 
Albiglutide will be administered subcutaneously once weekly in a population of patients 
with Type 2 diabetes and a previous history of cardiovascular disease and who do not 
have optimal glycaemic control). The duration of the ancillary study will mirror that of 
the HARMONY-Outcomes trial. The number of sites that will participate in the ancillary 
study depends upon the outcome of the site EHR capabilities assessment described in 
Section 11.7.3.2 (Site Selection) below. Five study sites recruiting 12-15 subjects each 
would enable a descriptive assessment of Objectives 1 and 2, whilst, if feasible, 500-1000 
subjects at EHR-enabled sites would permit greater precision to be achieved in the 
assessment of Objective 3.

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Amended text:
The ancillary study will be conducted in conjunction with the HARMONY-Outcomes 
trial, a randomised, double blind, parallel-group, placebo-masked, controlled study to 
evaluate the effect of albiglutide on cardiovascular events in patients with Type 2 
diabetes. Albiglutide will be administered subcutaneously once weekly in a population of 
patients with Type 2 diabetes and a previous history of cardiovascular disease and who 
do not have optimal glycaemic control. The majority of research activities in the ancillary 
study will take place following the close of the HARMONY Outcomes Trial, with 
specified timelines laid out in objective-specific workplans. Data extracted from the EHR 
for the purpose of the ancillary study will cover the time period from randomization into 
the main HARMONY Outcomes Trial study through the end of that study. Objective 1 
will include a qualitative survey for which all global sites with an EHR who express 
interest in participating will be invited to participate. In select sites, Objective 1 will also 
include the application of a screening algorithm to support the quantitative aspect of the 
analysis. For Objectives 2 and 3, select U.S. sites with specific technical capabilities will 
participate, as well as select countries where relevant national-level electronic health data 
are available and accessible.
11.7.3.2.
Data Flow Strategies – Introduction
The HARMONY EHR ancillary study will utilize two data flows, termed the DataMart 
and National strategies, to gather and analyze data.  The DataMart strategy will support 
work done at select U.S. sites, in order to access electronic health record data from 
patients enrolled in the main HARMONY Outcomes trial at these sites.  This strategy 
encompasses the quantitative section of Objective 1, as well as the entirety of Objectives 
2 and 3.  The National Strategy will support work done with global national partners, in 
order to access national electronic health data for patients enrolled in the main 
HARMONY Outcomes trial.  This strategy will encompass only Objectives 2 and 3.  
More detailed information regarding these strategies can be found below in section 3.4.
Appendix 7 Section 11.7.3.2 Site Selection (amended to Section 11.7.3.3)
Original text:
Sites from the main trial will be selected to participate.  As part of the overall site 
selection process for the main trial, potential sites complete a feasibility survey to gauge 
their suitability for participation in the HARMONY-Outcomes trial.  In addition to 
questions regarding experience with long-term outcome trials in general and specific 
features of the planned trial, the feasibility survey includes questions about site readiness 
for an EHR-facilitated trial.  Specific topics include:

Existence of an EHR system;

Current use of EHR to screen for potential study participants;

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
Types of information currently contained in EHR  (inpatient visits, outpatient 
visits, laboratory results, medications) 

Prior participation in a study that used EHR data for patient screening, follow-up, 
and/or data collection; and

Local EHR support to assist with research studies.
Sites who meet minimum qualifications based on this survey (respond affirmatively 
regarding the existence of an EHR system and local EHR support to assist with research 
studies), and who have confirmed an interest in participating in the ancillary study will be 
approached for a more in-depth assessment of capabilities.  Specific topics include:

Current capability to extract EHR-type data from a data warehouse;

Data domains currently included in the data warehouse (e.g., demographics, vital 
signs, diagnoses, procedures, medications prescribed, laboratory tests, and death);

Coding terminologies used for each domain of data;

Institutional processes and policies for using EHR-type data for clinical research; 

Institutional experience extracting, transforming, and loading warehouse data into 
a research DataMart that conforms with standardized specifications; and

Familiarity with or participation in distributed research networks.  
Subsequent structured discussions with individual sites may be necessary to explore 
capabilities and suitability for the ancillary study.  For example, engagement of the health 
system’s Information Technology (IT) personnel will be essential but is challenging to 
gauge in a written survey.  Key site selection criteria include:

Fully implemented EHR system 

Access to an enterprise data warehouse or clinical data repository that stores 
structured data from the EHR and is updated at least weekly.

Availability of necessary data

Engagement of health system IT and analytical personnel
The advantage of a multi-stage, rapid assessment of capabilities is that it allows for a 
relatively short feasibility survey that can be completed reliably by a study coordinator. 
Detailed technical questions are reserved for the individuals who provide EHR support 
for research studies.

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Amended text:
Table.4
HARMONY Outcomes Site and Country Participation by Ancillary 
Study Objective
Objective
Sites
Select Countries
Selected U.S. 
Sites with 
Technical 
Capabilities* 
(DataMart 
Strategy)
Global Sites 
with an 
Implemented 
EHR System 
U.S. 
VA 
Sites
U.S.** and Global 
Partners*** (National 
Strategy)
1: 
Qualitative
X
X
1: 
Quantitative
X
X
2
X
X
X
3
X
X
X
*Technical capabilities include ability to extract data from the EHR and transform to a common data 
format
**The U.S. National Strategy will acquire Medicare Claims data for Medicare beneficiaries enrolled as 
participants in HARMONY Outcomes U.S. sites.  A U.S. site may participate in both the U.S. DataMart 
Strategy and/or the U.S. National Strategy.
***Country selection considerations (dataset): 1) common person-level identifier, or equivalent data that 
can be used to link consented trial participants with national-level data  2) coverage of ~100% of defined 
population, and 3) availability of EHR events of interest
Objective 1 – Qualitative Site Selection
All HARMONY Outcomes sites (global) with an EHR will be invited to participate in the 
qualitative survey of Objective 1 of the ancillary study.
Objectives 1 (Quantitative), 2, 3 – Technical Site Selection in the DataMart Strategy
As part of the overall site selection process for the HARMONY Outcomes Trial, potential 
U.S. sites completed a feasibility survey to gauge their interest and suitability for 
participation in the technical components of the EHR Ancillary Study (ability to extract 
data from the EHR and transform to a common data format). The surveys included 
questions regarding experience with long-term outcome trials in general and specific 
features of the planned trial. 
Key criteria used for selection of participating US sites for the technical components of 
Objectives 1 (Quantitative), 2, and 3 of the EHR-Ancillary Study include: 
•
Existence of an EHR 

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•
Types of information currently contained in EHR;
•
Current capability to extract EHR-type data from a data warehouse;
•
Institutional processes and policies for using EHR-type data for clinical research; 
•
Institutional experience extracting, transforming, and loading warehouse data into 
a research DataMart that conforms with standardized specifications; and
•
Access to an enterprise data warehouse or clinical data repository that stores 
structured data from the EHR and is updated at least weekly.
•
Engagement of health system IT and analytical personnel
Objectives 2 and 3 – Technical National Partner Selection in the National Strategy
In select countries (Denmark, U.K. (England and Scotland), Sweden, Norway, and the 
United States), national partners will be asked to access existing national-level data 
sources to address Objectives 2 and 3. Key criteria used for the selection of participating 
countries include: 
•
Existence of an electronic health data source that covers either all of the national 
population or a defined population;
•
Availability of a common person level identifier(s) or equivalent data that can be 
used to link consented trial participants with national-level data;
•
Timely availability of information that can define the EHR events of interest (e.g. 
inpatient encounters and diagnoses, death or transfer out of population);  
•
An academic collaborator who has access and experience with the ethical, 
regulatory and technical requirements of using the data source
Appendix 7 Section 11.7.3.3 Data Flows (amended to Section 11.7.3.4)
Original text:
The methods for data extraction and capture will require a partnership between study site 
teams (site principal investigator, site study coordinator, and site technical support), 
GSK, and the DCRI Data Management Team.
The study will utilize PopMedNet, a software application that enables the creation, 
operation, and governance of research networks.  It allows partners to maintain physical 
and operational control over their data while allowing authorized users to send queries to 
the data. PopMedNet consists of two layers: a security layer where access controls and 
permissions are established and a layer of virtual pipes through which questions are sent 
from requestor to responder. The PopMedNet software consists of a web-based “network 
portal” and a DataMart Client application that is installed at each site. PopMedNet 

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employs a “publish-and-subscribe” architecture that does not require a hole through an 
institutional firewall, but rather allows institutions to pull a query behind the firewall for 
manual or automated execution. 
In research networks with a common data model, PopMedNet is used to distribute 
executable code that institutions can choose to pull behind their firewall, run against the 
data in that appropriate format, and return results to the requestor. Security 
documentation will be provided to all participating sites.   
The data flow for this ancillary study will be as follows: 
a) The study site’s EHR system will not be changed and will continue to operate as 
implemented.  Data from the thousands of tables in the EHR will be integrated on 
a nightly basis into a data warehouse that supports research needs (the term EHR 
is used to mean the system that collects, displays, and stores transactional health 
care data).
b) With guidance from the DCRI Data Management Team, the study site’s technical 
team will extract, transform, and load data from the enterprise data warehouse (or 
clinical data repository) to a Cohort DataMart according to the specifications of 
the common data model.  A common data model standardizes the definition, 
content and format of data across sites to enable efficient, cross-site querying. The 
Cohort DataMart will be refreshed from the existing Data Warehouse on a 
biweekly basis. The Cohort DataMart includes Protected Health Information 
(PHI) for a broadly defined cohort of potential study participants and will remain 
behind institutional firewalls. 
c) Data from Pre-Screening logs completed as part of the main study will be 
captured in a database stored in the same area as the Cohort DataMart to facilitate 
characterization of the screening funnel.  Data from the pre-screening log will 
enable comparisons of characteristics of potential participants identified via 
algorithm with patients screened and enrolled. 
d) When a participant is randomized into the study, the study coordinator will enter 
key subject identifiers (the main trial identifier (ID), Medical Record Number 
(MRN) equivalent, study randomization date) into the Key Identifier spread sheet.
e) Via PopMedNet, the DCRI Data Management Team will distribute code that 
extracts data for randomized participants from the Cohort DataMart into the Study 
DataMart using the Key Identifier table. Trial ID and randomization date from the 
Key Identifier table will be included in the Study DataMart. Data for randomized 
patients at each site will be returned to the DCRI via the HARMONY-Outcomes 
trial EHR Ancillary Study Query Portal. 
f)
Via PopMedNet, the DCRI will distribute executable code (e.g., SQL program) 
that will query the Study DataMart for potential study endpoints.  [See Section a)b 
for case-finding algorithm]. 
g) Potential cases (identified via case-finding algorithm) will be returned to the 
Study Coordinator who will record the dispensation of each potential case in the 
Case-finding Dispensation Log stored in the Study DataMart (i.e., recorded in the 
eCRF/not recorded in the eCRF and reasons).

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h) The Study DataMart containing randomized patient data will be transferred from 
each site to the DCRI on a regular basis (anticipated quarterly with specific 
frequency to be determined).  
Required data elements from the main clinical trial dataset for EHR Ancillary Study sites 
will be transferred from GSK to the DCRI after the completion of the study. The DCRI 
will merge data elements from the main clinical trial dataset with Study DataMart data to 
create the EHR Ancillary Study Dataset.
Amended text:
Qualitative Data Sources (Objective 1)
Objective 1 will survey study coordinators to obtain information on trial enrollment 
workflows, with a focus on how EHR systems are routinely used in the screening 
process, and what works best to facilitate this process. This objective will collect primary 
data through qualitative surveys and focus groups with study coordinators from 
participating sites to identify best practices and barriers to the use of EHR data for trial 
screening and enrolment. 
First, a topic guide will be developed and tested with a small number of study 
coordinators to identify major survey themes. After revising and finalizing the guide, 
Webex focus groups will be conducted with coordinators to identify other relevant 
content. A report of findings will be generated based on a systematic analysis of the focus 
groups. A qualitative survey will then be developed based on topic guide testing, focus 
group report and feedback from survey experts and GSK team. The survey will be 
administered to study coordinators at participating sites.  Survey data will then be 
analysed and a data report will be generated. 
We will also conduct a qualitative assessment of enrollment “funnels” at the site level, 
where enrollment funnel is defined as the process by which the population of potentially 
eligible participants is narrowed to the final enrolled study population. This qualitative 
assessment will focus on reasons for non-enrollment among eligible patients at the site 
level. Each site will report the criteria used to generate the list of potentially eligible trial 
participants so that we can describe where the enrollment funnel begins and how it is 
narrowed down from potentially eligible subjects to those enrolled in the trial.
DataMart Strategy Data Flows (Objectives 1 [Quantitative], 2, and 3)
For the analyses based on technical components in Objectives 1, 2, and 3, select sites 
with technical capabilities participating in the EHR Ancillary Study will be required to 
convert relevant patient data from their EHR system into a Research DataMart, based on 
a common data model. A common data model standardizes the definition, content and 
format of data across sites to enable a single standardized view that can be used for 
querying. This is essential since EHR data are stored in different ways at different sites. 
The common data model for the ancillary study will be adapted from the PCORnet 
Common Data Model and may include the following data areas: demographics, 
encounters, diagnoses, procedures, and selected laboratory results. The study site’s EHR 
system will not be changed and will continue to operate as implemented. The Research 

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DataMart includes Protected Health Information (PHI) and will remain behind 
institutional firewalls.
The methods for extracting useful information from the Research Datamart will require a 
partnership between study site teams (site principal investigator, site study coordinator, 
and site technical support), GSK, and the DCRI Data Management Team. The study will 
utilize secure mechanisms to distribute queries to participating sites and receive results.  
Many sites will use Aqueduct, a software application that enables the creation, operation, 
and governance of research networks.  It allows partners to maintain physical and 
operational control over their data while allowing authorized users to send queries to the 
data. 
The DCRI Data Management Team will distribute code that extracts and returns data for 
randomized participants from the Research DataMart. These data from randomized 
participants across all participating sites will make up a subset of the EHR Ancillary 
study dataset. 
Required data elements of interest regarding baseline demographics and outcome events 
from the main HARMONY trial dataset will be transferred from GSK to DCRI after the 
completion of the study. DCRI will merge these data elements with the datamart EHR 
Ancillary study dataset.
National Strategy Data Flows (Objective 2 and 3)
Similarly, Objectives 2 and 3, as applied on the national level, will compare baseline 
characteristics and outcomes ascertained from the main HARMONY trial dataset with 
data from national electronic health data. However, the methods to access, extract and 
transfer data will be adapted to each participating country and will be guided by the 
expertise of the academic collaborator. Country specific methods will be used to 1) 
access national-level electronic health data (for example, Medicare data in the U.S.), 2) 
use patient level identifier(s) to link HARMONY trial participants, and 3) transfer de-
identified patient-level national electronic health data to DCRI to create the National 
Strategy EHR ancillary dataset and compare data elements of interest regarding baseline 
demographics and outcome events from the main HARMONY trial dataset.  The final 
analysis dataset will be constructed after the end of the main HARMONY Outcomes trial 
and the data latency period, which is defined as the delay from the initial generation of 
EHR data or claims files to the availability of an analysis-ready dataset.
Appendix 7 Section 11.7.4.1 Sample Size Expectations
Original text:
The objectives of this ancillary study are exploratory (not confirmatory) in nature and not 
intended to be sufficiently powered to confirm a pre-determined level of sensitivity and 
specificity.  The number of sites and subjects that will participate in the ancillary study 
depends upon the outcome of the site EHR capabilities assessment described in Section 
11.7.3.2 (Site Selection). Five study sites recruiting 12-15 subjects each would enable a 

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descriptive assessment of Objectives 1 and 2, whilst, if feasible, 500-1000 subjects at 
EHR-enabled sites would permit greater precision to be achieved in the assessment of 
Objective 3.
Amended text:
The objectives of this ancillary study are exploratory (not confirmatory) in nature and not 
intended to be sufficiently powered to confirm a pre-determined level of sensitivity and 
specificity.  The qualitative portion of Objective 1 will be open to participation from any 
interested Global site with an EHR. The technical components (datamarts) of Objectives 
1, 2, and 3 of the ancillary study will target recruitment of ~7 U.S. sites, each recruiting 
12-15 subjects, to support the study aims.  The DataMart strategy will also utilize 
approximately 8 U.S. VA sites. The datasets generated using country-specific data for 
Objectives 2 and 3 are intended to include all randomized participants across 
HARMONY sites in each participating country.
Appendix 7 Section 11.7.4.2 deleted.
Original text:
Because any survey administered for this objective will be a site-level survey, analysis of 
the survey data will be performed across all sites. For quantities of interest, frequencies 
with percentages for categorical measures and means with standard deviations for 
continuous measures will be presented.
Appendix 7 Section 11.7.4.3 (now 11.7.4.2) renamed General Analytical Approach (was 
General Analytic Approach for Objective 1 and Objective 2)
Original text:
The goals of both Objective 2 and Objective 3 involve evaluating the performance of 
algorithms that map EHR-based data into concepts present in the clinical trial dataset.  
The actual measures recorded in the clinical trial dataset will be considered the reference 
standard against which these algorithm-based measures are compared.

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Table 4
Overall performance of EHR-based algorithms for baseline 
characteristics, using clinical trial data as the reference standard / 
Categorical variables
Reference standard
(Clinical trial data)
New measure  
(EHR Ancillary Study data)
Condition present
Condition absent
Condition present
True positive
(TP)
False positive 
(FP)
Condition absent
False negative
(FN)
True negative
(TN)
For categorical variables, estimated performance metrics will be based on the 2x2 cross-tabulation 
of values in the EHR Ancillary Study dataset with values in the clinical trial dataset (Table 4) and 
include:

Overall agreement = (TP + TN) / (TP + FP + FN + TN)

Sensitivity = TP / (TP + FN)

Specificity = TN / (FP + TN)

Positive predictive value = TP / (TP + FP)

Negative predictive value = TN / (FN + TN)

Accuracy or efficiency = (TP + TN) / (TP+TN+FP+FN)
For dichotomous measures, each of these proportions is immediately calculable.  For 
measures having more than two levels, multiple dichotomous measures will be created in 
order to calculate these proportions. Confidence intervals (95%) will be reported around 
these quantities. (See Table 5 as an example).
Table 5
Overall performance of EHR-based algorithms for baseline 
characteristics, using clinical trial data as the reference standard / 
Categorical variables
Measure
Overall 
agreement
(95% CI)
Sensitivity
(95% CI)
Specificity
(95% CI)
Positive 
predictive 
value 
(95% CI)
Negative 
predictive 
value 
(95% CI)
Measure 1
xx.x 
(xx.x – xx.x)
xx.x 
(xx.x – xx.x)
xx.x 
(xx.x – xx.x)
xx.x 
(xx.x – xx.x)
xx.x 
(xx.x – xx.x)
Measure 2
xx.x 
(xx.x – xx.x)
xx.x 
(xx.x – xx.x)
xx.x 
(xx.x – xx.x)
xx.x 
(xx.x – xx.x)
xx.x 
(xx.x – xx.x)
.....
.....
.....
.....
.....
.....
Reported on 0–100 scale
For continuous measures, bias will be calculated as the difference between values in the 
EHR Ancillary Study dataset and values in the clinical trial dataset.  The mean and 

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standard deviation of the bias along with a 95% confidence interval will be reported.  In 
Bland-Altman analyses of agreement between continuous measures, the standard 
deviation of the bias is referred to as the precision, while the 95% confidence interval is 
referred to as the limit of agreement. (See Table 6 as an example).
Table 6
Overall performance of EHR-based algorithms for baseline 
characteristics, using clinical trial data as the reference standard / 
Continuous variables
Bias
Measure
Mean (SD)
95% (CI)
Measure 1
xx.x
xx.x
Measure 2
xx.x
xx.x
.....
.....
.....
Due to the nature of EHR data, it is expected that there will be systematic differences 
between sites with respect to coding of clinical concepts.  All performance metrics will 
therefore initially be calculated by site. These site-specific results may be best reported 
graphically.
There is also interest in an assessment of algorithm performance across all sites.  
Hierarchical models will be used to combine data from all sites and estimate performance 
at the “average” site.  To estimate proportions (e.g. for overall agreement, sensitivity, 
specificity, etc. associated with categorical measures), models will be specified as:
logit (E (y) )=β0+γ0,,j
γ0,j~N(0,s2)
where sites are indexed by j.  The value of the proportion at the average site—when 
γ0=0—is  [1+exp (–β0 ) ]-1.  Patients included in the estimation of each model vary by 
performance metric and reflect the definitions above.  As an example, consider positive 
predictive value.  To estimate the positive predictive value of an algorithm, only subjects 
with true positive value and false positive values will be included.  True positives will be 
assigned Y=1 and false positive will be assigned Y=0. 
To estimate means (e.g. for bias associated with continuous variables), the model will be 
specified as:
E (y )=β0+ γ0,,j
γ0,,j ~ N(0,s2)
The value of the mean at the average site is β0.  
For all models, we will assess site heterogeneity by testing if s2=0.

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Amended text:
In Objective 1, the proportion of eligible patients identified by the computerized 
algorithm will be compared to the list of enrolled patients at participating sites. The goals 
of Objectives 2 and 3 involve evaluating the performance of algorithms that map EHR-
based data into concepts present in the clinical trial dataset.  Algorithms will be informed 
by general and therapeutic area-specific data standards, including the standards efforts of 
professional societies. Baseline characteristics and study endpoints in the ancillary study 
dataset will be defined using diagnosis codes and procedure codes.  Published algorithms 
will be used whenever possible and these algorithms will be updated as necessary to 
account for coding changes since publication. The actual measures recorded in the 
clinical trial dataset will be considered the reference standard against which these 
measures based on technical components are compared. 
For Objective 2, the performance of algorithms used to identify baseline characteristics 
will be evaluated. For Objective 3, the performance of algorithms used to identify trial 
events will be evaluated. Performance metrics will be calculated by site as well as across 
all sites.  Within the national data used for Objectives 2 and 3, all performance metrics 
will be calculated by country as well as across all countries.
Appendix 7 Section 11.7.4.4 & Section 11.7.4.5 deleted
Original text:
11.7.4.4. Objective 2: Evaluate the Fitness of EHR Data for Use in Populating the 
Baseline Characteristics in the eCRF
Algorithms will be defined to map EHR-based data in the Study Data Mart to specific 
concepts in the EHR Ancillary Study dataset that parallel concepts in the clinical trial 
dataset.  For Objective 2, the performance of algorithms used to identify baseline 
characteristics will be evaluated.  The baseline characteristic measures recorded in the 
clinical trial dataset will be considered the reference standard against which these 
algorithm-based measures are compared. 
11.7.4.5. Objective 3: Explore the Use of EHR Data to Find Events of Interest During 
Trial Follow-up
Algorithms will be defined to map EHR-based data in the Study Data Mart to specific 
concepts in the EHR Ancillary Study dataset that parallel concepts in the clinical trial 
dataset.  For Objective 3, the performance of algorithms used to identify trial events will 
be evaluated.  These algorithms will be evaluated against both the adjudicated events 
recorded in the clinical trial dataset and the identified potential events in the eCRF.  For 
each event, estimates of sensitivity and positive predictive value (described in Section
11.7.4.3) will be calculated and presented with 95% confidence intervals.  

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The GlaxoSmithKline group of companies
GLP116174
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A long term, randomised, double-blind, placebo-controlled study 
to determine the effect of albiglutide, when added to standard 
blood glucose lowering therapies, on major cardiovascular 
events in patients with Type 2 diabetes mellitus.  Harmony 
Outcomes Trial.
Compound Number:
GSK716155
Development Phase:
III/IV
Effective Date:
22-JUL-2015
Protocol Amendment Number:  02
Author (s): The protocol was developed by the members of the Executive Committee in
conjunction with Duke Clinical Research Institute and the Sponsor.
The following individuals provided substantial input during protocol development:
Non-sponsor:
 
(Executive Committee Co-Chair); 
 
(Executive Committee Co-Chair); 
Sponsor: 
 
Copyright 2015 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD
PPD
PPD
PPD

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The GlaxoSmithKline group of companies
GLP116174
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Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2014N193553_00
2014-SEP-25
Original
2014N193553_01
2014-NOV-24
Amendment No. 1
Clarification added regarding follow-up after discontinuation of investigational product.
Addition of safety assessment to dose adjustment visits.
Addition of Country Specific Requirements appendix.
Correction of typographical errors and inconsistent terminology.
2014N193553_02
2015-JUL-22
Amendment No. 2
Amendment to study phase for participating countries where albiglutide is not licensed.
Update list of Authors.
Update to Sponsor Information
Removal of discrepancy in level of pregnancy testing required for inclusion.
Reformatting of Time and Event table to improve clarity.
Addition of table of visits for subjects discontinuing investigational product (previously 
included in text) as an aid to investigators.
Addition of requirement of Mexican Ministry of Health to report events referred to 
Clinical Endpoint Committee from Mexican investigators as Serious Adverse Events.
Addition of requirement to record lipid results if they are available from subjects’ routine 
clinical care outside of the trial.
Clarify that TRIM-D should not be assessed at Baseline in subjects whose diabetes is 
treated by diet and exercise alone.
Simplification of description of safety analyses to properly reflect the planned reports.
Correction of typographical and process errors.

PPD

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SPONSOR INFORMATION PAGE
Clinical Study Identifier: GLP116174
Sponsor Legal Registered Address:
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford, Middlesex, TW8 9GS, UK
Sponsor Contact Address
GlaxoSmithKline Research & Development Limited
Iron Bridge Road 
Stockley Park West, Uxbridge, Middlesex, UB11 1BU, UK
Telephone: 
GlaxoSmithKline Research & Development Limited
2301 Renaissance Boulevard
Building #510
Post Office Box 61540
King of Prussia, Pennsylvania 19406, USA
Telephone number:
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline affiliate 
company (or designee). Where applicable, the details of the Sponsor and contact person 
will be provided to the relevant regulatory authority as part of the clinical trial 
submission.
Sponsor Medical Monitor Contact Information: 
Dr 
2301 Renaissance Boulevard
REN0410
King of Prussia, Pennsylvania 19406, USA
Email:
Telephone number: Office: 
                                Cell: 
 
                                Out of hours: 
Sponsor Serious Adverse Events (SAE) Contact Information:
Dr 
As above for Medical Monitor Contact
Regulatory Agency Identifying Number(s):
Investigational New Drug (IND) Number: IND65177
European Drug Regulatory Authorities Clinical Trials (EudraCT) No. 2014-001824-32.
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number GLP116174
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date

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TABLE OF CONTENTS
PAGE
LIST OF ABBREVIATIONS...........................................................................................10
PROTOCOL SUMMARY...............................................................................................12
1.
INTRODUCTION....................................................................................................15
1.1.
Background ................................................................................................15
1.2.
Rationale ....................................................................................................16
2.
OBJECTIVES AND ENDPOINTS...........................................................................17
3.
STUDY DESIGN ....................................................................................................18
3.1.
Overall Design ............................................................................................18
3.2.
Standard of Care ........................................................................................19
3.3.
Discussion of Design ..................................................................................20
3.4.
Benefit:Risk Assessment ............................................................................21
3.4.1.
Risk Assessment .........................................................................21
3.4.1.1.
Identified Risks...........................................................21
3.4.1.2.
Potential Risks............................................................23
3.4.2.
Benefit Assessment.....................................................................24
3.4.3.
Overall Benefit:Risk Conclusion...................................................25
4.
SUBJECT SELECTION AND WITHDRAWAL CRITERIA.......................................25
4.1.
Inclusion Criteria.........................................................................................25
4.2.
Exclusion Criteria........................................................................................27
4.3.
Screening/BaselineFailures ........................................................................28
4.4.
Criteria for Early Discontinuation of Investigational Product ........................28
4.4.1.
Early Discontinuation of Investigational Product...........................28
4.4.2.
Reasons for Discontinuation of Investigational Product................29
4.4.3.
Liver Chemistry Stopping Criteria ................................................29
4.4.4.
eGFR Stopping Criteria................................................................31
4.5.
Procedures for Subject Follow-up ...............................................................32
4.5.1.
Withdrawal of Consent for Contact...............................................32
4.5.2.
Subjects Deemed Lost to Follow-up.............................................33
5.
STUDY TREATMENTS..........................................................................................33
5.1.
Investigational Product and Other Study Treatment....................................33
5.2.
Treatment Assignment................................................................................34
5.3.
Blinding.......................................................................................................35
5.4.
Product Accountability ................................................................................35
5.5.
Treatment Compliance................................................................................36
5.6.
Concomitant Medications and Non-Drug Therapies....................................36
5.6.1.
Permitted Medications and Non-Drug Therapies..........................36
5.6.2.
Prohibited Medications and Non-Drug Therapies.........................37
5.7.
Treatment after the End of the Study ..........................................................37
5.8.
Treatment of Study Treatment Overdose....................................................37
6.
STUDY ASSESSMENTS AND PROCEDURES .....................................................37
6.1.
Critical Baseline Assessments....................................................................41
6.2.
Safety .........................................................................................................41
6.2.1.
Cardiovascular Events.................................................................41

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6.2.1.1.
Other CV Events ........................................................42
6.2.2.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........42
6.2.2.1.
Time period and Frequency for collecting AE 
and SAE information...................................................43
6.2.2.2.
Method of Detecting AEs and SAEs ...........................44
6.2.2.3.
Follow-up of AEs and SAEs........................................44
6.2.2.4.
Sentinel Events ..........................................................44
6.2.2.5.
Regulatory Reporting Requirements for SAEs............44
6.2.3.
Adverse Events of Special Interest ..............................................45
6.2.4.
Clinically Important Microvascular Events....................................46
6.2.5.
Pregnancy ...................................................................................47
6.2.6.
Clinical Laboratory Assessments .................................................47
6.2.6.1.
Estimated Glomerular Filtration Rate (eGFR) .............48
6.2.7.
Physical examination ...................................................................49
6.3.
Value Evidence and Outcomes...................................................................49
6.3.1.
Value Evidence and Outcomes Assessments..............................49
6.3.1.1.
Treatment Related Impact Measure – Diabetes 
(TRIM-D) ....................................................................49
6.3.1.2.
EQ-5D ........................................................................49
6.3.1.3.
Exploratory Diabetes Management Questions............50
6.3.1.4.
Healthcare Resource Utilisation..................................50
6.4.
Genetic Research.......................................................................................51
7.
DATA MANAGEMENT ...........................................................................................51
8.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS...................................51
8.1.
Hypotheses.................................................................................................51
8.2.
Study Design Considerations......................................................................51
8.2.1.
Sample Size Assumptions ...........................................................51
8.2.2.
Sample Size Sensitivity for MACE non-inferiority.........................52
8.2.3.
Sample Size Re-estimation..........................................................52
8.3.
Data Analysis Considerations .....................................................................52
8.3.1.
Analysis Populations....................................................................52
8.3.2.
Analysis Data Set ........................................................................53
8.3.3.
Treatment Comparisons ..............................................................53
8.3.3.1.
Primary Comparisons of Interest ................................54
8.3.3.2.
Other Comparisons of Interest....................................54
8.3.4.
Interim Analysis ...........................................................................54
8.3.5.
Multiplicity Controls......................................................................54
8.3.6.
Key Elements of Analysis Plan ....................................................56
8.3.6.1.
Primary Analysis.........................................................56
8.3.6.2.
Secondary Endpoint Analysis .....................................57
8.3.6.3.
Subgroup Analysis......................................................58
8.3.6.4.
Other Safety Analyses................................................58
8.3.6.5.
Value Evidence and Outcomes Analyses ...................59
9.
STUDY CONDUCT CONSIDERATIONS ...............................................................59
9.1.
Posting of Information on Publicly Available Clinical Trial Registers............59
9.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................59
9.3.
Quality Control (Study Monitoring) ..............................................................60
9.4.
Quality Assurance.......................................................................................60

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9.5.
Study and Site Closure ...............................................................................61
9.6.
Records Retention......................................................................................61
9.7.
Provision of Study Results to Investigators, Posting of Information 
on Publicly Available Clinical Trials Registers and Publication....................62
9.8.
Independent Data Monitoring Committee (IDMC) .......................................62
9.9.
Pancreatitis Adjudication Committee...........................................................62
10. REFERENCES.......................................................................................................64
11. APPENDICES........................................................................................................67
11.1.
Appendix 1: Genetic Research ...................................................................67
11.2.
Appendix 2: GSK Modified List of Highly Effective Methods for 
Avoiding Pregnancy in Females of Reproductive Potential (FRP)...............73
11.3.
Appendix 3: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................74
11.4.
Appendix 4: Liver Safety Drug Restart Guidelines ......................................78
11.5.
Appendix 5: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................80
11.5.1.
Definition of Adverse Events........................................................80
11.5.2.
Definition of Serious Adverse Events...........................................81
11.5.3.
Recording of AEs and SAEs ........................................................83
11.5.4.
Evaluating AEs and SAEs............................................................84
11.5.5.
Reporting of SAEs to GSK...........................................................85
11.6.
Appendix 6: Collection of Pregnancy Information........................................86
11.7.
Appendix 7: Electronic Health Record Ancillary Study ................................87
11.7.1.
Introduction..................................................................................87
11.7.1.1.
Background ................................................................87
11.7.1.2.
Literature Review .......................................................87
11.7.1.3.
Ancillary Study Rationale............................................88
11.7.2.
Ancillary Study OBJECTIVES......................................................89
11.7.2.1.
Primary Objectives .....................................................89
11.7.2.2.
Secondary Objective ..................................................89
11.7.3.
Ancillary Study design..................................................................90
11.7.3.1.
Study Design..............................................................90
11.7.3.2.
Site Selection .............................................................90
11.7.3.3.
Data Flows .................................................................91
11.7.3.4.
Study Procedures and Processes...............................93
11.7.3.4.1.
DCRI ......................................................93
11.7.3.4.2.
Sites .......................................................95
11.7.4.
DATA ANALYSIS.........................................................................96
11.7.4.1.
Sample Size Expectations..........................................96
11.7.4.2.
Objective 1: Assess the Barriers to Using as 
EHR-Generated List of Patients to Facilitate 
Trial Enrollment ..........................................................96
11.7.4.3.
General Analytic Approach for Objective 1 and
Objective 2 .................................................................96
11.7.4.4.
Objective 2: Evaluate the Fitness of EHR Data 
for Use in Populating the Baseline 
Characteristics in the eCRF........................................98
11.7.4.5.
Objective 3: Explore the Use of EHR Data to 
Find Events of Interest During Trial Follow-up ............98
11.8.
Appendix 8: Country Specific Requirements.............................................100

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11.9.
Appendix 9: Protocol Amendment Changes..............................................101
11.9.1.
Changes Resulting from Protocol Amendment 1........................101
11.9.2.
Changes Resulting from Protocol Amendment 2........................105

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LIST OF ABBREVIATIONS
ACCF
American College of Cardiology Foundation
ADA
American Diabetes Association
AE
adverse event
AHA
American Heart Association
ALT (SGPT)
alanine aminotransferase (serum glutamic pyruvic 
transaminase)
ANCOVA
analysis of covariance
AST (SGOT)
aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase)
BI
baseline basal insulin population
BMI
body mass index
bpm
beats per minute
CABG
coronary artery bypass graft
CAD
coronary artery disease
CEC
Cardiovascular Endpoint Committee
CI
confidence interval
CPK
creatine phosphokinase 
CONSORT
Consolidated Standards of Reporting Trials
DCRI
Duke Clinical Research Institute
DNA
deoxyribonucleic acid
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
EHR
electronic health record
ESC
European Society of Cardiology
FDA
US Food and Drug Administration
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
HbA1c
glycated haemoglobin
hCG
human chorionic gonadotrophin
HDLc
high density lipoprotein cholesterol
HLA
human leukocyte antigen 
HRT
hormone replacement therapy
IB
Investigator’s Brochure
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
INR
international normal range
IRB
Institutional Review Board
ITT
intent-to-treat
IVRS
Interactive Voice Response System

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KM
Kaplan-Meier
LDH
lactate dehydrogenase
LFT
liver function test
LDLc
low density lipoprotein cholesterol
MACE
major adverse cardiovascular event
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MEN-2
multiple endocrine neoplasia type 2
MSDS
Material Safety Data Sheet
MTC
medullary thyroid cancer
NHLBI
National Heart, Lung and Blood Institute
NI
non-insulin population
PAD
peripheral arterial disease
PD
pharmacodynamics
PHI
Protected Health Information
PK
pharmacokinetics
PP
per protocol
RAP
Reporting Analysis Plan
RR
relative risk
s.c.
subcutaneous
SAE
serious adverse event
SRM
Study Reference Manual
SU
sulfonylureas
TC
total cholesterol
Tg
triglycerides
TIA
transient ischemic attack
TRIM-D
Treatment Related Impact Measures-D
ULN
upper limit of normal range
WHF
World Heart Federation
WHO
World Health Organization
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
EQ-5D
PopMedNet
SAS

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PROTOCOL SUMMARY
Rationale
Albiglutide is a novel analogue of glucagon-like peptide-1 (GLP-1) with a sufficiently 
long half-life to permit once a week injection. Albiglutide is licensed for the treatment of 
type 2 diabetes as an adjunct to diet and exercise, as monotherapy, or in combination with 
existing therapies, including basal insulin. The Food and Drug Administration (FDA) has 
issued guidance on evaluating cardiovascular risk in new anti-diabetic therapies to treat 
type 2 diabetes [FDA Guidance for Industry, 2008].  For a premarketing application that 
contains a meta-analysis of major adverse cardiovascular events (MACE) for which the 
upper bound of the 95 percent confidence interval for the relative risk is between 1.3 and 
1.8, a post-marketing trial generally will be necessary to definitively show that the upper 
bound of the two-sided 95 percent confidence interval for the estimated risk ratio is less 
than 1.3.  The MACE meta-analysis of the albiglutide Phase III program  (primary 
endpoint cardiovascular death, myocardial infarction, stroke and hospitalization for 
unstable angina), whilst ruling out an upper bound of the confidence interval for 
cardiovascular events of 1.8, was not able to rule out (due to a relatively small number of 
events) a relative risk (RR) upper bound of 1.3.  For this reason GlaxoSmithKline (GSK) 
will conduct this cardiovascular outcome study as a US post-marketing requirement, to 
evaluate the effect of albiglutide on cardiovascular events in subjects with type 2 
diabetes.
Objectives/Endpoints
Objectives
Endpoints
Primary
To determine whether 
albiglutide is non-inferior with 
respect to MACE when added 
to glycaemic standard of care 
versus standard of care alone

Time to first occurrence of MACE (cardiovascular death, 
myocardial infarction,  or stroke) [Non-inferiority]
Secondary
To supplement the primary 
objective by further 
characterization of the effects of 
albiglutide on cardiovascular 
outcomes 

Time to first occurrence of MACE [Superiority](1 see footnote)

Time to first occurrence of the following:

MACE or urgent revascularisation for unstable angina

The individual components of the primary endpoint

Cardiovascular death or hospitalization due to heart failure
To evaluate the effects of 
albiglutide on metabolic 
management of type 2 diabetes

Time to initiation of insulin of more than 3 months duration for 
those subjects not treated with insulin at study start (1 see footnote)

Time to initiation of prandial insulin in those subjects on basal insulin at 
study start

The proportion of subjects achieving glycaemic control (HbA1c ≤ 
7.0% at final assessment) with no severe hypoglycaemic incidents 
and weight gain <5% of body weight (1 see footnote)

The time to first occurrence of a clinically important microvascular 
event (see Section 6.2.4)

Change in glycated haemoglobin (HbA1c)

Change in body weight

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Objectives
Endpoints

Patient reported outcomes from Treatment Related Impact Measures-
D (TRIM-D)/EQ5D
To evaluate the safety of 
albiglutide

All cause mortality

Non-fatal serious adverse events (SAEs)

Adverse events (AEs) leading to discontinuation of investigational 
product 

AE of special interest (see Section 6.2.3)

Change in estimated glomerular filtration rate (eGFR) calculated using 
Modification of Diet in Renal Disease (MDRD) formula

Change in blood pressure and heart rate
1.
If the primary endpoint meets the criteria for non-inferiority, a multiple comparisons adjustment strategy will 
be performed for these 3 secondary endpoints as specified in the Section 8.3.5.
Overall Design
This is a randomised, double blind, parallel group, placebo-controlled study. 
Treatment Arms and Duration
All subjects will receive standard of care for their diabetes and cardiovascular health 
which can be adjusted by the healthcare professional responsible for the subject during 
the study according to clinical need and with close adherence to professional society 
treatment guidelines.  The study comparison is thus between albiglutide added to 
standard of care and standard of care alone.  Placebo injections will be used to ensure 
study assessments are performed without knowledge of treatment assignment.  Treatment 
with albiglutide or placebo will be randomly allocated in a 1:1 ratio.  The starting dose of 
albiglutide is 30 mg weekly which may be up-titrated to 50mg weekly if further 
improvement of glycaemic control is required. 
The study will be event driven, i.e. follow up will continue until it is projected that 
approximately 611 adjudicated MACE events will have occurred. Consequently, the 
maximum duration of the study for an individual participant is dependent both on the 
time taken for recruitment and the MACE event rate, and is estimated to be between 3 
and 5 years. 
An Independent Data Monitoring Committee (IDMC) will have study oversight to ensure 
participant safety and scientific integrity of the data.
Type and Number of Subjects
A total of 9400 subjects with type 2 diabetes and a previous history of cardiovascular  
disease and who do not have optimal glycaemic control will be studied. 
Analysis
The study’s primary question is whether albiglutide is non-inferior by a margin of 1.3 
with respect to its effect on adjudicated MACE, when added to glycaemic standard of 
care, versus standard of care alone. The primary analysis is an Intent-to-Treat (ITT) 

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analysis of the time to the first occurrence of MACE using Cox’s Proportional Hazard 
regression.  

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1.
INTRODUCTION
1.1.
Background
Diabetes affects an estimated 347 million people worldwide, with type 2 diabetes 
accounting for more than 90% of cases [WHO, 2013]. The primary manifestation of this 
disease is chronic hyperglycaemia, resulting from resistance to insulin action at a cellular 
and molecular level and a relative inadequacy in the secretion of endogenous insulin 
[American Diabetes Association, 2014]. Chronic hyperglycaemia has been firmly 
established as a key factor in the development of microvascular complications 
(retinopathy, nephropathy, and neuropathy).  Individuals with type 2 diabetes are also at 
greatly elevated risk of cardiovascular disease.
The management of glycaemia in individuals with type 2 diabetes consists of diet, 
exercise, and weight reduction together with oral anti-diabetic drug, injectable agents 
such as GLP-1 receptor agonists or insulin therapy, to achieve near normoglycaemia as 
reflected by a target HbA1c level of 7%, where possible, without significant 
hypoglycaemia or other adverse effects of treatment. Despite the large number of 
available therapeutic agents, a high proportion of subjects fail to achieve or maintain 
target HbA1c levels [Khunti, 2013] owing to the inexorable decline in endogenous 
insulin production characteristic of the disease, and limitations in existing treatments. 
New agents with complementary mechanisms (permitting combination use) or more 
favourable safety profiles are needed to help more subjects achieve glycaemic targets. 
GLP-1 is secreted by intestinal L-cells in response to ingestion of food. In a healthy 
individual, it plays an important role regulating postprandial blood glucose by stimulating 
glucose-dependent insulin secretion by the pancreas. GLP-1 suppresses glucagon 
secretion, leading to reduced hepatic glucose output. It also delays gastric emptying time 
and slows small bowel motility, delaying food absorption and slowing the rate of glucose 
appearance in the blood. In patients with type 2 diabetes the postprandial rise in 
endogenous GLP-1 is absent or reduced [Vilsbøll, 2001]. 
GLP-1 receptor agonists have been developed as anti-hyperglycemic therapy for type 2 
diabetes to replace or supplement endogenous GLP-1 in order to increase meal-related 
insulin secretion, reduce inappropriate glucagon secretion, and slow GI motility. They 
have demonstrated substantial effectiveness in improving glycaemic control while 
mitigating the risk of hypoglycaemia and weight gain commonly associated with some of 
the other treatments for type 2 diabetes [Stonehouse, 2012].  
Albiglutide is a novel analogue of GLP-1 generated through a genetic fusion of 2 
modified recombinant human GLP-1 molecules linked in tandem to recombinant human 
albumin. Albiglutide is licensed for the treatment of type 2 diabetes as an adjunct to diet 
and exercise, as monotherapy, or in combination with existing therapies (oral anti-
diabetic therapies or basal insulin).  It has been granted marketing authorisation by the 
European Medicines Agency (EMA) (March 2014) and the FDA (April 2014).  Details of 
the clinical trial results can be found in the Investigator Brochure (IB).

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1.2.
Rationale
The FDA has issued guidance on evaluating cardiovascular risk in new anti-diabetic 
therapies to treat type 2 diabetes [FDA Guidance for Industry, 2008]. For a premarketing 
application that contains a meta-analysis of MACE, for which the upper bound of the 95 
percent confidence interval for the relative risk is between 1.3 and 1.8, a post-marketing 
trial may be necessary to definitively show that the upper bound of the two-sided 95 
percent confidence interval for the estimated risk ratio is less than 1.3.
The MACE + meta-analysis of the albiglutide Phase III program (primary endpoint 
cardiovascular death, myocardial infarction, stroke and hospitalization for unstable 
angina), whilst ruling out an upper bound of the confidence interval for cardiovascular 
events of 1.8, was not able to rule out (due to a relatively small number of events) a RR 
upper bound of 1.3. For this reason GSK will conduct this cardiovascular outcome study 
as a US post-marketing requirement, to evaluate the effect of albiglutide on 
cardiovascular events in subjects with type 2 diabetes. 
Preclinical studies have provided evidence that GLP-1 receptor stimulation favourably 
effects endothelial function, recovery from ischemic injury, and myocardial function in 
animals [reviewed in Okerson, 2012]. Albiglutide reduced infarct size assessed 24 hours 
after 30 minutes temporary left anterior descending coronary artery occlusion in 
normoglycaemic rats [Bao, 2011]. GLP-1 infusion has been shown to improve 
endothelial function in subjects with stable coronary disease [Nystrom, 2004]. In subjects 
with ST-segment elevation myocardial infarction treated with primary percutaneous 
coronary intervention, the GLP-1 receptor agonist, exenatide, administered at the time of 
reperfusion has been reported to increase myocardial salvage [Lønborg, 2012].  In the 
Phase III studies, small mean increases in heart rate (1 to 2 bpm) and a higher incidence 
of atrial fibrillation/flutter events were observed with albiglutide.  It is difficult to predict 
whether these preclinical and clinical findings will translate into effect on major 
cardiovascular events.

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2.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
To determine whether 
albiglutide is non-inferior with 
respect to MACE when added 
to glycaemic standard of care 
versus standard of care alone

Time to first occurrence of MACE (cardiovascular death, 
myocardial infarction,  or stroke) [Non-inferiority]
Secondary
To supplement the primary 
objective by further 
characterization of the effects of 
albiglutide on cardiovascular 
outcomes 

Time to first occurrence of MACE [Superiority](1 see footnote)

Time to first occurrence of the following:

MACE or urgent revascularisation for unstable angina

The individual components of the primary endpoint

Cardiovascular death or hospitalization due to heart failure
To evaluate the effects of 
albiglutide on metabolic 
management of type 2 diabetes

Time to initiation of insulin of more than 3 months duration for 
those subjects not treated with insulin at study start (1 see footnote)

Time to initiation of prandial insulin in those subjects on basal insulin at 
study start

The proportion of subjects achieving glycaemic control (HbA1c ≤ 
7.0% at final assessment) with no severe hypoglycaemic incidents 
and weight gain <5% of body weight (1 see footnote)

The time to first occurrence of a clinically important microvascular 
event (see Section 6.2.4)

Change in HbA1c

Change in body weight

Patient reported outcomes from TRIM-D/EQ5D
To evaluate the safety of 
albiglutide

All cause mortality

Non-fatal SAEs

AEs leading to discontinuation of investigational product 

AE of special interest (see Section 6.2.3)

Change in eGFR calculated using MDRD formula

Change in blood pressure and heart rate
Exploratory
To evaluate patient reported 
experience of diabetes treatment

Patient reported outcomes from study specific questionnaire
To evaluate (at a subset of sites) 
barriers to using the electronic 
health record (EHR) to facilitate 
trial enrolment and the quality of 
EHR data for use in populating 
baseline characteristics and 
identifying events of interest 
during trial follow-up.2

Workflow impact of an EHR-generated list of subjects to facilitate trial 
enrolment. 

Concordance, sensitivity, specificity, and accuracy of baseline 
characteristics extracted from the EHR compared with those reported 
on the electronic case report form (eCRF)3

Concordance, sensitivity, specificity, and accuracy of EHR-identified 
events compared with study events 3,4
1.
If the primary endpoint meets the criteria for non-inferiority, a multiple comparisons adjustment strategy will 
be performed for these 3 secondary endpoints as specified in the Section 8.3.5.
2.
Details are provided in a separate EHR ancillary study protocol (Appendix 7).  Results from this exploratory 
investigation will be reported separately from the main clinical study report.
3.
Comparison of EHR identified events with study events will be conducted in the same data subset.
4.
Analyses to be undertaken after the main trial results are published.

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3.
STUDY DESIGN
3.1.
Overall Design
This is a randomised, double blind, parallel-group, placebo-controlled, multicentre study.  
In countries where marketing authorization has been granted to albiglutide for the 
treatment of type 2 diabetes it is classified as a Phase IV study, elsewhere is should be 
considered to be a Phase III study. This study will recruit approximately 9400 subjects 
with type 2 diabetes and a previous history of cardiovascular disease who are failing to 
achieve optimal glycaemic control on their current anti-hyperglycaemic regimen. 
Subjects will be randomised in a 1:1 ratio to albiglutide or albiglutide matching placebo 
administered once weekly by subcutaneous (s.c.) injection.  
All subjects will receive standard of care which can be adjusted by their usual care 
provider(s) during the study according to clinical need (See Section 3.2). The study 
comparison is between albiglutide added to standard of care and standard of care alone.  
The starting dose of albiglutide will be 30 mg once weekly. If at any stage after 5 weeks 
of treatment the subject needs to have intensified therapy to improve glycaemic control, 
the dose of investigational product should be increased before altering the doses of or 
adding other glucose-lowering medication. This treatment decision will be the 
responsibility of the investigator. In this case the subject will called in for an unscheduled 
visit to increase the dose from 30 mg to 50mg. Subjects randomly assigned to albiglutide 
matching placebo will also go through the increased dose procedure to maintain study 
blind. If a subject experiences tolerability issues with the higher, 50mg dose then the 
investigator may decrease the dose back to 30 mg without the need for an unscheduled 
visit to supervise down titration. Use of GLP-1 receptor agonists will be prohibited but 
other glucose-lowering medications permitted, provided they are not contraindicated for 
the individual subject concerned.
This study is designed with minimal intervention above normal clinical care of subjects 
with type 2 diabetes, whilst allowing thorough evaluation of  cardiovascular and other 
events of special interest (Section 6.2.3), thus investigating the safety of albiglutide in the 
typical clinical situation.  Sites will employ pre-screening to assess potential subjects for 
study entry. Screening and randomisation can then occur at the same visit or in close 
proximity depending on scheduling.  Contact with subjects will be every four months 
after the randomisation visit. HbA1c will be measured at 4 month clinic visits. Serum 
creatinine and liver function tests (LFTs) will be measured and a targeted physical 
assessment performed at 8 month clinic visits (Table 1). 
The study will be event driven, i.e., follow up will continue until it is projected that 
approximately 611 adjudicated MACE events will have occurred. Consequently, the 
maximum duration of the study for an individual participant is dependent both on the 
time taken for recruitment and the MACE event rate, and is estimated to be between 3 
and 5 years. If the observed rate for MACE is 2.0% or 3.0%, the mean follow-up will be 
3.2 or 2.2 years, respectively.  

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An Executive Committee will be the main decision-making body for the study, in 
collaboration with the Sponsor (GSK).  It is charged with the overall scientific, 
professional and operational conduct of the study.  Amongst other roles pre-specified in 
its Charter, the Executive Committee will ensure proper study conduct and conformance 
to the protocol, consider and agree  changes to the protocol based on emerging scientific 
and/or clinical advances (e.g., new emerging data with other GLP-1 receptor agonists), 
advise on the selection of study sites and assist in subject recruitment strategies.
An IDMC will have study oversight to ensure participant safety and scientific integrity of 
the data (Section 9.8), an independent Cardiovascular Endpoint Committee (CEC) 
blinded to treatment allocation will adjudicate cardiovascular outcome events (Section 
6.2.1) and a Pancreatitis Adjudication Committee will adjudicate potential events of 
pancreatitis.
Subject completion is defined as completion of all periods of the study up to and 
including any follow-up period.
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 (Table 1), are essential and required for study 
conduct. 
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Reference Manual (SRM). The SRM will provide 
the site personnel with administrative and detailed technical information that does not 
impact subject safety.
3.2.
Standard of Care
Anti-hyperglcaemic and cardiovascular medications will be used at the discretion of the 
usual care provider(s) (or investigator if also the usual care provider), who will be 
informed of the patient’s enrolment in the trial, the use of blinded trial medication, and 
that use of GLP-1 receptor agonists  (other than the use of  randomised albiglutide)  is 
contraindicated during the trial period. Usual care providers will be encouraged to follow 
the most up to date guidelines for diabetes and cardiovascular care based upon local and 
institutional practice patterns and any relevant published practice guidelines (e.g., 
Inzucchi, 2012).  Treatment for type 2 diabetes will be captured by name and total daily 
dose at the time of study visits, while other relevant (cardiovascular) concomitant 
medications will be collected only as drug classes (see Section 5.6.1). 
During the study investigators are expected to monitor patients’ type 2 diabetes regimens 
and communicate with usual care providers, who will be responsible for adjusting their
regimen in order to achieve locally-appropriate HbA1c goals.  The Executive Committee 
and National Country Leaders will encourage investigators to follow clinical care 
practice guidelines published by national and international societies regarding type 2 
diabetes over the course of the trial.  These practice guideline goals will be 
individualized, with the understanding that currently applicable glycaemic guidelines 
may vary among different geographic regions.  With adherence to local custom and laws 

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(including privacy regulations such as the Health Insurance Portability and 
Accountability Act), types of communication may be informal e.g. email or telephone 
exchanges, to enhance frequency and ease of two-way communication.
Any agent, with the exception of GLP-1 receptor agonists, is acceptable for reaching 
HbA1c goals.  If HbA1c goals are not met following adjustment with oral medications in 
patients not receiving insulin, an insulin regimen may be initiated. Patients already 
receiving insulin therapy may up-titrate insulin during the trial if necessary. Patients 
should be reminded to keep taking their blinded trial medication throughout the course of 
the trial even in the case after initiation of insulin.
The Executive Committee and National Country Leaders will also monitor the standard 
of care of management of diabetes and cardiovascular disease. Similar to the 
management of type 2 diabetes, sites and investigators will be expected to adhere to local 
clinical practice guidelines.  Sites will be provided training on clinical management 
guidelines to re-enforce standard of care adherence. Information on medications 
important to management of cardiovascular risk will be captured during study visits.  The 
Executive Committee and National Country Leaders will review on a periodic basis the 
use of medications for cardiovascular risk prevention to ensure patients are receiving 
standard of care. If there are unusually low goal attainments for standard of care, site 
investigators will be advised accordingly.
3.3.
Discussion of Design
This study is a clinical outcomes trial required by FDA as a post-marketing requirement 
to evaluate cardiovascular safety.  It will provide important information regarding the 
cardiovascular safety and metabolic effects of albiglutide treatment of subjects with type 
2 diabetes.  Sufficient MACE events must be observed during the study to permit the 
assessment of cardiovascular safety.  Consequently, to enter the study subjects must have 
established cardiovascular disease as well as type 2 diabetes. The study is powered on a 
predefined number of clinical events, consequently the number of subjects required and 
study duration may vary from that stated in the protocol.
This will be a double-blind, placebo-controlled study. All subjects will receive placebo or 
albiglutide in addition to usual standard of care for type 2 diabetes and cardiovascular 
disease, in order to assess the effect of albiglutide above that of currently available 
therapies alone.
The primary cardiovascular comparison will be to assess whether albiglutide is non-
inferior to placebo with respect to time to first MACE. Missing data may inappropriately 
bias comparison towards declaring non-inferiority. The longer the duration of a study, the 
more difficult it is to avoid loss to follow-up and other sources of missing data. The 
product of the projected duration of this study and the number of subjects to be studied is 
intended to minimize the risk of missing data whilst still permitting the assessment of the 
safety of albiglutide to be over an appreciable period of time. Every effort will be made 
to keep subjects on their assigned study medication according to the protocol.  Subjects 
who stop study medication will be followed throughout the whole study duration.  More 
details about procedures for subject follow-up are provided in Section 4.5.

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Phase III studies confirmed the glycaemic 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 glycaemia for at least 2 years in many subjects with type 2 
diabetes, an increase in dose to 50 mg weekly offered additional benefit without 
significant safety issues (See IB for further details).  
3.4.
Benefit:Risk Assessment
Albiglutide has been evaluated in an international programme of studies involving 
approximately 9000 subject-years of overall exposure to date (including over 4000 
subject-years of exposure to albiglutide). The programme included 8 well-controlled 
Phase III studies (including one in subjects with concurrent renal impairment), ranging in 
duration from 32 weeks to 3 years, and using both 30 mg and 50 mg once weekly dosing.  
This has permitted a thorough assessment of efficacy, safety, and tolerability in a 
population of subjects with type 2 diabetes that spanned newly diagnosed individuals 
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 
albiglutide can be found in the IB and in the product labelling for those countries where 
marketing authorisation has been granted.  The following section outlines the risk 
assessment and mitigation strategy for this protocol:  
3.4.1.
Risk Assessment
The identified and potential risks associated with the use of albiglutide, or the GLP-1 
receptor agonist class, as well as the mitigation strategy for key risks of clinical 
significance are provided below. Please refer to the IB for a thorough summary of the 
nonclinical and clinical experience with albiglutide as well as the complete Guidance for 
the Investigator. The risks associated with study comparator, placebo, are also provided 
below.  Subjects will have the AE profile of GLP-1 receptor agonists, and albiglutide in 
particular, explained to them by the investigator and via the informed consent form.
3.4.1.1.
Identified Risks
Pancreatitis. Acute pancreatitis has been reported in association with albiglutide and 
other GLP-1 receptor agonists in clinical trials and during  postmarketing experience. 
Albiglutide has not been studied in subjects with a history of pancreatitis to determine 
whether they are at increased risk for pancreatitis. Subjects with a history of pancreatitis 
or who are considered at significant risk of developing pancreatitis are excluded from 
entering the study. Subjects will be informed of the characteristic symptom of 
pancreatitis: persistent severe abdominal pain. If pancreatitis is suspected, investigational 
productshould be promptly discontinued and if pancreatitis is confirmed, investigational 
product will not be restarted.
Gastrointestinal events. Albiglutide has not been studied in subjects with severe 
gastrointestinal (GI) disease, including severe gastroparesis. Subjects with severe 
gastroparesis will be excluded from the study. Use of albiglutide and other GLP-1 

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receptor agonists can be  associated with GI side effects such as diarrhoea, nausea, and 
vomiting; the frequency of these events increased as renal function decreased.  These 
types of GI reactions can be associated with dehydration and worsened renal function. 
(see below and see Section 4.4.4). Other GI related adverse reactions with albiglutide 
include dyspepsia, gastro-oesophageal reflux disease and constipation.
Hypoglycaemia. Albiglutide’s mechanism of action is associated with a low intrinsic risk 
of significant hypoglycaemia. However, when used in combination with insulin (or 
insulin secretagogues) the risk of hypoglycaemia is increased. Investigators will be 
reminded that it may be necessary to reduce the dose of insulin or insulin secretagogues
when starting study medication to reduce the risk of hypoglycaemia. Routine standard of 
care for subjects treated with insulin secretagogues and insulin includes advice about 
avoidance of hypoglycaemia which will be reinforced.  All subjects are required to have a 
last indicator of glycemic control of above  HbA1c = 7% which is expected to reduce the 
risk of hypoglycaemia when starting albiglutide. 
Immunogenicity. Hypersensitivity reactions are of potential concern with any injected 
protein and were reported rarely in the Phase III programme. In the Phase III programme 
one subject (anti-albiglutide antibody negative) developed rash, itching and dyspnoea . 
Subjects with known allergy to any GLP-1 receptor agonist or excipients of albiglutide 
are excluded from the study.  Subjects will be informed of the symptoms of severe 
hypersensitivity or allergy and be advised to seek medical assistance immediately. In the 
Phase III programme approximately 5% of subjects developed anti-albiglutide antibodies.  
Subjects who tested positive for anti-albiglutide antibodies experienced a similar 
glycaemic response (HbA1c and fasting plasma glucose) to those who did not test 
positive for antibodies. Other than injection site reactions (see below), the overall safety 
profile appeared similar among the subset of subjects who did and those who did not test 
positive for anti-albiglutide antibodies.  Anti-albiglutide antibody formation is not 
expected to impact the overall safety of albiglutide treatment and therefore will not be 
measure routinely in this study. 
Injection site reactions. Albiglutide injections may cause rash, erythema or itching 
and/or other reactions at the site of injection. . Subjects will be advised that when 
injecting in the same region, to use a different injection site each week. In the Phase III 
program, most subjects with injection site reactions did not test positive for anti-
albiglutide antibodies. However, injection site reactions were reported more frequently 
among those who did test positive for anti-albiglutide antibodies (41% of the antidrug 
antibody positive subjects reported one or more injection site reactions) than among those 
who were consistently antibody negative (14% of the antidrug antibody negative subjects 
reported one or more injection site reactions) .  
Other adverse reactions (e.g. pneumonia, atrial fibrillation/flutter, and appendicitis). In 
the Phase III programme in type 2 diabetes, other possible albiglutide related adverse 
reactions were identified. These events occurred at a cumulative incidence <3% in studies 
up to 3 years in duration. These events were reported more frequently with albiglutide 
than comparators. 

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3.4.1.2.
Potential Risks
Thyroid C-cell tumours. GLP-1 receptor agonists, including albiglutide increase serum 
calcitonin in rodents and other GLP-1 receptor agonists are associated with thyroid C-cell 
focal hyperplasia and C-cell tumours in rodents  It is unknown whether GLP-1 receptor 
agonists are associated with thyroid C-cell tumours in humans, including medullary 
thyroid cancer (MTC). 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. Subjects with treatment emergent thyroid nodules should be referred to a specialist 
for evaluation in accordance with local treatment guidelines.  Routine monitoring of 
serum calcitonin is not recommended.  However, if serum calcitonin is found to be 
elevated the subject should be referred to a specialist for further evaluation. If MTC or 
other thyroid C-cell neoplasia is diagnosed, investigational product will be discontinued.
Other malignant neoplasms Concerns have been raised regarding use of incretin based 
therapies and other malignancies such as pancreatic cancer [Egan, 2014], malignancy 
when used in combination with insulin based on hypotheses of biological plausibility 
[European Public Assessment Report, 2014], and haematological malignancies [FDA 
Summary Basis of Approval, 2014].
Hepatotoxicity. Hepatotoxicity is an area of interest in drug development.  Patients with 
type 2 diabetes are at increased risk for liver enzyme abnormalities and disease related 
liver conditions.  One subject treated with albiglutide in the Phase III clinical programme 
developed probable drug induced liver injury with an asymptomatic elevation in alanine 
amino transferase (ALT) and total bilirubin although the cases 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 4.4.3).
Subject population with severe renal impairment (eGFR <30 mL/min/1.73m2).
Experience in type 2 diabetes subjects with severe renal impairment is limited (in the 
Phase III programme a total of 19 subjects with eGFR <30 mL/min/1.73m2 received 
albiglutide). 
In a Phase 3 study of patients with varying degrees of renal impairment, in the albiglutide 
group, on-therapy GI AEs occurred with a higher incidence and higher event rate in 
subjects with moderate and severe renal impairment compared to those with mild renal 
impairment. Because these GI events may lead to dehydration and worsen renal function, 
worsening renal function will be closely evaluated as an AE of special interest, serum 
creatinine will be measured every 8 months, and subjects will discontinue IP if eGFR 
falls below 15 mL/min/1.73m2. Subjects with known severe renal impairment are 
excluded from the study (see Section 4.4.4).
Drug Interactions.  Like other members of the class, albiglutide causes a delay in gastric 
emptying, and thereby has the potential to impact the absorption of concomitantly 
administered oral medications. During the development programme, drug interactions 
studies were conducted with digoxin, warfarin, oral contraceptives, and simvastatin 
which demonstrated no clinically relevant PK or PD effects. Investigators will be advised 

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to take the effect of albiglutide on gastric emptying into account when prescribing 
concomitant medication.
Pregnancy and Lactation.  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.  
Placebo control. In subjects treated with placebo, symptoms and long-term risks of 
hyperglycaemia may not improve or may worsen. During the study, intensification of 
glucose-lowering treatments other than study drug will be allowed in both treatment arms 
with a treat-to-target approach. Albiglutide placebo injections may cause injection site 
reactions. Subjects will be advised when injecting into the same region to use a different 
injection site each week.
3.4.2.
Benefit Assessment
In subjects with type 2 diabetes albiglutide treatment resulted in clinically relevant 
lowering of HbA1c at both the 30 mg and 50 mg doses when given as monotherapy and 
in combination with metformin, sulfonylureas (SUs), thiazolidinedione or basal insulin . 
The durability of the effect on glycaemic control was shown over a study period of up to 
3 years. Consistent with its mechanism of action, albiglutide was not associated with 
clinically relevant hypoglycaemia except when used in combination with an SU or 
insulin, and incidence rates with the combination were less than those reported with SUs 
or insulin alone. Treatment with albiglutide generally produced a steady reduction in 
weight over time.
For subjects not yet on insulin at the start of the study, data from the Phase III programme 
suggest that the use of albiglutide once weekly in a pen device may have the potential to 
delay the need to start daily insulin injections.  This will be formally assessed within this 
trial.  Similarly, it is possible that for those already taking basal insulin, albiglutide may 
delay the need to introduce short-acting prandial injections and for those taking 
basal/bolus or pre-mixed insulin, it may reduce the dosage of insulin and/or the number 
of daily injections needed to achieve good glycaemic control.  These will also be 
evaluated in the study.
Subjects in the placebo arm will also be receiving effective anti-hyperglycaemic 
medication which will be titrated up or down as required to improve or maintain 
glycaemic control, and therefore these subjects should also demonstrate reductions in 
HbA1c, though weight gain (rather than weight loss) may occur depending upon the 
medication selected.   

