Clinical trial NCT02229227
Conditions: Diabetes Mellitus, Type 2
Keywords: switch study albiglutide glucagon-like peptide-1 receptor agonist Type 2 diabetes mellitus basal-bolus insulin therapy
Sponsor: GlaxoSmithKline
Start date: 2014-11-21; Completion date: 2017-07-24
Enrollment: 814 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This Phase IIIb, randomized, open-label, parallel group, active control, multicenter, treat to-target study of 26 weeks' treatment duration will evaluate the efficacy and safety of once-weekly albiglutide as replacement of prandial insulin in subjects with type 2 diabetes mellitus (T2DM) failing to achieve adequate glycemic control on their current basal bolus insulin regimen (with or without metformin). Approximately 794 subjects will be randomly assigned in a 1:1 ratio to 1 of 2 treatment groups: albiglutide + insulin glargine (with insulin lispro discontinuation at Week 4) (with or without metformin) or to intensification of insulin glargine + insulin lispro (with or without metformin). The study will comprise 4 study periods : Screening (2 weeks), Standardization (4 weeks), Treatment (26 weeks), and Post treatment Follow up (4 weeks). The total duration of a subject's participation will be approximately 36 weeks.

Detailed description:

Arms: arm 1: During standardization period, subjects will transit from basal bolus regimen received during screening period to insulin glargine plus insulin lispro. During treatment period, subject will receive Albiglutide 30 milligrams (mg) weekly subcutaneous (SC) injection and insulin lispro dose will be downtitrated to half that used in the standardization period. At Week 4, Albiglutide will be uptitrated to 50 mg weekly SC injection and insulin lispro will be stopped for the remainder of the treatment Period. Insulin lispro may be re-introduced after Week 8 according to pre-defined hyperglycemia thresholds. Insulin will be adjusted according to protocol-defined insulin titration algorithms arm 2: During standardization period, subjects will transit from basal bolus regimen received during screening period to insulin glargine plus insulin lispro. During treatment period, subject will continue with the same doses as at the end of the standardization period and doses will be adjusted according to protocol-defined insulin titration algorithms
Interventions: intervention 1: Albiglutide intervention 2: Insulin Glargine and Insulin Lispro
Intervention descriptions: intervention 1: Albiglutide is intended for self-administration as a SC injection. It is provided as a fixed dose of 30 mg of albiglutide or 50 mg of albiglutide in a 0.5 mL injection volume, fully disposable pen injector intervention 2: Insulin glargine and insulin lispro will be provided as injection pens for SC injection

Protocol documents:
Prot_000.pdf: 
2013N187697_04
CONFIDENTIAL
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TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
Study 200977: Albiglutide + Insulin Glargine Versus Insulin 
Lispro + Insulin Glargine in the Treatment of Subjects With 
Type 2 Diabetes Mellitus: The Switch Study
Compound Number:
GSK716155
Development Phase:
IIIB
Effective Date:
24-SEP-2015
Protocol Amendment Number: 03
Author (s):
 
Copyright 2015 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
2013N187697_00
2014-JUL-23
Original
2013N187697_01
2014-AUG-14
Republished
Republished to update the PGx sections with the new ‘genetics’ language from new 
protocol template
2013N187697_02
2015-JUN-01
Amendment No. 1
Changes reflected in Protocol Amendment No. 1 have been included to address the 
following:

Clarify potentially confusing text

Add details of sensitivity analyses that will assess the impact of missing data for 
the noninferiority test

Introduce additional flexibility into glycemic eligibility criteria at Screening and 
to the process for transitioning subjects from their prior basal-bolus insulin 
therapy to insulin glargine and insulin lispro at the beginning of the 
Standardization Period, as well as provide additional flexibility to the investigator 
when adjusting insulin glargine and insulin lispro

Further mitigate the potential risk of hypoglycemia, as well as enhance subject 
education and training pertaining to hypoglycemic events

Add an optional fasting HbA1c test at Screening to aid investigators in the 
selection of subjects who may be good candidates for the study

Add a stimulated C-peptide assessment at Screening as a complimentary 
assessment for subjects to demonstrate reserve insulin secretory capacity

Incorporate other administrative changes
2013N187697_03
2015-JUN-10
Amendment No. 2, 
Country-Specific Protocol 
Amendment for Applicable 
Sites in Germany Only

The inclusion criterion pertaining to adequate contraception was updated to 
indicate that progestogen-only pills are only acceptable if they have a Pearl Index 
of less than 1.0.

A criterion was added to exclude persons who have been put in an institution 
because of official or legal order.

A criterion was added to exclude employees (or the employee’s relatives) of the 
sponsor, the contract research organization, or the investigative site. 


2013N187697_04
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2013N187697_04
2015-SEP-24
Amendment No. 3
Changes reflected in Protocol Amendment No. 3 have been included to address the 
following:

Correct SI units for select blood glucose concentrations (mmol/L) for insulin 
titration 

Combine global amendment 01 and country-specific amendments into a single 
protocol document. To aid clarity, country-specific requirements have been 
clearly identified

Incorporate other administrative changes


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SPONSOR INFORMATION PAGE
Clinical Study Identifier: Study 200977
Sponsor Legal Registered Address:
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
PPD is the contract research organization for this study.
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: 
Primary Medical Monitor (PPD Pharmacovigilance):
 MD
24-hour Safety Hotline: 
Fax: 
Sponsor Serious Adverse Events (SAE) Contact Information:
PPD Pharmacovigilance
North America
24-hour Safety Hotline: 
Fax: 
Regulatory Agency Identifying Number(s):
IND Number: 65177
EudraCT Number: 2014-001821-34
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 200977
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...........................................................................................11
PROTOCOL SUMMARY...............................................................................................13
1.
INTRODUCTION....................................................................................................21
1.1.
Background ................................................................................................21
1.2.
Rationale ....................................................................................................22
1.3.
Benefit-to-Risk Assessment........................................................................24
1.3.1.
Risk Assessment .........................................................................24
1.3.2.
Benefit Assessment.....................................................................30
1.3.3.
Overall Benefit-to-Risk Conclusion...............................................31
2.
OBJECTIVES AND ENDPOINTS...........................................................................31
3.
INVESTIGATIONAL PLAN.....................................................................................35
3.1.
Study Design ..............................................................................................35
3.2.
Discussion of Design ..................................................................................37
3.2.1.
Choice of Control.........................................................................37
3.2.2.
Duration of Treatment..................................................................37
3.2.3.
Intention of Standardization Period ..............................................38
3.2.4.
Dose of Albiglutide.......................................................................38
3.2.5.
Insulin Doses...............................................................................39
4.
SUBJECT SELECTION AND WITHDRAWAL CRITERIA.......................................39
4.1.
Number of Subjects ....................................................................................39
4.2.
Inclusion Criteria.........................................................................................39
4.3.
Exclusion Criteria........................................................................................41
4.4.
Additional Inclusion Criteria for Randomization...........................................43
4.5.
Withdrawal Criteria .....................................................................................43
4.5.1.
Early Withdrawal Visit ..................................................................45
4.6.
Screening/Standardization Failures ............................................................45
5.
STUDY TREATMENTS..........................................................................................46
5.1.
Investigational Product and Other Study Treatment....................................46
5.1.1.
Dosing Guidance During the Standardization Period ...................47
5.1.2.
Dosing Guidance During the Treatment Period............................48
5.1.3.
Dose Titration During the Treatment Period.................................49
5.1.3.1.
Albiglutide Titration.....................................................49
5.1.3.2.
Insulin Titration...........................................................49
5.1.3.3.
Intensive Subject Glycemic Surveillance and 
Management ..............................................................53
5.1.3.4.
Documentation of Insulin Titration ..............................54
5.1.3.5.
Re-introduction of Insulin Lispro in the 
Albiglutide Treatment Group.......................................54
5.2.
Treatment Assignment................................................................................56
5.3.
Blinding.......................................................................................................56
5.4.
Product Accountability ................................................................................56
5.5.
Treatment Compliance................................................................................57
5.6.
Concomitant Medications and Nondrug Therapies......................................57


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5.6.1.
Permitted Medications and Nondrug Therapies ...........................57
5.6.2.
Prohibited Medications and Nondrug Therapies...........................58
5.7.
Treatment Between Week 26 (End of Treatment)/Early Withdrawal 
and After the Follow-up Visit .......................................................................58
5.7.1.
Treatment Between Week 26 (End of Treatment)/Early 
Withdrawal and Follow-up............................................................58
5.7.2.
Treatment After the Follow-up Visit..............................................59
5.8.
Treatment of Study Treatment Overdose....................................................59
6.
STUDY ASSESSMENTS AND PROCEDURES .....................................................60
6.1.
Critical Baseline Assessments....................................................................66
6.2.
Efficacy.......................................................................................................66
6.2.1.
Efficacy Assessments..................................................................66
6.2.1.1.
HbA1c and FPG...........................................................66
6.2.1.2.
Body Weight...............................................................66
6.2.2.
Blood Glucose Monitoring............................................................66
6.2.2.1.
Home Blood Glucose Monitoring ................................66
6.2.2.2.
8-Point Self-Monitored Blood Glucose Profile.............67
6.2.3.
Hypoglycemic Events...................................................................68
6.2.4.
Diabetic Dietary, Exercise, and Home Blood Glucose 
Monitoring Advice ........................................................................68
6.2.5.
Daily Insulin Use..........................................................................68
6.3.
Safety .........................................................................................................68
6.3.1.
Hypoglycemic Events...................................................................68
6.3.2.
Height and Vital Sign Measurements...........................................70
6.3.3.
Electrocardiograms......................................................................70
6.3.4.
Physical Examinations.................................................................70
6.3.5.
Clinical Laboratory Testing ..........................................................71
6.3.5.1.
Estimated Glomerular Filtration Rate..........................73
6.3.6.
Liver Chemistry Stopping and Follow-up Criteria .........................73
6.3.7.
Adverse Events............................................................................76
6.3.7.1.
Definition of an AE......................................................76
6.3.7.2.
Definition of an SAE ...................................................77
6.3.7.3.
Sentinel Events ..........................................................78
6.3.8.
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs.........................................................78
6.3.9.
Adverse Events of Special Interest ..............................................79
6.3.9.1.
Cardiovascular Events................................................79
6.3.9.2.
Death Events..............................................................80
6.3.9.3.
Injection Site Reactions and Potential Systemic 
Allergic Reactions (e.g., Rashes, Urticaria, 
Angioedema, or Anaphylaxis).....................................80
6.3.9.4.
Pancreatitis ................................................................81
6.3.9.5.
Pancreatic Cancer......................................................81
6.3.9.6.
Medullary Thyroid Cancer...........................................81
6.3.9.7.
Diabetic Retinopathy ..................................................81
6.3.9.8.
Pneumonia .................................................................82
6.3.9.9.
Atrial Fibrillation/Atrial Flutter......................................82
6.3.10.
Pregnancy ...................................................................................82
6.3.11.
Time Period and Frequency of Detecting AEs and SAEs.............83
6.3.12.
Method of Detecting AEs and SAEs.............................................83


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6.3.13.
Prompt Reporting of Serious Adverse Events and Other 
Events to GSK/PPD.....................................................................83
6.3.13.1.
Regulatory Reporting Requirements for SAEs............85
6.4.
Health Outcomes........................................................................................85
6.4.1.
Health Outcome Assessments Not Included as Primary or 
Key Secondary Endpoints............................................................85
6.4.1.1.
TRIM-Diabetes Questionnaire ....................................85
6.4.1.2.
Hypoglycemia Fear Survey-II Questionnaire ..............86
6.5.
Genetics .....................................................................................................86
6.6.
Novel Biomarkers .......................................................................................86
6.7.
Tracking of Albiglutide Pen Injector Failures and User Errors .....................86
7.
DATA MANAGEMENT ...........................................................................................87
8.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS...................................87
8.1.
Hypotheses.................................................................................................87
8.2.
Study Design Considerations......................................................................87
8.2.1.
Sample Size Assumptions ...........................................................87
8.2.2.
Sample Size Sensitivity................................................................88
8.2.3.
Sample Size Re-estimation..........................................................89
8.3.
Data Analysis Considerations .....................................................................89
8.3.1.
Analysis Populations....................................................................89
8.3.2.
Analysis Data Sets.......................................................................89
8.3.3.
Treatment Comparisons ..............................................................90
8.3.3.1.
Primary Comparisons of Interest ................................90
8.3.3.2.
Other Comparisons of Interest....................................91
8.3.4.
Interim Analysis ...........................................................................92
8.3.5.
Key Elements of Analysis Plan ....................................................92
8.3.5.1.
Efficacy Analyses .......................................................92
8.3.5.1.1.
Impact of Missing Data on Primary 
Endpoint .................................................92
8.3.5.1.2.
Extent of Missing Primary Analysis 
Data........................................................92
8.3.5.1.3.
Reasons for Withdrawal..........................92
8.3.5.1.4.
Handling of Missing Data........................93
8.3.5.2.
Safety Analyses..........................................................94
8.3.5.3.
Health Outcomes Analyses ........................................95
8.3.5.4.
Genetic Analyses .......................................................95
8.3.5.5.
Novel Biomarker(s) Analyses .....................................95
9.
STUDY CONDUCT CONSIDERATIONS ...............................................................96
9.1.
Posting of Information on Publicly Available Clinical Trial Registers............96
9.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................96
9.3.
Quality Control (Study Monitoring) ..............................................................97
9.4.
Quality Assurance.......................................................................................97
9.5.
Study and Site Closure ...............................................................................97
9.6.
Records Retention......................................................................................98
9.7.
Provision of Study Results to Investigators, Posting of Information 
on Publicly Available Clinical Trials Registers and Publication....................98
9.8.
Pancreatitis Adjudication Committee...........................................................99


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10. REFERENCES.....................................................................................................100
11. APPENDICES......................................................................................................105
11.1.
Appendix 1 - Genetic Research ................................................................105
11.2.
Appendix 2: Liver Chemistry Stopping and Follow-up Criteria...................108
11.3.
Appendix 3: Treatment-Related Impact Measure – Diabetes 
Questionnaire ...........................................................................................109
11.4.
Appendix 4: Hypoglycemia Fear Survey-II Questionnaire, Worry 
Subscale...................................................................................................112
11.5.
Appendix 5: Country-Specific Requirements.............................................113
11.5.1.
German-Specific Eligibility Requirements ..................................113
11.5.2.
French Administrative Considerations and Specific 
Requirements ............................................................................113
11.6.
Appendix 6: Protocol Changes..................................................................118


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LIST OF ABBREVIATIONS
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ANSM
Agence nationale de sécurité du médicament et des produits 
de santé
AST
aspartate aminotransferase
β-HCG
β-human chorionic gonadotropin
CNIL
Commission nationale de l'informatique et des Libertés
CRA
clinical research assistant
CTR
clinical trial registry
CV
cardiovascular
dL
deciliter
ECG
electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
FA
full analysis
FDA
Food and Drug Administration
FPG
fasting plasma glucose
g
gram
GCP
Good Clinical Practice
GI
gastrointestinal
GLP-1
glucagon-like peptide-1
GLP-1R
glucagon-like peptide-1 receptor
GSK
GlaxoSmithKline
HbA1c
glycosylated hemoglobin
HFS-II
hypoglycemia fear survey-II
IB
investigator’s brochure
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IgM
immunoglobulin M
INR
international normalized ratio
IRB
Institutional Review Board
IT
information technology
IU
international unit
IVRS
interactive voice response system
kg
kilogram
L
liter
LMCF
last mean carried forward
m
meter
MAR
missing at random
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities 
mg
milligram
MI
myocardial infarction


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min
minute
mL
milliliter
mmol
millimole
MMRM
mixed-effect model with repeated measures
MNAR
missing not at random
OAD
oral antidiabetic
OC RDC
Oracle Clinical Remote Data Capture System
PAC
pancreatitis adjudication committee
PK
pharmacokinetic
PP
per protocol
RAP
reporting and analysis plan
SAE
serious adverse event
SMBG
self-monitored blood glucose
SPM
Study Procedures Manual
SU
sulfonylurea
T2DM
type 2 diabetes mellitus
TRIM-Diabetes
treatment-related impact measure for diabetes
TSH
thyroid-stimulating hormone
ULN
upper limit of normal
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
HFS-II
Humalog
Lantus
MedDRA
TRIM-Diabetes


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PROTOCOL SUMMARY
Rationale
The therapeutic aim of mealtime insulin is to blunt postprandial glycemic excursions, 
which can be extreme in some individuals, resulting in poor control during the day 
[Inzucchi, 2012]. Well-managed basal-bolus therapy provides a flexible way of 
controlling glucose throughout the day and night since dosing can be timed to 
approximate nondiabetic endogenous insulin release. However, in practice, basal-bolus 
insulin therapy is quite challenging to manage well for both physicians and patients. 
Moreover, declining health and cognition tend to exacerbate the insulin management 
challenge in many older type 2 diabetes mellitus (T2DM) patients. In comparison to 
endogenous insulin, basal-bolus insulin therapy comes with a plethora of issues 
[Swinnen, 2009; McCoy, 2012; Hessler, 2014], such as

Dose-dependent increased risk of hypoglycemia 

Dose-dependent increased mortality risk associated with hypoglycemia; 

Increased risk of weight gain

Encumbered quality of life associated with need to balance insulin dosing and 
carbohydrate intake, in both timing and magnitude

Cost and stress of multiple daily injections

Earlier loss of independence with aging due to the complexities of diabetes 
management with insulin 
Treatments that diminish insulin demand and preserve or enhance β-cell function are 
expected to result in better glycemic control and diminished risk of these insulin therapy 
complications.
Combining a marketed glucagon-like peptide-1 receptor (GLP-1R) agonist with basal 
insulin is part of the current treatment armamentarium for T2DM; however, none of these 
agents are currently indicated for use in product labeling with bolus insulin. Two studies 
have reported reductions in prandial insulin doses following the addition of exenatide 
with no major hypoglycemic events [Yoon, 2009; Viswanathan, 2007]. Liraglutide, when 
used in combination with a basal-bolus insulin regimen in patients with T2DM, allowed 
for a reduction in total and bolus insulin doses [Lane, 2014]. However, the Association of 
British Clinical Diabetologists’ audit revealed a worsening of glycemic control for almost 
50% of patients who stopped insulin therapy upon initiation of exenatide; thus, it is 
recommended that insulin be reduced but not discontinued once a significant glycemic 
improvement has been observed after initiating therapy with a GLP-1R agonist [Thong, 
2011]. The difficulty of how fast and how far to downtitrate insulin doses without 
compromising glycemic control has been recognized in reviews of GLP-1R agonists 
[Holst, 2013] and is still an open question.
The Phase IIIa clinical development program for albiglutide included 2 studies with 
insulin, both open-label, the first comparing albiglutide with insulin glargine 
(Study GLP112754) and the second comparing albiglutide when added on to insulin 


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glargine versus insulin lispro added on to insulin glargine (Study GLP108486). At their 
respective primary endpoints (Week 52 in Study GLP112754 and Week 26 in 
Study GLP108486), both studies showed that albiglutide was statistically noninferior to 
each insulin treatment approach with regard to HbA1c and demonstrated that albiglutide 
could be used as an alternative to insulin therapy in patients with late-stage T2DM. 
Despite comparable glucose lowering, albiglutide therapy was associated with 
approximately 1.5- to 2-fold less symptomatic hypoglycemia and with weight loss rather 
than weight gain compared with the addition of insulin (treatment difference of 1.5 to 
2.6 kg). 
This study will evaluate the efficacy and safety of once-weekly albiglutide administered 
in combination with basal insulin as a replacement for bolus insulin in subjects with 
T2DM who are currently managed with a basal-bolus insulin regimen but who are not 
achieving glycemic treatment goals. It is expected that subjects switched to albiglutide 
plus basal insulin (with discontinuation of bolus insulin therapy) compared with those 
intensifying basal-bolus insulin therapy will be able to maintain glycemic control with 
less hypoglycemia and less weight gain, while also demonstrating a reduced total daily 
insulin requirement and reduced number of weekly injections (e.g., 28 injections per 
week [7 basal insulin and up to 21 bolus insulin injections] in basal-bolus-treated subjects 
compared with potentially 8 injections per week [1 weekly albiglutide injection and 
7 basal injections] in subjects switching to basal insulin plus albiglutide). 
Data from this study will support the concept that albiglutide is a potential alternative to 
bolus insulin that will simplify insulin therapy in subjects with T2DM that do not reach 
adequate control with basal-bolus therapy.
Objectives and Endpoints
Objective
Endpoint
Primary

To evaluate the glycemic effectiveness of 
once-weekly albiglutide as replacement of 
prandial insulin in subjects with T2DM 
receiving basal-bolus insulin therapy

Change from Baseline in HbA1c at Week 26
Secondary
Key Secondary

To determine the proportion of subjects 
treated with once-weekly albiglutide that are 
able to replace prandial insulin without the 
need for re-introduction of insulin lispro

Proportion of subjects treated with 
once-weekly albiglutide that are able to 
discontinue insulin lispro at Week 4 and do 
not meet prespecified criteria for severe, 
persistent hyperglycemia through Week 26 

To demonstrate a significant difference in 
the frequency of hypoglycemic events 
between treatment groups

Percentage of subjects with severe or 
documented symptomatic hypoglycemia 
through Week 26 (see Section 6.3.1)

To demonstrate a significant difference in 
body weight between treatment groups

Change from Baseline in body weight at 
Week 26 and over time


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Objective
Endpoint

To demonstrate a significant reduction in 
total daily dose of insulin between treatment 
groups

Total daily insulin dose at Week 26
Supportive Secondary

To assess additional glycemic parameters, 
achievement of HbA1c treatment goals, 
body weight, and total daily insulin dose

Additional glycemic parameters:

HbA1c change from Baseline over time

Fasting plasma glucose (FPG) change 
from Baseline at Week 26 and over 
time

Achievement of HbA1c treatment goals:

Proportion of subjects achieving a 
HbA1c <7.0% at Week 26 and over time

Proportion of subjects achieving a 
HbA1c <6.5% at Week 26 and over time

Incidence and time to meeting prespecified 
criteria for severe, persistent hyperglycemia 
at Week 26 

Additional assessments of daily insulin 
doses:

Total daily insulin dose (24-hour total 
international units [IU] and total units/kg 
body weight) over the 3 days preceding 
the Baseline/Randomization and 
Week 4, 10, and 18 visits

Total daily basal insulin (insulin 
glargine) (24-hour total IU and total 
units/kg body weight) over the 3 days 
preceding the Baseline/Randomization 
and Week 4, 10, 18, and 26 visits

Total daily bolus insulin (insulin lispro) 
(24-hour total IU and total units/kg body 
weight) over the 3 days preceding the 
Baseline/Randomization and Week 4, 
10, 18, and 26 visits

Total number of weekly insulin injections 
(7 days) to achieve glycemic control at 
Baseline/Randomization and Week 4, 10, 
18, and 26

Composite endpoints (after 26 weeks of 
treatment):

Percentage of subjects achieving 
HbA1c <7.0% without weight gain

Percentage of subjects achieving 
HbA1c <7.0% without severe or 
documented symptomatic 
hypoglycemia


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Objective
Endpoint

Percentage of subjects achieving 
HbA1c <7.0% without weight gain and 
without severe or documented 
hypoglycemia

To evaluate the safety and tolerability of the 
2 treatment groups

Adverse events (AEs) and serious AEs 
(SAEs), including AEs and SAEs leading to 
discontinuation of randomized study 
medication

Other AEs of special interest (for example, 
cardiovascular [CV] events, gastrointestinal 
[GI] events, injection site reactions, potential 
systemic allergic reactions, pancreatitis, 
pancreatic cancer, medullary thyroid 
cancer, malignant neoplasms following 
treatment with insulin, diabetic retinopathy 
events, appendicitis, liver events, 
pneumonia, and atrial fibrillation/flutter)

Assessments of hypoglycemia:

Percentage and number of events of 
hypoglycemia with confirmed home 
blood glucose monitoring and/or 
third-party intervention through 
Week 26 (i.e., severe, documented 
symptomatic, and asymptomatic 
hypoglycemic events, see 
Section 6.3.1) in 3-month intervals (i.e., 
from Baseline/Randomization to 
Week 12, >Week 12 to Week 26)

Incidence of hypoglycemic events (in 
total and by each category as defined 
by the American Diabetes Association 
criteria)

Incidence of daytime hypoglycemia (in 
total and by category), defined as 
hypoglycemic events with an onset 
between 06:00 hours and 00:00 hours 
(inclusive), and nocturnal hypoglycemia 
(in total and by category), defined as 
hypoglycemic events with an onset 
between 00:01 hours and 05:59 hours 
(inclusive)

Incidence of hypoglycemia with blood 
glucose <56 mg/dL (<3.1 mmol/L), 
regardless of symptoms

Assessment of clinical laboratory tests 
(hematology, clinical chemistry, urinalysis, 


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Objective
Endpoint
β-human chorionic gonadotropin [β-HCG], 
lipid panel)

Assessment of vital sign measurements 
(Note: Weight is assessed as part of 
efficacy), 12-lead electrocardiogram (ECG) 
findings, and physical examination findings
Exploratory

To compare the effects between the 
2 treatment groups on patient-reported 
outcomes to diabetes medication and to 
further assess glycemic parameter, weight, 
and composite endpoints

Patient-reported outcomes to diabetes 
medication at Baseline/Randomization, 
Week 10, and Week 26:

Treatment-related impact measure for 
diabetes (TRIM-Diabetes) questionnaire

Hypoglycemia fear survey-II (HFS-II) 
worry subscale

Additional glycemic parameter, weight, and 
composite endpoints:

HbA1c change from Baseline at 
Week 26 by baseline FPG tertiles

FPG change from Baseline at Week 26 
by baseline FPG tertiles

24-hour glucose profile: 8-point 
self-monitored blood glucose (SMBG) 
profile at Baseline/Randomization, 
Week 10, and Week 26 (before and 
120 minutes after the 3 main meals, at 
bedtime, and at 2 AM)

Mean daily blood glucose based on the 
8-point SMBG profile at 
Baseline/Randomization, Week 10, and 
Week 26

Number (and percentage) of subjects 
with 1 kg weight gain at Week 26

Percentage of subjects achieving 
HbA1c <7.0% without weight gain and 
without hypoglycemia with blood 
glucose <56 mg/dL (<3.1 mmol/L) 
regardless of symptoms at Week 26

Proportion of subjects treated with
once-weekly albiglutide that are able to 
totally replace or decrease prandial 
insulin without worsening HbA1c control 
(worsening defined as >0.3% increase 
in HbA1c compared with baseline HbA1c) 
at Week 26

Analysis of genetic sampling may also be 
performed

Genetic sampling


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Objective
Endpoint

Analysis of novel biomarkers may also be 
performed

Novel biomarker analysis may be 
performed; a decision on whether to 
analyze novel biomarker samples may be 
made after review of efficacy and safety 
endpoints at the end of the study or other 
emerging information that may become 
available during the study
Study Design

This Phase IIIb, randomized, open-label, parallel-group, active-control, multicenter, 
treat-to-target study of 26 weeks’ treatment duration will evaluate the efficacy and 
safety of once-weekly albiglutide as replacement of prandial insulin in subjects with 
T2DM.