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Finally, as a result of participating in a clinical trial, each subject will receive more 
contact with the study site than would be performed as part of their usual standard of 
care.
3.4.3.
Overall Benefit:Risk Conclusion
Taking into account the measures taken to minimise risk to subjects participating in this 
study, the known and potential risks identified with albiglutide are justified by the 
benefits have been demonstrated in subjects with type 2 diabetes.
4.
SUBJECT SELECTION AND WITHDRAWAL CRITERIA
4.1.
Inclusion Criteria
Specific information regarding warnings, precautions, contraindications, AEs, and other 
pertinent information on the GSK investigational product or other study treatment that 
may impact subject eligibility is provided in the IB for albiglutide and in the product 
label for those countries where marketing authorisation has been granted.
Deviations from inclusion criteria are not allowed because they can potentially jeopardise 
the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential.   
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
1. Men or women at least 40 years old with a diagnosis of type 2 diabetes.
2. Established cardiovascular disease, including at least 1 of the following:
a. Coronary artery disease with EITHER of the following:
Documented history of spontaneous myocardial infarction, at least 30 days 
prior to Screening.
Documented coronary artery disease (CAD) ≥ 50% stenosis in 1 or more 
major epicardial coronary arteries, determined by invasive angiography, or 
history of surgical or percutaneous (balloon and/or stent) coronary 
revascularization procedure (at least 30 days prior to Screening for 
percutaneous procedures and at least 5 years prior to Screening for coronary 
artery bypass graft (CABG)).
b. Cerebrovascular disease – ANY of the following:
Documented history of ischaemic stroke, at least 90 days prior to study entry.
Carotid arterial disease with 50% stenosis documented by carotid 
ultrasound, magnetic resonance imaging or angiography, with or without 
symptoms of neurologic deficit.

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Carotid vascular procedure (e.g. stenting or surgical revascularisation), at 
least 30 days prior to Screening.
c. Peripheral arterial disease (PAD) with EITHER of the following: 
intermittent claudication and ankle:brachial index < 0.9 in at least one ankle 
prior non-traumatic amputation, or peripheral vascular procedure (e.g. 
stenting or surgical revascularisation), due to peripheral arterial ischaemia.
3. HbA1c >7.0% (53 mmol/mol) based on the most recent documented laboratory 
assessment measured no more than 6 months prior to randomization. Local 
laboratory HbA1c values taken as part of usual care are permitted.
4. Female: subject is eligible to participate if she is not pregnant (as confirmed by a 
negative urine 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 GSK 
Modified List of Highly Effective Methods for Avoiding Pregnancy in Females 
of Reproductive Potential (FRP) (e.g, combined oral contraceptive pill; see 
Appendix 2) 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.
This 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. 
Other situations in which contraception in FRP may not need to be mandated 
should be discussed with the Medical Monitor.
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 oestradiol 
<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.
5. Able and willing to provide informed consent.

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4.2.
Exclusion Criteria
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardise the scientific integrity of the study, regulatory acceptability or subject safety. 
Therefore, adherence to the criteria as specified in the protocol is essential. 
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
1. eGFR calculated using MDRD formula <30mL/min/1.73m2 (based on the most 
recent documented serum creatinine laboratory assessment measured no more than 6 
months prior to randomization. Local laboratory creatinine values taken as part of 
usual care are permitted) or renal replacement therapy.
2. Use of a GLP-1 receptor agonist at Screening.
3. Severe gastroparesis requiring therapy within 6 months prior to Screening. 
4. History of pancreatitis or considered clinically at significant risk of developing 
pancreatitis during the course of the study (e.g. due to symptomatic gallstones, 
excess alcohol use).
5. Personal or family history of medullary carcinoma of the thyroid or subject with 
MEN-2. Personal history of pancreatic neuroendocrine tumours. In the opinion of the 
investigator, the subject has a medical history which might affect his / her ability to 
remain in the study for its entire duration, or which might limit management, such as 
life expectancy of <5 years (e.g. due to active malignancy).
6. Subject has a medical history which in the opinion of the investigator might limit the 
individual’s ability to take trial treatments for the duration of the study or to 
otherwise complete the study.
7. Breastfeeding, pregnancy, or planning a pregnancy during the course of the study. 
Pregnancy test will be required in women of child bearing potential. Women who 
have undergone a sterilisation procedure or who are clearly post-menopausal will not 
be required to undergo pregnancy testing.  Women who have developed spontaneous 
secondary amenorrhoea of 12 months or more where post-menopausal status is in 
doubt, a blood sample where FSH >40MU/ml and oestrodiol <40 pg/mL (<140
pmol/L) are simultaneously measured will be considered confirmatory.
8. Known allergy to any GLP-1 receptor agonist or excipients of albiglutide.
9. Use of another investigational product within 30 days or according to local 
regulations, or currently enrolled in a study of an investigational device.
10. Any other reason the investigator deems the subject to be unsuitable for the study.

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4.3.
Screening/BaselineFailures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomised.  In order to ensure transparent reporting of screen 
failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements [Schulz, 2010], and respond to queries from regulatory 
authorities, a minimal set of screen failure information is required including 
Demography, Screen Failure details, Eligibility Criteria, and any SAEs.
Re-screening of subjects who did not meet the eligibility criteria for HbA1c or creatinine 
based on local laboratory values taken as part of usual care is permitted. If values were 
based on laboratory results as part of usual care then one re-test is permitted within the 
protocol at Screening. Any future re-screening will be based on laboratory results 
obtained as part of usual care.
4.4.
Criteria for Early Discontinuation of Investigational Product
The primary analysis will be conducted on an ITT analysis basis so it is important that 
every subject is followed for the duration of the study, regardless of whether the subject 
continues to take investigational product, unless consent for all follow up is actively 
withdrawn.
The requirements for handling early discontinuations from investigational product are 
described below. Details of the requirements for subject follow-up are provided in 
Section 4.5.
4.4.1.
Early Discontinuation of Investigational Product
If a subject chooses to discontinue investigational product between scheduled face-to-
face visits they should be encouraged to contact the investigator site by telephone.  
Subjects should first be counselled to consider temporary discontinuation of 
investigational product prior to choosing to discontinue investigational product 
permanently, unless the reason for discontinuation is one of those listed below (Reasons 
for Discontinuation of Investigational Product).  If the discontinuation is permanent, the 
subject should be asked to attend the clinic as soon as possible to complete the 
assessments as for the final study visit (see Table 1) and then continue in the study for 
follow-up. The procedures for follow-up for a subject who permanently discontinues 
treatment with investigational product prior to the study end are given in Section 4.5. 
In all cases, reasons for discontinuation of investigational product and the date of last 
dose will be recorded. 

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4.4.2.
Reasons for Discontinuation of Investigational Product
Any subject experiencing the following will be required to discontinue investigational 
product:

AE:

Pancreatitis, acute or chronic. 

Pancreatic cancer.

MTC or other thyroid C-cell neoplasia.  In subjects where a treatment emergent 
thyroid nodule is identified, if serum calcitonin is measured at the discretion of 
the Investigator (e.g., per local guidelines) and found to be >100 ng/L this 
should prompt further investigation for MTC and potential interruption or 
discontinuation of investigational product until diagnosis has been resolved.

Liver chemistry abnormalities exceeding the threshold criteria outlined in 
Section 4.4.3

Severe allergic/hypersensitivity reactions that are considered by the investigator 
to be attributable to investigational product or without a likely alternative 
aetiology.

Other AE which, in the opinion of the investigator precludes continuation of 
dosing.

eGFR<15ml/min/1.73m2 (Section 4.4.4) or the need for renal replacement therapy.

Subject becomes pregnant during the study.

Need for chronic use of a prohibited concomitant medication (Section 5.6.2)

Decision by subject or proxy.

Sponsor terminated study.

Investigator site closed and subject was unable to transfer to another investigative 
site.
If investigational product is discontinued, the subject should continue in the study and be 
followed until the final study visit as detailed in Section 4.5.
4.4.3.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event aetiology (in alignment with the FDA 
premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf

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Phase III-IV Liver Chemistry Stopping and Increased Monitoring Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus 
Bilirubin≥2x
ULN (>35% 
direct) or plus
INR>1.5, if 
measured*
Possible  
Hy’s Law
ALT≥3xULN
ALT
≥8xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
No
Yes
Yes
Yes
No
No
No
See algorithm 
for continued 
therapy with 
increased liver 
chemistry 
monitoring
Yes
*INR value not applicable to subjects on anticoagulants 
ALT 
≥3xULN 
but 
<8xULN
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*

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Liver safety required actions and follow up assessments section can be found in 
Appendix 3.
Phase III-IV 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*
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 3.
Drug re-challenge following drug induced liver injury is not allowed. 
Restart may be considered if GSK Medical Governance approval is granted (see 
Appendix 4 for details). Restart refers to resuming study treatment following liver 
stopping events in which there is a clear underlying cause (other than DILI) of the liver 
event (e.g. biliary obstruction, pancreatic events, hypotension, acute viral hepatitis). 
Furthermore, there should be no evidence of alcoholic hepatitis or hypersensitivity, and 
the study treatment should not be associated with human leukocyte antigen (HLA) 
markers of liver injury.
4.4.4.
eGFR Stopping Criteria
A baseline eGFR ≥ 30mL/min/1.73m2 is a requirement for entering the study. Subjects 
can continue to take investigational product if functioning well as long as eGFR is 
≥15mL/min/1.73m2. 
During this study, if a subject’s eGFR approaches 30mL/min/1.73m2 closer monitoring of 
renal function is considered prudent, according to standard clinical practice. Particular 

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care should be taken to monitor renal function in subjects with renal impairment 
reporting severe adverse GI events. If eGRF is <15mL/min//1.73m2 and considered 
irreversible based on consecutive measurements the investigational product should be 
discontinued, the subject continue in the study and be followed until the final study visit. 
If eGRF is <15mL/min/1.73m2 and the patient is considered to have temporary acute 
kidney injury that is potentially reversible, the investigational product should be 
temporarily discontinued until the eGRF is stable and ≥15mL/min//1.73m2. Events 
considered to reflect worsening renal function should be reported as SAE/AEs and 
targeted eCRFs completed for this AE of special interest (Section 6.2.3).
4.5.
Procedures for Subject Follow-up
As described in Section 4.4, subjects who permanently discontinue investigational 
product will be asked to attend the clinic as soon as possible.  They will continue in the 
study for follow-up. Five weeks (1 week) after discontinuation of investigational 
product, subjects will be contacted for a follow-up by telephone.  They will be asked to 
return to clinic according to the 8 monthly visit schedule and in addition be contacted by 
telephone at a time corresponding to the 4-monthly visit they would have otherwise made 
to replenish study medication supply. If instead of these interim telephone contacts the 
subject prefers to attend clinic every 4 months as originally scheduled that is an 
acceptable alternative.
If a subject permanently discontinues investigational product and is unable to attend visits 
in-person, he/she will be contacted by telephone or other methods to assess study 
outcomes and vital status, unless the subject has specifically withdrawn consent for all 
forms of contact. Follow-up of subjects who withdraw consent for contact is described 
below.
Every effort should be made to educate the subjects on the importance of remaining in 
the study and attending scheduled study visits including those required after early 
discontinuation of investigational product. 
Other subject follow-up options to collect study outcomes and vital status should be 
pursued according to local laws and regulations. If one of these alternate methods to 
collect study outcomes and vital status is acceptable to the subject, then the subject will 
be deemed not to have withdrawn consent for follow-up.
4.5.1.
Withdrawal of Consent for Contact
Subjects who no longer wish to attend study visits in-person will be asked to be contacted 
by telephone or other methods to assess study outcomes and vital status.  However, if a 
subject specifically withdraws consent to be contacted for additional information, no 
further study visits or study-related telephone contacts can be conducted. Information 
regarding study outcomes or vital status will continue to be collected from available 
sources including those in the public domain. Additionally, alternative permitted options 
to obtain study outcomes and vital status will be reviewed based on accepted local laws 
and regulations. For any subject who withdraws consent for contact, the study site will be 

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asked to document the discussion with the subject regarding each of the contact options 
that were offered.
4.5.2.
Subjects Deemed Lost to Follow-up
Finally, investigators should make every effort to contact subjects who are deemed lost to 
follow-up and who have not withdrawn consent to follow-up contacts, including pursuing 
any alternative contact methods permitted by local regulations. Where permitted, a third 
party may be used to locate alternative subject contact information that will be provided 
to the investigator. All attempts to contact subjects will be documented in the subject’s 
eCRF and source notes. 
Should a subject fail to attend the clinic for a required study visit, the site should attempt 
to contact the subject and re-schedule the missed visit as soon as possible. The site should 
also counsel the subject on the importance of maintaining the assigned visit schedule. In 
cases where the subject does not return for the rescheduled visit or cannot be reached to 
reschedule the missed visit, the site should make every effort to regain contact with the 
subject. Should the subject continue to be unreachable, then and only then will he/she be 
considered “Lost to Follow-up”. Nonetheless, efforts to attempt to locate and contact the 
subject will continue until the study end. 
5.
STUDY TREATMENTS
5.1.
Investigational Product and Other Study Treatment
Albiglutide (and albiglutide matching placebo) will be provided as a fixed-dose, fully 
disposable pen injector system for delivery of the investigational product (albiglutide or
albiglutide matching placebo) from a prefilled dual chamber glass cartridge that is an 
integral part of the pen. The pen is intended for single use by the subject. It is designed 
for manual reconstitution of the dose, priming and insertion of the pen needle, and 
manual injection by the subject. 
Albiglutide (or albiglutide matching placebo) is intended for self-administration as a 
subcutaneous injection in the abdomen, thigh or upper arm region.  Rotation of use of 
injection sites is recommended. Albiglutide and insulin may be injected in the same body 
region but the injections should not be adjacent to each other.  The albiglutide pen 
includes a mechanical locking system that prevents the user from manipulating the dose 
button before the cartridge has been fully reconstituted. Reconstitution is performed 
through rotation of the pen housing parts. The pen is designed to work with standard pen 
needles.
When the injector pen product is reconstituted by the subject, a neutral, isotonic solution 
is produced. Separate pens are required to deliver either 30 mg of albiglutide, 50 mg of 
albiglutide, or matching placebo in a 0.5-mL injection volume.
The contents of the label will be in accordance with all applicable regulatory 
requirements.

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Under normal conditions of handling and administration, investigational product is not 
expected to pose significant safety risks to site staff.  Take adequate precautions to avoid 
direct eye or skin contact and the generation of aerosols or mists. Notify the monitor of 
any unintentional occupational exposure.  A Material Safety Data Sheet (MSDS) 
describing the occupational hazards and recommended handling precautions will be 
provided to site staff if required by local laws or will otherwise be available from GSK 
upon request.
The investigational product (albiglutide and albiglutide matching placebo) must be stored 
in a secure area at 2°C to 8°C and protected from freezing. Each site must maintain a 
temperature log.  Access to and administration of the investigational product will be 
limited to the investigator and authorised site staff (investigator or designee).  
Investigational product must be dispensed or administered only to subjects enrolled in the 
study and in accordance with the protocol.
Procedures for the disposal of unused study treatment will be provided in the SRM.
Investigational product (albiglutide or albiglutide matching placebo) will be administered 
once weekly by subcutaneous injection. The first dose is to be administered at the clinic. 
The starting dose of albiglutide will be 30 mg once weekly.  If at any stage after 5 weeks 
of treatment in the opinion of the investigator the subject needs to have intensified 
therapy to improve glycaemic control, the dose of investigational product should be 
increased before altering the doses of other glucose-lowering medication. In this case the 
subject will called in for an unscheduled visit to supervise an increase in dose from 30 mg 
to 50 mg.  Subjects randomly assigned to albiglutide matching placebo will also go 
through the increased dose procedure to maintain study blind. If a subject experiences 
tolerability issues with the higher, 50mg dose then the investigator may decrease the dose 
back to 30 mg without the need for an unscheduled visit to supervise down titration, other 
than for the subject to collect pens of the correct dose.
Albiglutide (or albiglutide matching placebo) may be administered at any time of day 
without regard to meals. Preferably, it should be administered once a week on the same 
day each week. The day of weekly administration can be changed if necessary as long as 
the last dose was administered 4 or more days previously. If a dose is missed, it should be 
administered as soon as possible within 3 days after the missed dose. Thereafter, subjects 
can resume dosing on their usual day of administration. If it is more than 3 days after the 
missed dose, subjects should wait and administer their next regularly scheduled weekly 
dose.  
If a subject misses 4 or more consecutive doses, the investigator should contact the
medical monitor to discuss options for helping assure better compliance.
5.2.
Treatment Assignment
Subjects will be assigned to study treatment in accordance with the randomisation 
schedule.

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Randomised treatment assignment will be done via the Interactive Voice Response 
System (IVRS), and randomisation will be implemented based on a sequestered fixed 
randomisation schedule. Study centre personnel will call the IVRS once a subject has met 
all prerequisites for randomization; the IVRS will assign treatment.
Blinded study centre personnel will receive a randomisation notification indicating the 
unique subject identifier (randomisation number) and the date and time of randomisation. 
Each randomisation number will be a unique identifier. Once a randomisation number 
has been assigned, the number will not be reused even if the subject withdraws before 
receiving any investigational product. Details of the treatment assignment process are 
contained in the SRM.
5.3.
Blinding
This is a double-blind study, neither the subject nor the study physician will know which 
of the two treatments (albiglutide or placebo) the subject is receiving.
The investigator or treating physician may unblind a subject’s treatment assignment only 
in the case of an emergency or in the event of a serious medical condition, when 
knowledge of the study treatment is essential for the appropriate clinical 
management or welfare of the subject, as judged by the investigator.  Investigators 
have direct access to the subject’s individual study treatment.  It is preferred (but not 
mandatory) that the investigator first contacts the GSK Medical Monitor or appropriate 
GSK study personnel to discuss options before unblinding the subject’s treatment 
assignment.  If GSK study personnel are not contacted before the unblinding, the 
investigator must notify GSK as soon as possible after unblinding, but without revealing 
the treatment assignment of the unblinded subject, unless that information is important 
for the safety of subjects currently in the study.  The date and reason for the unblinding 
must be fully documented in the appropriate data collection tool.
If a subject is unblinded by the investigator or treating physician then discontinuation of 
investigational product treatment for that subject will be at the discretion of the 
investigator. However, the subject should continue to be followed in the study (see 
Section 4.5).
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any subject with an SAE.  If the SAE requires that an expedited 
regulatory report be sent to one or more regulatory agencies, a copy of the report, 
identifying the subject’s treatment assignment, may be sent to clinical investigators in 
accordance with local regulations and/or GSK policy.
5.4.
Product Accountability
In accordance with local regulatory requirements, the investigator, designated site staff, 
or head of the medical institution (where applicable) must document the amount of 
investigational product dispensed and/or administered to study subjects, the amount 
returned unused by study subjects, and the amount received from and returned to GSK, 

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when applicable.  Product accountability records must be maintained throughout the 
course of the study.
5.5.
Treatment Compliance
Subjects will be instructed to return all unused and used injector pens at the visits 
specified in the Time and Events Table (Table 1) in order to perform drug accountability 
and determine compliance. Subjects will be provided with a sharps container for the 
disposal of used pens.  To comply with health and safety considerations there will be no 
count made of used pens; only returned unused pens will be counted. In addition, subjects 
will be provided with a pre-printed card at each dispensing visit to record the date of each 
dose. The card is to be returned at the next dispensing visit with the unused pens.
5.6.
Concomitant Medications and Non-Drug Therapies
5.6.1.
Permitted Medications and Non-Drug Therapies
The usual care provider will manage the subjects according to standard of care, following 
local prescribing information. Close adherence to professional society guidelines for 
standard of care therapies in type 2 diabetes and cardiovascular disease will be 
emphasized during study conduct. Standard of care is described in greater detail in 
Section 3.2.
Unless specified as a prohibited medication in Section 5.6.2, all concomitant medications 
should be considered permitted provided they are not contraindicated for the individual 
subject concerned.
Like other members of the class, albiglutide causes a delay in gastric emptying, and 
thereby has the potential to impact the absorption of concomitantly administered oral 
medications.  This should be taken into account by investigators when prescribing 
concomitant medication.
It may be necessary to reduce the dose of concomitantly administered insulin 
secretagogues (such as SUs) or insulin to reduce the risk of hypoglycaemia when starting 
albiglutide.
All concomitant anti-hyperglycaemic medications (name of agent, total daily dose, start 
and stop dates) will be recorded in the eCRF at each visit. Concomitant cardiovascular 
medications taken during the study will also be recorded at each visit by class of agent.
Additionally, all medications used within the 30 days prior to the onset and throughout 
the duration of an SAE, AE of special interest (Section 6.2.3), or an AE leading to 
discontinuation of investigational product will be recorded as individual agents, reason 
for use, together with start dates (and stop dates if applicable) and any changes since any 
previous AE.

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5.6.2.
Prohibited Medications and Non-Drug Therapies
Subjects may not take a GLP-1 receptor agonist (other than blinded investigational 
product), nor any investigational drug, during the study (and any follow-up period after 
discontinuing investigational product).
If a subject receives a prohibited medication, a protocol deviation will be recorded.
5.7.
Treatment after the End of the Study
Following the final study visit subjects will be contacted by telephone 5 1 weeks after 
last dose of study medication to assess any AEs ongoing since the last visit or newly 
emergent. 
Subjects will be treated as deemed appropriate by the investigator following the end of 
the study. Investigational product will not be provided to subjects by GSK after the end 
of the study.
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 investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition whether or not GSK is providing specific 
post study treatment.
5.8.
Treatment of Study Treatment Overdose
No data are available with regard to albiglutide overdose in humans. The highest 
recommended dose of albiglutide is 50 mg once weekly.
During clinical studies of subjects with type 2 diabetes, the highest dose of albiglutide 
administered was 100 mg subcutaneously every four weeks for 12 weeks. This dose was 
associated with an increased frequency of nausea, vomiting, and headache. 
There is no specific antidote for overdose with albiglutide. In the event of a suspected 
overdose, the appropriate supportive clinical care should be instituted, as dictated by the 
subject’s clinical status. Anticipated symptoms of an overdose may be severe nausea, 
vomiting or headache.  A prolonged period of observation and treatment for these 
symptoms may be necessary, taking into account the half-life of albiglutide (5 days).
6.
STUDY ASSESSMENTS AND PROCEDURES
The schedule of study assessments is shown in Table 1 and Table 2. Detailed procedures 
for each assessment are provided in the SRM.

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Table 1
Time and Events Table
Procedures1,2
Screening3
Randomization3
/Baseline 
(can be same day as 
Screening Visit)
Study Drug 
Check Phone 
Call
(4-6 wks post 
rand.)
Clinic Visit Month 4 
18 days then 
every 4 months 
18 days throughout 
the study
Unscheduled 
dose 
adjustment visit
(if warranted)
Final study 
clinic 
visit4 (or early 
withdrawal)
Follow up Phone 
Call
5 1 weeks after 
last IP dose
Written informed consent  
X
Review of Inc/excl criteria
X
X
Demography & directed medical history
X
Assessment of MACE  and micro-vascular events
X
X
HbA1c
X5
X
X
Serum creatinine (eGFR)
X5
X (alternate visits) 2
X
Liver Function Tests (LFTs)6
X
X (alternate visits) 2
X
Record available information on most recent lipid 
assessment 7
X
X (annually)
X
Genetic sampling8
X
Patient reported outcomes questionnaires9
X10
X (alternate visits) 2
X
Key concomitant non-diabetes medication
X
X
X
X
Diabetes medication
X
X
X
X
Study drug reminder
X
X
X
Physical examination11
X
X (alternate visits) 2
X
SAEs, AEs of special interest, AEs leading to IP 
discontinuation 
X
X
X
X
X
X
Pregnancy test12
X
X
Study drug dispense/compliance13
X
X
X
X
1. Subjects who discontinue investigational product should be handled as described in Section 4.4 and Section 4.5 and in Table 2.
2. Assessments at month 8, 16, 24 etc. will include patient reported outcomes questionnaires, serum creatinine (eGFR), LFTs and physical examination. Those at months 4, 12, 20 
etc do not. .
3. Screening and Randomisation can occur at the same visit if all eligibility information is available. If Screening and Randomisation occur at the same visit assessments should not 
be duplicated.
4. Once it is projected that the target number of MACE events will have been collected, a 3 month window will be defined for conducting the final, face to face visit.
5. HbA1c and creatinine assessed using local laboratories at Screening visit and measured no more than 6 months prior to randomisation. If HbA1c or creatinine have not been 
assessed in the previous 6 months assessments to be performed via a central laboratory and results available prior to randomization. The investigator has the discretion to repeat 

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screening HbA1c, and/or creatinine, based on clinical rationale even if previously available local results meet the eligibility criteria to allow the investigator to accommodate the 
possibility of change between screening and randomisation.
6. Liver function tests: ALT, AST, alkaline phosphatase, bilirubin, GGT. Blood samples for LFTs at randomization must be collected prior to the first dose of investigational product.
7. Lipid values (TC, LDLc, HDLc, Tg) to be recorded as available from routine clinical care at baseline and annually thereafter. If results are unavailable, lipids tests are not to be 
performed for the study.
8. Informed consent for genetic research must be obtained before collecting a sample.  This can be collected at any time after genetic consent has been obtained and  randomisation
has occurred.
9. TRIM-D, EQ-5D and study specific questionnaire (details in Section 6.3).
10. TRIM-D is not required for subjects whose diabetes is treated by diet and exercise alone at Baseline.
11. See Section 6.2.7.  
12. Only applies to women of child bearing potential. At screening perform urine pregnancy test.  If positive, send serum sample to the central laboratory for confirmation. At 
Randomisation perform a urine pregnancy test. If result is positive do not randomize the subject. If the urine pregnancy test is negative then the subject can be randomised. If 
Screening and Randomisation are to take place at the same visit then follow the instructions for Screening. See Section 6.2.6.
13. Study drug dispensing not performed at final visit, compliance check not performed at Randomisation.

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Table 2
Time and Events Table for Subjects Who Permanently Discontinue IP Prior to the End of the Study
Procedures
Clinic visit as soon 
after permanent 
discontinuation of 
IP as possible
Phone Call
5 1 week 
after last IP 
dose
Continue contact schedule 
established at randomisation
4 monthly 1 month. 
Telephone 1,2
Continue contact schedule 
established at randomisation 
4 monthly 1 month. 
Clinic visit 1,3
Final study clinic 
visit 4
Assessment of MACE  and micro-vascular events
X
X
X
X
HbA1c
X
X
X
Serum creatinine (eGFR)
X
X
X
Liver Function Tests (LFTs)5
X
X
X
Record available information on most recent lipid 
assessment6
X
X (annually)
X (annually)
X
Patient reported outcomes questionnaire7
X
Key concomitant non-diabetes medication
X
X
X
X
X
Diabetes medication
X
X
X
X
X
Physical examination8
X
X
X
AEs leading to IP discontinuation
X
SAEs, AEs of special interest, 
X
X
X
X
X
Study drug compliance
X
1. After subjects permanently discontinue IP, follow-up should continue on the 4-monthly schedule established at randomisation.
2. Where a subject would have been scheduled to attend clinic at months 4, 12, 20, 28 etc after randomisation, a telephone contact will be performed instead (with assessments as 
shown above).
3. Where a subject would have been scheduled to attend clinic at months 8, 16, 24, 32 etc after randomisation, a clinic visit will be performed (with assessments as shown above).
If a subject who has permanently discontinued IP is unable to attend clinic then they will be contacted by telephone instead and the telephone contact assessments will be 
performed.
4. Once it is projected that the target number of MACE events will have been collected, a 3 month window will be defined for conducting the final, face to face visit.
5. Liver function tests: ALT, AST, alkaline phosphatase, bilirubin, GGT.
6. Lipid values (TC, LDLc, HDLc, Tg) to be recorded as available from routine clinical care annually. If results are unavailable, lipids tests are not to be performed for the study.
7. TRIM-D, EQ-5D and study specific questionnaire (details in Section 6.3).
8. See Section 6.2.7.  

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6.1.
Critical Baseline Assessments
Disease, and therapy history, including cardiovascular medical history/risk factors will be 
assessed at Baseline. Investigators are encouraged to implement lifestyle modifications 
and adjust or initiate the appropriate pharmacotherapy throughout the study as 
recommended by current locally followed therapeutic cardiovascular and diabetes 
guidelines for participants in the study.  Screening and randomisation can occur at the 
same visit depending on availability of information to determine eligibility of the subject 
to enter the study.
6.2.
Safety
The following sections provide further detail on the safety assessments.  Planned time 
points for all safety assessments are listed in the Time and Events Table (Table 1).  
Unscheduled visits will occur as medically necessary. Detailed procedures for obtaining 
each assessment are provided in the SRM.
Safety endpoints are described in Section 2 and will include monitoring of cardiovascular 
events (Section 6.2.1), deaths, AEs of special interest (Section 6.2.3), clinically 
significant microvascular events (Section 6.2.4), SAEs and AEs leading to 
discontinuation of investigational product.
Liver chemistry stopping and follow-up criteria and AEs are described in Section 4.4.3
and Appendix 3.
6.2.1.
Cardiovascular Events
Events referred to the CEC by the investigator as potential endpoints or transient 
ischemic attacks (TIAs) will not be collected or reported as SAEs, regardless of the 
adjudication outcome (Section 6.2.2)1. These events will be reviewed by an Independent 
Data Monitoring Committee (Section 9.8).
The CEC will review and adjudicate the following clinical events:

Myocardial infarction

Stroke

Unstable angina requiring hospitalization

Hospitalization for heart failure

Sudden cardiac death

TIA
                                                
1 There is one exception to this statement. Per requirement of the Mexican Ministry of Health, all events 
referred to the CEC by Mexican investigators will also be submitted as SAEs to the Mexican Ministry 
of Health.

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
In addition, all clinical events submitted for adjudication and all other SAEs with a
fatal outcome will be reviewed and adjudicated to classify the cause of death as 
cardiovascular or non-cardiovascular.
When the local investigator reported event and the CEC decision on the nature of the 
event differ, the CEC’s decision will be considered final. The detailed descriptions of the 
endpoint (and TIA) definitions necessary for adjudication are contained within the CEC 
Charter (available on request). The guiding principle will be the “2014 ACC/AHA Key 
Data Elements and Definitions for Cardiovascular and Stroke End Point Events for 
Clinical Trials” [ACC/AHA, 2014] and the “Third Universal Definition of Myocardial 
Infarction” endorsed by the European Society of Cardiology (ESC), the American 
College of Cardiology Foundation (ACCF), the American Heart Association (AHA), and 
the World Heart Federation (WHF) [Thygesen, 2012].
Source documentation required to support the adjudication of the events is described in 
the SRM.  Recording of potential endpoint and TIA events in the eCRF and submission 
of source documentation will be required for clinical events meeting reporting criteria 
whether or not an endpoint event is suspected by the investigator.
6.2.1.1.
Other CV Events
GSK has identified other CV events of special interest for all clinical studies. 
Investigators will be required to fill out event specific data collection tools for the 
following cardiovascular events which meet SAEs criteria or are non-serious events that 
result in discontinuation of investigational product:  

Arrhythmias (other than atrial fibrillation/flutter, see Section 6.2.3) 

Valvulopathy

Pulmonary hypertension

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularisation (other than urgent revascularisation for unstable angina, a 
component of a secondary endpoint)
This information should be recorded in the specific cardiovascular eCRF within one 
week. 
6.2.2.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 5.
The investigator or site staff will be responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE.  
For this study events of myocardial infarction, stroke, unstable angina requiring urgent 
revascularization, hospitalization for heart failure, TIA and sudden cardiac death will not 

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be collected or reported as AEs or SAEs. These events will be collected separately, 
subjected to blinded adjudication by an independent CEC using prespecified diagnostic 
criteria, and reported separately (Section 6.2.1.1). All other events that meet serious 
criteria as defined in Appendix 5 should be reported as SAEs.
All events with an outcome of death will be adjudicated to classify the cause of death as 
specifically cardiovascular or non-cardiovascular. Any event resulting in death should be 
reported as a SAE unless the event is myocardial infartion, stroke, unstable angina w/ 
urgent revascularization, Heart failure, TIA or sudden cardiac death which the protocol 
specifies are not to be collected as adverse events. 
The study will not collect all non-serious AEs. Non-serious AEs leading to 
discontinuation of investigational product and non-serious AEs of special interest (see 
Section 6.2.3) will be collected. 
Any events not specifically addressed above should be reported as an AE or SAE 
according to the definitions in Appendix 5. 
6.2.2.1.
Time period and Frequency for collecting AE and SAE information

AEs and SAEs will be collected from the start of Study Treatment until the follow-
up contact (see Section 6.2.2.3), at the timepoints specified in the Time and Events 
Table (Table 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.

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. 

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Appendix 5.

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 5.

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6.2.2.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting SAEs. Open-ended and non-
leading verbal questioning of the subject is the preferred method to inquire about SAE 
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?” 
Additionally subjects will be asked specific questions about the occurrence of AEs of 
special interest (Section 6.2.3).
6.2.2.3.
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 6.2.3) 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 4.5). Further information on follow-up procedures is given in 
Appendix 5.
6.2.2.4.
Sentinel Events
A Sentinel Event is a GSK-defined SAE that is not necessarily drug-related but has been 
associated historically with adverse reactions for other drugs and is therefore worthy of 
heightened pharmacovigilance. Medical monitor review of all SAEs for possible Sentinel 
Events is mandated at GSK.  The GSK medical monitor may request additional clinical 
information on an urgent basis if a possible Sentinel Event is identified on SAE review. 
The current GSK-defined Sentinel Events are listed below:

Acquired Long QT Syndrome

Agranulocytosis/severe neutropenia 

Anaphylaxis and anaphylactoid reactions (see also Section 6.2.3)

Hepatotoxicity (see also Section 6.2.3)

Acute renal failure

Seizure

Stevens Johnson syndrome/toxic epidermal necrosis
6.2.2.5.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK or designee of SAEs and non-serious AEs 
related to study treatment (even for non- interventional post-marketing studies) is 

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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.
6.2.3.
Adverse Events of Special Interest
The investigator or site staff will be responsible for detecting, documenting and reporting 
events the following AEs of special interest:

Development of thyroid cancer 

Haematologic malignancy

Pancreatic cancer 

Pancreatitis 

Injection site reactions

Immunological reactions (e.g., drug hypersensitivity reactions involving 
anaphylaxis/anaphylactoid reactions, acute bronchoconstriction, angioedema, and/or 
acute urticaria) 

Severe hypoglycaemia events (which includes all events meeting the definition of 
SAEs Appendix 5)

Hepatic events

Hepatic enzyme elevations (including GGT)

Serious GI events

Appendicitis

Atrial fibrillation/flutter

Pneumonia

Worsening renal function

Diabetic retinopathy

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The results of any investigation should be recorded in the relevant sections of the 
subjects’ eCRFs. In addition, for thyroid, pancreas or haematological malignancies 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. In subjects where a treatment 
emergent thyroid nodule is identified, if serum calcitonin is measured at the discretion of 
the Investigator (e.g., per local guidelines) and found to be >100 ng/L this should prompt 
further investigation for MTC and potential interruption or discontinuation of 
investigational product until diagnosis has been resolved. If MTC or other thyroid C-cell 
neoplasia is diagnosed, albiglutide will be discontinued.
A Pancreatitis Adjudication Committee composed of independent specialists in 
gastroenterology will review all cases of possible pancreatitis. 
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 in the SRM.  These 
events should be reported as AEs or SAEs based on the clinical evaluation of the subject. 
The reactions should be followed to completion as typical for any AE or SAE.  Subjects 
with allergic or drug hypersensitivity reactions that are considered by the investigator to 
be attributable to investigational product or without a likely alternative aetiology should 
have investigational product withdrawn and not re-introduced.
Episodes of severe hypoglycaemia will be recorded according to subject report.  Severe 
hypoglycaemic incidents will be defined as those episodes of hypoglycaemic symptoms 
for which the subject required assistance from another person and from which the subject 
recovered promptly after oral carbohydrate, intravenous glucose, glucagon administration 
or other resuscitative actions (definition per ADA Workgroup on Hypoglycaemia 
[Seaquist, 2013]).  Additionally, all episodes of hypoglycaemic symptoms which in the 
investigator’s opinion meet the definition of a SAE (defined in Appendix 5) will be 
included as severe hypoglycaemic episodes. During this study, if a subject’s eGFR 
approaches 30mL/min/1.73m2 closer monitoring of renal function is considered prudent, 
according to standard clinical practice. If eGRF is <15mL/min//1.73m2 follow the 
procedure set out in Section 4.4.4.
6.2.4.
Clinically Important Microvascular Events
Clinically important microvascular events are defined as the following: need for renal 
transplant or dialysis, new diabetes-related blindness, and procedures (laser 
photocoagulation or anti-vascular endothelial growth factor treatment or vitrectomy for 
diabetic retinopathy/eye disease).  Clinically important microvascular events will be 
reported as recorded in the eCRF by the investigator without adjudication.

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The AEs associated with the above outcomes or treatments should be reported separately 
as an AE or SAE according to the definitions in Appendix 5.
6.2.5.
Pregnancy

If a subject becomes pregnant during the study they should discontinue 
Investigational Product.

Details of all pregnancies in female subjects will be collected after the start of 
dosing and until the end of the Post-treatment Follow-up Period.

If a pregnancy is reported then the investigator should inform GSK within 2 weeks 
of learning of the pregnancy and should follow the procedures outlined in Appendix 
6.
6.2.6.
Clinical Laboratory Assessments
All protocol required laboratory assessments must be conducted in accordance with the 
Laboratory Manual, and Protocol Time and Events Schedule (Table 1).  Details for the 
preparation and shipment of samples will be provided by the laboratory and are detailed 
in the laboratory manual. Reference ranges for all central laboratory safety parameters 
will be provided to the site.
If additional non-protocol specified laboratory assessments result in a change in subject 
management or are considered clinically significant by the investigator (e.g., SAE or AE 
of special interest or dose modification) the results must be recorded in the CRF.
Refer to the SRM/laboratory manual for appropriate processing and handling of samples 
to avoid duplicate and/or additional blood draws.
The following laboratory assessments will be performed: serum creatinine, HbA1c, liver 
function tests [AST (SGOT), ALT (SGPT), alkaline phosphatase, bilirubin, GGT], and 
urine and serum hCG pregnancy test (for women of child bearing potential). All study-
required laboratory assessments will be performed by a central laboratory, with the 
exception of HbA1c and creatinine at Screening and urine pregnancy test at 
Screening/Randomization. 
Screening HbA1c and serum creatinine
Screening HbA1c and serum creatinine values should be based on the most recent local 
laboratory values taken as part of usual care within the previous 6 months and the values 
entered into the eCRF. These assessments must have been performed at an accredited
laboratory.  HbA1c screening results must be either Diabetes Control and Complications 
Trial (DCCT) aligned or International Federation of Clinical Chemistry and Laboratory 
Medicine (IFCC) standardized.  HbA1c screening results from point of care equipment 
are acceptable provided that the equipment is maintained by an accredited laboratory.  If 
HbA1c or creatinine have not been assessed in the previous 6 months, laboratory 
assessments will be performed via the central laboratory to determine eligibility (if a 
local laboratory is used in error the results are acceptable for determining eligibility). The 

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investigator has the discretion to repeat screening HbA1c, and/or creatinine, based on 
clinical rationale even if previously available local results meet the eligibility criteria to 
allow the investigator to accommodate the possibility of change between screening and 
randomisation.
Re-screening of subjects who did not meet the eligibility criteria for HbA1c or creatinine 
based on local laboratory values taken as part of usual care is permitted. If values were 
based on laboratory results as part of usual care then one re-test is permitted within the 
protocol at Screening. Any future re-screening will be based on laboratory results 
obtained as part of usual care.
Pregnancy testing (for women of childbearing potential)
At the screening visit perform a urine pregnancy test. If the urine pregnancy test is 
positive, send a serum blood sample to the central laboratory for confirmation of 
pregnancy. 
At the Randomisation visit perform a urine pregnancy test. If the result is positive do not 
randomize the subject. If the urine pregnancy test is negative then the subject can be 
randomised (provided all other eligibility criteria have been met).
If Screening and Randomisation are to take place at the same visit then follow the 
instructions for Screening. Do not randomise if the urine pregnancy test is positive; send 
a serum blood sample to the central laboratory for confirmation of pregnancy. If the urine 
pregnancy test is negative then the subject can be randomised at the same visit (provided 
all other eligibility criteria have been met).
Lipids
Where serum lipid tests have been performed as part of the subject’s routine clinical care 
(i.e. not as a study procedure) the most recent results should be recorded at baseline and 
annually thereafter.  The lipid parameters to be recorded are total cholesterol (TC), low 
density lipoprotein cholesterol (LDLc), high density lipoprotein (HDLc) and triglycerides 
(Tg).
If any or all of these results are not already available from the subject’s records then 
separate lipid tests should not be performed solely for the study.
6.2.6.1.
Estimated Glomerular Filtration Rate (eGFR)
Serum creatinine will be measured every 8 months by a central laboratory. 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).

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6.2.7.
Physical examination
A general physical examination, including height and neck (thyroid), will be performed at 
randomization. A targeted physical examination will be performed at all other time points 
as specified in the Time and Events Table (Table 1). The targeted physical examination 
will evaluate the cardiovascular system and injection sites and will include measurement 
of blood pressure and heart rate taken with the subject either in a semi-recumbent or 
seated position after at least a 5-minute rest period.
6.3.
Value Evidence and Outcomes
6.3.1.
Value Evidence and Outcomes Assessments
6.3.1.1.
Treatment Related Impact Measure – Diabetes (TRIM-D)
In order to evaluate satisfaction with treatment and to compare satisfaction across 
treatment groups, the TRIM-D questionnaire will be self administered by all subjects at 
baseline (except for subjects whose diabetes is treated by diet and exercise alone) and all 
subjects at each 8 month visit (and, to the extent possible, at the time of study completion 
or withdrawal from the study).
The TRIM-D, developed in 2009, is a 28-item treatment satisfaction measure scored to 
produce 5 sub-scale scores (Treatment Burden, Daily Life, Diabetes Management, 
Psychological Health, and Compliance) as well as a total score. It is available in a wide 
range of translations.
The TRIM-D development, in accordance with the principles of the Food and Drug 
Administration Patient Reported Outcome Guidance document, was based on findings 
from the published literature including content from already-existing treatment 
satisfaction measures as well as significant input from subjects with type 1 and with type 
2 diabetes and from expert diabetes clinicians.  The TRIM-D has been evaluated in a 
sample of 507 subjects (74% with type 2 diabetes) and has been shown to have 
acceptable reliability and validity [Brod, 2009a]. Its responsiveness was also evaluated 
in a sample of 242 subjects (71% with type 2 diabetes) and found to be acceptable [Brod, 
2009b].  Some preliminary work has been done on estimating its minimal important 
difference but this needs further exploration [Brod, 2009b].
6.3.1.2.
EQ-5D
The EQ-5D will be self-administered by subjects in order to measure generic health 
status. Combining the EQ-5D with the disease-specific TRIM-D, which is designed to 
have maximum sensitivity to relevant aspects of disease related treatment, will provide a 
more robust evaluation of the impact of treatments for type 2 diabetes and allow for 
clearer interpretation of study results.  TRIM-D results, if consistent with the general 
trends seen in the EQ-5D, will have enhanced credibility.

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The EQ-5D is a standardized instrument used to evaluate generic health-related quality of 
life. It is applicable to a wide range of health conditions and treatments, and it provides a 
simple descriptive profile and a single index value for health status.  It is also used to 
provide utilities, or preference weights, for use in economic (cost effectiveness) 
evaluations.  It is available in 141 self complete official language versions.
The EQ-5D has been used extensively in studies to measure the impact of type 2 diabetes 
and treatments for the disease. A systematic review identified 54 publications reporting 
EQ-5D responses and 39 papers presenting evidence on the measurement properties of 
the EQ-5D in this population [Janssen, 2011].  This evidence supported the validity, 
reliability, and responsiveness of the EQ-5D for evaluating health-related quality of life 
in subjects with type 2 diabetes.  Other studies reported that index scores from the EQ-5D 
have been shown to be an independent predictor of the risk of mortality, future vascular 
events, and other complications in people with type 2 diabetes [Clarke, 2009]. In 
addition, the SHIELD longitudinal study (1,741 respondents with type 2 diabetes and 
4,543 without diabetes) used the EQ-5D to assess the 5-year changes in health-related 
quality of life in type 2 diabetes [Grandy, 2012].
6.3.1.3.
Exploratory Diabetes Management Questions
In addition to the standardised instruments described above, patient experience in relation 
to the management of their diabetes will be evaluated in a subset of sites using a small 
number of self-administered diabetes management questions. These types of customized 
questions have been used successfully in asthma and in diabetes when patients are 
involved with goal-setting [Juniper, 1992; Anderson, 2010]. This tailored approach is an 
opportunity to capture data in the study that are not otherwise available from standard 
PRO measures such as the TRIM-D and the EQ-5D. As an exploratory endpoint, this set 
of questions (3 items at baseline, and at each 8 month follow-up visit) imposes very little 
patient or site burden, but can offer critical insight into the one area of the patient’s 
choosing that s/he finds most difficult to manage. In addition, this patient-centred 
endpoint has the potential to be sensitive to changes over time.
These questions have been developed by GSK based on factors identified as important to
subjects in the development of published, validated and reliable subject reported 
outcomes instruments in type 2 diabetes.
6.3.1.4.
Healthcare Resource Utilisation
Data will be collected on the following heathcare resource use:

All cause hospitalisations and related healthcare resource use.
Healthcare resource use data  will be collected in order to facilitate subsequent health-
economic analyses comparing costs between albiglutide added to standard of care and 
placebo added to standard of care (cost is not an end point in the study). 
Data on all-cause hospitalizations and related inpatient healthcare resource use will be 
collected.  This will include:

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
All-Cause hospitalisation including: Admission and discharge diagnoses 
(primary and secondary), length of stay, level/type of ward, and time spent in 
Intensive Therapy Unit (or equivalent).
6.4.
Genetic Research
Information regarding genetic research is included in Appendix 1.  
7.
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.

Adverse events and concomitant medications terms will be coded using MedDRA 
(Medical Dictionary for Regulatory Activities) and an internal validated medication 
dictionary, GSKDrug.  

CRFs (including queries and audit trails) will be retained by GSK, and copies will be 
sent to the investigator to maintain as the investigator copy.  Subject initials will not 
be collected or transmitted to GSK according to GSK policy.
8.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS
8.1.
Hypotheses
This trial will examine the following primary question:

Whether albiglutide is non inferior by a margin of 1.3 with respect to its effect on 
adjudicated MACE, when added to glycaemic standard of care, versus standard of 
care alone. Letting λ1 = hazard ratio for time to first MACE for albiglutide vs 
placebo, then:
Null hypothesis: log λ1 ≥ log(1.3)
Alternative hypothesis: log λ1 < log(1.3)
8.2.
Study Design Considerations
8.2.1.
Sample Size Assumptions
The primary outcome will be analyzed such that the overall Type 1 error is no greater 
than 5% (two-sided).  Specifically, the non-inferiority assessment of albiglutide 
compared to placebo will be conducted at 0.05 level, requiring one-sided significance at 
0.025.  

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The power for MACE non-inferiority is calculated via the asymptotic variance and 
normality of the maximum likelihood estimator for the log-hazard ratio. Assuming a true 
hazard ratio of 1.0, 611 events will be needed to have 90% power to rule out non-
inferiority margin of 1.3 for the hazard ratio with type I error of 0.05.  The study duration 
will be event-driven.  A total of 9400 subjects will be enrolled and followed until it is 
projected that approximately 611 adjudicated MACE events will have occurred. If the 
observed rate for MACE is 2.0% or 3.0%, the mean follow-up will be 3.2 or 2.2 years 
respectively, assuming that the number of subjects lost to follow-up accounts for 1% or 
less.  
8.2.2.
Sample Size Sensitivity for MACE non-inferiority
9400 subjects will be enrolled to cumulate the first MACE events experienced by 611 
unique subjects. The study duration may vary depending on actual MACE event rate and 
duration of enrolment period.
Table 3
Total Study Duration Sensitivity for Varying MACE Event Rate and 
Duration of Recruitment
Duration of recruitment
1.5 yrs
2.0 yrs
2.5 yrs
3.0 yrs
MACE rate (% pa)
2.0
4.1yrs
4.4yrs
4.6yrs
4.9yrs
2.5
3.4 yrs
3.7yrs
3.9yrs
4.2yrs
3.0
3.0yrs
3.2yrs
3.5yrs
3.8yrs
3.5
2.7yrs
2.9yrs
3.2yrs
3.4yrs
8.2.3.
Sample Size Re-estimation
The aggregate blinded event-rate data will be periodically reviewed by the Executive 
Committee and the sponsor. The study has an event-driven design. Should emerging data 
diverge significantly from protocol assumptions, the total sample size and/or follow up 
time may be adjusted, within the bounds of feasibility, to achieve the event target.
8.3.
Data Analysis Considerations
8.3.1.
Analysis Populations
The intent-to-treat (ITT) population will include all randomly assigned subjects. The ITT 
subjects will be analyzed according to randomised treatment. The inference for primary 
objectives in the study will be made from ITT population.

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Per-protocol Population (PP) will exclude the subjects who have major protocol 
violations. Per-protocol analysis will include Per-protocol population only and their data 
upon to the time of discontinuation of investigational product plus 56 days.
The non-insulin population (NI) will include all subjects in the ITT population who are 
not on insulin at baseline. Inference for the time to insulin endpoint will be made from 
the NI population. 
The baseline basal insulin user population (BI) will include all subjects in the ITT 
population who are on basal insulin, but not on other insulin at baseline. Inference for the 
time to prandial insulin endpoint will be made on BI population.
The safety population will include all enrolled subjects who receive at least 1 dose of 
study treatment. The safety population subjects will be analyzed according to the 
treatment received. The safety population will be used for analyses of safety objectives.
Other analysis populations will be defined in the RAP. 
8.3.2.
Analysis Data Set
For time to event data, censoring time for subjects who lost to follow-up is defined as 
following:

For primary analysis, subjects who are lost to follow-up will be censored at the date 
of last evidence of confirmatory status for MACE events. 

For on-treatment analysis, censoring date will be the last dose date. 

For on-therapy analysis (on-treatment+56 days), censoring date will be the last dose 
date+56 days.

For analysis of all cause of mortality, censoring date will be the latest date known 
alive.
8.3.3.
Treatment Comparisons
Demographic and baseline characteristics (e.g., gender, age, racial or ethnic origin, height 
and weight, body mass index (BMI), blood pressure and other characteristics) will be 
summarized for each treatment group.  In addition, smoking and alcohol habits, diabetic 
and cardiovascular medical history, baseline laboratory results, and prior medications will 
be summarized by treatment group.  Binary and ordinal characteristics will be 
summarized by counts and percentages, while continuous variables will be represented by 
mean and standard deviations or medians and percentiles, as appropriate.  Any variables 
with treatment imbalances may be considered as covariates for further analysis of an 
exploratory nature.  Such covariates will be identified on the basis of the clinical 
relevance of the observed treatment difference.

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8.3.3.1.
Primary Comparisons of Interest
The primary endpoint will be the time to the first occurrence of MACE over the full 
duration of the study. A p-value for the primary endpoint will be calculated from a Cox 
Proportional Hazards (PH) regression model with treatment group as the only covariate 
for the hypotheses described in Section 8.1.
8.3.3.2.
Other Comparisons of Interest
For other analyses incidence rates will be presented for binary data and summary 
statistics (mean, median, standard deviation, minimum, and maximum) will be presented 
for continuous data.  Time to event endpoints will be evaluated via the p-value from a 
Cox PH regression model with treatment as the only covariate.  Furthermore, summary 
statistics of change from baseline for HbA1c will be presented along with percent of 
subjects within ranges of clinical interest (e.g., HbA1c < 7.0%).  Available lipid data will 
be summarized for descriptive purposes.
8.3.4.
Interim Analysis
An IDMC will monitor progress of the study and ensure that it meets the highest 
standards of ethics and subject safety.    All cardiovascular event data, together with other 
safety data, will be sent to the IDMC for review at approximately every 6 months after 
the first subject has been randomised to receive treatment.  This frequency may be 
adjusted, if deemed necessary by the IDMC, depending on the enrolment rates and the 
rate of safety events.  There are no plans to stop the study early for a non-inferiority or 
benefit claim, however should the IDMC identify in the course of its scheduled reviews 
overwhelming evidence of MACE benefit (e.g., p < 0.001), with directionally consistent 
findings on all-cause mortality, the IDMC might consider recommending early stopping.  
This approach essentially preserves the final alpha for the end-of-study analysis at 5% 
and hence there are no plans to adjust the final alpha on account on safety reviews 
conducted by the IDMC. The IDMC charter, reporting and procedures are outlined in 
separate documents.
8.3.5.
Multiplicity Controls
A multiple comparisons adjustment strategy will be implemented for the multiple 
inferential tests among the primary endpoint and secondary endpoints of MACE 
superiority, time to insulin and composite metabolic endpoint.
The strategy will use a combination of gatekeeper and Hommel procedure. The first step 
is to evaluate the MACE non-inferiority of the albiglutide group vs the placebo group at a 
one-sided alpha=0.025 level. If the result of non-inferiority is significant, MACE 
superiority, time-to-insulin and composite metabolic endpoint will be tested 
simultaneously using the Hommel procedure with alpha=0.05.  The above multiplicity 
control approach will preserve the study’s nominal significance level of 0.05. The test 
order is illustrated in the diagram below.

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Hommel Procedure for secondary endpoints is described below:
Three hypothesis tests for MACE superiority, time-to-insulin, and composite metabolic 
endpoint are subject to be adjusted by the Hommel procedure. Let P(1), P(2) and P(3) 
represent the ordered p-values that P(3) > P(2) > P(1) and H(1), H(2) and H(3) are 
corresponding hypotheses. 
If P(3)< 0.05, reject H(3), H(2), H(1). End of test.
If P(3) ≥0.05 and P(2) < 0.05/2, accept H(3), reject H(2), H(1). End of test.
If P(3)≥0.05 and P(2)≥0.05/2 and P(1) < 0.05/3, accept H(3), H(2), reject H(1). End of 
test.
If P(3)≥0.05, P(1)≥ 0.05/3 and 0.05/2≤ P(2)< 0.05*2/3, accept H(3), H(2), reject H(1). 
End of test.
If P(3)≥0.05, P(2)≥ 0.05*2/3 and P(1)≥ 0.05/3, accept H(3),,H(2) and H(1).
Other Secondary Endpoints and Subgroup Analysis
The following secondary endpoints will provide supportive evidence for cardiovascular 
safety and will not use any multiplicity adjustment procedure. 

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
Components of primary endpoint (MACE = cardiovascular death, MI, stroke)

MACE + urgent revascularisation for unstable angina

Cardiovascular death or hospitalisation for heart failure
Other secondary endpoints which do not qualify for formal statistical hypothesis testing 
will be analyzed and have results presented with confidence interval and nominal p-
values:

Mean HbA1c  at scheduled visits and change from baseline

Mean body weight at scheduled visits and change from baseline

Mean eGFR at scheduled visits and change from baseline

Time to initiation of prandial insulin

Composite microvascular endpoint
To examine the degree of consistency of the overall treatment effect in terms of important 
prognostic factors, subgroup analyses of the primary outcomes will be performed based 
on subject demographics and baseline characteristics. These exploratory subgroup 
analyses will not be adjusted for multiple comparisons and will be interpreted 
descriptively.
8.3.6.
Key Elements of Analysis Plan
Any deviations from the original analysis planned in the protocol agreed upon prior to 
finalization of the RAP, will be described in that document. Any additional changes to 
the planned analysis in the RAP will be described in the final clinical study report.
8.3.6.1.
Primary Analysis
The primary analysis is an ITT analysis of the time to the first occurrence of MACE over 
the full duration of the study. Time to event analyses will be performed using Cox’s 
Proportional Hazard regression with SAS PHREG with treatment group as the only 
covariate.  Data for subjects without a primary event will be censored.
Treatment differences will be estimated via the hazard ratio and its 95% confidence 
interval (CI). 
The hypothesis of non-inferiority of albiglutide relative to placebo group with hazard 
ratio less than 1.3 with respect to cardiovascular risk will be tested at the end of the study 
when ~611 first MACE events are cumulated.  
The strength of evidence for non-inferiority will be determined by testing the hypothesis 
that the observed hazard ratio is significantly different from the null margin of 1.3 (one-
sided p < 0.025 for such a test being equivalent to the upper 95% confidence limit after 
multiplicity adjustment for the hazard ratio being less than 1.3).  The absolute risk 
difference per 100 PY and superiority p-value for albiglutide vs. placebo will also be 
presented.

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The product-limit estimates of the probabilities (and their standard errors) of first MACE 
over time will be computed and displayed as Kaplan-Meier (KM) survival curves for  
albiglutide and placebo groups.  The KM curves will also be presented corresponding to 
the above comparisons.
The total number of all MACE or any of its components will be analyzed by Poisson 
regression model. The incidence rate per 100 person-years, relative risk and their 95% CI 
will be presented. Number of subjects who experienced at least one event, 2 or 3 or more 
MACE or its components will also be summarized by treatment group.
As sensitivity analyses, the analyses described above will be repeated using events occur 
while on-treatment and events occur during the period of on-treatment plus 56 days post 
last dose.
8.3.6.2.
Secondary Endpoint Analysis
Endpoints that supplement the primary objective by further characterization of the effects 
of albiglutide on cardiovascular outcomes endpoints: 

MACE superiority will be evaluated using the same Cox regression model as the 
primary analysis of MACE non-inferiority.

Supportive endpoints including the time to first occurrence of adjudicated MACE or 
urgent revascularisation for unstable angina, time to first occurrence of individual 
components of MACE, time to first occurrence of cardiovascular death or 
hospitalisation for heart failure will be analyzed using a proportional Cox regression 
model similarly as the primary endpoint.
Endpoints that evaluate the effects of albiglutide on metabolic management of type 2 
diabetes: 

Among the subjects who are not on insulin at baseline (NI population), time to 
insulin will be analyzed using a proportional Cox regression model similar to the 
primary MACE analysis. The product-limit estimates of the probabilities (and their 
standard errors) of adding insulin over time will be computed and displayed as 
Kaplan-Meier (KM) survival curves for albiglutide and  placebo treatment groups. 
The KM curves will also be presented corresponding to the above comparisons.

Composite of the proportion of those achieving good control (HbA1c ≤ 7.0%) AND 
no severe hypoglycaemic incidents AND weight gain <5% at the end of the study 
would be evaluated utilize nonparametric, covariance-adjusted, extended Mantel-
Haenszel tests. Additional analysis will be provided for scheduled visits. Nominal p-
values and 95% CIs will be presented for these visits. Time to introduction of 
prandial insulin in those on basal insulin orals anti-hyperglycemic drugs at baseline 
will be analyzed using a Cox PH model and KM method similar to the primary 
endpoint.

Composite of microvascular events will be analyzed using a proportional Cox 
regression model and KM method similar to the primary endpoint.

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
HbA1c, body weight and eGFR will be analyzed using a repeated mixed effect 
model. The least square means, 95%CIs and nominal p-values will be presented.

Additional analysis will be performed to assess the incidence rate of recurrent severe 
hypoglycaemic events between treatment groups during the course of the study. A 
repeated Poisson regression model including treatment and visit as factors will be 
used to test treatment difference with offset for person years. An unstructured 
working correlation matrix will be used in the iterative estimation process. The 
model-adjusted least square incidence rate for each treatment as well as the treatment 
difference of the incidence rate will be reported. Events of severe hypoglycaemia 
will also be summarized descriptively by treatment group. Additional summary by 
baseline HbA1c, renal status and age subgroup will also be provided.
Further analysis details will be provided in the RAP.
8.3.6.3.
Subgroup Analysis
Separate subgroup analyses of the primary outcomes will be performed based on subject 
demographics and baseline characteristics.  Subgroups may include sex, age group, BMI, 
whether subjects have history of a previous cardiovascular event, and baseline HbA1C, 
background of anti-hyperglycaemia treatment etc. The detail of subgroups will be pre-
specified in the RAP.  Consistency of treatment effects will be assessed using Cox 
regression, along with the 95% confidence intervals for the relative risk or hazard ratios 
for each subgroup a nominal alpha level for interaction of 0.10 will be used.  The effect 
of treatment interaction with subgroups will also explored; however as the number of 
these subgroup variables may be large, the probability of observing at least one 
statistically significant result may be high.  Thus these additional analyses will be 
considered exploratory regardless of the p-value associated with any interaction.
Further details will be provided in the RAP.
8.3.6.4.
Other Safety Analyses
Subject demographics, medical history, prior and concomitant medications, vital sign 
measurements, laboratory values, physical examination assessments, will be summarized 
by treatment group using descriptive statistics. 
For continuous variables, these summaries will include sample size, mean, median, 
standard deviation, minimum, and maximum. For categorical variables, the summaries 
will include frequencies and corresponding percentages. 
For SAEs, AEs leading to permanent IP withdrawal  and AEs of special interest, the 
number and percentage of subjects, total number of events and incidence density will be 
presented by treatment group and overall at the SOC and Preferred Term (PT) level. 
Relative Risk and its 95% CI may also be presented on a targeted basis. The time to first 
occurrence of specific events will be summarized.
All cause mortality will be summarized by treatment group and analyzed using a Cox PH 
model similarly as the-primary endpoint.

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All events sent to CEC (including TIAs) will be summarized.
Pancreatitis events will be adjudicated by the independent Pancreatitis Adjudication 
Committee. The information for investigator reported pancreatitis events and its 
adjudication results will be summarized.
Further analysis details will be provided in the RAP.
8.3.6.5.
Value Evidence and Outcomes Analyses
TRIM-D total score and score for each domain will be summarized descriptively by 
treatment group and scheduled visit. Score changes from baseline will be compared
between treatments for each visit by an ANCOVA model.
For EQ-5D, subjects’ responses at each visit for the 5 domains will be summarized 
categorically by treatment group, together with the summary of utility score at each visit 
and change from baseline by treatment group. Change from baseline will be compared 
between treatment groups for each visit by an ANCOVA model. 
For study specific PRO questions, responses will be summarized descriptively by 
treatment group and scheduled visit. 
Healthcare resource use will be summarized by treatment group and visit. 
Further analysis details will be provided in the RAP.
9.
STUDY CONDUCT CONSIDERATIONS
9.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrolment of subjects begins.
9.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a site, GSK will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH E6 Good Clinical Practice 
(GCP), all applicable subject privacy requirements, and the guiding principles of the 
current version of the Declaration of Helsinki.  This includes, but is not limited to, the 
following:

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
IRB/IEC review and favourable opinion/approval of the study protocol and 
amendments as applicable

Signed informed consent  to be obtained for each subject before participation in the 
study (and for amendments as applicable)

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol deviations 
to IRB/IEC)

GSK will provide full details of the above procedures, either verbally, in writing, or 
both.
Signed informed consent must be obtained for each subject prior to participation in the 
study
The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.  Optional assessments 
(including those in a separate protocol and/or under separate informed consent) and the 
clinical protocol should be concurrently submitted for approval unless regulation requires 
separate submission.  Approval of the optional assessments may occur after approval is 
granted for the clinical protocol where required by regulatory authorities.  In this 
situation, written approval of the clinical protocol should state that approval of optional 
assessments is being deferred and the study, with the exception of the optional 
assessments, can be initiated.
9.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK monitors will contact the site prior to the start of the study to review with the 
site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and GSK requirements.  

When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the CRF will 
serve as the source document.
GSK will monitor the study to ensure that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any other 
study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents.
9.4.
Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK 
may conduct a quality assurance assessment and/or audit of the site records, and the 

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regulatory agencies may conduct a regulatory inspection at any time during or after 
completion of the study. 

In the event of an assessment, audit or inspection, the investigator (and institution) 
must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all 
relevant documents and to allocate their time and the time of their staff to discuss the 
conduct of the study, any findings/relevant issues and to implement any corrective 
and/or preventative actions to address any findings/issues identified.
9.5.
Study and Site Closure

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.
9.6.
Records Retention

Following closure of the study, the investigator or the head of the medical institution 
(where applicable) must maintain all site study records (except for those required by 
local regulations to be maintained elsewhere), in a safe and secure location.  

The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review in 
conjunction with assessment of the facility, supporting systems, and relevant site 
staff.  

Where permitted by local laws/regulations or institutional policy, some or all of these 
records can be maintained in a format other than hard copy (e.g., microfiche, 
scanned, electronic); however, caution needs to be exercised before such action is 
taken.  

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
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.
9.7.
Provision of Study Results to Investigators, Posting of 
Information on Publicly Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
GSK will provide the investigator with the randomisation codes for their site only after 
completion of the full statistical analysis.
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy.
9.8.
Independent Data Monitoring Committee (IDMC)
An IDMC will be utilized in this study to ensure external objective medical and/or 
statistical review of safety and/or efficacy issues in order to protect the ethical and safety 
interests of subjects and to protect the scientific validity of the study.  The schedule of 
any planned interim analysis and the analysis plan for IDMC review is described in the 
charter.
9.9.
Pancreatitis Adjudication Committee
Detailed information on suspected pancreatitis events will be collected on special pages 
of the eCRF. A Pancreatitis Adjudication Committee composed of independent 
specialists in gastroenterology will review cases of possible pancreatitis. Details of this 

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committee and case adjudication are described in the committee’s charter available on 
request.

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10.
REFERENCES
ACC/AHA Key Data Elements and Definitions for Cardiovascular and Stroke End Point 
Events for Clinical Trials, February 4 2014 (peer review draft version)
American Diabetes Association (ADA). Diagnosis and classification of diabetes mellitus. 
Diabetes Care, 2014; 37 (Suppl 1): S81-S90.
Anderson DR, Christison-Lagay J, and Procter-Gray E. Self-Management goal setting in 
a community health center: the impact of goal attainment on diabetes outcomes. Diabetes 
Spectrum 23.2 (2010): 97-105.
Bao W, Aravindhan K, Alsaid H et al. Albiglutide, a long-lasting glucagon-like peptide-1 
analog, protects the rat heart against ischemia/reperfusion injury: evidence for improving 
cardiac metabolic efficiency.  PLoS One 6: e23570. 2011
Brod, M., Christensen, T., Kongsø, J. H. & Bushnell, D. M. Examining and interpreting 
responsiveness of the Diabetes Medication Satisfaction measure. J. Med. Econ. 12, 309–
316 (2009b).
Brod, M., Hammer, M., Christensen, T., Lessard, S. & Bushnell, D. M. Understanding 
and assessing the impact of treatment in diabetes: the Treatment-Related Impact 
Measures for Diabetes and Devices (TRIM-Diabetes and TRIM-Diabetes Device). Health 
Qual. Life Outcomes 7, 83 (2009a).
Butler AE, Campbell-Thompson M, Gurlo T, et al. Marked expansion of exocrine and 
endocrine pancreas with incretin therapy in humans with increased exocrine pancreas 
dysplasia and the potential for glucagon-producing neuroendocrine tumors. Diabetes. 
2013;62(7):2595-604.
Clarke PM, Hayes AJ, Glasziou PG, et al. Using the EQ-5D index score as a predictor of 
outcomes in patients with type 2 diabetes. Med Care 2009; 47: 61-68.
Cooper DS, Doherty GM, Haugen BR et al. Management guidelines for patients with 
thyroid nodules and differentiated thyroid cancer. Thyroid. 2006;16(2):109-142. 
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. 
European Public Assessment Report (EPAR) for Eperzan. 2014.Available at: 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/00273
5/human_med_001735.jsp&mid=WC0b01ac058001d124
FDA Summary Basis of Approval. 2014. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/125431Orig1s000TOC.cfm
Fu AZ, Qiu Y, Radican L, Yin DD, Mavros P. Pre-existing cardiovascular diseases and 
glycemic control in patients with type 2 diabetes mellitus in Europe: a matched cohort 
study. Cardiovasc Diabetol. 2010; 9:15.

2014N193553_02
CONFIDENTIAL
GLP116174
65
Grandy S, Fox KM. Change in health status (EQ-5D) over 5 years among individuals 
with and without type 2 diabetes mellitus in the SHIELD longitudinal study. Health and 
Quality of Life Outcomes 2012;10:99.
Guidance for Industry. Diabetes Mellitus: Developing Drugs and Therapeutic Biologics 
for Treatment and Prevention. U.S. Department of Health and Human Services. Food and 
Drug Administration. Center for Drug Evaluation and Research (CDER). February 2008 
Clinical/Medical. Available at http://www.fda.gov/cder/guidance/index.htm.
Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauk M, Peters AL, 
Tsapas A, Wender R, Matthews DR. Management of Hyperglycemia in Type 2 Diabetes: 
A Patient-Centered Approach Position Statement of the American Diabetes Association 
(ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 
2012; 35: 1364-1379
Janssen MF, Lubetkin EI, Sekhobo JP, Pickard AS. The use of the EQ-5D preference-
based health status measure in adults with Type 2 diabetes mellitus. Diabet Med 2011; 
28(4):395-413.
Juniper EF, Guyatt GH, Epstein RS, Ferrie PJ, Jaeschke R, Hiller TK. Evaluation of 
impairment of health-related quality of life in asthma: development of a questionnaire for 
use in clinical trials. Thorax 1992; 47: 76-83.
Khunti K, Andersen M, Wolden ML, Davies MJ and Thorsted BL. Clinical Inertia in 
People With Type 2 Diabetes. Diabetes Care. 2013; 36:3411-3417
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. 
Levey AS, Stevens LA, Schmid CH et al. A new equation to estimate glomerular 
filtration rate.  Ann Intern Med. 2009; 150: 604-12.
Lønborg J, Vejlstrup N, Kelbaek H et al. Exenatide reduces reperfusion injury in patients 
with ST-segment elevation myocardial infarction.  Eur Heart J 2012; 33: 1491-9.
Nystrom T, Gutniak MK, Zhang Q et al. Effects of glucagon-like peptide-1 on 
endothelial function in type 2 diabetes patients with stable coronary disease. Am J 
Physiol Endocrinol Metab 2004; 287: E1209-15.
Okerson T and Chilton RJ. The cardiovascular effects of GLP-1 receptor agonists. 
Cardiovascular Therapeutics 2012; 30: e146-155.
Pacini F, Schlumberger M, Dralle H et al. European consensus for the management of 
patients with differentiated thyroid carcinoma of the follicular epithelium. Eur J 
Endocrinol. 2006;154(6):787-803.

2014N193553_02
CONFIDENTIAL
GLP116174
66
Schulz KF, Altman DG, Moher D for the CONSORT Group. CONSORT 2010 
Statement: updated guidelines for reporting parallel group randomised trials. Available 
at: http://www. consort-
statement.org/Media/Default/Downloads/CONSORT%202010%20Statement/CONSORT
%202010%20Statement%20(BMJ).pdf
Seaquist E, Anderson J, Childs B, et al. Hypoglycemia and diabetes: A report of a 
workgroup of the American Diabetes Association and the Endocrine Society. Diabetes 
Care. 2013;36:1384-1395.
Stonehouse AH, Darsow T, Maggs DG. Incretin-based therapies. J Diabetes 
2012;4(1):55-67.
Thygesen K, Alpert JS, Jaffe AS etal. Third universal definition of myocardial 
infarction. European Heart Journal. 2012; 33: 2551–2567
Vilsbøll T, Krarup T, Deacon CF, Madsbad S, Holst JJ. Reduced postprandial 
concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic 
patients. Diabetes. 2001; 50(3):609-13.
World Health Organization (WHO). Diabetes Fact Sheet. October 2013. Available at 
http://www.who.int/mediacentre/factsheets/fs312/en/ (Accessed Apr 3, 2014).

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11.
APPENDICES
11.1.
Appendix 1: Genetic Research
Background
Genetics is the study of variability in drug response due to hereditary factors in 
populations.  There is increasing evidence that an individual's genetic background (i.e., 
genotype) may impact the pharmacokinetics (absorption, distribution, metabolism, 
elimination), pharmacodynamics (relationship between concentrations and 
pharmacologic effects or the time course of pharmacologic effects) and/or clinical 
outcome (in terms of efficacy and/or safety and tolerability).  Some reported examples of 
genetic associations with safety/adverse events include:
Drug
Disease
Gene Variant
Outcome
Abacavir
HIV 
[Hetherington, 
2002; 
Mallal, 2002; 
Mallal, 2008]
HLA-B* 57:01 
(Human 
Leukocyte 
Antigen B)
Carriage of the HLA-B*57:01 variant has been 
shown to increase a patient's risk for 
experiencing hypersensitivity to abacavir.  
Prospective HLA-B*57:01 screening and 
exclusion of HLA-B*57:01 positive patients 
from abacavir treatment significantly 
decreased the incidence of abacavir 
hypersensitivity.  Treatment guidelines and 
abacavir product labelling in the United States 
and Europe now recommend (US) or require 
(EU) prospective HLA-B*57:01 screening prior 
to initiation of abacavir to reduce the incidence 
of abacavir hypersensitivity.  HLA-B*57:01
screening should supplement but must never 
replace clinical risk management strategies for 
abacavir hypersensitivity.
Carbamaze
pine
Seizure, Bipolar 
disorders & 
Analgesia 
[Chung, 2010; 
Ferrell, 2008]
HLA-B*15:02
Independent studies indicated that patients of 
East Asian ancestry who carry HLA-B*15:02
are at higher risk of Stevens-Johnson 
Syndrome and toxic epidermal necrolysis.  
Regulators, including the US FDA and the 
Taiwanese TFDA, have updated the 
carbamazepine drug label to indicate that 
patients with ancestry in genetically at risk 
populations should be screened for the 
presence of HLA-B*15:02 prior to initiating 
treatment with carbamazepine.

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Drug
Disease
Gene Variant
Outcome
Irinotecan
Cancer 
[Innocenti, 2004; 
Liu, 2008; 
Schulz, 2009]
UGT1A1*28
Variations in the UGT1A1 gene can influence 
a patient’s ability to break down irinotecan, 
which can lead to increased blood levels of the 
drug and a higher risk of side effects. A dose 
of irinotecan that is safe for one patient with a 
particular UGT1A1 gene variation might be too 
high for another patient without this variation, 
raising the risk of certain side-effects that 
include neutropenia following initiation of 
Irinotecan treatment.  The irinotecan drug 
label indicates that individuals who have two 
copies of the UGT1A1*28 variant are at 
increased risk of neutropenia.  A genetic blood 
test is available that can detect variations in 
the gene.    
A key component to successful genetic research is the collection of samples during the 
conduct of clinical studies.
Collection of whole blood samples, even when no a priori hypothesis has been identified, 
may enable genetic analysis to be conducted if at any time it appears that there is a 
potential unexpected or unexplained variation in response to albiglutide.
Genetic Research Objectives
The objective of genetic research (if there is a potential unexpected or unexplained 
variation) is to investigate a relationship between genetic factors and response to 
albiglutide.  If at any time it appears there is potential variability in response in this 
clinical study or in a series of clinical studies with albiglutide, the following objectives 
may be investigated – the relationship between genetic variants and study treatment with 
respect to:

Safety and/or tolerability 

Efficacy
Study Population
Any subject who is enrolled in the clinical study, can participate in genetic research.  Any 
subject who has received an allogeneic bone marrow transplant must be excluded from 
genetic research.
Subject participation in the genetic research is voluntary and refusal to participate will 
not indicate withdrawal from the clinical study or result in any penalty or loss of benefits 
to which the subject would otherwise be entitled.

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Study Assessments and Procedures
Blood samples can be taken for deoxyribonucleic acid (DNA) extraction and used in 
genetic assessments.
If taking blood samples: in addition to any blood samples taken for the clinical study, a 
whole blood sample (~6ml) will be collected for the genetic research using a tube 
containing EDTA.  It is recommended that the blood sample be taken at the first 
opportunity after a subject has been randomised and provided informed consent for 
geneticresearch, but may be taken at any time while the subject is participating in the 
clinical study.

The genetic sample is labelled (or “coded”) with a study specific number that 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).  The 
blood sample is taken on a single occasion unless a duplicate sample is required due 
to inability to utilise the original sample.  
The DNA extracted from the blood sample may be subjected to sample quality control 
analysis.  This analysis will involve the genotyping of several genetic markers to confirm 
the integrity of individual samples.  If inconsistencies are noted in the analysis, then those 
samples may be destroyed.
The need to conduct genetic analysis may be identified after a study (or a set of studies) 
of albiglutide has been completed and the clinical study data reviewed.  In some cases, 
the samples may not be studied. e.g., no questions are raised about how people respond to 
albiglutide.
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 use samples collected from the study for 
the purpose stated in this protocol and in the informed consent form.  
Subjects can request their sample to be destroyed at any time.
Subject Withdrawal from Study
If a subject who has consented to participate in geneticresearch 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 geneticsample, if already collected:

Continue to participate in genetic research with the geneticsample retained for 
analysis 

Withdraw from geneticresearch and destroy the geneticsample 
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 

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the site study records. The investigator should forward the Pharmacogenetic Sample 
Destruction Request Form to GSK as directed on the form. This can be done at any time 
when a subject wishes to withdraw from  genetic research or have their sample destroyed 
whether during the study or during the retention period following close of the main study.
Screen and Baseline Failures
If a blood sample for genetic research has been collected and it is determined that the 
subject does not meet the entry criteria for participation in the clinical study, then the 
investigator should instruct the participant 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.
Analyses
1.
Specific genes may be studied that encode the drug targets, or drug mechanism of 
action pathways, drug metabolizing enzymes, drug transporters or which may 
underpin adverse events, disease risk or drug response. These candidate genes may 
include a common set of ADME (Absorption, Distribution, Metabolism and 
Excretion) genes that are studied to determine the relationship between gene variants 
or treatment response and/or tolerance. 
In addition, continuing research may identify other enzymes, transporters, proteins or 
receptors that may be involved in response to albiglutide.  The genes that may code for 
these proteins may also be studied.
2.
Genome-wide scans involving a large number of polymorphic markers (e.g., single 
nucleotide polymorphisms) at defined locations in the genome, often correlated with 
a candidate gene, may be studied to determine the relationship between genetic 
variants and treatment response or tolerance. This approach is often employed when 
a definitive candidate gene(s) does not exist and/or the potential genetic effects are 
not well understood. 
If applicable and genetic research is conducted, appropriate statistical analysis methods 
will be used to evaluate pharmacogenetic data in the context of the other clinical data. 
Results of genetic investigations will be reported either as part of the main clinical study 
report or as a separate report. Endpoints of interest from all comparisons will be 
descriptively and/or graphically summarised as appropriate to the data.  A detailed 
description of the analysis to be performed will be documented in the study reporting and 
analysis plan (RAP) or in a separate pharmacogenetics RAP, as appropriate.  
Informed Consent
Subjects who do not wish to participate in geneticresearch may still participate in the 
clinical study.  Genetic informed consent must be obtained prior to any blood being taken 
for genetic research.

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Provision of Study Results and Confidentiality of Subject’s Genetic Data
GSK may summarise the genetic research results in the clinical study report, or 
separately, or may publish the results in scientific journals. 
GSK does not inform the investigator, subject, or anyone else (e.g., family members, 
study investigators, primary care physicians, 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.
References
Chung WH, Hung SL, Chen YT. Genetic predisposition of life-threatening antiepileptic-
induced skin reactions.  Expert Opin. Drug Saf. 2010; 9: 15-21.
Ferrell PB, McLeod HL.  Carbamazepine, HLA-B*1502 and risk of Stevens-Johnson 
syndrome and toxic epidermal necrolysis: US FDA recommendations.  
Pharmacogenomics. 2008; 9: 1543-1546.
Hetherington S, Hughes AR, Mosteller M, Shortino D, Baker KL, Spreen W, Lai E, 
Davies K, Handley A, Dow DJ, Fling ME, Stocum M, Bowman C, Thurmond LM, Roses 
AD. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. 
Lancet. 2002; 359:1121-1122.
Innocenti F, Undevia SD, Iyer L, Chen PX, Das S, Kocherginsky M, Karrison T, Janisch 
L, Ramirez J, Rudin CM, Vokes EE, Ratain MJ.  Genetic variants in the UDP-
glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J 
Clin Oncol 2004; 22: 1382-1388.
Liu CY, Chen PM, Chiou TJ, Liu JH, Lin JK, Lin TC, Chen WS, Jiang JK, Wang HS, 
Wang WS.  UGT1A1*28 polymorphism predicts irinotecan-induced severe toxicities 
without affecting treatment outcome and survival in patients with metastatic colorectal 
carcinoma.  Cancer. 2008; 112: 1932-1940.
Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, Sayer D, Castley A, Mamotte 
C, Maxwell D, James I.  Association between presence of HLA-B*5701, HLA-DR7, and 
HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir.  
Lancet. 2002; 359:727-732.
Mallal S, Phillips E, Carosi G, Molina JM, Workman C, Tomazic J, Jägel-Guedes E, 
Rugina S, Kozyrev O, Cid JF, Hay P, Nolan D, Hughes S, Hughes A, Ryan S, Fitch N, 
Thorborn D, Benbow A; PREDICT-1 Study Team.  HLA-B*5701 screening for 
hypersensitivity to abacavir. N Engl J Med. 2008; 358; 568-579
Schulz C, Heinemann V, Schalhorn A, Moosmann N, Zwingers T, Boeck S, Giessen C, 
Stemmler HJ. UGT1A1 gene polymorphism: Impact on toxicity and efficacy of 

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irinotecan-based regimens in metastatic colorectal cancer.  World J. Gastroenterol. 2009; 
15: 5058-5066.

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11.2.
Appendix 2: GSK Modified List of Highly Effective Methods 
for Avoiding Pregnancy in Females of Reproductive 
Potential (FRP)
1.
Contraceptive subdermal implant that meets effectiveness criteria including a <1% 
rate of failure per year, as stated in the product label.
2.
Intrauterine device or intrauterine system that meets effectiveness criteria including a 
<1% rate of failure per year, as stated in the product label [Trussell, 2011]
3.
Oral Contraceptive, either combined or progestogen alone [Trussell, 2011] 
4.
Injectable progestogen [Trussell, 2011]
5.
Contraceptive vaginal ring [Trussell, 2011]
6.
Percutaneous contraceptive patches [Trussell, 2011]
7.
Male partner sterilization prior to the female subject's entry into the study, and this 
male is the sole partner for that subject. The information on the male sterility can 
come from interview with the subject on her male partner’s medical history.
8.
Male condom combined with a female diaphragm, with or without a vaginal 
spermicide (foam, gel, film, cream, or suppository). In the UK it is a country-specific 
requirement of the regulatory authority (Medicines and Healthcare Products 
Regulatory Agency) that a vaginal spermicide be used.
These allowed methods of contraception have a failure rate of less than 1% per year but 
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.
References
Trussell J, Contraceptive Efficacy. In: Hatcher RA, Trussell J, Nelson AL, Cates W, 
Kowal D, and Policar M (editors). Contraceptive Technology: Twentieth Revised 
Edition. New York: Ardent Media, 2011.Table 26-1

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11.3.
Appendix 3: Liver Safety Required Actions and Follow up 
Assessments
Phase III-IV liver chemistry stopping and increased monitoring criteria have been 
designed to assure subject safety and evaluate liver event aetiology (in alignment with the 
FDA premarketing clinical liver safety guidance).  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
Phase III-IV liver chemistry stopping criteria and required follow up assessments 
Liver Chemistry Stopping Criteria - Liver Stopping Event
ALT-absolute
ALT 8xULN
ALT Increase
ALT 5xULN but <8xULN  persists for 2 weeks
ALT 3xULN but <5xULN  persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot 
Monitor
ALT 5xULN but <8xULN and cannot be monitored weekly for 2 weeks
ALT 3xULN but <5xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be 
related to  liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue  study treatment 

Report the event to GSK within 24 hours

Complete the liver event CRF and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries 
resolve , stabilize, or return to within baseline 
(see MONITORING below)

Do not restart subject with study treatment 
unless allowed per protocol and GSK Medical 
Governance approval is granted (refer to  

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 3 half lives (15 
days)  of last dose6

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN.

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Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments
Appendix 5)

If restart is not granted, permanently 
discontinue study treatment and continue 
subject in the study for any protocol specified 
follow up assessments 

Re-challenge is not allowed.
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

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 high 
pressure liquid chromatography assay 
(quantifies potential acetaminophen 
contribution to liver injury in subjects with 
definite or likely acetaminophen use in the 
preceding week [James, 2009]). NOTE: 
not required in China

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms

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1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to subjects receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)   
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
5.
If hepatitis delta antibody assay cannot be performed,, it can be replaced with a PCR of hepatitis D RNA virus 
(where needed) [Le Gal, 2005].
6.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM.  
Phase III-IV 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.

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References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Protein Adduct in Adults with 
Acetaminophen Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-
1784.
Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P, Gault E.  Quantification 
of Hepatitis Delta Virus RNA in Serum by Consensus Real-Time PCR Indicates 
Different Patterns of Virological Response to Interferon Therapy in Chronically Infected 
Patients.  J Clin Microbiol. 2005;43(5):2363–2369. 

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11.4.
Appendix 4: Liver Safety Drug Restart Guidelines
If subject meets liver chemistry stopping criteria do not restart subject with study 
treatment unless:

GSK Medical Governance approval is granted (as described below),

Ethics and/or IRB approval is obtained, if required, and

Separate consent for treatment restart is signed by the subject
If GSK Medical Governance approval to restart the subject with study treatment is not
granted, then the subject must permanently discontinue study treatment and may 
continue in the study for protocol-specified follow up assessments.
Restart Following Transient Resolving Liver Stopping Events Not Related to Study 
Treatment
Restart refers to resuming study treatment following liver stopping events in which there 
is a clear underlying cause (other than DILI) of the liver event (e.g. biliary obstruction, 
pancreatic events, hypotension, acute viral hepatitis). Furthermore, there should be no 
evidence of alcoholic hepatitis or hypersensitivity, and the study treatment should not be 
associated with HLA markers of liver injury.
Approval by GSK for study treatment restart can be considered where:

Investigator  requests consideration for study treatment restart if liver chemistries 
have a clear underlying cause (e.g., biliary obstruction, hypotension and liver 
chemistries have improved to normal or are within 1.5 x baseline and ALT 
<3xULN).

Restart risk factors (e.g. fever, rash, eosinophilia, or hypersensitivity, alcoholic 
hepatitis, possible study treatment-induced liver injury) or study treatment has an 
HLA genetic marker associated with liver injury (e.g. lapatinib, abacavir, 
amoxicillin/clavulanate) are reviewed and excluded.

Ethics Committee or Institutional Review Board approval of study treatment restart 
must be obtained, as required.

If restart of study treatment is approved by GSK Medical Governance in writing, the 
subject must be provided with a clear description of the possible benefits and risks of 
study treatment administration, including the possibility of recurrent, more severe 
liver injury or death.  

The subject must also provide signed informed consent specifically for the study 
treatment restart.  Documentation of informed consent must be recorded in the study 
chart.  

Study treatment must be administered at the dose specified by GSK.

Subjects approved by GSK Medical Governance for restarting study treatment must 
return to the clinic once a week for liver chemistry tests until stable liver chemistries 
have been demonstrated and then laboratory monitoring may resume as per protocol. 

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
If after study treatment re-start, subject meets protocol-defined liver chemistry 
stopping criteria, follow usual stopping criteria instructions.

GSK Medical Monitor, and the Ethics Committee or Institutional Review Board as 
required, must be informed of the subject’s outcome following study treatment 
restart. 

GSK to be notified of any adverse events, as per Section 6.2.2 and Appendix 5

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11.5.
Appendix 5: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
11.5.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a subject 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 unfavourable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (haematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae).

The signs and symptoms and/or clinical sequelae resulting from lack of efficacy will 
be reported if they fulfil the definition of an AE or SAE.  Also, "lack of efficacy" or 
"failure of expected pharmacological action" also constitutes an AE or SAE.

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Events NOT meeting definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 
condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
11.5.2.
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 fulfils any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.

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

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11.5.3.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the CRF

It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to GSK in lieu of completion of the GSK, AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK.  In this instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to 
submission of to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.

Subject-completed Value Evidence and Outcomes questionnaires and the collection 
of AE data are independent components of the study.

Responses to each question in the Value Evidence and Outcomes questionnaire will 
be treated in accordance with standard scoring and statistical procedures detailed by 
the scale’s developer.

The use of a single question from a multidimensional health survey to designate a 
cause-effect relationship to an AE is inappropriate.

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11.5.4.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. - an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of his/her assessment.

For each AE/SAE the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK.  However, it is very important 
that the investigator always make an assessment of causality for every event 
prior to the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.

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Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.

The investigator is obligated to assist.  This may include additional laboratory tests 
or investigations, histopathological examinations or consultation with other health 
care professionals.

If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide GSK with a copy of any post-mortem findings, 
including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
11.5.5.
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 safety designee as detailed in the 
Study Reference Manual

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.

Site will enter the SAE data into the electronic system as soon as it becomes 
available.

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 or the SAE coordinator by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.

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11.6.
Appendix 6: Collection of Pregnancy Information

Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study

Information will be recorded on the appropriate form and submitted to GSK within 2 
weeks of learning of a subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on mother and infant, which will be 
forwarded to GSK.  Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date. 

Any termination of pregnancy will be reported, regardless of foetal 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 5. 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

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11.7.
Appendix 7: Electronic Health Record Ancillary Study
11.7.1.
Introduction
11.7.1.1.
Background
Clinical researchers and policy makers want to move towards embedding clinical trials 
directly within health care delivery systems in order to increase the relevance, speed, and 
efficiency of clinical research [Richesson, 2013]. The assumption is that the capabilities 
offered by Electronic Health Records (EHRs), along with concurrent changes in health 
care organization and delivery, and the development of a learning health system will 
transform the way clinical research is conducted [Etheredge, 2007; Greene, 2012]. 
In 2011, the National Heart, Lung, and Blood Institute (NHLBI) convened the NHLBI 
Working Group on Electronic Health Records: Research Priorities to Improve 
Cardiopulmonary Health in Clinical Practice. As part of their mission, this working group 
identified key research, policy, and training priorities [Curtis, 2014]. A key research 
priority was to leverage EHR tools to facilitate the efficient implementation of 
randomized clinical trials. Specific areas highlighted for increased efficiency included 
efficient data collection and outcome surveillance and confirmation.
11.7.1.2.
Literature Review
Electronic Health Records were primarily designed to document patient care and 
facilitate billing and reimbursement. The large amount of electronic data that are captured 
may also facilitate clinical research and public health surveillance.5 Despite the 
complexity of EHR data, national networks have begun to use these data to improve 
public health and generate real-world evidence [Toh, 2012]. The Patient Centered 
Outcomes Research network (PCORnet) (pcornet.org) is a research network that is 
currently being designed to support observational comparative effectiveness research and 
clinical trials that are embedded in clinical care settings [Fleurence, 2014]. Similarly, the 
NIH Health Care Systems Research Collaboratory (nihcollaboratory.org) is creating 
infrastructure to improve the conduct of embedded clinical trials. One ongoing NIH 
Collaboratory trial is the Time to Reduce Mortality in End-Stage Renal Disease study 
(TiME) (clinicaltrials.gov identifier: NCT02019225). TiME is a large cluster-
randomized, pragmatic trial that will evaluate the effects of systematic implementation of 
hemodialysis sessions of at least four hours versus usual hemodialysis care. The trial 
involves data acquisition from EHR systems through a partnership between academic 
investigators and two health care provider organizations with different electronic data 
systems. There are several other recent examples of clinical trials that were embedded in 
health care delivery systems [Gulliford, 2014; van Staa, 2014]. For instance, one recent 
study evaluated the use of an electronic decision support tool to improve risk factor 
control (i.e., blood pressure and cholesterol) following a cerebrovascular event with 
outcome data collected from the EHR [Dregan, 2014]. While the specific intervention 
was not shown to be efficacious, data acquisition via EHR sources was robust and 
implemented at a low cost.

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11.7.1.3.
Ancillary Study Rationale
Despite these earlier studies demonstrating the potential opportunities with EHR-based 
data acquisition, our understanding of how EHR-based platforms might increase the 
efficiency of data collection, outcome surveillance, and confirmation in an integrated 
manner is unknown. EHRs are inherently heterogeneous, with each implementation 
different from the next. The barriers to using EHR-generated lists of patients to facilitate 
trial enrolment, the fitness of EHR data for populating baseline characteristics in an 
electronic case report form (eCRF) and the use of EHR data to find events of interest 
during trial follow-up are not well characterized. 
EHR systems contain a wealth of clinical data about patients who are connected to the 
health care delivery system and may be eligible for enrollment in a clinical trial.  
Anecdotal reports suggest that identification of potential patients using the EHR increases 
the number of patients to be screened but may not consistently translate to an increased 
number of patients enrolled. Causes are likely multi-factorial and may include the 
translatability of inclusion and exclusion criteria to structured clinical data, the algorithm 
used to identify potential patients, institutional restrictions regarding unsolicited patient 
contact, and others. There is a need to empirically assess the barriers to using an EHR-
generated list of patients to facilitate trial enrollment. 
Structured data captured in the EHR may be similar to data elements specified in baseline 
patient characteristics in the eCRF, yet EHR data are collected primarily to support 
clinical care and reimbursement needs.  Their fitness for use as source data for selected 
data elements of the baseline patient characteristics in the eCRF has not been established.  
During routine trial follow-up, study coordinators typically gather information from 
various sources including direct patient contact and medical records of the enrolling 
institution and outside facilities to document events for study participants.  Evidence 
from the West of Scotland Coronary Prevention Study suggests that cardiovascular 
endpoints can be ascertained from routinely recorded EHR-type data, but classification 
was imperfect [Barry, 2013].There is a need to specifically assess the utility of EHR data 
acquisition for follow-up events across multiple health systems.
In summary, the EHR is a rich source of clinical data, but is designed specifically to 
support clinical care delivery and reimbursement needs. The assumption that EHR data 
are fit for use in high-quality clinical research has not been rigorously evaluated.  To 
provide evidence to address this knowledge gap, GlaxoSmithKline (GSK) and Duke 
Clinical Research Institute (DCRI) are committed to conducting an exploratory EHR 
Ancillary Study embedded within a large pragmatic clinical trial at selected study sites. 
The overarching goal is to further our understanding of how EHR data can be organized 
into a query-able format to facilitate a more efficient, reliable, and cost-effective research 
process.  The proposed empirical work is exploratory in nature and both qualitative and 
quantitative.

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11.7.2.
Ancillary Study OBJECTIVES
11.7.2.1.
Primary Objectives
Objective 1: Assess the barriers to using an EHR-generated list of patients to 
facilitate trial enrollment.
Through site study coordinator surveys, workflow assessment, analysis of electronic 
screening logs, comparisons of enrolled patients with patients identified via algorithm, 
this retrospective objective will describe the screening “funnel” and identify factors 
responsible for narrowing the funnel from the pool of potentially eligible patients to those 
enrolled in the clinical trial.  Barriers for using EHR systems for this purpose will be 
assessed at the site level and common cross-site themes will be identified. 
Objective 2:  Evaluate the fitness of EHR data for use in populating the baseline 
characteristics in the eCRF
After study completion and within selected data areas (e.g., demographics, medical 
history, concomitant medications), the level of agreement between data extracted from 
the EHR and data documented on the baseline eCRF (reference standard) will be 
evaluated. Additionally the performance of algorithms developed to identify 
comorbidities and other clinical concepts will be assessed at the site level and aggregated, 
where appropriate.  
Objective 3:  Explore the use of EHR data to find events of interest during trial 
follow-up 
Case-finding algorithms will be developed for select specified endpoints (i.e., myocardial 
infarction, stroke, unstable angina, heart failure as outlined in the main study protocol), 
run during the conduct of the trial, and used to identify potential cases for follow-up by 
the study coordinator. The site study coordinator will record the dispensation of each 
potential case so that reconciliation can occur between eCRF documented events and 
EHR-generated potential events. Safety event reporting will proceed as outlined in the 
main study protocol (Main Protocol Section 6.2). At the conclusion of the study, the yield 
of case-finding algorithms will be evaluated along with the performance of EHR-based 
algorithms with eCRF-reported as well as adjudicated eCRF-reported events (reference 
standard).
11.7.2.2.
Secondary Objective
As a secondary objective, an assessment of the general utility and feasibility of EHR-
based outcome acquisition from the coordinator perspective through surveys and 
standardized workflow assessments will be conducted.  

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11.7.3.
Ancillary Study design
11.7.3.1.
Study Design
The ancillary study will occur in the context of the HARMONY-Outcomes trial, a 
randomised, double blind, parallel-group, placebo-masked, controlled study to evaluate 
the effect of albiglutide on cardiovascular events in patients with Type 2 diabetes. 
Albiglutide will be administered subcutaneously once weekly in a population of patients 
with Type 2 diabetes and a previous history of cardiovascular disease and who do not 
have optimal glycaemic control). The duration of the ancillary study will mirror that of 
the HARMONY-Outcomes trial. The number of sites that will participate in the ancillary 
study depends upon the outcome of the site EHR capabilities assessment described in 
Section 11.7.3.2 (Site Selection) below. Five study sites recruiting 12-15 subjects each 
would enable a descriptive assessment of Objectives 1 and 2, whilst, if feasible, 500-1000 
subjects at EHR-enabled sites would permit greater precision to be achieved in the 
assessment of Objective 3.
11.7.3.2.
Site Selection
Sites from the main trial will be selected to participate.  As part of the overall site 
selection process for the main trial, potential sites complete a feasibility survey to gauge 
their suitability for participation in the HARMONY-Outcomes trial.  In addition to 
questions regarding experience with long-term outcome trials in general and specific 
features of the planned trial, the feasibility survey includes questions about site readiness 
for an EHR-facilitated trial.  Specific topics include:

Existence of an EHR system;

Current use of EHR to screen for potential study participants;

Types of information currently contained in EHR  (inpatient visits, outpatient 
visits, laboratory results, medications) 

Prior participation in a study that used EHR data for patient screening, follow-up, 
and/or data collection; and

Local EHR support to assist with research studies.
Sites who meet minimum qualifications based on this survey (respond affirmatively 
regarding the existence of an EHR system and local EHR support to assist with research 
studies), and who have confirmed an interest in participating in the ancillary study will be 
approached for a more in-depth assessment of capabilities.  Specific topics include:

Current capability to extract EHR-type data from a data warehouse;

Data domains currently included in the data warehouse (e.g., demographics, vital 
signs, diagnoses, procedures, medications prescribed, laboratory tests, and death);

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
Coding terminologies used for each domain of data;

Institutional processes and policies for using EHR-type data for clinical research; 

Institutional experience extracting, transforming, and loading warehouse data into 
a research DataMart that conforms with standardized specifications; and

Familiarity with or participation in distributed research networks.  
Subsequent structured discussions with individual sites may be necessary to explore 
capabilities and suitability for the ancillary study.  For example, engagement of the health 
system’s Information Technology (IT) personnel will be essential but is challenging to 
gauge in a written survey.  Key site selection criteria include:

Fully implemented EHR system 

Access to an enterprise data warehouse or clinical data repository that stores 
structured data from the EHR and is updated at least weekly.

Availability of necessary data

Engagement of health system IT and analytical personnel
The advantage of a multi-stage, rapid assessment of capabilities is that it allows for a 
relatively short feasibility survey that can be completed reliably by a study coordinator. 
Detailed technical questions are reserved for the individuals who provide EHR support 
for research studies.  
11.7.3.3.
Data Flows
The methods for data extraction and capture will require a partnership between study site 
teams (site principal investigator, site study coordinator, and site technical support), 
GSK, and the DCRI Data Management Team.
The study will utilize PopMedNet, a software application that enables the creation, 
operation, and governance of research networks.  It allows partners to maintain physical 
and operational control over their data while allowing authorized users to send queries to 
the data. PopMedNet consists of two layers: a security layer where access controls and 
permissions are established and a layer of virtual pipes through which questions are sent 
from requestor to responder. The PopMedNet software consists of a web-based “network 
portal” and a DataMart Client application that is installed at each site. PopMedNet 
employs a “publish-and-subscribe” architecture that does not require a hole through an 
institutional firewall, but rather allows institutions to pull a query behind the firewall for 
manual or automated execution. 
In research networks with a common data model, PopMedNet is used to distribute 
executable code that institutions can choose to pull behind their firewall, run against the 
data in that appropriate format, and return results to the requestor. Security 
documentation will be provided to all participating sites.   

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The data flow for this ancillary study will be as follows: 
a) The study site’s EHR system will not be changed and will continue to operate as 
implemented.  Data from the thousands of tables in the EHR will be integrated on 
a nightly basis into a data warehouse that supports research needs (the term EHR 
is used to mean the system that collects, displays, and stores transactional health 
care data).
b) With guidance from the DCRI Data Management Team, the study site’s technical 
team will extract, transform, and load data from the enterprise data warehouse (or 
clinical data repository) to a Cohort DataMart according to the specifications of 
the common data model.  A common data model standardizes the definition, 
content and format of data across sites to enable efficient, cross-site querying. The 
Cohort DataMart will be refreshed from the existing Data Warehouse on a 
biweekly basis. The Cohort DataMart includes Protected Health Information 
(PHI) for a broadly defined cohort of potential study participants and will remain 
behind institutional firewalls. 
c) Data from Pre-Screening logs completed as part of the main study will be 
captured in a database stored in the same area as the Cohort DataMart to facilitate 
characterization of the screening funnel.  Data from the pre-screening log will 
enable comparisons of characteristics of potential participants identified via 
algorithm with patients screened and enrolled. 
d) When a participant is randomized into the study, the study coordinator will enter 
key subject identifiers (the main trial identifier (ID), Medical Record Number 
(MRN) equivalent, study randomization date) into the Key Identifier spread sheet.
e) Via PopMedNet, the DCRI Data Management Team will distribute code that 
extracts data for randomized participants from the Cohort DataMart into the Study 
DataMart using the Key Identifier table. Trial ID and randomization date from the 
Key Identifier table will be included in the Study DataMart. Data for randomized 
patients at each site will be returned to the DCRI via the HARMONY-Outcomes 
trial EHR Ancillary Study Query Portal. 
f)
Via PopMedNet, the DCRI will distribute executable code (e.g., SQL program) 
that will query the Study DataMart for potential study endpoints.  [See Section 
11.7.3.4.1b for case-finding algorithm]. 
g) Potential cases (identified via case-finding algorithm) will be returned to the 
Study Coordinator who will record the dispensation of each potential case in the 
Case-finding Dispensation Log stored in the Study DataMart (i.e., recorded in the 
eCRF/not recorded in the eCRF and reasons).
h) The Study DataMart containing randomized patient data will be transferred from 
each site to the DCRI on a regular basis (anticipated quarterly with specific 
frequency to be determined).  
i)
Required data elements from the main clinical trial dataset for EHR Ancillary 
Study sites will be transferred from GSK to the DCRI after the completion of the 
study. The DCRI will merge data elements from the main clinical trial dataset 
with Study DataMart data to create the EHR Ancillary Study Dataset.

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11.7.3.4.
Study Procedures and Processes
11.7.3.4.1. DCRI
a) Establish broad definition of cohort 
A broad cohort identification algorithm will be developed based on selected inclusion 
criteria outlined in the main study protocol. Selected criteria for inclusion into the cohort 
include:

Age > 40 years old

Diagnosis of Type 2 diabetes, broadly defined by diagnosis codes and 
medications prescribed (See 4.4 for information about algorithms to be used.)

Established cardiovascular disease (See Section 11.7.4.4 for information about 
algorithms to be used)
Participating sites will be required to run the “cohort algorithm” within their EHR 
systems to create the Cohort DataMart which will be used as a basis for Objective #1. 
b) Specify contents of the EHR Ancillary Study research DataMart
EHR data are stored in many different ways. A common data model standardizes the 
definition, content and format of data across sites to enable a single standardized view 
that can be used for querying. Sites participating in this ancillary study will be required to 
transform their data into a common data model that will be designed to be intuitive and 
user-friendly. Investigators and analysts with prior experience using research data will 
not need additional skills or knowledge to use the common data model. The DCRI team 
will manage questions and issues that arise regarding transforming data into the CDM.
The EHR Ancillary Study Common Data format will be adapted from the Patient 
Centered Outcomes Research Network (PCORnet) Common Data Model 
(http://pcornet.org/resource-center/pcornet-common-data-model/)and may include the 
following data areas:  

Demographic

Encounter

Diagnosis

Procedure

Medications prescribed

Laboratory results, selected 

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c)
Develop data characterization routines
As previously described, participating sites will transform local data into the study 
common data model. The DCRI Data Management Team will develop and distribute 
code to query the content of tables formatted according to the common data model. The 
distributed code will generate aggregate output tables that help determine whether the 
data conform to specifications, maintain integrity across variables and across tables, and 
trend as expected over time. The data quality review and characterization process will 
help to ensure that the data meets reasonable standards for data transformation 
consistency and quality.  
DCRI’s team will evaluate the creation of the Cohort DataMart using standard programs 
distributed to each study site for execution behind institutional firewalls.  
d)
Develop and distribute test queries 
A series of simple test queries will be developed and distributed to sites for execution 
against a simulated data set, structured according to the common data model. The test 
queries will help each site become familiar with PopMedNet and distributed querying 
without concern about querying against protected health information.
e)
Develop algorithms for analytic variables
Algorithms to map EHR-based data in the Study DataMart to baseline characteristics and 
study endpoints in the EHR Ancillary Study dataset will be defined using diagnosis codes 
(ICD-9-CM and ICD-10-CM) and procedure codes (ICD-9-CM and ICD-10-PCS).  
Published algorithms will be used whenever possible.  Examples of published algorithms 
utilized in the past include: 

CMS chronic condition categories: https://www.ccwdata.org/web/guest/condition-
categories

Quan, H., Sundararajan, V., Halfon, P., Fong, A., Burnand, B., Luthi, J. C., ... & 
Ghali, W. A. (2005). Coding algorithms for defining comorbidities in ICD-9-CM 
and ICD-10 administrative data. Medical Care, 1130-1139. 
http://www.ncbi.nlm.nih.gov/pubmed/16224307

Elixhauser, A., Steiner, C., Harris, D. R., & Coffey, R. M. (1998). Comorbidity 
measures for use with administrative data. Medical Care, 36(1), 8-27. 
http://www.ncbi.nlm.nih.gov/pubmed/9431328
These algorithms will be updated as necessary to account for coding changes since 
publication.  And, if not provided, mapping of diagnosis codes from ICD-9-CM to ICD-
10-CM and mapping of procedure codes from ICD-9-CM to ICD-10-PCS will be done 
using the general equivalence mappings provided by Centers for Medicare & Medicaid 
Services (CMS):

Diagnosis code crosswalk: http://www.cms.gov/Medicare/Coding/ICD10/2014-
ICD-10-CM-and-GEMs.html

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
Procedure code crosswalk: http://www.cms.gov/Medicare/Coding/ICD10/2014-
ICD-10-PCS.html
Algorithms used to identify specific medications dispensed will be defined using 
different drug identification coding systems in use by study sites.  These systems could 
include:

NDC codes [from RxNav, a browser for drug information available from the U.S. 
National Library of Medicine]

DIN codes [from Health Canada drug product database]

ATC codes [from WHO Collaborating Centre for Drug Statistics Methodology]
11.7.3.4.2. Sites
Participating study sites will:

Extract, transform, and load (ETL) data into a physical instance of an adapted 
PCORnet Common Data Model.  Sites will document the mapping from the EHR 
to the Common Data Model.

Install PopMedNet

Refresh the Cohort DataMart on a biweekly basis

Execute data characterization and test queries after each refresh and on an as-
needed basis.  
Site study coordinators will be required to complete pre-screening logs on all potential 
study participants meeting minimum eligibility requirements (age >40, Type 2 diabetes, 
established cardiovascular disease) identified via any mechanism (i.e., reviewing lists of 
scheduled office patients, reviewing lists of recently discharged diabetes patients, EHR-
facilitated algorithm). Pre-screening logs will capture the following information:

Pre-screening number

Pre-screening date

Inclusion criteria not met

Exclusion criteria met

Other criteria
Site study coordinators will complete a screening survey which will describe the site’s 
current process for screening. A description of screening barriers will be included.

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11.7.4.
DATA ANALYSIS
11.7.4.1.
Sample Size Expectations
The objectives of this ancillary study are exploratory (not confirmatory) in nature and not 
intended to be sufficiently powered to confirm a pre-determined level of sensitivity and 
specificity.  The number of sites and subjects that will participate in the ancillary study 
depends upon the outcome of the site EHR capabilities assessment described in Section 
11.7.3.2 (Site Selection). Five study sites recruiting 12-15 subjects each would enable a 
descriptive assessment of Objectives 1 and 2, whilst, if feasible, 500-1000 subjects at 
EHR-enabled sites would permit greater precision to be achieved in the assessment of 
Objective 3.
11.7.4.2.
Objective 1: Assess the Barriers to Using as EHR-Generated List of 
Patients to Facilitate Trial Enrollment
Because any survey administered for this objective will be a site-level survey, analysis of 
the survey data will be performed across all sites. For quantities of interest, frequencies 
with percentages for categorical measures and means with standard deviations for 
continuous measures will be presented.   
11.7.4.3.
General Analytic Approach for Objective 1 and Objective 2
The goals of both Objective 2 and Objective 3 involve evaluating the performance of 
algorithms that map EHR-based data into concepts present in the clinical trial dataset.  
The actual measures recorded in the clinical trial dataset will be considered the reference 
standard against which these algorithm-based measures are compared.
Table 4
Overall performance of EHR-based algorithms for baseline 
characteristics, using clinical trial data as the reference standard / 
Categorical variables
Reference standard
(Clinical trial data)
New measure  
(EHR Ancillary Study data)
Condition present
Condition absent
Condition present
True positive
(TP)
False positive 
(FP)
Condition absent
False negative
(FN)
True negative
(TN)
For categorical variables, estimated performance metrics will be based on the 2x2 cross-tabulation 
of values in the EHR Ancillary Study dataset with values in the clinical trial dataset (Table 4) and 
include:

Overall agreement = (TP + TN) / (TP + FP + FN + TN)

Sensitivity = TP / (TP + FN)

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
Specificity = TN / (FP + TN)

Positive predictive value = TP / (TP + FP)

Negative predictive value = TN / (FN + TN)

Accuracy or efficiency = (TP + TN) / (TP+TN+FP+FN)
For dichotomous measures, each of these proportions is immediately calculable.  For 
measures having more than two levels, multiple dichotomous measures will be created in 
order to calculate these proportions. Confidence intervals (95%) will be reported around 
these quantities. (See Table 5 as an example).
Table 5
Overall performance of EHR-based algorithms for baseline 
characteristics, using clinical trial data as the reference standard / 
Categorical variables
Measure
Overall 
agreement
(95% CI)
Sensitivity
(95% CI)
Specificity
(95% CI)
Positive 
predictive 
value 
(95% CI)
Negative 
predictive 
value 
(95% CI)
Measure 1
xx.x 
(xx.x – xx.x)
xx.x 
(xx.x – xx.x)
xx.x 
(xx.x – xx.x)
xx.x 
(xx.x – xx.x)
xx.x 
(xx.x – xx.x)
Measure 2
xx.x 
(xx.x – xx.x)
xx.x 
(xx.x – xx.x)
xx.x 
(xx.x – xx.x)
xx.x 
(xx.x – xx.x)
xx.x 
(xx.x – xx.x)
.....
.....
.....
.....
.....
.....
Reported on 0–100 scale
For continuous measures, bias will be calculated as the difference between values in the 
EHR Ancillary Study dataset and values in the clinical trial dataset.  The mean and 
standard deviation of the bias along with a 95% confidence interval will be reported.  In 
Bland-Altman analyses of agreement between continuous measures, the standard 
deviation of the bias is referred to as the precision, while the 95% confidence interval is 
referred to as the limit of agreement. (See Table 6 as an example).
Table 6
Overall performance of EHR-based algorithms for baseline 
characteristics, using clinical trial data as the reference standard / 
Continuous variables
Bias
Measure
Mean (SD)
95% (CI)
Measure 1
xx.x
xx.x
Measure 2
xx.x
xx.x
.....
.....
.....
Due to the nature of EHR data, it is expected that there will be systematic differences 
between sites with respect to coding of clinical concepts.  All performance metrics will 
therefore initially be calculated by site. These site-specific results may be best reported 
graphically.

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There is also interest in an assessment of algorithm performance across all sites.  
Hierarchical models will be used to combine data from all sites and estimate performance 
at the “average” site.  To estimate proportions (e.g. for overall agreement, sensitivity, 
specificity, etc. associated with categorical measures), models will be specified as:
logit (E (y) )=β0+γ0,,j
γ0,j~N(0,s2)
where sites are indexed by j.  The value of the proportion at the average site—when 
γ0=0—is  [1+exp (–β0 ) ]-1.  Patients included in the estimation of each model vary by 
performance metric and reflect the definitions above.  As an example, consider positive 
predictive value.  To estimate the positive predictive value of an algorithm, only subjects 
with true positive value and false positive values will be included.  True positives will be 
assigned Y=1 and false positive will be assigned Y=0. 
To estimate means (e.g. for bias associated with continuous variables), the model will be 
specified as:
E (y )=β0+ γ0,,j
γ0,,j ~ N(0,s2)
The value of the mean at the average site is β0.  
For all models, we will assess site heterogeneity by testing if s2=0.
11.7.4.4.
Objective 2: Evaluate the Fitness of EHR Data for Use in Populating the 
Baseline Characteristics in the eCRF
Algorithms will be defined to map EHR-based data in the Study Data Mart to specific 
concepts in the EHR Ancillary Study dataset that parallel concepts in the clinical trial 
dataset.  For Objective 2, the performance of algorithms used to identify baseline 
characteristics will be evaluated.  The baseline characteristic measures recorded in the 
clinical trial dataset will be considered the reference standard against which these 
algorithm-based measures are compared. 
11.7.4.5.
Objective 3: Explore the Use of EHR Data to Find Events of Interest 
During Trial Follow-up
Algorithms will be defined to map EHR-based data in the Study Data Mart to specific 
concepts in the EHR Ancillary Study dataset that parallel concepts in the clinical trial 
dataset.  For Objective 3, the performance of algorithms used to identify trial events will 
be evaluated.  These algorithms will be evaluated against both the adjudicated events 
recorded in the clinical trial dataset and the identified potential events in the eCRF.  For 
each event, estimates of sensitivity and positive predictive value (described in Section 
11.7.4.3) will be calculated and presented with 95% confidence intervals.  

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References
Barry SJ, Dinnett E, Kean S, Gaw A, Ford I. Are routinely collected NHS administrative 
records suitable for endpoint identification in clinical trials? Evidence from the West of 
Scotland Coronary Prevention Study. PloS one. 2013; 8(9):e75379.
Curtis LH, Brown J, Platt R. Four Health Data Networks Illustrate The Potential For A 
Shared National Multipurpose Big-Data Network. Health Affairs. July 1, 2014; 
33(7):1178-1186.
Dregan A, van Staa TP, McDermott L, et al. Point-of-Care Cluster Randomized Trial in 
Stroke Secondary Prevention Using Electronic Health Records. Stroke. July 1, 2014; 
45(7):2066-2071.
Etheredge LM. A rapid-learning health system. Health affairs. Mar-Apr 2007; 
26(2):w107-118.
Fleurence RL, Beal AC, Sheridan SE, Johnson LB, Selby JV. Patient-Powered Research 
Networks Aim To Improve Patient Care And Health Research. Health Affairs. July 1, 
2014; 33(7):1212-1219.
Greene SM, Reid RJ, Larson EB. Implementing the learning health system: from concept 
to action. Annals of internal medicine. Aug 7 2012;157(3):207-210.
Gulliford MC, van Staa T, Dregan A, et al. Electronic Health Records for Intervention 
Research: A Cluster Randomized Trial to Reduce Antibiotic Prescribing in Primary Care 
(eCRT Study). The Annals of Family Medicine. July 1, 2014; 12(4):344-351.
NHLBI Working Group on Electronic Health Records: Research Priorities to Improve 
Cardiopulmonary Health in Clinical Practice. 2011. 
http://www.nhlbi.nih.gov/meetings/workshops/ehr.htm. Accessed Jan 28, 2013.
Richesson RL, Hammond WE, Nahm M, et al. Electronic health records based 
phenotyping in next-generation clinical trials: a perspective from the NIH Health Care 
Systems Collaboratory. Journal of the American Medical Informatics Association: 
JAMIA. Dec 2013; 20(e2):e226-231.
Toh S, Reichman ME, Houstoun M, et al. COmparative risk for angioedema associated 
with the use of drugs that target the renin-angiotensin-aldosterone system. Archives of 
Internal Medicine. 2012; 172(20):1582-1589.
van Staa T, Dyson L, McCann G, et al. The opportunities and challenges of pragmatic 
point-of-care randomised trials using routinely collected electronic records: evaluations 
of two exemplar trials. Health Technol Assess. 2014/07/11 2014; 18(43).

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11.8.
Appendix 8: Country Specific Requirements

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11.9.
Appendix 9: Protocol Amendment Changes
11.9.1.
Changes Resulting from Protocol Amendment 1
This amendment is applicable to all participating countries.
Summary of Changes
1. Correction of typographical error in Exclusion criterion 7.
2. Clarification wording added to the description of when subjects should have 
telephone follow-up after discontinuing investigational product (IP).  Subjects 
should have the telephone follow-up 5 1 weeks after their last dose of IP 
whether they had continued IP through to the Final study visit, or discontinued 
before the Final study visit.
3. Time and Event Table modified to add adverse event checking (SAE, AEs of 
special interest, AEs leading to IP discontinuation) to dose adjustment visits, and 
to correct footnote assignment/typographical errors.
4. Revision of terminology used to describe unstable angina events referred for CEC 
adjudication to correctly reflect review process to be adopted by CEC.
5. Addition of Country Specific Requirements appendix (Appendix 8).
List of Specific Changes
Section 4.2, Exclusion criteria; criterion 7, fourth sentence.
Original text:
Women who have developed spontaneous secondary amenorrhoea of 12 months or more 
where post-menopausal status is in doubt, a blood sample where FSH >40MU/ml and 
oestrodiol <40 pg/mL (<14 pmol/L) are simultaneously measured will be considered 
confirmatory.
Amended text:
Women who have developed spontaneous secondary amenorrhoea of 12 months or more 
where post-menopausal status is in doubt, a blood sample where FSH >40MU/ml and 
oestrodiol <40 pg/mL (<140 pmol/L) are simultaneously measured will be considered 
confirmatory.

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Section 4.5 Procedures for Subject Follow-up
Original text:
As described in Section 4.4, subjects who permanently discontinue investigational 
product will be asked to attend the clinic as soon as possible.  They will continue in the 
study for follow-up. They will be asked to return to clinic according to the 8 monthly 
visit schedule and in addition be contacted by telephone at a time corresponding to the 4-
monthly visit they would have otherwise made to replenish study medication supply.  If 
instead of these interim telephone contacts the subject prefers to attend clinic every 4 
months as originally scheduled that is an acceptable alternative.
Amended text:
As described in Section 4.4, subjects who permanently discontinue investigational 
product will be asked to attend the clinic as soon as possible.  They will continue in the 
study for follow-up. Five weeks (1 week) after discontinuation of investigational 
product, subjects will be contacted for a follow-up by telephone.  They will be asked to 
return to clinic according to the 8 monthly visit schedule and in addition be contacted by 
telephone at a time corresponding to the 4-monthly visit they would have otherwise made 
to replenish study medication supply.  If instead of these interim telephone contacts the 
subject prefers to attend clinic every 4 months as originally scheduled that is an 
acceptable alternative.

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Table 1 Time and Events Table
Original text:
Procedures1,2
Screening2
Randomization3
/Baseline 
(can be same day 
as Screening 
Visit)
Study Drug 
Check Phone
Call
(4-6 wks post 
and.)
Clinic Visit Month 4 
18 days then 
every 8 months 
18 days throughout 
the study
Unscheduled 
dose 
adjustment 
visit
(if warranted)
Clinic Visit Month 8 
18 days then 
every 8 months 
18 days throughout 
the study
Final study 
clinic 
visit4 (or 
early 
withdrawal)
Post-Study Follow up 
Phone Call
5 1 weeks after last 
IP dose
SAEs, AEs of special interest, AEs 
leading to IP discontinuation 
X
X
X
X
X
X
1.    Subjects who discontinue investigational product should be handled as described in Section 4.4.
11.  Study drug dispensing not performed at final visit, compliance check not performed at Screening.
Amended text:
Procedures1,2
Screening3
Randomization3
/Baseline 
(can be same day 
as Screening 
Visit)
Study Drug 
Check Phone 
Call
(4-6 wks post 
rand.)
Clinic Visit Month 4 
18 days then 
every 8 months 
18 days throughout 
the study
Unscheduled 
dose 
adjustment 
visit
(if warranted)
Clinic Visit Month 8 
18 days then 
every 8 months 
18 days throughout 
the study
Final study 
clinic 
visit4 (or 
early 
withdrawal)
Post-Study Follow up 
Phone Call
5 1 weeks after last 
IP dose
SAEs, AEs of special interest, AEs 
leading to IP discontinuation 
X
X
X
X
X
X
X
1.    Subjects who discontinue investigational product should be handled as described in Section 4.4 and Section 4.5.
11.  Study drug dispensing not performed at final visit, compliance check not performed at Randomisation.

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Section 6.2.1 Cardiovascular Events
Original text:
The CEC will review and adjudicate the following clinical events:

Myocardial infarction

Stroke

Unstable angina requiring revascularization

Hospitalization for heart failure

Sudden cardiac death

TIA

In addition, all clinical events submitted for adjudication and all other SAEs with a 
fatal outcome will be reviewed and adjudicated to classify the cause of death as 
cardiovascular or non-cardiovascular.
Amended text:
The CEC will review and adjudicate the following clinical events:

Myocardial infarction

Stroke

Unstable angina requiring hospitalization

Hospitalization for heart failure

Sudden cardiac death

TIA

In addition, all clinical events submitted for adjudication and all other SAEs with a 
fatal outcome will be reviewed and adjudicated to classify the cause of death as 
cardiovascular or non-cardiovascular.
Appendix 8 – Country Specific Requirements
Appendix 8 added (not in original text). This is a blank page headed “11.8.Appendix 8: 
Country Specific Requirements” to serve as a placeholder to be replaced by each 
participating GSK Country Medical Department with the appropriate text upon receipt of 
the protocol and before they distribute it further within their country.

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11.9.2.
Changes Resulting from Protocol Amendment 2
This amendment is applicable to all participating countries (with the exception of item 8 
below which is specific to Mexico).
Summary of Changes
1. Amendment to indicate that the study should be considered Phase III in countries 
where albiglutide has not been granted marketing authorisation and Phase IV in 
countries where it has been.
2.
Update to list of protocol authors.
3. Update to Sponsor Medical Monitor Contact Information.
4. Correction of terminology in Treatment Assignment section.
5. Removal of discrepancy between inclusion criterion 4 which wrongly indicates a 
negative serum pregnancy test is required to exclude pregnancy and the Time & 
Event table (Section 6), Section 6.2.6 Clinical Laboratory Assessments, the model 
consent form and the Study Reference Manual (which all correctly indicate that 
the requirement is for a negative urine test).
6. Time and Event Table 1 re-formatted as some investigators had found it 
confusing.
7. Addition of a Time and Event table of assessments to be performed for patients 
permanently discontinuing IP (Table 2).  The visits and telephone contact to be 
performed for patients discontinuing IP had been described in text previously but 
an additional tabular format was recommended to aid investigators.
8. Mexican Ministry of Health requirement to report events referred to CEC by 
Mexican investigators to also be reported to the Ministry as SAEs.
9. Addition of requirement to record lipid results if they are available from subjects’
routine clinical care outside of the trial.
10. Clarify that TRIM-D should not be assessed at Baseline in subjects whose 
diabetes is treated by diet and exercise alone.
11. Corrections to Data Analysis and Statistical Considerations Section to make it
more terminologically correct.
12. Simplification of description of information in Section 8.3.6.4 Other Safety 
Analyses to properly reflect the planned reports.
13. Correction of typographical error in spelling of spermicide.
14. Correction of recipient of faxed SAE reports if the electronic CRF is unavailable. 

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List of Specific Changes
Title Page
Original text:
Development Phase: IV
Amended text:
Development Phase: III/IV
Original text:
Author (s): The protocol was developed by the members of the Executive Committee in
conjunction with Duke Clinical Research Institute and the Sponsor.
The following individuals provided substantial input during protocol development:
Non-sponsor:
(Executive Committee Co-Chair);
(Executive Committee Co-
Chair);
Sponsor:
Amended text:
Author (s): The protocol was developed by the members of the Executive Committee in 
conjunction with Duke Clinical Research Institute and the Sponsor.
The following individuals provided substantial input during protocol development:
Non-sponsor:
 
(Executive Committee Co-Chair);
 
(Executive Committee Co-Chair);
Sponsor:
Sponsor Information Page, Sponsor Medical Monitor Contact Information
Original text:
Sponsor Medical Monitor Contact Information: 
Dr 
2301 Renaissance Boulevard
REN0410
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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King of Prussia, Pennsylvania 19406, USA
Email:
Fax:
Telephone number: Office: 
                                Cell: 
 
                                Out of hours: 
Amended text:
Sponsor Medical Monitor Contact Information: 
Dr 
2301 Renaissance Boulevard
REN0410
King of Prussia, Pennsylvania 19406, USA
Email:
Fax:
Telephone number: Office: 
                                Cell: 
 
                                Out of hours: 
List of Abbreviations
Original text:
Did not include the abbreviations added in amendment.
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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Amended text:
HDLc
high density lipoprotein cholesterol
LDLc
low density lipoprotein cholesterol
Tg
triglycerides
TC
total cholesterol
Section 3.1 Overall Design, first paragraph
Original text:
This is a Phase IV, randomised, double blind, parallel-group, placebo-controlled, 
multicentre study.
Amended text:
This is a Phase IV, randomised, double blind, parallel-group, placebo-controlled, 
multicentre study.  In countries where marketing authorization has been granted to 
albiglutide for the treatment of type 2 diabetes it is classified as a Phase IV study, 
elsewhere is should be considered to be a Phase III study.
Section 4.1 Inclusion Criteria; criterion 4, first sentence
Original text:
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:
Amended text:
Female: subject is eligible to participate if she is not pregnant (as confirmed by a negative 
serum urine human chorionic gonadotrophin (hCG) test for females of reproductive 
potential only), not breastfeeding, and at least one of the following conditions applies:
Section 5.2 Treatment Assignment; final paragraph
Original text:
Blinded study centre personnel will receive a randomisation notification indicating only 
the unique subject identifier and the date and time of randomisation. 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 investigational product. 
Details of the treatment assignment process are contained in the SRM.
Amended text:
Blinded study centre personnel will receive a randomisation notification indicating only
the unique subject identifier (randomisation number) and the date and time of 

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randomisation. Each randomisation subject number will be a unique identifier. Once a 
randomisation subject number has been assigned, the number will not be reused even if 
the subject withdraws before receiving any investigational product. Details of the 
treatment assignment process are contained in the SRM.

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Table 1 Time and Events Table
Original text:
Procedures1,2
Screening3 Randomization3
/Baseline 
(can be same day 
as Screening 
Visit)
Study Drug 
Check Phone 
Call
(4-6 wks post 
rand.)
Clinic Visit Month 4 
18 days then 
every 8 months 
18 days throughout 
the study
Unscheduled 
dose 
adjustment 
visit
(if warranted)
Clinic Visit Month 8 
18 days then 
every 8 months 
18 days throughout 
the study
Final study 
clinic 
visit4 (or 
early 
withdrawal)
Follow up Phone Call
5 1 weeks after last 
IP dose
Written informed consent  
X
Review of Inc/excl criteria
X
X
Demography & directed medical history
X
Assessment of MACE  and micro-vascular 
events
X
X
X
HbA1c
X5
X
X
X
Serum creatinine (eGFR)
X5
X
X
Liver Function Tests6
X
X
X
Genetic sampling7
X
Patient reported outcomes questionnaires8
X
X
X
Key concomitant non-diabetes medication
X
X
X
X
X
Diabetes medication
X
X
X
X
X
Study drug reminder
X
X
X
X
Physical examination9
X
X
X
SAEs, AEs of special interest, AEs leading 
to IP discontinuation 
X
X
X
X
X
X
X
Pregnancy test10
X
X
Study drug dispense/compliance11
X
X
X
X
X
1.
Subjects who discontinue investigational product should be handled as described in Section 4.4 and Section 4.5. 
2.
Assessments per the Month 4 visit will alternate with those per the Month 8 visit throughout the study i.e., assessments at months 4, 12, 20 etc will be per Month 4; those at month 
8, 16, 24 etc..will be per Month 8.
3.
Screening and Randomisation can occur at the same visit if all eligibility information is available. If Screening and Randomisation occur at the same visit assessments should not 
be duplicated.
4.
Once it is projected that the target number of MACE events will have been collected, a 3 month window will be defined for conducting the final, face to face visit.
5.
HbA1c and creatinine assessed using local laboratories at Screening visit and measured no more than 6 months prior to randomisation. If HbA1c or creatinine have not been 
assessed in the previous 6 months assessments to be performed via a central laboratory and results available prior to randomization. The investigator has the discretion to repeat 

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screening HbA1c, and/or creatinine, based on clinical rationale even if previously available local results meet the eligibility criteria to allow the investigator to accommodate the 
possibility of change between screening and randomisation.
6.
Liver function tests: ALT, AST, alkaline phosphatase, bilirubin, GGT. Blood samples for LFTs at randomization must be collected prior to the first dose of investigational product.
7.
Informed consent for genetic research must be obtained before collecting a sample.  Genetics sample can be collected at any time after genetic consent has been obtained and 
the subject has beenr randomised.
8.
TRIM-D, EQ-5D and study specific questionnaire (details in Section 6.3).
9.
See Section 6.2.7.  
10. Only applies to women of child bearing potential. At screening perform urine pregnancy test.  If positive, send serum sample to the central laboratory for confirmation. At 
Randomisation perform a urine pregnancy test. If result is positive do not randomize the subject. If the urine pregnancy test is negative then the subject can be randomised. If 
Screening and Randomisation are to take place at the same visit then follow the instructions for Screening. See Section 6.2.6.
11. Study drug dispensing not performed at final visit, compliance check not performed at Randomisation
Amended text:
Procedures1,2
Screening3
Randomization3
/Baseline 
(can be same day as 
Screening Visit)
Study Drug 
Check 
Phone Call
(4-6 wks post 
rand.)
Clinic Visit Month 4 
18 days then 
every 8 4 months 
18 days 
throughout the 
study
Unscheduled 
dose 
adjustment visit
(if warranted)
Clinic Visit 
Month 8 18 
days then every 
8 months 18 
days throughout 
the study
Final study 
clinic 
visit4 (or early 
withdrawal)
Follow up 
Phone Call
5 1 weeks 
after last IP 
dose
Written informed consent  
X
Review of Inc/excl criteria
X
X
Demography & directed medical history
X
Assessment of MACE  and micro-vascular 
events
X
X
X
HbA1c
X5
X
X
X
Serum creatinine (eGFR)
X5
X (alternate visits) 
2
X
X
Liver Function Tests (LFTs)6
X
X (alternate visits) 
2
X
X
Record available information on most 
recent lipid assessment7
X
X (annually)
X
Genetic sampling78
X
Patient reported outcomes questionnaires89
X10
X (alternate visits) 
2
X
X
Key concomitant non-diabetes medication
X
X
X
X
X

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Procedures1,2
Screening3
Randomization3
/Baseline 
(can be same day as 
Screening Visit)
Study Drug 
Check 
Phone Call
(4-6 wks post 
rand.)
Clinic Visit Month 4 
18 days then 
every 8 4 months 
18 days 
throughout the 
study
Unscheduled 
dose 
adjustment visit
(if warranted)
Clinic Visit 
Month 8 18 
days then every 
8 months 18 
days throughout 
the study
Final study 
clinic 
visit4 (or early 
withdrawal)
Follow up 
Phone Call
5 1 weeks 
after last IP 
dose
Diabetes medication
X
X
X
X
X
Study drug reminder
X
X
X
X
Physical examination911
X
X (alternate visits) 
2
X
X
SAEs, AEs of special interest, AEs leading to 
IP discontinuation 
X
X
X
X
X
X
X
Pregnancy test1012
X
X
Study drug dispense/compliance1113
X
X
X
X
X
1.
Subjects who discontinue investigational product should be handled as described in Section 4.4 and Section 4.5 and in Table 2. 
2.
Assessments per the Month 4 visit will alternate with those per the Month 8 visit throughout the study i.e., assessments at months 4, 12, 20 etc will be per Month 4; those at month 
8, 16, 24 etc..will be per Month 8.Assessments at month 8, 16, 24 etc. will include patient reported outcomes questionnaires, serum creatinine (eGFR), liver function 
tests and physical examination. Those at months 4, 12, 20 etc do not.
3.
Screening and Randomisation can occur at the same visit if all eligibility information is available. If Screening and Randomisation occur at the same visit assessments should not 
be duplicated.
4.
Once it is projected that the target number of MACE events will have been collected, a 3 month window will be defined for conducting the final, face to face visit.
5.
HbA1c and creatinine assessed using local laboratories at Screening visit and measured no more than 6 months prior to randomisation. If HbA1c or creatinine have not been 
assessed in the previous 6 months assessments to be performed via a central laboratory and results available prior to randomization. The investigator has the discretion to repeat 
screening HbA1c, and/or creatinine, based on clinical rationale even if previously available local results meet the eligibility criteria to allow the investigator to accommodate the 
possibility of change between screening and randomisation.
6.
Liver function tests: ALT, AST, alkaline phosphatase, bilirubin, GGT. Blood samples for LFTs at randomization must be collected prior to the first dose of investigational product.
7.
Lipid values (TC, LDLc, HDLc, Tg) to be recorded as available from routine clinical care at baseline and annually thereafter. If results are unavailable, lipid tests are 
not to be performed for the study.
8.
Informed consent for genetic research must be obtained before collecting a sample.  Genetics sampleThis can be collected at any time after genetic consent has been obtained 
and the subject has been randomisdrandomisation has occurred.
9.
TRIM-D, EQ-5D and study specific questionnaire (details in Section 6.3).
10. TRIM-D is not required for subjects whose diabetes is treated by diet and exercise alone at Baseline.
11. See Section 6.2.7.  
12. Only applies to women of child bearing potential. At screening perform urine pregnancy test.  If positive, send serum sample to the central laboratory for confirmation. At 
Randomisation perform a urine pregnancy test. If result is positive do not randomize the subject. If the urine pregnancy test is negative then the subject can be randomised. If 
Screening and Randomisation are to take place at the same visit then follow the instructions for Screening. See Section 6.2.6.
13. Study drug dispensing not performed at final visit, compliance check not performed at Randomisation

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Section 6 Study Assessments and Procedures; insertion of the following table after Table 1
Table 7
Time and Events Table for Subjects Who Permanently Discontinue IP Prior to the End of the Study
Procedures
Clinic visit as soon 
after permanent 
discontinuation of 
IP as possible
Phone Call
5 1 week 
after last IP 
dose
Continue contact schedule 
established at randomisation 
4 monthly 1 month. 
Telephone 1,2
Continue contact schedule 
established at randomisation 
4 monthly 1 month. 
Clinic visit 1,3
Final study clinic 
visit 4
Assessment of MACE  and micro-vascular events
X
X
X
X
HbA1c
X
X
X
Serum creatinine (eGFR)
X
X
X
Liver Function Tests (LFTs)5
X
X
X
Record available information on most recent lipid 
assessment6
X
X (annually)
X (annually)
X
Patient reported outcomes questionnaire7
X
Key concomitant non-diabetes medication
X
X
X
X
X
Diabetes medication
X
X
X
X
X
Physical examination8
X
X
X
AEs leading to IP discontinuation
X
SAEs, AEs of special interest, 
X
X
X
X
X
Study drug compliance
X
1. After subjects permanently discontinue IP, follow-up should continue on the 4-monthly schedule established at randomisation.
2. Where a subject would have been scheduled to attend clinic at months 4, 12, 20, 28 etc after randomisation, a telephone contact will be performed instead (with assessments as
shown above).
3. Where a subject would have been scheduled to attend clinic at months 8, 16, 24, 32 etc after randomisation, a clinic visit will be performed (with assessments as shown above).
If a subject who has permanently discontinued IP is unable to attend clinic then they will be contacted by telephone instead and the telephone contact assessments will be 
performed.
4. Once it is projected that the target number of MACE events will have been collected, a 3 month window will be defined for conducting the final, face to face visit.
5. Liver function tests: ALT, AST, alkaline phosphatase, bilirubin, GGT.
6. Lipid values (TC, LDLc, HDLc, Tg) to be recorded as available from routine clinical care annually. If results are unavailable, lipids tests are not to be performed for the study.
7. TRIM-D, EQ-5D and study specific questionnaire (details in Section 6.3).
8. See Section 6.2.7.  