Subjects with inadequate glycemic control (glycosylated hemoglobin [HbA1c] ≥7.0% 
and ≤9.5% at Screening) on their current basal-bolus insulin regimen (with or 
without metformin) despite at least 3 months of treatment will be recruited into the 
study. Subjects who achieve an HbA1c value ≥7.0% and ≤9.0% following the 
Standardization Period will be randomized into the study.

The intensification of basal-bolus insulin therapy (i.e., insulin glargine plus insulin 
lispro) according to predefined treat-to-target titration algorithms will serve as the 
active control.

Subjects taking metformin as background antidiabetic medication will remain on 
their current dose for the duration of their participation in the study, unless a decline 
in kidney function results in a contraindication for metformin use. 

The study will comprise 4 study periods: Screening (2 weeks), Standardization 
(4 weeks), Treatment (26 weeks), and Posttreatment Follow-up (4 weeks). The total 
duration of a subject’s participation will be approximately 36 weeks. Subjects will 
have 10 study center visits and approximately 18 telephone calls to monitor insulin 
titration.

During the Screening Period (Week -6 through Week -5), subjects will provide 
written informed consent and undergo procedures to determine eligibility for study 
participation.

After Screening, subjects meeting all eligibility criteria will enter a 4-week 
Standardization Period to transition from their current basal-bolus regimen to insulin 
glargine plus insulin lispro. Subjects already on insulin glargine plus insulin lispro 
will also enter the Standardization Period. 

During the Standardization Period, the basal-bolus insulin regimen may be adjusted 
to achieve glycemic targets as close to normal as possible without untoward 
hypoglycemia in accordance with product labeling in the respective country and 
standard of care at the study center.


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
After the Standardization Period, subjects meeting additional criteria for 
randomization will be stratified by screening HbA1c value (<8.0% versus ≥8.0%), 
age (<65 years versus 65 years), and current background metformin (metformin use 
versus no metformin use). Approximately 794 subjects will be randomly assigned in 
a 1:1 ratio such that

Approximately 397 subjects are randomly assigned to albiglutide + insulin 
glargine (with or without metformin) 

Approximately 397 subjects are randomly assigned to intensification of insulin 
glargine + insulin lispro (with or without metformin)

Randomized treatment assignment will be done via an interactive voice response 
system, and randomization will be implemented based on a sequestered fixed 
randomization schedule.

Subjects in both the albiglutide plus insulin glargine and insulin glargine plus insulin 
lispro treatment groups will follow standardized insulin titration algorithms (separate 
algorithms for insulin glargine and insulin lispro) throughout the Treatment Period to 
achieve prespecified fasting and/or postprandial glucose targets.

Dosing during the Treatment Period will be as described below: 
Medication
Albiglutide + Insulin Glargine Group
Insulin Glargine + Insulin Lispro Group
Albiglutide
Baseline/Randomization: Start weekly SC 
injection at 30 mg.
Week 4: Uptitrate to 50 mg weekly SC 
injection for the remainder of the Treatment 
Period.
None
Insulin lispro
Baseline/Randomization: Each insulin lispro 
dose will be downtitrated to half that used in 
the Standardization Period.1
Week 4: Stop insulin lispro for the remainder 
of the Treatment Period; insulin lispro may be 
re-introduced after Week 8 (See 
Section 5.1.3.5)
Baseline/Randomization: Continue at the same 
doses as at the end of the Standardization 
Period and adjust doses as per instructions in 
Section 5.1.3.2.
Insulin glargine
Continue at the same dose as at the end of 
the Standardization Period1 and adjust dose 
as per instructions in Section 5.1.3.2.
Continue at the same dose as at the end of the 
Standardization Period and adjust dose as per 
instructions in Section 5.1.3.2.
Metformin
Subjects will remain on their current dose for 
the duration of their participation in the 
study.2
Subjects will remain on their current dose for the 
duration of their participation in the study.2
Re-introduction of 
insulin lispro (if 
required)
After Week 8: See Section 5.1.3.5
Not applicable
SC = subcutaneous.
1.
As described in Section 1.3.1, the risk of hypoglycemia is increased when albiglutide is used in combination with 
insulin; therefore, subjects may require a lower dose of insulin and should be monitored closely.
2.
Unless a decline in kidney function results in a contraindication for metformin use. Metformin is to be stopped if 
the subject’s estimated glomerular filtration rate, calculated according to the Modification of Diet in Renal Disease
formula, decreases during the study to a level where metformin is contraindicated according to its label (as 
appropriate for each participating country).


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
Subjects randomly assigned to treatment with albiglutide who continue to experience 
significant postprandial glucose excursions (i.e., >180 mg/dL [>10.0 mmol/L]) may 
have prandial insulin lispro re-introduced after Week 8 (i.e., 4 weeks after 
discontinuation of insulin lispro and uptitration to albiglutide 50 mg) according to a
standardized, stepwise approach.
Study Assessments
Efficacy Assessments

HbA1c

FPG

Body weight

Hypoglycemia

8-point SMBG profile

Daily insulin doses

Weekly insulin injections

TRIM-Diabetes questionnaire

HFS-II worry subscale
Safety Assessments

Hypoglycemic events

AEs and SAEs

Other AEs of special interest

Pregnancy

Clinical laboratory tests

Vital sign measurements

12-lead ECGs

Physical examinations


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1.
INTRODUCTION
1.1.
Background
Diabetes affects an estimated 346 million people worldwide, with type 2 diabetes 
mellitus (T2DM) accounting for more than 90% of these cases [WHO, 2013; 
CDC, 2011]. The primary manifestation of this disease is chronic hyperglycemia, 
resulting from resistance to insulin action at a cellular and molecular level and a relative 
inadequacy in the secretion of endogenous insulin [ADA, 2012]. Chronic hyperglycemia 
has been firmly established as a key factor in the development of microvascular
complications (retinopathy, nephropathy, and neuropathy) and to a lesser extent, 
macrovascular complications. The rapidly increasing incidence and prevalence of T2DM 
is a major worldwide healthcare issue due to increased patient morbidity and mortality 
and the costs associated with the management of these complications.
The intent of glycemia management in subjects with T2DM is to achieve normoglycemia 
and prevent the development of microvascular and macrovascular complications. The 
American Diabetes Association and the European Association for the Study of Diabetes 
recommend an individualized approach, targeting a glycosylated hemoglobin (HbA1c) 
level of <7.0%, or as low as possible, without signiﬁcant hypoglycemia or other adverse 
effects of treatment [Inzucchi, 2015; Inzucchi, 2012]. More stringent HbA1c targets might 
be considered in selected patients; conversely, less stringent HbA1c goals are appropriate 
for other patients such as those with a history of severe hypoglycemia, limited life 
expectancy, advanced complications, or extensive comorbid conditions.
The medical management of patients with T2DM consists of lifestyle interventions (i.e., 
diet, exercise, and weight reduction) together with oral antidiabetics (OADs), 
glucagon-like peptide-1 receptor (GLP-1R) agonists, or insulin therapy, as appropriate 
[Inzucchi, 2012]. Type 2 diabetes mellitus is a progressive disease characterized by 
worsening β-cell function over time. Patients will require higher doses and additional 
agents in an effort to achieve glycemic targets and many will require the addition of 
insulin to their treatment regimen to maintain glycemic control [Inzucchi, 2012]. Insulin 
therapy is commonly initiated with “basal” insulin typically administered as once-daily 
long-acting insulin analogues that aim to mimic the constant physiologic release of 
insulin that regulates metabolism and hepatic glucose production. When basal insulin 
alone fails to achieve appropriate glycemic targets, prandial insulin (administered as 
rapid-acting insulin analogues or regular insulin given with meals) is often added. 
Prandial insulin replacement is intended to mimic the postmeal insulin response to 
nutrient intake.
While insulin treatment is the cornerstone therapy for patients with T2DM that cannot be 
adequately controlled with OADs, insulin treatment fails to restore normal or near to 
normal glycemia in the majority of patients. Critical factors influencing the limitations of 
insulin therapy in T2DM include an increased risk of hypoglycemia, weight gain, failure 
to achieve consistent preprandial and postprandial glucose control, broad fluctuations in 
plasma glucose during the day, fear and discomfort among patients and physicians about 
these unintended effects, potential impact on quality of life, and poor treatment 


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compliance. Therefore, a clear unmet medical need remains for diabetes medications that 
restore glycemic control in patients on insulin therapy, without increasing the risks of 
hypoglycemia, weight gain, loss of quality of life, and poor compliance with treatment 
[Edelman, 2002].
Glucagon-like peptide-1 receptor agonists (e.g., exenatide, liraglutide, and lixisenatide) 
are therapeutic agents for the treatment of T2DM that stimulate insulin secretion in a 
glucose-dependent manner, suppress glucagon secretion with a low risk of hypoglycemia, 
delay gastric emptying, increase satiety, and are associated with modest weight reduction. 
The GLP-1R agonists lower fasting plasma glucose (FPG) levels and reduce postprandial 
glucose excursions. In addition, in preclinical models GLP-1R agonists stimulated 
transcription of genes important for glucose-dependent insulin secretion and promoted 
β-cell neogenesis [Gautier, 2005].
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 the amino terminus 
of recombinant human albumin. Albiglutide has been developed for the treatment of 
T2DM as an adjunct to diet and exercise, as monotherapy, or in combination with 
existing therapies and has been approved by the US Food and Drug Administration 
(FDA) and the European Medicines Agency (EMA). In a Phase III clinical trial, 
albiglutide in combination with insulin glargine demonstrated an acceptable benefit:risk, 
controlling HbA1c to target levels of <7.0% and <6.5%, providing clinically meaningful 
reductions in FPG, and favoring weight reduction with positive effects on the need for 
hyperglycemia rescue [GlaxoSmithKline Document Number 2011N126139_00; 
GlaxoSmithKline Document Number RM/2006/00602/07].
1.2.
Rationale
The therapeutic aim of mealtime insulin is to blunt postprandial glycemic excursions, 
which can be extreme in some individuals, resulting in poor control during the day 
[Inzucchi, 2012]. Well-managed basal-bolus therapy provides a flexible way of 
controlling glucose throughout the day and night since dosing can be timed to 
approximate nondiabetic endogenous insulin release. However, in practice, basal-bolus 
insulin therapy is challenging to manage for both physicians and patients. Moreover, 
declining health and cognition tend to exacerbate the insulin management challenge in 
many older T2DM patients. In comparison to endogenous insulin, basal-bolus insulin 
therapy comes with a plethora of issues [Swinnen, 2009; McCoy, 2012; Hessler, 2014], 
such as

Dose-dependent increased risk of hypoglycemia

Dose-dependent increased mortality risk associated with hypoglycemia

Increased risk of weight gain

Encumbered quality of life associated with need to balance insulin dosing and 
carbohydrate intake, in both timing and magnitude


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
Cost and stress of multiple daily injections

Earlier loss of independence with aging due to the complexities of diabetes 
management with insulin 
Treatments that diminish insulin demand and preserve or enhance β-cell function are 
expected to result in better glycemic control and diminished risk of these insulin therapy 
complications.
Combining a marketed GLP-1R agonist with basal insulin is part of the current treatment 
armamentarium for T2DM; however, none of these agents are currently indicated for use 
in product labeling with bolus insulin. Two studies have reported reductions in prandial 
insulin doses following the addition of exenatide with no major hypoglycemic events 
[Yoon, 2009; Viswanathan, 2007]. Liraglutide, when used in combination with a 
basal-bolus insulin regimen in patients with T2DM, allowed for a reduction in total and 
bolus insulin doses [Lane, 2014]. However, the Association of British Clinical 
Diabetologists’ audit revealed a worsening of glycemic control for almost 50% of 
patients who stopped insulin therapy upon initiation of exenatide; thus, it is 
recommended that insulin be reduced but not discontinued once a significant glycemic 
improvement has been observed after initiating therapy with a GLP-1R agonist [Thong, 
2011]. The difficulty of how fast and how far to downtitrate insulin doses without 
compromising glycemic control has been recognized in reviews of GLP-1R agonists 
[Holst, 2013] and is still an open question.
The Phase IIIa clinical development program for albiglutide included 2 studies with 
insulin, both open-label, the first comparing albiglutide with insulin glargine 
(Study GLP112754) and the second comparing albiglutide when added on to insulin 
glargine versus insulin lispro added on to insulin glargine (Study GLP108486). At their 
respective primary endpoints (Week 52 in Study GLP112754 and Week 26 in Study 
GLP108486), both studies showed that albiglutide was statistically noninferior to each 
insulin treatment approach with regard to HbA1c and demonstrated that albiglutide could 
be used as an alternative to insulin therapy in patients with late-stage T2DM. Despite 
comparable glucose lowering, albiglutide therapy was associated with approximately 1.5-
to 2-fold less symptomatic hypoglycemia and with weight loss rather than weight gain 
compared with the addition of insulin (treatment difference of 1.5 to 2.6 kg). 
This study will evaluate the efficacy and safety of once-weekly albiglutide administered 
in combination with basal insulin as a replacement for bolus insulin in subjects with 
T2DM who are currently managed with a basal-bolus insulin regimen but who are not 
achieving glycemic treatment goals. It is expected that subjects switched to albiglutide 
plus basal insulin (with discontinuation of bolus insulin therapy) compared with those 
intensifying basal-bolus insulin therapy will be able to maintain glycemic control with 
less hypoglycemia and less weight gain, while also demonstrating a reduced total daily 
insulin requirement and reduced number of weekly injections (e.g., 28 injections per
week [7 basal insulin and up to 21 bolus insulin injections] in basal-bolus-treated subjects 
compared with potentially 8 injections per week [1 weekly albiglutide injection and 
7 basal injections] in subjects switching to basal insulin plus albiglutide). 


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Data from this study will support the concept that albiglutide is a potential alternative to 
bolus insulin that will simplify insulin therapy in subjects with T2DM that do not reach 
adequate control with basal-bolus therapy.
1.3.
Benefit-to-Risk Assessment
Albiglutide has been evaluated in a comprehensive global program of studies involving 
approximately 9000 patient-years of overall exposure to date (including over 
4000 patient-years of exposure to albiglutide), with 8 well-controlled Phase III studies 
(including 1 study in subjects with concurrent renal impairment), ranging in duration 
from 32 weeks to 3 years and using both 30-mg and 50-mg once-weekly dosing. This has 
permitted a robust assessment of efficacy, safety, and tolerability in a representative 
T2DM population that spanned newly diagnosed subjects treated with diet and exercise 
alone through subjects on background oral monotherapy, oral dual therapy, oral triple 
therapy, and basal insulin.
Summaries of findings from both clinical and nonclinical studies conducted with 
albiglutide can be found in the investigator’s brochure (IB) [GlaxoSmithKline Document 
Number RM/2006/00602/07; GlaxoSmithKline Document Number 2014N203025_00], 
subsequent IB updates, and the product label. The following section outlines the risk 
assessment and mitigation strategy for this protocol.
1.3.1.
Risk Assessment
Key risks (identified and potential) associated with the use of albiglutide, or the GLP-1R 
agonist class, as well as the mitigation strategy for key risks of clinical significance are 
provided in Table 1. Please refer to the IB [GlaxoSmithKline Document Number 
RM/2006/00602/07; GlaxoSmithKline Document Number 2014N203025_00] and any 
subsequent IB updates for a thorough summary of the nonclinical and clinical experience 
with albiglutide as well as the complete guidance for the investigator (IB Section 6). In 
addition, the risks associated with study participation, study procedures, or comparators 
are also included in Table 1.


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Table 1
Risk Assessment for Albiglutide (GSK716155)
Risk of Clinical Significance
Data/Rationale for Risk
Mitigation Strategy
Investigational Product: (albiglutide [GSK716155])
Identified Risks
Pancreatitis
[identified risk]
In clinical trials, acute pancreatitis has 
been reported in association with 
albiglutide and other GLP-1R agonists 
(refer to Section 5.4.5.2 and Section 6 
of the IB).
Albiglutide has not been studied in 
subjects with a history of pancreatitis 
to determine whether these subjects 
are at increased risk for pancreatitis.
Specific eligibility and withdrawal 
criteria (see Section 4)
Risk communication via guidance for 
investigators (IB Section 6) and 
informed consent form for subjects
Gastrointestinal (GI) events
[identified risks]
Albiglutide has not been studied in 
subjects with severe GI disease, 
including severe gastroparesis.
Use of albiglutide and other GLP-1R 
agonists may be associated with GI 
AEs (e.g., diarrhea, nausea, and 
vomiting) (refer to Section 5.4.5.4 and 
Section 6 of the IB).
Specific GI eligibility criteria (see 
Section 4)
Risk communication via guidance for 
investigators (IB Section 6) and 
informed consent form for subjects
Hypoglycemia
[identified risk]
Albiglutide’s mechanism of action is 
associated with a low intrinsic risk of 
significant hypoglycemia; however, 
when used in combination with insulin 
secretagogues (such as SUs) or 
insulin, the risk of hypoglycemia is 
increased (refer to Section 5.4.5.1 and 
Section 6 of the IB).
Subjects on concurrent SU are 
excluded (see Section 4.2).
Close monitoring for hypoglycemia 
and need for intervention via frequent 
contact with subjects who will 
self-monitor blood glucose (see 
Section 4.5 and Section 5.1.3.2)
Risk communication via guidance for 
investigators (IB Section 6) and 
informed consent form for subjects


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Risk of Clinical Significance
Data/Rationale for Risk
Mitigation Strategy
Immunogenicity (e.g., clinical 
sequelae of antidrug antibodies, 
severe hypersensitivity reactions, 
other immune-related events)
[identified risk]
In the Phase III program, 
approximately 5% of subjects 
developed anti-albiglutide antibodies, 
but based on available clinical data, 
anti-albiglutide antibody formation is 
not expected to impact the overall 
safety or efficacy of albiglutide 
treatment (refer to Section 5.6.1 of the 
IB).
Although most subjects with injection 
site reactions were antibody negative 
(approximately 85%), injection site 
reactions were reported more 
frequently for antibody-positive 
subjects (approximately 41%) than 
antibody-negative subjects 
(approximately 14%).
Hypersensitivity reactions are of 
potential concern with any injected 
protein and were reported rarely in the 
Phase III program (refer to Section 
5.4.5.5 and Section 6 of the IB).
Specific eligibility and withdrawal 
criteria (see Section 4)
Risk communication via informed 
consent form for subjects
Injection site reactions
[identified risk]
Albiglutide is given as an SC injection 
in the abdomen, thigh, or upper arm 
and may cause rash, erythema, 
and/or itching at the injection site (IB 
Section 5.4.5.6).
Risk communication via guidance for 
investigators (IB Section 6) and 
informed consent form for subjects
Subjects will be advised to use a 
different injection site each week.
Other adverse reactions
(e.g., pneumonia, atrial 
fibrillation/atrial flutter, appendicitis, 
and hypersensitivity reactions)
[identified risks]
In the Phase III program, other 
adverse reactions were observed with 
a cumulative incidence of <3% in 
studies up to 3 years in duration 
(Refer to Section 5.4.5.10, 
Section 5.4.5.11, and Section 6 of the 
IB).
Risk communication via guidance for 
investigators (IB Section 6) and 
informed consent form for subjects


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Risk of Clinical Significance
Data/Rationale for Risk
Mitigation Strategy
Investigational Product: (albiglutide [GSK716155])
Potential Risks
Thyroid C-cell tumors
[potential risk]
This potential risk arises from 
nonclinical rodent studies where GLP-
1R agonists have been associated 
with increases in serum calcitonin, 
thyroid C-cell focal hyperplasia, and 
C-cell tumors. The relevance of these 
observations to humans is uncertain. 
In Phase III studies of up to 3 years in 
duration, albiglutide was not 
associated with clinically relevant 
increases in serum calcitonin (refer to 
Section 5.4.5.3 and Section 6 of the 
IB).
Subjects with a personal or family 
history of MTC or with multiple 
endocrine neoplasia syndrome type 2 
are excluded (see Section 4.3).
Risk communication via guidance for 
investigators (IB Section 6) and 
informed consent form for subjects
Other malignant neoplasms
(e.g., pancreatic cancer or 
malignancy when used in 
combination with insulin)
[potential risks]
Theoretical concern for pancreatic 
cancer associated with GLP-1–based 
therapies (DPP-IV inhibitors and 
GLP-1R agonists) is under evaluation 
by regulatory authorities [Egan, 2014] 
and has thus far concluded that a 
causal relationship cannot be 
established currently, but they will 
continue to investigate as more data 
become available.
Theoretical concern raised by the 
European Union regulatory authorities 
is based on their concern for the 
biological plausibility of a tumor-
promoting effect when a GLP-1 
agonist is combined with insulin.
Risk communication via guidance for 
investigators (IB Section 6) and 
informed consent form for subjects
Cardiovascular (CV) safety of 
antidiabetic therapy
[potential risk]
T2DM is associated with an elevated 
risk of CV disease. Global regulatory 
agencies require new antidiabetic 
therapies to demonstrate that the new 
therapy is not associated with an 
unacceptable increase in CV risk 
(refer to Section 5.4.5.8 of the IB). 
In the Phase III registration program, 
an independent Clinical Endpoint 
Committee prospectively adjudicated 
blinded CV events. The final CV 
meta-analysis showed no increased 
CV risk (MACE+ composed of CV 
death, MI, stroke, and hospitalization 
for unstable angina) with albiglutide 
versus all comparators (refer to 
Section 5.4.5.8 of the IB; MACE+ 
hazard ratio = 1.00; 95% 
CI: 0.68, 1.49).
Risk communication via guidance for 
investigators (IB Section 6) and 
informed consent form for subjects


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Risk of Clinical Significance
Data/Rationale for Risk
Mitigation Strategy
Hepatotoxicity
[potential risk]
One subject in the Phase III clinical 
program developed a probable 
drug-induced liver injury with an 
asymptomatic elevation in ALT and 
total bilirubin, although the case had 
some atypical features and 
complicating factors (refer to 
Section 5.4.5.7 of the IB). 
Specific eligibility and withdrawal 
criteria (see Section 4)
Investigational Product: (albiglutide [GSK716155])
Additional Considerations
Patient population with
severe renal impairment
(eGFR <30 mL/min/1.73 m2)
Experience in T2DM patients with 
severe renal impairment is very 
limited.
Subjects with severe renal (eGFR 
<30 mL/min/1.73 m2) impairment 
receiving albiglutide experienced a 
higher frequency of diarrhea, nausea, 
and vomiting compared with subjects 
with mild/moderate renal impairment 
(refer to Section 5.4.6 and Section 6 
of the IB).
Subjects with severe renal impairment 
are excluded from this study (see 
Section 4.3).
Specific monitoring guidance provided 
(see Section 5.1.1 and 
Section 6.3.5.1).
Risk communication via guidance for 
investigators (IB Section 6) and 
informed consent form for subjects
Drug interactions
Albiglutide causes a delay in gastric 
emptying and thereby has the 
potential to impact the absorption of 
concomitantly administered oral 
medications (refer to Section 5.2.1.2, 
Section 5.2.5, and Section 6 of the 
IB).
Drug interaction studies have been 
conducted with digoxin, warfarin, oral 
contraceptives, and simvastatin, which 
demonstrated no clinically relevant PK 
or PD effects. 
Risk communication via guidance for 
investigators (IB Section 6) and 
informed consent form for subjects
Pregnancy and lactation
Studies in animals have shown 
reproductive toxicity. The potential risk 
for humans is unknown (refer to 
Section 4.4.6 and Section 6 of the IB).
It is not known if albiglutide is secreted 
into human milk during lactation. 
Given that albiglutide is an 
albumin-based protein therapeutic, it
is likely to be present in human milk.
Decreased body weight in offspring 
was observed in mice treated with 
albiglutide during gestation and 
lactation.
Specific eligibility and withdrawal 
criteria (see Section 4)
Risk communication via guidance for 
investigators (IB Section 6) and 
informed consent form for subjects
Study Design or Procedures
Standardization Period
Converting to insulin glargine and 
insulin lispro during the 
Specific withdrawal criteria and 
monitoring guidelines (see 


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Risk of Clinical Significance
Data/Rationale for Risk
Mitigation Strategy
Standardization Period may result in
glycemic excursions, potentially 
leading to hypoglycemic events or 
worsening hyperglycemia.
Section 4.5.1 and Section 5.1.1)
Risk communication via guidance for 
investigators (IB Section 6) and 
informed consent form for subjects
The conversion from prior basal-bolus 
insulin regimen to insulin glargine and 
insulin lispro will be performed in a 
manner consistent with product 
labelling for each treatment (see 
Section 5.1.1).
Potential risk for significant 
postprandial glucose excursions 
(i.e., >180 mg/dL [>10.0 mmol/L]) 
following discontinuation of insulin 
lispro in the once-weekly albiglutide 
treatment group
Currently there are no accepted 
guidelines for downtitrating the total 
daily dose of insulin, particularly to 
guide the discontinuation of 
rapid-acting prandial insulin or the 
initiation of GLP-1R agonists in 
patients treated with basal-bolus 
insulin therapy.
Per the protocol study design, 
subjects randomly assigned to the 
albiglutide treatment group will reduce 
insulin lispro by 50% at 
Baseline/Randomization, followed by 
complete (100%) discontinuation of 
insulin lispro at Week 4 (see 
Section 5.1.2).
Subjects randomly assigned to the 
albiglutide treatment group who 
continue to experience significant 
postprandial glucose excursions (i.e., 
>180 mg/dL [>10.0 mmol/L]) may 
have prandial insulin lispro 
re-introduced after Week 8 (see 
Section 5.1.3.5).
Other
Insulin glargine and insulin lispro
Hypoglycemia is the most common 
adverse effect associated with the use 
of insulins. The risk of hypoglycemia 
increases with tighter glycemic control 
(refer to the product labels for insulin 
glargine and insulin lispro, 
respectively, [Lantus US Package 
Insert, 2013; Humalog US Package 
Insert, 2013]). 
Other less frequent important risks 
include hypersensitivity and allergic 
reactions, hypokalemia, weight gain, 
lipodystrophy following long-term 
administration, peripheral edema, and 
fluid retention and heart failure with
concomitant use of PPAR-γ agonists. 
Intensification or rapid improvement in 
glucose control has been associated 
with a transitory, reversible 
ophthalmologic refraction disorder, 
worsening of diabetic retinopathy, and 
acute painful peripheral neuropathy. 
Subject education on the signs and 
symptoms of hypoglycemia (including 
nocturnal hypoglycemia), common 
causes of hypoglycemia, appropriate 
methods to help prevent 
hypoglycemia, and on the 
self-treatment of hypoglycemic 
episodes (see Section 6.3.1)
Close monitoring for hypoglycemia 
and need for intervention (e.g., insulin 
dose adjustment, withdrawal from 
study participation) via frequent 
contact with subjects, who will 
self-monitor blood glucose (see 
Section 4.5, Section 5.1.3.3, and 
Section 6.2.2)
Risk communication via guidance for 
investigators (IB Section 6) and 
informed consent form for subjects