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Section 6.2.1 Cardiovascular Events; footnote added to end of first sentence.
Original text:
Events referred to the CEC by the investigator as potential endpoints or transient 
ischemic attacks (TIAs) will not be collected or reported as SAEs, regardless of the 
adjudication outcome (Section 6.2.2).
Amended text:
Events referred to the CEC by the investigator as potential endpoints or transient 
ischemic attacks (TIAs) will not be collected or reported as SAEs, regardless of the 
adjudication outcome (Section 6.2.2).1
Footnote:
1 There is one exception to this statement. Per requirement of the Mexican Ministry of 
Health, all events referred to the CEC by Mexican investigators will also be submitted 
as SAEs to the Mexican Ministry of Health.
Section 6.2.6 Clinical Laboratory Assessments; text to be inserted at end of sub-section
Lipids
Where serum lipid tests have been performed as part of the subject’s routine clinical 
care (i.e. not as a study procedure) the most recent results should be recorded at 
baseline and annually thereafter.  The lipid parameters to be recorded are total 
cholesterol (TC), low density lipoprotein cholesterol (LDLc), high density lipoprotein 
(HDLc) and triglycerides (Tg).
If any or all of these results are not already available from the subject’s records then 
separate lipid tests should not be performed solely for the study.
Section 6.3.1.1. Treatment Related Impact Measure – Diabetes (TRIM-D)
Original Text:
In order to evaluate satisfaction with treatment and to compare satisfaction across 
treatment groups, the TRIM-D questionnaire will be self administered by all subjects at 
baseline and at each 8 month visit (and, to the extent possible, at the time of study 
completion or withdrawal from the study).
Amended Text:
In order to evaluate satisfaction with treatment and to compare satisfaction across 
treatment groups, the TRIM-D questionnaire will be self administered by all subjects at 
baseline (except for subjects whose diabetes is treated by diet and exercise alone) and all 
subjects at each 8 month visit (and, to the extent possible, at the time of study completion 
or withdrawal from the study).

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Section 8.3.3.1 Primary Comparisons of Interest, second sentence
Original text:
The primary endpoint will be the time to the first occurrence of MACE over the full 
duration of the study. A p-value for the primary endpoint will be calculated from a Cox 
regression model with treatment group as the only covariate for the hypotheses described 
in Section 8.1.
Amended text:
The primary endpoint will be the time to the first occurrence of MACE over the full 
duration of the study. A p-value for the primary endpoint will be calculated from a Cox 
Proportional Hazards (PH) regression model with treatment group as the only covariate 
for the hypotheses described in Section 8.1.
Section 8.3.3.2. Other Comparisons of Interest, insertion of two new sentences:
Original text:
For other analyses incidence rates will be presented for binary data and summary 
statistics (mean, median, standard deviation, minimum, and maximum) will be presented 
for continuous data.  Furthermore, summary statistics of change from baseline for HbA1c 
will be presented along with percent of subjects within ranges of clinical interest (e.g., 
HbA1c < 7.0%).
Amended text:
For other analyses incidence rates will be presented for binary data and summary 
statistics (mean, median, standard deviation, minimum, and maximum) will be presented 
for continuous data.  Time to event endpoints will be evaluated via the p-value from a 
Cox PH regression model with treatment as the only covariate.  Furthermore, summary 
statistics of change from baseline for HbA1c will be presented along with percent of 
subjects within ranges of clinical interest (e.g., HbA1c < 7.0%).  Available lipid data will 
be summarized for descriptive purposes.
Section 8.3.6.2. Secondary Endpoint Analysis
Original text:

Composite of the proportion of those achieving good control (HbA1c ≤ 7.0%) AND 
no severe hypoglycaemic incidents AND weight gain <5% at the end of the study 
would be evaluated utilize nonparametric, covariance-adjusted, extended Mantel-
Haenszel tests. Additional analysis will be provided for scheduled visits. Nominal p-
values and 95% CIs will be presented for these visits. Time to introduction of 
prandial insulin in those on basal insulin orals anti-hyperglycemic drugs at baseline 
will be analyzed using PH model / log-rank test and KM method similar to the 
primary endpoint.

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
Composite of microvascular events will be analyzed using a proportional Cox 
regression model / log-rank test and KM method similar to the primary endpoint.
Amended text:

Composite of the proportion of those achieving good control (HbA1c ≤ 7.0%) AND 
no severe hypoglycaemic incidents AND weight gain <5% at the end of the study 
would be evaluated utilize nonparametric, covariance-adjusted, extended Mantel-
Haenszel tests. Additional analysis will be provided for scheduled visits. Nominal p-
values and 95% CIs will be presented for these visits. Time to introduction of 
prandial insulin in those on basal insulin orals anti-hyperglycemic drugs at baseline 
will be analyzed using a Cox PH model / log-rank test and KM method similar to the 
primary endpoint.

Composite of microvascular events will be analyzed using a proportional Cox 
regression model / log-rank test and KM method similar to the primary endpoint.
Section 8.3.6.4. Other Safety Analyses, paragraphs 3, 4 and 5.
Original text:
For SAEs, AEs leading to withdrawal  and AEs of special interest occurring after 
discontinuation of investigational product, the number and percentage of subjects , total 
number of events, incidence density and event rate will be presented by treatment group 
and overall at the SOC, High Level Term and Preferred Term (PT) level. Relative Risk 
for each event and its 95% CI will also be presented. The time to first occurrence of the 
specific events and the time of the event with respect to the preceding dose of study 
medication will be summarized.
All cause mortality will be summarized by treatment group and analyzed using PH model 
similarly as the-primary endpoint.
All events sent to CEC (including TIAs) will be grouped by type based on the standard 
MedDRA queries that correspond to cardiovascular and cerebrovascular events. 
Adjudication results will be summarized by event type and treatment group. A by subject 
listing of these events will be generated.  The listing will include seriousness, severity, 
whether event is a reason for early study drug discontinuation or study withdrawal, and 
adjudication results.
Pancreatitis events will be adjudicated by the independent Pancreatitis Adjudication 
Committee. The information for investigator reported pancreatitis events and its 
adjudication results will be provided.
Amended text:
For SAEs, AEs leading to permanent IP withdrawal  and AEs of special interest 
occurring after discontinuation of investigational product, the number and percentage of 
subjects, total number of events, and incidence density and event rate will be presented 
by treatment group and overall at the SOC, High Level Term and Preferred Term (PT) 
level. Relative Risk for each event and its 95% CI willmay also be presented on a 

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targeted basis. The time to first occurrence of the specific events and the time of the 
event with respect to the preceding dose of study medication will be summarized.
All cause mortality will be summarized by treatment group and analyzed using a Cox PH 
model similarly as the primary endpoint.
All events sent to CEC (including TIAs) will be summarized. grouped by type based on 
the standard MedDRA queries that correspond to cardiovascular and cerebrovascular 
events. Adjudication results will be summarized by event type and treatment group. A by 
subject listing of these events will be generated.  The listing will include seriousness, 
severity, whether event is a reason for early study drug discontinuation or study 
withdrawal, and adjudication results.
Pancreatitis events will be adjudicated by the independent Pancreatitis Adjudication 
Committee. The information for investigator reported pancreatitis events and its 
adjudication results will be summarizedprovided.
Section 8.3.6.5 Value Evidence and Outcomes Analyses
Original Text:
TRIM-D total score and score for each domain will be summarized descriptively by 
treatment group and scheduled visit. Score changes from baseline will be compared 
between treatments for each visit by ANCOVA an model.
Amended Text:
TRIM-D total score and score for each domain will be summarized descriptively by 
treatment group and scheduled visit. Score changes from baseline will be compared 
between treatments for each visit by an ANCOVA an model.
Section 11.2  Appendix 2: GSK Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP), final listed item
Original text:
8.
Male condom combined with a female diaphragm, with or without a vaginal 
spermicide (foam, gel, film, cream, or suppository). In the UK it is a country-specific 
requirement of the regulatory authority (Medicines and Healthcare Products 
Regulatory Agency) that a vaginal spermcide be used.
Amended text:
8.
Male condom combined with a female diaphragm, with or without a vaginal 
spermicide (foam, gel, film, cream, or suppository). In the UK it is a country-specific 

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requirement of the regulatory authority (Medicines and Healthcare Products 
Regulatory Agency) that a vaginal spermcidespermicide be used.
Section 11.5.5 Reporting of SAEs to GSK, edit to second bullet, insertion of new third 
bullet
Original text:

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 or the SAE 
coordinator
Amended text:

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 or the SAE 
coordinatorsafety designee as detailed in the Study Reference Manual

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.

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The GlaxoSmithKline group of companies
GLP116174
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A long term, randomised, double blind, placebo-controlled study 
to determine the effect of albiglutide, when added to standard 
blood glucose lowering therapies, on major cardiovascular 
events in patients with Type 2 diabetes mellitus
Harmony Outcomes Trial
Compound Number:
GSK716155
Development Phase:
IV
Effective Date:
24-NOV-2014
Protocol Amendment Number:  1
Author (s): The protocol was developed by the members of the Executive Committee in 
conjunction with Duke Clinical Research Institute and the Sponsor.
The following individuals provided substantial input during protocol development:
Non-sponsor:
(Executive Committee Co-Chair); 
(Executive Committee Co-
Chair);
Sponsor:
 
Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2014N193553_00
2014-SEP-25
Original
2014N193553_01
2014-NOV-24
Amendment No. 1
Clarification added regarding follow-up after discontinuation of investigational product.
Addition of safety assessment to dose adjustment visits.
Addition of Country Specific Requirements appendix.
Correction of typographical errors and inconsistent terminology.
Copyright 2014 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD
PPD
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PPD
PPD

PPD

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SPONSOR INFORMATION PAGE
Clinical Study Identifier: GLP116174
Sponsor Legal Registered Address:
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford, Middlesex, TW8 9GS, UK
Sponsor Contact Address
GlaxoSmithKline Research & Development Limited
Iron Bridge Road 
Stockley Park West, Uxbridge, Middlesex, UB11 1BU, UK
Telephone: 
GlaxoSmithKline Research & Development Limited
2301 Renaissance Boulevard
Building #510
Post Office Box 61540
King of Prussia, Pennsylvania 19406, USA
Telephone number:
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline affiliate 
company (or designee). Where applicable, the details of the Sponsor and contact person 
will be provided to the relevant regulatory authority as part of the clinical trial 
submission.
Sponsor Medical Monitor Contact Information: 
Dr
2301 Renaissance Boulevard
REN0410
King of Prussia, Pennsylvania 19406, USA
Email:
Fax:
Telephone number: Office: 
                                Cell: 
 
                                Out of hours: 
Sponsor Serious Adverse Events (SAE) Contact Information:
Dr 
As above for Medical Monitor Contact
Regulatory Agency Identifying Number(s):
Investigational New Drug (IND) Number: IND65177
European Drug Regulatory Authorities Clinical Trials (EudraCT) No. 2014-001824-32.
PPD
PPD
PPD
PPD
PPD
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PPD
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number GLP116174
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 Signature:
Date

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TABLE OF CONTENTS
PAGE
LIST OF ABBREVIATIONS.............................................................................................9
PROTOCOL SUMMARY...............................................................................................11
1.
INTRODUCTION....................................................................................................13
1.1.
Background ................................................................................................13
1.2.
Rationale ....................................................................................................14
2.
OBJECTIVES AND ENDPOINTS...........................................................................15
3.
STUDY DESIGN ....................................................................................................16
3.1.
Overall Design ............................................................................................16
3.2.
Standard of Care ........................................................................................17
3.3.
Discussion of Design ..................................................................................18
3.4.
Benefit:Risk Assessment ............................................................................19
3.4.1.
Risk Assessment .........................................................................19
3.4.1.1.
Identified Risks...........................................................19
3.4.1.2.
Potential Risks............................................................20
3.4.2.
Benefit Assessment.....................................................................22
3.4.3.
Overall Benefit:Risk Conclusion...................................................23
4.
SUBJECT SELECTION AND WITHDRAWAL CRITERIA.......................................23
4.1.
Inclusion Criteria.........................................................................................23
4.2.
Exclusion Criteria........................................................................................24
4.3.
Screening/BaselineFailures ........................................................................25
4.4.
Criteria for Early Discontinuation of Investigational Product ........................26
4.4.1.
Early Discontinuation of Investigational Product...........................26
4.4.2.
Reasons for Discontinuation of Investigational Product................26
4.4.3.
Liver Chemistry Stopping Criteria ................................................27
4.4.4.
eGFR Stopping Criteria................................................................28
4.5.
Procedures for Subject Follow-up ...............................................................29
4.5.1.
Withdrawal of Consent for Contact...............................................29
4.5.2.
Subjects Deemed Lost to Follow-up.............................................30
5.
STUDY TREATMENTS..........................................................................................30
5.1.
Investigational Product and Other Study Treatment....................................30
5.2.
Treatment Assignment................................................................................31
5.3.
Blinding.......................................................................................................32
5.4.
Product Accountability ................................................................................32
5.5.
Treatment Compliance................................................................................33
5.6.
Concomitant Medications and Non-Drug Therapies....................................33
5.6.1.
Permitted Medications and Non-Drug Therapies..........................33
5.6.2.
Prohibited Medications and Non-Drug Therapies.........................33
5.7.
Treatment after the End of the Study ..........................................................34
5.8.
Treatment of Study Treatment Overdose....................................................34
6.
STUDY ASSESSMENTS AND PROCEDURES .....................................................34
6.1.
Critical Baseline Assessments....................................................................36
6.2.
Safety .........................................................................................................36
6.2.1.
Cardiovascular Events.................................................................36

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6.2.1.1.
Other CV Events ........................................................37
6.2.2.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........37
6.2.2.1.
Time period and Frequency for collecting AE 
and SAE information...................................................38
6.2.2.2.
Method of Detecting AEs and SAEs ...........................38
6.2.2.3.
Follow-up of AEs and SAEs........................................39
6.2.2.4.
Sentinel Events ..........................................................39
6.2.2.5.
Regulatory Reporting Requirements for SAEs............39
6.2.3.
Adverse Events of Special Interest ..............................................40
6.2.4.
Clinically Important Microvascular Events....................................41
6.2.5.
Pregnancy ...................................................................................41
6.2.6.
Clinical Laboratory Assessments .................................................42
6.2.6.1.
Estimated Glomerular Filtration Rate (eGFR) .............43
6.2.7.
Physical examination ...................................................................43
6.3.
Value Evidence and Outcomes...................................................................43
6.3.1.
Value Evidence and Outcomes Assessments..............................43
6.3.1.1.
Treatment Related Impact Measure – Diabetes 
(TRIM-D) ....................................................................43
6.3.1.2.
EQ-5D ........................................................................44
6.3.1.3.
Exploratory Diabetes Management Questions............44
6.3.1.4.
Healthcare Resource Utilisation..................................45
6.4.
Genetic Research.......................................................................................45
7.
DATA MANAGEMENT ...........................................................................................45
8.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS...................................46
8.1.
Hypotheses.................................................................................................46
8.2.
Study Design Considerations......................................................................46
8.2.1.
Sample Size Assumptions ...........................................................46
8.2.2.
Sample Size Sensitivity for MACE non-inferiority.........................46
8.2.3.
Sample Size Re-estimation..........................................................47
8.3.
Data Analysis Considerations .....................................................................47
8.3.1.
Analysis Populations....................................................................47
8.3.2.
Analysis Data Set ........................................................................48
8.3.3.
Treatment Comparisons ..............................................................48
8.3.3.1.
Primary Comparisons of Interest ................................48
8.3.3.2.
Other Comparisons of Interest....................................48
8.3.4.
Interim Analysis ...........................................................................49
8.3.5.
Multiplicity Controls......................................................................49
8.3.6.
Key Elements of Analysis Plan ....................................................51
8.3.6.1.
Primary Analysis.........................................................51
8.3.6.2.
Secondary Endpoint Analysis .....................................52
8.3.6.3.
Subgroup Analysis......................................................53
8.3.6.4.
Other Safety Analyses................................................53
8.3.6.5.
Value Evidence and Outcomes Analyses ...................54
9.
STUDY CONDUCT CONSIDERATIONS ...............................................................54
9.1.
Posting of Information on Publicly Available Clinical Trial Registers............54
9.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................55
9.3.
Quality Control (Study Monitoring) ..............................................................55
9.4.
Quality Assurance.......................................................................................56

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9.5.
Study and Site Closure ...............................................................................56
9.6.
Records Retention......................................................................................57
9.7.
Provision of Study Results to Investigators, Posting of Information 
on Publicly Available Clinical Trials Registers and Publication....................57
9.8.
Independent Data Monitoring Committee (IDMC) .......................................58
9.9.
Pancreatitis Adjudication Committee...........................................................58
10. REFERENCES.......................................................................................................59
11. APPENDICES........................................................................................................62
11.1.
Appendix 1: Genetic Research ...................................................................62
11.2.
Appendix 2: GSK Modified List of Highly Effective Methods for 
Avoiding Pregnancy in Females of Reproductive Potential (FRP)...............68
11.3.
Appendix 3: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................69
11.4.
Appendix 4: Liver Safety Drug Restart Guidelines ......................................73
11.5.
Appendix 5: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................75
11.5.1.
Definition of Adverse Events........................................................75
11.5.2.
Definition of Serious Adverse Events...........................................76
11.5.3.
Recording of AEs and SAEs ........................................................78
11.5.4.
Evaluating AEs and SAEs............................................................79
11.5.5.
Reporting of SAEs to GSK...........................................................80
11.6.
Appendix 6: Collection of Pregnancy Information........................................81
11.7.
Appendix 7: Electronic Health Record Ancillary Study ................................82
11.7.1.
Introduction..................................................................................82
11.7.1.1.
Background ................................................................82
11.7.1.2.
Literature Review .......................................................82
11.7.1.3.
Ancillary Study Rationale............................................83
11.7.2.
Ancillary Study OBJECTIVES......................................................84
11.7.2.1.
Primary Objectives .....................................................84
11.7.2.2.
Secondary Objective ..................................................84
11.7.3.
Ancillary Study design..................................................................85
11.7.3.1.
Study Design..............................................................85
11.7.3.2.
Site Selection .............................................................85
11.7.3.3.
Data Flows .................................................................86
11.7.3.4.
Study Procedures and Processes...............................88
11.7.3.4.1.
DCRI ......................................................88
11.7.3.4.2.
Sites .......................................................90
11.7.4.
DATA ANALYSIS.........................................................................91
11.7.4.1.
Sample Size Expectations..........................................91
11.7.4.2.
Objective 1: Assess the Barriers to Using as 
EHR-Generated List of Patients to Facilitate 
Trial Enrollment ..........................................................91
11.7.4.3.
General Analytic Approach for Objective 1 and 
Objective 2 .................................................................91
11.7.4.4.
Objective 2: Evaluate the Fitness of EHR Data 
for Use in Populating the Baseline 
Characteristics in the eCRF........................................93
11.7.4.5.
Objective 3: Explore the Use of EHR Data to 
Find Events of Interest During Trial Follow-up ............93
11.8.
Appendix 8: Country Specific Requirements...............................................95

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11.9.
Appendix 9: Protocol Amendment Changes................................................96
11.9.1.
Changes Resulting from Protocol Amendment 1..........................96

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LIST OF ABBREVIATIONS
ACCF
American College of Cardiology Foundation
ADA
American Diabetes Association
AE
adverse event
AHA
American Heart Association
ALT (SGPT)
alanine aminotransferase (serum glutamic pyruvic 
transaminase)
ANCOVA
analysis of covariance
AST (SGOT)
aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase)
BI
baseline basal insulin population
BMI
body mass index
bpm
beats per minute
CABG
coronary artery bypass graft
CAD
coronary artery disease
CEC
Cardiovascular Endpoint Committee
CI
confidence interval
CPK
creatine phosphokinase 
CONSORT
Consolidated Standards of Reporting Trials
DCRI
Duke Clinical Research Institute
DNA
deoxyribonucleic acid
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
EHR
electronic health record
ESC
European Society of Cardiology
FDA
US Food and Drug Administration
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
HbA1c
glycated haemoglobin
hCG
human chorionic gonadotrophin
HLA
human leukocyte antigen 
HRT
hormone replacement therapy
IB
Investigator’s Brochure
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
INR
international normal range
IRB
Institutional Review Board
ITT
intent-to-treat
IVRS
Interactive Voice Response System
KM
Kaplan-Meier

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LDH
lactate dehydrogenase
LFT
liver function test
MACE
major adverse cardiovascular event
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MEN-2
multiple endocrine neoplasia type 2
MSDS
Material Safety Data Sheet
MTC
medullary thyroid cancer
NHLBI
National Heart, Lung and Blood Institute
NI
non-insulin population
PAD
peripheral arterial disease
PD
pharmacodynamics
PHI
Protected Health Information
PK
pharmacokinetics
PP
per protocol
RAP
Reporting Analysis Plan
RR
relative risk
s.c.
subcutaneous
SAE
serious adverse event
SRM
Study Reference Manual
SU
sulfonylureas
TIA
transient ischemic attack
TRIM-D
Treatment Related Impact Measures-D
ULN
upper limit of normal range
WHF
World Heart Federation
WHO
World Health Organization
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
EQ-5D
PopMedNet
SAS

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PROTOCOL SUMMARY
Rationale
Albiglutide is a novel analogue of glucagon-like peptide-1 (GLP-1) with a sufficiently 
long half-life to permit once a week injection. Albiglutide is licensed for the treatment of 
type 2 diabetes as an adjunct to diet and exercise, as monotherapy, or in combination with 
existing therapies, including basal insulin. The Food and Drug Administration (FDA) has 
issued guidance on evaluating cardiovascular risk in new anti-diabetic therapies to treat 
type 2 diabetes [FDA Guidance for Industry, 2008].  For a premarketing application that 
contains a meta-analysis of major adverse cardiovascular events (MACE) for which the 
upper bound of the 95 percent confidence interval for the relative risk is between 1.3 and 
1.8, a post-marketing trial generally will be necessary to definitively show that the upper 
bound of the two-sided 95 percent confidence interval for the estimated risk ratio is less 
than 1.3.  The MACE meta-analysis of the albiglutide Phase III program  (primary 
endpoint cardiovascular death, myocardial infarction, stroke and hospitalization for 
unstable angina), whilst ruling out an upper bound of the confidence interval for 
cardiovascular events of 1.8, was not able to rule out (due to a relatively small number of 
events) a relative risk (RR) upper bound of 1.3.  For this reason GlaxoSmithKline (GSK) 
will conduct this cardiovascular outcome study as a US post-marketing requirement, to 
evaluate the effect of albiglutide on cardiovascular events in subjects with type 2 
diabetes.
Objectives/Endpoints
Objectives
Endpoints
Primary
To determine whether 
albiglutide is non-inferior with 
respect to MACE when added 
to glycaemic standard of care 
versus standard of care alone

Time to first occurrence of MACE (cardiovascular death, 
myocardial infarction,  or stroke) [Non-inferiority]
Secondary
To supplement the primary 
objective by further 
characterization of the effects of 
albiglutide on cardiovascular 
outcomes 

Time to first occurrence of MACE [Superiority](1 see footnote)

Time to first occurrence of the following:

MACE or urgent revascularisation for unstable angina

The individual components of the primary endpoint

Cardiovascular death or hospitalization due to heart failure
To evaluate the effects of 
albiglutide on metabolic 
management of type 2 diabetes

Time to initiation of insulin of more than 3 months duration for 
those subjects not treated with insulin at study start (1 see footnote)

Time to initiation of prandial insulin in those subjects on basal insulin at 
study start

The proportion of subjects achieving glycaemic control (HbA1c ≤ 
7.0% at final assessment) with no severe hypoglycaemic incidents 
and weight gain <5% of body weight (1 see footnote)

The time to first occurrence of a clinically important microvascular 
event (see Section 6.2.4)

Change in glycated haemoglobin (HbA1c)

Change in body weight

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Objectives
Endpoints

Patient reported outcomes from Treatment Related Impact Measures-
D (TRIM-D)/EQ5D
To evaluate the safety of 
albiglutide

All cause mortality

Non-fatal serious adverse events (SAEs)

Adverse events (AEs) leading to discontinuation of investigational 
product 

AE of special interest (see Section 6.2.3)

Change in estimated glomerular filtration rate (eGFR) calculated using 
Modification of Diet in Renal Disease (MDRD) formula

Change in blood pressure and heart rate
1.
If the primary endpoint meets the criteria for non-inferiority, a multiple comparisons adjustment strategy will be 
performed for these 3 secondary endpoints as specified in the Section 8.3.5.
Overall Design
This is a randomised, double blind, parallel group, placebo-controlled study. 
Treatment Arms and Duration
All subjects will receive standard of care for their diabetes and cardiovascular health 
which can be adjusted by the healthcare professional responsible for the subject during 
the study according to clinical need and with close adherence to professional society 
treatment guidelines.  The study comparison is thus between albiglutide added to 
standard of care and standard of care alone.  Placebo injections will be used to ensure 
study assessments are performed without knowledge of treatment assignment.  Treatment 
with albiglutide or placebo will be randomly allocated in a 1:1 ratio.  The starting dose of 
albiglutide is 30 mg weekly which may be up-titrated to 50mg weekly if further 
improvement of glycaemic control is required. 
The study will be event driven, i.e. follow up will continue until it is projected that 
approximately 611 adjudicated MACE events will have occurred. Consequently, the 
maximum duration of the study for an individual participant is dependent both on the 
time taken for recruitment and the MACE event rate, and is estimated to be between 3 
and 5 years. 
An Independent Data Monitoring Committee (IDMC) will have study oversight to ensure 
participant safety and scientific integrity of the data.
Type and Number of Subjects
A total of 9400 subjects with type 2 diabetes and a previous history of cardiovascular  
disease and who do not have optimal glycaemic control will be studied. 
Analysis
The study’s primary question is whether albiglutide is non-inferior by a margin of 1.3 
with respect to its effect on adjudicated MACE, when added to glycaemic standard of 
care, versus standard of care alone. The primary analysis is an Intent-to-Treat (ITT) 
analysis of the time to the first occurrence of MACE using Cox’s Proportional Hazard 
regression.  

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1.
INTRODUCTION
1.1.
Background
Diabetes affects an estimated 347 million people worldwide, with type 2 diabetes 
accounting for more than 90% of cases [WHO, 2013]. The primary manifestation of this 
disease is chronic hyperglycaemia, resulting from resistance to insulin action at a cellular 
and molecular level and a relative inadequacy in the secretion of endogenous insulin 
[American Diabetes Association, 2014]. Chronic hyperglycaemia has been firmly 
established as a key factor in the development of microvascular complications 
(retinopathy, nephropathy, and neuropathy).  Individuals with type 2 diabetes are also at 
greatly elevated risk of cardiovascular disease.
The management of glycaemia in individuals with type 2 diabetes consists of diet, 
exercise, and weight reduction together with oral anti-diabetic drug, injectable agents 
such as GLP-1 receptor agonists or insulin therapy, to achieve near normoglycaemia as 
reflected by a target HbA1c level of 7%, where possible, without significant 
hypoglycaemia or other adverse effects of treatment. Despite the large number of 
available therapeutic agents, a high proportion of subjects fail to achieve or maintain 
target HbA1c levels [Khunti, 2013] owing to the inexorable decline in endogenous 
insulin production characteristic of the disease, and limitations in existing treatments. 
New agents with complementary mechanisms (permitting combination use) or more 
favourable safety profiles are needed to help more subjects achieve glycaemic targets. 
GLP-1 is secreted by intestinal L-cells in response to ingestion of food. In a healthy 
individual, it plays an important role regulating postprandial blood glucose by stimulating 
glucose-dependent insulin secretion by the pancreas. GLP-1 suppresses glucagon 
secretion, leading to reduced hepatic glucose output. It also delays gastric emptying time 
and slows small bowel motility, delaying food absorption and slowing the rate of glucose 
appearance in the blood. In patients with type 2 diabetes the postprandial rise in 
endogenous GLP-1 is absent or reduced [Vilsbøll, 2001]. 
GLP-1 receptor agonists have been developed as anti-hyperglycemic therapy for type 2 
diabetes to replace or supplement endogenous GLP-1 in order to increase meal-related 
insulin secretion, reduce inappropriate glucagon secretion, and slow GI motility. They 
have demonstrated substantial effectiveness in improving glycaemic control while 
mitigating the risk of hypoglycaemia and weight gain commonly associated with some of 
the other treatments for type 2 diabetes [Stonehouse, 2012].  
Albiglutide is a novel analogue of GLP-1 generated through a genetic fusion of 2 
modified recombinant human GLP-1 molecules linked in tandem to recombinant human 
albumin. Albiglutide is licensed for the treatment of type 2 diabetes as an adjunct to diet 
and exercise, as monotherapy, or in combination with existing therapies (oral anti-
diabetic therapies or basal insulin).  It has been granted marketing authorisation by the 
European Medicines Agency (EMA) (March 2014) and the FDA (April 2014).  Details of 
the clinical trial results can be found in the Investigator Brochure (IB).

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1.2.
Rationale
The FDA has issued guidance on evaluating cardiovascular risk in new anti-diabetic 
therapies to treat type 2 diabetes [FDA Guidance for Industry, 2008]. For a premarketing 
application that contains a meta-analysis of MACE, for which the upper bound of the 95 
percent confidence interval for the relative risk is between 1.3 and 1.8, a post-marketing 
trial may be necessary to definitively show that the upper bound of the two-sided 95 
percent confidence interval for the estimated risk ratio is less than 1.3.
The MACE + meta-analysis of the albiglutide Phase III program (primary endpoint 
cardiovascular death, myocardial infarction, stroke and hospitalization for unstable 
angina), whilst ruling out an upper bound of the confidence interval for cardiovascular 
events of 1.8, was not able to rule out (due to a relatively small number of events) a RR 
upper bound of 1.3. For this reason GSK will conduct this cardiovascular outcome study 
as a US post-marketing requirement, to evaluate the effect of albiglutide on 
cardiovascular events in subjects with type 2 diabetes. 
Preclinical studies have provided evidence that GLP-1 receptor stimulation favourably 
effects endothelial function, recovery from ischemic injury, and myocardial function in 
animals [reviewed in Okerson, 2012]. Albiglutide reduced infarct size assessed 24 hours 
after 30 minutes temporary left anterior descending coronary artery occlusion in 
normoglycaemic rats [Bao, 2011]. GLP-1 infusion has been shown to improve 
endothelial function in subjects with stable coronary disease [Nystrom, 2004]. In subjects 
with ST-segment elevation myocardial infarction treated with primary percutaneous 
coronary intervention, the GLP-1 receptor agonist, exenatide, administered at the time of 
reperfusion has been reported to increase myocardial salvage [Lønborg, 2012].  In the 
Phase III studies, small mean increases in heart rate (1 to 2 bpm) and a higher incidence 
of atrial fibrillation/flutter events were observed with albiglutide.  It is difficult to predict 
whether these preclinical and clinical findings will translate into effect on major 
cardiovascular events.

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2.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
To determine whether 
albiglutide is non-inferior with 
respect to MACE when added 
to glycaemic standard of care 
versus standard of care alone

Time to first occurrence of MACE (cardiovascular death, 
myocardial infarction,  or stroke) [Non-inferiority]
Secondary
To supplement the primary 
objective by further 
characterization of the effects of 
albiglutide on cardiovascular 
outcomes 

Time to first occurrence of MACE [Superiority](1 see footnote)

Time to first occurrence of the following:

MACE or urgent revascularisation for unstable angina

The individual components of the primary endpoint

Cardiovascular death or hospitalization due to heart failure
To evaluate the effects of 
albiglutide on metabolic 
management of type 2 diabetes

Time to initiation of insulin of more than 3 months duration for 
those subjects not treated with insulin at study start (1 see footnote)

Time to initiation of prandial insulin in those subjects on basal insulin at 
study start

The proportion of subjects achieving glycaemic control (HbA1c ≤ 
7.0% at final assessment) with no severe hypoglycaemic incidents 
and weight gain <5% of body weight (1 see footnote)

The time to first occurrence of a clinically important microvascular 
event (see Section 6.2.4)

Change in HbA1c

Change in body weight

Patient reported outcomes from TRIM-D/EQ5D
To evaluate the safety of 
albiglutide

All cause mortality

Non-fatal SAEs

AEs leading to discontinuation of investigational product 

AE of special interest (see Section 6.2.3)

Change in eGFR calculated using MDRD formula

Change in blood pressure and heart rate
Exploratory
To evaluate patient reported 
experience of diabetes treatment

Patient reported outcomes from study specific questionnaire
To evaluate (at a subset of sites) 
barriers to using the electronic 
health record (EHR) to facilitate 
trial enrolment and the quality of 
EHR data for use in populating 
baseline characteristics and 
identifying events of interest 
during trial follow-up.2

Workflow impact of an EHR-generated list of subjects to facilitate trial 
enrolment. 

Concordance, sensitivity, specificity, and accuracy of baseline 
characteristics extracted from the EHR compared with those reported 
on the electronic case report form (eCRF)3

Concordance, sensitivity, specificity, and accuracy of EHR-identified 
events compared with study events 3,4

1.
If the primary endpoint meets the criteria for non-inferiority, a multiple comparisons adjustment strategy will be 
performed for these 3 secondary endpoints as specified in the Section 8.3.5.
2.
Details are provided in a separate EHR ancillary study protocol (Appendix 7).  Results from this exploratory 
investigation will be reported separately from the main clinical study report.
3.
Comparison of EHR identified events with study events will be conducted in the same data subset.
4.
Analyses t o be undertaken after the main trial results are published.

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3.
STUDY DESIGN
3.1.
Overall Design
This is a Phase IV, randomised, double blind, parallel-group, placebo-controlled, 
multicentre study.  This study will recruit approximately 9400 subjects with type 2 
diabetes and a previous history of cardiovascular disease who are failing to achieve 
optimal glycaemic control on their current anti-hyperglycaemic regimen. Subjects will be 
randomised in a 1:1 ratio to albiglutide or albiglutide matching placebo administered 
once weekly by subcutaneous (s.c.) injection.  
All subjects will receive standard of care which can be adjusted by their usual care 
provider(s) during the study according to clinical need (See Section 3.2). The study 
comparison is between albiglutide added to standard of care and standard of care alone.  
The starting dose of albiglutide will be 30 mg once weekly. If at any stage after 5 weeks 
of treatment the subject needs to have intensified therapy to improve glycaemic control, 
the dose of investigational product should be increased before altering the doses of or 
adding other glucose-lowering medication. This treatment decision will be the 
responsibility of the investigator. In this case the subject will called in for an unscheduled 
visit to increase the dose from 30 mg to 50mg. Subjects randomly assigned to albiglutide 
matching placebo will also go through the increased dose procedure to maintain study 
blind. If a subject experiences tolerability issues with the higher, 50mg dose then the 
investigator may decrease the dose back to 30 mg without the need for an unscheduled 
visit to supervise down titration. Use of GLP-1 receptor agonists will be prohibited but 
other glucose-lowering medications permitted, provided they are not contraindicated for 
the individual subject concerned.
This study is designed with minimal intervention above normal clinical care of subjects 
with type 2 diabetes, whilst allowing thorough evaluation of  cardiovascular and other 
events of special interest (Section 6.2.3), thus investigating the safety of albiglutide in the 
typical clinical situation.  Sites will employ pre-screening to assess potential subjects for 
study entry. Screening and randomisation can then occur at the same visit or in close 
proximity depending on scheduling.  Contact with subjects will be every four months 
after the randomisation visit. HbA1c will be measured at 4 month clinic visits. Serum 
creatinine and liver function tests (LFTs) will be measured and a targeted physical 
assessment performed at 8 month clinic visits (Table 1). 
The study will be event driven, i.e., follow up will continue until it is projected that 
approximately 611 adjudicated MACE events will have occurred. Consequently, the 
maximum duration of the study for an individual participant is dependent both on the 
time taken for recruitment and the MACE event rate, and is estimated to be between 3 
and 5 years. If the observed rate for MACE is 2.0% or 3.0%, the mean follow-up will be 
3.2 or 2.2 years, respectively.  
An Executive Committee will be the main decision-making body for the study, in 
collaboration with the Sponsor (GSK).  It is charged with the overall scientific,
professional and operational conduct of the study.  Amongst other roles pre-specified in 

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its Charter, the Executive Committee will ensure proper study conduct and conformance 
to the protocol, consider and agree  changes to the protocol based on emerging scientific 
and/or clinical advances (e.g., new emerging data with other GLP-1 receptor agonists), 
advise on the selection of study sites and assist in subject recruitment strategies.
An IDMC will have study oversight to ensure participant safety and scientific integrity of 
the data (Section 9.8), an independent Cardiovascular Endpoint Committee (CEC) 
blinded to treatment allocation will adjudicate cardiovascular outcome events (Section 
6.2.1) and a Pancreatitis Adjudication Committee will adjudicate potential events of 
pancreatitis.
Subject completion is defined as completion of all periods of the study up to and 
including any follow-up period.
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 (Table 1), are essential and required for study 
conduct. 
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Reference Manual (SRM). The SRM will provide 
the site personnel with administrative and detailed technical information that does not 
impact subject safety.
3.2.
Standard of Care
Anti-hyperglcaemic and cardiovascular medications will be used at the discretion of the 
usual care provider(s) (or investigator if also the usual care provider), who will be 
informed of the patient’s enrolment in the trial, the use of blinded trial medication, and 
that use of GLP-1 receptor agonists  (other than the use of  randomised albiglutide)  is 
contraindicated during the trial period. Usual care providers will be encouraged to follow 
the most up to date guidelines for diabetes and cardiovascular care based upon local and 
institutional practice patterns and any relevant published practice guidelines (e.g., 
Inzucchi, 2012).  Treatment for type 2 diabetes will be captured by name and total daily 
dose at the time of study visits, while other relevant (cardiovascular) concomitant 
medications will be collected only as drug classes (see Section 5.6.1). 
During the study investigators are expected to monitor patients’ type 2 diabetes regimens 
and communicate with usual care providers, who will be responsible for adjusting their
regimen in order to achieve locally-appropriate HbA1c goals.  The Executive Committee 
and National Country Leaders will encourage investigators to follow clinical care 
practice guidelines published by national and international societies regarding type 2 
diabetes over the course of the trial.  These practice guideline goals will be 
individualized, with the understanding that currently applicable glycaemic guidelines 
may vary among different geographic regions.  With adherence to local custom and laws 
(including privacy regulations such as the Health Insurance Portability and 
Accountability Act), types of communication may be informal e.g. email or telephone 
exchanges, to enhance frequency and ease of two-way communication.

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Any agent, with the exception of GLP-1 receptor agonists, is acceptable for reaching 
HbA1c goals.  If HbA1c goals are not met following adjustment with oral medications in 
patients not receiving insulin, an insulin regimen may be initiated. Patients already 
receiving insulin therapy may up-titrate insulin during the trial if necessary. Patients 
should be reminded to keep taking their blinded trial medication throughout the course of 
the trial even in the case after initiation of insulin.
The Executive Committee and National Country Leaders will also monitor the standard 
of care of management of diabetes and cardiovascular disease. Similar to the 
management of type 2 diabetes, sites and investigators will be expected to adhere to local 
clinical practice guidelines.  Sites will be provided training on clinical management 
guidelines to re-enforce standard of care adherence. Information on medications 
important to management of cardiovascular risk will be captured during study visits.  The 
Executive Committee and National Country Leaders will review on a periodic basis the 
use of medications for cardiovascular risk prevention to ensure patients are receiving 
standard of care. If there are unusually low goal attainments for standard of care, site 
investigators will be advised accordingly.
3.3.
Discussion of Design
This study is a clinical outcomes trial required by FDA as a post-marketing requirement 
to evaluate cardiovascular safety.  It will provide important information regarding the 
cardiovascular safety and metabolic effects of albiglutide treatment of subjects with type 
2 diabetes.  Sufficient MACE events must be observed during the study to permit the 
assessment of cardiovascular safety.  Consequently, to enter the study subjects must have 
established cardiovascular disease as well as type 2 diabetes. The study is powered on a 
predefined number of clinical events, consequently the number of subjects required and 
study duration may vary from that stated in the protocol.
This will be a double-blind, placebo-controlled study. All subjects will receive placebo or 
albiglutide in addition to usual standard of care for type 2 diabetes and cardiovascular 
disease, in order to assess the effect of albiglutide above that of currently available 
therapies alone.
The primary cardiovascular comparison will be to assess whether albiglutide is non-
inferior to placebo with respect to time to first MACE. Missing data may inappropriately 
bias comparison towards declaring non-inferiority. The longer the duration of a study, the 
more difficult it is to avoid loss to follow-up and other sources of missing data. The 
product of the projected duration of this study and the number of subjects to be studied is 
intended to minimize the risk of missing data whilst still permitting the assessment of the 
safety of albiglutide to be over an appreciable period of time. Every effort will be made 
to keep subjects on their assigned study medication according to the protocol.  Subjects 
who stop study medication will be followed throughout the whole study duration.  More 
details about procedures for subject follow-up are provided in Section 4.5.
Phase III studies confirmed the glycaemic 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 glycaemia for at least 2 years in many subjects with type 2 

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diabetes, an increase in dose to 50 mg weekly offered additional benefit without 
significant safety issues (See IB for further details).  
3.4.
Benefit:Risk Assessment
Albiglutide has been evaluated in an international programme of studies involving 
approximately 9000 subject-years of overall exposure to date (including over 4000 
subject-years of exposure to albiglutide). The programme included 8 well-controlled 
Phase III studies (including one in subjects with concurrent renal impairment), ranging in 
duration from 32 weeks to 3 years, and using both 30 mg and 50 mg once weekly dosing.  
This has permitted a thorough assessment of efficacy, safety, and tolerability in a 
population of subjects with type 2 diabetes that spanned newly diagnosed individuals 
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 
albiglutide can be found in the IB and in the product labelling for those countries where 
marketing authorisation has been granted.  The following section outlines the risk 
assessment and mitigation strategy for this protocol:  
3.4.1.
Risk Assessment
The identified and potential risks associated with the use of albiglutide, or the GLP-1 
receptor agonist class, as well as the mitigation strategy for key risks of clinical 
significance are provided below. Please refer to the IB for a thorough summary of the 
nonclinical and clinical experience with albiglutide as well as the complete Guidance for 
the Investigator. The risks associated with study comparator, placebo, are also provided 
below.  Subjects will have the AE profile of GLP-1 receptor agonists, and albiglutide in 
particular, explained to them by the investigator and via the informed consent form.
3.4.1.1.
Identified Risks
Pancreatitis. Acute pancreatitis has been reported in association with albiglutide and 
other GLP-1 receptor agonists in clinical trials and during  postmarketing experience. 
Albiglutide has not been studied in subjects with a history of pancreatitis to determine 
whether they are at increased risk for pancreatitis. Subjects with a history of pancreatitis 
or who are considered at significant risk of developing pancreatitis are excluded from 
entering the study. Subjects will be informed of the characteristic symptom of 
pancreatitis: persistent severe abdominal pain. If pancreatitis is suspected, investigational 
productshould be promptly discontinued and if pancreatitis is confirmed, investigational 
product will not be restarted.
Gastrointestinal events. Albiglutide has not been studied in subjects with severe 
gastrointestinal (GI) disease, including severe gastroparesis. Subjects with severe 
gastroparesis will be excluded from the study. Use of albiglutide and other GLP-1 
receptor agonists can be  associated with GI side effects such as diarrhoea, nausea, and 
vomiting; the frequency of these events increased as renal function decreased.  These 
types of GI reactions can be associated with dehydration and worsened renal function. 

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(see below and see Section 4.4.4). Other GI related adverse reactions with albiglutide 
include dyspepsia, gastro-oesophageal reflux disease and constipation.
Hypoglycaemia. Albiglutide’s mechanism of action is associated with a low intrinsic risk 
of significant hypoglycaemia. However, when used in combination with insulin (or 
insulin secretagogues) the risk of hypoglycaemia is increased. Investigators will be 
reminded that it may be necessary to reduce the dose of insulin or insulin secretagogues 
when starting study medication to reduce the risk of hypoglycaemia. Routine standard of 
care for subjects treated with insulin secretagogues and insulin includes advice about 
avoidance of hypoglycaemia which will be reinforced.  All subjects are required to have a 
last indicator of glycemic control of above  HbA1c = 7% which is expected to reduce the 
risk of hypoglycaemia when starting albiglutide. 
Immunogenicity. Hypersensitivity reactions are of potential concern with any injected 
protein and were reported rarely in the Phase III programme. In the Phase III programme 
one subject (anti-albiglutide antibody negative) developed rash, itching and dyspnoea . 
Subjects with known allergy to any GLP-1 receptor agonist or excipients of albiglutide 
are excluded from the study.  Subjects will be informed of the symptoms of severe 
hypersensitivity or allergy and be advised to seek medical assistance immediately. In the 
Phase III programme approximately 5% of subjects developed anti-albiglutide antibodies.  
Subjects who tested positive for anti-albiglutide antibodies experienced a similar 
glycaemic response (HbA1c and fasting plasma glucose) to those who did not test 
positive for antibodies. Other than injection site reactions (see below), the overall safety 
profile appeared similar among the subset of subjects who did and those who did not test 
positive for anti-albiglutide antibodies.  Anti-albiglutide antibody formation is not 
expected to impact the overall safety of albiglutide treatment and therefore will not be 
measure routinely in this study. 
Injection site reactions. Albiglutide injections may cause rash, erythema or itching 
and/or other reactions at the site of injection. . Subjects will be advised that when 
injecting in the same region, to use a different injection site each week. In the Phase III 
program, most subjects with injection site reactions did not test positive for anti-
albiglutide antibodies. However, injection site reactions were reported more frequently 
among those who did test positive for anti-albiglutide antibodies (41% of the antidrug 
antibody positive subjects reported one or more injection site reactions) than among those 
who were consistently antibody negative (14% of the antidrug antibody negative subjects 
reported one or more injection site reactions) .  
Other adverse reactions (e.g. pneumonia, atrial fibrillation/flutter, and appendicitis). In 
the Phase III programme in type 2 diabetes, other possible albiglutide related adverse 
reactions were identified. These events occurred at a cumulative incidence <3% in studies 
up to 3 years in duration. These events were reported more frequently with albiglutide 
than comparators. 
3.4.1.2.
Potential Risks
Thyroid C-cell tumours. GLP-1 receptor agonists, including albiglutide increase serum 
calcitonin in rodents and other GLP-1 receptor agonists are associated with thyroid C-cell 

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focal hyperplasia and C-cell tumours in rodents  It is unknown whether GLP-1 receptor 
agonists are associated with thyroid C-cell tumours in humans, including medullary 
thyroid cancer (MTC). 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. Subjects with treatment emergent thyroid nodules should be referred to a specialist 
for evaluation in accordance with local treatment guidelines.  Routine monitoring of 
serum calcitonin is not recommended.  However, if serum calcitonin is found to be 
elevated the subject should be referred to a specialist for further evaluation. If MTC or 
other thyroid C-cell neoplasia is diagnosed, investigational product will be discontinued.
Other malignant neoplasms Concerns have been raised regarding use of incretin based 
therapies and other malignancies such as pancreatic cancer [Egan, 2014], malignancy 
when used in combination with insulin based on hypotheses of biological plausibility 
[European Public Assessment Report , 2014], and haematological malignancies [FDA 
Summary Basis of Approval, 2014].
Hepatotoxicity. Hepatotoxicity is an area of interest in drug development.  Patients with 
type 2 diabetes are at increased risk for liver enzyme abnormalities and disease related 
liver conditions.  One subject treated with albiglutide in the Phase III clinical programme 
developed probable drug induced liver injury with an asymptomatic elevation in alanine 
amino transferase (ALT) and total bilirubin although the cases 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 4.4.3).
Subject population with severe renal impairment (eGFR <30 mL/min/1.73m2).
Experience in type 2 diabetes subjects with severe renal impairment is limited (in the 
Phase III programme a total of 19 subjects with eGFR <30 mL/min/1.73m2 received 
albiglutide). 
In a Phase 3 study of patients with varying degrees of renal impairment, in the albiglutide 
group, on-therapy GI AEs occurred with a higher incidence and higher event rate in 
subjects with moderate and severe renal impairment compared to those with mild renal 
impairment. Because these GI events may lead to dehydration and worsen renal function, 
worsening renal function will be closely evaluated as an AE of special interest, serum 
creatinine will be measured every 8 months, and subjects will discontinue IP if eGFR 
falls below 15 mL/min/1.73m2. Subjects with known severe renal impairment are 
excluded from the study (see Section 4.4.4).
Drug Interactions.  Like other members of the class, albiglutide causes a delay in gastric 
emptying, and thereby has the potential to impact the absorption of concomitantly 
administered oral medications. During the development programme, drug interactions 
studies were conducted with digoxin, warfarin, oral contraceptives, and simvastatin 
which demonstrated no clinically relevant PK or PD effects. Investigators will be advised 
to take the effect of albiglutide on gastric emptying into account when prescribing 
concomitant medication.
Pregnancy and Lactation.  Studies in animals have shown reproductive toxicity.  The 
potential risk for humans is unknown. It is not known if albiglutide is secreted into 

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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.  
Placebo control. In subjects treated with placebo, symptoms and long-term risks of 
hyperglycaemia may not improve or may worsen. During the study, intensification of 
glucose-lowering treatments other than study drug will be allowed in both treatment arms 
with a treat-to-target approach. Albiglutide placebo injections may cause injection site 
reactions. Subjects will be advised when injecting into the same region to use a different 
injection site each week.
3.4.2.
Benefit Assessment
In subjects with type 2 diabetes albiglutide treatment resulted in clinically relevant 
lowering of HbA1c at both the 30 mg and 50 mg doses when given as monotherapy and 
in combination with metformin, sulfonylureas (SUs), thiazolidinedione or basal insulin . 
The durability of the effect on glycaemic control was shown over a study period of up to 
3 years. Consistent with its mechanism of action, albiglutide was not associated with 
clinically relevant hypoglycaemia except when used in combination with an SU or 
insulin, and incidence rates with the combination were less than those reported with SUs 
or insulin alone. Treatment with albiglutide generally produced a steady reduction in 
weight over time.
For subjects not yet on insulin at the start of the study, data from the Phase III programme 
suggest that the use of albiglutide once weekly in a pen device may have the potential to 
delay the need to start daily insulin injections.  This will be formally assessed within this 
trial.  Similarly, it is possible that for those already taking basal insulin, albiglutide may 
delay the need to introduce short-acting prandial injections and for those taking 
basal/bolus or pre-mixed insulin, it may reduce the dosage of insulin and/or the number 
of daily injections needed to achieve good glycaemic control.  These will also be 
evaluated in the study.
Subjects in the placebo arm will also be receiving effective anti-hyperglycaemic 
medication which will be titrated up or down as required to improve or maintain 
glycaemic control, and therefore these subjects should also demonstrate reductions in 
HbA1c, though weight gain (rather than weight loss) may occur depending upon the 
medication selected.   
Finally, as a result of participating in a clinical trial, each subject will receive more 
contact with the study site than would be performed as part of their usual standard of 
care.

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3.4.3.
Overall Benefit:Risk Conclusion
Taking into account the measures taken to minimise risk to subjects participating in this 
study, the known and potential risks identified with albiglutide are justified by the 
benefits have been demonstrated in subjects with type 2 diabetes.
4.
SUBJECT SELECTION AND WITHDRAWAL CRITERIA
4.1.
Inclusion Criteria
Specific information regarding warnings, precautions, contraindications, AEs, and other 
pertinent information on the GSK investigational product or other study treatment that 
may impact subject eligibility is provided in the IB for albiglutide and in the product 
label for those countries where marketing authorisation has been granted.
Deviations from inclusion criteria are not allowed because they can potentially jeopardise 
the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential.   
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
1. Men or women at least 40 years old with a diagnosis of type 2 diabetes.
2. Established cardiovascular disease, including at least 1 of the following:
a. Coronary artery disease with EITHER of the following:
Documented history of spontaneous myocardial infarction, at least 30 days 
prior to Screening.
Documented coronary artery disease (CAD) ≥ 50% stenosis in 1 or more 
major epicardial coronary arteries, determined by invasive angiography, or 
history of surgical or percutaneous (balloon and/or stent) coronary 
revascularization procedure (at least 30 days prior to Screening for 
percutaneous procedures and at least 5 years prior to Screening for coronary 
artery bypass graft (CABG)).
b. Cerebrovascular disease – ANY of the following:
Documented history of ischaemic stroke, at least 90 days prior to study entry.
Carotid arterial disease with 50% stenosis documented by carotid 
ultrasound, magnetic resonance imaging or angiography, with or without 
symptoms of neurologic deficit.
Carotid vascular procedure (e.g. stenting or surgical revascularisation), at 
least 30 days prior to Screening.
c. Peripheral arterial disease (PAD) with EITHER of the following: 
intermittent claudication and ankle:brachial index < 0.9 in at least one ankle 

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prior non-traumatic amputation, or peripheral vascular procedure (e.g. 
stenting or surgical revascularisation), due to peripheral arterial ischaemia.
3. HbA1c >7.0% (53 mmol/mol) based on the most recent documented laboratory 
assessment measured no more than 6 months prior to randomization. Local 
laboratory HbA1c values taken as part of usual care are permitted.
4. 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 GSK 
Modified List of Highly Effective Methods for Avoiding Pregnancy in Females 
of Reproductive Potential (FRP) (e.g, combined oral contraceptive pill; see 
Appendix 2) 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.
This 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. 
Other situations in which contraception in FRP may not need to be mandated 
should be discussed with the Medical Monitor.
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 oestradiol 
<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.
5. Able and willing to provide informed consent.
4.2.
Exclusion Criteria
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardise the scientific integrity of the study, regulatory acceptability or subject safety. 
Therefore, adherence to the criteria as specified in the protocol is essential. 
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:

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1. eGFR calculated using MDRD formula <30mL/min/1.73m2 (based on the most 
recent documented serum creatinine laboratory assessment measured no more than 6 
months prior to randomization. Local laboratory creatinine values taken as part of 
usual care are permitted) or renal replacement therapy.
2. Use of a GLP-1 receptor agonist at Screening.
3. Severe gastroparesis requiring therapy within 6 months prior to Screening. 
4. History of pancreatitis or considered clinically at significant risk of developing 
pancreatitis during the course of the study (e.g. due to symptomatic gallstones, 
excess alcohol use).
5. Personal or family history of medullary carcinoma of the thyroid or subject with 
MEN-2. Personal history of pancreatic neuroendocrine tumours. In the opinion of the 
investigator, the subject has a medical history which might affect his / her ability to 
remain in the study for its entire duration, or which might limit management, such as 
life expectancy of <5 years (e.g. due to active malignancy).
6. Subject has a medical history which in the opinion of the investigator might limit the 
individual’s ability to take trial treatments for the duration of the study or to 
otherwise complete the study.
7. Breastfeeding, pregnancy, or planning a pregnancy during the course of the study. 
Pregnancy test will be required in women of child bearing potential. Women who 
have undergone a sterilisation procedure or who are clearly post-menopausal will not 
be required to undergo pregnancy testing.  Women who have developed spontaneous 
secondary amenorrhoea of 12 months or more where post-menopausal status is in 
doubt, a blood sample where FSH >40MU/ml and oestrodiol <40 pg/mL (<140
pmol/L) are simultaneously measured will be considered confirmatory.
8. Known allergy to any GLP-1 receptor agonist or excipients of albiglutide.
9. Use of another investigational product within 30 days or according to local 
regulations, or currently enrolled in a study of an investigational device.
10. Any other reason the investigator deems the subject to be unsuitable for the study.
4.3.
Screening/BaselineFailures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomised.  In order to ensure transparent reporting of screen 
failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements [Schulz, 2010], and respond to queries from regulatory 
authorities, a minimal set of screen failure information is required including 
Demography, Screen Failure details, Eligibility Criteria, and any SAEs.

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Re-screening of subjects who did not meet the eligibility criteria for HbA1c or creatinine 
based on local laboratory values taken as part of usual care is permitted. If values were
based on laboratory results as part of usual care then one re-test is permitted within the 
protocol at Screening. Any future re-screening will be based on laboratory results 
obtained as part of usual care.
4.4.
Criteria for Early Discontinuation of Investigational Product
The primary analysis will be conducted on an ITT analysis basis so it is important that 
every subject is followed for the duration of the study, regardless of whether the subject 
continues to take investigational product, unless consent for all follow up is actively 
withdrawn.
The requirements for handling early discontinuations from investigational product are 
described below. Details of the requirements for subject follow-up are provided in 
Section 4.5.
4.4.1.
Early Discontinuation of Investigational Product
If a subject chooses to discontinue investigational product between scheduled face-to-
face visits they should be encouraged to contact the investigator site by telephone.  
Subjects should first be counselled to consider temporary discontinuation of 
investigational product prior to choosing to discontinue investigational product 
permanently, unless the reason for discontinuation is one of those listed below (Reasons 
for Discontinuation of Investigational Product).  If the discontinuation is permanent, the 
subject should be asked to attend the clinic as soon as possible to complete the 
assessments as for the final study visit (see Table 1) and then continue in the study for 
follow-up. The procedures for follow-up for a subject who permanently discontinues 
treatment with investigational product prior to the study end are given in Section 4.5. 
In all cases, reasons for discontinuation of investigational product and the date of last 
dose will be recorded. 
4.4.2.
Reasons for Discontinuation of Investigational Product
Any subject experiencing the following will be required to discontinue investigational 
product:

AE:

Pancreatitis, acute or chronic. 

Pancreatic cancer.

MTC or other thyroid C-cell neoplasia.  In subjects where a treatment emergent 
thyroid nodule is identified, if serum calcitonin is measured at the discretion of 
the Investigator (e.g., per local guidelines) and found to be >100 ng/L this 
should prompt further investigation for MTC and potential interruption or 
discontinuation of investigational product until diagnosis has been resolved.

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
Liver chemistry abnormalities exceeding the threshold criteria outlined in 
Section 4.4.3

Severe allergic/hypersensitivity reactions that are considered by the investigator 
to be attributable to investigational product or without a likely alternative 
aetiology.

Other AE which, in the opinion of the investigator precludes continuation of 
dosing.

eGFR<15ml/min/1.73m2 (Section 4.4.4) or the need for renal replacement therapy.

Subject becomes pregnant during the study.

Need for chronic use of a prohibited concomitant medication (Section 5.6.2)

Decision by subject or proxy.

Sponsor terminated study.

Investigator site closed and subject was unable to transfer to another investigative 
site.
If investigational product is discontinued, the subject should continue in the study and be 
followed until the final study visit as detailed in Section 4.5.
4.4.3.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event aetiology (in alignment with the FDA 
premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
Phase III-IV Liver Chemistry Stopping and Increased Monitoring Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus 
Bilirubin≥2x
ULN (>35% 
direct) or plus
INR>1.5, if 
measured*
Possible  
Hy’s Law
ALT≥3xULN
ALT
≥8xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
No
Yes
Yes
Yes
No
No
No
See algorithm 
for continued 
therapy with 
increased liver 
chemistry 
monitoring
Yes
*INR value not applicable to subjects on anticoagulants 
ALT 
≥3xULN 
but 
<8xULN
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*

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Liver safety required actions and follow up assessments section can be found in 
Appendix 3.
Phase III-IV 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*
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 3.
Drug re-challenge following drug induced liver injury is not allowed. 
Restart may be considered if GSK Medical Governance approval is granted (see 
Appendix 4 for details). Restart refers to resuming study treatment following liver 
stopping events in which there is a clear underlying cause (other than DILI) of the liver 
event (e.g. biliary obstruction, pancreatic events, hypotension, acute viral hepatitis). 
Furthermore, there should be no evidence of alcoholic hepatitis or hypersensitivity, and 
the study treatment should not be associated with human leukocyte antigen (HLA) 
markers of liver injury.
4.4.4.
eGFR Stopping Criteria
A baseline eGFR ≥ 30mL/min/1.73m2 is a requirement for entering the study. Subjects 
can continue to take investigational product if functioning well as long as eGFR is 
≥15mL/min/1.73m2. 
During this study, if a subject’s eGFR approaches 30mL/min/1.73m2 closer monitoring 
of renal function is considered prudent, according to standard clinical practice. Particular 

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care should be taken to monitor renal function in subjects with renal impairment 
reporting severe adverse GI events. If eGRF is <15mL/min//1.73m2 and considered 
irreversible based on consecutive measurements the investigational product should be 
discontinued, the subject continue in the study and be followed until the final study visit. 
If eGRF is <15mL/min/1.73m2 and the patient is considered to have temporary acute 
kidney injury that is potentially reversible, the investigational product should be 
temporarily discontinued until the eGRF is stable and ≥15mL/min//1.73m2 .Events 
considered to reflect worsening renal function should be reported as SAE/AEs and 
targeted eCRFs completed for this AE of special interest (Section 6.2.3).
4.5.
Procedures for Subject Follow-up
As described in Section 4.4, subjects who permanently discontinue investigational 
product will be asked to attend the clinic as soon as possible.  They will continue in the 
study for follow-up. Five weeks (1 week) after discontinuation of investigational 
product, subjects will be contacted for a follow-up by telephone.  They will be asked to 
return to clinic according to the 8 monthly visit schedule and in addition be contacted by 
telephone at a time corresponding to the 4-monthly visit they would have otherwise made 
to replenish study medication supply. If instead of these interim telephone contacts the 
subject prefers to attend clinic every 4 months as originally scheduled that is an 
acceptable alternative.
If a subject permanently discontinues investigational product and is unable to attend visits 
in-person, he/she will be contacted by telephone or other methods to assess study 
outcomes and vital status, unless the subject has specifically withdrawn consent for all 
forms of contact. Follow-up of subjects who withdraw consent for contact is described 
below.
Every effort should be made to educate the subjects on the importance of remaining in 
the study and attending scheduled study visits including those required after early 
discontinuation of investigational product. 
Other subject follow-up options to collect study outcomes and vital status should be 
pursued according to local laws and regulations. If one of these alternate methods to 
collect study outcomes and vital status is acceptable to the subject, then the subject will 
be deemed not to have withdrawn consent for follow-up.
4.5.1.
Withdrawal of Consent for Contact
Subjects who no longer wish to attend study visits in-person will be asked to be contacted 
by telephone or other methods to assess study outcomes and vital status.  However, if a 
subject specifically withdraws consent to be contacted for additional information, no 
further study visits or study-related telephone contacts can be conducted. Information 
regarding study outcomes or vital status will continue to be collected from available 
sources including those in the public domain. Additionally, alternative permitted options 
to obtain study outcomes and vital status will be reviewed based on accepted local laws 
and regulations. For any subject who withdraws consent for contact, the study site will be 

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asked to document the discussion with the subject regarding each of the contact options 
that were offered.
4.5.2.
Subjects Deemed Lost to Follow-up
Finally, investigators should make every effort to contact subjects who are deemed lost to 
follow-up and who have not withdrawn consent to follow-up contacts, including pursuing 
any alternative contact methods permitted by local regulations. Where permitted, a third 
party may be used to locate alternative subject contact information that will be provided 
to the investigator. All attempts to contact subjects will be documented in the subject’s 
eCRF and source notes. 
Should a subject fail to attend the clinic for a required study visit, the site should attempt 
to contact the subject and re-schedule the missed visit as soon as possible. The site should 
also counsel the subject on the importance of maintaining the assigned visit schedule. In 
cases where the subject does not return for the rescheduled visit or cannot be reached to 
reschedule the missed visit, the site should make every effort to regain contact with the 
subject. Should the subject continue to be unreachable, then and only then will he/she be 
considered “Lost to Follow-up”. Nonetheless, efforts to attempt to locate and contact the 
subject will continue until the study end. 
5.
STUDY TREATMENTS
5.1.
Investigational Product and Other Study Treatment
Albiglutide (and albiglutide matching placebo) will be provided as a fixed-dose, fully 
disposable pen injector system for delivery of the investigational product (albiglutide or
albiglutide matching placebo) from a prefilled dual chamber glass cartridge that is an 
integral part of the pen. The pen is intended for single use by the subject. It is designed 
for manual reconstitution of the dose, priming and insertion of the pen needle, and 
manual injection by the subject. 
Albiglutide (or albiglutide matching placebo) is intended for self-administration as a 
subcutaneous injection in the abdomen, thigh or upper arm region.  Rotation of use of 
injection sites is recommended. Albiglutide and insulin may be injected in the same body 
region but the injections should not be adjacent to each other.  The albiglutide pen 
includes a mechanical locking system that prevents the user from manipulating the dose 
button before the cartridge has been fully reconstituted. Reconstitution is performed 
through rotation of the pen housing parts. The pen is designed to work with standard pen 
needles.
When the injector pen product is reconstituted by the subject, a neutral, isotonic solution 
is produced. Separate pens are required to deliver either 30 mg of albiglutide, 50 mg of 
albiglutide, or matching placebo in a 0.5-mL injection volume.
The contents of the label will be in accordance with all applicable regulatory 
requirements.

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Under normal conditions of handling and administration, investigational product is not 
expected to pose significant safety risks to site staff.  Take adequate precautions to avoid 
direct eye or skin contact and the generation of aerosols or mists. Notify the monitor of 
any unintentional occupational exposure.  A Material Safety Data Sheet (MSDS) 
describing the occupational hazards and recommended handling precautions will be 
provided to site staff if required by local laws or will otherwise be available from GSK 
upon request.
The investigational product (albiglutide and albiglutide matching placebo) must be stored 
in a secure area at 2°C to 8°C and protected from freezing. Each site must maintain a 
temperature log.  Access to and administration of the investigational product will be 
limited to the investigator and authorised site staff (investigator or designee).  
Investigational product must be dispensed or administered only to subjects enrolled in the 
study and in accordance with the protocol.
Procedures for the disposal of unused study treatment will be provided in the SRM.
Investigational product (albiglutide or albiglutide matching placebo) will be administered 
once weekly by subcutaneous injection. The first dose is to be administered at the clinic. 
The starting dose of albiglutide will be 30 mg once weekly.  If at any stage after 5 weeks 
of treatment in the opinion of the investigator the subject needs to have intensified 
therapy to improve glycaemic control, the dose of investigational product should be 
increased before altering the doses of other glucose-lowering medication. In this case the 
subject will called in for an unscheduled visit to supervise an increase in dose from 30 mg 
to 50 mg.  Subjects randomly assigned to albiglutide matching placebo will also go 
through the increased dose procedure to maintain study blind. If a subject experiences 
tolerability issues with the higher, 50mg dose then the investigator may decrease the dose 
back to 30 mg without the need for an unscheduled visit to supervise down titration, other 
than for the subject to collect pens of the correct dose.
Albiglutide (or albiglutide matching placebo) may be administered at any time of day 
without regard to meals. Preferably, it should be administered once a week on the same 
day each week. The day of weekly administration can be changed if necessary as long as 
the last dose was administered 4 or more days previously. If a dose is missed, it should be 
administered as soon as possible within 3 days after the missed dose. Thereafter, subjects 
can resume dosing on their usual day of administration. If it is more than 3 days after the 
missed dose, subjects should wait and administer their next regularly scheduled weekly 
dose.  
If a subject misses 4 or more consecutive doses, the investigator should contact the
medical monitor to discuss options for helping assure better compliance.
5.2.
Treatment Assignment
Subjects will be assigned to study treatment in accordance with the randomisation 
schedule.

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Randomised treatment assignment will be done via the Interactive Voice Response 
System (IVRS), and randomisation will be implemented based on a sequestered fixed 
randomisation schedule. Study centre personnel will call the IVRS once a subject has met 
all prerequisites for randomization; the IVRS will assign treatment.
Blinded study centre personnel will receive a randomisation notification indicating only 
the unique subject identifier and the date and time of randomisation. 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 investigational product. 
Details of the treatment assignment process are contained in the SRM.
5.3.
Blinding
This is a double-blind study, neither the subject nor the study physician will know which 
of the two treatments (albiglutide or placebo) the subject is receiving.
The investigator or treating physician may unblind a subject’s treatment assignment only 
in the case of an emergency or in the event of a serious medical condition, when 
knowledge of the study treatment is essential for the appropriate clinical 
management or welfare of the subject, as judged by the investigator.  Investigators 
have direct access to the subject’s individual study treatment.  It is preferred (but not 
mandatory) that the investigator first contacts the GSK Medical Monitor or appropriate 
GSK study personnel to discuss options before unblinding the subject’s treatment 
assignment.  If GSK study personnel are not contacted before the unblinding, the 
investigator must notify GSK as soon as possible after unblinding, but without revealing 
the treatment assignment of the unblinded subject, unless that information is important 
for the safety of subjects currently in the study.  The date and reason for the unblinding 
must be fully documented in the appropriate data collection tool.
If a subject is unblinded by the investigator or treating physician then discontinuation of 
investigational product treatment for that subject will be at the discretion of the 
investigator. However, the subject should continue to be followed in the study (see 
Section 4.5).
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any subject with an SAE.  If the SAE requires that an expedited 
regulatory report be sent to one or more regulatory agencies, a copy of the report, 
identifying the subject’s treatment assignment, may be sent to clinical investigators in 
accordance with local regulations and/or GSK policy.
5.4.
Product Accountability
In accordance with local regulatory requirements, the investigator, designated site staff, 
or head of the medical institution (where applicable) must document the amount of 
investigational product dispensed and/or administered to study subjects, the amount 
returned unused by study subjects, and the amount received from and returned to GSK, 
when applicable.  Product accountability records must be maintained throughout the 
course of the study.

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5.5.
Treatment Compliance
Subjects will be instructed to return all unused and used injector pens at the visits 
specified in the Time and Events Table (Table 1) in order to perform drug accountability 
and determine compliance. Subjects will be provided with a sharps container for the 
disposal of used pens.  To comply with health and safety considerations there will be no 
count made of used pens; only returned unused pens will be counted. In addition, subjects 
will be provided with a pre-printed card at each dispensing visit to record the date of each 
dose. The card is to be returned at the next dispensing visit with the unused pens.
5.6.
Concomitant Medications and Non-Drug Therapies
5.6.1.
Permitted Medications and Non-Drug Therapies
The usual care provider will manage the subjects according to standard of care, following 
local prescribing information. Close adherence to professional society guidelines for 
standard of care therapies in type 2 diabetes and cardiovascular disease will be 
emphasized during study conduct. Standard of care is described in greater detail in 
Section 3.2.
Unless specified as a prohibited medication in Section 5.6.2, all concomitant medications 
should be considered permitted provided they are not contraindicated for the individual 
subject concerned.
Like other members of the class, albiglutide causes a delay in gastric emptying, and 
thereby has the potential to impact the absorption of concomitantly administered oral 
medications.  This should be taken into account by investigators when prescribing 
concomitant medication.
It may be necessary to reduce the dose of concomitantly administered insulin 
secretagogues (such as SUs) or insulin to reduce the risk of hypoglycaemia when starting 
albiglutide.
All concomitant anti-hyperglycaemic medications (name of agent, total daily dose, start 
and stop dates) will be recorded in the eCRF at each visit. Concomitant cardiovascular 
medications taken during the study will also be recorded at each visit by class of agent.
Additionally, all medications used within the 30 days prior to the onset and throughout 
the duration of an SAE, AE of special interest (Section 6.2.3), or an AE leading to 
discontinuation of investigational product will be recorded as individual agents, reason 
for use, together with start dates (and stop dates if applicable) and any changes since any 
previous AE.
5.6.2.
Prohibited Medications and Non-Drug Therapies
Subjects may not take a GLP-1 receptor agonist (other than blinded investigational 
product), nor any investigational drug, during the study (and any follow-up period after 
discontinuing investigational product).

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If a subject receives a prohibited medication, a protocol deviation will be recorded.
5.7.
Treatment after the End of the Study
Following the final study visit subjects will be contacted by telephone 5 1 weeks after 
last dose of study medication to assess any AEs ongoing since the last visit or newly 
emergent. 
Subjects will be treated as deemed appropriate by the investigator following the end of 
the study. Investigational product will not be provided to subjects by GSK after the end 
of the study.
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 investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition whether or not GSK is providing specific 
post study treatment.
5.8.
Treatment of Study Treatment Overdose
No data are available with regard to albiglutide overdose in humans. The highest 
recommended dose of albiglutide is 50 mg once weekly.
During clinical studies of subjects with type 2 diabetes, the highest dose of albiglutide 
administered was 100 mg subcutaneously every four weeks for 12 weeks. This dose was 
associated with an increased frequency of nausea, vomiting, and headache. 
There is no specific antidote for overdose with albiglutide. In the event of a suspected 
overdose, the appropriate supportive clinical care should be instituted, as dictated by the 
subject’s clinical status. Anticipated symptoms of an overdose may be severe nausea, 
vomiting or headache.  A prolonged period of observation and treatment for these 
symptoms may be necessary, taking into account the half-life of albiglutide (5 days).
6.
STUDY ASSESSMENTS AND PROCEDURES
The schedule of study assessments is shown in Table 1. Detailed procedures for each 
assessment are provided in the SRM.

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Table 1
Time and Events Table
Procedures1,2
Screening3
Randomization3
/Baseline 
(can be same day 
as Screening Visit)
Study Drug Check 
Phone Call
(4-6 wks post 
rand.)
Clinic Visit Month 4 
18 days then every 8 
months 18 days 
throughout the study
Unscheduled 
dose adjustment 
visit
(if warranted)
Clinic Visit Month 8 
18 days then every 8 
months 18 days 
throughout the study
Final study 
clinic 
visit4 (or early 
withdrawal)
Follow up Phone Call
5 1 weeks after last IP 
dose
Written informed consent  
X
Review of Inc/excl criteria
X
X
Demography & directed medical history
X
Assessment of MACE  and micro-vascular events
X
X
X
HbA1c
X5
X
X
X
Serum creatinine (eGFR)
X5
X
X
Liver Function Tests6
X
X
X
Genetic sampling7
X
Patient reported outcomes questionnaires8
X
X
X
Key concomitant non-diabetes medication
X
X
X
X
X
Diabetes medication
X
X
X
X
X
Study drug reminder
X
X
X
X
Physical examination9
X
X
X
SAEs, AEs of special interest, AEs leading to IP 
discontinuation 
X
X
X
X
X
X
X
Pregnancy test10
X
X
Study drug dispense/compliance11
X
X
X
X
X
1.
Subjects who discontinue investigational product should be handled as described in Section 4.4 and Section 4.5. 
2.
Assessments per the Month 4 visit will alternate with those per the Month 8 visit throughout the study i.e., assessments at months 4, 12, 20 etc will be per Month 4; those at month 8, 16, 24 etc..will 
be per Month 8.
3.
Screening and Randomisation can occur at the same visit if all eligibility information is available. If Screening and Randomisation occur at the same visit assessments should not be duplicated.
4.
Once it is projected that the target number of MACE events will have been collected, a 3 month window will be defined for conducting the final, face to face visit.
5.
HbA1c and creatinine assessed using local laboratories at Screening visit and measured no more than 6 months prior to randomisation. If HbA1c or creatinine have not been assessed in the previous 
6 months assessments to be performed via a central laboratory and results available prior to randomization. The investigator has the discretion to repeat screening HbA1c, and/or creatinine, based 
on clinical rationale even if previously available local results meet the eligibility criteria to allow the investigator to accommodate the possibility of change between screening and randomisation.
6.
Liver function tests: ALT, AST, alkaline phosphatase, bilirubin, GGT. Blood samples for LFTs at randomization must be collected prior to the first dose of investigational product.
7.
Informed consent for genetic research must be obtained before collecting a sample.  Genetics sample can be collected at any time after genetic consent has been obtained and the subject has been 
randomised.
8.
TRIM-D, EQ-5D and study specific questionnaire (details in Section 6.3).
9.
See Section 6.2.7.  
10.
Only applies to women of child bearing potential. At screening perform urine pregnancy test.  If positive, send serum sample to the central laboratory for confirmation. At Randomisation perform a 
urine pregnancy test. If result is positive do not randomize the subject. If the urine pregnancy test is negative then the subject can be randomised. If Screening and Randomisation are to take place at 
the same visit then follow the instructions for Screening. See Section 6.2.6.
11.
Study drug dispensing not performed at final visit, compliance check not performed at Randomisation.

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6.1.
Critical Baseline Assessments
Disease, and therapy history, including cardiovascular medical history/risk factors will be 
assessed at Baseline. Investigators are encouraged to implement lifestyle modifications 
and adjust or initiate the appropriate pharmacotherapy throughout the study as 
recommended by current locally followed therapeutic cardiovascular and diabetes 
guidelines for participants in the study.  Screening and randomisation can occur at the 
same visit depending on availability of information to determine eligibility of the subject 
to enter the study.
6.2.
Safety
The following sections provide further detail on the safety assessments.  Planned time 
points for all safety assessments are listed in the Time and Events Table (Table 1).  
Unscheduled visits will occur as medically necessary. Detailed procedures for obtaining 
each assessment are provided in the SRM.
Safety endpoints are described in Section 2 and will include monitoring of cardiovascular 
events (Section 6.2.1), deaths, AEs of special interest (Section 6.2.3), clinically 
significant microvascular events (Section 6.2.4), SAEs and AEs leading to 
discontinuation of investigational product.
Liver chemistry stopping and follow-up criteria and AEs are described in Section 4.4.3
and Appendix 3.
6.2.1.
Cardiovascular Events
Events referred to the CEC by the investigator as potential endpoints or transient 
ischemic attacks (TIAs) will not be collected or reported as SAEs, regardless of the 
adjudication outcome (Section 6.2.2). These events will be reviewed by an Independent 
Data Monitoring Committee (Section 9.8).
The CEC will review and adjudicate the following clinical events:

Myocardial infarction

Stroke

Unstable angina requiring hospitalization

Hospitalization for heart failure

Sudden cardiac death

TIA

In addition, all clinical events submitted for adjudication and all other SAEs with a 
fatal outcome will be reviewed and adjudicated to classify the cause of death as 
cardiovascular or non-cardiovascular.

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When the local investigator reported event and the CEC decision on the nature of the 
event differ, the CEC’s decision will be considered final. The detailed descriptions of the 
endpoint (and TIA) definitions necessary for adjudication are contained within the CEC 
Charter (available on request). The guiding principle will be the “2014 ACC/AHA Key 
Data Elements and Definitions for Cardiovascular and Stroke End Point Events for 
Clinical Trials” [ACC/AHA, 2014] and the “Third Universal Definition of Myocardial 
Infarction” endorsed by the European Society of Cardiology (ESC), the American 
College of Cardiology Foundation (ACCF), the American Heart Association (AHA), and 
the World Heart Federation (WHF) [Thygesen, 2012].
Source documentation required to support the adjudication of the events is described in 
the SRM.  Recording of potential endpoint and TIA events in the eCRF and submission 
of source documentation will be required for clinical events meeting reporting criteria 
whether or not an endpoint event is suspected by the investigator.
6.2.1.1.
Other CV Events
GSK has identified other CV events of special interest for all clinical studies. 
Investigators will be required to fill out event specific data collection tools for the 
following cardiovascular events which meet SAEs criteria or are non-serious events that 
result in discontinuation of investigational product:  

Arrhythmias (other than atrial fibrillation/flutter, see Section 6.2.3) 

Valvulopathy

Pulmonary hypertension

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularisation (other than urgent revascularisation for unstable angina, a 
component of a secondary endpoint)
This information should be recorded in the specific cardiovascular eCRF within one 
week. 
6.2.2.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 5.
The investigator or site staff will be responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE.  
For this study events of myocardial infarction, stroke, unstable angina requiring urgent 
revascularization, hospitalization for heart failure, TIA and sudden cardiac death will not 
be collected or reported as AEs or SAEs. These events will be collected separately, 
subjected to blinded adjudication by an independent CEC using prespecified diagnostic 
criteria, and reported separately (Section 6.2.1.1). All other events that meet serious 
criteria as defined in Appendix 5 should be reported as SAEs.

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All events with an outcome of death will be adjudicated to classify the cause of death as 
specifically cardiovascular or non-cardiovascular. Any event resulting in death should be 
reported as a SAE unless the event is myocardial infartion, stroke, unstable angina w/ 
urgent revascularization, Heart failure, TIA or sudden cardiac death which the protocol 
specifies are not to be collected as adverse events. 
The study will not collect all non-serious AEs. Non-serious AEs leading to 
discontinuation of investigational product and non-serious AEs of special interest (see 
Section 6.2.3) will be collected. 
Any events not specifically addressed above should be reported as an AE or SAE 
according to the definitions in Appendix 5. 
6.2.2.1.
Time period and Frequency for collecting AE and SAE information

AEs and SAEs will be collected from the start of Study Treatment until the follow-
up contact (see Section 6.2.2.3), at the timepoints specified in the Time and Events 
Table (Table 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.

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. 

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Appendix 5.

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 5.
6.2.2.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting SAEs. Open-ended and non-
leading verbal questioning of the subject is the preferred method to inquire about SAE 
occurrence.  Appropriate questions include:

“How are you feeling?” 

“Have you had any (other) medical problems since your last visit/contact?” 

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
“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?” 
Additionally subjects will be asked specific questions about the occurrence of AEs of 
special interest (Section 6.2.3).
6.2.2.3.
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 6.2.3) 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 4.5). Further information on follow-up procedures is given in 
Appendix 5.
6.2.2.4.
Sentinel Events
A Sentinel Event is a GSK-defined SAE that is not necessarily drug-related but has been 
associated historically with adverse reactions for other drugs and is therefore worthy of 
heightened pharmacovigilance. Medical monitor review of all SAEs for possible Sentinel 
Events is mandated at GSK.  The GSK medical monitor may request additional clinical 
information on an urgent basis if a possible Sentinel Event is identified on SAE review. 
The current GSK-defined Sentinel Events are listed below:

Acquired Long QT Syndrome

Agranulocytosis/severe neutropenia 

Anaphylaxis and anaphylactoid reactions (see also Section 6.2.3)

Hepatotoxicity (see also Section 6.2.3)

Acute renal failure

Seizure

Stevens Johnson syndrome/toxic epidermal necrosis
6.2.2.5.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK or designee of SAEs and non-serious AEs 
related to study treatment (even for non- interventional post-marketing studies) is 
essential so that legal obligations and ethical responsibilities towards the safety of 
subjects and the safety of a product under clinical investigation are met. 
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators.

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Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
6.2.3.
Adverse Events of Special Interest
The investigator or site staff will be responsible for detecting, documenting and reporting 
events the following AEs of special interest:

Development of thyroid cancer 

Haematologic malignancy

Pancreatic cancer 

Pancreatitis 

Injection site reactions

Immunological reactions (e.g., drug hypersensitivity reactions involving 
anaphylaxis/anaphylactoid reactions, acute bronchoconstriction, angioedema, and/or 
acute urticaria) 

Severe hypoglycaemia events (which includes all events meeting the definition of 
SAEs Appendix 5)

Hepatic events

Hepatic enzyme elevations (including GGT)

Serious GI events

Appendicitis

Atrial fibrillation/flutter

Pneumonia

Worsening renal function

Diabetic retinopathy
The results of any investigation should be recorded in the relevant sections of the 
subjects’ eCRFs. In addition, for thyroid, pancreas or haematological malignancies 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. In subjects where a treatment 
emergent thyroid nodule is identified, if serum calcitonin is measured at the discretion of 
the Investigator (e.g., per local guidelines) and found to be >100 ng/L this should prompt 

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further investigation for MTC and potential interruption or discontinuation of 
investigational product until diagnosis has been resolved. If MTC or other thyroid C-cell 
neoplasia is diagnosed, albiglutide will be discontinued.
A Pancreatitis Adjudication Committee composed of independent specialists in 
gastroenterology will review all cases of possible pancreatitis. 
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 in the SRM.  These 
events should be reported as AEs or SAEs based on the clinical evaluation of the subject. 
The reactions should be followed to completion as typical for any AE or SAE.  Subjects 
with allergic or drug hypersensitivity reactions that are considered by the investigator to 
be attributable to investigational product or without a likely alternative aetiology should 
have investigational product withdrawn and not re-introduced.
Episodes of severe hypoglycaemia will be recorded according to subject report.  Severe 
hypoglycaemic incidents will be defined as those episodes of hypoglycaemic symptoms 
for which the subject required assistance from another person and from which the subject 
recovered promptly after oral carbohydrate, intravenous glucose, glucagon administration 
or other resuscitative actions (definition per ADA Workgroup on Hypoglycaemia 
[Seaquist, 2013]).  Additionally, all episodes of hypoglycaemic symptoms which in the 
investigator’s opinion meet the definition of a SAE (defined in Appendix 5) will be 
included as severe hypoglycaemic episodes. During this study, if a subject’s eGFR 
approaches 30mL/min/1.73m2 closer monitoring of renal function is considered prudent, 
according to standard clinical practice. If eGRF is <15mL/min//1.73m2 follow the 
procedure set out in Section 4.4.4.
6.2.4.
Clinically Important Microvascular Events
Clinically important microvascular events are defined as the following: need for renal 
transplant or dialysis, new diabetes-related blindness, and procedures (laser 
photocoagulation or anti-vascular endothelial growth factor treatment or vitrectomy for 
diabetic retinopathy/eye disease).  Clinically important microvascular events will be 
reported as recorded in the eCRF by the investigator without adjudication.
The AEs associated with the above outcomes or treatments should be reported separately 
as an AE or SAE according to the definitions in Appendix 5.
6.2.5.
Pregnancy

If a subject becomes pregnant during the study they should discontinue 
Investigational Product.

Details of all pregnancies in female subjects will be collected after the start of 
dosing and until the end of the Post-treatment Follow-up Period.

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
If a pregnancy is reported then the investigator should inform GSK within 2 weeks 
of learning of the pregnancy and should follow the procedures outlined in Appendix 
6.
6.2.6.
Clinical Laboratory Assessments
All protocol required laboratory assessments must be conducted in accordance with the 
Laboratory Manual, and Protocol Time and Events Schedule (Table 1).  Details for the 
preparation and shipment of samples will be provided by the laboratory and are detailed 
in the laboratory manual. Reference ranges for all central laboratory safety parameters 
will be provided to the site.
If additional non-protocol specified laboratory assessments result in a change in subject 
management or are considered clinically significant by the investigator (e.g., SAE or AE 
of special interest or dose modification) the results must be recorded in the CRF.
Refer to the SRM/laboratory manual for appropriate processing and handling of samples 
to avoid duplicate and/or additional blood draws.
The following laboratory assessments will be performed: serum creatinine, HbA1c, liver 
function tests [AST (SGOT), ALT (SGPT), alkaline phosphatase, bilirubin, GGT], and 
urine and serum hCG pregnancy test (for women of child bearing potential). All study-
required laboratory assessments will be performed by a central laboratory, with the
exception of HbA1c and creatinine at Screening and urine pregnancy test at 
Screening/Randomization. 
Screening HbA1c and serum creatinine
Screening HbA1c and serum creatinine values should be based on the most recent local 
laboratory values taken as part of usual care within the previous 6 months and the values 
entered into the eCRF. These assessments must have been performed at an accredited
laboratory.  HbA1c screening results must be either Diabetes Control and Complications 
Trial (DCCT) aligned or International Federation of Clinical Chemistry and Laboratory 
Medicine (IFCC) standardized.  HbA1c screening results from point of care equipment 
are acceptable provided that the equipment is maintained by an accredited laboratory.  If 
HbA1c or creatinine have not been assessed in the previous 6 months, laboratory 
assessments will be performed via the central laboratory to determine eligibility (if a 
local laboratory is used in error the results are acceptable for determining eligibility). The 
investigator has the discretion to repeat screening HbA1c, and/or creatinine, based on 
clinical rationale even if previously available local results meet the eligibility criteria to 
allow the investigator to accommodate the possibility of change between screening and 
randomisation.
Re-screening of subjects who did not meet the eligibility criteria for HbA1c or creatinine 
based on local laboratory values taken as part of usual care is permitted. If values were 
based on laboratory results as part of usual care then one re-test is permitted within the 
protocol at Screening. Any future re-screening will be based on laboratory results 
obtained as part of usual care.

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Pregnancy testing (for women of childbearing potential)
At the screening visit perform a urine pregnancy test. If the urine pregnancy test is 
positive, send a serum blood sample to the central laboratory for confirmation of 
pregnancy. 
At the Randomisation visit perform a urine pregnancy test. If the result is positive do not 
randomize the subject. If the urine pregnancy test is negative then the subject can be 
randomised (provided all other eligibility criteria have been met).
If Screening and Randomisation are to take place at the same visit then follow the 
instructions for Screening. Do not randomise if the urine pregnancy test is positive; send 
a serum blood sample to the central laboratory for confirmation of pregnancy. If the urine 
pregnancy test is negative then the subject can be randomised at the same visit (provided 
all other eligibility criteria have been met).
6.2.6.1.
Estimated Glomerular Filtration Rate (eGFR)
Serum creatinine will be measured every 8 months by a central laboratory. 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).
6.2.7.
Physical examination
A general physical examination, including height and neck (thyroid), will be performed at 
randomization. A targeted physical examination will be performed at all other time points 
as specified in the Time and Events Table (Table 1). The targeted physical examination 
will evaluate the cardiovascular system and injection sites and will include measurement 
of blood pressure and heart rate taken with the subject either in a semi-recumbent or 
seated position after at least a 5-minute rest period.
6.3.
Value Evidence and Outcomes
6.3.1.
Value Evidence and Outcomes Assessments
6.3.1.1.
Treatment Related Impact Measure – Diabetes (TRIM-D)
In order to evaluate satisfaction with treatment and to compare satisfaction across 
treatment groups, the TRIM-D questionnaire will be self administered by all subjects at 
baseline and at each 8 month visit (and, to the extent possible, at the time of study 
completion or withdrawal from the study).
The TRIM-D, developed in 2009, is a 28-item treatment satisfaction measure scored to 
produce 5 sub-scale scores (Treatment Burden, Daily Life, Diabetes Management, 

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Psychological Health, and Compliance) as well as a total score. It is available in a wide 
range of translations.
The TRIM-D development, in accordance with the principles of the Food and Drug 
Administration Patient Reported Outcome Guidance document, was based on findings 
from the published literature including content from already-existing treatment 
satisfaction measures as well as significant input from subjects with type 1 and with type 
2 diabetes and from expert diabetes clinicians.  The TRIM-D has been evaluated in a 
sample of 507 subjects (74% with type 2 diabetes) and has been shown to have 
acceptable reliability and validity [Brod, 2009a]. Its responsiveness was also evaluated 
in a sample of 242 subjects (71% with type 2 diabetes) and found to be acceptable [Brod, 
2009b].  Some preliminary work has been done on estimating its minimal important 
difference but this needs further exploration [Brod, 2009b].
6.3.1.2.
EQ-5D
The EQ-5D will be self-administered by subjects in order to measure generic health 
status. Combining the EQ-5D with the disease-specific TRIM-D, which is designed to 
have maximum sensitivity to relevant aspects of disease related treatment, will provide a 
more robust evaluation of the impact of treatments for type 2 diabetes and allow for 
clearer interpretation of study results.  TRIM-D results, if consistent with the general 
trends seen in the EQ-5D, will have enhanced credibility.
The EQ-5D is a standardized instrument used to evaluate generic health-related quality of 
life. It is applicable to a wide range of health conditions and treatments, and it provides a 
simple descriptive profile and a single index value for health status.  It is also used to 
provide utilities, or preference weights, for use in economic (cost effectiveness) 
evaluations.  It is available in 141 self complete official language versions.
The EQ-5D has been used extensively in studies to measure the impact of type 2 diabetes 
and treatments for the disease. A systematic review identified 54 publications reporting 
EQ-5D responses and 39 papers presenting evidence on the measurement properties of 
the EQ-5D in this population [Janssen, 2011].  This evidence supported the validity, 
reliability, and responsiveness of the EQ-5D for evaluating health-related quality of life 
in subjects with type 2 diabetes.  Other studies reported that index scores from the EQ-5D 
have been shown to be an independent predictor of the risk of mortality, future vascular 
events, and other complications in people with type 2 diabetes [Clarke, 2009]. In 
addition, the SHIELD longitudinal study (1,741 respondents with type 2 diabetes and 
4,543 without diabetes) used the EQ-5D to assess the 5-year changes in health-related 
quality of life in type 2 diabetes [Grandy, 2012].
6.3.1.3.
Exploratory Diabetes Management Questions
In addition to the standardised instruments described above, patient experience in relation 
to the management of their diabetes will be evaluated in a subset of sites using a small 
number of self-administered diabetes management questions. These types of customized 
questions have been used successfully in asthma and in diabetes when patients are 
involved with goal-setting [Juniper, 1992; Anderson, 2010]. This tailored approach is an 

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opportunity to capture data in the study that are not otherwise available from standard 
PRO measures such as the TRIM-D and the EQ-5D. As an exploratory endpoint, this set 
of questions (3 items at baseline, and at each 8 month follow-up visit) imposes very little 
patient or site burden, but can offer critical insight into the one area of the patient’s 
choosing that s/he finds most difficult to manage. In addition, this patient-centred 
endpoint has the potential to be sensitive to changes over time.
These questions have been developed by GSK based on factors identified as important to 
subjects in the development of published, validated and reliable subject reported 
outcomes instruments in type 2 diabetes.
6.3.1.4.
Healthcare Resource Utilisation
Data will be collected on the following heathcare resource use:

All cause hospitalisations and related healthcare resource use.
Healthcare resource use data  will be collected in order to facilitate subsequent health-
economic analyses comparing costs between albiglutide added to standard of care and 
placebo added to standard of care (cost is not an end point in the study). 
Data on all-cause hospitalizations and related inpatient healthcare resource use will be 
collected.  This will include:

All-Cause hospitalisation including: Admission and discharge diagnoses 
(primary and secondary), length of stay, level/type of ward, and time spent in 
Intensive Therapy Unit (or equivalent).
6.4.
Genetic Research
Information regarding genetic research is included in Appendix 1.  
7.
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.

Adverse events and concomitant medications terms will be coded using MedDRA 
(Medical Dictionary for Regulatory Activities) and an internal validated medication 
dictionary, GSKDrug.  

CRFs (including queries and audit trails) will be retained by GSK, and copies will be 
sent to the investigator to maintain as the investigator copy.  Subject initials will not 
be collected or transmitted to GSK according to GSK policy.

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8.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS
8.1.
Hypotheses
This trial will examine the following primary question:

Whether albiglutide is non inferior by a margin of 1.3 with respect to its effect on 
adjudicated MACE, when added to glycaemic standard of care, versus standard of 
care alone. Letting λ1 = hazard ratio for time to first MACE for albiglutide vs 
placebo, then:
Null hypothesis: log λ1 ≥ log(1.3)
Alternative hypothesis: log λ1 < log(1.3)
8.2.
Study Design Considerations
8.2.1.
Sample Size Assumptions
The primary outcome will be analyzed such that the overall Type 1 error is no greater 
than 5% (two-sided).  Specifically, the non-inferiority assessment of albiglutide 
compared to placebo will be conducted at 0.05 level, requiring one-sided significance at 
0.025.  
The power for MACE non-inferiority is calculated via the asymptotic variance and 
normality of the maximum likelihood estimator for the log-hazard ratio. Assuming a true 
hazard ratio of 1.0, 611 events will be needed to have 90% power to rule out non-
inferiority margin of 1.3 for the hazard ratio with type I error of 0.05.  The study duration 
will be event-driven.  A total of 9400 subjects will be enrolled and followed until it is 
projected that approximately 611 adjudicated MACE events will have occurred. If the 
observed rate for MACE is 2.0% or 3.0%, the mean follow-up will be 3.2 or 2.2 years 
respectively, assuming that the number of subjects lost to follow-up accounts for 1% or 
less.  
8.2.2.
Sample Size Sensitivity for MACE non-inferiority
9400 subjects will be enrolled to cumulate the first MACE events experienced by 611 
unique subjects. The study duration may vary depending on actual MACE event rate and 
duration of enrolment period.

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Table 2
Total Study Duration Sensitivity for Varying MACE Event Rate and 
Duration of Recruitment
Duration of recruitment
1.5 yrs
2.0 yrs
2.5 yrs
3.0 yrs
MACE rate (% pa)
2.0
4.1yrs
4.4yrs
4.6yrs
4.9yrs
2.5
3.4 yrs
3.7yrs
3.9yrs
4.2yrs
3.0
3.0yrs
3.2yrs
3.5yrs
3.8yrs
3.5
2.7yrs
2.9yrs
3.2yrs
3.4yrs
8.2.3.
Sample Size Re-estimation
The aggregate blinded event-rate data will be periodically reviewed by the Executive 
Committee and the sponsor. The study has an event-driven design. Should emerging data 
diverge significantly from protocol assumptions, the total sample size and/or follow up 
time may be adjusted, within the bounds of feasibility, to achieve the event target.
8.3.
Data Analysis Considerations
8.3.1.
Analysis Populations
The intent-to-treat (ITT) population will include all randomly assigned subjects. The ITT 
subjects will be analyzed according to randomised treatment. The inference for primary 
objectives in the study will be made from ITT population.
Per-protocol Population (PP) will exclude the subjects who have major protocol 
violations. Per-protocol analysis will include Per-protocol population only and their data 
upon to the time of discontinuation of investigational product plus 56 days.
The non-insulin population (NI) will include all subjects in the ITT population who are 
not on insulin at baseline. Inference for the time to insulin endpoint will be made from 
the NI population. 
The baseline basal insulin user population (BI) will include all subjects in the ITT 
population who are on basal insulin, but not on other insulin at baseline. Inference for the 
time to prandial insulin endpoint will be made on BI population.
The safety population will include all enrolled subjects who receive at least 1 dose of 
study treatment. The safety population subjects will be analyzed according to the 
treatment received. The safety population will be used for analyses of safety objectives.

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Other analysis populations will be defined in the RAP. 
8.3.2.
Analysis Data Set
For time to event data, censoring time for subjects who lost to follow-up is defined as 
following:

For primary analysis, subjects who are lost to follow-up will be censored at the date 
of last evidence of confirmatory status for MACE events. 

For on-treatment analysis, censoring date will be the last dose date. 

For on-therapy analysis (on-treatment+56 days), censoring date will be the last dose 
date+56 days.

For analysis of all cause of mortality, censoring date will be the latest date known 
alive.
8.3.3.
Treatment Comparisons
Demographic and baseline characteristics (e.g., gender, age, racial or ethnic origin, height 
and weight, body mass index (BMI), blood pressure and other characteristics) will be 
summarized for each treatment group.  In addition, smoking and alcohol habits, diabetic 
and cardiovascular medical history, baseline laboratory results, and prior medications will 
be summarized by treatment group.  Binary and ordinal characteristics will be 
summarized by counts and percentages, while continuous variables will be represented by 
mean and standard deviations or medians and percentiles, as appropriate.  Any variables 
with treatment imbalances may be considered as covariates for further analysis of an 
exploratory nature.  Such covariates will be identified on the basis of the clinical 
relevance of the observed treatment difference.
8.3.3.1.
Primary Comparisons of Interest
The primary endpoint will be the time to the first occurrence of MACE over the full 
duration of the study. A p-value for the primary endpoint will be calculated from a Cox 
regression model with treatment group as the only covariate for the hypotheses described 
in Section 8.1.
8.3.3.2.
Other Comparisons of Interest
For other analyses incidence rates will be presented for binary data and summary 
statistics (mean, median, standard deviation, minimum, and maximum) will be presented 
for continuous data.  Furthermore, summary statistics of change from baseline for HbA1c 
will be presented along with percent of subjects within ranges of clinical interest (e.g., 
HbA1c < 7.0%).

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8.3.4.
Interim Analysis
An IDMC will monitor progress of the study and ensure that it meets the highest 
standards of ethics and subject safety.    All cardiovascular event data, together with other 
safety data, will be sent to the IDMC for review at approximately every 6 months after 
the first subject has been randomised to receive treatment.  This frequency may be 
adjusted, if deemed necessary by the IDMC, depending on the enrolment rates and the 
rate of safety events.  There are no plans to stop the study early for a non-inferiority or 
benefit claim, however should the IDMC identify in the course of its scheduled reviews 
overwhelming evidence of MACE benefit (e.g., p < 0.001), with directionally consistent 
findings on all-cause mortality, the IDMC might consider recommending early stopping.  
This approach essentially preserves the final alpha for the end-of-study analysis at 5% 
and hence there are no plans to adjust the final alpha on account on safety reviews 
conducted by the IDMC. The IDMC charter, reporting and procedures are outlined in 
separate documents.
8.3.5.
Multiplicity Controls
A multiple comparisons adjustment strategy will be implemented for the multiple 
inferential tests among the primary endpoint and secondary endpoints of MACE 
superiority, time to insulin and composite metabolic endpoint.
The strategy will use a combination of gatekeeper and Hommel procedure. The first step 
is to evaluate the MACE non-inferiority of the albiglutide group vs the placebo group at a 
one-sided alpha=0.025 level. If the result of non-inferiority is significant, MACE 
superiority, time-to-insulin and composite metabolic endpoint will be tested 
simultaneously using the Hommel procedure with alpha=0.05.  The above multiplicity 
control approach will preserve the study’s nominal significance level of 0.05. The test 
order is illustrated in the diagram below.

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Hommel Procedure for secondary endpoints is described below:
Three hypothesis testsfor MACE superiority, time-to-insulin, and composite metabolic 
endpoint are subject to be adjusted by the Hommel procedure. Let P(1), P(2) and P(3) 
represent the ordered p-values that P(3) > P(2) > P(1) and H(1), H(2) and H(3) are 
corresponding hypotheses. 
If P(3)< 0.05, reject H(3), H(2), H(1). End of test.
If P(3) ≥0.05 and P(2) < 0.05/2, accept H(3), reject H(2), H(1). End of test.
If P(3)≥0.05 and P(2)≥0.05/2 and P(1) < 0.05/3, accept H(3), H(2), reject H(1). End of 
test.
If P(3)≥0.05, P(1)≥ 0.05/3 and 0.05/2≤ P(2)< 0.05*2/3, accept H(3), H(2), reject H(1). 
End of test.
If P(3)≥0.05, P(2)≥ 0.05*2/3 and P(1)≥ 0.05/3, accept H(3),,H(2) and H(1).
Other Secondary Endpoints and Subgroup Analysis
The following secondary endpoints will provide supportive evidence for cardiovascular 
safety and will not use any multiplicity adjustment procedure. 

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
Components of primary endpoint (MACE = cardiovascular death, MI, stroke)

MACE + urgent revascularisation for unstable angina

Cardiovascular death or hospitalisation for heart failure
Other secondary endpoints which do not qualify for formal statistical hypothesis testing 
will be analyzed and have results presented with confidence interval and nominal p-
values:

Mean HbA1c  at scheduled visits and change from baseline

Mean body weight at scheduled visits and change from baseline

Mean eGFR at scheduled visits and change from baseline

Time to initiation of prandial insulin

Composite microvascular endpoint
To examine the degree of consistency of the overall treatment effect in terms of important 
prognostic factors, subgroup analyses of the primary outcomes will be performed based 
on subject demographics and baseline characteristics. These exploratory subgroup 
analyses will not be adjusted for multiple comparisons and will be interpreted 
descriptively.
8.3.6.
Key Elements of Analysis Plan
Any deviations from the original analysis planned in the protocol agreed upon prior to 
finalization of the RAP, will be described in that document. Any additional changes to 
the planned analysis in the RAP will be described in the final clinical study report.
8.3.6.1.
Primary Analysis
The primary analysis is an ITT analysis of the time to the first occurrence of MACE over 
the full duration of the study. Time to event analyses will be performed using Cox’s 
Proportional Hazard regression with SAS PHREG with treatment group as the only 
covariate.  Data for subjects without a primary event will be censored.
Treatment differences will be estimated via the hazard ratio and its 95% confidence 
interval (CI). 
The hypothesis of non-inferiority of albiglutide relative to placebo group with hazard 
ratio less than 1.3 with respect to cardiovascular risk will be tested at the end of the study 
when ~611 first MACE events are cumulated.  
The strength of evidence for non-inferiority will be determined by testing the hypothesis 
that the observed hazard ratio is significantly different from the null margin of 1.3 (one-
sided p < 0.025 for such a test being equivalent to the upper 95% confidence limit after 
multiplicity adjustment for the hazard ratio being less than 1.3).  The absolute risk 
difference per 100 PY and superiority p-value for albiglutide vs. placebo will also be 
presented.

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The product-limit estimates of the probabilities (and their standard errors) of first MACE 
over time will be computed and displayed as Kaplan-Meier (KM) survival curves for  
albiglutide and placebo groups.  The KM curves will also be presented corresponding to 
the above comparisons.
The total number of all MACE or any of its components will be analyzed by Poisson 
regression model. The incidence rate per 100 person-years, relative risk and their 95% CI 
will be presented. Number of subjects who experienced at least one event, 2 or 3 or more 
MACE or its components will also be summarized by treatment group.
As sensitivity analyses, the analyses described above will be repeated using events occur 
while on-treatment and events occur during the period of on-treatment plus 56 days post 
last dose.
8.3.6.2.
Secondary Endpoint Analysis
Endpoints that supplement the primary objective by further characterization of the effects 
of albiglutide on cardiovascular outcomes endpoints: 

MACE superiority will be evaluated using the same Cox regression model as the 
primary analysis of MACE non-inferiority.

Supportive endpoints including the time to first occurrence of adjudicated MACE or 
urgent revascularisation for unstable angina, time to first occurrence of individual 
components of MACE, time to first occurrence of cardiovascular death or 
hospitalisation for heart failure will be analyzed using a proportional Cox regression 
model similarly as the primary endpoint.
Endpoints that evaluate the effects of albiglutide on metabolic management of type 2 
diabetes: 

Among the subjects who are not on insulin at baseline (NI population), time to 
insulin will be analyzed using a proportional Cox regression model similar to the 
primary MACE analysis. The product-limit estimates of the probabilities (and their 
standard errors) of adding insulin over time will be computed and displayed as 
Kaplan-Meier (KM) survival curves for albiglutide and  placebo treatment groups. 
The KM curves will also be presented corresponding to the above comparisons.

Composite of the proportion of those achieving good control (HbA1c ≤ 7.0%) AND 
no severe hypoglycaemic incidents AND weight gain <5% at the end of the study 
would be evaluated utilize nonparametric, covariance-adjusted, extended Mantel-
Haenszel tests. Additional analysis will be provided for scheduled visits. Nominal p-
values and 95% CIs will be presented for these visits. Time to introduction of 
prandial insulin in those on basal insulin orals anti-hyperglycemic drugs at baseline 
will be analyzed using PH model / log-rank test and KM method similar to the 
primary endpoint.

Composite of microvascular events will be analyzed using a proportional Cox 
regression model / log-rank test and KM method similar to the primary endpoint.

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
HbA1c, body weight and eGFR will be analyzed using a repeated mixed effect 
model. The least square means, 95%CIs and nominal p-values will be presented.

Additional analysis will be performed to assess the incidence rate of recurrent severe 
hypoglycaemic events between treatment groups during the course of the study. A 
repeated Poisson regression model including treatment and visit as factors will be 
used to test treatment difference with offset for person years. An unstructured 
working correlation matrix will be used in the iterative estimation process. The 
model-adjusted least square incidence rate for each treatment as well as the treatment 
difference of the incidence rate will be reported. Events of severe hypoglycaemia 
will also be summarized descriptively by treatment group. Additional summary by 
baseline HbA1c, renal status and age subgroup will also be provided.
Further analysis details will be provided in the RAP.
8.3.6.3.
Subgroup Analysis
Separate subgroup analyses of the primary outcomes will be performed based on subject 
demographics and baseline characteristics.  Subgroups may include sex, age group, BMI, 
whether subjects have history of a previous cardiovascular event, and baseline HbA1C, 
background of anti-hyperglycaemia treatment etc. The detail of subgroups will be pre-
specified in the RAP.  Consistency of treatment effects will be assessed using Cox 
regression, along with the 95% confidence intervals for the relative risk or hazard ratios 
for each subgroup a nominal alpha level for interaction of 0.10 will be used.  The effect 
of treatment interaction with subgroups will also explored; however as the number of 
these subgroup variables may be large, the probability of observing at least one 
statistically significant result may be high.  Thus these additional analyses will be 
considered exploratory regardless of the p-value associated with any interaction.
Further details will be provided in the RAP.
8.3.6.4.
Other Safety Analyses
Subject demographics, medical history, prior and concomitant medications, vital sign 
measurements, laboratory values, physical examination assessments, will be summarized 
by treatment group using descriptive statistics. 
For continuous variables, these summaries will include sample size, mean, median, 
standard deviation, minimum, and maximum. For categorical variables, the summaries 
will include frequencies and corresponding percentages. 
For SAEs, AEs leading to withdrawal  and AEs of special interest occurring after 
discontinuation of investigational product, the number and percentage of subjects , total 
number of events, incidence density and event rate will be presented by treatment group 
and overall at the SOC, High Level Term and Preferred Term (PT) level. Relative Risk 
for each event and its 95% CI will also be presented. The time to first occurrence of the 
specific events and the time of the event with respect to the preceding dose of study 
medication will be summarized.

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All cause mortality will be summarized by treatment group and analyzed using PH model 
similarly as the-primary endpoint.
All events sent to CEC (including TIAs) will be grouped by type based on the standard 
MedDRA queries that correspond to cardiovascular and cerebrovascular events. 
Adjudication results will be summarized by event type and treatment group. A by subject 
listing of these events will be generated.  The listing will include seriousness, severity, 
whether event is a reason for early study drug discontinuation or study withdrawal, and 
adjudication results.
Pancreatitis events will be adjudicated by the independent Pancreatitis Adjudication 
Committee. The information for investigator reported pancreatitis events and its 
adjudication results will be provided.
Further analysis details will be provided in the RAP.
8.3.6.5.
Value Evidence and Outcomes Analyses
TRIM-D total score and score for each domain will be summarized descriptively by 
treatment group and scheduled visit. Score changes from baseline will be compared 
between treatments for each visit by ANCOVA an model
For EQ-5D, subjects’ responses at each visit for the 5 domains will be summarized
categorically by treatment group, together with the summary of utility score at each visit 
and change from baseline by treatment group. Change from baseline will be compared 
between treatment groups for each visit by an ANCOVA model. 
For study specific PRO questions, responses will be summarized descriptively by 
treatment group and scheduled visit. 
Healthcare resource use will be summarized by treatment group and visit. 
Further analysis details will be provided in the RAP.
9.
STUDY CONDUCT CONSIDERATIONS
9.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrolment of subjects begins.

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9.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a site, GSK will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH E6 Good Clinical Practice 
(GCP), all applicable subject privacy requirements, and the guiding principles of the 
current version of the Declaration of Helsinki.  This includes, but is not limited to, the 
following:

IRB/IEC review and favourable opinion/approval of the study protocol and 
amendments as applicable

Signed informed consent  to be obtained for each subject before participation in the 
study (and for amendments as applicable)

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol deviations 
to IRB/IEC)

GSK will provide full details of the above procedures, either verbally, in writing, or 
both.
Signed informed consent must be obtained for each subject prior to participation in the 
study
The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.  Optional assessments 
(including those in a separate protocol and/or under separate informed consent) and the 
clinical protocol should be concurrently submitted for approval unless regulation requires 
separate submission.  Approval of the optional assessments may occur after approval is 
granted for the clinical protocol where required by regulatory authorities.  In this 
situation, written approval of the clinical protocol should state that approval of optional 
assessments is being deferred and the study, with the exception of the optional 
assessments, can be initiated.
9.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK monitors will contact the site prior to the start of the study to review with the 
site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and GSK requirements.  

When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the CRF will 
serve as the source document.
GSK will monitor the study to ensure that the:

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
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.
9.4.
Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK 
may conduct a quality assurance assessment and/or audit of the site records, and the 
regulatory agencies may conduct a regulatory inspection at any time during or after 
completion of the study. 

In the event of an assessment, audit or inspection, the investigator (and institution) 
must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all 
relevant documents and to allocate their time and the time of their staff to discuss the 
conduct of the study, any findings/relevant issues and to implement any corrective 
and/or preventative actions to address any findings/issues identified.
9.5.
Study and Site Closure

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.

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9.6.
Records Retention

Following closure of the study, the investigator or the head of the medical institution 
(where applicable) must maintain all site study records (except for those required by 
local regulations to be maintained elsewhere), in a safe and secure location.  

The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review in 
conjunction with assessment of the facility, supporting systems, and relevant site 
staff.  

Where permitted by local laws/regulations or institutional policy, some or all of these 
records can be maintained in a format other than hard copy (e.g., microfiche, 
scanned, electronic); however, caution needs to be exercised before such action is 
taken.  

The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, including 
re-generating a hard copy, if required.  Furthermore, the investigator must ensure 
there is an acceptable back-up of these reproductions and that an acceptable quality 
control process exists for making these reproductions.

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.
9.7.
Provision of Study Results to Investigators, Posting of 
Information on Publicly Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
GSK will provide the investigator with the randomisation codes for their site only after 
completion of the full statistical analysis.

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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.
9.8.
Independent Data Monitoring Committee (IDMC)
An IDMC will be utilized in this study to ensure external objective medical and/or 
statistical review of safety and/or efficacy issues in order to protect the ethical and safety 
interests of subjects and to protect the scientific validity of the study.  The schedule of 
any planned interim analysis and the analysis plan for IDMC review is described in the 
charter.
9.9.
Pancreatitis Adjudication Committee
Detailed information on suspected pancreatitis events will be collected on special pages 
of the eCRF. A Pancreatitis Adjudication Committee composed of independent 
specialists in gastroenterology will review cases of possible pancreatitis. Details of this 
committee and case adjudication are described in the committee’s charter available on 
request.

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10.
REFERENCES
ACC/AHA Key Data Elements and Definitions for Cardiovascular and Stroke End Point 
Events for Clinical Trials, February 4 2014 (peer review draft version)
American Diabetes Association (ADA). Diagnosis and classification of diabetes mellitus. 
Diabetes Care, 2014; 37 (Suppl 1): S81-S90.
Anderson DR, Christison-Lagay J, and Procter-Gray E. Self-Management goal setting in 
a community health center: the impact of goal attainment on diabetes outcomes. Diabetes 
Spectrum 23.2 (2010): 97-105.
Bao W, Aravindhan K, Alsaid H et al. Albiglutide, a long-lasting glucagon-like peptide-1 
analog, protects the rat heart against ischemia/reperfusion injury: evidence for improving 
cardiac metabolic efficiency.  PLoS One 6: e23570. 2011
Brod, M., Christensen, T., Kongsø, J. H. & Bushnell, D. M. Examining and interpreting 
responsiveness of the Diabetes Medication Satisfaction measure. J. Med. Econ. 12, 309–
316 (2009b).
Brod, M., Hammer, M., Christensen, T., Lessard, S. & Bushnell, D. M. Understanding 
and assessing the impact of treatment in diabetes: the Treatment-Related Impact 
Measures for Diabetes and Devices (TRIM-Diabetes and TRIM-Diabetes Device). Health 
Qual. Life Outcomes 7, 83 (2009a).
Butler AE, Campbell-Thompson M, Gurlo T, et al. Marked expansion of exocrine and 
endocrine pancreas with incretin therapy in humans with increased exocrine pancreas 
dysplasia and the potential for glucagon-producing neuroendocrine tumors. Diabetes. 
2013;62(7):2595-604.
Clarke PM, Hayes AJ, Glasziou PG, et al. Using the EQ-5D index score as a predictor of 
outcomes in patients with type 2 diabetes. Med Care 2009; 47: 61-68.
Cooper DS, Doherty GM, Haugen BR et al. Management guidelines for patients with 
thyroid nodules and differentiated thyroid cancer. Thyroid. 2006;16(2):109-142. 
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. 
European Public Assessment Report (EPAR) for Eperzan. 2014.Available at: 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/00273
5/human_med_001735.jsp&mid=WC0b01ac058001d124
FDA Summary Basis of Approval. 2014. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/125431Orig1s000TOC.cfm
Fu AZ, Qiu Y, Radican L, Yin DD, Mavros P. Pre-existing cardiovascular diseases and 
glycemic control in patients with type 2 diabetes mellitus in Europe: a matched cohort 
study. Cardiovasc Diabetol. 2010; 9:15.

2014N193553_01
CONFIDENTIAL
GLP116174
60
Grandy S, Fox KM. Change in health status (EQ-5D) over 5 years among individuals 
with and without type 2 diabetes mellitus in the SHIELD longitudinal study. Health and 
Quality of Life Outcomes 2012;10:99.
Guidance for Industry. Diabetes Mellitus: Developing Drugs and Therapeutic Biologics 
for Treatment and Prevention. U.S. Department of Health and Human Services. Food and 
Drug Administration. Center for Drug Evaluation and Research (CDER). February 2008 
Clinical/Medical. Available at http://www.fda.gov/cder/guidance/index.htm.
Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauk M, Peters AL, 
Tsapas A, Wender R, Matthews DR. Management of Hyperglycemia in Type 2 Diabetes: 
A Patient-Centered Approach Position Statement of the American Diabetes Association 
(ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 
2012; 35: 1364-1379
Janssen MF, Lubetkin EI, Sekhobo JP, Pickard AS. The use of the EQ-5D preference-
based health status measure in adults with Type 2 diabetes mellitus. Diabet Med 2011; 
28(4):395-413.
Juniper EF, Guyatt GH, Epstein RS, Ferrie PJ, Jaeschke R, Hiller TK. Evaluation of 
impairment of health-related quality of life in asthma: development of a questionnaire for 
use in clinical trials. Thorax 1992; 47: 76-83.
Khunti K, Andersen M, Wolden ML, Davies MJ and Thorsted BL. Clinical Inertia in 
People With Type 2 Diabetes. Diabetes Care. 2013; 36:3411-3417
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. 
Levey AS, Stevens LA, Schmid CH et al. A new equation to estimate glomerular 
filtration rate.  Ann Intern Med. 2009; 150: 604-12.
Lønborg J, Vejlstrup N, Kelbaek H et al. Exenatide reduces reperfusion injury in patients 
with ST-segment elevation myocardial infarction.  Eur Heart J 2012; 33: 1491-9.
Nystrom T, Gutniak MK, Zhang Q et al. Effects of glucagon-like peptide-1 on 
endothelial function in type 2 diabetes patients with stable coronary disease. Am J 
Physiol Endocrinol Metab 2004; 287: E1209-15.
Okerson T and Chilton RJ. The cardiovascular effects of GLP-1 receptor agonists. 
Cardiovascular Therapeutics 2012; 30: e146-155.
Pacini F, Schlumberger M, Dralle H et al. European consensus for the management of 
patients with differentiated thyroid carcinoma of the follicular epithelium. Eur J 
Endocrinol. 2006;154(6):787-803.

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Schulz KF, Altman DG, Moher D for the CONSORT Group. CONSORT 2010 
Statement: updated guidelines for reporting parallel group randomised trials. Available 
at: http://www. consort-
statement.org/Media/Default/Downloads/CONSORT%202010%20Statement/CONSORT
%202010%20Statement%20(BMJ).pdf
Seaquist E, Anderson J, Childs B, et al. Hypoglycemia and diabetes: A report of a 
workgroup of the American Diabetes Association and the Endocrine Society. Diabetes 
Care. 2013;36:1384-1395.
Stonehouse AH, Darsow T, Maggs DG. Incretin-based therapies. J Diabetes 
2012;4(1):55-67.
Thygesen K, Alpert JS, Jaffe AS etal. Third universal definition of myocardial 
infarction. European Heart Journal. 2012; 33: 2551–2567
Vilsbøll T, Krarup T, Deacon CF, Madsbad S, Holst JJ. Reduced postprandial 
concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic 
patients. Diabetes. 2001; 50(3):609-13.
World Health Organization (WHO). Diabetes Fact Sheet. October 2013. Available at 
http://www.who.int/mediacentre/factsheets/fs312/en/ (Accessed Apr 3, 2014).

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11.
APPENDICES
11.1.
Appendix 1: Genetic Research
Background
Genetics is the study of variability in drug response due to hereditary factors in 
populations.  There is increasing evidence that an individual's genetic background (i.e., 
genotype) may impact the pharmacokinetics (absorption, distribution, metabolism, 
elimination), pharmacodynamics (relationship between concentrations and 
pharmacologic effects or the time course of pharmacologic effects) and/or clinical 
outcome (in terms of efficacy and/or safety and tolerability).  Some reported examples of 
genetic associations with safety/adverse events include:
Drug
Disease
Gene Variant
Outcome
Abacavir
HIV 
[Hetherington, 
2002; 
Mallal, 2002; 
Mallal, 2008]
HLA-B* 57:01 
(Human 
Leukocyte 
Antigen B)
Carriage of the HLA-B*57:01 variant has been 
shown to increase a patient's risk for 
experiencing hypersensitivity to abacavir.  
Prospective HLA-B*57:01 screening and 
exclusion of HLA-B*57:01 positive patients 
from abacavir treatment significantly 
decreased the incidence of abacavir 
hypersensitivity.  Treatment guidelines and 
abacavir product labelling in the United States 
and Europe now recommend (US) or require 
(EU) prospective HLA-B*57:01 screening prior 
to initiation of abacavir to reduce the incidence 
of abacavir hypersensitivity.  HLA-B*57:01
screening should supplement but must never 
replace clinical risk management strategies for 
abacavir hypersensitivity.

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Drug
Disease
Gene Variant
Outcome
Carbamaze
pine
Seizure, Bipolar 
disorders & 
Analgesia 
[Chung, 2010; 
Ferrell, 2008]
HLA-B*15:02
Independent studies indicated that patients of 
East Asian ancestry who carry HLA-B*15:02
are at higher risk of Stevens-Johnson 
Syndrome and toxic epidermal necrolysis.  
Regulators, including the US FDA and the 
Taiwanese TFDA, have updated the 
carbamazepine drug label to indicate that 
patients with ancestry in genetically at risk 
populations should be screened for the 
presence of HLA-B*15:02 prior to initiating 
treatment with carbamazepine.
Irinotecan
Cancer 
[Innocenti, 2004; 
Liu, 2008; 
Schulz, 2009]
UGT1A1*28
Variations in the UGT1A1 gene can influence 
a patient’s ability to break down irinotecan, 
which can lead to increased blood levels of the 
drug and a higher risk of side effects. A dose 
of irinotecan that is safe for one patient with a 
particular UGT1A1 gene variation might be too 
high for another patient without this variation, 
raising the risk of certain side-effects that 
include neutropenia following initiation of 
Irinotecan treatment.  The irinotecan drug 
label indicates that individuals who have two 
copies of the UGT1A1*28 variant are at 
increased risk of neutropenia.  A genetic blood 
test is available that can detect variations in 
the gene.    
A key component to successful genetic research is the collection of samples during the 
conduct of clinical studies.
Collection of whole blood samples, even when no a priori hypothesis has been identified, 
may enable genetic analysis to be conducted if at any time it appears that there is a 
potential unexpected or unexplained variation in response to albiglutide.
Genetic Research Objectives
The objective of genetic research (if there is a potential unexpected or unexplained 
variation) is to investigate a relationship between genetic factors and response to 
albiglutide.  If at any time it appears there is potential variability in response in this 
clinical study or in a series of clinical studies with albiglutide, the following objectives 
may be investigated – the relationship between genetic variants and study treatment with 
respect to:

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
Safety and/or tolerability 

Efficacy
Study Population
Any subject who is enrolled in the clinical study, can participate in genetic research.  Any 
subject who has received an allogeneic bone marrow transplant must be excluded from 
genetic research.
Subject participation in the genetic research is voluntary and refusal to participate will 
not indicate withdrawal from the clinical study or result in any penalty or loss of benefits 
to which the subject would otherwise be entitled.
Study Assessments and Procedures
Blood samples can be taken for deoxyribonucleic acid (DNA) extraction and used in 
genetic assessments.
If taking blood samples: in addition to any blood samples taken for the clinical study, a 
whole blood sample (~6ml) will be collected for the genetic research using a tube 
containing EDTA.  It is recommended that the blood sample be taken at the first 
opportunity after a subject has been randomised and provided informed consent for 
geneticresearch, but may be taken at any time while the subject is participating in the 
clinical study.

The genetic sample is labelled (or “coded”) with a study specific number that 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).  The 
blood sample is taken on a single occasion unless a duplicate sample is required due 
to inability to utilise the original sample.  
The DNA extracted from the blood sample may be subjected to sample quality control 
analysis.  This analysis will involve the genotyping of several genetic markers to confirm 
the integrity of individual samples.  If inconsistencies are noted in the analysis, then those 
samples may be destroyed.
The need to conduct genetic analysis may be identified after a study (or a set of studies) 
of albiglutide has been completed and the clinical study data reviewed.  In some cases, 
the samples may not be studied. e.g., no questions are raised about how people respond to 
albiglutide.
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 use samples collected from the study for 
the purpose stated in this protocol and in the informed consent form.  
Subjects can request their sample to be destroyed at any time.

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Subject Withdrawal from Study
If a subject who has consented to participate in geneticresearch 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 geneticsample, if already collected:

Continue to participate in genetic research with the geneticsample retained for 
analysis 

Withdraw from geneticresearch and destroy the geneticsample 
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. The investigator should forward the Pharmacogenetic Sample 
Destruction Request Form to GSK as directed on the form. This can be done at any time 
when a subject wishes to withdraw from  genetic research or have their sample destroyed 
whether during the study or during the retention period following close of the main study.
Screen and Baseline Failures
If a blood sample for genetic research has been collected and it is determined that the 
subject does not meet the entry criteria for participation in the clinical study, then the 
investigator should instruct the participant 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.
Analyses
1.
Specific genes may be studied that encode the drug targets, or drug mechanism of 
action pathways, drug metabolizing enzymes, drug transporters or which may 
underpin adverse events, disease risk or drug response. These candidate genes may 
include a common set of ADME (Absorption, Distribution, Metabolism and 
Excretion) genes that are studied to determine the relationship between gene variants 
or treatment response and/or tolerance. 
In addition, continuing research may identify other enzymes, transporters, proteins or 
receptors that may be involved in response to albiglutide.  The genes that may code for 
these proteins may also be studied.
2.
Genome-wide scans involving a large number of polymorphic markers (e.g., single 
nucleotide polymorphisms) at defined locations in the genome, often correlated with 
a candidate gene, may be studied to determine the relationship between genetic 
variants and treatment response or tolerance. This approach is often employed when 
a definitive candidate gene(s) does not exist and/or the potential genetic effects are 
not well understood. 
If applicable and genetic research is conducted, appropriate statistical analysis methods 
will be used to evaluate pharmacogenetic data in the context of the other clinical data. 

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Results of genetic investigations will be reported either as part of the main clinical study 
report or as a separate report. Endpoints of interest from all comparisons will be 
descriptively and/or graphically summarised as appropriate to the data.  A detailed 
description of the analysis to be performed will be documented in the study reporting and 
analysis plan (RAP) or in a separate pharmacogenetics RAP, as appropriate.  
Informed Consent
Subjects who do not wish to participate in geneticresearch may still participate in the 
clinical study.  Genetic informed consent must be obtained prior to any blood being taken 
for genetic research.
Provision of Study Results and Confidentiality of Subject’s Genetic Data
GSK may summarise the genetic research results in the clinical study report, or 
separately, or may publish the results in scientific journals. 
GSK does not inform the investigator, subject, or anyone else (e.g., family members, 
study investigators, primary care physicians, 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.
References
Chung WH, Hung SL, Chen YT. Genetic predisposition of life-threatening antiepileptic-
induced skin reactions.  Expert Opin. Drug Saf. 2010; 9: 15-21.
Ferrell PB, McLeod HL.  Carbamazepine, HLA-B*1502 and risk of Stevens-Johnson 
syndrome and toxic epidermal necrolysis: US FDA recommendations.  
Pharmacogenomics. 2008; 9: 1543-1546.
Hetherington S, Hughes AR, Mosteller M, Shortino D, Baker KL, Spreen W, Lai E, 
Davies K, Handley A, Dow DJ, Fling ME, Stocum M, Bowman C, Thurmond LM, Roses 
AD. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. 
Lancet. 2002; 359:1121-1122.
Innocenti F, Undevia SD, Iyer L, Chen PX, Das S, Kocherginsky M, Karrison T, Janisch 
L, Ramirez J, Rudin CM, Vokes EE, Ratain MJ.  Genetic variants in the UDP-
glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J 
Clin Oncol 2004; 22: 1382-1388.
Liu CY, Chen PM, Chiou TJ, Liu JH, Lin JK, Lin TC, Chen WS, Jiang JK, Wang HS, 
Wang WS.  UGT1A1*28 polymorphism predicts irinotecan-induced severe toxicities 
without affecting treatment outcome and survival in patients with metastatic colorectal 
carcinoma.  Cancer. 2008; 112: 1932-1940.