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Risk of Clinical Significance
Data/Rationale for Risk
Mitigation Strategy
However, long-term glycemic control 
decreases the risk of diabetic 
retinopathy and neuropathy.
AE = adverse event; ALT = alanine aminotransferase; CI = confidence interval; CV = cardiovascular; 
DPP-IV = dipeptidyl peptidase-IV; eGFR = estimated glomerular filtration rate; GI = gastrointestinal; 
GLP-1R = glucagon-like peptide-1 receptor; GSK = GlaxoSmithKline; IB = investigator’s brochure; MACE = major 
adverse cardiovascular event; MI = myocardial infarction; MTC = medullary thyroid carcinoma; 
PD = pharmacodynamic; PK = pharmacokinetic; PPAR = peroxisome proliferator-activated receptor; 
SC = subcutaneous; SU = sulfonylurea; T2DM = type 2 diabetes mellitus.
1.3.2.
Benefit Assessment
The clinical data from the Phase IIIa development program show that once-weekly
albiglutide treatment (both the 30- and 50-mg doses), in a single-dose pen device, results 
in clinically relevant lowering of HbA1c and FPG in T2DM patients, when given as 
monotherapy and in combination with metformin, sulfonylurea (SU), thiazolidinedione, 
and basal insulin (refer to Section 5.5 of the IB) [GlaxoSmithKline Document Number 
RM/2006/00602/07]. Furthermore, the durability of the effect on these glycemic 
parameters has been shown over a study period of 3 years. Body weight decreased 
slightly or remained stable during treatment, which is of benefit considering that 
continuous weight gain is a clinical problem in this patient group. Maintaining body 
weight while decreasing HbA1c is therefore considered a beneficial effect of importance.
As previously noted (see Section 1.1), the use of albiglutide in combination with insulin 
or in an active-controlled study versus insulin has been evaluated in separate clinical 
studies: 1 study comparing albiglutide with insulin glargine (Study GLP112754) and a 
second study comparing albiglutide with insulin lispro when added on to insulin glargine 
(Study GLP108486). In both of these studies, albiglutide was shown to be statistically 
noninferior to each insulin treatment approach with regard to HbA1c at the primary 
endpoint (Week 52 in Study GLP112754 and Week 26 in Study GLP108486) and 
demonstrated that albiglutide could be used as an alternative to insulin therapy in patients 
with late-stage T2DM. Despite comparable glucose lowering, albiglutide therapy was 
associated with approximately 1.5- to 2-fold less symptomatic hypoglycemia and with 
weight loss rather than weight gain compared with the addition of insulin (treatment 
difference of 1.5 to 2.6 kg).
In this study, where albiglutide treatment will be added to a regimen of insulin glargine, 
subjects are expected to achieve similar benefits (reductions in HbA1c and FPG with 
weight loss or weight remaining stable) as seen in the previous Phase III studies. Subjects 
in the albiglutide group will also receive fewer subcutaneous injections per week than 
subjects in the insulin lispro group (8 versus 28, respectively).
Subjects in the insulin glargine plus insulin lispro group will also be receiving effective 
antihyperglycemic medication, which will be titrated up or down to clinically relevant 
glycemic targets, and therefore these subjects should demonstrate reductions in HbA1c
and FPG, though weight gain may occur. Subjects may also receive the benefit of fewer 
injection site reactions and gastrointestinal (GI) events, based on the results from Study 


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GLP108486 (albiglutide versus insulin lispro, both added on to insulin glargine) where 
subjects in the insulin lispro plus insulin glargine treatment group experienced fewer such 
events than subjects in the albiglutide plus insulin glargine group. 
Finally, as a result of participating in a clinical trial, each subject will receive more 
contact with the study center, have diet and exercise advice reinforced at each visit, and 
have more regular HbA1c assessments than would be performed as part of their usual 
standard of care.
1.3.3.
Overall Benefit-to-Risk Conclusion
Taking into account the measures taken to minimize risk to subjects participating in this 
study, the potential risks identified in association with albiglutide are justified by the 
anticipated benefits that may be afforded to subjects with T2DM.
Knowledge from this study will contribute to the overall benefit-to-risk profile of 
albiglutide. The results from this study may help physicians better understand T2DM, 
treatment for T2DM, which types of subjects are more likely to benefit from treatment 
with albiglutide, or which types of subjects are more likely to have side effects from 
albiglutide.
2.
OBJECTIVES AND ENDPOINTS
Objective
Endpoint
Primary

To evaluate the glycemic effectiveness of 
once-weekly albiglutide as replacement of 
prandial insulin in subjects with T2DM 
receiving basal-bolus insulin therapy

Change from Baseline in HbA1c at Week 26
Secondary
Key Secondary

To determine the proportion of subjects 
treated with once-weekly albiglutide that are 
able to replace prandial insulin without the 
need for re-introduction of insulin lispro

Proportion of subjects treated with 
once-weekly albiglutide that are able to 
discontinue insulin lispro at Week 4 and do 
not meet prespecified criteria for severe, 
persistent hyperglycemia through Week 26 

To demonstrate a significant difference in 
the frequency of hypoglycemic events 
between treatment groups

Percentage of subjects with severe or 
documented symptomatic hypoglycemia 
through Week 26 (see Section 6.3.1)

To demonstrate a significant difference in 
body weight between treatment groups

Change from Baseline in body weight at 
Week 26 and over time

To demonstrate a significant reduction in 
total daily dose of insulin between treatment 
groups

Total daily insulin dose at Week 26


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Objective
Endpoint
Supportive Secondary

To assess additional glycemic parameters, 
achievement of HbA1c treatment goals, 
body weight, and total daily insulin dose

Additional glycemic parameters:

HbA1c change from Baseline over time

FPG change from Baseline at Week 26 
and over time

Achievement of HbA1c treatment goals:

Proportion of subjects achieving a 
HbA1c <7.0% at Week 26 and over time

Proportion of subjects achieving a 
HbA1c <6.5% at Week 26 and over time

Incidence and time to meeting prespecified 
criteria for severe, persistent hyperglycemia 
at Week 26 

Additional assessments of daily insulin 
doses:

Total daily insulin dose (24-hour total 
international units [IU] and total units/kg 
body weight) over the 3 days preceding 
the Baseline/Randomization and 
Week 4, 10, and 18 visits

Total daily basal insulin (insulin 
glargine) (24-hour total IU and total 
units/kg body weight) over the 3 days 
preceding the Baseline/Randomization 
and Week 4, 10, 18, and 26 visits

Total daily bolus insulin (insulin lispro) 
(24-hour total IU and total units/kg body 
weight) over the 3 days preceding the 
Baseline/Randomization and Week 4, 
10, 18, and 26 visits

Total number of weekly insulin injections 
(7 days) to achieve glycemic control at 
Baseline/Randomization and Week 4, 10, 
18, and 26

Composite endpoints (after 26 weeks of 
treatment):

Percentage of subjects achieving 
HbA1c <7.0% without weight gain

Percentage of subjects achieving 
HbA1c <7.0% without severe or 
documented symptomatic 
hypoglycemia

Percentage of subjects achieving 
HbA1c <7.0% without weight gain and 
without severe or documented 
hypoglycemia


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Objective
Endpoint

To evaluate the safety and tolerability of the 
2 treatment groups

Adverse events (AEs) and serious AEs 
(SAEs), including AEs and SAEs leading to 
discontinuation of randomized study 
medication

Other AEs of special interest (for example, 
cardiovascular [CV] events, GI events, 
injection site reactions, potential systemic 
allergic reactions, pancreatitis, pancreatic 
cancer, medullary thyroid cancer, malignant 
neoplasms following treatment with insulin, 
diabetic retinopathy events, appendicitis, 
liver events, pneumonia, and atrial 
fibrillation/flutter)

Assessments of hypoglycemia:

Percentage and number of events of 
hypoglycemia with confirmed home 
blood glucose monitoring and/or 
third-party intervention through 
Week 26 (i.e., severe, documented 
symptomatic, and asymptomatic 
hypoglycemic events, see 
Section 6.3.1) in 3-month intervals (i.e., 
from Baseline/Randomization to 
Week 12, >Week 12 to Week 26)

Incidence of hypoglycemic events (in 
total and by each category as defined 
by the American Diabetes Association 
criteria)

Incidence of daytime hypoglycemia (in 
total and by category), defined as 
hypoglycemic events with an onset 
between 06:00 hours and 00:00 hours 
(inclusive), and nocturnal hypoglycemia 
(in total and by category), defined as 
hypoglycemic events with an onset 
between 00:01 hours and 05:59 hours 
(inclusive)

Incidence of hypoglycemia with blood 
glucose <56 mg/dL (<3.1 mmol/L), 
regardless of symptoms

Assessment of clinical laboratory tests 
(hematology, clinical chemistry, urinalysis, 
β-human chorionic gonadotropin [β-HCG], 
lipid panel)

Assessment of vital sign measurements 
(Note: Weight is assessed as part of 


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Objective
Endpoint
efficacy), 12-lead electrocardiogram (ECG) 
findings, and physical examination findings
Exploratory

To compare the effects between the 
2 treatment groups on patient-reported 
outcomes to diabetes medication and to 
further assess glycemic parameter, weight, 
and composite endpoints

Patient-reported outcomes to diabetes 
medication at Baseline/Randomization, 
Week 10, and Week 26:

Treatment-related impact measure for 
diabetes (TRIM-Diabetes) questionnaire

Hypoglycemia fear survey-II (HFS-II) 
worry subscale

Additional glycemic parameter, weight, and 
composite endpoints:

HbA1c change from Baseline at 
Week 26 by baseline FPG tertiles

FPG change from Baseline at Week 26 
by baseline FPG tertiles

24-hour glucose profile: 8-point 
self-monitored blood glucose (SMBG) 
profile at Baseline/Randomization, 
Week 10, and Week 26 (before and 
120 minutes after the 3 main meals, at 
bedtime, and at 2 AM)

Mean daily blood glucose based on the 
8-point SMBG profile at 
Baseline/Randomization, Week 10, and 
Week 26

Number (and percentage) of subjects 
with 1 kg weight gain at Week 26

Percentage of subjects achieving 
HbA1c <7.0% without weight gain and 
without hypoglycemia with blood 
glucose <56 mg/dL (<3.1 mmol/L) 
regardless of symptoms at Week 26

Proportion of subjects treated with 
once-weekly albiglutide that are able to 
totally replace or decrease prandial 
insulin without worsening HbA1c control 
(worsening defined as >0.3% increase 
in HbA1c compared with baseline HbA1c) 
at Week 26

Analysis of genetic sampling may also be 
performed

Genetic sampling

Analysis of novel biomarkers may also be 
performed

Novel biomarker analysis may be 
performed; a decision on whether to 
analyze novel biomarker samples may be 
made after review of efficacy and safety 


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Objective
Endpoint
endpoints at the end of the study or other 
emerging information that may become 
available during the study
3.
INVESTIGATIONAL PLAN
3.1.
Study Design
This Phase IIIb, randomized, open-label, parallel-group, active-control, multicenter, 
treat-to-target study of 26 weeks’ treatment duration will evaluate the efficacy and safety 
of once-weekly albiglutide as replacement of prandial insulin in subjects with T2DM 
failing to achieve adequate glycemic control on their current basal-bolus insulin regimen 
(with or without metformin). In this study, the intensification of basal-bolus insulin 
therapy (i.e., insulin glargine plus insulin lispro) according to predefined treat-to-target 
titration algorithms will serve as the active control.
The study will comprise 4 study periods (Figure 1): Screening (2 weeks), Standardization 
(4 weeks), Treatment (26 weeks), and Posttreatment Follow-up (4 weeks). The total 
duration of a subject’s participation will be approximately 36 weeks.
Figure 1
Study Design
SC = subcutaneous; T2DM = type 2 diabetes mellitus; TDD = total daily dose.
Note: Subjects on metformin will continue on the same dose throughout the study, except if the subject’s estimated 
glomerular filtration rate, calculated according to the Modification of Diet in Renal Disease formula, decreases 
during the study to a level where metformin is contraindicated according to its label (as appropriate for each 
participating country), in which case metformin is to be stopped.
1.
At Baseline/Randomization, albiglutide will be started at 30 mg once weekly with uptitration to albiglutide 50 mg 
once weekly at Week 4. Subjects randomly assigned to this treatment group will reduce insulin lispro by 50% at 
Baseline/Randomization, followed by complete (100%) discontinuation of insulin lispro at Week 4.
During the Screening Period (Week -6 through Week -5), subjects will provide written 
informed consent and undergo procedures to determine eligibility for study participation. 


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Note: A fasting HbA1c value may be determined using a Metrika kit (Metrika, Inc, 
Sunnyvale, California) or other finger-stick procedure to provide an initial guide of 
subject eligibility for investigators. The test is not required. The HbA1c value obtained at 
this screening visit is to be used as a guide for the investigator. If the investigator feels 
that a subject is a good candidate for the study, the subject should continue with the 
screening visit and have HbA1c assessed through the central laboratory. The central 
laboratory measure will serve as the official HbA1c value to determine subject eligibility 
for entry into the Standardization Phase. 
After Screening, subjects meeting all eligibility criteria will enter a 4-week 
Standardization Period to transition from their current basal-bolus regimen to insulin 
glargine plus insulin lispro. Subjects already on insulin glargine plus insulin lispro will 
also enter the Standardization Period. During the Standardization Period, the basal-bolus 
insulin regimen may be adjusted to achieve glycemic targets as close to normal as 
possible without untoward hypoglycemia in accordance with product labeling in the 
respective country and standard of care at the study center. Subjects will also receive 
training on the use of albiglutide injector pens and sterile techniques for 
self-administration in preparation for the Treatment Period, during which the 
investigational product (albiglutide) will be administered at home. See Section 5.1 for 
further details. 
After the Standardization Period, subjects meeting additional criteria for randomization 
will be stratified by screening HbA1c value (<8.0% versus ≥8.0%), age (<65 years versus 
65 years), and current use of background metformin (metformin use versus no 
metformin use). Approximately 794 subjects will be randomly assigned to 1 of 2 
treatment groups in a 1:1 ratio such that

Approximately 397 subjects are randomly assigned to albiglutide + insulin 
glargine (with insulin lispro discontinuation at Week 4) (with or without 
metformin) 

Approximately 397 subjects are randomly assigned to intensification of insulin 
glargine + insulin lispro (with or without metformin)
In this treat-to-target study, subjects in both the albiglutide plus insulin glargine and 
insulin glargine plus insulin lispro treatment groups will follow standardized insulin 
titration algorithms (separate algorithms for insulin glargine and insulin lispro) 
throughout the Treatment Period to achieve prespecified fasting and/or postprandial 
glucose targets; see Section 5.1.3.2. The treat-to-target study design should equalize 
glycemic efficacy between the treatment groups, thus allowing for comparison of other 
measures of clinical utility (e.g., differences in hypoglycemia, body weight, total daily 
dose of insulin, number of injections per week, and patient-reported outcomes). 
Subjects randomly assigned to treatment with albiglutide who continue to experience 
significant postprandial glucose excursions (i.e., >180 mg/dL [>10.0 mmol/L]) may have 
prandial insulin lispro re-introduced after Week 8 (i.e., 4 weeks after discontinuation of 
insulin lispro and uptitration to albiglutide 50 mg) according to a standardized, stepwise 
approach. See Section 5.1.3.5 for further details.


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Subjects will have 10 study center visits (Table 5) and approximately 18 telephone calls 
(Table 6) to monitor and adjust insulin glargine and insulin lispro doses.
Potential events of pancreatitis will be adjudicated by an independent pancreatitis 
adjudication committee (PAC).
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Procedures Manual (SPM). The SPM will provide 
the site personnel with administrative and detailed technical information that does not 
impact subject safety.
With respect to the study conduct, subject completion is defined as completion of all 
periods of the study up to and including the Follow-up visit. For the primary analysis, 
subject completion is defined as completion of all periods of the study up to and 
including the Treatment 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 Tables, are essential and required for study conduct.
There will be no compassionate use of study medication once a subject completes or 
withdraws early from the study.
3.2.
Discussion of Design
3.2.1.
Choice of Control
Due to the progressive β-cell dysfunction that characterizes T2DM, many patients will 
eventually require insulin replacement therapy. Unless the patient is markedly 
hyperglycemic, initial insulin therapy is typically “basal” insulin alone [Holman, 2009]. 
Basal insulin (such as neutral protamine Hagedorn, insulin glargine, insulin detemir, or 
insulin degludec) provides relatively uniform insulin coverage throughout the day and 
night, mainly to control blood glucose by suppressing hepatic glucose production in 
between meals and during sleep. Although the majority of patients with T2DM requiring 
insulin therapy can be successfully treated with basal insulin alone, some will require 
prandial insulin therapy due to low functional β-cell mass, high insulin resistance, or 
both. Prandial insulins are shorter-acting insulins (such as regular insulin, insulin lispro, 
insulin aspart, or insulin glulisine), which may be dosed just before the meal (i.e., “bolus” 
insulin therapy). The control group in this study will utilize a basal-bolus regimen, the 
current standard of care. In this treat-to-target study, the active control group will be 
intensification of insulin glargine + insulin lispro according to predefined titration 
algorithms.
3.2.2.
Duration of Treatment
Albiglutide has demonstrated efficacy in T2DM subjects, as monotherapy and in 
combination with existing antidiabetic medication, in Phase III studies of various 
duration ranging from 32 weeks to 156 weeks. This Phase IIIb study, with a treatment 


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period of 26 weeks is sufficient to assess the primary, secondary, and safety endpoints of 
the study and is consistent with regulatory authority recommendations for evaluating 
efficacy and safety in patients with T2DM [FDA Guidance for Industry, 2008; EMA
Guidance, 2012].
3.2.3.
Intention of Standardization Period
Standardizing the type and frequency of basal and bolus insulin during this period is 
important to decrease the confounding variability associated with multiple combinations 
of insulins that would add substantial complexity to the insulin titration algorithms, thus 
complicating the interpretation of study results. The intent of the 4-week Standardization 
Period is to allow subjects to transition from their current basal insulin and bolus insulin 
to insulin glargine and insulin lispro (if not already taking them) and achieve a level of 
familiarity with this combination prior to randomization.
3.2.4.
Dose of Albiglutide
Data from the 8 Phase III studies (Studies GLP108486, GLP112753, GLP112754, 
GLP112755, GLP112756, GLP112757, GLP114179, and GLP114130) confirmed that 
albiglutide 30-mg and 50-mg doses both showed robust efficacy and safety. Although a 
30-mg dose of albiglutide is effective at controlling glycemia for at least 2 years in many 
subjects, an increase in dose to 50 mg weekly offers additional benefit, as demonstrated 
in Study GLP112756 and Study GLP114179. In other Phase III studies 
(Studies GLP108486, GLP112754, GLP112757, and GLP112753), the dose of 
albiglutide was increased to 50 mg according to clinical need, reflecting “real world” 
practice; this titration occurred in 69% of subjects during the period up to the primary 
endpoint in each study and confirmed the benefit of albiglutide uptitration. Importantly, 
the improvements in glycemic parameters after increasing to 50 mg albiglutide weekly 
occurred across all the concurrent background antidiabetic therapies included in the 
albiglutide studies (i.e., Study GLP108486 in which albiglutide was added on to insulin 
glargine [OAD agents] and compared with insulin lispro added to insulin glargine 
[OADs] and Study GLP112754 in which albiglutide was compared with insulin 
glargine in subjects failing on background metformin SU). The 50-mg dose of 
albiglutide therefore provides additional glycemic benefit without significant safety 
issues, as shown in Study GLP112756 in which there was both a 30-mg treatment arm 
and a 50-mg treatment arm (30 mg for 12 weeks followed by uptitration to 50 mg) and in 
the 4 optional uptitration Phase III studies, where the data suggested no dose response 
that was likely to meaningfully impact the safety or tolerability profile. 
The albiglutide dose in this study will start at 30 mg weekly and be increased to 50 mg 
weekly at Week 4. Therefore, this schedule will allow for a more homogeneous 
comparison of albiglutide (at 1 dose) to insulin lispro versus an individualized optional 
uptitration scheme based on glycemic thresholds (as in 4 of the Phase III studies), where 
uptitration occurred at various times during the study (as needed) and resulted in a mix of 
both 30-mg and 50-mg doses.


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3.2.5.
Insulin Doses
The starting dose for basal insulin (insulin glargine) in the Standardization Period should 
be the same (or 20% lower if the subject enters the study on 2 doses of basal insulin), on 
a unit-for-unit basis, as that taken by the subject during Screening; see Section 5.1.1 for 
additional details. 
The starting dose for bolus insulin (insulin lispro) in the Standardization Period should be 
the same, on a unit-for-unit basis, as that taken by the subject during Screening; see 
Section 5.1.1 for additional details and guidance regarding permitted changes at the 
discretion of the investigator.
During the Treatment Period, the study will allow individualization of the insulin dose in 
both treatment groups (i.e., insulin glargine in the albiglutide treatment group and both 
insulin glargine and insulin lispro in the basal-bolus treatment group), with a 
treat-to-target approach and a titration regimen based on SMBG values and other 
important information, such as hypoglycemia (Table 3 and Table 4).
4.
SUBJECT SELECTION AND WITHDRAWAL CRITERIA
4.1.
Number of Subjects
A sufficient number of subjects will be screened to randomly assign approximately 
794 subjects. Assuming that 15% of subjects will withdraw early or be lost to follow-up, 
approximately 674 evaluable subjects (approximately 337 subjects per treatment group) 
are required to complete the study.
4.2.
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 [GlaxoSmithKline Document Number 
RM/2006/00602/07; GlaxoSmithKline Document Number 2014N203025_00], any 
subsequent IB updates, and the package inserts for insulin glargine, insulin lispro, and 
metformin. See Section 5.1 for details.
Deviations from inclusion criteria are not allowed because they can potentially jeopardize 
the scientific integrity of the study, regulatory acceptability, or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential.
Subjects eligible for enrollment in the study must meet all of the following criteria:
1.
Male or female, 18 to 75 years of age (inclusive at the time of Screening) with 
T2DM
2.
HbA1c ≥7.0% and ≤9.5% at Screening. If the first screening HbA1c does not meet the 
eligibility criterion, the HbA1c value may be checked up to 2 times during Screening, 


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and if the average of these determinations meets the criterion, the subject may be 
eligible for further participation in the study
3.
Currently treated with a basal-bolus insulin regimen (with or without metformin) for 
at least 3 months before Screening. The subject must be taking the following:

Basal insulin (1 or 2 daily injections of neutral protamine Hagedorn insulin, 
insulin glargine, insulin detemir, or insulin degludec)
AND

Bolus insulin (at least 2 injections of regular insulin, insulin glulisine, insulin 
aspart, or insulin lispro) with a total daily dose of bolus insulin 70 units

In addition, the total daily dose of insulin must be ≤140 units

If taking metformin, a stable dose for at least 8 weeks before Screening
Note: Subject should not have received any other antidiabetic medication within 
30 days before Screening (e.g., GLP-1R agonist, dipeptidyl peptidase-IV inhibitor, 
SU, meglitinide, sodium-glucose transporter 2 inhibitor, or thiazolidinedione). 
Subjects receiving commercially available premixed basal and prandial insulin are not 
eligible for this study.
4.
Fasting C-peptide 0.8 ng/mL (0.26 nmol/L). If the fasting C-peptide is 
<0.8 ng/mL (<0.26 nmol/L) but stimulated C-peptide 90 minutes after a standardized 
mixed meal is 1.5 ng/mL (0.5 nmol/L), the subject may be eligible for further 
participation in the study [Jones, 2013; Maldonado, 2005] 
Note: Plasma glucose will also be measured 90 minutes after the standardized mixed 
meal; if the concurrent plasma glucose collected 90 minutes after the standardized 
mixed meal is not 144.0 mg/dL (8.0 mmol/L), the stimulated C-peptide test may 
be repeated during an unscheduled visit.
5.
Body mass index ≤40 kg/m2
6.
Thyroid-stimulating hormone (TSH) level is normal or clinically euthyroid as 
demonstrated by further thyroid tests (e.g., free T4)
7.
Female subjects of childbearing potential (i.e., not surgically sterile and/or not 
postmenopausal) must be practicing adequate contraception (as defined below) for 
the duration of participation in the study including the 4-week Posttreatment 
Follow-up Period

Abstinence from penile-vaginal intercourse, when this is the female’s preferred 
and usual lifestyle 

Oral contraceptive, either combined or progestogen alone
For subjects participating at sites in Germany: progestogen-only pills are only 
acceptable if they have a Pearl Index of less than 1.0 (e.g., those containing 75 g 
desogestrel)

Injectable progestogen


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
Implants of etonogestrel or levonorgestrel

Estrogenic vaginal ring

Percutaneous contraceptive patches

Intrauterine device or intrauterine system that has a failure rate of less than 1% 
per year when used consistently and correctly as stated in the product label

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 the site personnel’s review of the female subject’s 
medical records, medical examination of the subject and/or semen analysis, or 
interview with the female subject on her male partner’s medical history.