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Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, Sayer D, Castley A, Mamotte 
C, Maxwell D, James I.  Association between presence of HLA-B*5701, HLA-DR7, and 
HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir.  
Lancet. 2002; 359:727-732.
Mallal S, Phillips E, Carosi G, Molina JM, Workman C, Tomazic J, Jägel-Guedes E, 
Rugina S, Kozyrev O, Cid JF, Hay P, Nolan D, Hughes S, Hughes A, Ryan S, Fitch N, 
Thorborn D, Benbow A; PREDICT-1 Study Team.  HLA-B*5701 screening for 
hypersensitivity to abacavir. N Engl J Med. 2008; 358; 568-579
Schulz C, Heinemann V, Schalhorn A, Moosmann N, Zwingers T, Boeck S, Giessen C, 
Stemmler HJ. UGT1A1 gene polymorphism: Impact on toxicity and efficacy of 
irinotecan-based regimens in metastatic colorectal cancer.  World J. Gastroenterol. 2009; 
15: 5058-5066.

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11.2.
Appendix 2: GSK Modified List of Highly Effective Methods 
for Avoiding Pregnancy in Females of Reproductive 
Potential (FRP)
1.
Contraceptive subdermal implant that meets effectiveness criteria including a <1% 
rate of failure per year, as stated in the product label.
2.
Intrauterine device or intrauterine system that meets effectiveness criteria including a 
<1% rate of failure per year, as stated in the product label [Trussell, 2011]
3.
Oral Contraceptive, either combined or progestogen alone [Trussell, 2011] 
4.
Injectable progestogen [Trussell, 2011]
5.
Contraceptive vaginal ring [Trussell, 2011]
6.
Percutaneous contraceptive patches [Trussell, 2011]
7.
Male partner sterilization prior to the female subject's entry into the study, and this 
male is the sole partner for that subject. The information on the male sterility can 
come from interview with the subject on her male partner’s medical history.
8.
Male condom combined with a female diaphragm, with or without a vaginal 
spermicide (foam, gel, film, cream, or suppository). In the UK it is a country-specific 
requirement of the regulatory authority (Medicines and Healthcare Products 
Regulatory Agency) that a vaginal spermcide be used.
These allowed methods of contraception have a failure rate of less than 1% per year but 
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.
References
Trussell J, Contraceptive Efficacy. In: Hatcher RA, Trussell J, Nelson AL, Cates W, 
Kowal D, and Policar M (editors). Contraceptive Technology: Twentieth Revised 
Edition. New York: Ardent Media, 2011.Table 26-1

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11.3.
Appendix 3: Liver Safety Required Actions and Follow up 
Assessments
Phase III-IV liver chemistry stopping and increased monitoring criteria have been 
designed to assure subject safety and evaluate liver event aetiology (in alignment with the 
FDA premarketing clinical liver safety guidance).  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
Phase III-IV liver chemistry stopping criteria and required follow up assessments 
Liver Chemistry Stopping Criteria - Liver Stopping Event
ALT-absolute
ALT 8xULN
ALT Increase
ALT 5xULN but <8xULN  persists for 2 weeks
ALT 3xULN but <5xULN  persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2 
ALT 3xULN and INR>1.5, if INR measured
Cannot 
Monitor
ALT 5xULN but <8xULN and cannot be monitored weekly for 2 weeks
ALT 3xULN but <5xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be 
related to  liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue  study treatment 

Report the event to GSK within 24 hours

Complete the liver event CRF and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries 
resolve , stabilize, or return to within baseline 
(see MONITORING below)

Do not restart subject with study treatment 
unless allowed per protocol and GSK Medical 
Governance approval is granted (refer to  

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 3 half lives (15 
days)  of last dose6

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN.

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Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments
Appendix 5)

If restart is not granted, permanently 
discontinue study treatment and continue 
subject in the study for any protocol specified 
follow up assessments 

Re-challenge is not allowed.
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

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 high 
pressure liquid chromatography assay 
(quantifies potential acetaminophen 
contribution to liver injury in subjects with 
definite or likely acetaminophen use in the 
preceding week [James, 2009]). NOTE: 
not required in China

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms

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1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to subjects receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)   
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
5.
If hepatitis delta antibody assay cannot be performed,, it can be replaced with a PCR of hepatitis D RNA virus 
(where needed) [Le Gal, 2005].
6.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM.  
Phase III-IV 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.

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References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Protein Adduct in Adults with 
Acetaminophen Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-
1784.
Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P, Gault E.  Quantification 
of Hepatitis Delta Virus RNA in Serum by Consensus Real-Time PCR Indicates 
Different Patterns of Virological Response to Interferon Therapy in Chronically Infected 
Patients.  J Clin Microbiol. 2005;43(5):2363–2369. 

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11.4.
Appendix 4: Liver Safety Drug Restart Guidelines
If subject meets liver chemistry stopping criteria do not restart subject with study 
treatment unless:

GSK Medical Governance approval is granted (as described below),

Ethics and/or IRB approval is obtained, if required, and

Separate consent for treatment restart is signed by the subject
If GSK Medical Governance approval to restart the subject with study treatment is not
granted, then the subject must permanently discontinue study treatment and may 
continue in the study for protocol-specified follow up assessments.
Restart Following Transient Resolving Liver Stopping Events Not Related to Study 
Treatment
Restart refers to resuming study treatment following liver stopping events in which there 
is a clear underlying cause (other than DILI) of the liver event (e.g. biliary obstruction, 
pancreatic events, hypotension, acute viral hepatitis). Furthermore, there should be no 
evidence of alcoholic hepatitis or hypersensitivity, and the study treatment should not be 
associated with HLA markers of liver injury.
Approval by GSK for study treatment restart can be considered where:

Investigator  requests consideration for study treatment restart if liver chemistries 
have a clear underlying cause (e.g., biliary obstruction, hypotension and liver 
chemistries have improved to normal or are within 1.5 x baseline and ALT 
<3xULN).

Restart risk factors (e.g. fever, rash, eosinophilia, or hypersensitivity, alcoholic 
hepatitis, possible study treatment-induced liver injury) or study treatment has an 
HLA genetic marker associated with liver injury (e.g. lapatinib, abacavir, 
amoxicillin/clavulanate) are reviewed and excluded.

Ethics Committee or Institutional Review Board approval of study treatment restart 
must be obtained, as required.

If restart of study treatment is approved by GSK Medical Governance in writing, the 
subject must be provided with a clear description of the possible benefits and risks of 
study treatment administration, including the possibility of recurrent, more severe 
liver injury or death.  

The subject must also provide signed informed consent specifically for the study 
treatment restart.  Documentation of informed consent must be recorded in the study 
chart.  

Study treatment must be administered at the dose specified by GSK.

Subjects approved by GSK Medical Governance for restarting study treatment must 
return to the clinic once a week for liver chemistry tests until stable liver chemistries 
have been demonstrated and then laboratory monitoring may resume as per protocol. 

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
If after study treatment re-start, subject meets protocol-defined liver chemistry 
stopping criteria, follow usual stopping criteria instructions.

GSK Medical Monitor, and the Ethics Committee or Institutional Review Board as 
required, must be informed of the subject’s outcome following study treatment 
restart. 

GSK to be notified of any adverse events, as per Section 6.2.2 and Appendix 5

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11.5.
Appendix 5: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
11.5.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a subject 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 unfavourable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (haematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae).

The signs and symptoms and/or clinical sequelae resulting from lack of efficacy will 
be reported if they fulfil the definition of an AE or SAE.  Also, "lack of efficacy" or 
"failure of expected pharmacological action" also constitutes an AE or SAE.

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Events NOT meeting definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 
condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
11.5.2.
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:
c.
Results in death
d.
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.
e.
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 fulfils any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.

Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.

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f.
Results in disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhoea, influenza, 
and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday 
life functions but do not constitute a substantial disruption
g.
Is a congenital anomaly/birth defect
h.
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
i.
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** > 1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick.  If fractionation is unavailable and ALT 3xULN 
and total bilirubin 2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.

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11.5.3.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the CRF

It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to GSK in lieu of completion of the GSK, AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK.  In this instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to 
submission of to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.

Subject-completed Value Evidence and Outcomes questionnaires and the collection 
of AE data are independent components of the study.

Responses to each question in the Value Evidence and Outcomes questionnaire will 
be treated in accordance with standard scoring and statistical procedures detailed by 
the scale’s developer.

The use of a single question from a multidimensional health survey to designate a 
cause-effect relationship to an AE is inappropriate.

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11.5.4.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. - an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of his/her assessment.

For each AE/SAE the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK.  However, it is very important 
that the investigator always make an assessment of causality for every event 
prior to the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.

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Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.

The investigator is obligated to assist.  This may include additional laboratory tests 
or investigations, histopathological examinations or consultation with other health 
care professionals.

If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide GSK with a copy of any post-mortem findings, 
including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
11.5.5.
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 or the SAE 
coordinator

Site will enter the SAE data into the electronic system as soon as it becomes 
available.

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 or the SAE coordinator by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.

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11.6.
Appendix 6: Collection of Pregnancy Information

Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study

Information will be recorded on the appropriate form and submitted to GSK within 2 
weeks of learning of a subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on mother and infant, which will be 
forwarded to GSK.  Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date. 

Any termination of pregnancy will be reported, regardless of foetal 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 5. 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

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11.7.
Appendix 7: Electronic Health Record Ancillary Study
11.7.1.
Introduction
11.7.1.1.
Background
Clinical researchers and policy makers want to move towards embedding clinical trials 
directly within health care delivery systems in order to increase the relevance, speed, and 
efficiency of clinical research [Richesson, 2013]. The assumption is that the capabilities 
offered by Electronic Health Records (EHRs), along with concurrent changes in health 
care organization and delivery, and the development of a learning health system will 
transform the way clinical research is conducted [Etheredge, 2007; Greene 2007]. 
In 2011, the National Heart, Lung, and Blood Institute (NHLBI) convened the NHLBI 
Working Group on Electronic Health Records: Research Priorities to Improve 
Cardiopulmonary Health in Clinical Practice. As part of their mission, this working group 
identified key research, policy, and training priorities [Curtis, 2014]. A key research 
priority was to leverage EHR tools to facilitate the efficient implementation of 
randomized clinical trials. Specific areas highlighted for increased efficiency included 
efficient data collection and outcome surveillance and confirmation.
11.7.1.2.
Literature Review
Electronic Health Records were primarily designed to document patient care and 
facilitate billing and reimbursement. The large amount of electronic data that are captured 
may also facilitate clinical research and public health surveillance.5 Despite the 
complexity of EHR data, national networks have begun to use these data to improve 
public health and generate real-world evidence [Toh, 2012]. The Patient Centered 
Outcomes Research network (PCORnet) (pcornet.org) is a research network that is 
currently being designed to support observational comparative effectiveness research and 
clinical trials that are embedded in clinical care settings [Fleurence, 2014]. Similarly, the 
NIH Health Care Systems Research Collaboratory (nihcollaboratory.org) is creating 
infrastructure to improve the conduct of embedded clinical trials. One ongoing NIH 
Collaboratory trial is the Time to Reduce Mortality in End-Stage Renal Disease study 
(TiME) (clinicaltrials.gov identifier: NCT02019225). TiME is a large cluster-
randomized, pragmatic trial that will evaluate the effects of systematic implementation of 
hemodialysis sessions of at least four hours versus usual hemodialysis care. The trial 
involves data acquisition from EHR systems through a partnership between academic 
investigators and two health care provider organizations with different electronic data 
systems. There are several other recent examples of clinical trials that were embedded in 
health care delivery systems [Gulliford, 2014; van Staa, 2014]. For instance, one recent 
study evaluated the use of an electronic decision support tool to improve risk factor 
control (i.e., blood pressure and cholesterol) following a cerebrovascular event with 
outcome data collected from the EHR [Dregan, 2014]. While the specific intervention 
was not shown to be efficacious, data acquisition via EHR sources was robust and 
implemented at a low cost.

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11.7.1.3.
Ancillary Study Rationale
Despite these earlier studies demonstrating the potential opportunities with EHR-based 
data acquisition, our understanding of how EHR-based platforms might increase the 
efficiency of data collection, outcome surveillance, and confirmation in an integrated 
manner is unknown. EHRs are inherently heterogeneous, with each implementation 
different from the next. The barriers to using EHR-generated lists of patients to facilitate 
trial enrolment, the fitness of EHR data for populating baseline characteristics in an 
electronic case report form (eCRF) and the use of EHR data to find events of interest 
during trial follow-up are not well characterized. 
EHR systems contain a wealth of clinical data about patients who are connected to the 
health care delivery system and may be eligible for enrollment in a clinical trial.  
Anecdotal reports suggest that identification of potential patients using the EHR increases 
the number of patients to be screened but may not consistently translate to an increased 
number of patients enrolled. Causes are likely multi-factorial and may include the 
translatability of inclusion and exclusion criteria to structured clinical data, the algorithm 
used to identify potential patients, institutional restrictions regarding unsolicited patient 
contact, and others. There is a need to empirically assess the barriers to using an EHR-
generated list of patients to facilitate trial enrollment. 
Structured data captured in the EHR may be similar to data elements specified in baseline 
patient characteristics in the eCRF, yet EHR data are collected primarily to support 
clinical care and reimbursement needs.  Their fitness for use as source data for selected 
data elements of the baseline patient characteristics in the eCRF has not been established.  
During routine trial follow-up, study coordinators typically gather information from 
various sources including direct patient contact and medical records of the enrolling 
institution and outside facilities to document events for study participants.  Evidence 
from the West of Scotland Coronary Prevention Study suggests that cardiovascular 
endpoints can be ascertained from routinely recorded EHR-type data, but classification 
was imperfect [Barry, 2013].There is a need to specifically assess the utility of EHR data 
acquisition for follow-up events across multiple health systems.
In summary, the EHR is a rich source of clinical data, but is designed specifically to 
support clinical care delivery and reimbursement needs. The assumption that EHR data 
are fit for use in high-quality clinical research has not been rigorously evaluated.  To 
provide evidence to address this knowledge gap, GlaxoSmithKline (GSK) and Duke 
Clinical Research Institute (DCRI) are committed to conducting an exploratory EHR 
Ancillary Study embedded within a large pragmatic clinical trial at selected study sites. 
The overarching goal is to further our understanding of how EHR data can be organized 
into a query-able format to facilitate a more efficient, reliable, and cost-effective research 
process.  The proposed empirical work is exploratory in nature and both qualitative and 
quantitative.

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11.7.2.
Ancillary Study OBJECTIVES
11.7.2.1.
Primary Objectives
Objective 1: Assess the barriers to using an EHR-generated list of patients to 
facilitate trial enrollment.
Through site study coordinator surveys, workflow assessment, analysis of electronic 
screening logs, comparisons of enrolled patients with patients identified via algorithm, 
this retrospective objective will describe the screening “funnel” and identify factors 
responsible for narrowing the funnel from the pool of potentially eligible patients to those 
enrolled in the clinical trial.  Barriers for using EHR systems for this purpose will be 
assessed at the site level and common cross-site themes will be identified. 
Objective 2:  Evaluate the fitness of EHR data for use in populating the baseline 
characteristics in the eCRF
After study completion and within selected data areas (e.g., demographics, medical 
history, concomitant medications), the level of agreement between data extracted from 
the EHR and data documented on the baseline eCRF (reference standard) will be 
evaluated. Additionally the performance of algorithms developed to identify 
comorbidities and other clinical concepts will be assessed at the site level and aggregated, 
where appropriate.  
Objective 3:  Explore the use of EHR data to find events of interest during trial 
follow-up 
Case-finding algorithms will be developed for select specified endpoints (i.e., myocardial 
infarction, stroke, unstable angina, heart failure as outlined in the main study protocol), 
run during the conduct of the trial, and used to identify potential cases for follow-up by 
the study coordinator. The site study coordinator will record the dispensation of each 
potential case so that reconciliation can occur between eCRF documented events and 
EHR-generated potential events. Safety event reporting will proceed as outlined in the 
main study protocol (Main Protocol Section 6.2). At the conclusion of the study, the yield 
of case-finding algorithms will be evaluated along with the performance of EHR-based 
algorithms with eCRF-reported as well as adjudicated eCRF-reported events (reference 
standard).
11.7.2.2.
Secondary Objective
As a secondary objective, an assessment of the general utility and feasibility of EHR-
based outcome acquisition from the coordinator perspective through surveys and 
standardized workflow assessments will be conducted.  

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11.7.3.
Ancillary Study design
11.7.3.1.
Study Design
The ancillary study will occur in the context of the HARMONY-Outcomes trial, a 
randomised, double blind, parallel-group, placebo-masked, controlled study to evaluate 
the effect of albiglutide on cardiovascular events in patients with Type 2 diabetes. 
Albiglutide will be administered subcutaneously once weekly in a population of patients 
with Type 2 diabetes and a previous history of cardiovascular disease and who do not 
have optimal glycaemic control). The duration of the ancillary study will mirror that of 
the HARMONY-Outcomes trial. The number of sites that will participate in the ancillary 
study depends upon the outcome of the site EHR capabilities assessment described in 
Section 11.7.3.2 (Site Selection) below. Five study sites recruiting 12-15 subjects each 
would enable a descriptive assessment of Objectives 1 and 2, whilst, if feasible, 500-1000 
subjects at EHR-enabled sites would permit greater precision to be achieved in the 
assessment of Objective 3.
11.7.3.2.
Site Selection
Sites from the main trial will be selected to participate.  As part of the overall site 
selection process for the main trial, potential sites complete a feasibility survey to gauge 
their suitability for participation in the HARMONY-Outcomes trial.  In addition to 
questions regarding experience with long-term outcome trials in general and specific 
features of the planned trial, the feasibility survey includes questions about site readiness 
for an EHR-facilitated trial.  Specific topics include:

Existence of an EHR system;

Current use of EHR to screen for potential study participants;

Types of information currently contained in EHR  (inpatient visits, outpatient 
visits, laboratory results, medications) 

Prior participation in a study that used EHR data for patient screening, follow-up, 
and/or data collection; and

Local EHR support to assist with research studies.
Sites who meet minimum qualifications based on this survey (respond affirmatively 
regarding the existence of an EHR system and local EHR support to assist with research 
studies), and who have confirmed an interest in participating in the ancillary study will be 
approached for a more in-depth assessment of capabilities.  Specific topics include:

Current capability to extract EHR-type data from a data warehouse;

Data domains currently included in the data warehouse (e.g., demographics, vital 
signs, diagnoses, procedures, medications prescribed, laboratory tests, and death);

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
Coding terminologies used for each domain of data;

Institutional processes and policies for using EHR-type data for clinical research; 

Institutional experience extracting, transforming, and loading warehouse data into 
a research DataMart that conforms with standardized specifications; and

Familiarity with or participation in distributed research networks.  
Subsequent structured discussions with individual sites may be necessary to explore 
capabilities and suitability for the ancillary study.  For example, engagement of the health 
system’s Information Technology (IT) personnel will be essential but is challenging to 
gauge in a written survey.  Key site selection criteria include:

Fully implemented EHR system 

Access to an enterprise data warehouse or clinical data repository that stores 
structured data from the EHR and is updated at least weekly.

Availability of necessary data

Engagement of health system IT and analytical personnel
The advantage of a multi-stage, rapid assessment of capabilities is that it allows for a 
relatively short feasibility survey that can be completed reliably by a study coordinator. 
Detailed technical questions are reserved for the individuals who provide EHR support 
for research studies.  
11.7.3.3.
Data Flows
The methods for data extraction and capture will require a partnership between study site 
teams (site principal investigator, site study coordinator, and site technical support), 
GSK, and the DCRI Data Management Team.
The study will utilize PopMedNet, a software application that enables the creation, 
operation, and governance of research networks.  It allows partners to maintain physical 
and operational control over their data while allowing authorized users to send queries to 
the data. PopMedNet consists of two layers: a security layer where access controls and 
permissions are established and a layer of virtual pipes through which questions are sent 
from requestor to responder. The PopMedNet software consists of a web-based “network 
portal” and a DataMart Client application that is installed at each site. PopMedNet 
employs a “publish-and-subscribe” architecture that does not require a hole through an 
institutional firewall, but rather allows institutions to pull a query behind the firewall for 
manual or automated execution. 
In research networks with a common data model, PopMedNet is used to distribute 
executable code that institutions can choose to pull behind their firewall, run against the 
data in that appropriate format, and return results to the requestor. Security 
documentation will be provided to all participating sites.   

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The data flow for this ancillary study will be as follows: 
a) The study site’s EHR system will not be changed and will continue to operate as 
implemented.  Data from the thousands of tables in the EHR will be integrated on 
a nightly basis into a data warehouse that supports research needs (the term EHR 
is used to mean the system that collects, displays, and stores transactional health 
care data).
b) With guidance from the DCRI Data Management Team, the study site’s technical 
team will extract, transform, and load data from the enterprise data warehouse (or 
clinical data repository) to a Cohort DataMart according to the specifications of 
the common data model.  A common data model standardizes the definition, 
content and format of data across sites to enable efficient, cross-site querying. The 
Cohort DataMart will be refreshed from the existing Data Warehouse on a 
biweekly basis. The Cohort DataMart includes Protected Health Information 
(PHI) for a broadly defined cohort of potential study participants and will remain 
behind institutional firewalls. 
c) Data from Pre-Screening logs completed as part of the main study will be 
captured in a database stored in the same area as the Cohort DataMart to facilitate 
characterization of the screening funnel.  Data from the pre-screening log will 
enable comparisons of characteristics of potential participants identified via 
algorithm with patients screened and enrolled. 
d) When a participant is randomized into the study, the study coordinator will enter 
key subject identifiers (the main trial identifier (ID), Medical Record Number 
(MRN) equivalent, study randomization date) into the Key Identifier spread sheet.
e) Via PopMedNet, the DCRI Data Management Team will distribute code that 
extracts data for randomized participants from the Cohort DataMart into the Study 
DataMart using the Key Identifier table. Trial ID and randomization date from the 
Key Identifier table will be included in the Study DataMart. Data for randomized 
patients at each site will be returned to the DCRI via the HARMONY-Outcomes 
trial EHR Ancillary Study Query Portal. 
f)
Via PopMedNet, the DCRI will distribute executable code (e.g., SQL program) 
that will query the Study DataMart for potential study endpoints.  [See Section 
11.7.3.4.1b for case-finding algorithm]. 
g) Potential cases (identified via case-finding algorithm) will be returned to the 
Study Coordinator who will record the dispensation of each potential case in the 
Case-finding Dispensation Log stored in the Study DataMart (i.e., recorded in the 
eCRF/not recorded in the eCRF and reasons).
h) The Study DataMart containing randomized patient data will be transferred from 
each site to the DCRI on a regular basis (anticipated quarterly with specific 
frequency to be determined).  
i)
Required data elements from the main clinical trial dataset for EHR Ancillary 
Study sites will be transferred from GSK to the DCRI after the completion of the 
study. The DCRI will merge data elements from the main clinical trial dataset 
with Study DataMart data to create the EHR Ancillary Study Dataset.

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11.7.3.4.
Study Procedures and Processes
11.7.3.4.1. DCRI
a) Establish broad definition of cohort 
A broad cohort identification algorithm will be developed based on selected inclusion 
criteria outlined in the main study protocol. Selected criteria for inclusion into the cohort 
include:

Age > 40 years old

Diagnosis of Type 2 diabetes, broadly defined by diagnosis codes and 
medications prescribed (See 4.4 for information about algorithms to be used.)

Established cardiovascular disease (See Section 11.7.4.4 for information about 
algorithms to be used)
Participating sites will be required to run the “cohort algorithm” within their EHR 
systems to create the Cohort DataMart which will be used as a basis for Objective #1. 
b) Specify contents of the EHR Ancillary Study research DataMart
EHR data are stored in many different ways. A common data model standardizes the 
definition, content and format of data across sites to enable a single standardized view 
that can be used for querying. Sites participating in this ancillary study will be required to 
transform their data into a common data model that will be designed to be intuitive and 
user-friendly. Investigators and analysts with prior experience using research data will 
not need additional skills or knowledge to use the common data model. The DCRI team 
will manage questions and issues that arise regarding transforming data into the CDM.
The EHR Ancillary Study Common Data format will be adapted from the Patient 
Centered Outcomes Research Network (PCORnet) Common Data Model 
(http://pcornet.org/resource-center/pcornet-common-data-model/)and may include the 
following data areas:  

Demographic

Encounter

Diagnosis

Procedure

Medications prescribed

Laboratory results, selected 

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c)
Develop data characterization routines
As previously described, participating sites will transform local data into the study 
common data model. The DCRI Data Management Team will develop and distribute 
code to query the content of tables formatted according to the common data model. The 
distributed code will generate aggregate output tables that help determine whether the 
data conform to specifications, maintain integrity across variables and across tables, and 
trend as expected over time. The data quality review and characterization process will 
help to ensure that the data meets reasonable standards for data transformation 
consistency and quality.  
DCRI’s team will evaluate the creation of the Cohort DataMart using standard programs 
distributed to each study site for execution behind institutional firewalls.  
d)
Develop and distribute test queries 
A series of simple test queries will be developed and distributed to sites for execution 
against a simulated data set, structured according to the common data model. The test 
queries will help each site become familiar with PopMedNet and distributed querying 
without concern about querying against protected health information.
e)
Develop algorithms for analytic variables
Algorithms to map EHR-based data in the Study DataMart to baseline characteristics and 
study endpoints in the EHR Ancillary Study dataset will be defined using diagnosis codes 
(ICD-9-CM and ICD-10-CM) and procedure codes (ICD-9-CM and ICD-10-PCS).  
Published algorithms will be used whenever possible.  Examples of published algorithms 
utilized in the past include: 

CMS chronic condition categories: https://www.ccwdata.org/web/guest/condition-
categories

Quan, H., Sundararajan, V., Halfon, P., Fong, A., Burnand, B., Luthi, J. C., ... & 
Ghali, W. A. (2005). Coding algorithms for defining comorbidities in ICD-9-CM 
and ICD-10 administrative data. Medical Care, 1130-1139. 
http://www.ncbi.nlm.nih.gov/pubmed/16224307

Elixhauser, A., Steiner, C., Harris, D. R., & Coffey, R. M. (1998). Comorbidity 
measures for use with administrative data. Medical Care, 36(1), 8-27. 
http://www.ncbi.nlm.nih.gov/pubmed/9431328
These algorithms will be updated as necessary to account for coding changes since 
publication.  And, if not provided, mapping of diagnosis codes from ICD-9-CM to ICD-
10-CM and mapping of procedure codes from ICD-9-CM to ICD-10-PCS will be done 
using the general equivalence mappings provided by Centers for Medicare & Medicaid 
Services (CMS):

Diagnosis code crosswalk: http://www.cms.gov/Medicare/Coding/ICD10/2014-
ICD-10-CM-and-GEMs.html

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
Procedure code crosswalk: http://www.cms.gov/Medicare/Coding/ICD10/2014-
ICD-10-PCS.html
Algorithms used to identify specific medications dispensed will be defined using 
different drug identification coding systems in use by study sites.  These systems could 
include:

NDC codes [from RxNav, a browser for drug information available from the U.S. 
National Library of Medicine]

DIN codes [from Health Canada drug product database]

ATC codes [from WHO Collaborating Centre for Drug Statistics Methodology]
11.7.3.4.2. Sites
Participating study sites will:

Extract, transform, and load (ETL) data into a physical instance of an adapted 
PCORnet Common Data Model.  Sites will document the mapping from the EHR 
to the Common Data Model.

Install PopMedNet

Refresh the Cohort DataMart on a biweekly basis

Execute data characterization and test queries after each refresh and on an as-
needed basis.  
Site study coordinators will be required to complete pre-screening logs on all potential 
study participants meeting minimum eligibility requirements (age >40, Type 2 diabetes, 
established cardiovascular disease) identified via any mechanism (i.e., reviewing lists of 
scheduled office patients, reviewing lists of recently discharged diabetes patients, EHR-
facilitated algorithm). Pre-screening logs will capture the following information:

Pre-screening number

Pre-screening date

Inclusion criteria not met

Exclusion criteria met

Other criteria
Site study coordinators will complete a screening survey which will describe the site’s 
current process for screening. A description of screening barriers will be included.

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11.7.4.
DATA ANALYSIS
11.7.4.1.
Sample Size Expectations
The objectives of this ancillary study are exploratory (not confirmatory) in nature and not 
intended to be sufficiently powered to confirm a pre-determined level of sensitivity and 
specificity.  The number of sites and subjects that will participate in the ancillary study 
depends upon the outcome of the site EHR capabilities assessment described in Section 
11.7.3.2 (Site Selection). Five study sites recruiting 12-15 subjects each would enable a 
descriptive assessment of Objectives 1 and 2, whilst, if feasible, 500-1000 subjects at 
EHR-enabled sites would permit greater precision to be achieved in the assessment of 
Objective 3.
11.7.4.2.
Objective 1: Assess the Barriers to Using as EHR-Generated List of 
Patients to Facilitate Trial Enrollment
Because any survey administered for this objective will be a site-level survey, analysis of 
the survey data will be performed across all sites. For quantities of interest, frequencies 
with percentages for categorical measures and means with standard deviations for 
continuous measures will be presented.   
11.7.4.3.
General Analytic Approach for Objective 1 and Objective 2
The goals of both Objective 2 and Objective 3 involve evaluating the performance of 
algorithms that map EHR-based data into concepts present in the clinical trial dataset.  
The actual measures recorded in the clinical trial dataset will be considered the reference 
standard against which these algorithm-based measures are compared.
Table 3
Overall performance of EHR-based algorithms for baseline 
characteristics, using clinical trial data as the reference standard / 
Categorical variables
Reference standard
(Clinical trial data)
New measure  
(EHR Ancillary Study data)
Condition present
Condition absent
Condition present
True positive
(TP)
False positive 
(FP)
Condition absent
False negative
(FN)
True negative
(TN)
For categorical variables, estimated performance metrics will be based on the 2x2 cross-tabulation 
of values in the EHR Ancillary Study dataset with values in the clinical trial dataset (Table 3) and 
include:

Overall agreement = (TP + TN) / (TP + FP + FN + TN)

Sensitivity = TP / (TP + FN)

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
Specificity = TN / (FP + TN)

Positive predictive value = TP / (TP + FP)

Negative predictive value = TN / (FN + TN)

Accuracy or efficiency = (TP + TN) / (TP+TN+FP+FN)
For dichotomous measures, each of these proportions is immediately calculable.  For 
measures having more than two levels, multiple dichotomous measures will be created in 
order to calculate these proportions. Confidence intervals (95%) will be reported around 
these quantities. (See Table 4 as an example).
Table 4
Overall performance of EHR-based algorithms for baseline 
characteristics, using clinical trial data as the reference standard / 
Categorical variables
Measure
Overall 
agreement
(95% CI)
Sensitivity
(95% CI)
Specificity
(95% CI)
Positive 
predictive 
value 
(95% CI)
Negative 
predictive 
value 
(95% CI)
Measure 1
xx.x 
(xx.x – xx.x)
xx.x 
(xx.x – xx.x)
xx.x 
(xx.x – xx.x)
xx.x 
(xx.x – xx.x)
xx.x 
(xx.x – xx.x)
Measure 2
xx.x 
(xx.x – xx.x)
xx.x 
(xx.x – xx.x)
xx.x 
(xx.x – xx.x)
xx.x 
(xx.x – xx.x)
xx.x 
(xx.x – xx.x)
.....
.....
.....
.....
.....
.....
Reported on 0–100 scale
For continuous measures, bias will be calculated as the difference between values in the 
EHR Ancillary Study dataset and values in the clinical trial dataset.  The mean and 
standard deviation of the bias along with a 95% confidence interval will be reported.  In 
Bland-Altman analyses of agreement between continuous measures, the standard 
deviation of the bias is referred to as the precision, while the 95% confidence interval is 
referred to as the limit of agreement. (See Table 5 as an example).
Table 5
Overall performance of EHR-based algorithms for baseline 
characteristics, using clinical trial data as the reference standard / 
Continuous variables
Bias
Measure
Mean (SD)
95% (CI)
Measure 1
xx.x
xx.x
Measure 2
xx.x
xx.x
.....
.....
.....
Due to the nature of EHR data, it is expected that there will be systematic differences 
between sites with respect to coding of clinical concepts.  All performance metrics will 

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therefore initially be calculated by site. These site-specific results may be best reported 
graphically.
There is also interest in an assessment of algorithm performance across all sites.  
Hierarchical models will be used to combine data from all sites and estimate performance 
at the “average” site.  To estimate proportions (e.g. for overall agreement, sensitivity, 
specificity, etc. associated with categorical measures), models will be specified as:
logit (E (y) )=β0+γ0,,j
γ0,j~N(0,s2)
where sites are indexed by j.  The value of the proportion at the average site—when 
γ0=0—is  [1+exp (–β0 ) ]-1.  Patients included in the estimation of each model vary by 
performance metric and reflect the definitions above.  As an example, consider positive 
predictive value.  To estimate the positive predictive value of an algorithm, only subjects 
with true positive value and false positive values will be included.  True positives will be 
assigned Y=1 and false positive will be assigned Y=0. 
To estimate means (e.g. for bias associated with continuous variables), the model will be 
specified as:
E (y )=β0+ γ0,,j
γ0,,j ~ N(0,s2)
The value of the mean at the average site is β0.  
For all models, we will assess site heterogeneity by testing if s2=0.
11.7.4.4.
Objective 2: Evaluate the Fitness of EHR Data for Use in Populating the 
Baseline Characteristics in the eCRF
Algorithms will be defined to map EHR-based data in the Study Data Mart to specific 
concepts in the EHR Ancillary Study dataset that parallel concepts in the clinical trial 
dataset.  For Objective 2, the performance of algorithms used to identify baseline 
characteristics will be evaluated.  The baseline characteristic measures recorded in the 
clinical trial dataset will be considered the reference standard against which these 
algorithm-based measures are compared. 
11.7.4.5.
Objective 3: Explore the Use of EHR Data to Find Events of Interest 
During Trial Follow-up
Algorithms will be defined to map EHR-based data in the Study Data Mart to specific 
concepts in the EHR Ancillary Study dataset that parallel concepts in the clinical trial 
dataset.  For Objective 3, the performance of algorithms used to identify trial events will 
be evaluated.  These algorithms will be evaluated against both the adjudicated events 
recorded in the clinical trial dataset and the identified potential events in the eCRF.  For 
each event, estimates of sensitivity and positive predictive value (described in Section 
11.7.4.3) will be calculated and presented with 95% confidence intervals.  

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References
Barry SJ, Dinnett E, Kean S, Gaw A, Ford I. Are routinely collected NHS administrative 
records suitable for endpoint identification in clinical trials? Evidence from the West of 
Scotland Coronary Prevention Study. PloS one. 2013; 8(9):e75379.
Curtis LH, Brown J, Platt R. Four Health Data Networks Illustrate The Potential For A 
Shared National Multipurpose Big-Data Network. Health Affairs. July 1, 2014; 
33(7):1178-1186.
Dregan A, van Staa TP, McDermott L, et al. Point-of-Care Cluster Randomized Trial in 
Stroke Secondary Prevention Using Electronic Health Records. Stroke. July 1, 2014; 
45(7):2066-2071.
Etheredge LM. A rapid-learning health system. Health affairs. Mar-Apr 2007; 
26(2):w107-118.
Fleurence RL, Beal AC, Sheridan SE, Johnson LB, Selby JV. Patient-Powered Research 
Networks Aim To Improve Patient Care And Health Research. Health Affairs. July 1, 
2014; 33(7):1212-1219.
Greene SM, Reid RJ, Larson EB. Implementing the learning health system: from concept 
to action. Annals of internal medicine. Aug 7 2012;157(3):207-210.
Gulliford MC, van Staa T, Dregan A, et al. Electronic Health Records for Intervention 
Research: A Cluster Randomized Trial to Reduce Antibiotic Prescribing in Primary Care 
(eCRT Study). The Annals of Family Medicine. July 1, 2014; 12(4):344-351.
NHLBI Working Group on Electronic Health Records: Research Priorities to Improve 
Cardiopulmonary Health in Clinical Practice. 2011. 
http://www.nhlbi.nih.gov/meetings/workshops/ehr.htm. Accessed Jan 28, 2013.
Richesson RL, Hammond WE, Nahm M, et al. Electronic health records based 
phenotyping in next-generation clinical trials: a perspective from the NIH Health Care 
Systems Collaboratory. Journal of the American Medical Informatics Association: 
JAMIA. Dec 2013; 20(e2):e226-231.
Toh S, Reichman ME, Houstoun M, et al. COmparative risk for angioedema associated 
with the use of drugs that target the renin-angiotensin-aldosterone system. Archives of 
Internal Medicine. 2012; 172(20):1582-1589.
van Staa T, Dyson L, McCann G, et al. The opportunities and challenges of pragmatic 
point-of-care randomised trials using routinely collected electronic records: evaluations 
of two exemplar trials. Health Technol Assess. 2014/07/11 2014; 18(43).

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11.8.
Appendix 8: Country Specific Requirements

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11.9.
Appendix 9: Protocol Amendment Changes
11.9.1.
Changes Resulting from Protocol Amendment 1
This amendment is applicable to all participating countries.
Summary of Changes
1. Correction of typographical error in Exclusion criterion 7.
2. Clarification wording added to the description of when subjects should have 
telephone follow-up after discontinuing investigational product (IP).  Subjects 
should have the telephone follow-up 5 1 weeks after their last dose of IP
whether they had continued IP through to the Final study visit, or discontinued 
before the Final study visit.
3. Time and Event Table modified to add adverse event checking (SAE, AEs of 
special interest, AEs leading to IP discontinuation) to dose adjustment visits, and 
to correct footnote assignment/typographical errors.
4. Revision of terminology used to describe unstable angina events referred for CEC 
adjudication to correctly reflect review process to be adopted by CEC.
5. Addition of Country Specific Requirements appendix (Appendix 8).
List of Specific Changes
Section 4.2, Exclusion criteria; criterion 7, fourth sentence.
Original text:
Women who have developed spontaneous secondary amenorrhoea of 12 months or more 
where post-menopausal status is in doubt, a blood sample where FSH >40MU/ml and 
oestrodiol <40 pg/mL (<14 pmol/L) are simultaneously measured will be considered 
confirmatory.
Amended text:
Women who have developed spontaneous secondary amenorrhoea of 12 months or more 
where post-menopausal status is in doubt, a blood sample where FSH >40MU/ml and 
oestrodiol <40 pg/mL (<140 pmol/L) are simultaneously measured will be considered 
confirmatory.

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Section 4.5 Procedures for Subject Follow-up
Original text:
As described in Section 4.4, subjects who permanently discontinue investigational 
product will be asked to attend the clinic as soon as possible.  They will continue in the 
study for follow-up. They will be asked to return to clinic according to the 8 monthly 
visit schedule and in addition be contacted by telephone at a time corresponding to the 4-
monthly visit they would have otherwise made to replenish study medication supply.  If 
instead of these interim telephone contacts the subject prefers to attend clinic every 4 
months as originally scheduled that is an acceptable alternative.
Amended text:
As described in Section 4.4, subjects who permanently discontinue investigational 
product will be asked to attend the clinic as soon as possible.  They will continue in the 
study for follow-up. Five weeks (1 week) after discontinuation of investigational 
product, subjects will be contacted for a follow-up by telephone.  They will be asked to 
return to clinic according to the 8 monthly visit schedule and in addition be contacted by 
telephone at a time corresponding to the 4-monthly visit they would have otherwise made 
to replenish study medication supply.  If instead of these interim telephone contacts the 
subject prefers to attend clinic every 4 months as originally scheduled that is an 
acceptable alternative.

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Table 1 Time and Events Table
Original text:
Procedures1,2
Screening2
Randomization3
/Baseline 
(can be same day 
as Screening 
Visit)
Study Drug 
Check Phone 
Call
(4-6 wks post 
and.)
Clinic Visit Month 4 
18 days then 
every 8 months 
18 days throughout 
the study
Unscheduled 
dose 
adjustment 
visit
(if warranted)
Clinic Visit Month 8 
18 days then 
every 8 months 
18 days throughout 
the study
Final study 
clinic 
visit4 (or 
early 
withdrawal)
Post-Study Follow up 
Phone Call
5 1 weeks after last 
IP dose
SAEs, AEs of special interest, AEs 
leading to IP discontinuation 
X
X
X
X
X
X
1.    Subjects who discontinue investigational product should be handled as described in Section 4.4.
11.  Study drug dispensing not performed at final visit, compliance check not performed at Screening.
Amended text:
Procedures1,2
Screening3
Randomization3
/Baseline 
(can be same day 
as Screening 
Visit)
Study Drug 
Check Phone 
Call
(4-6 wks post 
rand.)
Clinic Visit Month 4 
18 days then 
every 8 months 
18 days throughout 
the study
Unscheduled 
dose 
adjustment 
visit
(if warranted)
Clinic Visit Month 8 
18 days then 
every 8 months 
18 days throughout 
the study
Final study 
clinic 
visit4 (or 
early 
withdrawal)
Post-Study Follow up 
Phone Call
5 1 weeks after last 
IP dose
SAEs, AEs of special interest, AEs 
leading to IP discontinuation 
X
X
X
X
X
X
X
1.    Subjects who discontinue investigational product should be handled as described in Section 4.4 and Section 4.5.
11.  Study drug dispensing not performed at final visit, compliance check not performed at Randomisation.

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Section 6.2.1 Cardiovascular Events
Original text:
The CEC will review and adjudicate the following clinical events:

Myocardial infarction

Stroke

Unstable angina requiring revascularization

Hospitalization for heart failure

Sudden cardiac death

TIA

In addition, all clinical events submitted for adjudication and all other SAEs with a 
fatal outcome will be reviewed and adjudicated to classify the cause of death as 
cardiovascular or non-cardiovascular.
Amended text:
The CEC will review and adjudicate the following clinical events:

Myocardial infarction

Stroke

Unstable angina requiring hospitalization

Hospitalization for heart failure

Sudden cardiac death

TIA

In addition, all clinical events submitted for adjudication and all other SAEs with a 
fatal outcome will be reviewed and adjudicated to classify the cause of death as 
cardiovascular or non-cardiovascular.
Appendix 8 – Country Specific Requirements
Appendix 8 added (not in original text). This is a blank page headed “11.8.Appendix 8: 
Country Specific Requirements” to serve as a placeholder to be replaced by each 
participating GSK Country Medical Department with the appropriate text upon receipt of 
the protocol and before they distribute it further within their country.

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TITLE PAGE
Division:  Worldwide Development
Information Type: Clinical Protocol
Title:
A long term, randomised, double blind, placebo-controlled study 
to determine the effect of albiglutide, when added to standard 
blood glucose lowering therapies, on major cardiovascular 
events in patients with Type 2 diabetes mellitus 
Harmony Outcomes Trial
Compound Number:
GSK716155
Development Phase
IV
Effective Date:
25-SEP-2014
Subject: Type 2 diabetes, albiglutide, cardiovascular outcomes, cardiovascular risk, 
safety.
Author(s): The protocol was developed by the members of the Executive Committee in 
conjunction with Duke Clinical Research Institute and the Sponsor.
The following individuals provided substantial input during protocol development:
Non-sponsor:
(Executive Committee Co-Chair); 
(Executive Committee Co-
Chair);
Sponsor:
Copyright 2014 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD
PPD
PPD
PPD
PPD

PPD

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SPONSOR INFORMATION PAGE
Clinical Study Identifier: GLP116174
Sponsor Legal Registered Address:
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford, Middlesex, TW8 9GS, UK
Sponsor Contact Address
GlaxoSmithKline Research & Development Limited
Iron Bridge Road
Stockley Park West, Uxbridge, Middlesex, UB11 1BU, UK
Telephone: 
GlaxoSmithKline Research & Development Limited
2301 Renaissance Boulevard
Building #510
Post Office Box 61540
King of Prussia, Pennsylvania 19406, USA
Telephone number:
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline affiliate 
company (or designee). Where applicable, the details of the Sponsor and contact person 
will be provided to the relevant regulatory authority as part of the clinical trial 
submission.
Sponsor Medical Monitor Contact Information: 
Dr 
2301 Renaissance Boulevard
REN0410
King of Prussia, Pennsylvania 19406, USA
Email:
Fax:
Telephone number: Office: 
                               Cell: 
 
                               Out of hours: 
Sponsor Serious Adverse Events (SAE) Contact Information:
Dr 
As above for Medical Monitor Contact
Regulatory Agency Identifying Number(s):
Investigational New Drug (IND) Number: IND65177
European Drug Regulatory Authorities Clinical Trials (EudraCT) No. 2014-001824-32.
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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INVESTIGATOR PROTOCOL AGREEMENT PAGE
I confirm agreement to conduct the study in compliance with the protocol.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described clinical 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 Signature
Date

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TABLE OF CONTENTS
PAGE
LIST OF ABBREVIATIONS.............................................................................................8
PROTOCOL SUMMARY...............................................................................................10
1.
INTRODUCTION....................................................................................................12
1.1.
Background ................................................................................................12
1.2.
Rationale ....................................................................................................13
2.
OBJECTIVES AND ENDPOINTS...........................................................................14
3.
STUDY DESIGN ....................................................................................................15
3.1.
Overall Design ............................................................................................15
3.2.
Standard of Care ........................................................................................16
3.3.
Discussion of Design ..................................................................................17
3.4.
Benefit:Risk Assessment ............................................................................18
3.4.1.
Risk Assessment .........................................................................18
3.4.1.1.
Identified Risks...........................................................18
3.4.1.2.
Potential Risks............................................................19
3.4.2.
Benefit Assessment.....................................................................21
3.4.3.
Overall Benefit:Risk Conclusion...................................................22
4.
SUBJECT SELECTION AND WITHDRAWAL CRITERIA.......................................22
4.1.
Inclusion Criteria.........................................................................................22
4.2.
Exclusion Criteria........................................................................................23
4.3.
Screening/BaselineFailures ........................................................................24
4.4.
Criteria for Early Discontinuation of Investigational Product ........................25
4.4.1.
Early Discontinuation of Investigational Product...........................25
4.4.2.
Reasons for Discontinuation of Investigational Product................25
4.4.3.
Liver Chemistry Stopping Criteria ................................................26
4.4.4.
eGFR Stopping Criteria................................................................27
4.5.
Procedures for Subject Follow-up ...............................................................28
4.5.1.
Withdrawal of Consent for Contact...............................................28
4.5.2.
Subjects Deemed Lost to Follow-up.............................................29
5.
STUDY TREATMENTS..........................................................................................29
5.1.
Investigational Product and Other Study Treatment....................................29
5.2.
Treatment Assignment................................................................................30
5.3.
Blinding.......................................................................................................31
5.4.
Product Accountability ................................................................................31
5.5.
Treatment Compliance................................................................................31
5.6.
Concomitant Medications and Non-Drug Therapies....................................32
5.6.1.
Permitted Medications and Non-Drug Therapies..........................32
5.6.2.
Prohibited Medications and Non-Drug Therapies.........................32
5.7.
Treatment after the End of the Study ..........................................................33
5.8.
Treatment of Study Treatment Overdose....................................................33
6.
STUDY ASSESSMENTS AND PROCEDURES .....................................................33
6.1.
Critical Baseline Assessments....................................................................35
6.2.
Safety .........................................................................................................35
6.2.1.
Cardiovascular Events.................................................................35

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6.2.1.1.
Other CV Events ........................................................36
6.2.2.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........36
6.2.2.1.
Time period and Frequency for collecting AE 
and SAE information...................................................37
6.2.2.2.
Method of Detecting AEs and SAEs ...........................37
6.2.2.3.
Follow-up of AEs and SAEs........................................38
6.2.2.4.
Sentinel Events ..........................................................38
6.2.2.5.
Regulatory Reporting Requirements for SAEs............38
6.2.3.
Adverse Events of Special Interest ..............................................39
6.2.4.
Clinically Important Microvascular Events....................................40
6.2.5.
Pregnancy ...................................................................................40
6.2.6.
Clinical Laboratory Assessments .................................................41
6.2.6.1.
Estimated Glomerular Filtration Rate (eGFR) .............42
6.2.7.
Physical examination ...................................................................42
6.3.
Value Evidence and Outcomes...................................................................42
6.3.1.
Value Evidence and Outcomes Assessments..............................42
6.3.1.1.
Treatment Related Impact Measure – Diabetes 
(TRIM-D) ....................................................................42
6.3.1.2.
EQ-5D ........................................................................43
6.3.1.3.
Exploratory Diabetes Management Questions............43
6.3.1.4.
Healthcare Resource Utilisation..................................44
6.4.
Genetic Research.......................................................................................44
7.
DATA MANAGEMENT ...........................................................................................44
8.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS...................................45
8.1.
Hypotheses.................................................................................................45
8.2.
Study Design Considerations......................................................................45
8.2.1.
Sample Size Assumptions ...........................................................45
8.2.2.
Sample Size Sensitivity for MACE non-inferiority.........................45
8.2.3.
Sample Size Re-estimation..........................................................46
8.3.
Data Analysis Considerations .....................................................................46
8.3.1.
Analysis Populations....................................................................46
8.3.2.
Analysis Data Set ........................................................................47
8.3.3.
Treatment Comparisons ..............................................................47
8.3.3.1.
Primary Comparisons of Interest ................................47
8.3.3.2.
Other Comparisons of Interest....................................47
8.3.4.
Interim Analysis ...........................................................................47
8.3.5.
Multiplicity Controls......................................................................48
8.3.6.
Key Elements of Analysis Plan ....................................................50
8.3.6.1.
Primary Analysis.........................................................50
8.3.6.2.
Secondary Endpoint Analysis .....................................51
8.3.6.3.
Subgroup Analysis......................................................52
8.3.6.4.
Other Safety Analyses................................................52
8.3.6.5.
Value Evidence and Outcomes Analyses ...................53
9.
STUDY CONDUCT CONSIDERATIONS ...............................................................53
9.1.
Posting of Information on Publicly Available Clinical Trial Registers............53
9.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................54
9.3.
Quality Control (Study Monitoring) ..............................................................54
9.4.
Quality Assurance.......................................................................................55

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9.5.
Study and Site Closure ...............................................................................55
9.6.
Records Retention......................................................................................56
9.7.
Provision of Study Results to Investigators, Posting of Information 
on Publicly Available Clinical Trials Registers and Publication....................56
9.8.
Independent Data Monitoring Committee (IDMC) .......................................57
9.9.
Pancreatitis Adjudication Committee...........................................................57
10. REFERENCES.......................................................................................................58
11. APPENDICES........................................................................................................61
11.1.
Appendix 1: Genetic Research ...................................................................61
11.2.
Appendix 2: GSK Modified List of Highly Effective Methods for 
Avoiding Pregnancy in Females of Reproductive Potential (FRP)...............67
11.3.
Appendix 3: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................68
11.4.
Appendix 4: Liver Safety Drug Restart Guidelines ......................................72
11.5.
Appendix 5: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................74
11.5.1.
Definition of Adverse Events........................................................74
11.5.2.
Definition of Serious Adverse Events...........................................75
11.5.3.
Recording of AEs and SAEs ........................................................76
11.5.4.
Evaluating AEs and SAEs............................................................77
11.5.5.
Reporting of SAEs to GSK...........................................................78
11.6.
Appendix 6: Collection of Pregnancy Information........................................80
11.7.
Appendix 7: Electronic Health Record Ancillary Study ................................81
11.7.1.
Introduction..................................................................................81
11.7.1.1.
Background ................................................................81
11.7.1.2.
Literature Review .......................................................81
11.7.1.3.
Ancillary Study Rationale............................................82
11.7.2.
Ancillary Study OBJECTIVES......................................................83
11.7.2.1.
Primary Objectives .....................................................83
11.7.2.2.
Secondary Objective ..................................................83
11.7.3.
Ancillary Study design..................................................................83
11.7.3.1.
Study Design..............................................................83
11.7.3.2.
Site Selection .............................................................84
11.7.3.3.
Data Flows .................................................................85
11.7.3.4.
Study Procedures and Processes...............................87
11.7.3.4.1.
DCRI ......................................................87
11.7.3.4.2.
Sites .......................................................89
11.7.4.
DATA ANALYSIS.........................................................................90
11.7.4.1.
Sample Size Expectations..........................................90
11.7.4.2.
Objective 1: Assess the Barriers to Using as 
EHR-Generated List of Patients to Facilitate 
Trial Enrollment ..........................................................90
11.7.4.3.
General Analytic Approach for Objective 1 and 
Objective 2 .................................................................90
11.7.4.4.
Objective 2: Evaluate the Fitness of EHR Data 
for Use in Populating the Baseline 
Characteristics in the eCRF........................................92
11.7.4.5.
Objective 3: Explore the Use of EHR Data to 
Find Events of Interest During Trial Follow-up ............92

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LIST OF ABBREVIATIONS
ACCF
American College of Cardiology Foundation
ADA
American Diabetes Association
AE
adverse event
AHA
American Heart Association
ALT (SGPT)
alanine aminotransferase (serum glutamic pyruvic 
transaminase)
ANCOVA
analysis of covariance
AST (SGOT)
aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase)
BI
baseline basal insulin population
BMI
body mass index
bpm
beats per minute
CABG
coronary artery bypass graft
CAD
coronary artery disease
CEC
Cardiovascular Endpoint Committee
CI
confidence interval
CPK
creatine phosphokinase 
CONSORT
Consolidated Standards of Reporting Trials
DCRI
Duke Clinical Research Institute
DNA
deoxyribonucleic acid
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
EHR
electronic health record
ESC
European Society of Cardiology
FDA
US Food and Drug Administration
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
HbA1c
glycated haemoglobin
hCG
human chorionic gonadotrophin
HLA
human leukocyte antigen 
HRT
hormone replacement therapy
IB
Investigator’s Brochure
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
INR
international normal range
IRB
Institutional Review Board
ITT
intent-to-treat
IVRS
Interactive Voice Response System
KM
Kaplan-Meier

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LDH
lactate dehydrogenase
LFT
liver function test
MACE
major adverse cardiovascular event
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MEN-2
multiple endocrine neoplasia type 2
MSDS
Material Safety Data Sheet
MTC
medullary thyroid cancer
NHLBI
National Heart, Lung and Blood Institute
NI
non-insulin population
PAD
peripheral arterial disease
PD
pharmacodynamics
PHI
Protected Health Information
PK
pharmacokinetics
PP
per protocol
RAP
Reporting Analysis Plan
RR
relative risk
s.c.
subcutaneous
SAE
serious adverse event
SRM
Study Reference Manual
SU
sulfonylureas
TIA
transient ischemic attack
TRIM-D
Treatment Related Impact Measures-D
ULN
upper limit of normal range
WHF
World Heart Federation
WHO
World Health Organization
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
EQ-5D
PopMedNet
SAS

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PROTOCOL SUMMARY
Rationale
Albiglutide is a novel analogue of glucagon-like peptide-1 (GLP-1) with a sufficiently 
long half-life to permit once a week injection. Albiglutide is licensed for the treatment of 
type 2 diabetes as an adjunct to diet and exercise, as monotherapy, or in combination with 
existing therapies, including basal insulin. The Food and Drug Administration (FDA) has 
issued guidance on evaluating cardiovascular risk in new anti-diabetic therapies to treat 
type 2 diabetes [FDA Guidance for Industry, 2008].  For a premarketing application that 
contains a meta-analysis of major adverse cardiovascular events (MACE) for which the 
upper bound of the 95 percent confidence interval for the relative risk is between 1.3 and 
1.8, a post-marketing trial generally will be necessary to definitively show that the upper 
bound of the two-sided 95 percent confidence interval for the estimated risk ratio is less 
than 1.3.  The MACE meta-analysis of the albiglutide Phase III program (primary 
endpoint cardiovascular death, myocardial infarction, stroke and hospitalization for 
unstable angina), whilst ruling out an upper bound of the confidence interval for 
cardiovascular events of 1.8, was not able to rule out (due to a relatively small number of 
events) a relative risk (RR) upper bound of 1.3. For this reason GlaxoSmithKline (GSK)
will conduct this cardiovascular outcome study as a US post-marketing requirement, to 
evaluate the effect of albiglutide on cardiovascular events in subjects with type 2 
diabetes.
Objectives/Endpoints
Objectives
Endpoints
Primary
To determine whether albiglutide 
is non-inferior with respect to 
MACE when added to glycaemic 
standard of care versus standard 
of care alone

Time to first occurrence of MACE (cardiovascular death, 
myocardial infarction,  or stroke) [Non-inferiority]
Secondary
To supplement the primary objective 
by further characterization of the 
effects of albiglutide on 
cardiovascular outcomes 

Time to first occurrence of MACE [Superiority](1 see footnote)

Time to first occurrence of the following:

MACE or urgent revascularisation for unstable angina

The individual components of the primary endpoint

Cardiovascular death or hospitalization due to heart failure
To evaluate the effects of albiglutide 
on metabolic management of type 2 
diabetes

Time to initiation of insulin of more than 3 months duration for
those subjects not treated with insulin at study start. (1 see 
footnote)

Time to initiation of prandial insulin in those subjects on basal 
insulin at study start

The proportion of subjects achieving glycaemic control 
(HbA1c ≤ 7.0% at final assessment) with no severe 
hypoglycaemic incidents and weight gain <5% of body weight.
(1 see footnote)

The time to first occurrence of a clinically important microvascular 
event (see Section 6.2.4)

Change in glycated haemoglobin (HbA1c)

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Objectives
Endpoints

Change in body weight

Patient reported outcomes from Treatment Related Impact 
Measures-D (TRIM-D)/EQ5D
To evaluate the safety of albiglutide

All cause mortality

Non-fatal serious adverse events (SAEs)

Adverse events (AEs) leading to discontinuation of investigational 
product 

AE of special interest (see Section 6.2.3)

Change in estimated glomerular filtration rate (eGFR) calculated 
using Modification of Diet in Renal Disease (MDRD) formula

Change in blood pressure and heart rate
1.
If the primary endpoint meets the criteria for non-inferiority, a multiple comparisons adjustment strategy will be 
performed for these 3 secondary endpoints as specified in the Section 8.3.5.
Overall Design
This is a randomised, double blind, parallel group, placebo-controlled study.
Treatment Arms and Duration
All subjects will receive standard of care for their diabetes and cardiovascular health
which can be adjusted by the healthcare professional responsible for the subject during 
the study according to clinical need and with close adherence to professional society 
treatment guidelines. The study comparison is thus between albiglutide added to 
standard of care and standard of care alone.  Placebo injections will be used to ensure 
study assessments are performed without knowledge of treatment assignment.  Treatment 
with albiglutide or placebo will be randomly allocated in a 1:1 ratio.  The starting dose of 
albiglutide is 30 mg weekly which may be up-titrated to 50mg weekly if further 
improvement of glycaemic control is required. 
The study will be event driven, i.e. follow up will continue until it is projected that 
approximately 611 adjudicated MACE events will have occurred. Consequently, the 
maximum duration of the study for an individual participant is dependent both on the 
time taken for recruitment and the MACE event rate, and is estimated to be between 3 
and 5 years. 
An Independent Data Monitoring Committee (IDMC) will have study oversight to ensure 
participant safety and scientific integrity of the data.
Type and Number of Subjects
A total of 9400 subjects with type 2 diabetes and a previous history of cardiovascular 
disease and who do not have optimal glycaemic control will be studied. 
Analysis
The study’s primary question is whether albiglutide is non-inferior by a margin of 1.3 
with respect to its effect on adjudicated MACE, when added to glycaemic standard of 
care, versus standard of care alone. The primary analysis is an Intent-to-Treat (ITT) 
analysis of the time to the first occurrence of MACE using Cox’s Proportional Hazard 
regression.  

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1.
INTRODUCTION
1.1.
Background
Diabetes affects an estimated 347 million people worldwide, with type 2 diabetes 
accounting for more than 90% of cases [WHO, 2013]. The primary manifestation of this
disease is chronic hyperglycaemia, resulting from resistance to insulin action at a cellular 
and molecular level and a relative inadequacy in the secretion of endogenous insulin 
[American Diabetes Association, 2014]. Chronic hyperglycaemia has been firmly 
established as a key factor in the development of microvascular complications 
(retinopathy, nephropathy, and neuropathy).  Individuals with type 2 diabetes are also at 
greatly elevated risk of cardiovascular disease.
The management of glycaemia in individuals with type 2 diabetes consists of diet, 
exercise, and weight reduction together with oral anti-diabetic drug, injectable agents 
such as GLP-1 receptor agonists or insulin therapy, to achieve near normoglycaemia as 
reflected by a target HbA1c level of 7%, where possible, without significant 
hypoglycaemia or other adverse effects of treatment. Despite the large number of 
available therapeutic agents, a high proportion of subjects fail to achieve or maintain 
target HbA1c levels [Khunti, 2013] owing to the inexorable decline in endogenous 
insulin production characteristic of the disease, and limitations in existing treatments. 
New agents with complementary mechanisms (permitting combination use) or more 
favourable safety profiles are needed to help more subjects achieve glycaemic targets. 
GLP-1 is secreted by intestinal L-cells in response to ingestion of food. In a healthy 
individual, it plays an important role regulating postprandial blood glucose by stimulating 
glucose-dependent insulin secretion by the pancreas. GLP-1 suppresses glucagon 
secretion, leading to reduced hepatic glucose output. It also delays gastric emptying time 
and slows small bowel motility, delaying food absorption and slowing the rate of glucose 
appearance in the blood. In patients with type 2 diabetes the postprandial rise in 
endogenous GLP-1 is absent or reduced [Vilsbøll, 2001]. 
GLP-1 receptor agonists have been developed as anti-hyperglycemic therapy for type 2 
diabetes to replace or supplement endogenous GLP-1 in order to increase meal-related 
insulin secretion, reduce inappropriate glucagon secretion, and slow GI motility. They 
have demonstrated substantial effectiveness in improving glycaemic control while 
mitigating the risk of hypoglycaemia and weight gain commonly associated with some of 
the other treatments for type 2 diabetes [Stonehouse, 2012].  
Albiglutide is a novel analogue of GLP-1 generated through a genetic fusion of 2 
modified recombinant human GLP-1 molecules linked in tandem to recombinant human 
albumin. Albiglutide is licensed for the treatment of type 2 diabetes as an adjunct to diet 
and exercise, as monotherapy, or in combination with existing therapies (oral anti-
diabetic therapies or basal insulin).  It has been granted marketing authorisation by the
European Medicines Agency (EMA) (March 2014) and the FDA (April 2014).  Details of 
the clinical trial results can be found in the Investigator Brochure (IB).

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1.2.
Rationale
The FDA has issued guidance on evaluating cardiovascular risk in new anti-diabetic 
therapies to treat type 2 diabetes [FDA Guidance for Industry, 2008]. For a premarketing 
application that contains a meta-analysis of MACE, for which the upper bound of the 95 
percent confidence interval for the relative risk is between 1.3 and 1.8, a post-marketing 
trial may be necessary to definitively show that the upper bound of the two-sided 95 
percent confidence interval for the estimated risk ratio is less than 1.3.
The MACE + meta-analysis of the albiglutide Phase III program (primary endpoint 
cardiovascular death, myocardial infarction, stroke and hospitalization for unstable 
angina), whilst ruling out an upper bound of the confidence interval for cardiovascular 
events of 1.8, was not able to rule out (due to a relatively small number of events) a RR 
upper bound of 1.3. For this reason GSK will conduct this cardiovascular outcome study
as a US post-marketing requirement, to evaluate the effect of albiglutide on 
cardiovascular events in subjects with type 2 diabetes. 
Preclinical studies have provided evidence that GLP-1 receptor stimulation favourably 
effects endothelial function, recovery from ischemic injury, and myocardial function in 
animals [reviewed in Okerson, 2012]. Albiglutide reduced infarct size assessed 24 hours 
after 30 minutes temporary left anterior descending coronary artery occlusion in 
normoglycaemic rats [Bao, 2011]. GLP-1 infusion has been shown to improve 
endothelial function in subjects with stable coronary disease [Nystrom, 2004]. In subjects 
with ST-segment elevation myocardial infarction treated with primary percutaneous 
coronary intervention, the GLP-1 receptor agonist, exenatide, administered at the time of 
reperfusion has been reported to increase myocardial salvage [Lønborg, 2012].  In the 
Phase III studies, small mean increases in heart rate (1 to 2 bpm) and a higher incidence 
of atrial fibrillation/flutter events were observed with albiglutide.  It is difficult to predict 
whether these preclinical and clinical findings will translate into effect on major 
cardiovascular events.

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2.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
To determine whether 
albiglutide is non-inferior with 
respect to MACE when added 
to glycaemic standard of care 
versus standard of care alone

Time to first occurrence of MACE (cardiovascular death, 
myocardial infarction, or stroke) [Non-inferiority]
Secondary
To supplement the primary 
objective by further 
characterization of the effects of 
albiglutide on cardiovascular 
outcomes 

Time to first occurrence of MACE [Superiority](1 see footnote)

Time to first occurrence of the following:

MACE or urgent revascularisation for unstable angina

The individual components of the primary endpoint

Cardiovascular death or hospitalization due to heart failure
To evaluate the effects of
albiglutide on metabolic 
management of type 2 diabetes

Time to initiation of insulin of more than 3 months duration for 
those subjects not treated with insulin at study start (1 see footnote)

Time to initiation of prandial insulin in those subjects on basal insulin at 
study start

The proportion of subjects achieving glycaemic control (HbA1c ≤ 
7.0% at final assessment) with no severe hypoglycaemic incidents 
and weight gain <5% of body weight (1 see footnote)

The time to first occurrence of a clinically important microvascular 
event (see Section 6.2.4)

Change in HbA1c

Change in body weight

Patient reported outcomes from TRIM-D/EQ5D
To evaluate the safety of 
albiglutide

All cause mortality

Non-fatal SAEs

AEs leading to discontinuation of investigational product 

AE of special interest (see Section 6.2.3)

Change in eGFR calculated using MDRD formula

Change in blood pressure and heart rate
Exploratory
To evaluate patient reported 
experience of diabetes treatment

Patient reported outcomes from study specific questionnaire
To evaluate (at a subset of sites) 
barriers to using the electronic 
health record (EHR) to facilitate 
trial enrolment and the quality of 
EHR data for use in populating 
baseline characteristics and 
identifying events of interest 
during trial follow-up.2

Workflow impact of an EHR-generated list of subjects to facilitate trial 
enrolment. 

Concordance, sensitivity, specificity, and accuracy of baseline 
characteristics extracted from the EHR compared with those reported 
on the electronic case report form (eCRF)3

Concordance, sensitivity, specificity, and accuracy of EHR-identified 
events compared with study events 3,4

1.
If the primary endpoint meets the criteria for non-inferiority, a multiple comparisons adjustment strategy will be 
performed for these 3 secondary endpoints as specified in the Section 8.3.5.
2.
Details are provided in a separate EHR ancillary study protocol (Appendix 7).  Results from this exploratory 
investigation will be reported separately from the main clinical study report.
3.
Comparison of EHR identified events with study events will be conducted in the same data subset.
4.
Analyses t o be undertaken after the main trial results are published.

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3.
STUDY DESIGN
3.1.
Overall Design
This is a Phase IV, randomised, double blind, parallel-group, placebo-controlled,
multicentre study. This study will recruit approximately 9400 subjects with type 2 
diabetes and a previous history of cardiovascular disease who are failing to achieve 
optimal glycaemic control on their current anti-hyperglycaemic regimen. Subjects will be 
randomised in a 1:1 ratio to albiglutide or albiglutide matching placebo administered 
once weekly by subcutaneous (s.c.) injection.
All subjects will receive standard of care which can be adjusted by their usual care 
provider(s) during the study according to clinical need (See Section 3.2). The study 
comparison is between albiglutide added to standard of care and standard of care alone.  
The starting dose of albiglutide will be 30 mg once weekly. If at any stage after 5 weeks 
of treatment the subject needs to have intensified therapy to improve glycaemic control, 
the dose of investigational product should be increased before altering the doses of or 
adding other other glucose-lowering medication. This treatment decision will be the 
responsibility of the investigator. In this case the subject will called in for an unscheduled
visit to increase the dose from 30 mg to 50mg. Subjects randomly assigned to albiglutide 
matching placebo will also go through the increased dose procedure to maintain study 
blind. If a subject experiences tolerability issues with the higher, 50mg dose then the 
investigator may decrease the dose back to 30 mg without the need for an unscheduled 
visit to supervise down titration. Use of GLP-1 receptor agonists will be prohibited but 
other glucose-lowering medications permitted, provided they are not contraindicated for 
the individual subject concerned.
This study is designed with minimal intervention above normal clinical care of subjects 
with type 2 diabetes, whilst allowing thorough evaluation of  cardiovascular and other 
events of special interest (Section 6.2.3), thus investigating the safety of albiglutide in the 
typical clinical situation.  Sites will employ pre-screening to assess potential subjects for 
study entry. Screening and randomisation can then occur at the same visit or in close 
proximity depending on scheduling.  Contact with subjects will be every four months 
after the randomisation visit. HbA1c will be measured at 4 month clinic visits. Serum 
creatinine and liver function tests (LFTs) will be measured and a targeted physical 
assessment performed at 8 month clinic visits (Table 1). 
The study will be event driven, i.e., follow up will continue until it is projected that 
approximately 611 adjudicated MACE events will have occurred. Consequently, the 
maximum duration of the study for an individual participant is dependent both on the 
time taken for recruitment and the MACE event rate, and is estimated to be between 3 
and 5 years. If the observed rate for MACE is 2.0% or 3.0%, the mean follow-up will be 
3.2 or 2.2 years, respectively.  
An Executive Committee will be the main decision-making body for the study, in 
collaboration with the Sponsor (GSK).  It is charged with the overall scientific, 
professional and operational conduct of the study.  Amongst other roles pre-specified in 

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its Charter, the Executive Committee will ensure proper study conduct and conformance 
to the protocol, consider and agree changes to the protocol based on emerging scientific 
and/or clinical advances (e.g., new emerging data with other GLP-1 receptor agonists), 
advise on the selection of study sites and assist in subject recruitment strategies.
An IDMC will have study oversight to ensure participant safety and scientific integrity of 
the data (Section 9.8), an independent Cardiovascular Endpoint Committee (CEC) 
blinded to treatment allocation will adjudicate cardiovascular outcome events (Section 
6.2.1) and a Pancreatitis Adjudication Committee will adjudicate potential events of 
pancreatitis.
Subject completion is defined as completion of all periods of the study up to and 
including any follow-up period.
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 (Table 1), are essential and required for study 
conduct. 
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Reference Manual (SRM). The SRM will provide 
the site personnel with administrative and detailed technical information that does not 
impact subject safety.
3.2.
Standard of Care
Anti-hyperglcaemic and cardiovascular medications will be used at the discretion of the 
usual care provider(s) (or investigator if also the usual care provider), who will be 
informed of the patient’s enrolment in the trial, the use of blinded trial medication, and 
that use of GLP-1 receptor agonists  (other than the use of  randomised albiglutide) is 
contraindicated during the trial period. Usual care providers will be encouraged to follow
the most up to date guidelines for diabetes and cardiovascular care based upon local and 
institutional practice patterns and any relevant published practice guidelines (e.g.,
Inzucchi, 2012).  Treatment for type 2 diabetes will be captured by name and total daily 
dose at the time of study visits, while other relevant (cardiovascular) concomitant 
medications will be collected only as drug classes (see Section 5.6.1). 
During the study investigators are expected to monitor patients’ type 2 diabetes regimens 
and communicate with usual care providers, who will be responsible for adjusting their
regimen in order to achieve locally-appropriate HbA1c goals.  The Executive Committee 
and National Country Leaders will encourage investigators to follow clinical care 
practice guidelines published by national and international societies regarding type 2 
diabetes over the course of the trial.  These practice guideline goals will be 
individualized, with the understanding that currently applicable glycaemic guidelines 
may vary among different geographic regions.  With adherence to local custom and laws 
(including privacy regulations such as the Health Insurance Portability and 
Accountability Act), types of communication may be informal e.g. email or telephone 
exchanges, to enhance frequency and ease of two-way communication.

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Any agent, with the exception of GLP-1 receptor agonists, is acceptable for reaching 
HbA1c goals.  If HbA1c goals are not met following adjustment with oral medications in 
patients not receiving insulin, an insulin regimen may be initiated. Patients already 
receiving insulin therapy may up-titrate insulin during the trial if necessary. Patients 
should be reminded to keep taking their blinded trial medication throughout the course of 
the trial even in the case after initiation of insulin.
The Executive Committee and National Country Leaders will also monitor the standard 
of care of management of diabetes and cardiovascular disease. Similar to the 
management of type 2 diabetes, sites and investigators will be expected to adhere to local 
clinical practice guidelines.  Sites will be provided training on clinical management 
guidelines to re-enforce standard of care adherence. Information on medications
important to management of cardiovascular risk will be captured during study visits.  The 
Executive Committee and National Country Leaders will review on a periodic basis the 
use of medications for cardiovascular risk prevention to ensure patients are receiving 
standard of care. If there are unusually low goal attainments for standard of care, site 
investigators will be advised accordingly.
3.3.
Discussion of Design
This study is a clinical outcomes trial required by FDA as a post-marketing requirement 
to evaluate cardiovascular safety.  It will provide important information regarding the 
cardiovascular safety and metabolic effects of albiglutide treatment of subjects with type 
2 diabetes.  Sufficient MACE events must be observed during the study to permit the
assessment of cardiovascular safety.  Consequently, to enter the study subjects must have 
established cardiovascular disease as well as type 2 diabetes. The study is powered on a 
predefined number of clinical events, consequently the number of subjects required and 
study duration may vary from that stated in the protocol.
This will be a double-blind, placebo-controlled study. All subjects will receive placebo or 
albiglutide in addition to usual standard of care for type 2 diabetes and cardiovascular 
disease, in order to assess the effect of albiglutide above that of currently available 
therapies alone.
The primary cardiovascular comparison will be to assess whether albiglutide is non-
inferior to placebo with respect to time to first MACE. Missing data may inappropriately 
bias comparison towards declaring non-inferiority. The longer the duration of a study, the 
more difficult it is to avoid loss to follow-up and other sources of missing data. The 
product of the projected duration of this study and the number of subjects to be studied is 
intended to minimize the risk of missing data whilst still permitting the assessment of the 
safety of albiglutide to be over an appreciable period of time. Every effort will be made 
to keep subjects on their assigned study medication according to the protocol.  Subjects 
who stop study medication will be followed throughout the whole study duration.  More 
details about procedures for subject follow-up are provided in Section 4.5.
Phase III studies confirmed the glycaemic 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 glycaemia for at least 2 years in many subjects with type 2 

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diabetes, an increase in dose to 50 mg weekly offered additional benefit without 
significant safety issues (See IB for further details).  
3.4.
Benefit:Risk Assessment
Albiglutide has been evaluated in an international programme of studies involving 
approximately 9000 subject-years of overall exposure to date (including over 4000 
subject-years of exposure to albiglutide). The programme included 8 well-controlled 
Phase III studies (including one in subjects with concurrent renal impairment), ranging in 
duration from 32 weeks to 3 years, and using both 30 mg and 50 mg once weekly dosing.  
This has permitted a thorough assessment of efficacy, safety, and tolerability in a 
population of subjects with type 2 diabetes that spanned newly diagnosed individuals 
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 
albiglutide can be found in the IB and in the product labelling for those countries where 
marketing authorisation has been granted.  The following section outlines the risk 
assessment and mitigation strategy for this protocol:  
3.4.1.
Risk Assessment
The identified and potential risks associated with the use of albiglutide, or the GLP-1 
receptor agonist class, as well as the mitigation strategy for key risks of clinical 
significance are provided below. Please refer to the IB for a thorough summary of the 
nonclinical and clinical experience with albiglutide as well as the complete Guidance for 
the Investigator. The risks associated with study comparator, placebo, are also provided
below.  Subjects will have the AE profile of GLP-1 receptor agonists, and albiglutide in 
particular, explained to them by the investigator and via the informed consent form.
3.4.1.1.
Identified Risks
Pancreatitis. Acute pancreatitis has been reported in association with albiglutide and 
other GLP-1 receptor agonists in clinical trials and during  postmarketing experience.
Albiglutide has not been studied in subjects with a history of pancreatitis to determine 
whether they are at increased risk for pancreatitis. Subjects with a history of pancreatitis 
or who are considered at significant risk of developing pancreatitis are excluded from 
entering the study. Subjects will be informed of the characteristic symptom of 
pancreatitis: persistent severe abdominal pain. If pancreatitis is suspected, investigational 
productshould be promptly discontinued and if pancreatitis is confirmed, investigational 
product will not be restarted.
Gastrointestinal events. Albiglutide has not been studied in subjects with severe 
gastrointestinal (GI) disease, including severe gastroparesis. Subjects with severe 
gastroparesis will be excluded from the study. Use of albiglutide and other GLP-1
receptor agonists can be associated with GI side effects such as diarrhoea, nausea, and 
vomiting; the frequency of these events increased as renal function decreased.  These 
types of GI reactions can be associated with dehydration and worsened renal function. 

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(see below and see Section 4.4.4). Other GI related adverse reactions with albiglutide 
include dyspepsia, gastro-oesophageal reflux disease and constipation.
Hypoglycaemia. Albiglutide’s mechanism of action is associated with a low intrinsic risk 
of significant hypoglycaemia. However, when used in combination with insulin (or 
insulin secretagogues) the risk of hypoglycaemia is increased. Investigators will be 
reminded that it may be necessary to reduce the dose of insulin or insulin secretagogues 
when starting study medication to reduce the risk of hypoglycaemia. Routine standard of 
care for subjects treated with insulin secretagogues and insulin includes advice about 
avoidance of hypoglycaemia which will be reinforced.  All subjects are required to have a 
last indicator of glycemic control of above HbA1c = 7% which is expected to reduce the 
risk of hypoglycaemia when starting albiglutide. 
Immunogenicity. Hypersensitivity reactions are of potential concern with any injected 
protein and were reported rarely in the Phase III programme. In the Phase III programme 
one subject (anti-albiglutide antibody negative) developed rash, itching and dyspnoea . 
Subjects with known allergy to any GLP-1 receptor agonist or excipients of albiglutide 
are excluded from the study.  Subjects will be informed of the symptoms of severe 
hypersensitivity or allergy and be advised to seek medical assistance immediately. In the 
Phase III programme approximately 5% of subjects developed anti-albiglutide antibodies.  
Subjects who tested positive for anti-albiglutide antibodies experienced a similar 
glycaemic response (HbA1c and fasting plasma glucose) to those who did not test 
positive for antibodies. Other than injection site reactions (see below), the overall safety 
profile appeared similar among the subset of subjects who did and those who did not test 
positive for anti-albiglutide antibodies.  Anti-albiglutide antibody formation is not 
expected to impact the overall safety of albiglutide treatment and therefore will not be 
measure routinely in this study. 
Injection site reactions. Albiglutide injections may cause rash, erythema or itching 
and/or other reactions at the site of injection. . Subjects will be advised that when 
injecting in the same region, to use a different injection site each week. In the Phase III 
program, most subjects with injection site reactions did not test positive for anti-
albiglutide antibodies. However, injection site reactions were reported more frequently 
among those who did test positive for anti-albiglutide antibodies (41% of the antidrug 
antibody positive subjects reported one or more injection site reactions) than among those 
who were consistently antibody negative (14% of the antidrug antibody negative subjects 
reported one or more injection site reactions) .  
Other adverse reactions (e.g. pneumonia, atrial fibrillation/flutter, and appendicitis). In 
the Phase III programme in type 2 diabetes, other possible albiglutide related adverse 
reactions were identified. These events occurred at a cumulative incidence <3% in studies 
up to 3 years in duration. These events were reported more frequently with albiglutide 
than comparators. 
3.4.1.2.
Potential Risks
Thyroid C-cell tumours. GLP-1 receptor agonists, including albiglutide increase serum 
calcitonin in rodents and other GLP-1 receptor agonists are associated with thyroid C-cell 
focal hyperplasia and C-cell tumours in rodents  It is unknown whether GLP-1 receptor

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agonists are associated with thyroid C-cell tumours in humans, including medullary 
thyroid cancer (MTC). 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. Subjects with treatment emergent thyroid nodules should be referred to a specialist 
for evaluation in accordance with local treatment guidelines.  Routine monitoring of 
serum calcitonin is not recommended.  However, if serum calcitonin is found to be 
elevated the subject should be referred to a specialist for further evaluation. If MTC or 
other thyroid C-cell neoplasia is diagnosed, investigational product will be discontinued.
Other malignant neoplasms Concerns have been raised regarding use of incretin based 
therapies and other malignancies such as pancreatic cancer [Egan, 2014], malignancy 
when used in combination with insulin based on hypotheses of biological plausibility 
[European Public Assessment Report , 2014], and haematological malignancies [FDA 
Summary Basis of Approval, 2014].
Hepatotoxicity. Hepatotoxicity is an area of interest in drug development.  Patients with 
type 2 diabetes are at increased risk for liver enzyme abnormalities and disease related 
liver conditions. One subject treated with albiglutide in the Phase III clinical programme
developed probable drug induced liver injury with an asymptomatic elevation in alanine 
amino transferase (ALT) and total bilirubin although the cases 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 4.4.3).
Subject population with severe renal impairment (eGFR <30 mL/min/1.73m2).
Experience in type 2 diabetes subjects with severe renal impairment is limited (in the 
Phase III programme a total of 19 subjects with eGFR <30 mL/min/1.73m2 received 
albiglutide). 
In a Phase 3 study of patients with varying degrees of renal impairment, in the albiglutide 
group, on-therapy GI AEs occurred with a higher incidence and higher event rate in 
subjects with moderate and severe renal impairment compared to those with mild renal 
impairment. Because these GI events may lead to dehydration and worsen renal function, 
worsening renal function will be closely evaluated as an AE of special interest, serum 
creatinine will be measured every 8 months, and subjects will discontinue IP if eGFR 
falls below 15 mL/min/1.73m2. Subjects with known severe renal impairment are 
excluded from the study (see Section 4.4.4).
Drug Interactions.  Like other members of the class, albiglutide causes a delay in gastric 
emptying, and thereby has the potential to impact the absorption of concomitantly 
administered oral medications. During the development programme, drug interactions 
studies were conducted with digoxin, warfarin, oral contraceptives, and simvastatin 
which demonstrated no clinically relevant PK or PD effects. Investigators will be advised 
to take the effect of albiglutide on gastric emptying into account when prescribing 
concomitant medication.
Pregnancy and Lactation.  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 

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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.  
Placebo control. In subjects treated with placebo, symptoms and long-term risks of 
hyperglycaemia may not improve or may worsen. During the study, intensification of 
glucose-lowering treatments other than study drug will be allowed in both treatment arms 
with a treat-to-target approach. Albiglutide placebo injections may cause injection site 
reactions. Subjects will be advised when injecting into the same region to use a different 
injection site each week.
3.4.2.
Benefit Assessment
In subjects with type 2 diabetes albiglutide treatment resulted in clinically relevant 
lowering of HbA1c at both the 30 mg and 50 mg doses when given as monotherapy and 
in combination with metformin, sulfonylureas (SUs), thiazolidinedione or basal insulin . 
The durability of the effect on glycaemic control was shown over a study period of up to 
3 years. Consistent with its mechanism of action, albiglutide was not associated with 
clinically relevant hypoglycaemia except when used in combination with an SU or 
insulin, and incidence rates with the combination were less than those reported with SUs 
or insulin alone. Treatment with albiglutide generally produced a steady reduction in 
weight over time.
For subjects not yet on insulin at the start of the study, data from the Phase III programme 
suggest that the use of albiglutide once weekly in a pen device may have the potential to
delay the need to start daily insulin injections.  This will be formally assessed within this 
trial.  Similarly, it is possible that for those already taking basal insulin, albiglutide may 
delay the need to introduce short-acting prandial injections and for those taking 
basal/bolus or pre-mixed insulin, it may reduce the dosage of insulin and/or the number 
of daily injections needed to achieve good glycaemic control.  These will also be 
evaluated in the study.
Subjects in the placebo arm will also be receiving effective anti-hyperglycaemic 
medication which will be titrated up or down as required to improve or maintain 
glycaemic control, and therefore these subjects should also demonstrate reductions in 
HbA1c, though weight gain (rather than weight loss) may occur depending upon the 
medication selected.   
Finally, as a result of participating in a clinical trial, each subject will receive more 
contact with the study site than would be performed as part of their usual standard of 
care.

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3.4.3.
Overall Benefit:Risk Conclusion
Taking into account the measures taken to minimise risk to subjects participating in this 
study, the known and potential risks identified with albiglutide are justified by the 
benefits have been demonstrated in subjects with type 2 diabetes.
4.
SUBJECT SELECTION AND WITHDRAWAL CRITERIA
4.1.
Inclusion Criteria
Specific information regarding warnings, precautions, contraindications, AEs, and other 
pertinent information on the GSK investigational product or other study treatment that 
may impact subject eligibility is provided in the IB for albiglutide and in the product 
label for those countries where marketing authorisation has been granted.
Deviations from inclusion criteria are not allowed because they can potentially jeopardise 
the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential.   
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
1. Men or women at least 40 years old with a diagnosis of type 2 diabetes.
2. Established cardiovascular disease, including at least 1 of the following:
a. Coronary artery disease with EITHER of the following:
Documented history of spontaneous myocardial infarction, at least 30 days 
prior to Screening.
Documented coronary artery disease (CAD) ≥ 50% stenosis in 1 or more 
major epicardial coronary arteries, determined by invasive angiography, or 
history of surgical or percutaneous (balloon and/or stent) coronary 
revascularization procedure (at least 30 days prior to Screening for 
percutaneous procedures and at least 5 years prior to Screening for coronary 
artery bypass graft (CABG)).
b. Cerebrovascular disease – ANY of the following:
Documented history of ischaemic stroke, at least 90 days prior to study entry.
Carotid arterial disease with 50% stenosis documented by carotid 
ultrasound, magnetic resonance imaging or angiography, with or without 
symptoms of neurologic deficit.
Carotid vascular procedure (e.g. stenting or surgical revascularisation), at 
least 30 days prior to Screening.
c. Peripheral arterial disease (PAD) with EITHER of the following:
intermittent claudication and ankle:brachial index < 0.9 in at least one ankle
prior non-traumatic amputation, or peripheral vascular procedure (e.g. 
stenting or surgical revascularisation), due to peripheral arterial ischaemia.

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3. HbA1c >7.0% (53 mmol/mol) based on the most recent documented laboratory 
assessment measured no more than 6 months prior to randomization. Local 
laboratory HbA1c values taken as part of usual care are permitted.
4. 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 GSK 
Modified List of Highly Effective Methods for Avoiding Pregnancy in Females 
of Reproductive Potential (FRP) (e.g, combined oral contraceptive pill; see 
Appendix 2) 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.
This 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. 
Other situations in which contraception in FRP may not need to be mandated 
should be discussed with the Medical Monitor.
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 oestradiol 
<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.
5. Able and willing to provide informed consent.
4.2.
Exclusion Criteria
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardise the scientific integrity of the study, regulatory acceptability or subject safety. 
Therefore, adherence to the criteria as specified in the protocol is essential. 
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
1. eGFR calculated using MDRD formula <30mL/min/1.73m2 (based on the most 
recent documented serum creatinine laboratory assessment measured no more than 6 

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months prior to randomization. Local laboratory creatinine values taken as part of 
usual care are permitted) or renal replacement therapy.
2. Use of a GLP-1 receptor agonist at Screening.
3. Severe gastroparesis requiring therapy within 6 months prior to Screening.
4. History of pancreatitis or considered clinically at significant risk of developing 
pancreatitis during the course of the study (e.g. due to symptomatic gallstones, 
excess alcohol use).
5. Personal or family history of medullary carcinoma of the thyroid or subject with 
MEN-2. Personal history of pancreatic neuroendocrine tumours. In the opinion of the 
investigator, the subject has a medical history which might affect his / her ability to 
remain in the study for its entire duration, or which might limit management, such as 
life expectancy of <5 years (e.g. due to active malignancy).
6. Subject has a medical history which in the opinion of the investigator might limit the 
individual’s ability to take trial treatments for the duration of the study or to 
otherwise complete the study.
7. Breastfeeding, pregnancy, or planning a pregnancy during the course of the study. 
Pregnancy test will be required in women of child bearing potential. Women who 
have undergone a sterilisation procedure or who are clearly post-menopausal will not 
be required to undergo pregnancy testing.  Women who have developed spontaneous 
secondary amenorrhoea of 12 months or more where post-menopausal status is in 
doubt, a blood sample where FSH >40MU/ml and oestrodiol <40 pg/mL (<14 
pmol/L) are simultaneously measured will be considered confirmatory.
8. Known allergy to any GLP-1 receptor agonist or excipients of albiglutide.
9. Use of another investigational product within 30 days or according to local 
regulations, or currently enrolled in a study of an investigational device.
10. Any other reason the investigator deems the subject to be unsuitable for the study.
4.3.
Screening/BaselineFailures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomised.  In order to ensure transparent reporting of screen 
failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements [Schulz, 2010], and respond to queries from regulatory 
authorities, a minimal set of screen failure information is required including 
Demography, Screen Failure details, Eligibility Criteria, and any SAEs.
Re-screening of subjects who did not meet the eligibility criteria for HbA1c or creatinine 
based on local laboratory values taken as part of usual care is permitted. If values were 
based on laboratory results as part of usual care then one re-test is permitted within the 

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protocol at Screening. Any future re-screening will be based on laboratory results 
obtained as part of usual care.
4.4.
Criteria for Early Discontinuation of Investigational Product
The primary analysis will be conducted on an ITT analysis basis so it is important that 
every subject is followed for the duration of the study, regardless of whether the subject
continues to take investigational product, unless consent for all follow up is actively 
withdrawn.
The requirements for handling early discontinuations from investigational product are 
described below. Details of the requirements for subject follow-up are provided in 
Section 4.5.
4.4.1.
Early Discontinuation of Investigational Product
If a subject chooses to discontinue investigational product between scheduled face-to-
face visits they should be encouraged to contact the investigator site by telephone.  
Subjects should first be counselled to consider temporary discontinuation of 
investigational product prior to choosing to discontinue investigational product 
permanently, unless the reason for discontinuation is one of those listed below (Reasons 
for Discontinuation of Investigational Product).  If the discontinuation is permanent, the 
subject should be asked to attend the clinic as soon as possible to complete the 
assessments as for the final study visit (see Table 1) and then continue in the study for 
follow-up. The procedures for follow-up for a subject who permanently discontinues 
treatment with investigational product prior to the study end are given in Section 4.5. 
In all cases, reasons for discontinuation of investigational product and the date of last 
dose will be recorded. 
4.4.2.
Reasons for Discontinuation of Investigational Product
Any subject experiencing the following will be required to discontinue investigational 
product:

AE:

Pancreatitis, acute or chronic. 

Pancreatic cancer.

MTC or other thyroid C-cell neoplasia.  In subjects where a treatment emergent 
thyroid nodule is identified, if serum calcitonin is measured at the discretion of 
the Investigator (e.g., per local guidelines) and found to be >100 ng/L this 
should prompt further investigation for MTC and potential interruption or 
discontinuation of investigational product until diagnosis has been resolved.

Liver chemistry abnormalities exceeding the threshold criteria outlined in 
Section 4.4.3

Severe allergic/hypersensitivity reactions that are considered by the investigator 
to be attributable to investigational product or without a likely alternative 
aetiology.

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
Other AE which, in the opinion of the investigator precludes continuation of 
dosing.

eGFR<15ml/min/1.73m2 (Section 4.4.4) or the need for renal replacement therapy.

Subject becomes pregnant during the study.

Need for chronic use of a prohibited concomitant medication (Section 5.6.2)

Decision by subject or proxy.

Sponsor terminated study.

Investigator site closed and subject was unable to transfer to another investigative 
site.
If investigational product is discontinued, the subject should continue in the study and be 
followed until the final study visit as detailed in Section 4.5.
4.4.3.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event aetiology (in alignment with the FDA 
premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
Phase III-IV Liver Chemistry Stopping and Increased Monitoring Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
Plus 
Bilirubin≥2x
ULN (>35% 
direct) or plus
INR>1.5, if 
measured*
Possible  
Hy’s Law
ALT≥3xULN
ALT
≥8xULN
Plus
Symptoms of 
liver injury
or 
hypersensitivity
No
Yes
Yes
Yes
No
No
No
See algorithm 
for continued 
therapy with 
increased liver 
chemistry 
monitoring
Yes
*INR value not applicable to subjects on anticoagulants 
ALT 
≥3xULN 
but 
<8xULN
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*

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Liver safety required actions and follow up assessments section can be found in 
Appendix 3.
Phase III-IV 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*
Liver Safety Required Actions and Follow up Assessments Section can be found in
Appendix 3.
Drug re-challenge following drug induced liver injury is not allowed. 
Restart may be considered if GSK Medical Governance approval is granted (see 
Appendix 4 for details). Restart refers to resuming study treatment following liver 
stopping events in which there is a clear underlying cause (other than DILI) of the liver 
event (e.g. biliary obstruction, pancreatic events, hypotension, acute viral hepatitis). 
Furthermore, there should be no evidence of alcoholic hepatitis or hypersensitivity, and 
the study treatment should not be associated with human leukocyte antigen (HLA)
markers of liver injury.
4.4.4.
eGFR Stopping Criteria
A baseline eGFR ≥ 30mL/min/1.73m2 is a requirement for entering the study. Subjects 
can continue to take investigational product if functioning well as long as eGFR is 
≥15mL/min/1.73m2. 
During this study, if a subject’s eGFR approaches 30mL/min/1.73m2 closer monitoring 
of renal function is considered prudent, according to standard clinical practice. Particular 

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care should be taken to monitor renal function in subjects with renal impairment 
reporting severe adverse GI events. If eGRF is <15mL/min//1.73m2 and considered 
irreversible based on consecutive measurements the investigational product should be 
discontinued, the subject continue in the study and be followed until the final study visit. 
If eGRF is <15mL/min/1.73m2 and the patient is considered to have temporary acute 
kidney injury that is potentially reversible, the investigational product should be 
temporarily discontinued until the eGRF is stable and ≥15mL/min//1.73m2 .Events 
considered to reflect worsening renal function should be reported as SAE/AEs and 
targeted eCRFs completed for this AE of special interest (Section 6.2.3).
4.5.
Procedures for Subject Follow-up
As described in Section 4.4, subjects who permanently discontinue investigational 
product will be asked to attend the clinic as soon as possible.  They will continue in the 
study for follow-up. They will be asked to return to clinic according to the 8 monthly
visit schedule and in addition be contacted by telephone at a time corresponding to the 4-
monthly visit they would have otherwise made to replenish study medication supply.  If 
instead of these interim telephone contacts the subject prefers to attend clinic every 4
months as originally scheduled that is an acceptable alternative.
If a subject permanently discontinues investigational product and is unable to attend visits 
in-person, he/she will be contacted by telephone or other methods to assess study 
outcomes and vital status, unless the subject has specifically withdrawn consent for all 
forms of contact. Follow-up of subjects who withdraw consent for contact is described 
below.
Every effort should be made to educate the subjects on the importance of remaining in 
the study and attending scheduled study visits including those required after early 
discontinuation of investigational product. 
Other subject follow-up options to collect study outcomes and vital status should be 
pursued according to local laws and regulations. If one of these alternate methods to 
collect study outcomes and vital status is acceptable to the subject, then the subject will 
be deemed not to have withdrawn consent for follow-up.
4.5.1.
Withdrawal of Consent for Contact
Subjects who no longer wish to attend study visits in-person will be asked to be contacted 
by telephone or other methods to assess study outcomes and vital status.  However, if a 
subject specifically withdraws consent to be contacted for additional information, no 
further study visits or study-related telephone contacts can be conducted. Information 
regarding study outcomes or vital status will continue to be collected from available 
sources including those in the public domain. Additionally, alternative permitted options 
to obtain study outcomes and vital status will be reviewed based on accepted local laws 
and regulations. For any subject who withdraws consent for contact, the study site will be 
asked to document the discussion with the subject regarding each of the contact options 
that were offered.

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4.5.2.
Subjects Deemed Lost to Follow-up
Finally, investigators should make every effort to contact subjects who are deemed lost to 
follow-up and who have not withdrawn consent to follow-up contacts, including pursuing 
any alternative contact methods permitted by local regulations. Where permitted, a third 
party may be used to locate alternative subject contact information that will be provided 
to the investigator. All attempts to contact subjects will be documented in the subject’s 
eCRF and source notes. 
Should a subject fail to attend the clinic for a required study visit, the site should attempt 
to contact the subject and re-schedule the missed visit as soon as possible. The site should 
also counsel the subject on the importance of maintaining the assigned visit schedule. In 
cases where the subject does not return for the rescheduled visit or cannot be reached to 
reschedule the missed visit, the site should make every effort to regain contact with the 
subject. Should the subject continue to be unreachable, then and only then will he/she be 
considered “Lost to Follow-up”. Nonetheless, efforts to attempt to locate and contact the 
subject will continue until the study end. 
5.
STUDY TREATMENTS
5.1.
Investigational Product and Other Study Treatment
Albiglutide (and albiglutide matching placebo) will be provided as a fixed-dose, fully 
disposable pen injector system for delivery of the investigational product (albiglutide or 
albiglutide matching placebo) from a prefilled dual chamber glass cartridge that is an 
integral part of the pen. The pen is intended for single use by the subject. It is designed 
for manual reconstitution of the dose, priming and insertion of the pen needle, and 
manual injection by the subject. 
Albiglutide (or albiglutide matching placebo) is intended for self-administration as a 
subcutaneous injection in the abdomen, thigh or upper arm region.  Rotation of use of 
injection sites is recommended. Albiglutide and insulin may be injected in the same body 
region but the injections should not be adjacent to each other.  The albiglutide pen 
includes a mechanical locking system that prevents the user from manipulating the dose 
button before the cartridge has been fully reconstituted. Reconstitution is performed 
through rotation of the pen housing parts. The pen is designed to work with standard pen 
needles.
When the injector pen product is reconstituted by the subject, a neutral, isotonic solution 
is produced. Separate pens are required to deliver either 30 mg of albiglutide, 50 mg of 
albiglutide, or matching placebo in a 0.5-mL injection volume.
The contents of the label will be in accordance with all applicable regulatory 
requirements.
Under normal conditions of handling and administration, investigational product is not 
expected to pose significant safety risks to site staff.  Take adequate precautions to avoid 
direct eye or skin contact and the generation of aerosols or mists. Notify the monitor of 
any unintentional occupational exposure.  A Material Safety Data Sheet (MSDS) 

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describing the occupational hazards and recommended handling precautions will be 
provided to site staff if required by local laws or will otherwise be available from GSK 
upon request.
The investigational product (albiglutide and albiglutide matching placebo) must be stored 
in a secure area at 2°C to 8°C and protected from freezing. Each site must maintain a 
temperature log.  Access to and administration of the investigational product will be 
limited to the investigator and authorised site staff (investigator or designee).  
Investigational product must be dispensed or administered only to subjects enrolled in the 
study and in accordance with the protocol.
Procedures for the disposal of unused study treatment will be provided in the SRM.
Investigational product (albiglutide or albiglutide matching placebo) will be administered 
once weekly by subcutaneous injection. The first dose is to be administered at the clinic. 
The starting dose of albiglutide will be 30 mg once weekly.  If at any stage after 5 weeks 
of treatment in the opinion of the investigator the subject needs to have intensified 
therapy to improve glycaemic control, the dose of investigational product should be 
increased before altering the doses of other glucose-lowering medication. In this case the 
subject will called in for an unscheduled visit to supervise an increase in dose from 30 mg 
to 50 mg.  Subjects randomly assigned to albiglutide matching placebo will also go 
through the increased dose procedure to maintain study blind. If a subject experiences 
tolerability issues with the higher, 50mg dose then the investigator may decrease the dose 
back to 30 mg without the need for an unscheduled visit to supervise down titration, other 
than for the subject to collect pens of the correct dose.
Albiglutide (or albiglutide matching placebo) may be administered at any time of day 
without regard to meals. Preferably, it should be administered once a week on the same 
day each week. The day of weekly administration can be changed if necessary as long as 
the last dose was administered 4 or more days previously. If a dose is missed, it should be 
administered as soon as possible within 3 days after the missed dose. Thereafter, subjects 
can resume dosing on their usual day of administration. If it is more than 3 days after the 
missed dose, subjects should wait and administer their next regularly scheduled weekly 
dose.  
If a subject misses 4 or more consecutive doses, the investigator should contact the 
medical monitor to discuss options for helping assure better compliance.
5.2.
Treatment Assignment
Subjects will be assigned to study treatment in accordance with the randomisation 
schedule.
Randomised treatment assignment will be done via the Interactive Voice Response 
System (IVRS), and randomisation will be implemented based on a sequestered fixed 
randomisation schedule. Study centre personnel will call the IVRS once a subject has met 
all prerequisites for randomization; the IVRS will assign treatment.

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Blinded study centre personnel will receive a randomisation notification indicating only 
the unique subject identifier and the date and time of randomisation. 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 investigational product. 
Details of the treatment assignment process are contained in the SRM.
5.3.
Blinding
This is a double-blind study, neither the subject nor the study physician will know which 
of the two treatments (albiglutide or placebo) the subject is receiving.
The investigator or treating physician may unblind a subject’s treatment assignment only 
in the case of an emergency or in the event of a serious medical condition, when 
knowledge of the study treatment is essential for the appropriate clinical 
management or welfare of the subject, as judged by the investigator.  Investigators 
have direct access to the subject’s individual study treatment.  It is preferred (but not 
mandatory) that the investigator first contacts the GSK Medical Monitor or appropriate 
GSK study personnel to discuss options before unblinding the subject’s treatment 
assignment.  If GSK study personnel are not contacted before the unblinding, the 
investigator must notify GSK as soon as possible after unblinding, but without revealing 
the treatment assignment of the unblinded subject, unless that information is important 
for the safety of subjects currently in the study.  The date and reason for the unblinding 
must be fully documented in the appropriate data collection tool.
If a subject is unblinded by the investigator or treating physician then discontinuation of 
investigational product treatment for that subject will be at the discretion of the 
investigator. However, the subject should continue to be followed in the study (see 
Section 4.5).
GSK’s Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the 
treatment assignment for any subject with an SAE.  If the SAE requires that an expedited 
regulatory report be sent to one or more regulatory agencies, a copy of the report, 
identifying the subject’s treatment assignment, may be sent to clinical investigators in 
accordance with local regulations and/or GSK policy.
5.4.
Product Accountability
In accordance with local regulatory requirements, the investigator, designated site staff, 
or head of the medical institution (where applicable) must document the amount of 
investigational product dispensed and/or administered to study subjects, the amount 
returned unused by study subjects, and the amount received from and returned to GSK, 
when applicable. Product accountability records must be maintained throughout the 
course of the study.
5.5.
Treatment Compliance
Subjects will be instructed to return all unused and used injector pens at the visits 
specified in the Time and Events Table (Table 1) in order to perform drug accountability 
and determine compliance. Subjects will be provided with a sharps container for the 

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disposal of used pens.  To comply with health and safety considerations there will be no 
count made of used pens; only returned unused pens will be counted. In addition, subjects 
will be provided with a pre-printed card at each dispensing visit to record the date of each 
dose. The card is to be returned at the next dispensing visit with the unused pens.
5.6.
Concomitant Medications and Non-Drug Therapies
5.6.1.
Permitted Medications and Non-Drug Therapies
The usual care provider will manage the subjects according to standard of care, following 
local prescribing information. Close adherence to professional society guidelines for 
standard of care therapies in type 2 diabetes and cardiovascular disease will be 
emphasized during study conduct. Standard of care is described in greater detail in 
Section 3.2.
Unless specified as a prohibited medication in Section 5.6.2, all concomitant medications 
should be considered permitted provided they are not contraindicated for the individual 
subject concerned.
Like other members of the class, albiglutide causes a delay in gastric emptying, and 
thereby has the potential to impact the absorption of concomitantly administered oral 
medications.  This should be taken into account by investigators when prescribing 
concomitant medication.
It may be necessary to reduce the dose of concomitantly administered insulin 
secretagogues (such as SUs) or insulin to reduce the risk of hypoglycaemia when starting 
albiglutide.
All concomitant anti-hyperglycaemic medications (name of agent, total daily dose, start 
and stop dates) will be recorded in the eCRF at each visit. Concomitant cardiovascular 
medications taken during the study will also be recorded at each visit by class of agent.
Additionally, all medications used within the 30 days prior to the onset and throughout 
the duration of an SAE, AE of special interest (Section 6.2.3), or an AE leading to 
discontinuation of investigational product will be recorded as individual agents, reason 
for use, together with start dates (and stop dates if applicable) and any changes since any 
previous AE.
5.6.2.
Prohibited Medications and Non-Drug Therapies
Subjects may not take a GLP-1 receptor agonist (other than blinded investigational 
product), nor any investigational drug, during the study (and any follow-up period after 
discontinuing investigational product).
If a subject receives a prohibited medication, a protocol deviation will be recorded.

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5.7.
Treatment after the End of the Study
Following the final study visit subjects will be contacted by telephone 5 1 weeks after 
last dose of study medication to assess any AEs ongoing since the last visit or newly 
emergent. 
Subjects will be treated as deemed appropriate by the investigator following the end of 
the study. Investigational product will not be provided to subjects by GSK after the end 
of the study.
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 investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition whether or not GSK is providing specific 
post study treatment.
5.8.
Treatment of Study Treatment Overdose
No data are available with regard to albiglutide overdose in humans. The highest 
recommended dose of albiglutide is 50 mg once weekly.
During clinical studies of subjects with type 2 diabetes, the highest dose of albiglutide 
administered was 100 mg subcutaneously every four weeks for 12 weeks. This dose was 
associated with an increased frequency of nausea, vomiting, and headache. 
There is no specific antidote for overdose with albiglutide. In the event of a suspected 
overdose, the appropriate supportive clinical care should be instituted, as dictated by the 
subject’s clinical status. Anticipated symptoms of an overdose may be severe nausea, 
vomiting or headache.  A prolonged period of observation and treatment for these 
symptoms may be necessary, taking into account the half-life of albiglutide (5 days).
6.
STUDY ASSESSMENTS AND PROCEDURES
The schedule of study assessments is shown in Table 1. Detailed procedures for each 
assessment are provided in the SRM.

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Table 1
Time and Events Table
Procedures1,2
Screening2
Randomization3
/Baseline
(can be same day
as Screening Visit)
Study Drug Check 
Phone Call
(4-6 wks post 
and.)
Clinic Visit Month 4 
18 days then every 8
months 18 days 
throughout the study
Unscheduled 
dose adjustment 
visit
(if warranted)
Clinic Visit Month 8 
18 days then every 8 
months 18 days 
throughout the study
Final study 
clinic 
visit4 (or early 
withdrawal)
Post-Study Follow up 
Phone Call
5 1 weeks after last IP 
dose
Written informed consent  
X
Review of Inc/excl criteria
X
X
Demography & directed medical history
X
Assessment of MACE  and micro-vascular events
X
X
X
HbA1c
X5
X
X
X
Serum creatinine (eGFR)
X5
X
X
Liver Function Tests6
X
X
X
Genetic sampling7
X
Patient reported outcomes questionnaires8
X
X
X
Key concomitant non-diabetes medication
X
X
X
X
X
Diabetes medication
X
X
X
X
X
Study drug reminder
X
X
X
X
Physical examination9
X
X
X
SAEs, AEs of special interest, AEs leading to IP 
discontinuation 
X
X
X
X
X
X
Pregnancy test10
X
X
Study drug dispense/compliance11
X
X
X
X
X
1.
Subjects who discontinue investigational product should be handled as described in Section 4.4. 
2.
Assessments per the Month 4 visit will alternate with those per the Month 8 visit throughout the study i.e., assessments at months 4, 12, 20 etc will be per Month 4; those at month 8, 16, 24 etc..will 
be per Month 8.
3.
Screening and Randomisation can occur at the same visit if all eligibility information is available. If Screening and Randomisation occur at the same visit assessments should not be duplicated.
4.
Once it is projected that the target number of MACE events will have been collected, a 3 month window will be defined for conducting the final, face to face visit.
5.
HbA1c and creatinine assessed using local laboratories at Screening visit and measured no more than 6 months prior to randomisation. If HbA1c or creatinine have not been assessed in the previous 
6 months assessments to be performed via a central laboratory and results available prior to randomization. The investigator has the discretion to repeat screening HbA1c, and/or creatinine, based 
on clinical rationale even if previously available local results meet the eligibility criteria to allow the investigator to accommodate the possibility of change between screening and randomisation.
6.
Liver function tests: ALT, AST, alkaline phosphatase, bilirubin, GGT. Blood samples for LFTs at randomization must be collected prior to the first dose of investigational product.
7.
Informed consent for genetic research must be obtained before collecting a sample.  Genetics sample can be collected at any time after genetic consent has been obtained and the subject has been 
randomised.
8.
TRIM-D, EQ-5D and study specific questionnaire (details in Section 6.3).
9.
See Section 6.2.7. 
10.
Only applies to women of child bearing potential. At screening perform urine pregnancy test.  If positive, send serum sample to the central laboratory for confirmation. At Randomisation perform a 
urine pregnancy test. If result is positive do not randomize the subject. If the urine pregnancy test is negative then the subject can be randomised. If Screening and Randomisation are to take place at 
the same visit then follow the instructions for Screening. See Section 6.2.6.
11.
Study drug dispensing not performed at final visit, compliance check not performed at Screening.

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6.1.
Critical Baseline Assessments
Disease, and therapy history, including cardiovascular medical history/risk factors will be 
assessed at Baseline. Investigators are encouraged to implement lifestyle modifications 
and adjust or initiate the appropriate pharmacotherapy throughout the study as 
recommended by current locally followed therapeutic cardiovascular and diabetes 
guidelines for participants in the study.  Screening and randomisation can occur at the 
same visit depending on availability of information to determine eligibility of the subject
to enter the study.
6.2.
Safety
The following sections provide further detail on the safety assessments.  Planned time 
points for all safety assessments are listed in the Time and Events Table (Table 1).  
Unscheduled visits will occur as medically necessary. Detailed procedures for obtaining 
each assessment are provided in the SRM.
Safety endpoints are described in Section 2 and will include monitoring of cardiovascular
events (Section 6.2.1), deaths, AEs of special interest (Section 6.2.3), clinically 
significant microvascular events (Section 6.2.4), SAEs and AEs leading to 
discontinuation of investigational product.
Liver chemistry stopping and follow-up criteria and AEs are described in Section 4.4.3
and Appendix 3.
6.2.1.
Cardiovascular Events
Events referred to the CEC by the investigator as potential endpoints or transient 
ischemic attacks (TIAs) will not be collected or reported as SAEs, regardless of the 
adjudication outcome (Section 6.2.2). These events will be reviewed by an Independent 
Data Monitoring Committee (Section 9.8).
The CEC will review and adjudicate the following clinical events:

Myocardial infarction

Stroke

Unstable angina requiring revascularization

Hospitalization for heart failure

Sudden cardiac death

TIA

In addition, all clinical events submitted for adjudication and all other SAEs with a 
fatal outcome will be reviewed and adjudicated to classify the cause of death as 
cardiovascular or non-cardiovascular.
When the local investigator reported event and the CEC decision on the nature of the 
event differ, the CEC’s decision will be considered final. The detailed descriptions of the 

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endpoint (and TIA) definitions necessary for adjudication are contained within the CEC 
Charter (available on request). The guiding principle will be the “2014 ACC/AHA Key 
Data Elements and Definitions for Cardiovascular and Stroke End Point Events for 
Clinical Trials” [ACC/AHA, 2014] and the “Third Universal Definition of Myocardial 
Infarction” endorsed by the European Society of Cardiology (ESC), the American 
College of Cardiology Foundation (ACCF), the American Heart Association (AHA), and 
the World Heart Federation (WHF) [Thygesen, 2012].
Source documentation required to support the adjudication of the events is described in 
the SRM.  Recording of potential endpoint and TIA events in the eCRF and submission 
of source documentation will be required for clinical events meeting reporting criteria 
whether or not an endpoint event is suspected by the investigator.
6.2.1.1.
Other CV Events
GSK has identified other CV events of special interest for all clinical studies. 
Investigators will be required to fill out event specific data collection tools for the 
following cardiovascular events which meet SAEs criteria or are non-serious events that 
result in discontinuation of investigational product:  

Arrhythmias (other than atrial fibrillation/flutter, see Section 6.2.3) 

Valvulopathy

Pulmonary hypertension

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularisation (other than urgent revascularisation for unstable angina, a 
component of a secondary endpoint)
This information should be recorded in the specific cardiovascular eCRF within one 
week. 
6.2.2.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 5.
The investigator or site staff will be responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE.  
For this study events of myocardial infarction, stroke, unstable angina requiring urgent 
revascularization, hospitalization for heart failure, TIA and sudden cardiac death will not 
be collected or reported as AEs or SAEs. These events will be collected separately, 
subjected to blinded adjudication by an independent CEC using prespecified diagnostic 
criteria, and reported separately (Section 6.2.1.1). All other events that meet serious 
criteria as defined in Appendix 5 should be reported as SAEs.
All events with an outcome of death will be adjudicated to classify the cause of death as 
specifically cardiovascular or non-cardiovascular. Any event resulting in death should be 

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reported as a SAE unless the event is myocardial infartion, stroke, unstable angina w/ 
urgent revascularization, Heart failure, TIA or sudden cardiac death which the protocol 
specifies are not to be collected as adverse events. 
The study will not collect all non-serious AEs. Non-serious AEs leading to 
discontinuation of investigational product and non-serious AEs of special interest (see 
Section 6.2.3) will be collected. 
Any events not specifically addressed above should be reported as an AE or SAE 
according to the definitions in Appendix 5. 
6.2.2.1.
Time period and Frequency for collecting AE and SAE information

AEs and SAEs will be collected from the start of Study Treatment until the follow-
up contact (see Section 6.2.2.3), at the timepoints specified in the Time and Events 
Table (Table 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.

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. 

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Appendix 5.

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 5.
6.2.2.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting SAEs. Open-ended and non-
leading verbal questioning of the subject is the preferred method to inquire about SAE 
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?” 

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Additionally subjects will be asked specific questions about the occurrence of AEs of 
special interest (Section 6.2.3).
6.2.2.3.
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 6.2.3) 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 4.5). Further information on follow-up procedures is given in 
Appendix 5.
6.2.2.4.
Sentinel Events
A Sentinel Event is a GSK-defined SAE that is not necessarily drug-related but has been 
associated historically with adverse reactions for other drugs and is therefore worthy of 
heightened pharmacovigilance. Medical monitor review of all SAEs for possible Sentinel 
Events is mandated at GSK.  The GSK medical monitor may request additional clinical 
information on an urgent basis if a possible Sentinel Event is identified on SAE review. 
The current GSK-defined Sentinel Events are listed below:

Acquired Long QT Syndrome

Agranulocytosis/severe neutropenia 

Anaphylaxis and anaphylactoid reactions (see also Section 6.2.3)

Hepatotoxicity (see also Section 6.2.3)

Acute renal failure

Seizure

Stevens Johnson syndrome/toxic epidermal necrosis
6.2.2.5.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK or designee of SAEs and non-serious AEs 
related to study treatment (even for non- interventional post-marketing studies) is 
essential so that legal obligations and ethical responsibilities towards the safety of 
subjects and the safety of a product under clinical investigation are met. 
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.

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An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
6.2.3.
Adverse Events of Special Interest
The investigator or site staff will be responsible for detecting, documenting and reporting 
events the following AEs of special interest:

Development of thyroid cancer 

Haematologic malignancy

Pancreatic cancer 

Pancreatitis 

Injection site reactions

Immunological reactions (e.g., drug hypersensitivity reactions involving 
anaphylaxis/anaphylactoid reactions, acute bronchoconstriction, angioedema, and/or 
acute urticaria) 

Severe hypoglycaemia events (which includes all events meeting the definition of 
SAEs Appendix 5)

Hepatic events

Hepatic enzyme elevations (including GGT)

Serious GI events

Appendicitis

Atrial fibrillation/flutter

Pneumonia

Worsening renal function

Diabetic retinopathy
The results of any investigation should be recorded in the relevant sections of the 
subjects’ eCRFs. In addition, for thyroid, pancreas or haematological malignancies 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. In subjects where a treatment 
emergent thyroid nodule is identified, if serum calcitonin is measured at the discretion of 
the Investigator (e.g., per local guidelines) and found to be >100 ng/L this should prompt 
further investigation for MTC and potential interruption or discontinuation of 
investigational product until diagnosis has been resolved. If MTC or other thyroid C-cell 
neoplasia is diagnosed, albiglutide will be discontinued.

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A Pancreatitis Adjudication Committee composed of independent specialists in 
gastroenterology will review all cases of possible pancreatitis. 
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 in the SRM.  These 
events should be reported as AEs or SAEs based on the clinical evaluation of the subject. 
The reactions should be followed to completion as typical for any AE or SAE.  Subjects 
with allergic or drug hypersensitivity reactions that are considered by the investigator to 
be attributable to investigational product or without a likely alternative aetiology should 
have investigational product withdrawn and not re-introduced.
Episodes of severe hypoglycaemia will be recorded according to subject report.  Severe 
hypoglycaemic incidents will be defined as those episodes of hypoglycaemic symptoms 
for which the subject required assistance from another person and from which the subject 
recovered promptly after oral carbohydrate, intravenous glucose, glucagon administration 
or other resuscitative actions (definition per ADA Workgroup on Hypoglycaemia 
[Seaquist, 2013]).  Additionally, all episodes of hypoglycaemic symptoms which in the 
investigator’s opinion meet the definition of a SAE (defined in Appendix 5) will be 
included as severe hypoglycaemic episodes. During this study, if a subject’s eGFR 
approaches 30mL/min/1.73m2 closer monitoring of renal function is considered prudent, 
according to standard clinical practice. If eGRF is <15mL/min//1.73m2 follow the 
procedure set out in Section 4.4.4.
6.2.4.
Clinically Important Microvascular Events
Clinically important microvascular events are defined as the following: need for renal 
transplant or dialysis, new diabetes-related blindness, and procedures (laser 
photocoagulation or anti-vascular endothelial growth factor treatment or vitrectomy for 
diabetic retinopathy/eye disease).  Clinically important microvascular events will be 
reported as recorded in the eCRF by the investigator without adjudication.
The AEs associated with the above outcomes or treatments should be reported separately 
as an AE or SAE according to the definitions in Appendix 5.
6.2.5.
Pregnancy

If a subject becomes pregnant during the study they should discontinue 
Investigational Product.

Details of all pregnancies in female subjects will be collected after the start of 
dosing and until the end of the Post-treatment Follow-up Period.

If a pregnancy is reported then the investigator should inform GSK within 2 weeks 
of learning of the pregnancy and should follow the procedures outlined in Appendix 
6.

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6.2.6.
Clinical Laboratory Assessments
All protocol required laboratory assessments must be conducted in accordance with the 
Laboratory Manual, and Protocol Time and Events Schedule (Table 1). Details for the 
preparation and shipment of samples will be provided by the laboratory and are detailed 
in the laboratory manual. Reference ranges for all central laboratory safety parameters 
will be provided to the site.
If additional non-protocol specified laboratory assessments result in a change in subject 
management or are considered clinically significant by the investigator (e.g., SAE or AE
of special interest or dose modification) the results must be recorded in the CRF.
Refer to the SRM/laboratory manual for appropriate processing and handling of samples 
to avoid duplicate and/or additional blood draws.
The following laboratory assessments will be performed: serum creatinine, HbA1c, liver 
function tests [AST (SGOT), ALT (SGPT), alkaline phosphatase, bilirubin, GGT], and 
urine and serum hCG pregnancy test (for women of child bearing potential). All study-
required laboratory assessments will be performed by a central laboratory, with the 
exception of HbA1c and creatinine at Screening and urine pregnancy test at 
Screening/Randomization. 
Screening HbA1c and serum creatinine
Screening HbA1c and serum creatinine values should be based on the most recent local 
laboratory values taken as part of usual care within the previous 6 months and the values 
entered into the eCRF. These assessments must have been performed at an accredited
laboratory.  HbA1c screening results must be either Diabetes Control and Complications 
Trial (DCCT) aligned or International Federation of Clinical Chemistry and Laboratory 
Medicine (IFCC) standardized.  HbA1c screening results from point of care equipment 
are acceptable provided that the equipment is maintained by an accredited laboratory. If 
HbA1c or creatinine have not been assessed in the previous 6 months, laboratory 
assessments will be performed via the central laboratory to determine eligibility (if a 
local laboratory is used in error the results are acceptable for determining eligibility). The 
investigator has the discretion to repeat screening HbA1c, and/or creatinine, based on 
clinical rationale even if previously available local results meet the eligibility criteria to 
allow the investigator to accommodate the possibility of change between screening and 
randomisation.
Re-screening of subjects who did not meet the eligibility criteria for HbA1c or creatinine 
based on local laboratory values taken as part of usual care is permitted. If values were 
based on laboratory results as part of usual care then one re-test is permitted within the 
protocol at Screening. Any future re-screening will be based on laboratory results 
obtained as part of usual care.

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Pregnancy testing (for women of childbearing potential)
At the screening visit perform a urine pregnancy test. If the urine pregnancy test is 
positive, send a serum blood sample to the central laboratory for confirmation of 
pregnancy. 
At the Randomisation visit perform a urine pregnancy test. If the result is positive do not 
randomize the subject. If the urine pregnancy test is negative then the subject can be 
randomised (provided all other eligibility criteria have been met).
If Screening and Randomisation are to take place at the same visit then follow the 
instructions for Screening. Do not randomise if the urine pregnancy test is positive; send 
a serum blood sample to the central laboratory for confirmation of pregnancy. If the urine 
pregnancy test is negative then the subject can be randomised at the same visit (provided 
all other eligibility criteria have been met).
6.2.6.1.
Estimated Glomerular Filtration Rate (eGFR)
Serum creatinine will be measured every 8 months by a central laboratory. 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).
6.2.7.
Physical examination
A general physical examination, including height and neck (thyroid), will be performed at 
randomization. A targeted physical examination will be performed at all other time points 
as specified in the Time and Events Table (Table 1). The targeted physical examination
will evaluate the cardiovascular system and injection sites and will include measurement 
of blood pressure and heart rate taken with the subject either in a semi-recumbent or 
seated position after at least a 5-minute rest period.
6.3.
Value Evidence and Outcomes
6.3.1.
Value Evidence and Outcomes Assessments
6.3.1.1.
Treatment Related Impact Measure – Diabetes (TRIM-D)
In order to evaluate satisfaction with treatment and to compare satisfaction across 
treatment groups, the TRIM-D questionnaire will be self administered by all subjects at 
baseline and at each 8 month visit (and, to the extent possible, at the time of study 
completion or withdrawal from the study).
The TRIM-D, developed in 2009, is a 28-item treatment satisfaction measure scored to 
produce 5 sub-scale scores (Treatment Burden, Daily Life, Diabetes Management, 
Psychological Health, and Compliance) as well as a total score. It is available in a wide 
range of translations.

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The TRIM-D development, in accordance with the principles of the Food and Drug 
Administration Patient Reported Outcome Guidance document, was based on findings 
from the published literature including content from already-existing treatment 
satisfaction measures as well as significant input from subjects with type 1 and with type 
2 diabetes and from expert diabetes clinicians.  The TRIM-D has been evaluated in a 
sample of 507 subjects (74% with type 2 diabetes) and has been shown to have 
acceptable reliability and validity [Brod, 2009a]. Its responsiveness was also evaluated 
in a sample of 242 subjects (71% with type 2 diabetes) and found to be acceptable [Brod,
2009b].  Some preliminary work has been done on estimating its minimal important 
difference but this needs further exploration [Brod, 2009b].
6.3.1.2.
EQ-5D
The EQ-5D will be self-administered by subjects in order to measure generic health 
status. Combining the EQ-5D with the disease-specific TRIM-D, which is designed to 
have maximum sensitivity to relevant aspects of disease related treatment, will provide a 
more robust evaluation of the impact of treatments for type 2 diabetes and allow for 
clearer interpretation of study results.  TRIM-D results, if consistent with the general 
trends seen in the EQ-5D, will have enhanced credibility.
The EQ-5D is a standardized instrument used to evaluate generic health-related quality of 
life. It is applicable to a wide range of health conditions and treatments, and it provides a 
simple descriptive profile and a single index value for health status. It is also used to 
provide utilities, or preference weights, for use in economic (cost effectiveness) 
evaluations. It is available in 141 self complete official language versions.
The EQ-5D has been used extensively in studies to measure the impact of type 2 diabetes 
and treatments for the disease. A systematic review identified 54 publications reporting 
EQ-5D responses and 39 papers presenting evidence on the measurement properties of 
the EQ-5D in this population [Janssen, 2011]. This evidence supported the validity, 
reliability, and responsiveness of the EQ-5D for evaluating health-related quality of life 
in subjects with type 2 diabetes. Other studies reported that index scores from the EQ-5D 
have been shown to be an independent predictor of the risk of mortality, future vascular 
events, and other complications in people with type 2 diabetes [Clarke, 2009]. In 
addition, the SHIELD longitudinal study (1,741 respondents with type 2 diabetes and 
4,543 without diabetes) used the EQ-5D to assess the 5-year changes in health-related 
quality of life in type 2 diabetes [Grandy, 2012].
6.3.1.3.
Exploratory Diabetes Management Questions
In addition to the standardised instruments described above, patient experience in relation 
to the management of their diabetes will be evaluated in a subset of sites using a small 
number of self-administered diabetes management questions. These types of customized 
questions have been used successfully in asthma and in diabetes when patients are 
involved with goal-setting [Juniper, 1992; Anderson, 2010]. This tailored approach is an 
opportunity to capture data in the study that are not otherwise available from standard 
PRO measures such as the TRIM-D and the EQ-5D. As an exploratory endpoint, this set 
of questions (3 items at baseline, and at each 8 month follow-up visit) imposes very little 
patient or site burden, but can offer critical insight into the one area of the patient’s 

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choosing that s/he finds most difficult to manage. In addition, this patient-centred
endpoint has the potential to be sensitive to changes over time.
These questions have been developed by GSK based on factors identified as important to 
subjects in the development of published, validated and reliable subject reported 
outcomes instruments in type 2 diabetes.
6.3.1.4.
Healthcare Resource Utilisation
Data will be collected on the following heathcare resource use:

All cause hospitalisations and related healthcare resource use.
Healthcare resource use data  will be collected in order to facilitate subsequent health-
economic analyses comparing costs between albiglutide added to standard of care and 
placebo added to standard of care (cost is not an end point in the study). 
Data on all-cause hospitalizations and related inpatient healthcare resource use will be 
collected.  This will include:

All-Cause hospitalisation including: Admission and discharge diagnoses 
(primary and secondary), length of stay, level/type of ward, and time spent in 
Intensive Therapy Unit (or equivalent).
6.4.
Genetic Research
Information regarding genetic research is included in Appendix 1.  
7.
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.

Adverse events and concomitant medications terms will be coded using MedDRA 
(Medical Dictionary for Regulatory Activities) and an internal validated medication 
dictionary, GSKDrug.  

CRFs (including queries and audit trails) will be retained by GSK, and copies will be 
sent to the investigator to maintain as the investigator copy.  Subject initials will not 
be collected or transmitted to GSK according to GSK policy.

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8.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS
8.1.
Hypotheses
This trial will examine the following primary question:

Whether albiglutide is non inferior by a margin of 1.3 with respect to its effect on 
adjudicated MACE, when added to glycaemic standard of care, versus standard of 
care alone. Letting λ1 = hazard ratio for time to first MACE for albiglutide vs 
placebo, then:
Null hypothesis: log λ1 ≥ log(1.3)
Alternative hypothesis: log λ1 < log(1.3)
8.2.
Study Design Considerations
8.2.1.
Sample Size Assumptions
The primary outcome will be analyzed such that the overall Type 1 error is no greater 
than 5% (two-sided).  Specifically, the non-inferiority assessment of albiglutide 
compared to placebo will be conducted at 0.05 level, requiring one-sided significance at 
0.025.  
The power for MACE non-inferiority is calculated via the asymptotic variance and 
normality of the maximum likelihood estimator for the log-hazard ratio. Assuming a true 
hazard ratio of 1.0, 611 events will be needed to have 90% power to rule out non-
inferiority margin of 1.3 for the hazard ratio with type I error of 0.05.  The study duration 
will be event-driven.  A total of 9400 subjects will be enrolled and followed until it is 
projected that approximately 611 adjudicated MACE events will have occurred. If the 
observed rate for MACE is 2.0% or 3.0%, the mean follow-up will be 3.2 or 2.2 years 
respectively, assuming that the number of subjects lost to follow-up accounts for 1% or 
less.
8.2.2.
Sample Size Sensitivity for MACE non-inferiority
9400 subjects will be enrolled to cumulate the first MACE events experienced by 611 
unique subjects. The study duration may vary depending on actual MACE event rate and 
duration of enrolment period.

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Table 2
Total Study Duration Sensitivity for Varying MACE Event Rate and 
Duration of Recruitment
Duration of recruitment
1.5 yrs
2.0 yrs
2.5 yrs
3.0 yrs
MACE rate (% pa)
2.0
4.1yrs
4.4yrs
4.6yrs
4.9yrs
2.5
3.4 yrs
3.7yrs
3.9yrs
4.2yrs
3.0
3.0yrs
3.2yrs
3.5yrs
3.8yrs
3.5
2.7yrs
2.9yrs
3.2yrs
3.4yrs
8.2.3.
Sample Size Re-estimation
The aggregate blinded event-rate data will be periodically reviewed by the Executive 
Committee and the sponsor. The study has an event-driven design. Should emerging data 
diverge significantly from protocol assumptions, the total sample size and/or follow up 
time may be adjusted, within the bounds of feasibility, to achieve the event target.
8.3.
Data Analysis Considerations
8.3.1.
Analysis Populations
The intent-to-treat (ITT) population will include all randomly assigned subjects. The ITT 
subjects will be analyzed according to randomised treatment. The inference for primary 
objectives in the study will be made from ITT population.
Per-protocol Population (PP) will exclude the subjects who have major protocol 
violations. Per-protocol analysis will include Per-protocol population only and their data 
upon to the time of discontinuation of investigational product plus 56 days.
The non-insulin population (NI) will include all subjects in the ITT population who are 
not on insulin at baseline. Inference for the time to insulin endpoint will be made from 
the NI population. 
The baseline basal insulin user population (BI) will include all subjects in the ITT 
population who are on basal insulin, but not on other insulin at baseline. Inference for the 
time to prandial insulin endpoint will be made on BI population.
The safety population will include all enrolled subjects who receive at least 1 dose of 
study treatment. The safety population subjects will be analyzed according to the 
treatment received. The safety population will be used for analyses of safety objectives.
Other analysis populations will be defined in the RAP. 

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8.3.2.
Analysis Data Set
For time to event data, censoring time for subjects who lost to follow-up is defined as 
following:

For primary analysis, subjects who are lost to follow-up will be censored at the date 
of last evidence of confirmatory status for MACE events. 

For on-treatment analysis, censoring date will be the last dose date. 

For on-therapy analysis (on-treatment+56 days), censoring date will be the last dose 
date+56 days.