Male condom combined with a female diaphragm, either with or without a 
vaginal spermicide (foam, gel, film, cream, or suppository) [Hatcher, 2007]
8.
Willing and able to comply with all study procedures including performance of 
frequent SMBG profiles and use of an e-diary according to the protocol
9.
Able and willing to provide written informed consent after a thorough explanation of 
the study by the investigator or designee, which will include the opportunity for the 
subjects to ask questions
10. Suitable for participation in a treat-to-target study, including intensified basal-bolus 
insulin therapy utilizing the prespecified glycemic targets defined in the protocol
4.3.
Exclusion Criteria
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability, or subject safety. 
Therefore, adherence to the criteria as specified in the protocol is essential. 
Subjects meeting any of the following criteria must not be enrolled in the study:
1.
Type 1 diabetes mellitus
2.
History of cancer that has not been in full remission for at least 3 years before 
Screening. (A history of squamous cell or basal cell carcinoma of the skin or treated 
cervical intra-epithelial neoplasia I or II is allowed)
3.
Personal or family history of medullary thyroid carcinoma or multiple endocrine 
neoplasia type 2
4.
Current symptomatic biliary disease or history of acute or chronic pancreatitis
5.
Severe gastroparesis, i.e., requiring regular therapy within 6 months before 
Screening
6.
History of significant GI surgery that in the opinion of the investigator is likely to 
significantly affect upper GI or pancreatic function (e.g., gastric bypass and banding, 
antrectomy, Roux-en-Y bypass, gastric vagotomy, small bowel resection, or 
surgeries thought to significantly affect upper GI function)


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7.
History of hypoglycemia unawareness (i.e., the absence of autonomic warning 
symptoms before the development of neuroglycopenic symptoms such as blurred 
vision, difficulty speaking, feeling faint, difficulty thinking, and confusion) 
8.
Diabetic complications (e.g., active proliferative retinopathy or severe diabetic 
neuropathy) or any other clinically significant abnormality (including a psychiatric 
disorder) that, in the opinion of the investigator, may pose additional risk in 
administering the investigational product
9.
Clinically significant CV and/or cerebrovascular disease within 3 months before 
Screening including, but not limited to, the following:

Stroke or transient ischemic attack

Acute coronary syndrome (myocardial infarction [MI] or unstable angina not 
responsive to nitroglycerin)

Cardiac surgery or percutaneous coronary procedure
10. Any history of New York Heart Association class III or IV heart failure
11. Alanine aminotransferase (ALT) >2.5 × upper limit of normal (ULN) or bilirubin 
>1.5 × ULN (isolated bilirubin >1.5 × ULN is acceptable if bilirubin is fractionated 
and direct bilirubin <35%)
12. Unstable liver disease (as defined by the presence of ascites, encephalopathy, 
coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent 
jaundice), cirrhosis, known biliary abnormalities (with the exception of Gilbert’s 
syndrome or asymptomatic gallstones). (Chronic stable hepatitis B and C are 
acceptable if subject otherwise meets entry criteria and is not on active antiviral 
treatment [e.g., presence of hepatitis B surface antigen or positive hepatitis C test 
result within 3 months of Screening])
13. Hemoglobin <11 g/dL (<110 g/L) for male subjects and <10 g/dL (<100 g/L) for 
female subjects at Screening
14. Estimated glomerular filtration rate (eGFR) ≤30 mL/min/1.73 m2 (calculated using 
the Modification of Diet in Renal Disease [MDRD] formula) at Screening
Note: As the use of metformin in subjects with varying degrees of renal function 
may differ from country to country, use of metformin should be in accordance with 
the metformin product label within the participating country.
15. Fasting triglyceride level >750 mg/dL at Screening
16. Hemoglobinopathy that may affect proper interpretation of HbA1c
17. Known allergy to albiglutide or any product components (including yeast and human 
albumin), any other GLP-1 analogue, insulin, or other study medication’s excipients 
OR other contraindications (per the prescribing information) for the use of potential 
study medications (e.g., insulin glargine, insulin lispro)
18. Use of oral or systemically injected glucocorticoids within the 3 months before 
randomization or high likelihood of a requirement for prolonged treatment (>1 week) 
in the 6 months following randomization. However, short courses of oral steroids 
(single dose or multiple doses for up to 7 days) may be permitted provided these 


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cases are discussed with the medical monitor. Inhaled, intra-articular, epidural, and 
topical corticosteroids are allowed
19. Female subject is pregnant (confirmed by laboratory testing) or lactating
20. Receipt of any investigational drug within the 30 days or 5 half-lives, whichever is 
longer, before Screening, a history of receipt of an investigational antidiabetic drug 
within the 3 months before randomization, or receipt of albiglutide in previous 
studies
The following additional exclusion criteria apply for subjects participating at sites in 
Germany:
21. Persons who have been put in an institution because of official or legal order
22. Employees (or the employee’s relatives) of the sponsor, the contract research 
organization, or the investigative site, including the investigator or other site staff
4.4.
Additional Inclusion Criteria for Randomization
Subjects eligible for randomization in the study must meet the following additional 
criteria: 

HbA1c ≥7.0% and 9.0% at Week -1. If the subject does not qualify for 
randomization based on this criterion, the assessment may be repeated on a 
weekly basis for a maximum of 2 additional weeks before randomization. The 
mean of all HbA1c assessments (Week -1 plus the additional HbA1c assessments) 
must be ≥7.0% and 9.0% for the subject to be eligible for randomization (see 
Section 4.6). Note: If a subject has confirmed (by a central laboratory) HbA1c
<7.0% or >9.0% at Week -1 or the subject decides not to continue repeat testing, 
he or she will be considered a standardization failure (see Section 4.6)

FPG <280 mg/dL (15.5 mmol/L) at Week -1 (by a blood glucose meter at the site 
and confirmed by a central laboratory). If the subject does not qualify for 
randomization based on this criterion, the assessment may be repeated on a 
weekly basis for a maximum of 2 additional weeks before randomization. The 
mean of all FPG assessments (Week -1 plus the additional FPG assessments) must 
be <280 mg/dL (15.5 mmol/L) for the subject to be eligible for randomization 
(see Section 4.6). Note: If a subject has confirmed (by a central laboratory) FPG
≥280 mg/dL (15.5 mmol/L) at Week -1 or the subject decides not to continue 
repeat testing, he or she will be considered a standardization failure (see 
Section 4.6)
4.5.
Withdrawal Criteria
Every effort should be made to keep subjects in the study. The reasons for subjects not 
completing the study will be recorded.
The following will require withdrawal from the study:


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
AE, which, in the opinion of the investigator precludes effective participation of 
the subject or poses a safety concern

Elevation of liver function test results meeting any of the liver stopping criteria 
(see Section 6.3.6)

Severe allergic/hypersensitivity reaction that is considered by the investigator to 
be attributable to randomized study medication or without a likely alternative 
etiology (see Section 6.3.9.3)

Confirmed acute or chronic pancreatitis (see Section 6.3.9.4)

Confirmed medullary thyroid cancer (see Section 6.3.9.6)

Recurrent severe hypoglycemia or recurrent nocturnal hypoglycemia during the 
Treatment Period posing a potential risk to the subject, as judged by the 
investigator

Pregnancy or intention of becoming pregnant

Major protocol deviation if withdrawal from the study is mandated by the 
medical monitor (the investigator should discuss the protocol deviation with the 
medical monitor before withdrawing study medication)

GSK-defined Sentinel Event. The medical monitor will advise the investigator if 
an SAE meets the criteria of a true Sentinel Event (e.g., without a clear alternate 
etiology) for which withdrawal is required (see Section 6.3.7.3)
In addition, a subject may be withdrawn from the study for the following reasons:

FPG >270 mg/dL (15.0 mmol/L) at least 8 weeks after randomization on 
3 consecutive days (by blood glucose meter), which is confirmed by a central 
laboratory (to be done within 2 weeks of the home glucose monitoring). 
Continuation of the subject will be at the discretion of the investigator after 
consultation with the medical monitor 

Lost to follow-up

Study closed/terminated or investigator site closed (where subject transfer to 
another site is not possible)

Subject decision (reason to be documented in the electronic case report form 
[eCRF], if specified by the subject)

Investigator discretion 
Note: Use of a prohibited medication constitutes a protocol deviation. Continuation of the 
subject in the study will be discussed with the medical monitor, and the decision of 
continuation or withdrawal will be documented. 
Should a subject fail to attend the clinic for a required study visit, the site should attempt 
to contact the subject and reschedule the missed visit as soon as possible. The site should 
also counsel the subject on the importance of maintaining the assigned visit schedule and 
ascertain whether or not the subject wishes to and/or should continue in the study based 
on previous noncompliance. In cases where the subject does not return for the 


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rescheduled visit or cannot be reached to reschedule the missed visit, the site should 
make every effort to regain contact with the subject (3 telephone calls and if necessary a 
certified letter to the subject’s last known mailing address) so that they can appropriately 
be withdrawn from the study. These contact attempts should be documented in the 
subject’s medical record. Should the subject continue to be unreachable, then and only 
then will he/she be considered to have withdrawn from the study with a primary reason of 
“Lost to Follow-up.” For all other subjects withdrawing from the study, an alternative 
reason for discontinuation should be recorded in the eCRF. 
The half-life of albiglutide is approximately 5 days, and significant therapeutic 
concentrations can persist for 3 to 4 weeks after discontinuation. Therefore, the 
investigator should use caution when prescribing treatment after the withdrawal of active 
study medication, taking into consideration the long half-life of albiglutide. Thereafter, 
postwithdrawal treatments may be modified over time, as needed, at the investigator’s 
discretion.
Study medication withdrawal will require withdrawal from the study. Withdrawn subjects 
will not be replaced.
4.5.1.
Early Withdrawal Visit
Subjects who discontinue active participation in the study will no longer receive the 
randomized study medication. Immediately upon discontinuation from active 
participation in this study, these subjects should complete the early withdrawal treatment 
assessments and return for follow-up assessments 4 weeks later (Table 5). If the subjects 
are unable or unwilling to return for the follow-up assessments, GSK/PPD will make 
every effort to follow-up with the subjects or their physician or caregiver.
4.6.
Screening/Standardization Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
do not meet all inclusion (Section 4.2) and exclusion (Section 4.3) criteria to continue in 
Screening. Subjects failing to meet eligibility criteria may be rescreened after 2 weeks, as 
appropriate. In order to ensure transparent reporting of screen failure subjects, to meet the 
Consolidated Standards of Reporting Trials publishing requirements, and to respond to 
queries from regulatory authorities, a minimal set of screen failure information will be 
collected including demography, screen failure details, eligibility criteria, and any SAEs.
Standardization failures are defined as subjects who begin the Standardization Period but 
do not complete the Standardization Period or subsequently fail the Additional Inclusion 
Criteria for Randomization (Section 4.4), or subjects who decide not to continue repeat 
testing. Standardization failures may not be rescreened.


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5.
STUDY TREATMENTS
5.1.
Investigational Product and Other Study Treatment
All medications used in this study will be open-label. Albiglutide, insulin glargine, and 
insulin lispro will be provided for use in this study. Other background antidiabetic 
medication, e.g., metformin (if used) will not be provided by GSK.
Albiglutide
Albiglutide is provided as a fixed-dose, fully disposable pen injector system for delivery 
of the investigational product from a prefilled dual chamber glass cartridge that is an 
integral part of the pen. It is intended for single use by the subject. The pen is designed 
for manual reconstitution of the dose, priming and insertion of the pen needle, and 
manual injection by the subject.
Albiglutide is intended for self-administration as a subcutaneous injection in the 
abdomen, thigh, or upper arm region. The 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. The pen delivers either 30 mg of albiglutide or 50 mg of albiglutide 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, albiglutide is not expected to 
pose significant safety risks to site personnel. 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 describing the 
occupational hazards and recommended handling precautions will be provided to site 
personnel if required by local laws or will otherwise be available from GSK upon 
request.
Albiglutide 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 albiglutide will be limited to the 
investigator and authorized site staff. Albiglutide must be dispensed or administered only 
to subjects enrolled in the study and in accordance with the protocol.
Insulin Glargine and Insulin Lispro
Insulin glargine and insulin lispro injection pens for subcutaneous injection will be 
provided to all subjects, as appropriate, for the Standardization and Treatment Periods. 
Subjects will be instructed on the use and storage requirements for insulin glargine and 


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insulin lispro and will administer insulin glargine or insulin lispro as prescribed by their 
physician and in accordance with the package insert.
Insulin glargine should be self-administered as a subcutaneous injection once daily at 
bedtime in the abdomen, thigh, or upper arm region, and the injection sites rotated within 
a given injection area from 1 injection to the next.
Insulin lispro should be self-administered shortly before meals or, when necessary, soon 
after meals by subcutaneous injection in the upper arms, thighs, buttocks, or abdomen. 
Use of injection sites should be rotated so that the same site is not used more than 
approximately once per month. After injection, the site of injection should not be 
massaged.
Procedures for the disposal of unused study medication will be provided in the SPM.
5.1.1.
Dosing Guidance During the Standardization Period
Subjects will transfer from their basal-bolus therapy at the end of Screening to insulin 
glargine plus insulin lispro as detailed below. Subjects already on once-daily bedtime 
insulin glargine and meal-time insulin lispro will also enter the Standardization Period. 
Weekly telephone calls (if there is no scheduled study visit) must take place between 
the investigator and subject for the entire Standardization Period (Week -4 through 
Week -1) in order to make any needed insulin glargine or insulin lispro dose 
adjustments.
Insulin glargine

If the subject’s prestudy basal insulin is a once-daily regimen, transfer the subject to 
insulin glargine (subcutaneous injection) once daily at bedtime on a unit-per-unit 
basis. Note: At the discretion of the investigator, it is permissible to reduce the 
insulin glargine dose by up to 10%.

If the subject’s prestudy basal insulin is given twice daily, then the subject’s insulin 
glargine should be started once daily at bedtime at a dose that is 20% lower than the 
total daily prestudy basal dose.
During the Standardization Period, insulin glargine may be adjusted to achieve 
glycemic targets as close to normal as possible without untoward hypoglycemia in 
accordance with product labeling in the respective country and standards of care at 
the study center. The treat-to-target titration algorithm for insulin glargine 
(Section 5.1.3.2, Table 3) is intended for use only during the Treatment Period.
Insulin lispro

If the subject’s current regimen of bolus insulin is administered at each of the 3 main 
meals, transfer the subject’s therapy to insulin lispro on a unit-for-unit basis. Note: 
At the discretion of the investigator, it is permissible to reduce the total daily insulin 
lispro dose by up to 10%.


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
If the subject’s current regimen of bolus insulin is administered less than 3 times per 
day or more than 3 times per day, calculate the total daily bolus dose and divide it 
into 3 equal doses, administered with each of the 3 main meals. Alternatively, at the 
discretion of the investigator, if felt to be clinically preferable, it is permissible to 
allocate different starting doses of insulin lispro to each of the 3 main meals, 
maintaining the same total daily bolus dose. Note: As above, at the discretion of the 
investigator, it is permissible to reduce the total daily insulin lispro dose by up to 
10%.
During the Standardization Period, insulin lispro may be adjusted to achieve 
glycemic targets as close to normal as possible without untoward hypoglycemia in 
accordance with product labeling in the respective country and standards of care at 
the study center. The treat-to-target titration algorithm for insulin glargine 
(Section 5.1.3.2, Table 3) is intended for use only during the Treatment Period.
Metformin
Subjects taking metformin as background antidiabetic medication will remain on their 
current dose for the duration of their participation in the study, unless a decline in kidney 
function results in a contraindication for metformin use. Metformin is to be stopped if the 
subject’s eGFR, calculated according to the MDRD formula, decreases during the study 
to a level where metformin is contraindicated according to its label (as appropriate for 
each participating country).
5.1.2.
Dosing Guidance During the Treatment Period
The dosing guidance for albiglutide, insulin lispro, insulin glargine, and metformin from 
Baseline/Randomization through the end of the Treatment Period is summarized in
Table 2.
Table 2
Dosing Guidance for Albiglutide, Insulin Lispro, Insulin Glargine, 
and Metformin Treatment
Medication
Albiglutide + Insulin Glargine Group
Insulin Glargine + Insulin Lispro Group
Albiglutide
Baseline/Randomization: Start weekly SC 
injection at 30 mg.
Week 4: Uptitrate to 50 mg weekly SC 
injection for the remainder of the Treatment 
Period.
None
Insulin lispro
Baseline/Randomization: Each insulin lispro 
dose will be downtitrated to half that used in 
the Standardization Period.1
Week 4: Stop insulin lispro for the remainder 
of the Treatment Period; insulin lispro may be 
re-introduced after Week 8 (See 
Section 5.1.3.5)
Baseline/Randomization: Continue at the same 
doses as at the end of the Standardization 
Period and adjust doses as per instructions in 
Section 5.1.3.2.
Insulin glargine
Continue at the same dose as at the end of 
the Standardization Period1 and adjust dose 
as per instructions in Section 5.1.3.2.
Continue at the same dose as at the end of the 
Standardization Period and adjust dose as per 
instructions in Section 5.1.3.2.


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Medication
Albiglutide + Insulin Glargine Group
Insulin Glargine + Insulin Lispro Group
Metformin
Subjects will remain on their current dose for 
the duration of their participation in the 
study.2
Subjects will remain on their current dose for the 
duration of their participation in the study.2
Re-introduction of 
insulin lispro (if 
required)
After Week 8: See Section 5.1.3.5
Not applicable
SC = subcutaneous.
1.
As described in Section 1.3.1, the risk of hypoglycemia is increased when albiglutide is used in combination with 
insulin; therefore, subjects may require a lower dose of insulin and should be monitored closely.
2.
Unless a decline in kidney function results in a contraindication for metformin use. Metformin is to be stopped if 
the subject’s estimated glomerular filtration rate, calculated according to the Modification of Diet in Renal Disease
formula, decreases during the study to a level where metformin is contraindicated according to its label (as 
appropriate for each participating country).
5.1.3.
Dose Titration During the Treatment Period
5.1.3.1.
Albiglutide Titration
The albiglutide dose in this study will start at 30 mg weekly and be uptitrated at Week 4 
to 50 mg weekly.
Albiglutide may be administered at any time of day without regard to meals. 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 2 or more consecutive doses, the investigator should contact the 
medical monitor, who will make a decision (on a case-by-case basis) on whether the 
subject should be withdrawn from the study for noncompliance.
Note: In this study, downtitration of albiglutide 50 mg weekly to 30 mg weekly is not 
permitted.
5.1.3.2.
Insulin Titration
The intent of the American Diabetes Association and the European Association for the 
Study of Diabetes consensus statement for the treatment of T2DM is to maintain fasting 
and preprandial glucose values as close to a normal range as possible without untoward 
hypoglycemia or other adverse effects of treatment [Inzucchi, 2015; Inzucchi, 2012; 
Nathan, 2008; Nathan, 2006]. Less stringent HbA1c goals are appropriate for other 
subjects, such as those with a history of severe hypoglycemia, limited life expectancy, 
advanced complications, or extensive comorbid conditions.
All subjects should measure their blood glucose values as detailed in Section 6.2.2.
NOTE: The use of a GLP-1R agonist (albiglutide) is expected to decrease the need 
for exogenous insulin. Therefore, the investigator will need to ensure careful 


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follow-up of each subject accordingly, particularly during the first few weeks of 
treatment, and reduce insulin doses if the subject experiences hypoglycemia or there 
is a significant risk of hypoglycemia.
Weekly telephone calls (if there is no scheduled study visit) must take place between 
the investigator and subject from the start of the Treatment Period through 
Week 16 and at Week 22, Week 25, and as required until the end of the Treatment 
Period, in order to optimize insulin titration (Table 6).
Insulin Glargine Titration
Both treatment groups will follow the same insulin glargine titration algorithm during the 
Treatment Period.
The main focus for the initial insulin titration should be on the basal insulin given before 
bedtime. Although optimization of insulin glargine should continue throughout the 
Treatment Period, it is expected that the basal insulin dose will have been stabilized for 
all subjects after about 6 weeks.
Prior to each study visit and telephone contact during the Treatment Period, a 
recommended dose of insulin glargine will be based on the mean of the subject’s last 
3 available before breakfast SMBG values (at least 2 of which are consecutive) and the 
titration algorithm for insulin glargine provided in Table 3. It is important that the 
investigator use his or her medical judgment in determining whether or not the algorithm 
recommended dose adjustment is appropriate for a particular subject at each time point. 
Of importance, decisions should be made taking into consideration all available 
information, such as symptoms of hypoglycemia or hyperglycemia, current total daily 
dose of insulin, and previous responses to dose adjustments, as well as additional glucose 
measurements (lowest of the last 3 SMBG values, other SMBG values in the week 
preceding the dose adjustment decision, or FPG [from a central laboratory]).
If measurements from 3 days (at least 2 of which are consecutive) are not available, the 
dose adjustment should be delayed until the next scheduled study visit/telephone contact; 
unless in the investigator’s judgment, a dose adjustment is warranted. The subject should 
be retrained on the importance of SMBG measurements in this treat-to-target study.


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Table 3
Titration Algorithm for Recommended Insulin Glargine Dose 
Adjustment
Before Breakfast Blood Glucose1
Adjustment of Insulin Glargine (IU)2
mg/dL
mmol/L
<563
<3.13
-4
For a dose >50 U, consider 10% dose 
reduction
56 – 693
3.1 – 3.83
-2
For a dose >50 U, consider 5% dose 
reduction
70 – 79
3.9 – 4.4
-1
80 – 109 = Target
4.5 – 6.0 = Target
No adjustment
110 – 139
6.1 – 7.7
+2
140 – 179
7.8 – 9.9
+4
180
10.0
+6
If severe hypoglycemia (requiring assistance) or any other clinically 
significant hypoglycemia (e.g., nocturnal hypoglycemia) was 
documented since the last dose adjustment
Decrease insulin dose 10% to 15%, at the 
investigator’s discretion
1.
Mean of measurements from the last 3 available days (at least 2 of which are consecutive) in the week before 
the next study visit/telephone contact. If measurements from 3 days (at least 2 of which are consecutive) are 
not available, the dose adjustment should be delayed until the next scheduled study visit/telephone contact;
unless in the investigator’s judgment, a dose adjustment is warranted. The subject should be retrained on the 
importance of self-monitored blood glucose measurements.
2. 
Modified based on the insulin titration algorithms in the BEGIN basal-bolus type 2 study [Garber, 2012] and 
other published treat-to-target studies [Rosenstock, 2008; Abrahamson, 2012; Mathieu, 2014; Riddle, 2014].
3.
Investigator may defer adjustment if there is an obvious reason for the low value such as a missed meal.


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Any insulin titration that differs from the algorithm recommended dose must be 
commented on by the investigator and the reason documented on the appropriate page of 
the eCRF. If adequate documentation is not provided in the eCRF, a protocol deviation 
will be recorded. 
If the before breakfast glucose target has been achieved, but it is felt that the basal insulin 
needs further optimization, then alternatives (e.g., moving the basal injection to the 
morning or splitting the basal dose into twice daily injections) can be discussed with the 
medical monitor overseeing the titration and documented.
Insulin Lispro Titration
Insulin titration should start with insulin glargine given before bedtime. After about 
6 weeks, it is expected that the basal insulin glargine dose will have been stabilized and 
the insulin lispro titration may begin.
Following randomization to study medication, insulin lispro will be titrated differently in 
each treatment group.
In the albiglutide plus insulin glargine group, the insulin lispro dose will be downtitrated 
at the Baseline/Randomization visit to half that used at the end of the Standardization 
Period. At Week 4, insulin lispro will be completely discontinued and should remain 
discontinued for the remainder of the Treatment Period; unless the subject meets the 
criteria for insulin lispro re-introduction (see Section 5.1.3.5).
In the insulin glargine plus insulin lispro treatment group, the dose adjustment of insulin 
lispro given in association with a meal is based on the blood glucose measurements taken 
prior to the subsequent meal. Therefore, blood glucose measurements taken Prior to 
Lunch are utilized to adjust the dose of insulin lispro taken with breakfast, the blood 
glucose measurements taken Prior to Dinner are utilized to adjust the dose of insulin 
lispro taken with lunch, and the blood glucose measurements taken Prior to Bedtime are 
utilized to adjust the dose of insulin lispro taken with dinner. Following 
Baseline/Randomization, the main focus for the initial insulin titration should be on the 
basal insulin before considering changes in the bolus insulin, unless the investigator finds 
it absolutely necessary to adjust the bolus insulin first. 
Prior to each study visit and telephone contact during the Treatment Period, a 
recommended dose of insulin lispro for each specific meal will be based on the mean of 
the subject’s last 3 available preprandial SMBG values (at least 2 of which are 
consecutive) and the titration algorithm for insulin lispro provided in Table 4. It is 
important that the investigator use his or her medical judgment in determining whether or 
not the algorithm recommended dose adjustment is appropriate for a particular subject at 
each time point. Of importance, decisions should be made taking into consideration all 
available information, such as symptoms of hypoglycemia or hyperglycemia, current total 
daily dose and distribution of insulin lispro doses, and previous responses to dose 
adjustments, as well as additional glucose measurements (lowest of the last 3 SMBG 
values, other SMBG values in the week preceding the dose adjustment decision, or FPG 
[from a central laboratory]) other than the mandatory ones.


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If measurements from 3 days (at least 2 of which are consecutive) are not available, the 
dose adjustment should be delayed until the next scheduled study visit/telephone contact, 
unless in the investigator’s judgment, a dose adjustment is warranted at that time. The 
subject should be retrained on the importance of SMBG measurements in this 
treat-to-target study. 
Table 4
Titration Algorithm for Recommended Insulin Lispro Dose 
Adjustment
Prior to Lunch, Prior to Dinner, Prior to Bedtime Blood Glucose1
Adjustment of Lispro Insulin 
(U)2
mg/dL
mmol/L
99 without obvious explanation
5.5 without obvious explanation
-23
For a dose >50 U, consider a 5% 
to 10% dose reduction at the 
discretion of the investigator
100 – 119 = Target
5.6 – 6.6 = Target
No adjustment
120 – 139
6.7 – 7.7
+2
140 – 179
7.8 – 9.9
+3
180
10.0
+4
If severe hypoglycemia (requiring assistance) or any other clinically significant 
hypoglycemia was documented since the last dose adjustment
Decrease insulin dose at the 
investigator’s discretion (i.e., 
10% to 15%)
1.
Mean of measurements from the last 3 available days (at least 2 of which are consecutive) in the week before the 
next study visit/telephone contact. If measurements from 3 days (at least 2 of which are consecutive) are not 
available, the dose adjustment should be delayed until the next scheduled study visit/telephone contact, unless in 
the investigator’s judgment, a dose adjustment is warranted at that time. The subject should be retrained on the 
importance of self-monitored blood glucose measurements (SMBG).
2.
Modified based on the insulin titration algorithms in the BEGIN basal-bolus type 2 study [Garber, 2012] and other 
published treat-to-target studies [Rosenstock, 2008; Abrahamson, 2012; Mathieu, 2014; Riddle, 2014].
3.
For subjects with an SMBG value less than 70 mg/dL without obvious explanation, insulin lispro may be stopped 
at the investigator’s discretion.
Any insulin titration that differs from the algorithm recommended dose must be 
commented on by the investigator and the reason must be documented on the appropriate 
page of the eCRF. If adequate documentation is not provided in the eCRF, a protocol 
deviation will be recorded. 
5.1.3.3.
Intensive Subject Glycemic Surveillance and Management
In this treat-to-target study, which includes the discontinuation of prandial insulin in 
subjects randomly allocated to the albiglutide plus insulin glargine treatment arm as well 
as the intensification of basal-bolus insulin in subjects randomly allocated to the insulin 
glargine plus insulin lispro treatment arm, it is important that subjects receive adequate 
diabetic patient education and training and detailed clear explanations regarding all 
required study procedures related to glycemic management (see Section 6.2.4 and 
Section 6.2.5). It is also imperative that study investigators closely monitor available 
subject information and apply prompt medical judgment as necessary to maintain 
appropriate glycemic control.
To facilitate subject surveillance by the study investigator, the investigator will have 
access to information collected in the subject’s e-diary, such as daily SMBG 


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measurements (see Section 6.2.2), daily insulin use (see Section 6.2.5), and 
subject-reported hypoglycemia (see Section 6.3.1). In addition, study investigators will 
receive notification of extreme SMBG measurements (i.e., SMBG measurements 
50 mg/dL [2.8 mmol/L] and SMBG between 50 to 60 mg/dL [2.8 to 3.3 mmol/L]), as 
well as episodes of severe hypoglycemia recorded in the subject’s e-diary. Additional 
details on these tools are provided in the accompanying SPM.
5.1.3.4.
Documentation of Insulin Titration
Surveillance of insulin titration and documentation will be performed centrally. Within 
approximately 3 business days after a subject’s study visit/telephone contact, the 
investigator must ensure that the following data are available for review by GSK/PPD:

Subject’s SMBG values from the last 3 available days (at least 2 of which are 
consecutive) in the week before the study visit/telephone contact

Insulin doses for 3 days (at least 2 of which are consecutive) in the week before the 
next study visit/telephone contact

Insulin doses recommended until the next study visit/telephone contact

Comments on any deviation to the insulin titration algorithms must be entered into 
the eCRFs
The data regarding titration deviations will be reviewed by GSK/PPD. Based on this 
information, an inquiry as to why the investigator chose to deviate from the titration 
algorithm may be made, particularly when details of any SMBG readings, time, and date, 
or hypoglycemic symptoms used in such a decision are not provided or lack clarity. Not 
all deviations will lead to inquiry. When the investigator receives an inquiry, a response 
with the reasons for not adhering to the titration guideline should be sent to GSK/PPD 
within approximately 3 days. Depending on the response, additional inquiries may be 
sent.
5.1.3.5.
Re-introduction of Insulin Lispro in the Albiglutide Treatment Group
Basal insulin plus once-weekly albiglutide may not provide adequate control of 
postprandial hyperglycemia in some subjects previously treated with basal-bolus insulin 
therapy. For subjects randomly assigned to treatment with albiglutide who continue to 
experience significant postprandial glucose excursions (i.e., >180 mg/dL 
[>10.0 mmol/L]), insulin lispro may be re-introduced after Week 8 (i.e., 4 weeks after 
discontinuation of insulin lispro and uptitration to albiglutide 50 mg). Re-introduction of 
insulin lispro will follow the standardized, stepwise approach as shown in Figure 2.
Following the re-introduction of insulin lispro, subjects will remain in the study and 
continue to take insulin lispro in addition to randomly assigned once-weekly albiglutide 
and background insulin glargine. As determined by the investigator, subjects requiring 
re-introduction of insulin lispro may be seen more frequently by arranging unscheduled 
visits until their glycemic control has stabilized.


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Figure 2
Re-introduction Algorithm for Insulin Lispro
HbA1c = glycosylated hemoglobin. SMBG = self-monitored blood glucose.
Note: Figure modified with permissions (pending) from [Abrahamson 2012].
1.
Post-breakfast (Prior to Lunch), post-lunch (Prior to Dinner), or post-dinner (i.e., Prior to Bedtime).
2.
Mean of measurements from the last 3 available days (at least 2 of which are consecutive) in week before the 
next study visit/telephone contact. If measurements from 3 days (at least 2 of which are consecutive) are not 
available, the dose adjustment should be delayed until the next scheduled study visit/telephone contact; unless in 
the investigator’s judgment, a dose adjustment is warranted. The subject should be retrained on the importance of 
SMBG measurements.
3.
For insulin lispro dose titration, see Section 5.1.3.2, Table 4.
The algorithm in Figure 2 for re-introduction of insulin lispro should apply in the 
majority of circumstances; however, as the intent of glycemia management in subjects 
with T2DM is to individualize treatment goals to achieve a target HbA1c level as close to 
normal as possible without signiﬁcant hypoglycemia or other adverse effects of 
treatment, the investigator should use his/her judgment in determining benefit:risk of 
further insulin dose adjustment and modification, accordingly. In the event a subject 
experiences significant evidence of hyperglycemia (e.g., symptoms of polyuria and 
polydipsia and laboratory evidence of hyperglycemia) and the investigator determines 
that further dose adjustment with insulin is not in the best interest of the subject and that 
the subject requires rescue with another antidiabetic medication, the subject should be 
discontinued from the study and the appropriate rescue therapy initiated. Additionally, 
subjects not achieving a predefined threshold for glycemic control (confirmed persistent 
FPG 270 mg/dL [15.0 mmol/L]) at least 8 weeks after randomization may be considered 


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for study withdrawal based on the discretion of the investigator and the medical monitor 
(see Withdrawal Criteria in Section 4.5).
5.2.
Treatment Assignment
Randomized treatment assignment will be done via the interactive voice response system 
(IVRS), and randomization will be implemented based on a sequestered fixed 
randomization schedule. Site personnel will call the IVRS to execute each randomization 
and initiate shipment of the investigational product once a subject has met all 
prerequisites for randomization and has completed all scheduled screening and 
standardization procedures. 
Subjects will be assigned to study treatment in accordance with the randomization 
schedule. Eligible subjects will be stratified by screening HbA1c value (<8.0% 
versus ≥8.0%), age (<65 years versus 65 years), and current use of background 
metformin (metformin use versus no metformin use). 
Approximately 794 subjects will be randomly assigned to 1 of the following 2 open-label 
treatment groups in a 1:1 ratio such that

Approximately 397 subjects are randomly assigned to albiglutide + insulin glargine 
(with or without metformin)

Approximately 397 subjects are randomly assigned to intensification of insulin 
glargine + insulin lispro (with or without metformin)
Site personnel will receive a randomization notification indicating the unique subject 
identifier, the treatment assignment, and the date and time of randomization. Each subject 
number will be a unique identifier. Once a subject number has been assigned, the number 
will not be reused even if the subject withdraws before receiving any randomized study 
medication. 
5.3.
Blinding
This will be an open-label study. An open-label study design was selected because insulin 
lispro is an injectable medication and thus double-blinding the study would require 
multiple dummy injections, which may not be in the best interest of the subject. 
Additionally, because insulin lispro will only be discontinued in the albiglutide treatment 
group, it is not feasible to blind the study. Furthermore, use of an objective laboratory 
endpoint will help mitigate bias that might otherwise be introduced if an open-label study 
design was not adopted. 
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 by study subjects, and the amount received from and returned to GSK, when 


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applicable. Product accountability records must be maintained throughout the course of 
the study.
5.5.
Treatment Compliance
Accountability will be done for the investigational product (albiglutide) and other study 
treatments (insulin glargine and insulin lispro) at the time points specified in the Time 
and Events Table (Table 5). Subjects will be instructed to return all unused 
investigational product and used injector pens in order to perform drug accountability and 
determine compliance.
Acceptable overall compliance for IP (albiglutide) and other study treatments (insulin 
glargine and insulin lispro) in this study will be 80%. Site personnel should confirm that 
subjects are taking their doses of albiglutide and insulin glargine and lispro insulin, if 
appropriate, as prescribed by their physician. Adherence will be monitored for the 
duration of the study. 
Subjects will be instructed to take their metformin as prescribed by their physician and 
will continue on this dose for the duration of their participation in the study unless there 
is a decline in kidney function (Section 5.1.1 and Table 2). Adherence to dosing 
instructions for metformin will be monitored for the duration of the study.
5.6.
Concomitant Medications and Nondrug Therapies
All medications taken at any time from 3 months prior to Screening to the Follow-up visit 
will be recorded in the eCRF. The minimum requirement is that drug name and the dates 
of administration are to be recorded.
5.6.1.
Permitted Medications and Nondrug Therapies
Note: Albiglutide causes a delay of gastric emptying and thereby has the potential to 
impact the absorption of concomitantly administered oral medications. During the 
albiglutide development program, drug interaction studies were conducted with digoxin, 
warfarin, oral contraceptives, and simvastatin, which demonstrated no clinically relevant 
pharmacokinetic (PK) or pharmacodynamic effects. Investigators should use clinical 
judgment and caution when prescribing concomitant medications.
The following concomitant medications are permitted:

As-needed use of prescription and over-the-counter medications at the discretion of 
the investigator
Although stable doses of all concomitant medications are preferable, changes in 
medications during the study to appropriately treat clinical conditions that might arise, 
including worsening blood pressure control and dyslipidemia, are allowed.
Subjects will be monitored for renal function (eGFR calculated using the MDRD 
formula) during the study. Metformin and concomitant medications should always be 


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used within the label recommendations and stopped or adjusted according to the status of 
renal function and clinical conditions of the subject.
Investigators must adhere to the local labeling of the respective country (e.g., the 
summary of product characteristics in relevant European countries or the FDA-approved 
prescribing information) for all nonexcluded medications.
5.6.2.
Prohibited Medications and Nondrug Therapies
Subjects must not use any of the following medications:

Any antidiabetic medications (e.g., GLP-1R agonist, dipeptidyl peptidase-IV 
inhibitor, SU, thiazolidinedione, meglitinide, sodium-glucose transporter 2 inhibitor, 
or commercially available premixed basal and prandial insulin) other than the 
treatment they have been randomly assigned to, insulin glargine, insulin lispro, and 
their current regimen of background metformin, if applicable, being taken at 
Screening. 

Oral or systemically injected corticosteroids (inhaled, intra-articular, epidural, and 
topical corticosteroids are allowed); short courses of oral steroids (single dose or 
multiple doses for up to 7 days) may be permitted provided these cases are discussed 
with the medical monitor

Antiretroviral drugs

Prescription and over-the-counter weight loss drugs
If a subject receives a prohibited medication, a protocol deviation will be reported and 
continuation in the study will be discussed with and agreed upon by the medical monitor.
5.7.
Treatment Between Week 26 (End of Treatment)/Early 
Withdrawal and After the Follow-up Visit
5.7.1.
Treatment Between Week 26 (End of Treatment)/Early Withdrawal 
and Follow-up
After completion of the end-of-treatment (Week 26) or early withdrawal visits, subjects 
will return to the study center in 4 weeks for the Follow-up visit. During this time, 
subjects will continue insulin glargine or insulin glargine plus insulin lispro to maintain 
adequate glycemic control.
For subjects in the albiglutide plus insulin glargine treatment arm, the last dose of 
once-weekly albiglutide will occur at Week 25. As needed, insulin lispro may also be 
re-introduced during this period according to the re-introduction of insulin lispro 
algorithm provided in Section 5.1.3.5. Insulin glargine alone (in subjects for whom 
insulin lispro has not been re-introduced) or insulin glargine and insulin lispro (in 
subjects for whom insulin lispro has been re-introduced) can be adjusted to achieve or 
maintain glycemic targets as close to normal as possible without untoward hypoglycemia 


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in accordance with product labeling in the respective country and standards of care at the 
study center. 
For subjects in the insulin glargine plus insulin lispro treatment arm, both insulin glargine 
and insulin lispro may be adjusted to achieve or maintain glycemic targets as close to 
normal as possible without untoward hypoglycemia in accordance with product labeling 
in the respective country and standards of care at the study center. 
Note: During this time, subjects must not use any prohibited medications or nondrug 
therapies (see Section 5.6.2).
5.7.2.
Treatment After the Follow-up Visit
No poststudy treatment will be provided by GSK.
After completion of the Week 26 visit, subjects will return to the study center in 4 weeks 
for the Follow-up visit and will complete the study. No poststudy treatment will be 
provided by GSK. 
The investigator is responsible for ensuring that consideration has been given to the 
poststudy care of the subject’s medical condition whether or not GSK is providing 
specific poststudy treatment.
Note: The half-life of albiglutide is approximately 5 days, and significant therapeutic 
concentrations can persist for 3 to 4 weeks after discontinuation. Therefore, the 
investigator should use caution when prescribing treatment after the withdrawal of active 
study medication, taking into consideration the long half-life of albiglutide. Thereafter, 
postwithdrawal treatments may be modified over time, as needed, at the investigator’s 
discretion.
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 T2DM, the highest dose of albiglutide administered was 100 mg 
subcutaneously every 4 weeks for 12 weeks. This dose was associated with an increased 
frequency of nausea, vomiting, and headache. There is no specific antidote for overdose 
with albiglutide. In the event of a suspected overdose, the appropriate supportive clinical 
care should be instituted, as dictated by the subject’s clinical status. Anticipated 
symptoms of an overdose may be severe nausea, vomiting, or headache. A prolonged 
period of observation and treatment for these symptoms may be necessary, taking into 
account the half-life of albiglutide (5 days).
Excess insulin administration may cause hypoglycemia and hypokalemia. If an overdose
of insulin glargine or insulin lispro occurs, the investigator should consult the approved 
product label for advice. Subjects should be monitored closely even after treatment of the 
acute event; recurrence should be managed appropriately.


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6.
STUDY ASSESSMENTS AND PROCEDURES
Study assessments and times are presented in Table 5. Telephone contact and times are 
presented in Table 6. Study center visits through Week 16, inclusive, and all telephone 
contacts will have a visit window of 3 days; study center visits occurring after Week 16 
will have a visit window of 7 days. Subjects will not be considered out of compliance if 
visit windows extend because of extraordinary events that make it impossible for subjects 
to complete a visit within the visit window (e.g., holidays, vacations, personal 
emergencies). However, determination of the maximum visit window deviation is at the 
discretion of the medical monitor.


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Table 5
Time and Events Table – Study Visits
Study Procedure
Screening
Standardization
Treatment
(For scheduled telephone calls, see Table 6)
Early 
Withdrawal 
Visit1
Follow-up
Visit
Baseline/
Randomization
Visit
1
2
3
4
5
6
7
8
9
10
Week2
-6 to -5
-43
-1
03
4
53
103
183
263,4
30
Obtain written informed consent
x
Obtain subject demography
x
Obtain medical history
x
Obtain disease history 
x
Obtain therapy history
x
Review of inclusion/exclusion criteria
x
x
x
x
Review of randomization criteria
x
Efficacy Assessments
Dispense home glucose monitoring device and 
e-diary
x
Collect e-diary from subject
x
Provide advice on diet, exercise, home 
glucose monitoring, and hypoglycemia5
x
x
x
x
x
x
x
x
x
x
Obtain 8-point SMBG profile6
x
x
x
Review glucose monitoring with subject5
x
x
x
x
x
x
x
x
x
Administer diabetes questionnaires7
x
x
x
x
Obtain daily insulin dose information8
x
x
x
x
x
x
x
Safety Assessments
Review concomitant medication
x
x
x
x
x
x
x
x
x
x
x
Perform physical examination9
x
x
x
x
x
Check visual acuity and funduscopy10
x
x
x
Obtain vital sign measurements11
x
x
x
x
x
x
x
x
x
x
x
Obtain body mass index information11
x
Perform 12-lead ECG12
x
x
x
x
Assess for adverse events
x
x
x
x
x
x
x
x
x
x
Assess for serious adverse events
x
x
x
x
x
x
x
x
x
x
x
Assess for hypoglycemic events13
x
x
x
x
x
x
x
x
x
x


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Study Procedure
Screening
Standardization
Treatment
(For scheduled telephone calls, see Table 6)
Early 
Withdrawal 
Visit1
Follow-up
Visit
Baseline/
Randomization
Visit
1
2
3
4
5
6
7
8
9
10
Week2
-6 to -5
-43
-1
03
4
53
103
183
263,4
30
Laboratory Assessments
Subject to fast overnight14
x
x
x
x
x
x
x
x
x
Obtain hematology sample15
x
x
x
x
x
x
Obtain chemistry sample16
x
x17
x
x18
x18
x
x18
x
x
x
Obtain urinalysis sample19
x
x
x
x
Obtain TSH sample20
x
Obtain genetics sample21
x
Obtain urine pregnancy test22
x
x
x
x
x
x
Obtain HBsAg and hepatitis C antibody23 
samples
x
Obtain HbA1c sample
x24
x25
x
x
x
x
x
x
x
Obtain fasting C-peptide sample26
x
Obtain stimulated C-peptide sample 
90 minutes after administration of a 
mixed-meal26
x
Obtain lipid panel27
x
x
x
x
x
Obtain biomarker sample
x
x
x
Investigational product
Dispense investigational product or insulin 
glargine and insulin lispro28
x
x
x
x
x
x
x
x
Assess investigational product and other study 
treatment compliance
x
x
x
x
x
x
x
Reduce or discontinue insulin lispro 
(albiglutide treatment group ONLY)29
x
x
Albiglutide uptitration to 50 mg (albiglutide 
treatment group ONLY)
x
Review the need for insulin glargine and/or 
insulin lispro adjustment30
x
x
x
x
x
x
x
x
x
Register the subject’s visit into the IVRS31
x
x
x
x31
x
x
x
x
x
x
ECG = electrocardiogram; HbA1c = glycosylated hemoglobin, HBsAg = hepatitis B surface antigen; IVRS = interactive voice response system; TSH = thyroid-stimulating hormone.


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1.
After completion of the early withdrawal assessments, subjects should return 4 weeks later for the Follow-up visit. In subjects who are withdrawn from the study due to an allergic 
or hypersensitivity reaction that is not reasonably attributed to another cause, a serum sample will be taken 8 weeks after stopping study medication for immunogenicity testing.
2.
Study visits through Week 16, inclusive, will have a visit window of ±3 days; study visits occurring after Week 16 will have a visit window of ±7 days. Subjects will not be 
considered out of compliance if visit windows extend because of extraordinary events (e.g., holidays, vacations, personal emergencies). However, determination of the maximum 
visit window deviation will be at the discretion of the medical monitor.
3.
Telephone calls to occur between study visits (if no study visit is scheduled, weekly from the start of the Standardization Period through Week 16, inclusive, and at Week 22, 25, 
and as required until the end of the Treatment Period [Table 6]) to advise subjects on insulin glargine and insulin lispro dose adjustments (see Section 5.1.1 and Section 5.1.3.2), 
adverse event monitoring, hypoglycemia monitoring, and concomitant medication usage.
4.
The last dose of albiglutide is Week 25 for those subjects assigned to albiglutide + insulin glargine. 
5.
Standard diabetic dietary, exercise, and home blood glucose monitoring advice to be provided at Visit 2 (Week -4) and reinforced at each study site visit through the 
end-of-treatment visit. Subjects will monitor their glucose according to instructions. The investigator will review the glucose meter readings and adjust insulin glargine and insulin 
lispro doses in accordance with product labeling in the respective country and standard of care at the study center during the Standardization Period and per Table 3 and Table 4, 
respectively, during the Treatment Period. At each visit through the end-of-treatment visit (Visit 9; Week 26), subjects should be trained on the signs and symptoms of 
hypoglycemia, including nocturnal hypoglycemia, as well as the common causes of hypoglycemia. Subjects should also be educated on appropriate methods to help prevent 
hypoglycemia. It is also particularly important to advise subjects to contact the study site before any potential dietary change, as this may necessitate a change in insulin doses to 
avoid the development of hypoglycemia. Subjects should also be educated on how to treat hypoglycemia. For additional information, see Section 6.3.1.
6.
An 8-point SMBG profile assessment (before and 2 hours after breakfast, lunch, and dinner; at bedtime; and at 2 AM): 3 times in the week prior to the Baseline/Randomization visit 
(Visit 4, Week 0), Visit 7 (Week 10), and Visit 9 (Week 26). 
7.
Treatment-related impact measure for diabetes (TRIM-Diabetes) and hypoglycemia fear survey-II (HFS-II) questionnaires to be administered prior to all other study assessments.
8.
Daily insulin use to be recorded in the subject diary, at least 3 days preceding study visit/telephone contact at Week 1 through Week 16, inclusive, and at Week 18, 22, 25, and 26.
9.
Perform complete physical examination at Screening and Week 26. Perform brief physical examination at other time points.
10. For the Screening assessment, a documented examination within six months of the Screening visit would also be acceptable but only when there was NO clinical change (e.g., 
decrease in visual acuity/visual field) since the last prior funduscopy. The end of treatment/early withdrawal assessment eye exam should be carried out by the investigator.
11. Height measured and body mass index calculated at Screening only. Weight, blood pressure, and heart rate (pulse); obtain blood pressure and pulse after sitting for at least 
5 minutes.
12. All 12-lead ECGs to be performed before measurement of vital signs and collection of blood samples for laboratory testing. Subjects to be semirecumbent for 10 to 15 minutes 
before obtaining the ECG.
13. See Section 6.3.1 for hypoglycemic events criteria and reporting requirements. Subjects will be asked to report hypoglycemic events that occur between study visits in a diary.
14. Fasting is defined as no food or drink (except water) for at least 8 hours before blood draw.
15. Hematology to include complete blood count with red blood cell indices, white blood cell count differential, and platelet count.
16. Clinical chemistry to include glucose, blood urea nitrogen, creatinine, sodium, potassium, chloride, carbon dioxide, calcium, total protein, albumin, total bilirubin, direct bilirubin, 
alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, -glutamyltransferase, uric acid, magnesium, and phosphorus. Calculate estimated glomerular 


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filtration rate using the Modification of Diet in Renal Disease formula.
17. Fasting plasma glucose only.
18. Fasting plasma glucose, creatinine, alanine aminotransferase, total bilirubin, direct bilirubin, -glutamyltransferase, and alkaline phosphatase only.
19. Urinalysis to include specific gravity, pH, glucose, ketones, microalbumin, creatinine, blood, leukocyte esterase, and nitrites. (If warranted, a microscopic evaluation will be 
completed.)
20. Thyroid-stimulating hormone assessment at Screening only. Free T4 (reflex) will be measured if TSH is above upper limit of normal.
21. Blood sample for genetic research can be collected at any time during the study after the genetics informed consent has been obtained and the subject has been randomly 
assigned to treatment group.
22. Urine pregnancy test for women of childbearing potential only and at any time that pregnancy is suspected. 
23. If hepatitis C antibody is positive, an RNA polymerase chain reaction should be performed on the same sample to confirm the result.
24. As described in Section 3.1, an optional fasting HbA1c value may be determined using a Metrika kit or other finger-stick procedure to provide an initial guide of subject eligibility for 
investigators.
25. If the HbA1c value at Week -1 is not 7.0% and 9.0%, the assessment may be repeated on a weekly basis for a maximum of 2 additional weeks before randomization. The mean 
of all HbA1c assessments (Week -1 plus the additional HbA1c assessments) must be 7.0% and 9.0% for the subject to be eligible for randomization. Note: If a subject has 
confirmed (by a central laboratory) HbA1c <7.0% and >9.0% at Week -1 or the subject decides not to continue repeat testing, he or she will be considered a standardization failure.
26. Subjects will have both fasting C-peptide and stimulated C-peptide testing. If the fasting C-peptide is <0.8 ng/mL (<0.26 nmol/L) but stimulated C-peptide 90 minutes after a 
standardized mixed meal is 1.5 ng/mL (0.5 nmol/L), the subject meets the C-peptide inclusion criterion.
27. Total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, and free fatty acids.
28. Insulin glargine and insulin lispro will be dispensed during the Standardization Period at Visit 2 (Week -4) with additional dispensing at Visit 3 (Week -1) optional as needed to 
ensure adequate supply up to Visit 4 (Week 0). Dispense albiglutide, insulin glargine, and insulin lispro, as appropriate, according to randomization at Baseline/Randomization. 
See Section 5.7 for additional information regarding insulin usage after Week 26/Early Withdrawal.
29. For subjects randomly assigned to the albiglutide plus insulin glargine treatment group ONLY, reduce insulin lispro by 50% at Baseline/Randomization followed by complete 
(100%) discontinuation of insulin lispro at Week 4. No downtitration of insulin lispro occurs in the insulin glargine plus insulin lispro treatment group.
30. During the Standardization Period, adjust insulin glargine and insulin lispro, as required, in accordance with product labeling in the respective country and standard of care at the 
study center. During the Treatment Period, titrate insulin glargine and/or insulin lispro according to Table 3 and Table 4, respectively. Titration should be based on the mean of 
measurements from the last 3 available days (at least 2 of which are consecutive) in the week before the next study visit/telephone contact. If measurements from 3 days (at least 
2 of which are consecutive) are not available, the dose adjustment should be delayed until the next scheduled study visit/telephone contact; unless in the investigator’s judgment, 
a dose adjustment is warranted. The subject should be retrained on the importance of self-monitored blood glucose measurements.
31. Randomization to occur at the Baseline/Randomization visit.


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Table 6
Time and Events Table – Telephone Calls
Study Procedure
Week
Standardization
Treatment
Perform telephone contact with subject at the time points specified (±3 days)
and as required for appropriate management of the subject
Follow-
up
-3
-2
1
2
3
6
7
8
9
11
12
13
14
15
16
22
25
28
Efficacy assessments
Review glucose monitoring with subject1
x
x2
x
x
x
x
x
x
x2
x
x
x
x
x
x
x
x2
x
Review the need for dose titration1
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Obtain daily insulin dose information3
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Safety assessments
Review of concomitant medication
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Assess for AEs/SAEs
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Assess for hypoglycemic events4
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
AE = adverse event; SAE = serious adverse event.
1.
During the Standardization Period, adjust insulin glargine and insulin lispro in accordance with product labeling in the respective country and standards of care at the study 
center. During the Treatment Period, titrate insulin glargine and/or insulin lispro according to Table 3 and Table 4, respectively. Titration should be based on the mean of 
measurements from the last 3 available days (at least 2 of which are consecutive) in the week before the next study visit/telephone contact. If measurements from 3 days (at 
least 2 of which are consecutive) are not available, the dose adjustment should be delayed until the next scheduled study visit/telephone contact; unless in the investigator’s 
judgment, a dose adjustment is warranted. The subject should be retrained on the importance of SMBG measurements.
2.
Remind subjects to perform 8-point SMBG profile assessment (before and 2 hours after breakfast, lunch, and dinner; at bedtime; and at 2 AM): 3 times in the week prior to the 
Baseline/Randomization visit (Visit 4, Week 0), Visit 7 (Week 10), and Visit 9 (Week 26).
3.
Daily insulin use to be recorded in the subject diary, at least 3 days preceding study visit/telephone contact at Week 1 through Week 16, inclusive, and at Week 18, 22, 25, 
and 26.
4.
See Section 6.3.1 for hypoglycemic events criteria and reporting requirements.


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6.1.
Critical Baseline Assessments
Before any study-specific procedure is performed, valid informed consent must be 
obtained.
Critical baseline assessments will include: HbA1c, body weight, FPG, and total daily dose 
of insulin (including insulin glargine and insulin lispro). 
Cardiovascular medical history/risk factors will be assessed at Baseline/Randomization.
6.2.
Efficacy
6.2.1.
Efficacy Assessments
6.2.1.1.
HbA1c and FPG
Glycosylated hemoglobin and FPG will be measured at the time points specified in the 
Time and Events Table (Table 5).
6.2.1.2.
Body Weight
Body weight will be measured at the time points specified in the Time and Events Table 
(Table 5). Body weight should be measured to the nearest 0.1 kg on a standard calibrated 
scale. Subjects should be dressed in light indoor clothes (no coat, jacket, etc.) without 
shoes and with a voided bladder. The same equipment should be used wherever possible.
6.2.2.
Blood Glucose Monitoring
6.2.2.1.
Home Blood Glucose Monitoring
All subjects in the study should be instructed to measure and record blood glucose values 
from their glucose meter a minimum of 4 times per day at the following times (except 
prior to Baseline/Randomization, Week 10, and Week 26 where an 8-point SMBG profile 
will be performed; see Section 6.2.2.2):

Before breakfast (at least 8 hours without food intake)

Prior to Lunch

Prior to Dinner

At Bedtime
In addition, based on consultation with the investigator, the subject may be required on 
occasion to monitor at other time points (e.g., 2 hours after a meal or at approximately 
3 AM) if such monitoring is deemed necessary and appropriate by the investigator.