For analysis of all cause of mortality, censoring date will be the latest date known 
alive.
8.3.3.
Treatment Comparisons
Demographic and baseline characteristics (e.g., gender, age, racial or ethnic origin, height 
and weight, body mass index (BMI), blood pressure and other characteristics) will be 
summarized for each treatment group.  In addition, smoking and alcohol habits, diabetic 
and cardiovascular medical history, baseline laboratory results, and prior medications will 
be summarized by treatment group.  Binary and ordinal characteristics will be 
summarized by counts and percentages, while continuous variables will be represented by 
mean and standard deviations or medians and percentiles, as appropriate.  Any variables 
with treatment imbalances may be considered as covariates for further analysis of an 
exploratory nature.  Such covariates will be identified on the basis of the clinical 
relevance of the observed treatment difference.
8.3.3.1.
Primary Comparisons of Interest
The primary endpoint will be the time to the first occurrence of MACE over the full 
duration of the study. A p-value for the primary endpoint will be calculated from a Cox 
regression model with treatment group as the only covariate for the hypotheses described 
in Section 8.1.
8.3.3.2.
Other Comparisons of Interest
For other analyses incidence rates will be presented for binary data and summary 
statistics (mean, median, standard deviation, minimum, and maximum) will be presented 
for continuous data. Furthermore, summary statistics of change from baseline for HbA1c
will be presented along with percent of subjects within ranges of clinical interest (e.g.,
HbA1c < 7.0%).
8.3.4.
Interim Analysis
An IDMC will monitor progress of the study and ensure that it meets the highest 
standards of ethics and subject safety.    All cardiovascular event data, together with other 
safety data, will be sent to the IDMC for review at approximately every 6 months after 
the first subject has been randomised to receive treatment.  This frequency may be 

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adjusted, if deemed necessary by the IDMC, depending on the enrolment rates and the 
rate of safety events. There are no plans to stop the study early for a non-inferiority or 
benefit claim, however should the IDMC identify in the course of its scheduled reviews 
overwhelming evidence of MACE benefit (e.g., p < 0.001), with directionally consistent 
findings on all-cause mortality, the IDMC might consider recommending early stopping.  
This approach essentially preserves the final alpha for the end-of-study analysis at 5% 
and hence there are no plans to adjust the final alpha on account on safety reviews 
conducted by the IDMC. The IDMC charter, reporting and procedures are outlined in 
separate documents.
8.3.5.
Multiplicity Controls
A multiple comparisons adjustment strategy will be implemented for the multiple 
inferential tests among the primary endpoint and secondary endpoints of MACE 
superiority, time to insulin and composite metabolic endpoint.
The strategy will use a combination of gatekeeper and Hommel procedure. The first step 
is to evaluate the MACE non-inferiority of the albiglutide group vs the placebo group at a 
one-sided alpha=0.025 level. If the result of non-inferiority is significant, MACE 
superiority, time-to-insulin and composite metabolic endpoint will be tested 
simultaneously using the Hommel procedure with alpha=0.05.  The above multiplicity 
control approach will preserve the study’s nominal significance level of 0.05. The test 
order is illustrated in the diagram below.

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Hommel Procedure for secondary endpoints is described below:
Three hypothesis testsfor MACE superiority, time-to-insulin, and composite metabolic 
endpoint are subject to be adjusted by the Hommel procedure. Let P(1), P(2) and P(3) 
represent the ordered p-values that P(3) > P(2) > P(1) and H(1), H(2) and H(3) are 
corresponding hypotheses. 
If P(3)< 0.05, reject H(3), H(2), H(1). End of test.
If P(3) ≥0.05 and P(2) < 0.05/2, accept H(3), reject H(2), H(1). End of test.
If P(3)≥0.05 and P(2)≥0.05/2 and P(1) < 0.05/3, accept H(3), H(2), reject H(1). End of 
test.
If P(3)≥0.05, P(1)≥ 0.05/3 and 0.05/2≤ P(2)< 0.05*2/3, accept H(3), H(2), reject H(1). 
End of test.
If P(3)≥0.05, P(2)≥ 0.05*2/3 and P(1)≥ 0.05/3, accept H(3),,H(2) and H(1).

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Other Secondary Endpoints and Subgroup Analysis
The following secondary endpoints will provide supportive evidence for cardiovascular
safety and will not use any multiplicity adjustment procedure. 

Components of primary endpoint (MACE = cardiovascular death, MI, stroke)

MACE + urgent revascularisation for unstable angina

Cardiovascular death or hospitalisation for heart failure
Other secondary endpoints which do not qualify for formal statistical hypothesis testing 
will be analyzed and have results presented with confidence interval and nominal p-
values:

Mean HbA1c at scheduled visits and change from baseline

Mean body weight at scheduled visits and change from baseline

Mean eGFR at scheduled visits and change from baseline

Time to initiation of prandial insulin

Composite microvascular endpoint
To examine the degree of consistency of the overall treatment effect in terms of important 
prognostic factors, subgroup analyses of the primary outcomes will be performed based 
on subject demographics and baseline characteristics. These exploratory subgroup 
analyses will not be adjusted for multiple comparisons and will be interpreted 
descriptively.
8.3.6.
Key Elements of Analysis Plan
Any deviations from the original analysis planned in the protocol agreed upon prior to 
finalization of the RAP, will be described in that document. Any additional changes to 
the planned analysis in the RAP will be described in the final clinical study report.
8.3.6.1.
Primary Analysis
The primary analysis is an ITT analysis of the time to the first occurrence of MACE over 
the full duration of the study. Time to event analyses will be performed using Cox’s 
Proportional Hazard regression with SAS PHREG with treatment group as the only 
covariate.  Data for subjects without a primary event will be censored.
Treatment differences will be estimated via the hazard ratio and its 95% confidence 
interval (CI).
The hypothesis of non-inferiority of albiglutide relative to placebo group with hazard 
ratio less than 1.3 with respect to cardiovascular risk will be tested at the end of the study 
when ~611 first MACE events are cumulated.  

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The strength of evidence for non-inferiority will be determined by testing the hypothesis 
that the observed hazard ratio is significantly different from the null margin of 1.3 (one-
sided p < 0.025 for such a test being equivalent to the upper 95% confidence limit after 
multiplicity adjustment for the hazard ratio being less than 1.3).  The absolute risk 
difference per 100 PY and superiority p-value for albiglutide vs. placebo will also be 
presented.
The product-limit estimates of the probabilities (and their standard errors) of first MACE 
over time will be computed and displayed as Kaplan-Meier (KM) survival curves for 
albiglutide and placebo groups.  The KM curves will also be presented corresponding to 
the above comparisons.
The total number of all MACE or any of its components will be analyzed by Poisson 
regression model. The incidence rate per 100 person-years, relative risk and their 95% CI 
will be presented. Number of subjects who experienced at least one event, 2 or 3 or more 
MACE or its components will also be summarized by treatment group.
As sensitivity analyses, the analyses described above will be repeated using events occur 
while on-treatment and events occur during the period of on-treatment plus 56 days post 
last dose.
8.3.6.2.
Secondary Endpoint Analysis
Endpoints that supplement the primary objective by further characterization of the effects 
of albiglutide on cardiovascular outcomes endpoints:

MACE superiority will be evaluated using the same Cox regression model as the 
primary analysis of MACE non-inferiority.

Supportive endpoints including the time to first occurrence of adjudicated MACE or 
urgent revascularisation for unstable angina, time to first occurrence of individual 
components of MACE, time to first occurrence of cardiovascular death or 
hospitalisation for heart failure will be analyzed using a proportional Cox regression
model similarly as the primary endpoint.
Endpoints that evaluate the effects of albiglutide on metabolic management of type 2
diabetes:

Among the subjects who are not on insulin at baseline (NI population), time to 
insulin will be analyzed using a proportional Cox regression model similar to the 
primary MACE analysis. The product-limit estimates of the probabilities (and their 
standard errors) of adding insulin over time will be computed and displayed as 
Kaplan-Meier (KM) survival curves for albiglutide and  placebo treatment groups. 
The KM curves will also be presented corresponding to the above comparisons.

Composite of the proportion of those achieving good control (HbA1c ≤ 7.0%) AND 
no severe hypoglycaemic incidents AND weight gain <5% at the end of the study 
would be evaluated utilize nonparametric, covariance-adjusted, extended Mantel-
Haenszel tests. Additional analysis will be provided for scheduled visits. Nominal p-
values and 95% CIs will be presented for these visits. Time to introduction of 

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prandial insulin in those on basal insulin orals anti-hyperglycemic drugs at baseline 
will be analyzed using PH model / log-rank test and KM method similar to the 
primary endpoint.

Composite of microvascular events will be analyzed using a proportional Cox 
regression model / log-rank test and KM method similar to the primary endpoint.

HbA1c, body weight and eGFR will be analyzed using a repeated mixed effect 
model. The least square means, 95%CIs and nominal p-values will be presented.

Additional analysis will be performed to assess the incidence rate of recurrent severe 
hypoglycaemic events between treatment groups during the course of the study. A 
repeated Poisson regression model including treatment and visit as factors will be 
used to test treatment difference with offset for person years. An unstructured 
working correlation matrix will be used in the iterative estimation process. The 
model-adjusted least square incidence rate for each treatment as well as the treatment 
difference of the incidence rate will be reported. Events of severe hypoglycaemia 
will also be summarized descriptively by treatment group. Additional summary by 
baseline HbA1c, renal status and age subgroup will also be provided.
Further analysis details will be provided in the RAP.
8.3.6.3.
Subgroup Analysis
Separate subgroup analyses of the primary outcomes will be performed based on subject 
demographics and baseline characteristics.  Subgroups may include sex, age group, BMI, 
whether subjects have history of a previous cardiovascular event, and baseline HbA1C, 
background of anti-hyperglycaemia treatment etc. The detail of subgroups will be pre-
specified in the RAP.  Consistency of treatment effects will be assessed using Cox 
regression, along with the 95% confidence intervals for the relative risk or hazard ratios 
for each subgroup a nominal alpha level for interaction of 0.10 will be used.  The effect 
of treatment interaction with subgroups will also explored; however as the number of 
these subgroup variables may be large, the probability of observing at least one 
statistically significant result may be high.  Thus these additional analyses will be 
considered exploratory regardless of the p-value associated with any interaction.
Further details will be provided in the RAP.
8.3.6.4.
Other Safety Analyses
Subject demographics, medical history, prior and concomitant medications, vital sign 
measurements, laboratory values, physical examination assessments, will be summarized 
by treatment group using descriptive statistics. 
For continuous variables, these summaries will include sample size, mean, median, 
standard deviation, minimum, and maximum. For categorical variables, the summaries 
will include frequencies and corresponding percentages. 

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For SAEs, AEs leading to withdrawal  and AEs of special interest occurring after 
discontinuation of investigational product, the number and percentage of subjects , total 
number of events, incidence density and event rate will be presented by treatment group 
and overall at the SOC, High Level Term and Preferred Term (PT) level. Relative Risk 
for each event and its 95% CI will also be presented. The time to first occurrence of the 
specific events and the time of the event with respect to the preceding dose of study 
medication will be summarized.
All cause mortality will be summarized by treatment group and analyzed using PH model 
similarly as the-primary endpoint.
All events sent to CEC (including TIAs) will be grouped by type based on the standard 
MedDRA queries that correspond to cardiovascular and cerebrovascular events. 
Adjudication results will be summarized by event type and treatment group. A by subject 
listing of these events will be generated.  The listing will include seriousness, severity, 
whether event is a reason for early study drug discontinuation or study withdrawal, and 
adjudication results.
Pancreatitis events will be adjudicated by the independent Pancreatitis Adjudication 
Committee. The information for investigator reported pancreatitis events and its 
adjudication results will be provided.
Further analysis details will be provided in the RAP.
8.3.6.5.
Value Evidence and Outcomes Analyses
TRIM-D total score and score for each domain will be summarized descriptively by 
treatment group and scheduled visit. Score changes from baseline will be compared 
between treatments for each visit by ANCOVA an model
For EQ-5D, subjects’ responses at each visit for the 5 domains will be summarized 
categorically by treatment group, together with the summary of utility score at each visit 
and change from baseline by treatment group. Change from baseline will be compared 
between treatment groups for each visit by an ANCOVA model. 
For study specific PRO questions, responses will be summarized descriptively by 
treatment group and scheduled visit. 
Healthcare resource use will be summarized by treatment group and visit. 
Further analysis details will be provided in the RAP.
9.
STUDY CONDUCT CONSIDERATIONS
9.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrolment of subjects begins.

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9.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a site, GSK will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH E6 Good Clinical Practice 
(GCP), all applicable subject privacy requirements, and the guiding principles of the 
current version of the Declaration of Helsinki.  This includes, but is not limited to, the 
following:

IRB/IEC review and favourable opinion/approval of the study protocol and 
amendments as applicable

Signed informed consent  to be obtained for each subject before participation in the 
study (and for amendments as applicable)

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol deviations 
to IRB/IEC)

GSK will provide full details of the above procedures, either verbally, in writing, or 
both.
Signed informed consent must be obtained for each subject prior to participation in the 
study
The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.  Optional assessments 
(including those in a separate protocol and/or under separate informed consent) and the 
clinical protocol should be concurrently submitted for approval unless regulation requires 
separate submission.  Approval of the optional assessments may occur after approval is 
granted for the clinical protocol where required by regulatory authorities.  In this 
situation, written approval of the clinical protocol should state that approval of optional 
assessments is being deferred and the study, with the exception of the optional 
assessments, can be initiated.
9.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK monitors will contact the site prior to the start of the study to review with the 
site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and GSK requirements.  

When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the CRF will 
serve as the source document.
GSK will monitor the study to ensure that the:

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
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.
9.4.
Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK 
may conduct a quality assurance assessment and/or audit of the site records, and the 
regulatory agencies may conduct a regulatory inspection at any time during or after 
completion of the study. 

In the event of an assessment, audit or inspection, the investigator (and institution) 
must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all 
relevant documents and to allocate their time and the time of their staff to discuss the 
conduct of the study, any findings/relevant issues and to implement any corrective 
and/or preventative actions to address any findings/issues identified.
9.5.
Study and Site Closure

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.

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9.6.
Records Retention

Following closure of the study, the investigator or the head of the medical institution
(where applicable) must maintain all site study records (except for those required by 
local regulations to be maintained elsewhere), in a safe and secure location.  

The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review in 
conjunction with assessment of the facility, supporting systems, and relevant site 
staff.  

Where permitted by local laws/regulations or institutional policy, some or all of these 
records can be maintained in a format other than hard copy (e.g., microfiche, 
scanned, electronic); however, caution needs to be exercised before such action is 
taken.  

The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, including 
re-generating a hard copy, if required.  Furthermore, the investigator must ensure 
there is an acceptable back-up of these reproductions and that an acceptable quality 
control process exists for making these reproductions.

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.
9.7.
Provision of Study Results to Investigators, Posting of 
Information on Publicly Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
GSK will provide the investigator with the randomisation codes for their site only after 
completion of the full statistical analysis.

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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.
9.8.
Independent Data Monitoring Committee (IDMC)
An IDMC will be utilized in this study to ensure external objective medical and/or 
statistical review of safety and/or efficacy issues in order to protect the ethical and safety 
interests of subjects and to protect the scientific validity of the study.  The schedule of 
any planned interim analysis and the analysis plan for IDMC review is described in the 
charter.
9.9.
Pancreatitis Adjudication Committee
Detailed information on suspected pancreatitis events will be collected on special pages 
of the eCRF. A Pancreatitis Adjudication Committee composed of independent 
specialists in gastroenterology will review cases of possible pancreatitis. Details of this 
committee and case adjudication are described in the committee’s charter available on 
request.

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10.
REFERENCES
ACC/AHA Key Data Elements and Definitions for Cardiovascular and Stroke End Point 
Events for Clinical Trials, February 4 2014 (peer review draft version)
American Diabetes Association (ADA). Diagnosis and classification of diabetes mellitus. 
Diabetes Care, 2014; 37 (Suppl 1): S81-S90.
Anderson DR, Christison-Lagay J, and Procter-Gray E. Self-Management goal setting in 
a community health center: the impact of goal attainment on diabetes outcomes. Diabetes 
Spectrum 23.2 (2010): 97-105.
Bao W, Aravindhan K, Alsaid H et al. Albiglutide, a long-lasting glucagon-like peptide-1 
analog, protects the rat heart against ischemia/reperfusion injury: evidence for improving 
cardiac metabolic efficiency.  PLoS One 6: e23570. 2011
Brod, M., Christensen, T., Kongsø, J. H. & Bushnell, D. M. Examining and interpreting 
responsiveness of the Diabetes Medication Satisfaction measure. J. Med. Econ. 12, 309–
316 (2009b).
Brod, M., Hammer, M., Christensen, T., Lessard, S. & Bushnell, D. M. Understanding 
and assessing the impact of treatment in diabetes: the Treatment-Related Impact 
Measures for Diabetes and Devices (TRIM-Diabetes and TRIM-Diabetes Device). Health 
Qual. Life Outcomes 7, 83 (2009a).
Butler AE, Campbell-Thompson M, Gurlo T, et al. Marked expansion of exocrine and 
endocrine pancreas with incretin therapy in humans with increased exocrine pancreas 
dysplasia and the potential for glucagon-producing neuroendocrine tumors. Diabetes. 
2013;62(7):2595-604.
Clarke PM, Hayes AJ, Glasziou PG, et al. Using the EQ-5D index score as a predictor of 
outcomes in patients with type 2 diabetes. Med Care 2009; 47: 61-68.
Cooper DS, Doherty GM, Haugen BR et al. Management guidelines for patients with 
thyroid nodules and differentiated thyroid cancer. Thyroid. 2006;16(2):109-142. 
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. 
European Public Assessment Report (EPAR) for Eperzan. 2014.Available at: 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/00273
5/human_med_001735.jsp&mid=WC0b01ac058001d124
FDA Summary Basis of Approval. 2014. Available at:
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/125431Orig1s000TOC.cfm
Fu AZ, Qiu Y, Radican L, Yin DD, Mavros P. Pre-existing cardiovascular diseases and 
glycemic control in patients with type 2 diabetes mellitus in Europe: a matched cohort 
study. Cardiovasc Diabetol. 2010; 9:15.

2014N193553_00
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Grandy S, Fox KM. Change in health status (EQ-5D) over 5 years among individuals 
with and without type 2 diabetes mellitus in the SHIELD longitudinal study. Health and 
Quality of Life Outcomes 2012;10:99.
Guidance for Industry. Diabetes Mellitus: Developing Drugs and Therapeutic Biologics 
for Treatment and Prevention. U.S. Department of Health and Human Services. Food and 
Drug Administration. Center for Drug Evaluation and Research (CDER). February 2008 
Clinical/Medical. Available at http://www.fda.gov/cder/guidance/index.htm.
Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauk M, Peters AL, 
Tsapas A, Wender R, Matthews DR. Management of Hyperglycemia in Type 2 Diabetes: 
A Patient-Centered Approach Position Statement of the American Diabetes Association 
(ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 
2012; 35: 1364-1379
Janssen MF, Lubetkin EI, Sekhobo JP, Pickard AS. The use of the EQ-5D preference-
based health status measure in adults with Type 2 diabetes mellitus. Diabet Med 2011; 
28(4):395-413.
Juniper EF, Guyatt GH, Epstein RS, Ferrie PJ, Jaeschke R, Hiller TK. Evaluation of 
impairment of health-related quality of life in asthma: development of a questionnaire for 
use in clinical trials. Thorax 1992; 47: 76-83.
Khunti K, Andersen M, Wolden ML, Davies MJ and Thorsted BL. Clinical Inertia in 
People With Type 2 Diabetes. Diabetes Care. 2013; 36:3411-3417
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. 
Levey AS, Stevens LA, Schmid CH et al. A new equation to estimate glomerular 
filtration rate.  Ann Intern Med. 2009; 150: 604-12.
Lønborg J, Vejlstrup N, Kelbaek H et al. Exenatide reduces reperfusion injury in patients 
with ST-segment elevation myocardial infarction.  Eur Heart J 2012; 33: 1491-9.
Nystrom T, Gutniak MK, Zhang Q et al. Effects of glucagon-like peptide-1 on 
endothelial function in type 2 diabetes patients with stable coronary disease. Am J 
Physiol Endocrinol Metab 2004; 287: E1209-15.
Okerson T and Chilton RJ. The cardiovascular effects of GLP-1 receptor agonists. 
Cardiovascular Therapeutics 2012; 30: e146-155.
Pacini F, Schlumberger M, Dralle H et al. European consensus for the management of 
patients with differentiated thyroid carcinoma of the follicular epithelium. Eur J 
Endocrinol. 2006;154(6):787-803.

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Schulz KF, Altman DG, Moher D for the CONSORT Group. CONSORT 2010 
Statement: updated guidelines for reporting parallel group randomised trials. Available 
at: http://www. consort-
statement.org/Media/Default/Downloads/CONSORT%202010%20Statement/CONSORT
%202010%20Statement%20(BMJ).pdf
Seaquist E, Anderson J, Childs B, et al. Hypoglycemia and diabetes: A report of a 
workgroup of the American Diabetes Association and the Endocrine Society. Diabetes 
Care. 2013;36:1384-1395.
Stonehouse AH, Darsow T, Maggs DG. Incretin-based therapies. J Diabetes 
2012;4(1):55-67.
Thygesen K, Alpert JS, Jaffe AS etal. Third universal definition of myocardial 
infarction. European Heart Journal. 2012; 33: 2551–2567
Vilsbøll T, Krarup T, Deacon CF, Madsbad S, Holst JJ. Reduced postprandial 
concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic 
patients. Diabetes. 2001; 50(3):609-13.
World Health Organization (WHO). Diabetes Fact Sheet. October 2013. Available at 
http://www.who.int/mediacentre/factsheets/fs312/en/ (Accessed Apr 3, 2014).

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11.
APPENDICES
11.1.
Appendix 1: Genetic Research
Background
Genetics is the study of variability in drug response due to hereditary factors in 
populations.  There is increasing evidence that an individual's genetic background (i.e., 
genotype) may impact the pharmacokinetics (absorption, distribution, metabolism, 
elimination), pharmacodynamics (relationship between concentrations and 
pharmacologic effects or the time course of pharmacologic effects) and/or clinical 
outcome (in terms of efficacy and/or safety and tolerability).  Some reported examples of 
genetic associations with safety/adverse events include:
Drug
Disease
Gene Variant
Outcome
Abacavir
HIV 
[Hetherington, 
2002; 
Mallal, 2002; 
Mallal, 2008]
HLA-B* 57:01
(Human 
Leukocyte 
Antigen B)
Carriage of the HLA-B*57:01 variant has been 
shown to increase a patient's risk for 
experiencing hypersensitivity to abacavir.  
Prospective HLA-B*57:01 screening and 
exclusion of HLA-B*57:01 positive patients 
from abacavir treatment significantly 
decreased the incidence of abacavir 
hypersensitivity.  Treatment guidelines and 
abacavir product labelling in the United States 
and Europe now recommend (US) or require 
(EU) prospective HLA-B*57:01 screening prior 
to initiation of abacavir to reduce the incidence 
of abacavir hypersensitivity.  HLA-B*57:01
screening should supplement but must never 
replace clinical risk management strategies for 
abacavir hypersensitivity.

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Drug
Disease
Gene Variant
Outcome
Carbamaze
pine
Seizure, Bipolar 
disorders & 
Analgesia 
[Chung, 2010; 
Ferrell, 2008]
HLA-B*15:02
Independent studies indicated that patients of 
East Asian ancestry who carry HLA-B*15:02
are at higher risk of Stevens-Johnson 
Syndrome and toxic epidermal necrolysis.  
Regulators, including the US FDA and the 
Taiwanese TFDA, have updated the 
carbamazepine drug label to indicate that 
patients with ancestry in genetically at risk 
populations should be screened for the 
presence of HLA-B*15:02 prior to initiating 
treatment with carbamazepine.
Irinotecan
Cancer 
[Innocenti, 2004; 
Liu, 2008; 
Schulz, 2009]
UGT1A1*28
Variations in the UGT1A1 gene can influence 
a patient’s ability to break down irinotecan, 
which can lead to increased blood levels of the 
drug and a higher risk of side effects. A dose 
of irinotecan that is safe for one patient with a 
particular UGT1A1 gene variation might be too 
high for another patient without this variation, 
raising the risk of certain side-effects that 
include neutropenia following initiation of 
Irinotecan treatment.  The irinotecan drug 
label indicates that individuals who have two 
copies of the UGT1A1*28 variant are at 
increased risk of neutropenia. A genetic blood 
test is available that can detect variations in 
the gene.    
A key component to successful genetic research is the collection of samples during the 
conduct of clinical studies.
Collection of whole blood samples, even when no a priori hypothesis has been identified, 
may enable genetic analysis to be conducted if at any time it appears that there is a 
potential unexpected or unexplained variation in response to albiglutide.
Genetic Research Objectives
The objective of genetic research (if there is a potential unexpected or unexplained 
variation) is to investigate a relationship between genetic factors and response to
albiglutide.  If at any time it appears there is potential variability in response in this 
clinical study or in a series of clinical studies with albiglutide, the following objectives 
may be investigated – the relationship between genetic variants and study treatment with 
respect to:

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
Safety and/or tolerability 

Efficacy
Study Population
Any subject who is enrolled in the clinical study, can participate in genetic research.  Any 
subject who has received an allogeneic bone marrow transplant must be excluded from 
genetic research.
Subject participation in the genetic research is voluntary and refusal to participate will 
not indicate withdrawal from the clinical study or result in any penalty or loss of benefits 
to which the subject would otherwise be entitled.
Study Assessments and Procedures
Blood samples can be taken for deoxyribonucleic acid (DNA) extraction and used in 
genetic assessments.
If taking blood samples: in addition to any blood samples taken for the clinical study, a 
whole blood sample (~6ml) will be collected for the genetic research using a tube 
containing EDTA.  It is recommended that the blood sample be taken at the first 
opportunity after a subject has been randomised and provided informed consent for 
geneticresearch, but may be taken at any time while the subject is participating in the 
clinical study.

The genetic sample is labelled (or “coded”) with a study specific number that 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).  The
blood sample is taken on a single occasion unless a duplicate sample is required due 
to inability to utilise the original sample.  
The DNA extracted from the blood sample may be subjected to sample quality control 
analysis.  This analysis will involve the genotyping of several genetic markers to confirm 
the integrity of individual samples.  If inconsistencies are noted in the analysis, then those 
samples may be destroyed.
The need to conduct genetic analysis may be identified after a study (or a set of studies) 
of albiglutide has been completed and the clinical study data reviewed.  In some cases, 
the samples may not be studied. e.g., no questions are raised about how people respond to
albiglutide.
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 use samples collected from the study for 
the purpose stated in this protocol and in the informed consent form.  
Subjects can request their sample to be destroyed at any time.

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Subject Withdrawal from Study
If a subject who has consented to participate in geneticresearch 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 geneticsample, if already collected:

Continue to participate in genetic research with the geneticsample retained for 
analysis

Withdraw from geneticresearch and destroy the geneticsample 
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. The investigator should forward the Pharmacogenetic Sample 
Destruction Request Form to GSK as directed on the form. This can be done at any time 
when a subject wishes to withdraw from  genetic research or have their sample destroyed 
whether during the study or during the retention period following close of the main study.
Screen and Baseline Failures
If a blood sample for genetic research has been collected and it is determined that the 
subject does not meet the entry criteria for participation in the clinical study, then the 
investigator should instruct the participant 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.
Analyses
1.
Specific genes may be studied that encode the drug targets, or drug mechanism of 
action pathways, drug metabolizing enzymes, drug transporters or which may 
underpin adverse events, disease risk or drug response. These candidate genes may 
include a common set of ADME (Absorption, Distribution, Metabolism and 
Excretion) genes that are studied to determine the relationship between gene variants 
or treatment response and/or tolerance. 
In addition, continuing research may identify other enzymes, transporters, proteins or 
receptors that may be involved in response to albiglutide.  The genes that may code for 
these proteins may also be studied.
2.
Genome-wide scans involving a large number of polymorphic markers (e.g., single 
nucleotide polymorphisms) at defined locations in the genome, often correlated with 
a candidate gene, may be studied to determine the relationship between genetic 
variants and treatment response or tolerance. This approach is often employed when 
a definitive candidate gene(s) does not exist and/or the potential genetic effects are 
not well understood. 
If applicable and genetic research is conducted, appropriate statistical analysis methods 
will be used to evaluate pharmacogenetic data in the context of the other clinical data. 

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Results of genetic investigations will be reported either as part of the main clinical study 
report or as a separate report. Endpoints of interest from all comparisons will be 
descriptively and/or graphically summarised as appropriate to the data. A detailed 
description of the analysis to be performed will be documented in the study reporting and 
analysis plan (RAP) or in a separate pharmacogenetics RAP, as appropriate.  
Informed Consent
Subjects who do not wish to participate in geneticresearch may still participate in the 
clinical study.  Genetic informed consent must be obtained prior to any blood being taken 
for genetic research.
Provision of Study Results and Confidentiality of Subject’s Genetic Data
GSK may summarise the genetic research results in the clinical study report, or
separately, or may publish the results in scientific journals. 
GSK does not inform the investigator, subject, or anyone else (e.g., family members, 
study investigators, primary care physicians, 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.
References
Chung WH, Hung SL, Chen YT. Genetic predisposition of life-threatening antiepileptic-
induced skin reactions.  Expert Opin. Drug Saf. 2010; 9: 15-21.
Ferrell PB, McLeod HL.  Carbamazepine, HLA-B*1502 and risk of Stevens-Johnson 
syndrome and toxic epidermal necrolysis: US FDA recommendations.  
Pharmacogenomics. 2008; 9: 1543-1546.
Hetherington S, Hughes AR, Mosteller M, Shortino D, Baker KL, Spreen W, Lai E, 
Davies K, Handley A, Dow DJ, Fling ME, Stocum M, Bowman C, Thurmond LM, Roses 
AD. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. 
Lancet. 2002; 359:1121-1122.
Innocenti F, Undevia SD, Iyer L, Chen PX, Das S, Kocherginsky M, Karrison T, Janisch 
L, Ramirez J, Rudin CM, Vokes EE, Ratain MJ.  Genetic variants in the UDP-
glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J 
Clin Oncol 2004; 22: 1382-1388.
Liu CY, Chen PM, Chiou TJ, Liu JH, Lin JK, Lin TC, Chen WS, Jiang JK, Wang HS, 
Wang WS.  UGT1A1*28 polymorphism predicts irinotecan-induced severe toxicities 
without affecting treatment outcome and survival in patients with metastatic colorectal 
carcinoma.  Cancer. 2008; 112: 1932-1940.

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Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, Sayer D, Castley A, Mamotte 
C, Maxwell D, James I.  Association between presence of HLA-B*5701, HLA-DR7, and 
HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir.  
Lancet. 2002; 359:727-732.
Mallal S, Phillips E, Carosi G, Molina JM, Workman C, Tomazic J, Jägel-Guedes E, 
Rugina S, Kozyrev O, Cid JF, Hay P, Nolan D, Hughes S, Hughes A, Ryan S, Fitch N, 
Thorborn D, Benbow A; PREDICT-1 Study Team.  HLA-B*5701 screening for 
hypersensitivity to abacavir. N Engl J Med. 2008; 358; 568-579
Schulz C, Heinemann V, Schalhorn A, Moosmann N, Zwingers T, Boeck S, Giessen C, 
Stemmler HJ. UGT1A1 gene polymorphism: Impact on toxicity and efficacy of 
irinotecan-based regimens in metastatic colorectal cancer.  World J. Gastroenterol. 2009; 
15: 5058-5066.

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11.2.
Appendix 2: GSK Modified List of Highly Effective Methods 
for Avoiding Pregnancy in Females of Reproductive 
Potential (FRP)
1.
Contraceptive subdermal implant that meets effectiveness criteria including a <1% 
rate of failure per year, as stated in the product label.
2.
Intrauterine device or intrauterine system that meets effectiveness criteria including a 
<1% rate of failure per year, as stated in the product label [Trussell, 2011]
3.
Oral Contraceptive, either combined or progestogen alone [Trussell, 2011] 
4.
Injectable progestogen [Trussell, 2011]
5.
Contraceptive vaginal ring [Trussell, 2011]
6.
Percutaneous contraceptive patches [Trussell, 2011]
7.
Male partner sterilization prior to the female subject's entry into the study, and this 
male is the sole partner for that subject. The information on the male sterility can 
come from interview with the subject on her male partner’s medical history.
8.
Male condom combined with a female diaphragm, with or without a vaginal 
spermicide (foam, gel, film, cream, or suppository). In the UK it is a country-specific 
requirement of the regulatory authority (Medicines and Healthcare Products 
Regulatory Agency) that a vaginal spermcide be used.
These allowed methods of contraception have a failure rate of less than 1% per year but 
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.
References
Trussell J, Contraceptive Efficacy. In: Hatcher RA, Trussell J, Nelson AL, Cates W, 
Kowal D, and Policar M (editors). Contraceptive Technology: Twentieth Revised 
Edition. New York: Ardent Media, 2011.Table 26-1

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11.3.
Appendix 3: Liver Safety Required Actions and Follow up 
Assessments
Phase III-IV liver chemistry stopping and increased monitoring criteria have been 
designed to assure subject safety and evaluate liver event aetiology (in alignment with the 
FDA premarketing clinical liver safety guidance).  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
Phase III-IV liver chemistry stopping criteria and required follow up assessments 
Liver Chemistry Stopping Criteria - Liver Stopping Event
ALT-absolute
ALT 8xULN
ALT Increase
ALT 5xULN but <8xULN  persists for 2 weeks
ALT 3xULN but <5xULN  persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2 
ALT 3xULN and INR>1.5, if INR measured
Cannot 
Monitor
ALT 5xULN but <8xULN and cannot be monitored weekly for 2 weeks
ALT 3xULN but <5xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) believed to be 
related to  liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue  study treatment 

Report the event to GSK within 24 hours

Complete the liver event CRF and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries 
resolve , stabilize, or return to within baseline 
(see MONITORING below)

Do not restart subject with study treatment 
unless allowed per protocol and GSK Medical 
Governance approval is granted (refer to  

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 3 half lives (15 
days)  of last dose6

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 

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bilirubin2xULN.
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments
Appendix 5)

If restart is not granted, permanently 
discontinue study treatment and continue 
subject in the study for any protocol specified 
follow up assessments 

Re-challenge is not allowed.
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

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 high 
pressure liquid chromatography assay 
(quantifies potential acetaminophen 
contribution to liver injury in subjects with 
definite or likely acetaminophen use in the 
preceding week [James, 2009]). NOTE: 
not required in China

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 

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studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to subjects receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)   
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
5.
If hepatitis delta antibody assay cannot be performed,, it can be replaced with a PCR of hepatitis D RNA virus 
(where needed) [Le Gal, 2005].
6.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM.  
Phase III-IV 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-Protein Adduct in Adults with 
Acetaminophen Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-
1784.

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Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P, Gault E.  Quantification 
of Hepatitis Delta Virus RNA in Serum by Consensus Real-Time PCR Indicates 
Different Patterns of Virological Response to Interferon Therapy in Chronically Infected 
Patients.  J Clin Microbiol. 2005;43(5):2363–2369. 

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11.4.
Appendix 4: Liver Safety Drug Restart Guidelines
If subject meets liver chemistry stopping criteria do not restart subject with study 
treatment unless:
GSK Medical Governance approval is granted (as described below),
Ethics and/or IRB approval is obtained, if required, and
Separate consent for treatment restart is signed by the subject
If GSK Medical Governance approval to restart the subject with study treatment is not
granted, then the subject must permanently discontinue study treatment and may 
continue in the study for protocol-specified follow up assessments.
Restart Following Transient Resolving Liver Stopping Events Not Related to Study 
Treatment
Restart refers to resuming study treatment following liver stopping events in which there 
is a clear underlying cause (other than DILI) of the liver event (e.g. biliary obstruction, 
pancreatic events, hypotension, acute viral hepatitis). Furthermore, there should be no 
evidence of alcoholic hepatitis or hypersensitivity, and the study treatment should not be 
associated with HLA markers of liver injury.
Approval by GSK for study treatment restart can be considered where:

Investigator  requests consideration for study treatment restart if liver chemistries 
have a clear underlying cause (e.g., biliary obstruction, hypotension and liver 
chemistries have improved to normal or are within 1.5 x baseline and ALT 
<3xULN).

Restart risk factors (e.g. fever, rash, eosinophilia, or hypersensitivity, alcoholic 
hepatitis, possible study treatment-induced liver injury) or study treatment has an 
HLA genetic marker associated with liver injury (e.g. lapatinib, abacavir, 
amoxicillin/clavulanate) are reviewed and excluded.

Ethics Committee or Institutional Review Board approval of study treatment restart 
must be obtained, as required.

If restart of study treatment is approved by GSK Medical Governance in writing, the 
subject must be provided with a clear description of the possible benefits and risks of 
study treatment administration, including the possibility of recurrent, more severe 
liver injury or death.  

The subject must also provide signed informed consent specifically for the study 
treatment restart.  Documentation of informed consent must be recorded in the study 
chart.  

Study treatment must be administered at the dose specified by GSK.

Subjects approved by GSK Medical Governance for restarting study treatment must 
return to the clinic once a week for liver chemistry tests until stable liver chemistries 
have been demonstrated and then laboratory monitoring may resume as per protocol. 

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
If after study treatment re-start, subject meets protocol-defined liver chemistry 
stopping criteria, follow usual stopping criteria instructions.

GSK Medical Monitor, and the Ethics Committee or Institutional Review Board as 
required, must be informed of the subject’s outcome following study treatment 
restart. 

GSK to be notified of any adverse events, as per Section 6.2.2 and Appendix 5

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11.5.
Appendix 5: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
11.5.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a subject 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 unfavourable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (haematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae).

The signs and symptoms and/or clinical sequelae resulting from lack of efficacy will 
be reported if they fulfil the definition of an AE or SAE.  Also, "lack of efficacy" or 
"failure of expected pharmacological action" also constitutes an AE or SAE.
Events NOT meeting definition of an AE include:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the subject’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 
condition.

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
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
11.5.2.
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:
Results in death
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.
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 fulfils 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.
Results in disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhoea, influenza, 

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and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday 
life functions but do not constitute a substantial disruption
Is a congenital anomaly/birth defect
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
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.
11.5.3.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the CRF

It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to GSK in lieu of completion of the GSK, AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK.  In this instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to 
submission of to GSK.

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
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.

Subject-completed Value Evidence and Outcomes questionnaires and the collection 
of AE data are independent components of the study.

Responses to each question in the Value Evidence and Outcomes questionnaire will 
be treated in accordance with standard scoring and statistical procedures detailed by 
the scale’s developer.

The use of a single question from a multidimensional health survey to designate a 
cause-effect relationship to an AE is inappropriate.
11.5.4.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. - an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

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
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 CRF.

The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
11.5.5.
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 or the SAE 
coordinator

Site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the electronic data collection tool (e.g., 

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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 or the SAE coordinator by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.

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11.6.
Appendix 6: Collection of Pregnancy Information

Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study

Information will be recorded on the appropriate form and submitted to GSK within 2 
weeks of learning of a subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on mother and infant, which will be 
forwarded to GSK.  Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date. 

Any termination of pregnancy will be reported, regardless of foetal 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 5. 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

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11.7.
Appendix 7: Electronic Health Record Ancillary Study
11.7.1.
Introduction
11.7.1.1.
Background
Clinical researchers and policy makers want to move towards embedding clinical trials 
directly within health care delivery systems in order to increase the relevance, speed, and 
efficiency of clinical research [Richesson, 2013]. The assumption is that the capabilities 
offered by Electronic Health Records (EHRs), along with concurrent changes in health 
care organization and delivery, and the development of a learning health system will 
transform the way clinical research is conducted [Etheredge, 2007; Greene 2007]. 
In 2011, the National Heart, Lung, and Blood Institute (NHLBI) convened the NHLBI 
Working Group on Electronic Health Records: Research Priorities to Improve 
Cardiopulmonary Health in Clinical Practice. As part of their mission, this working group 
identified key research, policy, and training priorities [Curtis, 2014]. A key research 
priority was to leverage EHR tools to facilitate the efficient implementation of 
randomized clinical trials. Specific areas highlighted for increased efficiency included 
efficient data collection and outcome surveillance and confirmation.
11.7.1.2.
Literature Review
Electronic Health Records were primarily designed to document patient care and 
facilitate billing and reimbursement. The large amount of electronic data that are captured
may also facilitate clinical research and public health surveillance.5 Despite the 
complexity of EHR data, national networks have begun to use these data to improve 
public health and generate real-world evidence [Toh, 2012]. The Patient Centered 
Outcomes Research network (PCORnet) (pcornet.org) is a research network that is 
currently being designed to support observational comparative effectiveness research and 
clinical trials that are embedded in clinical care settings [Fleurence, 2014]. Similarly, the 
NIH Health Care Systems Research Collaboratory (nihcollaboratory.org) is creating 
infrastructure to improve the conduct of embedded clinical trials. One ongoing NIH 
Collaboratory trial is the Time to Reduce Mortality in End-Stage Renal Disease study 
(TiME) (clinicaltrials.gov identifier: NCT02019225). TiME is a large cluster-
randomized, pragmatic trial that will evaluate the effects of systematic implementation of 
hemodialysis sessions of at least four hours versus usual hemodialysis care. The trial 
involves data acquisition from EHR systems through a partnership between academic 
investigators and two health care provider organizations with different electronic data 
systems. There are several other recent examples of clinical trials that were embedded in 
health care delivery systems [Gulliford, 2014; van Staa, 2014]. For instance, one recent 
study evaluated the use of an electronic decision support tool to improve risk factor 
control (i.e., blood pressure and cholesterol) following a cerebrovascular event with 
outcome data collected from the EHR [Dregan, 2014]. While the specific intervention 
was not shown to be efficacious, data acquisition via EHR sources was robust and 
implemented at a low cost.

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11.7.1.3.
Ancillary Study Rationale
Despite these earlier studies demonstrating the potential opportunities with EHR-based 
data acquisition, our understanding of how EHR-based platforms might increase the 
efficiency of data collection, outcome surveillance, and confirmation in an integrated 
manner is unknown. EHRs are inherently heterogeneous, with each implementation 
different from the next. The barriers to using EHR-generated lists of patients to facilitate 
trial enrolment, the fitness of EHR data for populating baseline characteristics in an 
electronic case report form (eCRF) and the use of EHR data to find events of interest 
during trial follow-up are not well characterized. 
EHR systems contain a wealth of clinical data about patients who are connected to the 
health care delivery system and may be eligible for enrollment in a clinical trial.  
Anecdotal reports suggest that identification of potential patients using the EHR increases 
the number of patients to be screened but may not consistently translate to an increased 
number of patients enrolled. Causes are likely multi-factorial and may include the 
translatability of inclusion and exclusion criteria to structured clinical data, the algorithm 
used to identify potential patients, institutional restrictions regarding unsolicited patient 
contact, and others. There is a need to empirically assess the barriers to using an EHR-
generated list of patients to facilitate trial enrollment. 
Structured data captured in the EHR may be similar to data elements specified in baseline 
patient characteristics in the eCRF, yet EHR data are collected primarily to support 
clinical care and reimbursement needs.  Their fitness for use as source data for selected 
data elements of the baseline patient characteristics in the eCRF has not been established.  
During routine trial follow-up, study coordinators typically gather information from 
various sources including direct patient contact and medical records of the enrolling 
institution and outside facilities to document events for study participants.  Evidence 
from the West of Scotland Coronary Prevention Study suggests that cardiovascular 
endpoints can be ascertained from routinely recorded EHR-type data, but classification 
was imperfect [Barry, 2013].There is a need to specifically assess the utility of EHR data 
acquisition for follow-up events across multiple health systems.
In summary, the EHR is a rich source of clinical data, but is designed specifically to 
support clinical care delivery and reimbursement needs. The assumption that EHR data 
are fit for use in high-quality clinical research has not been rigorously evaluated.  To 
provide evidence to address this knowledge gap, GlaxoSmithKline (GSK) and Duke 
Clinical Research Institute (DCRI) are committed to conducting an exploratory EHR 
Ancillary Study embedded within a large pragmatic clinical trial at selected study sites. 
The overarching goal is to further our understanding of how EHR data can be organized 
into a query-able format to facilitate a more efficient, reliable, and cost-effective research 
process.  The proposed empirical work is exploratory in nature and both qualitative and 
quantitative.

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11.7.2.
Ancillary Study OBJECTIVES 
11.7.2.1.
Primary Objectives
Objective 1: Assess the barriers to using an EHR-generated list of patients to 
facilitate trial enrollment.
Through site study coordinator surveys, workflow assessment, analysis of electronic 
screening logs, comparisons of enrolled patients with patients identified via algorithm, 
this retrospective objective will describe the screening “funnel” and identify factors 
responsible for narrowing the funnel from the pool of potentially eligible patients to those 
enrolled in the clinical trial.  Barriers for using EHR systems for this purpose will be 
assessed at the site level and common cross-site themes will be identified. 
Objective 2:  Evaluate the fitness of EHR data for use in populating the baseline 
characteristics in the eCRF
After study completion and within selected data areas (e.g., demographics, medical 
history, concomitant medications), the level of agreement between data extracted from 
the EHR and data documented on the baseline eCRF (reference standard) will be 
evaluated. Additionally the performance of algorithms developed to identify 
comorbidities and other clinical concepts will be assessed at the site level and aggregated, 
where appropriate.  
Objective 3:  Explore the use of EHR data to find events of interest during trial 
follow-up 
Case-finding algorithms will be developed for select specified endpoints (i.e., myocardial 
infarction, stroke, unstable angina, heart failure as outlined in the main study protocol), 
run during the conduct of the trial, and used to identify potential cases for follow-up by 
the study coordinator. The site study coordinator will record the dispensation of each 
potential case so that reconciliation can occur between eCRF documented events and 
EHR-generated potential events. Safety event reporting will proceed as outlined in the 
main study protocol (Main Protocol Section 6.2). At the conclusion of the study, the yield 
of case-finding algorithms will be evaluated along with the performance of EHR-based 
algorithms with eCRF-reported as well as adjudicated eCRF-reported events (reference 
standard).
11.7.2.2.
Secondary Objective
As a secondary objective, an assessment of the general utility and feasibility of EHR-
based outcome acquisition from the coordinator perspective through surveys and 
standardized workflow assessments will be conducted.  
11.7.3.
Ancillary Study design
11.7.3.1.
Study Design
The ancillary study will occur in the context of the HARMONY-Outcomes trial, a 
randomised, double blind, parallel-group, placebo-masked, controlled study to evaluate 

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the effect of albiglutide on cardiovascular events in patients with Type 2 diabetes. 
Albiglutide will be administered subcutaneously once weekly in a population of patients 
with Type 2 diabetes and a previous history of cardiovascular disease and who do not 
have optimal glycaemic control). The duration of the ancillary study will mirror that of 
the HARMONY-Outcomes trial. The number of sites that will participate in the ancillary 
study depends upon the outcome of the site EHR capabilities assessment described in 
Section 11.7.3.2 (Site Selection) below. Five study sites recruiting 12-15 subjects each 
would enable a descriptive assessment of Objectives 1 and 2, whilst, if feasible, 500-1000 
subjects at EHR-enabled sites would permit greater precision to be achieved in the 
assessment of Objective 3.
11.7.3.2.
Site Selection
Sites from the main trial will be selected to participate.  As part of the overall site 
selection process for the main trial, potential sites complete a feasibility survey to gauge 
their suitability for participation in the HARMONY-Outcomes trial.  In addition to 
questions regarding experience with long-term outcome trials in general and specific 
features of the planned trial, the feasibility survey includes questions about site readiness 
for an EHR-facilitated trial.  Specific topics include:

Existence of an EHR system;

Current use of EHR to screen for potential study participants;

Types of information currently contained in EHR  (inpatient visits, outpatient 
visits, laboratory results, medications) 

Prior participation in a study that used EHR data for patient screening, follow-up, 
and/or data collection; and

Local EHR support to assist with research studies.
Sites who meet minimum qualifications based on this survey (respond affirmatively 
regarding the existence of an EHR system and local EHR support to assist with research 
studies), and who have confirmed an interest in participating in the ancillary study will be 
approached for a more in-depth assessment of capabilities.  Specific topics include:

Current capability to extract EHR-type data from a data warehouse;

Data domains currently included in the data warehouse (e.g., demographics, vital 
signs, diagnoses, procedures, medications prescribed, laboratory tests, and death);

Coding terminologies used for each domain of data;

Institutional processes and policies for using EHR-type data for clinical research; 

Institutional experience extracting, transforming, and loading warehouse data into 
a research DataMart that conforms with standardized specifications; and

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
Familiarity with or participation in distributed research networks.  
Subsequent structured discussions with individual sites may be necessary to explore 
capabilities and suitability for the ancillary study.  For example, engagement of the health 
system’s Information Technology (IT) personnel will be essential but is challenging to 
gauge in a written survey.  Key site selection criteria include:

Fully implemented EHR system 

Access to an enterprise data warehouse or clinical data repository that stores 
structured data from the EHR and is updated at least weekly.

Availability of necessary data

Engagement of health system IT and analytical personnel
The advantage of a multi-stage, rapid assessment of capabilities is that it allows for a 
relatively short feasibility survey that can be completed reliably by a study coordinator. 
Detailed technical questions are reserved for the individuals who provide EHR support 
for research studies.  
11.7.3.3.
Data Flows
The methods for data extraction and capture will require a partnership between study site 
teams (site principal investigator, site study coordinator, and site technical support), 
GSK, and the DCRI Data Management Team.
The study will utilize PopMedNet, a software application that enables the creation, 
operation, and governance of research networks.  It allows partners to maintain physical 
and operational control over their data while allowing authorized users to send queries to 
the data. PopMedNet consists of two layers: a security layer where access controls and 
permissions are established and a layer of virtual pipes through which questions are sent 
from requestor to responder. The PopMedNet software consists of a web-based “network 
portal” and a DataMart Client application that is installed at each site. PopMedNet 
employs a “publish-and-subscribe” architecture that does not require a hole through an 
institutional firewall, but rather allows institutions to pull a query behind the firewall for 
manual or automated execution. 
In research networks with a common data model, PopMedNet is used to distribute 
executable code that institutions can choose to pull behind their firewall, run against the 
data in that appropriate format, and return results to the requestor. Security 
documentation will be provided to all participating sites.   
The data flow for this ancillary study will be as follows: 
a) The study site’s EHR system will not be changed and will continue to operate as 
implemented.  Data from the thousands of tables in the EHR will be integrated on 
a nightly basis into a data warehouse that supports research needs (the term EHR 

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is used to mean the system that collects, displays, and stores transactional health 
care data).
b) With guidance from the DCRI Data Management Team, the study site’s technical 
team will extract, transform, and load data from the enterprise data warehouse (or 
clinical data repository) to a Cohort DataMart according to the specifications of 
the common data model.  A common data model standardizes the definition, 
content and format of data across sites to enable efficient, cross-site querying. The 
Cohort DataMart will be refreshed from the existing Data Warehouse on a 
biweekly basis. The Cohort DataMart includes Protected Health Information 
(PHI) for a broadly defined cohort of potential study participants and will remain 
behind institutional firewalls. 
c) Data from Pre-Screening logs completed as part of the main study will be 
captured in a database stored in the same area as the Cohort DataMart to facilitate 
characterization of the screening funnel.  Data from the pre-screening log will 
enable comparisons of characteristics of potential participants identified via 
algorithm with patients screened and enrolled. 
d) When a participant is randomized into the study, the study coordinator will enter 
key subject identifiers (the main trial identifier (ID), Medical Record Number 
(MRN) equivalent, study randomization date) into the Key Identifier spread sheet.
e) Via PopMedNet, the DCRI Data Management Team will distribute code that 
extracts data for randomized participants from the Cohort DataMart into the Study 
DataMart using the Key Identifier table. Trial ID and randomization date from the 
Key Identifier table will be included in the Study DataMart. Data for randomized 
patients at each site will be returned to the DCRI via the HARMONY-Outcomes 
trial EHR Ancillary Study Query Portal. 
f)
Via PopMedNet, the DCRI will distribute executable code (e.g., SQL program) 
that will query the Study DataMart for potential study endpoints.  [See Section 
11.7.3.4.1b for case-finding algorithm]. 
g) Potential cases (identified via case-finding algorithm) will be returned to the 
Study Coordinator who will record the dispensation of each potential case in the 
Case-finding Dispensation Log stored in the Study DataMart (i.e., recorded in the 
eCRF/not recorded in the eCRF and reasons).
h) The Study DataMart containing randomized patient data will be transferred from 
each site to the DCRI on a regular basis (anticipated quarterly with specific 
frequency to be determined).  
i)
Required data elements from the main clinical trial dataset for EHR Ancillary 
Study sites will be transferred from GSK to the DCRI after the completion of the 
study. The DCRI will merge data elements from the main clinical trial dataset 
with Study DataMart data to create the EHR Ancillary Study Dataset.

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11.7.3.4.
Study Procedures and Processes
11.7.3.4.1. DCRI
a) Establish broad definition of cohort 
A broad cohort identification algorithm will be developed based on selected inclusion 
criteria outlined in the main study protocol. Selected criteria for inclusion into the cohort 
include:

Age > 40 years old

Diagnosis of Type 2 diabetes, broadly defined by diagnosis codes and 
medications prescribed (See 4.4 for information about algorithms to be used.)

Established cardiovascular disease (See Section 11.7.4.4 for information about 
algorithms to be used)
Participating sites will be required to run the “cohort algorithm” within their EHR 
systems to create the Cohort DataMart which will be used as a basis for Objective #1. 
b) Specify contents of the EHR Ancillary Study research DataMart
EHR data are stored in many different ways. A common data model standardizes the 
definition, content and format of data across sites to enable a single standardized view 
that can be used for querying. Sites participating in this ancillary study will be required to 
transform their data into a common data model that will be designed to be intuitive and 
user-friendly. Investigators and analysts with prior experience using research data will 
not need additional skills or knowledge to use the common data model. The DCRI team 
will manage questions and issues that arise regarding transforming data into the CDM.
The EHR Ancillary Study Common Data format will be adapted from the Patient 
Centered Outcomes Research Network (PCORnet) Common Data Model 
(http://pcornet.org/resource-center/pcornet-common-data-model/)and may include the 
following data areas:  

Demographic

Encounter

Diagnosis

Procedure

Medications prescribed

Laboratory results, selected 

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c)
Develop data characterization routines
As previously described, participating sites will transform local data into the study 
common data model. The DCRI Data Management Team will develop and distribute 
code to query the content of tables formatted according to the common data model. The 
distributed code will generate aggregate output tables that help determine whether the 
data conform to specifications, maintain integrity across variables and across tables, and 
trend as expected over time. The data quality review and characterization process will 
help to ensure that the data meets reasonable standards for data transformation 
consistency and quality.  
DCRI’s team will evaluate the creation of the Cohort DataMart using standard programs 
distributed to each study site for execution behind institutional firewalls.  
d)
Develop and distribute test queries 
A series of simple test queries will be developed and distributed to sites for execution 
against a simulated data set, structured according to the common data model. The test 
queries will help each site become familiar with PopMedNet and distributed querying 
without concern about querying against protected health information.
e)
Develop algorithms for analytic variables
Algorithms to map EHR-based data in the Study DataMart to baseline characteristics and 
study endpoints in the EHR Ancillary Study dataset will be defined using diagnosis codes 
(ICD-9-CM and ICD-10-CM) and procedure codes (ICD-9-CM and ICD-10-PCS).  
Published algorithms will be used whenever possible.  Examples of published algorithms 
utilized in the past include: 

CMS chronic condition categories: https://www.ccwdata.org/web/guest/condition-
categories

Quan, H., Sundararajan, V., Halfon, P., Fong, A., Burnand, B., Luthi, J. C., ... & 
Ghali, W. A. (2005). Coding algorithms for defining comorbidities in ICD-9-CM 
and ICD-10 administrative data. Medical Care, 1130-1139. 
http://www.ncbi.nlm.nih.gov/pubmed/16224307

Elixhauser, A., Steiner, C., Harris, D. R., & Coffey, R. M. (1998). Comorbidity 
measures for use with administrative data. Medical Care, 36(1), 8-27. 
http://www.ncbi.nlm.nih.gov/pubmed/9431328
These algorithms will be updated as necessary to account for coding changes since 
publication.  And, if not provided, mapping of diagnosis codes from ICD-9-CM to ICD-
10-CM and mapping of procedure codes from ICD-9-CM to ICD-10-PCS will be done 
using the general equivalence mappings provided by Centers for Medicare & Medicaid 
Services (CMS):

Diagnosis code crosswalk: http://www.cms.gov/Medicare/Coding/ICD10/2014-
ICD-10-CM-and-GEMs.html

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
Procedure code crosswalk: http://www.cms.gov/Medicare/Coding/ICD10/2014-
ICD-10-PCS.html
Algorithms used to identify specific medications dispensed will be defined using 
different drug identification coding systems in use by study sites.  These systems could 
include:

NDC codes [from RxNav, a browser for drug information available from the U.S. 
National Library of Medicine]

DIN codes [from Health Canada drug product database]

ATC codes [from WHO Collaborating Centre for Drug Statistics Methodology]
11.7.3.4.2. Sites
Participating study sites will:

Extract, transform, and load (ETL) data into a physical instance of an adapted 
PCORnet Common Data Model.  Sites will document the mapping from the EHR 
to the Common Data Model.

Install PopMedNet

Refresh the Cohort DataMart on a biweekly basis

Execute data characterization and test queries after each refresh and on an as-
needed basis.  
Site study coordinators will be required to complete pre-screening logs on all potential 
study participants meeting minimum eligibility requirements (age >40, Type 2 diabetes, 
established cardiovascular disease) identified via any mechanism (i.e., reviewing lists of 
scheduled office patients, reviewing lists of recently discharged diabetes patients, EHR-
facilitated algorithm). Pre-screening logs will capture the following information:

Pre-screening number

Pre-screening date

Inclusion criteria not met

Exclusion criteria met

Other criteria
Site study coordinators will complete a screening survey which will describe the site’s 
current process for screening. A description of screening barriers will be included.

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11.7.4.
DATA ANALYSIS
11.7.4.1.
Sample Size Expectations
The objectives of this ancillary study are exploratory (not confirmatory) in nature and not 
intended to be sufficiently powered to confirm a pre-determined level of sensitivity and 
specificity.  The number of sites and subjects that will participate in the ancillary study 
depends upon the outcome of the site EHR capabilities assessment described in Section 
11.7.3.2 (Site Selection). Five study sites recruiting 12-15 subjects each would enable a 
descriptive assessment of Objectives 1 and 2, whilst, if feasible, 500-1000 subjects at 
EHR-enabled sites would permit greater precision to be achieved in the assessment of 
Objective 3.
11.7.4.2.
Objective 1: Assess the Barriers to Using as EHR-Generated List of 
Patients to Facilitate Trial Enrollment
Because any survey administered for this objective will be a site-level survey, analysis of 
the survey data will be performed across all sites. For quantities of interest, frequencies 
with percentages for categorical measures and means with standard deviations for 
continuous measures will be presented.   
11.7.4.3.
General Analytic Approach for Objective 1 and Objective 2
The goals of both Objective 2 and Objective 3 involve evaluating the performance of 
algorithms that map EHR-based data into concepts present in the clinical trial dataset.  
The actual measures recorded in the clinical trial dataset will be considered the reference 
standard against which these algorithm-based measures are compared.
Table 3
Overall performance of EHR-based algorithms for baseline 
characteristics, using clinical trial data as the reference standard / 
Categorical variables
Reference standard
(Clinical trial data)
New measure  
(EHR Ancillary Study data)
Condition present
Condition absent
Condition present
True positive
(TP)
False positive 
(FP)
Condition absent
False negative
(FN)
True negative
(TN)
For categorical variables, estimated performance metrics will be based on the 2x2 cross-tabulation 
of values in the EHR Ancillary Study dataset with values in the clinical trial dataset (Table 3) and 
include:
Overall agreement = (TP + TN) / (TP + FP + FN + TN)
Sensitivity = TP / (TP + FN)
Specificity = TN / (FP + TN)

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Positive predictive value = TP / (TP + FP)
Negative predictive value = TN / (FN + TN)
Accuracy or efficiency = (TP + TN) / (TP+TN+FP+FN)
For dichotomous measures, each of these proportions is immediately calculable.  For 
measures having more than two levels, multiple dichotomous measures will be created in 
order to calculate these proportions. Confidence intervals (95%) will be reported around 
these quantities. (See Table 4 as an example).
Table 4
Overall performance of EHR-based algorithms for baseline 
characteristics, using clinical trial data as the reference standard / 
Categorical variables
Measure
Overall 
agreement
(95% CI)
Sensitivity
(95% CI)
Specificity
(95% CI)
Positive 
predictive 
value 
(95% CI)
Negative 
predictive 
value 
(95% CI)
Measure 1
xx.x 
(xx.x – xx.x)
xx.x 
(xx.x – xx.x)
xx.x 
(xx.x – xx.x)
xx.x 
(xx.x – xx.x)
xx.x 
(xx.x – xx.x)
Measure 2
xx.x 
(xx.x – xx.x)
xx.x 
(xx.x – xx.x)
xx.x 
(xx.x – xx.x)
xx.x 
(xx.x – xx.x)
xx.x 
(xx.x – xx.x)
.....
.....
.....
.....
.....
.....
Reported on 0–100 scale
For continuous measures, bias will be calculated as the difference between values in the 
EHR Ancillary Study dataset and values in the clinical trial dataset.  The mean and 
standard deviation of the bias along with a 95% confidence interval will be reported.  In 
Bland-Altman analyses of agreement between continuous measures, the standard 
deviation of the bias is referred to as the precision, while the 95% confidence interval is 
referred to as the limit of agreement. (See Table 5 as an example).
Table 5
Overall performance of EHR-based algorithms for baseline 
characteristics, using clinical trial data as the reference standard / 
Continuous variables
Bias
Measure
Mean (SD)
95% (CI)
Measure 1
xx.x
xx.x
Measure 2
xx.x
xx.x
.....
.....
.....
Due to the nature of EHR data, it is expected that there will be systematic differences 
between sites with respect to coding of clinical concepts.  All performance metrics will 
therefore initially be calculated by site. These site-specific results may be best reported 
graphically.

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There is also interest in an assessment of algorithm performance across all sites.  
Hierarchical models will be used to combine data from all sites and estimate performance 
at the “average” site.  To estimate proportions (e.g. for overall agreement, sensitivity, 
specificity, etc. associated with categorical measures), models will be specified as:
logit (E (y) )=β0+γ0,,j
γ0,j~N(0,s2)
where sites are indexed by j.  The value of the proportion at the average site—when 
γ0=0—is  [1+exp (–β0 ) ]-1.  Patients included in the estimation of each model vary by 
performance metric and reflect the definitions above.  As an example, consider positive 
predictive value.  To estimate the positive predictive value of an algorithm, only subjects 
with true positive value and false positive values will be included.  True positives will be 
assigned Y=1 and false positive will be assigned Y=0. 
To estimate means (e.g. for bias associated with continuous variables), the model will be 
specified as:
E (y )=β0+ γ0,,j
γ0,,j ~ N(0,s2)
The value of the mean at the average site is β0.  
For all models, we will assess site heterogeneity by testing if s2=0.
11.7.4.4.
Objective 2: Evaluate the Fitness of EHR Data for Use in Populating the 
Baseline Characteristics in the eCRF
Algorithms will be defined to map EHR-based data in the Study Data Mart to specific 
concepts in the EHR Ancillary Study dataset that parallel concepts in the clinical trial 
dataset.  For Objective 2, the performance of algorithms used to identify baseline 
characteristics will be evaluated.  The baseline characteristic measures recorded in the 
clinical trial dataset will be considered the reference standard against which these 
algorithm-based measures are compared. 
11.7.4.5.
Objective 3: Explore the Use of EHR Data to Find Events of Interest 
During Trial Follow-up
Algorithms will be defined to map EHR-based data in the Study Data Mart to specific 
concepts in the EHR Ancillary Study dataset that parallel concepts in the clinical trial 
dataset.  For Objective 3, the performance of algorithms used to identify trial events will 
be evaluated.  These algorithms will be evaluated against both the adjudicated events 
recorded in the clinical trial dataset and the identified potential events in the eCRF.  For 
each event, estimates of sensitivity and positive predictive value (described in Section 
11.7.4.3) will be calculated and presented with 95% confidence intervals.  

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References
Barry SJ, Dinnett E, Kean S, Gaw A, Ford I. Are routinely collected NHS administrative 
records suitable for endpoint identification in clinical trials? Evidence from the West of 
Scotland Coronary Prevention Study. PloS one. 2013; 8(9):e75379.
Curtis LH, Brown J, Platt R. Four Health Data Networks Illustrate The Potential For A 
Shared National Multipurpose Big-Data Network. Health Affairs. July 1, 2014; 
33(7):1178-1186.
Dregan A, van Staa TP, McDermott L, et al. Point-of-Care Cluster Randomized Trial in 
Stroke Secondary Prevention Using Electronic Health Records. Stroke. July 1, 2014; 
45(7):2066-2071.
Etheredge LM. A rapid-learning health system. Health affairs. Mar-Apr 2007; 
26(2):w107-118.
Fleurence RL, Beal AC, Sheridan SE, Johnson LB, Selby JV. Patient-Powered Research 
Networks Aim To Improve Patient Care And Health Research. Health Affairs. July 1, 
2014; 33(7):1212-1219.
Greene SM, Reid RJ, Larson EB. Implementing the learning health system: from concept 
to action. Annals of internal medicine. Aug 7 2012;157(3):207-210.
Gulliford MC, van Staa T, Dregan A, et al. Electronic Health Records for Intervention 
Research: A Cluster Randomized Trial to Reduce Antibiotic Prescribing in Primary Care 
(eCRT Study). The Annals of Family Medicine. July 1, 2014; 12(4):344-351.
NHLBI Working Group on Electronic Health Records: Research Priorities to Improve 
Cardiopulmonary Health in Clinical Practice. 2011. 
http://www.nhlbi.nih.gov/meetings/workshops/ehr.htm. Accessed Jan 28, 2013.
Richesson RL, Hammond WE, Nahm M, et al. Electronic health records based 
phenotyping in next-generation clinical trials: a perspective from the NIH Health Care 
Systems Collaboratory. Journal of the American Medical Informatics Association: 
JAMIA. Dec 2013; 20(e2):e226-231.
Toh S, Reichman ME, Houstoun M, et al. COmparative risk for angioedema associated 
with the use of drugs that target the renin-angiotensin-aldosterone system. Archives of 
Internal Medicine. 2012; 172(20):1582-1589.
van Staa T, Dyson L, McCann G, et al. The opportunities and challenges of pragmatic 
point-of-care randomised trials using routinely collected electronic records: evaluations 
of two exemplar trials. Health Technol Assess. 2014/07/11 2014; 18(43).