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All results of home blood glucose monitoring will be stored in the subject’s glucose 
meter and communicated to the study site as directed by the investigator. The investigator 
will review the glucose meter readings at the study visit/telephone contact and adjust 
insulin glargine and insulin lispro doses. During the Standardization Period, insulin 
glargine and insulin lispro may be adjusted according to product labeling in the 
respective country and standard of care at the study center. During the Treatment Period, 
insulin glargine and/or insulin lispro will be adjusted per Table 3 and Table 4, 
respectively. Titration should be based on the mean of measurements from the last 
3 available days (at least 2 of which are consecutive) in the week before the next study 
visit/telephone contact. If measurements from 3 days (at least 2 of which are consecutive) 
are not available, the dose adjustment should be delayed until the next scheduled study 
visit/telephone contact; unless in the investigator’s judgment, a dose adjustment is 
warranted. The subject should be retrained on the importance of SMBG measurements. 
Additional glucose meter monitoring should be performed as per local practice. 
Surveillance of insulin titration will be performed as described in Section 5.1.3.3.
Weekly telephone calls (if there is no scheduled study visit) must take place between 
the investigator and subject from the start of the Standardization Period through 
Week 16 and at Week 22, Week 25, and as required until the end of the Treatment 
Period, in order to optimize insulin adjustments (Table 6).
NOTE: The use of a GLP-1R agonist (albiglutide) is expected to decrease the need 
for insulin and, therefore, the investigator will need to ensure careful follow-up of 
each subject accordingly.
6.2.2.2.
8-Point Self-Monitored Blood Glucose Profile
An 8-point glucose profile will be performed by the subject 3 times in the week prior to 
the Baseline/Randomization visit (Visit 4, Week 0), Visit 7 (Week 10), and Visit 9 
(Week 26). Subjects should be instructed to measure and record blood glucose values 
using their glucose meter at the following times:

Before breakfast (at least 8 hours without food intake)

2 hours post-breakfast

Before lunch

2 hours post-lunch

Before dinner

2 hours post-dinner

At bedtime

At 2 AM


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6.2.3.
Hypoglycemic Events
The incidence of severe and documented symptomatic hypoglycemic events through 
Week 26 will be evaluated as part of the efficacy assessments. Specific criteria for safety 
assessments related to monitoring hypoglycemic events are detailed in Section 6.3.1. 
6.2.4.
Diabetic Dietary, Exercise, and Home Blood Glucose Monitoring 
Advice
Standard diabetic dietary, exercise, and home blood glucose monitoring advice as well as 
on the signs and symptoms of hypoglycemia and on supplemental oral glucose treatment 
will be provided at Visit 2 (Week -2) and reinforced at each study site visit through the 
end-of-treatment visit (Week 26). In addition, subjects will be instructed to test their 
blood glucose any time they experience signs and symptoms of hypoglycemia to confirm 
that it is a hypoglycemic event (see Section 6.3.1).
6.2.5.
Daily Insulin Use
Subjects will record their daily insulin use in a diary. This information will be collected 
for at least 3 days before Baseline/Randomization and for at least 3 days preceding the 
study visit/telephone contact at Week 1 through Week 16, inclusive, and at Week 18, 
Week 22, Week 25, and Week 26. During each of these visits the investigator or designee 
will review the data recorded in the preceding 3 days, and if errors or gaps are identified 
(e.g., if the subject did not take insulin and had not entered “0 units,” the investigator will 
record the missing information from subject recall). Based on this information, mean 
daily insulin use over the 3 consecutive days (in units/kg body weight per day) will be 
calculated for each subject.
6.3.
Safety
The following sections provide detail on the safety assessments. Planned time points for 
all safety assessments are listed in the Time and Events Tables (Table 5 and Table 6). 
Unscheduled visits will occur as medically necessary. Detailed procedures for obtaining 
each assessment are provided in the SPM.
Liver chemistry stopping and follow-up criteria (including specific eCRF pages) and AEs 
are described in Section 6.3.6 and Section 6.3.7.1, respectively. The AEs of special 
interest are described in Section 6.3.9.
6.3.1.
Hypoglycemic Events
Specific criteria for monitoring hypoglycemic events have been designed to ensure 
subject safety and to closely monitor hypoglycemia.
At each visit through the end-of-treatment visit (Visit 9; Week 26), subjects should be 
trained on the signs and symptoms of hypoglycemia (e.g., hunger, confusion, dizziness, 
anxiety, increased heart rate, visual disturbances), including nocturnal hypoglycemia (i.e., 


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nightmares; night sweats; tired, irritable, or confused upon awakening), as well as the 
common causes of hypoglycemia. Subjects should also be educated on appropriate 
methods to help prevent hypoglycemia (i.e., strictly observe nutritional guidance from the 
physician or study site staff, consume small snacks before intense exercise, promptly 
communicate with the study site on “ill days” for additional guidance). It is also 
particularly important to advise subjects to contact the study site before any potential 
dietary change, as this may necessitate a change in insulin doses to avoid the 
development of hypoglycemia. Subjects should also be educated on how to treat 
hypoglycemia (e.g., oral glucose treatment with simple carbohydrates).
Subjects will be asked to report hypoglycemic events that occur between study visits 
using a diary. In this study, hypoglycemic events are defined according to 
recommendations by the American Diabetes Association and The Endocrine Society 
Workgroup on Hypoglycemia [Seaquist, 2013]. To aid correct classification and 
treatment of hypoglycemic events, subjects should be instructed to repeat SMBG 
measurements 70 mg/dL (3.9 mmol/L).
Severe Hypoglycemia

Severe hypoglycemia is an event requiring assistance of another person to 
actively administer carbohydrates, glucagon, or take other corrective actions. 
Plasma glucose concentrations may not be available during an event, but 
neurological recovery following the return of plasma glucose to normal is 
considered sufficient evidence that the event was induced by a low plasma 
glucose concentration 
Documented Symptomatic Hypoglycemia

Documented symptomatic hypoglycemia is an event during which typical 
symptoms of hypoglycemia are accompanied by a measured plasma glucose 
concentration 70 mg/dL (3.9 mmol/L) 
Asymptomatic Hypoglycemia

Asymptomatic hypoglycemia is an event not accompanied by typical symptoms 
of hypoglycemia but with a measured plasma glucose concentration 70 mg/dL 
(3.9 mmol/L) 
Probable Symptomatic Hypoglycemia

Probable symptomatic hypoglycemia is an event during which symptoms typical 
of hypoglycemia are not accompanied by a plasma glucose determination but 
that was presumably caused by a plasma glucose concentration 70 mg/dL 
(3.9 mmol/L) 


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Pseudohypoglycemia

Pseudohypoglycemia is an event during which the person with diabetes reports 
any of the typical symptoms of hypoglycemia with a measured plasma glucose 
concentration >70 mg/dL (>3.9 mmol/L) but approaching that level 
Importantly, any report by a subject in the eDiary of a hypoglycemic event should be 
assessed and classified by the investigator per the above definitions, and recorded as a 
non-serious or serious adverse event if appropriate.
Any hypoglycemic event, regardless of intensity, that satisfies the definition of an SAE 
(Section 6.3.7.2) should be categorized as outlined in this section and reported 
appropriately in the SAE eCRF page.
6.3.2.
Height and Vital Sign Measurements
Height will be measured and body mass index calculated at Screening only.
Assessment of vital signs (blood pressure and pulse rate) will be performed at every visit. 
During visits when ECGs are scheduled, vital sign measurements will be taken after the 
completion of the ECG sampling. Subjects may be either in a semirecumbent or seated 
position. During visits when ECGs are not scheduled, vital sign measurements will be 
taken while subjects are in a seated position after at least a 5-minute rest period. During 
visits where a blood draw is required, vital sign measurements will be taken prior to 
sample collection.
6.3.3.
Electrocardiograms
A single 12-lead ECG recording (with subject in semirecumbent position for 10 to 
15 minutes before obtaining the ECG) will be performed at the time points specified in 
the Time and Events Table (Table 5). All ECGs will be performed before measurement 
of vital signs and collection of blood samples for laboratory testing. 
Investigators must compare the baseline ECG with the Visit 1 (Screening) ECG. Any 
changes indicative of a new MI or unstable cardiovascular condition (i.e., life-threatening 
arrhythmia) should prompt the investigator to not administer the investigational 
product but rather to evaluate and treat the subject per local standard of care. If 
subsequent evaluation reveals that a new MI has occurred or unstable/accelerated angina 
is documented, then the subject will be removed from the study (as they have met an 
exclusion criterion). If subsequent evaluation reveals no evidence of ischemic damage or 
instability, then study treatment may proceed. If any screening ECG demonstrates a 
possible old MI that was unknown to the investigator and the subject, the subject should 
be evaluated and treated, as appropriate. 
6.3.4.
Physical Examinations
Either a complete physical examination or brief physical examination will be performed 
at the time points specified in the Time and Events Table (Table 5). Subjects will have 


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visual acuity assessed at the screening and end-of-treatment (Week 26) visits as part of 
their physical examination. Visual acuity will be assessed using standard Snellen eye 
examination and funduscopy (dilation is preferred but not required).
The complete physical examination will include evaluation of the following organ or 
body systems:

Skin (including injection site)

Head, eyes, ears, nose, and throat

Thyroid

Respiratory system

CV system

Abdomen (liver, spleen)

Lymph nodes

Central nervous system

Extremities
The brief physical examination will include evaluation of the following organ or body 
systems:

Skin (including injection site)

Respiratory system

CV system

Abdomen (liver, spleen)

Central nervous system
6.3.5.
Clinical Laboratory Testing
All protocol-required laboratory assessments, as defined in Table 5, must be performed 
by the central laboratory, Quest Diagnostics Clinical Laboratory. Laboratory assessments 
must be conducted in accordance with the Central Laboratory Manual and Protocol Time 
and Events Schedule. Laboratory requisition forms must be completed and samples must 
be clearly labelled with the subject number, protocol number, site/center number, and 
visit date. Details for the preparation and shipment of samples will be provided by Quest 
Diagnostics Clinical Laboratory. Reference ranges for all safety parameters will be 
provided to the site by Quest Diagnostics Clinical Laboratory.
If additional nonprotocol-specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification), the results must be recorded in the subject’s eCRF. Refer to the SPM for 
appropriate processing and handling of samples to avoid duplicate and/or additional 
blood draws.


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Hematology, clinical chemistry, urinalysis, and other laboratory assessments are detailed 
in the subsequent section and will be collected at time points specified in the Time and 
Events Table (Table 5). 
Prior to the collection of blood samples, subjects should be fasting (no food or drink 
[except water] for at least 8 hours before sample collection). During visits when ECGs 
and vital sign measurements are scheduled, blood samples will be collected after the 
completion of these assessments.
Hematology: 

Complete blood count with red blood cell indices, white blood cell count 
differential, and platelet count
Clinical Chemistry:

Glucose, blood urea nitrogen, creatinine, sodium, potassium, chloride, carbon 
dioxide, calcium, total protein, albumin, total bilirubin, direct bilirubin, alkaline 
phosphatase (ALP), ALT, aspartate aminotransferase (AST), 
-glutamyltransferase, uric acid, magnesium, and phosphorus
Urinalysis:

Specific gravity, pH, glucose, ketones, microalbumin, creatinine, blood, 
leukocyte esterase, and nitrites (If warranted, a microscopic evaluation will be 
completed)
Other urine tests at time points specified in the Time and Events Table (Table 5):

Urine pregnancy test (-HCG) for female subjects of childbearing potential
Other blood tests at time points specified in the Time and Events Table (Table 5):

HbA1c
o
Note: As described in Section 3.1, an optional fasting HbA1c value may 
be determined using a Metrika kit or other finger-stick procedure to 
provide an initial guide of subject eligibility for investigators.

Fasting C-peptide and stimulated C-peptide 90 minutes after a standardized mixed 
meal

TSH. If TSH is above the ULN, free T4 (reflex) will also be measured

Lipid panel: total cholesterol, low-density lipoprotein cholesterol, high-density 
lipoprotein cholesterol, triglycerides, and free fatty acids 

Hepatitis B surface antigen

Hepatitis C antibody. If hepatitis C antibody positive, an RNA polymerase chain 
reaction should be performed on the same sample to confirm the result


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6.3.5.1.
Estimated Glomerular Filtration Rate
In order to monitor kidney function, eGFR will be calculated using the MDRD formula 
[Levey, 2009] at time points specified in the Time and Events Table (Table 5), using the 
following formula:
eGFR (mL/min/1.73 m2) = 175 × (SCr)-1.154 × (Age)-0.203 × (0.742 if female) × 
(1.212 if African American), 
where SCr is serum creatinine.
6.3.6.
Liver Chemistry Stopping and Follow-up Criteria
Phase III-IV liver chemistry stopping and follow-up criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance).
Phase III-IV liver chemistry stopping criteria 1-5 are defined below and are presented in a 
figure in Appendix 2:
1.
ALT 3 × ULN and bilirubin 2 × ULN (>35% direct bilirubin) (or ALT 3 × ULN 
and international normalized ratio [INR] >1.5, if INR measured)
NOTE: If serum bilirubin fractionation is not immediately available, withdraw study 
medication for that subject if ALT 3 × ULN and bilirubin 2 × ULN. Serum 
bilirubin fractionation should be performed if testing is available. If testing is 
unavailable, record presence of detectable urinary bilirubin on dipstick, 
indicating direct bilirubin elevations and suggesting liver injury.
2.
ALT 8 × ULN
3.
ALT 5 × ULN but <8 × ULN persists for 2 weeks
4.
ALT 3 × ULN if associated with symptoms (new or worsening) believed to be 
related to hepatitis (such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, or jaundice) or hypersensitivity (such as fever, rash, or eosinophilia)
5.
ALT 5 × ULN but <8 × ULN and cannot be monitored weekly for 2 weeks
When any of the liver chemistry stopping criteria 1-5 is met, do the following:

Immediately withdraw investigational product for that subject

Report the event to GSK/PPD within 24 hours of learning its occurrence

Complete the liver event eCRF and SAE data collection tool if the event also meets 
the criteria for an SAE. All events of ALT 3 × ULN and bilirubin 2 × ULN 
(>35% direct) (or ALT 3 × ULN and INR>1.5, if INR measured); INR 
measurement is not required and the threshold value stated will not apply to subjects 
receiving anticoagulants), termed “Hy’s Law,” must be reported as an SAE 
(excluding studies of hepatic impairment or cirrhosis). 


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NOTE: If serum bilirubin fractionation is not immediately available, withdraw study 
medication for that subject if ALT 3 × ULN and bilirubin 2 × ULN. Serum 
bilirubin fractionation should be performed if testing is available. If testing is 
unavailable, record presence of detectable urinary bilirubin on dipstick, 
indicating direct bilirubin elevations and suggesting liver injury.

Complete the liver imaging and/or liver biopsy eCRFs if these tests are performed

Perform liver event follow-up assessments and monitor the subject until liver 
chemistries resolve, stabilize, or return to baseline values as described below

Withdraw the subject from the study (unless further safety follow-up is required) 
after completion of the liver chemistry monitoring as described below

Do not restart investigational product 
In addition, for criterion 1:

Make every reasonable attempt to have subjects return to clinic within 24 hours for 
repeat liver chemistries, liver event follow-up assessments (see below), and close 
monitoring

A specialist or hepatology consultation is recommended

Monitor subjects twice weekly until liver chemistries (ALT, AST, ALP, and 
bilirubin) resolve, stabilize, or return to within baseline values
For criteria 2, 3, 4, and 5:

Make every reasonable attempt to have subjects return to clinic within 24 to 
72 hours for repeat liver chemistries and liver event follow-up assessments (see 
below)

Monitor subjects weekly until liver chemistries (ALT, AST, ALP, and bilirubin) 
resolve, stabilize, or return to within baseline values; criterion 5 subjects should be 
monitored as frequently as possible.
Subjects with ALT 5 × ULN and <8 × ULN that exhibit a decrease to ALT 3 × ULN, 
but <5 × ULN and bilirubin <2 × ULN without hepatitis symptoms or rash, and who can 
be monitored weekly for 4 weeks:

Notify the GSK/PPD medical monitor within 24 hours of learning of the abnormality 
to discuss subject safety

Can continue investigational product 

Must return weekly for repeat liver chemistries (ALT, AST, ALP, and bilirubin) until 
they resolve, stabilize, or return to within baseline values

If at any time these subjects meet the liver chemistry stopping criteria, proceed as 
described above


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
If, after 4 weeks of monitoring, ALT <3 × ULN and bilirubin <2 × ULN, monitor 
subjects twice monthly until liver chemistries normalize or return to within baseline 
values
For criteria 1-5, make every attempt to carry out the liver event follow-up assessments
described below:

Viral hepatitis serology including:

Hepatitis A immunoglobulin M (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

Blood sample for PK analysis, obtained within 3 half-lives (15 days) of last dose. 
Record the date/time of the PK blood sample draw and the date/time of the last dose 
of investigational product prior to blood sample draw in the eCRF. If the date or time 
of the last dose is unclear, provide the subject’s best approximation. If the date/time 
of the last dose cannot be approximated OR a PK sample cannot be collected in the 
time period indicated above, do not obtain a PK sample. Instructions for sample 
handling and shipping are in the SPM. 

Serum creatine phosphokinase and lactate dehydrogenase

Fractionate bilirubin, if total bilirubin 2 × ULN

Obtain complete blood count with differential to assess eosinophilia

Record the appearance or worsening of clinical symptoms of hepatitis or 
hypersensitivity, such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash, or eosinophilia as relevant on the AE report form

Record use of concomitant medications, acetaminophen, herbal remedies, other 
over-the-counter medications, or putative hepatotoxins, on the concomitant 
medications report form

Record alcohol use on the liver event alcohol intake eCRF
The following are required for subjects with ALT 3 × ULN and bilirubin 2 × ULN 
(>35% direct) but are optional for other abnormal liver chemistries:

Antinuclear antibody, antismooth muscle antibody, and type 1 antiliver kidney 
microsomal antibodies and quantitative total immunoglobulin G (IgG or gamma 
globulins).

Serum acetaminophen adduct high-performance liquid chromatography assay 
(quantifies potential acetaminophen contribution to liver injury in subjects with 


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definite or likely acetaminophen use in the preceding week [James, 2009]). NOTE: 
not required in China.

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 
antibody. NOTE: If hepatitis delta antibody assay cannot be performed, it can be 
replaced with a polymerase chain reaction of hepatitis D RNA virus (where needed) 
[Le Gal, 2005].

Liver imaging (ultrasound, magnetic resonance, or computed tomography) to 
evaluate liver disease.
6.3.7.
Adverse Events
The investigator or site staff will be responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE.
6.3.7.1.
Definition of an AE
Any untoward medical occurrence in a patient or clinical investigation subject, 
temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product.
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product. For marketed medicinal products, this 
also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse.
Events meeting the definition of an AE include:

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study

Signs, symptoms, or the clinical sequelae of a suspected interaction

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE) unless this is an intentional overdose taken with possible suicidal/self-
harming intent. This should be reported regardless of sequelae.
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. However, the signs and symptoms and/or clinical sequelae 
resulting from lack of efficacy will be reported if they fulfil the definition of an AE or 
SAE.  
Events that do not meet the definition of an AE include:


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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

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
6.3.7.2.
Definition of an SAE
An SAE is 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 outpatient setting. Complications that occur during hospitalization are AEs. 
If a complication prolongs hospitalization or fulfills any other serious criteria, the 
event is serious. When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from Baseline is not considered an AE.
d.
Results in disability/incapacity, or
NOTE: The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (e.g., sprained ankle) which 
may interfere or prevent everyday life functions but do not constitute a substantial 
disruption.
e.
Is a congenital anomaly/birth defect
f.
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 


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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.
All events of possible drug-induced liver injury with hyperbilirubinemia defined as 
ALT 3 × ULN and bilirubin 2 × ULN (>35% direct) (or ALT 3 × ULN and 
INR>1.5, if INR measured) termed “Hy’s Law” events (INR measurement is not 
required and the threshold value stated will not apply to subjects receiving 
anticoagulants).
NOTE: Bilirubin fractionation is performed if testing is available. If testing is 
unavailable, record presence of detectable urinary bilirubin on dipstick indicating 
direct bilirubin elevations and suggesting liver injury. If testing is unavailable and a 
subject meets the criterion of total bilirubin 2 × ULN, then the event is still reported 
as an SAE. If INR is obtained, include values on the SAE form. INR elevations >1.5 
suggest severe liver injury.
6.3.7.3.
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/PPD 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 

Hepatotoxicity

Acute renal failure

Seizure

Stevens Johnson syndrome/toxic epidermal necrosis
6.3.8.
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECGs, radiological scans, vital sign measurements), 
including those that worsen from Baseline, and felt to be clinically significant in the 
medical and scientific judgment of the investigator are to be recorded as AEs or SAEs. 
However, any clinically significant safety assessments that are associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the subject’s condition, are not to be reported as AEs or SAEs.


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Liver chemistry stopping and follow-up criteria are described in Section 6.3.6.
6.3.9.
Adverse Events of Special Interest
In the Phase IIIa clinical development program, AEs of special interest included several 
areas of safety-related concern for the T2DM population, particularly for a GLP-1R 
agonist such as albiglutide. 
Specific eCRF pages will be used to capture additional details for the following AEs of 
special interest:

Hypoglycemic events (Section 6.3.1)

Liver events (Section 6.3.6)

CV events (Section 6.3.9.1)

Injection site reactions (Section 6.3.9.3)

Potential systemic allergic reactions (Section 6.3.9.3)

Pancreatitis (Section 6.3.9.4)

Medullary thyroid cancer (Section 6.3.9.6)

Diabetic retinopathy (Section 6.3.9.7)

Pneumonia (Section 6.3.9.8)

Atrial fibrillation/atrial flutter (Section 6.3.9.9)
The following additional AEs of special interest will be captured in the AE eCRF pages 
and analyzed as described in Section 8.3.5.2:

GI events

Pancreatic cancer (Section 6.3.9.5)

Malignant neoplasms

Appendicitis
6.3.9.1.
Cardiovascular Events
Investigators will be required to fill out event specific data collection tools for the 
following AEs and SAEs:  

MI/unstable angina

Congestive heart failure

Arrhythmias, including atrial fibrillation/flutter (see Section 6.3.9.9)

Valvulopathy

Pulmonary hypertension


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
Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
This information should be recorded in the specific CV eCRF within 1 week of when the 
AE/SAE(s) are first reported.
6.3.9.2.
Death Events
In addition, all deaths will require a specific death data collection tool to be completed. 
The death data collection tool includes questions regarding CV (including sudden cardiac 
death) and non-CV death.
This information should be recorded in the specific death eCRF within 1 week of when 
the death is first reported.
6.3.9.3.
Injection Site Reactions and Potential Systemic Allergic Reactions 
(e.g., Rashes, Urticaria, Angioedema, or Anaphylaxis)
Adverse events broadly evaluated as injection site reactions have been reported in 
subjects treated with albiglutide (refer to the IB for further information). Manifestations 
were generally mild to moderate and included localized rash, itching, redness, or pain in 
the area of the injection site. In some instances, reactions were noted to become more 
severe with subsequent injections. Injection site reactions should be reported as AEs or 
SAEs, as appropriate, and additional information on these events will be captured in 
specific eCRF pages.
Subjects should also be closely monitored for signs of potential allergic or drug 
hypersensitivity reactions including anaphylaxis, angioedema, generalized urticaria, 
rashes, dyspnea, or other potential manifestations of systemic allergic/immune reaction 
(e.g., glomerulopathy, vasculitides, and hematologic abnormalities). 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 not reasonably 
attributable to another cause should be withdrawn from the study and should not be 
rechallenged with albiglutide (see Section 4.5).
In the case of severe systemic allergic reactions that include anaphylaxis, angioedema, or 
other severe potential hypersensitivity reactions that cannot reasonably be attributed to 
another cause, five 1-mL serum samples should be obtained for immunogenicity testing 
(within 24 hours of the event if possible) and sent to the central laboratory (see details in 
the SPM) for immediate distribution to contracted testing facility for specific 
immunological testing (albiglutide-specific immunoglobulin E and other tests, as 
appropriate). A follow-up serum sample will be taken 8 weeks after final dose of study 
treatment in these subjects.


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6.3.9.4.
Pancreatitis
In clinical trials, acute pancreatitis has been reported in association with albiglutide and 
other GLP-1R agonists.
Subjects must be informed about the symptoms of pancreatitis in the subject information 
and instructed to contact the investigator immediately when they experience these 
symptoms. In the case of suspected pancreatitis, treatment with randomly assigned study 
medication should be withheld, and appropriate diagnostic measures initiated (clinical 
examination, laboratory parameters, diagnostic imaging). If the suspected pancreatitis is 
confirmed, the subject must be withdrawn from active treatment in the study.
Detailed information on suspected pancreatitis events will be collected in specific eCRF 
pages. Cases of suspected pancreatitis will be reviewed by an independent, blinded PAC 
(Section 9.8).
6.3.9.5.
Pancreatic Cancer
Recently, the FDA and the EMA independently undertook comprehensive evaluations of 
a safety signal arising from postmarketing reports of pancreatitis and pancreatic cancer in 
patients using incretin-based drugs [Egan, 2014; EMA, 2013]. These investigations, 
included examination of data from a 2013 research report revealing a possible pancreatic 
safety signal [Butler, 2013]. They concluded that a causal relationship could not be 
established; however, they will continue to investigate as more data become available.
As a result, events of pancreatic cancer occurring during the study will be carefully 
evaluated in addition to careful evaluation of malignancies more broadly, given the 
interest in the potential for malignancies when GLP-1R agonists are used in combination 
with insulin [EMA, 2014].
6.3.9.6.
Medullary Thyroid Cancer
Safety concerns regarding thyroid C-cell neoplasia were raised based on long-term rodent 
studies with GLP-1R agonists. If a thyroid nodule is detected at either Screening or 
during the study, this should be evaluated in view of the guidance documents that have 
recently been published in the United States and Europe [Cooper, 2009; Pacini, 2006]. 
For example, the American Thyroid Association Guidelines Taskforce and the European 
Thyroid Cancer Taskforce both recommend that the initial evaluation of a thyroid nodule 
detected by physical examination may include an ultrasound of the neck and fine-needle 
aspiration, as warranted. Additional examinations may also be required by the 
preliminary findings. If medullary thyroid cancer is diagnosed, study medication should 
be withdrawn. The results of any investigation should be recorded in specific eCRF 
pages.
6.3.9.7.
Diabetic Retinopathy
In the Phase III program for albiglutide, the incidence of retinopathy events was similar 
between the albiglutide group and all comparators (see IB for further information). 


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However, there was a higher incidence of retinopathy events when albiglutide was 
compared with placebo (4.0% of subjects, event rate 2.17/100 person-years versus 2.1% 
of subjects, event rate 1.19/100 person-years, respectively). Additionally, there was a 
higher incidence in subjects receiving 50-mg albiglutide compared with 30-mg 
albiglutide (5.0% versus 2.1%, respectively). As such, GSK will continue to collect 
information on diabetic retinopathy events.
Detailed information on diabetic retinopathy will be collected in specific eCRF pages.
6.3.9.8.
Pneumonia
In the Phase III program for albiglutide, there was a higher incidence of pneumonia 
events with albiglutide compared with other comparators (refer to the IB for further 
information) and as such, cases of pneumonia occurring during the study will be 
monitored.
Detailed information on pneumonia will be collected in specific eCRF pages.
6.3.9.9.
Atrial Fibrillation/Atrial Flutter
In the Phase III program for albiglutide, there was a higher incidence of atrial 
fibrillation/atrial flutter events with albiglutide compared with other comparators. These 
events were more common in subjects who were male, older, or had renal impairment 
(refer to the IB for further information). Cases of atrial fibrillation or atrial flutter 
occurring during the study will be monitored.
Detailed information on atrial fibrillation and atrial flutter will be collected in specific 
eCRF pages.
6.3.10.
Pregnancy
Any pregnancy that occurs during study participation (i.e., from Baseline/Randomization 
through the end of the Posttreatment Follow-up Period) must be reported using a clinical 
trial pregnancy form. To ensure subject safety, each pregnancy must be reported to 
GSK/PPD within 2 weeks of learning of its occurrence. The pregnancy must be followed 
up to determine outcome (including premature termination) and status of mother and 
child. Pregnancy complications and elective terminations for medical reasons must be 
reported as an AE or SAE. Spontaneous abortions must be reported as an SAE.
Any SAE occurring in association with a pregnancy brought to the investigator’s 
attention after the subject has completed the study and considered by the investigator as 
possibly related to the study treatment must be promptly reported to GSK/PPD.


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6.3.11.
Time Period and Frequency of Detecting AEs and SAEs
The investigator or site staff is responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE.
Adverse events will be collected from the start of the Standardization Period until the 
follow-up contact.
Serious AEs will be collected over the same time period as stated above for AEs. 
However, any SAEs assessed as related to study participation (e.g., study treatment, 
protocol-mandated procedures, invasive tests, or change in existing therapy) or related to 
a GSK concomitant medication, will be recorded from the time a subject consents to 
participate in the study up to and including any follow-up contact. All SAEs will be 
reported to GSK/PPD within 24 hours, as indicated in Section 6.3.13. 
6.3.12.
Method of Detecting AEs and SAEs
Care must be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and nonleading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence. Appropriate questions include:

“How are you feeling?”

“Have you had any (other) medical problems since your last visit/contact?” 

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?” 
6.3.13.
Prompt Reporting of Serious Adverse Events and Other Events 
to GSK/PPD
Serious AEs, pregnancies, and liver function abnormalities meeting predefined criteria 
will be reported promptly by the investigator to GSK/PPD as described in the following 
table once the investigator determines that the event meets the protocol definition for that 
event.


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Initial Reports
Follow-up Information on a Previous Report
Type of Event
Time Frame
Documents
Time Frame
Documents
All SAEs
24 hours
“SAE” data collection 
tool
24 hours
Updated “SAE” data 
collection tool
Cardiovascular or death 
event
Initial and 
follow-up reports 
to be completed 
within 1 week of 
when the CV 
event or death is 
reported 
“CV events” and/or 
“death” data 
collection tool(s) if 
applicable
Initial and follow-up 
reports to be 
completed within 
1 week of when the 
CV event or death is 
reported
Updated “CV events” 
and/or “death” data 
collection tool(s) if 
applicable
Pregnancy
2 weeks
“Pregnancy 
Notification Form”
2 weeks
“Pregnancy Follow-up 
Form”
Liver chemistry abnormalities
ALT3 × ULN and
Bilirubin2 × ULN (>35% 
direct) (or ALT3 × ULN 
and INR>1.5, if INR 
measured)1
24 hours2
“SAE” data collection 
tool. “Liver Event 
eCRF” and “Liver 
Imaging” and/or “Liver 
Biopsy” eCRFs, if 
applicable3
24 hours
Updated “SAE” data 
collection tool/“Liver 
Event” Documents3
ALT8 × ULN; 
ALT3 × ULN with 
hepatitis or rash or 
3 × ULN and <5 × ULN 
that persists 4 weeks
24 hours2
“Liver Event” 
Documents (defined 
above)3
24 hours
Updated “Liver Event” 
Documents3
ALT5 × ULN plus 
bilirubin <2 × ULN
24 hours2
“Liver Event” 
Documents (defined 
above) do not need 
completing unless 
elevations persist for 
2 weeks or subject 
cannot be monitored 
weekly for 2 weeks3
24 hours
Updated “Liver Event” 
Documents, if 
applicable3
ALT5 × ULN and 
bilirubin <2 × ULN that 
persists 2 weeks
24 hours2
“Liver Event” 
Documents (defined 
above)3
24 hours
Updated “Liver Event” 
Documents3
ALT3 × ULN and 
<5 × ULN and bilirubin 
<2 × ULN
24 hours2
“Liver Event” 
Documents (defined 
above) do not need 
completing unless 
elevations persist for 
4 weeks or subject 
cannot be monitored 
weekly for 4 weeks3
24 hours
Updated “Liver Event” 
Documents, if 
applicable3
ALT = alanine aminotransferase; CV = cardiovascular; eCRF = electronic case report form; INR = international 
normalized ratio; SAE = serious adverse event; ULN = upper limit of normal.
1.
An INR measurement is not required; if measured, the threshold value stated will not apply to subjects receiving 
anticoagulants.
2.
GSK/PPD must be contacted at onset of liver chemistry elevations to discuss subject safety
3.
Liver Event Documents (i.e., “Liver Event eCRF” and “Liver Imaging eCRF” and/or “Liver Biopsy eCRF,” as 
applicable) should be completed as soon as possible.
For detailed descriptions of liver chemistry abnormalities, see Section 6.3.6.


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The method of recording, evaluating, and following up of AEs and SAEs plus procedures 
for completing and transmitting SAE reports to GSK/PPD are provided in the SPM. 
Procedures for poststudy AEs/SAEs are provided in the SPM.
6.3.13.1.
Regulatory Reporting Requirements for SAEs
Prompt notification of SAEs by the investigator to GSK/PPD is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects are met.
GSK/PPD 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/PPD 
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/PPD 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/PPD will file it 
with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
6.4.
Health Outcomes
6.4.1.
Health Outcome Assessments Not Included as Primary or Key 
Secondary Endpoints
6.4.1.1.
TRIM-Diabetes Questionnaire
The TRIM-Diabetes questionnaire is a 28-item treatment satisfaction measure with 
5 domains assessing treatment burden, daily life, diabetes management, compliance, and 
psychological health. Measures can be scored independently for each domain or as a total 
score. Higher scores indicate a better health state. The recall period is the past 2 weeks. 
The TRIM-Diabetes questionnaire is provided in Appendix 3. 
The TRIM-Diabetes questionnaire was developed according to the FDA patient-reported 
outcome guidance [FDA Guidance for Industry, 2009], and is based on the literature and 
significant input from patients with both type 1 diabetes mellitus and T2DM and from 
endocrinologists and internists. Its measurement properties were assessed in 2 studies and 
the tool demonstrated acceptable reliability, validity, and responsiveness [Brod, 2009a; 
Brod, 2009b; Brod, 2011]. Further work is needed to support a minimal important 
difference [Brod, 2009b].
The TRIM-Diabetes questionnaire will be administered in this study to assess treatment 
satisfaction within each treatment group of the study. The questionnaire will be 
administered to subjects using a paper format, at time points specified in the Time and 
Events Table (Table 5).


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6.4.1.2.
Hypoglycemia Fear Survey-II Questionnaire
The HFS-II questionnaire is a 33-item questionnaire with 2 subscales that measure: 
1) behaviors to avoid hypoglycemia and its negative consequences and 2) worries about 
hypoglycemia and its negative consequences. This study will include the worry subscale 
only (18 items, score range 0 to 72). Responses use a 5-point Likert scale ranging from 
Never to Always. The HFS-II has a 6-month recall period. The HFS-II questionnaire is 
provided in Appendix 4.
The HFS-II questionnaire was developed in response to the phenomenon of 
insulin-dependent diabetics whose fear of experiencing hypoglycemic episodes led them 
to purposely maintain elevated blood glucose levels [Cox, 1987]. The psychometric 
measurement properties of the tool have been assessed and found to be acceptable 
[Irvine, 1994].
The HFS-II questionnaire will be administered in this study to assess worries about 
hypoglycemia within each treatment group. 
The questionnaire will be administered to subjects using a paper format, at time points 
specified in the schedule in the Time and Events Table (Table 5).
6.5.
Genetics
Information regarding genetic research is included in Appendix 1.
6.6.
Novel Biomarkers
With the subject’s consent, blood samples will be collected at Baseline/Randomization 
(Week 0) and at the end-of-treatment (Week 26) or early withdrawal visit (see Time and 
Events Table, Table 5) and may be used for the purposes of measuring novel biomarkers 
to identify factors that may influence T2DM and/or medically related conditions, as well 
as the biological and clinical responses to albiglutide. If relevant, this approach will be 
extended to include the identification of biomarkers associated with AEs. The timing of 
the collections may be adjusted on the basis of merging information in order to ensure 
optimal evaluation of the novel biomarkers.
Refusing to provide consent for the collection of these samples will not prevent the 
subject from participating in the rest of the study.
All samples will be retained for a maximum of 15 years after the last subject completes 
the trial.
6.7.
Tracking of Albiglutide Pen Injector Failures and User Errors
All albiglutide pen injector failures and user errors must be detected, documented, and 
reported by the investigator throughout the study. Detailed information on pen injector 
failures and user errors will be collected on the Injector Pen Failure Reporting Form.


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NOTE: Pen injector failures and user errors associated with  or result in events fulfilling 
the definition of an AE or SAE will follow the processes outlined in Section 6.3.7.
7.
DATA MANAGEMENT
For this study, subject data will be entered via an eCRF into Oracle Clinical Remote Data 
Capture (OC RDC) system. Subject data will be available for viewing through access to 
the OC RDC system. Data provided from other sources will be received, reconciled, 
combined and transferred to GSK at predetermined time points.
Management of clinical data will be performed in accordance with applicable PPD 
standards and data cleaning procedures to ensure the integrity and quality of the data, 
e.g., removing errors and inconsistencies in the data. Adverse events and concomitant 
medication terms will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) and a validated medication dictionary, GSKDrug.
The eCRFs (including queries and audit trails) will be sent at the end of the study in CD 
format to GSK to be retained. Each investigator will receive a copy of their site specific 
data in the same format to maintain as the investigator copy. In all cases, subject initials 
will not be collected or transmitted.
8.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS
8.1.
Hypotheses
The primary hypothesis to be tested is that albiglutide plus insulin glargine (with or 
without metformin) will provide glycemic control (as measured by HbA1c change from 
Baseline) noninferior to insulin lispro plus insulin glargine (with or without metformin) 
after 26 weeks of treatment in subjects with T2DM inadequately controlled on their 
current regimen of basal-bolus insulin therapy. If the null hypothesis of albiglutide 
inferiority is rejected, a test of superiority will be applied.
8.2.
Study Design Considerations
8.2.1.
Sample Size Assumptions
Approximately 794 subjects will be randomly assigned in a 1:1 ratio to 2 treatment 
groups as described in Section 5.2. Eligible subjects will be stratified by screening HbA1c
value (<8.0% versus ≥8.0%), age (<65 years versus ≥65 years), and use of metformin 
(metformin use versus no metformin use). Assuming that 15% of subjects will be 
withdrawn early or will be lost to follow-up, approximately 337 subjects in each 
treatment group will complete 26 weeks of study assessments. 
With 337 completed subjects in each of the 2 treatment groups, the study will have at 
least 90% power to reject the null hypothesis of inferiority for HbA1c change from 
Baseline, assuming a noninferiority margin of 0.3%, an expected treatment group 


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difference of 0.0%, and a standard deviation of 1.2%, using a 2-sample, 1-sided t test 
with a testwise significance level of 0.025. 
If noninferiority of albiglutide is established, superiority of albiglutide versus insulin 
lispro will be tested. Given the sample size of 337 completed subjects per treatment 
group and assuming a common standard deviation of 1.2, the minimum detectable 
difference in means between albiglutide and insulin lispro resulting in a significant test is 
0.18, with a power of 50% and a type I error rate of 0.05.
The noninferiority margin of 0.30 was selected based on the expected effect of the active 
control. The assumed effect in terms of the within-treatment mean HbA1c change from 
Baseline at Week 26 for the intensified basal-bolus insulin comparator (i.e., insulin 
glargine and insulin lispro) is at least 1.0% (M1 = 1.0%, as defined in Guidance for 
Industry Non-Inferiority Clinical Trials [FDA, 2010]). This assumption was based on 
data from subjects treated with insulin glargine and insulin lispro [Koivisto, 2011; 
Diamant, 2014; Garber, 2014]. The predefined margin of 0.30 that should be met in this 
trial preserves at least 70% of the assumed effect of the comparator (0.30 = 30% of 
M1 = M2, as defined in Guidance for Industry Non-Inferiority Clinical Trials) [FDA, 
2010.
8.2.2.
Sample Size Sensitivity
Figure 3 illustrates the power versus sample size (number of completed subjects per 
treatment group) to reject the null hypothesis of inferiority for HbA1c change from 
Baseline, assuming a noninferiority margin of 0.3%, an expected treatment group 
difference of 0.0%, and a standard deviation of 1.2%, using a 2-sample, 1-sided t test 
with a testwise significance level of 0.025.
Figure 3
Power Versus Sample Size at the Noninferiority Margin of 0.3%
N1 = sample size.


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8.2.3.
Sample Size Re-estimation
No sample size re-estimation is planned for this study.
8.3.
Data Analysis Considerations
8.3.1.
Analysis Populations
The Full Analysis (FA) Population will include all subjects randomly assigned to 
treatment. Randomly assigned subjects who do not receive any study treatment will also 
be included. The subjects in the FA Population will be analyzed according to randomized 
treatment. The FA Population is the primary population for all efficacy analyses. 
The Per-Protocol (PP) Population will include all FA subjects who complete study 
procedures through Week 26 or beyond and are compliant with the protocol. The subjects 
in the PP Population will be analyzed according to randomized treatment. The PP 
Population will be used for supportive analyses of key efficacy endpoints.
The Safety Population will include all subjects who receive at least 1 dose of randomized 
study medication. The subjects in the Safety Population will be analyzed according to the 
treatment received. The Safety Population will be used for all safety analyses. 
Other analysis populations will be defined in the reporting and analysis plan (RAP).
8.3.2.
Analysis Data Sets
Subjects withdrawn after not achieving a predefined threshold for glycemic control 
(confirmed FPG ≤270 mg/dL [15.0 mmol/L] at least 8 weeks after randomization) may 
be considered for study withdrawal. Subjects withdrawn for this reason will be 
considered to have completed the efficacy assessments for the primary analysis at the 
time of the assessment that triggers withdrawal.
Per the protocol, insulin lispro may be re-introduced after Week 8 for subjects in the 
albiglutide treatment group, following a standardized, stepwise approach. Efficacy and 
safety assessments after the re-introduction of lispro will be included in the statistical 
analysis as is, without special handling. 
Clinical sites will be clustered by geographic region since the number of subjects per 
clinical site is expected to be rather small. Geographic regions will be defined based on 
geographic proximity, similarity of medical practice in diabetes, and number of subjects 
per region. Subjects per region will be constrained such that the region with the largest 
sample size is no more than 3 times that of the region with the smallest sample size. The 
clustering will be specifically defined in the RAP after clinical site selection and 
randomization are complete.
In general, the baseline value for each variable is defined as the last measurement 
collected prior to the first dose of randomized study medication.


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Study day will be defined as the number of days from the first dose of randomized study 
medication. The date when a subject receives the first dose of randomized study 
medication is defined as Day 1. For events after the first dose date, study day is 
calculated as the difference in days between the first dose date and the date of interest, 
plus 1 day. For events that occur before the first dose date, study day is calculated as the 
difference in days between the first dose date and the date of interest. Thus, the day 
before first dose date is defined as Day -1.
In the conduct of the study, specific measures will be put in place to prevent and 
minimize missing data due to treatment withdrawals, noncompliance, etc. Upon study 
completion, the characteristics (frequency, causes) of the missing data, especially as 
related to the key efficacy endpoints, will be examined to inform the sensitivity analysis 
and imputation methods concerning missing data.
8.3.3.
Treatment Comparisons
8.3.3.1.
Primary Comparisons of Interest
The primary endpoint is the change from Baseline in HbA1c at Week 26. The primary 
analysis of the primary endpoint will be conducted using a mixed-effect model with 
repeated measures (MMRM) in the FA Population. The MMRM will only include 
nonmissing observations without imputation.
The model will include HbA1c change from Baseline at all postbaseline visits as 
dependent variables; treatment, region, age category, current use of metformin, visit 
week, treatment-by-week interaction, and baseline HbA1c-by-week interaction as fixed 
effects; baseline HbA1c as a continuous covariate; and subject as a random effect. 
Treatment effects estimates (and associated hypothesis tests) of albiglutide will be 
evaluated within this MMRM model as least squares means contrasts relative to insulin 
lispro. An unstructured covariance matrix will be used for the MMRM analysis, unless 
the model does not converge, in which case the covariance matrix will be decided upon 
model convergence status and the Akaike information criterion. 
The generalizability of the treatment effect will be evaluated within a supportive analysis 
of covariance (ANCOVA) model that adds terms for treatment-by-variable interaction. 
The variables to be interacted with treatment include baseline HbA1c, region, age 
category, and current use of metformin. Absence of a significant treatment-by-variable 
qualitative interaction at the 0.10 level will be interpreted as supportive of the use of the 
main-effects model to evaluate the treatment efficacy hypotheses.
The primary endpoint will also be analyzed using the same MMRM model in the 
PP Population as supportive analysis. 
Special attention will be paid to the handling of missing data in statistical analysis. The 
method for the primary analysis, MMRM, assumes missing at random. The sensitivity of 
the results of analysis to the method of handling missing values will be investigated, 
especially if the number of missing values is substantial or if the characteristics of 
missing values differ between treatment groups. Further details of the sensitivity analysis, 


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including imputation methods and assumptions about the missing data, are described in 
Section 8.3.5.1.
8.3.3.2.
Other Comparisons of Interest
A key secondary endpoint is the proportion of subjects treated with once-weekly 
albiglutide that are able to replace prandial insulin without the need for re-introduction of 
insulin lispro. The 95% confidence interval of the sample proportion will be estimated, 
stratified by region, age category, and current use of metformin. 
The proportion of subjects with hypoglycemia, as confirmed by plasma glucose 
monitoring <70 mg/dL (<3.9 mmol/L) and/or requiring third-party intervention through 
Week 26, will be compared between treatment groups, adjusting for baseline HbA1c
stratum, age group, current use of metformin, and region. 
Other binary secondary endpoints, such as the proportion of subjects achieving HbA1c
treatment goals at Week 26 and the proportion of subjects achieving composite secondary 
endpoints (i.e., criteria involving HbA1c target and hypoglycemia) will be analyzed 
analogous to the proportion of subjects with hypoglycemia. 
Continuous secondary endpoints, e.g., changes over time in HbA1c, FPG, and body 
weight, changes in daily insulin dose, changes in mean daily blood glucose based on 
8-point SMBG, and changes in total number of weekly insulin injections will be 
summarized descriptively and analyzed using an MMRM (observed data). In the MMRM 
for non-HbA1c endpoints, the corresponding baseline variable will be modeled as a 
covariate (in place of baseline HbA1c) for variance reduction and to adjust for any 
baseline differences in treatment groups attributable to chance as well as the 
randomization stratification variables (HbA1c stratum, age category, current use of 
metformin).
The number of hypoglycemic events with confirmed home blood glucose monitoring 
<70 mg/dL (<3.9 mmol/L) and/or requiring third-party intervention in 3-month intervals 
(i.e., from Baseline/Randomization to Week 12, >Week 12 to Week 26) will be compared 
between the treatment groups using a Poisson regression model with offset for the 
person-year, which will include treatment effect and covariates such as HbA1c stratum, 
age (<65 years versus ≥65 years), current use of metformin (metformin use versus no 
metformin use), and region.
The time to meeting prespecified criteria for severe, persistent hyperglycemia at Week 26 
will be analyzed for treatment group differences using pairwise log-rank tests within a 
Kaplan-Meier model. 
A multiple comparisons adjustment strategy will be implemented for the multiple 
inferential tests among the primary endpoint and key secondary endpoints to preserve the 
study’s nominal criterion significance level of 0.05. Further details will be specified in 
the RAP.


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8.3.4.
Interim Analysis
No interim analysis is planned for this study.
8.3.5.
Key Elements of Analysis Plan
8.3.5.1.
Efficacy Analyses
The primary analyses of the primary and secondary efficacy endpoints are described in 
Section 8.3.3. The details of any further planned analyses, including subgroup analysis 
and exploratory endpoints, will be provided in the RAP.
8.3.5.1.1.
Impact of Missing Data on Primary Endpoint
Missing data are not explicitly imputed in the primary MMRM analysis; although, there 
is an underlying assumption that data are missing at random, including those withdrawn 
for lack of efficacy. All available scheduled postbaseline assessments up to endpoint are 
utilized and, via modelling of the within subject correlation structure, the derived 
treatment difference at Week 26 is adjusted to take into account missing data. The 
MMRM analysis (using saturated fixed effects and an unstructured variance-covariance 
matrix) is considered appropriate as the primary method of analysis, as it has been shown 
to give sensible answers to on-treatment questions in a range of practical situations 
[Siddiqui, 2009].
8.3.5.1.2.
Extent of Missing Primary Analysis Data
Missing data is expected to arise mainly from subjects missing complete visits. The 
amount of missing data for those baseline covariates included in the statistical analysis is 
expected to be none or at worst minimal. If it should occur, that subject will effectively 
be lost to analysis. Missing data for HbA1c between two nonmissing visits will be 
considered missing at random (intermediate missing data).
In this study, subjects who withdraw from treatment will be withdrawn from the study. In 
the eCRF, the reason for treatment discontinuation and the reason for withdrawal from 
the study are collected separately. Whenever the HbA1c value at Week 26 is missing (end 
of the study), the reason can be determined based on available data in these two locations. 
The reason for missing data can be classified as follows:  safety, procedural (including 
withdrawal of consent), or lack of efficacy.
8.3.5.1.3.
Reasons for Withdrawal
Reasons for withdrawal are assumed to fall into three broad categories:

Procedural (e.g., lost to follow-up, withdrew consent, protocol deviation, study 
closed/terminated, and investigator discretion): In this case, it is expected that an 
assumption of missing at random (MAR) is appropriate for imputation of HbA1c
data after withdrawal.  


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
Safety (e.g., AE, subject reached protocol-defined stopping criteria): It is 
expected that, in most cases, any change in safety related to these reasons for 
withdrawal would have been captured prior to the subject withdrawing from the 
study. In Study GLP108486 (albiglutide versus lispro over background 
glargine), 5% of subjects in the albiglutide group and <1% in the lispro group 
had AEs leading to withdrawal of active treatment through Week 26. In the 
albiglutide group, the most common AE leading to withdrawal was injection site 
reaction (1.1%). Missing HbA1c values after withdrawal due to safety concerns 
will be considered to possibly be missing not at random (MNAR).

Lack of efficacy: In this treat-to-target study, a substantial number of cases of 
withdrawal due to lack of efficacy is not expected. Missing HbA1c values after 
withdrawal due to lack of efficacy are considered to possibly be MNAR.
Sensitivity analyses will be performed for data missing due to safety concerns or due to 
lack of efficacy.
8.3.5.1.4.
Handling of Missing Data
The impact of missing data will be explored, as outlined below, for the Full Analysis 
Population only.
Examination of Missing Data Patterns
To examine the nature of missing data, cohorts of subjects will be defined based on the 
scheduled assessments (HbA1c change from Baseline) that were completed at Weeks 4, 5, 
10, 18, 26. 
1.
Subjects who have week 4 assessment only
2.
Subjects who have assessments up to and including Week 5 only
3.
Subjects who have assessments up to and including Week 10 only
4.
Subjects who have assessments up to and including Week 18 only
5.
Subjects who have assessments up to and including Week 26.
The number and percentage of subjects on each treatment in the 5 cohorts defined here 
will be tabulated. Graphical methods will be used to examine changes from Baseline over 
time to assess the pattern of outcomes prior to withdrawal.
Sensitivity Analyses – Multiple Imputation
Sensitivity analyses using multiple imputation methods will be conducted. Firstly, 
missing data between two nonmissing time points will be considered missing at random.  
The following multiple imputation methods are proposed based on whether data are 
missing at random or not at random:
1.
All missing data assumed MAR: Imputation is based on means and 
variances-covariances from subjects in the same treatment group as the withdrawn 


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subject and is comparable to MMRM. The main differences are that this approach 
uses separate covariance parameter estimation for each arm, and also separate 
regression parameters are estimated on baseline covariates within each arm. This 
more complex parameterization of the imputation model compared with the analysis 
model is valid. This approach will be used for all data missing post withdrawal. Here 
the estimand is one where after withdrawal all subjects progress in a similar way to 
those who remain in the trial. We expect the MMRM and this to give similar 
answers. If so, then it indicates any difference between the primary MMRM analysis 
and multiple imputation sensitivity analysis is due to the assumed effect modification 
and the assumed rates of HbA1c increase after withdrawal, rather than anything to do 
with going from an MMRM approach to a multiple imputation approach.
2.
Missing due to lack of efficacy or due to safety concerns using last mean carried 
forward (LMCF), that is MNAR: This approach assumes that a constant rate of 
increase in HbA1c change from Baseline is experienced by subjects following 
withdrawal from the study for lack of efficacy or due to safety concerns. The MAR 
approach will be used for missing data due to procedural reasons. Sensitivity 
analyses using the LMCF approach will be performed using the following rates of 
HbA1c increase: 0%/month, 0.1%/month, and 0.2%/month to explore the potential 
impact as in a tipping-point analysis. For each treatment group, these 3 rates will be 
assumed, resulting in 9 scenarios. The resulting treatment differences and associated 
P-values for noninferiority will be tabulated against the varying rates of HbA1c
increase. This estimand is one where those who withdraw for lack of efficacy or for 
safety concerns are assumed to revert to an unstable treatment regimen with an 
increasing rate of HbA1c. 
For each imputation data set, an analysis of variance will be carried using Week 26 data, 
both actual and imputed, using the same covariates as in the primary analysis. Contrasts 
of interest will be estimated and then combined across imputations using standard 
multiple imputation rules.
Additional scenarios for sensitivity analysis may be added and described in the RAP.
8.3.5.2.
Safety Analyses
Subject demographics, medical history, prior and concomitant medications, study 
medication exposure, vital sign measurements, clinical laboratory values, 12-lead ECG 
readings, physical examination assessments, and AE rates 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. Some graphical summaries may be provided as well. No inferential testing 
will be performed on the safety variables.
For selected AEs of special interest, such as hypoglycemia, the exposure-adjusted 
incidence rate will also be calculated as the number of events in a given period divided by 
the total person time on treatment of subjects at risk within the same period. The 
exposure-adjusted incidence rate will be expressed as an annualized rate (expected 
number of events per 100 person-years).


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Adverse events will be coded using MedDRA. Adverse events will be summarized in 
various subsets, including treatment-emergent AEs, related AEs, AEs leading to 
treatment discontinuation or withdrawal from study, SAEs, fatal AEs, etc. Adverse events 
will also be summarized by maximum intensity (mild, moderate, and severe).
Treatment-emergent AEs will be defined as any AEs, regardless of relationship to the 
investigational product, that occur after the first dose of the randomized study 
medication. Treatment-emergent AEs will also be further defined as on-therapy or 
post-therapy AEs for summary purposes.
Treatment-related AEs will be defined as any AEs that are considered by the investigator 
to be possibly, probably, or definitely related to the investigational product. In addition, if 
relationship information is missing, the AE will be considered treatment related. 
Adverse events of special interest will also be summarized. 
The number and percentage of subjects reporting specific events, such as specific GI 
events and injection site reactions, at each study week will be summarized and plotted 
over time. Characteristics of specific events, such as time to first occurrence, occurrence 
relative to preceding dose, and duration, will be summarized. 
Hypoglycemic events will be analyzed separately from other AEs. All hypoglycemic 
events will be classified as severe, documented symptomatic, asymptomatic, probable 
symptomatic, and pseudohypoglycemia, as defined in Section 6.3.1.
Incidence (in total and by each category) of hypoglycemia, daytime hypoglycemia, and 
nocturnal hypoglycemia will be determined. Daytime hypoglycemia is defined as 
hypoglycemic events with an onset between 06:00 hours and 00.00 hours (inclusive). 
Nocturnal hypoglycemia is defined as hypoglycemic events with an onset between 
00:01 hour and 05:59 hours (inclusive). The incidence of hypoglycemia with blood 
glucose <56 mg/dL (<3.1 mmol/L), regardless of symptoms, will also be determined.
Estimated GFR will be calculated using the MDRD formula and summarized 
descriptively.
8.3.5.3.
Health Outcomes Analyses
Details for analyzing the data from the TRIM-Diabetes questionnaires and the HFS-II 
worry subscale will be provided in the RAP.
8.3.5.4.
Genetic Analyses
See Appendix 1 for details about the genetics analysis plan.
8.3.5.5.
Novel Biomarker(s) Analyses
After completion of the clinical trial, if biomarker investigations are performed on 
samples collected during the study, the results will be reported separately from the main 


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clinical study report. Any endpoints of interest from all comparisons will be descriptively 
and/or graphically summarized as appropriate to the data.
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 study site, GSK/PPD will obtain favorable opinion/approval from 
the appropriate regulatory agency to conduct the study in accordance with the 
International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) and 
applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements.
The study will be conducted in accordance with ICH GCP, all applicable subject privacy 
requirements, and the guiding principles of the current version of the Declaration of 
Helsinki (based on the initial version accepted in 1996), including, but not limited to:

IRB/IEC review and favorable opinion/approval of study protocol and any 
subsequent amendments.

Subject informed consent.

Investigator reporting requirements.
GSK/PPD will provide full details of the above procedures, either verbally, in writing, or 
both.
Written informed consent must be obtained from each subject prior to participation in the 
study.
In approving the clinical protocol the IEC/IRB and, where required, the applicable 
regulatory agency are also approving the optional assessments e.g., genetics assessments 
described in Appendix 1, unless otherwise indicated. Where permitted by regulatory 
authorities, approval of the optional assessments can occur after approval is obtained for 
the rest of the study. If so, then the written approval will clearly indicate approval of the 
optional assessments is being deferred and the study, except for the optional assessments, 
can be initiated. When the optional assessments are not approved, then the approval for 
the rest of the study will clearly indicate this and therefore, the optional assessments will 
not be conducted.


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9.3.
Quality Control (Study Monitoring)
In accordance with applicable regulations, GCP, and GSK/PPD procedures, GSK/PPD 
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/PPD requirements. When reviewing data collection procedures, the discussion will 
include identification, agreement, and documentation of data items for which the eCRF
will serve as the source document.
GSK/PPD 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/PPD 
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
The end of the study is when the last subject completes the Final follow-up visit 
(Week 30).
Upon completion or termination of the study, the GSK/PPD monitor will conduct site 
closure activities with the investigator or site staff (as appropriate), in accordance with 
applicable regulations, GCP, and GSK/PPD standard operating procedures.
GSK reserves the right to temporarily suspend or terminate the study at any time for 
reasons including (but not limited to) safety issues, ethical issues, or severe 
noncompliance. If GSK determines that such action is required, GSK/PPD will discuss 
the reasons for taking such action with the investigator or head of the medical institution 
(where applicable). When feasible, GSK/PPD will provide advance notice to the 
investigator or head of the medical institution of the impending action.


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If a study is suspended or terminated for safety reasons, GSK/PPD will promptly inform 
all investigators, heads of the medical institutions (where applicable), and/or institutions 
conducting the study. GSK/PPD will also promptly inform the relevant regulatory 
authorities of the suspension/termination along with the reasons for such action. Where 
required by applicable regulations, the investigator or head of the medical institution 
must inform the IRB/IEC promptly and provide the reason(s) for the 
suspension/termination.
9.6.
Records Retention
Following closure of the study, the investigator or 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 easily accessible when needed (e.g., for a GSK/PPD 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 the 
records may be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution must 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. In addition, they must meet accessibility and retrieval standards, 
including regeneration of a hard copy, if required. The investigator must also ensure that 
an acceptable back-up of the reproductions exists and that there is an acceptable quality 
control procedure in place for creating the reproductions.
GSK/PPD will inform the investigator of the time period for retaining the site records in 
order to comply with all applicable regulatory requirements. The minimum retention time 
will meet the strictest standard applicable to a particular site, as dictated by local 
laws/regulations, GSK/PPD standard operating procedures, and/or institutional 
requirements.
The investigator must notify GSK/PPD of any changes in the archival arrangements, 
including, but not limited to archival of records at an off-site facility or transfer of 
ownership of the records in the event that 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/PPD site or other mutually 
agreeable location.


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GSK/PPD 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/PPD will provide the investigator with the randomization codes for their site only 
after completion of the full statistical analysis.
The results summary will be posted to the Clinical Study Register no later than 8 months 
after the final primary completion date, the date that the final subject was examined or 
received an intervention for the purposes of final collection of data for the primary 
outcome. In addition, a manuscript will be submitted to a peer reviewed journal for 
publication no later than 18 months after the last subject’s last visit. When manuscript 
publication in a peer reviewed journal is not feasible, a statement will be added to the 
register to explain the reason for not publishing.
9.8.
Pancreatitis Adjudication Committee
A PAC composed of independent specialists in gastroenterology will review cases of 
possible pancreatitis. Details of this committee and case adjudication will be described in 
a separate charter.


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10.
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suspension versus insulin glargine once daily in basal-bolus therapies with insulin lispro 
in type 2 diabetes patients: a prospective randomized open-label trial. Diabetes Obes 
Metab. 2011;13(12):1149-57.
Lane W, Weinrib S, Rappaport J, Hale C. The effect of addition of liraglutide to 
high-dose intensive insulin therapy: a randomized prospective trial. Diabetes Obes 
Metab. 2014 Mar 3;doi: 10.1111/dom.12286. [Epub ahead of print].
Lantus [US Package Insert] Sanofi-Aventis US, LLC. Bridgewater (NJ); 2013. 11 p. 
Available from:  http://products.sanofi.us/lantus/lantus.pdf (Accessed 27 Feb 2014).
Le Gal F, Gordien E, Affolabi D, et al. 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):2363-9.
Levey AS, Stevens LA, Schmid CH, et al; CKD-EPI (Chronic Kidney Disease 
Epidemiology Collaboration). A new equation to estimate glomerular filtration rate. Ann 
Intern Med. 2009;150(9):604-12.
Maldonado MR, Otiniano ME, Cheema F, Rodriguez L, Balasubramanyam A. Factors 
associated with insulin discontinuation in subjects with ketosis-prone diabetes but 
preserved beta-cell function. Diabet Med. 2005;22(12):1744-50.
Mathieu C, Rodbard HW, Cariou B, et al; BEGIN: Victoza Add-On (NN1250-3948) 
study group. A comparison of adding liraglutide versus a single daily dose of insulin 
aspart to insulin degludec in subjects with type 2 diabetes (BEGIN: Victoza Add-On). 
Diabetes Obes Metab. 2014;16(7):636-44.
McCoy RG, Van Houten HK, Ziegenfuss JY, Shah ND, Wermers RA, Smith SA. 
Increased mortality of patients with diabetes reporting severe hypoglycemia. Diabetes 
Care. 2012;35:1897-901.
Nathan DM, Buse JB, Davidson MB, et al. Management of hyperglycemia in type 2 
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regarding thiazolidinediones: a consensus statement from the American Diabetes 
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Riddle MC, Rosenstock J, Vlajnic A, Gao L. Randomized, 1-year comparison of three 
ways to initiate and advance insulin for type 2 diabetes: twice-daily premixed insulin 
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prandial injections. Diabetes Obes Metab. 2014;16(5):396-402.
Rosenstock J, Ahmann AJ, Colon G, Scism-Bacon J, Jiang H, Martin S. Advancing 
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(glargine/lispro) therapy. Diabetes Care. 2008;31(1):20-5.
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11.
APPENDICES
11.1.
Appendix 1 - Genetic Research
Genetic Research Objectives and Analyses
The objectives of the genetic research are to investigate the relationship between genetic 
variants and: 

Response to medicine, including albiglutide, basal insulins, bolus insulins (prandial 
or rapid-acting insulins), or any concomitant medicines;

T2DM susceptibility, severity, and progression and related conditions
Genetic data may be generated while the study is underway or following completion of 
the study.  Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses). Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above.  Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives.
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in a Reporting and Analysis Plan 
(RAP) prior to initiation of the analysis. Planned analyses and results of genetic 
investigations will be reported either as part of the clinical RAP and study report, or in a 
separate genetics RAP and report, as appropriate.
Study Population
Any subject who is enrolled in the study can participate in genetic research.  Any subject 
who has received an allogeneic bone marrow transplant must be excluded from the 
genetic research.
Study Assessments and Procedures
A key component of successful genetic research is the collection of samples during
clinical studies. Collection of samples, even when no a priori hypothesis has been 
identified, may enable future genetic analyses to be conducted to help understand 
variability in disease and medicine response.  

A 6 ml sample will be taken for Deoxyribonucleic acid (DNA) extraction. A Blood 
sample is collected at the Baseline visit, after the subject has been randomized and 
provided informed consent for genetic research. Instructions for collection and 
shipping of the genetic sample are described in the laboratory manual. The DNA 
from the blood sample may undergo quality control analyses to confirm the integrity 
of the sample. If there are concerns regarding the quality of the sample, then the 
sample may be destroyed. The blood sample is taken on a single occasion unless a 
duplicate sample is required due to an inability to utilize the original sample.  


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The genetic sample is labelled (or “coded”) with the same study specific number used to 
label other samples and data in the study.   This number can be traced or linked back to 
the subject by the investigator or site staff. Coded samples do not carry personal 
identifiers (such as name or social security number). 
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study, or GSK may destroy the samples sooner.  GSK or those working 
with GSK (for example, other researchers) will only use samples collected from the study 
for the purpose stated in this protocol and in the informed consent form.  Samples may be 
used as part of the development of a companion diagnostic to support the GSK medicinal 
product.
Subjects can request their sample to be destroyed at any time.
Informed Consent
Subjects who do not wish to participate in the genetic research may still participate in the 
study.  Genetic informed consent must be obtained prior to any blood being taken.
Subject Withdrawal from Study
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample, if already 
collected:

Continue to participate in the genetic research in which case the genetic DNA sample 
is retained

Discontinue participation in the genetic research and destroy the genetic DNA 
sample 
If a subject withdraws consent for genetic research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in 
the site study records. 
Genotype data may be generated during the study or after completion of the study and 
may be analyzed during the study or stored for future analysis. 

If a subject withdraws consent for genetic research and genotype data has not been 
analyzed, it will not be analyzed or used for future research.  

Genetic data that has been analyzed at the time of withdrawn consent will continue 
to be stored and used, as appropriate. 
Screen and Baseline Failures
If a sample for genetic research has been collected and it is determined that the subject 
does not meet the entry criteria for participation in the study, then the investigator should 
instruct the subject that their genetic sample will be destroyed. No forms are required to 


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complete this process as it will be completed as part of the consent and sample 
reconciliation process.  In this instance a sample destruction form will not be available to 
include in the site files.
Provision of Study Results and Confidentiality of Subject’s Genetic Data
GSK may summarize the genetic research results in the clinical study report, or 
separately and may publish the results in scientific journals. 
GSK may share genetic research data with other scientists to further scientific 
understanding in alignment with the informed consent. GSK does not inform the subject, 
family members, insurers, or employers of individual genotyping results that are not 
known to be relevant to the subject’s medical care at the time of the study, unless 
required by law. This is due to the fact that the information generated from genetic 
studies is generally preliminary in nature, and therefore the significance and scientific 
validity of the results are undetermined. Further, data generated in a research laboratory 
may not meet regulatory requirements for inclusion in clinical care.


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11.2.
Appendix 2: Liver Chemistry Stopping and Follow-up 
Criteria
Phase III-IV Liver Safety Algorithms
ALT>3xULN
plus 
bilirubin >2x 
ULN (>35%
direct) (or plus
INR >1.5, if   
measured)*
No
Yes
Yes
•Instruct subject to stop investigational product (IP)
•Notify GSK within 24h and arrange clinical followup 
within 24-72h
•Perform liver chemistries and liver event follow up 
assessments (serology, PK sample etc as in protocol) 
•Complete liver event CRF, SAE data collection tool if 
appropriate, and liver imaging and/or biopsy CRFs if  
tests performed.
•Obtain weekly liver chemistries [**as far as possible in 
these subjects] until resolved, stabilised or returned to 
baseline 
•Withdraw subject from study after monitoring 
complete unless protocol has option to restart drug
•Instruct subject to stop investigational product (IP)
•Notify GSK and arrange clinical followup within 24h
•Perform liver chemistries and liver event follow up 
assessments (serology, PK sample etc as in protocol) 
•Report as SAE (excl. hepatic impairment or cirrhosis 
studies) and complete liver event CRF, SAE data 
collection tool, and liver imaging and/or biopsy CRFs if 
tests performed.
•Obtain twice weekly liver chemistries until resolved, 
stabilised or returned to baseline values
•Consultation with hepatologist/specialist recommended
•Withdraw subject from study after monitoring 
complete unless protocol has option to restart drug
Hepatitis 
symptoms
or rash?
No
Able to 
monitor 
weekly for 
4 weeks?
Yes
No**
Yes
Continue IP
Obtain twice 
monthly liver 
chemistries until 
normalised or 
back to baseline 
values
Yes
Yes
ALT<3xULN 
+ bilirubin 
<2xULN 
after ≤ 4 
wks?
Yes
ALT 
>5xULN 
but 
<8xULN
No
ALT  
>8xULN
Yes
ALT >5 
and 
<8xULN 
for > 2 
wks
Yes
No
ALT>3xULN 
but <5xULN + 
bilirubin 
<2xULN+no 
symptoms
No
Able to 
monitor 
weekly for 
> 2 wks?
No
No
Notify GSK within 24h 
to discuss subject 
safety; continue IP;
check liver chemistry 
weekly for 4 weeks
Yes
No
*INR value not applicable to subjects on anticoagulants
ALT = alanine aminotransferase; CRF = case report form; GSK = GlaxoSmithKline; INR = international normalized 
ratio; PK = pharmacokinetic; SAE = serious adverse event; ULN = upper limit of normal.


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11.3.
Appendix 3: Treatment-Related Impact Measure – Diabetes 
Questionnaire
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11.4.
Appendix 4: Hypoglycemia Fear Survey-II Questionnaire, 
Worry Subscale
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11.5.
Appendix 5: Country-Specific Requirements
11.5.1.
German-Specific Eligibility Requirements
Select eligibility criteria are specific to subjects participating at sites in Germany. 
Section 4.2 includes German-specific text for inclusion #7 (bullet 2) stipulating that 
progestogen-only pills are only acceptable if they have a Pearl Index of less than 1.0 
(e.g., those containing 75 g desogestrel)
Section 4.3 includes German-specific text for exclusion #21 and #22 stipulating subjects 
are not eligible for study participation if they have been put in an institution because of 
official or legal order, or if they are employees (or the employee’s relatives) of the 
sponsor, the contract research organization, or the investigative site, including the 
investigator or other site staff. 
11.5.2.
French Administrative Considerations and Specific
Requirements
This appendix includes all the requirements of the French law (n2004-806 of 9th
August 2004), and identifies, item per item, the mandatory modifications or additional 
information to the study protocol and includes specifics GSK requirements.
1. Concerning the “STUDY POPULATION”

In line with the local regulatory requirements, the following text in section 
“OTHER STUDY ELIGIBILITY CRITERIA CONSIDERATIONS”
(Section 4.4) is added :
A subject will be eligible for inclusion in this study if he /she is either affiliated to 
or beneficiary of a social security category.
It is the investigator’s responsibility to ensure and to document (in source 
document - patient notes) that the patient is either affiliated to or beneficiary of a 
social security category.

2. Concerning the “DATA ANALYSIS AND STATISTICAL 
CONSIDERATIONS” and specially in the “SAMPLE SIZE ASSUMPTION”
(Section 8.2.1)
The expected number of patients to be recruited in France is declared to the 
French regulatory authority.

3. Concerning the “STUDY CONDUCT CONSIDERATIONS”


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
In section “Regulatory and Ethical Considerations, Including the Informed 
Consent Process” (Section 9.2)
Concerning the process for informing the patient or his/her legally authorized 
representative, the following text is added : 
French Patient Informed Consent form is a document which summarizes the main 
features of the study and allows collection of the patient's written consent in 
duplicate. It also contains a reference to the authorisation of Agence nationale de 
sécurité du médicament et des produits de santé (ANSM), the French National 
Agency for Medicines and Health Products Safety) and the approval from the 
French Ethic committee.


In section concerning the “NOTIFICATION TO THE HOSPITAL DIRECTOR”
(Section 9.2) the following text is added:
In accordance with Article L1123-13 of the Public Health Code, the Hospital 
Director is informed of the commitment to the trial in his establishment. The 
Hospital Director is supplied with the protocol and any information needed for the 
financial disposition, the name of the investigator(s), the number of sites involved 
in his establishment and the estimated time schedule of the trial (R.1123-63).


In section concerning the “INFORMATION TO THE HOSPITAL 
PHARMACIST” (Section 9.2) the following text is added:
In accordance with Article R.1123-64 of the Public Health Code, the Hospital 
Pharmacist is informed of the commitment to the trial in his establishment. The 
Pharmacist is supplied with a copy of the protocol (which allows him to dispense 
the drug(s) of the trial according to the trial methodology), all information 
concerning the product(s) of the trial (e.g. included in the IB), the name of the 
investigator(s), the number of sites involved in his establishment and the 
estimated time schedule of the trial.


In section “DATA MANAGEMENT” (Section 7) the following text is 
added:
Within the framework of this clinical trial, data regarding the identity of the 
investigators and/or co-investigators and/or the pharmacist if applicable, involved 
in this clinical trial, and data regarding the patients recruited in this clinical trial 
(patient number, treatment number, patient status with respect to the clinical trial, 
dates of visit, medical data) will be collected and computerized in GSK data bases 
by GlaxoSmithKline Laboratory or on its behalf, for reasons of follow up, clinical 
trial management and using the results of said clinical trial. According to the Act 


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n° 78-17 of 6th January 1978 further modified, each of these people aforesaid has 
a right of access, correction and opposition on their own data through 
GlaxoSmithKline Laboratory (Clinical Operations Department).

4. Monitoring Visits (Section 9.3)
The Health Institution and the Investigator agree to receive on a regular basis a 
Clinical Research Assistant (CRA) of GLAXOSMITHKLINE or of a service 
provider designated by GLAXOSMITHKLINE. The Health Institution and the 
Investigator agree to be available for any phone call and to systematically answer 
to all correspondence regarding the Study from GLAXOSMITHKLINE or from a 
service provider designated by GLAXOSMITHKLINE. In addition, the Health 
Institution and the Investigator agree that the CRA or the service provider 
designated by GLAXOSMITHKLINE have direct access to all the data 
concerning the Study (test results, medical record, etc.). This consultation of the 
information by GLAXOSMITHKLINE is required to validate the data registered 
in the electronic Case Report Form (eCRF), in particular by comparing them 
directly to the source data. In accordance with the legal and regulatory 
requirements, the strictest confidentiality will be respected.

5. Data entry into the eCRF (Section 7)
The Health Institution and the Investigator agree to meet deadlines, terms and 
conditions of the Study’s eCRF use here below:
The Health Institution and the Investigator undertake:
1) That the Investigator and the staff of the investigator center make 
themselves available to attend the training concerning the computer 
system dedicated to the eCRF of the Study provided by 
GLAXOSMITHKLINE or by a company designated by 
GLAXOSMITHKLINE.
2) That the Investigator and the staff of the investigator center use the 
information technology (IT) Equipment loaned and/or the access codes 
only for the purpose of which they are intended and for which they have 
been entrusted to them, namely for the Study achievement, to the 
exclusion of any other use.
3) That the Investigator and the staff of the investigator center use the IT 
Equipment loaned according to the specifications and manufacturer’s 
recommendations which will have been provided by 
GLAXOSMITHKLINE.


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4) To keep the IT Equipment and/or access codes in a safe and secure place 
and to only authorize the use of this IT Equipment by investigator center 
staff designated by the principal investigator to enter the data of the Study.
5) That the Investigator and the staff of the investigator center enter the data 
of the eCRF related to a patient visit in the 3 days following the date of the 
patient visit or, for the patient test results, in the 3 days following the 
reception of the results of such tests.
6) That the Investigator resolves and returns to GLAXOSMITHKLINE the 
data queries issued by GLAXOSMITHKLINE or a service provider 
designated by GLAXOSMITHKLINE within 7 days after the reception of 
the request of clarification or in a period of one (1) day during the final 
stage of clarification of the data base or in such other period as provided 
by GLAXOSMITHKLINE and/or a company designated by 
GLAXOSMITHKLINE.
7) To be responsible for the installation and payment of the required Internet 
connections needed for the use of the IT Equipment, Computer systems 
and/or access codes.
8) To return at the end of the Study the IT Equipment and/or access codes to 
GLAXOSMITHKLINE or to any company designated by 
GLAXOSMITHKLINE and any training material and documentation. The 
IT Equipment cannot under any circumstances be kept by the Health 
Institution or the Investigator for any reason whatsoever.

6. CTR Publication (Section 9.7)
It is expressly specified that GLAXOSMITHKLINE and/or the Sponsor can make 
available to the public the results of the Study by the posting of the said results on 
a website of the GLAXOSMITHKLINE GROUP named Clinical Trial Registry 
(CTR) including the registration of all the clinical trials conduct by the 
GLAXOSMITHKLINE Group and this before or after the publication of such 
results by any other process.
7. Data Protection French Law of 6 January 1987 (CNIL) (Section 9.7)
In accordance with the Data Protection French Law of 6 January 1978 as 
modified, computer files used by GLAXOSMITHKLINE to monitor and follow 
the implementation and the progress of the Study are declared with the 
Commission nationale de l'informatique et des Libertés (CNIL) by 
GLAXOSMITHKLINE. The Investigator has regarding the processing data 
related to him a right of access, of rectification and of opposition with 
GLAXOSMITHKLINE in accordance with the legal provisions. This information 
can be transferred or be accessed to other entities of GLAXOSMITHKLINE 


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Group in France, Britain or United States, what the Investigator agrees by the 
signature of the present Protocol.



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11.6.
Appendix 6: Protocol Changes
Protocol Amendment Number 01
Protocol Amendment Number 01 is applicable to all clinical study centers participating in 
this study. Protocol changes specified in Amendment Number 01 are summarized as 
follows: 

Inclusion criterion 1 was updated to limit the upper age range to 75 years of age 
(inclusive at the time of Screening).

Inclusion criterion 2 was updated to increase the upper limit of the HbA1c value at 
Screening from 9.0% to 9.5%. In addition, an upper limit of 9.0% for the HbA1c
value at Week -1 (pertaining to the additional inclusion criteria for randomization) 
was added. The rationale for these changes was to facilitate enrollment into the 
Screening Period while still allowing only subjects with an HbA1c value between 
7.0% and 9.0%, inclusive, to be randomly assigned to study treatment.

Inclusion criterion 4 was updated to indicate that the simulated C-peptide value 
(added at Screening) may be used for the qualification of subjects who do not 
meet the fasting C-peptide value but who meet all other eligibility criteria. The 
rationale for this addition to the inclusion criterion was to better characterize and 
exclude insulin-deficient T2DM subjects from participating in this clinical study 
where prandial insulin will be withdrawn from subjects randomly allocated to 
albiglutide. In subjects treated with exogenous insulin, -cell stimulation in the 
fasting state may be reduced by the hypoglycemic effect of concomitant insulin 
administration [Jones, 2013; Maldonado, 2005].

Inclusion criterion 9 was updated to include a statement to indicate that informed 
consent would be provided after consultation with the investigator. The rationale 
for this change was to clarify that subjects would be given the opportunity to ask 
all of their questions and fully understand the study before providing consent to 
participate.

Inclusion criterion 10 was added to ensure that subjects enrolled in the study are 
suitable to participate in this treat-to-target study design, which includes 
intensified basal-bolus insulin therapy utilizing prespecified glycemic targets.

The withdrawal criteria were updated to clarify which obligatory reasons require a 
subject to be withdrawn from the study.

An additional phone call was added at Week 28. The rationale for this change was 
to monitor and adjust insulin glargine and insulin lispro doses between the 
Week 26/Early Withdrawal and Follow-up visit.

The titration algorithms for insulin glargine (Table 3) and insulin lispro (Table 4) 
were updated. The rationale for these changes was to simplify the instructions, 


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modify the increments for dose adjustments, and to provide additional dose 
reductions at the investigator’s discretion.
!
Included additional information regarding subject education and training on the 
signs and symptoms, common causes, and self-management of hypoglycemia. 
The rationale for these additions was to enhance the language in the original 
protocol to reinforce the importance of education and training.
!
Added an optional fasting HbA1c test at Screening using a Metrika kit or other 
finger-stick procedure to aid investigators in the selection of subjects who may be
good candidates for the study.
!
Figure 2 was updated to change the less than symbol to a greater than symbol in 
two places. The rationale for this change was that this was an error previously 
identified and addressed in a Note to File.
!
Additional sensitivity analyses to assess the impact of missing data for the 
noninferiority test have been described. The rationale for this addition was based 
on the explicit request of a Regulatory Agency.
!
Incorporated other administrative changes; the rationale for these changes is to 
ensure a clear and complete protocol for use at the study centers
Specific Changes in the Text
Title Page:
Authors:
 
 
Synopsis, Study Design:
!
Subjects with inadequate failing to achieve adequate glycemic control 
(glycosylated hemoglobin [HbA1c] ≥7.0% and ≤9.05% at Screening) on their 
current basal-bolus insulin regimen (with and or without metformin) despite at 
least 3 months of treatment will be recruited into the study. Subjects who 
achieve an HbA1c value ≥7.0% and ≤9.0% following the Standardization 
Period will be randomized into the study.
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Table 1, Risk Assessment for Albiglutide (GSK716155)
Risk of Clinical Significance: Insulin glargine and insulin lispro, Mitigation Strategy: 
Subject education on the signs and symptoms of hypoglycemia (including 
nocturnal hypoglycemia), common causes of hypoglycemia, appropriate methods 
to help prevent hypoglycemia, and on the self treatment of hypoglycemic episodes 
(see Section 6.3.1)
Close monitoring for hypoglycemia and need for intervention (e.g., insulin dose 
adjustment, withdrawal from study participation) via frequent contact with 
subjects, who will self monitor blood glucose (see Section 4.5, and 
Section 5.1.3.3, and Section 6.2.2)
Risk communication via guidance for investigators (IB Section 6) and informed 
consent form for subjects
Section 3.1, Study Design
Figure 1, Study Design
During the Screening Period (Week -6 through Week -5), subjects will provide written 
informed consent and undergo procedures to determine eligibility for study participation. 
Note: A fasting HbA1c value may be determined using a Metrika kit (Metrika, Inc, 
Sunnyvale, California) or other finger-stick procedure to provide an initial guide of 
subject eligibility for investigators. The test is not required. The HbA1c value 
obtained at this screening visit is to be used as a guide for the investigator. If the 
investigator feels that a subject is a good candidate for the study, the subject should 
continue with the screening visit and have HbA1c assessed through the central 
laboratory. The central laboratory measure will serve as the official HbA1c value to 
determine subject eligibility for entry into the Standardization Phase.


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Section 3.2.5, Insulin Doses
The starting dose for basal insulin (insulin glargine) in the Standardization Period will
should be the same (or 20% lower if the subject enters the study on 2 doses of basal 
insulin), on a unit-for-unit basis, as that taken by the subject during Screening; see 
Section 5.1.1 for additional details. 
The starting dose for bolus insulin (insulin lispro) in the Standardization Period will
should be the same, on a unit-for-unit basis, as that taken by the subject during 
Screening; see Section 5.1.1 for additional details and guidance regarding permitted 
changes at the discretion of the investigator.
During the Treatment Period, the study will allow individualization of the insulin dose in 
both treatment groups (i.e., insulin glargine in the albiglutide treatment group and both 
insulin glargine and insulin lispro in the basal bolus treatment group), with a 
treat-to-target approach and a titration regimen based on SMBG values and other 
important information, such as hypoglycemia FPG and/or postprandial glucose values
(Table 3 and Table 4).
Inclusion Criterion 1:
Male or female, 18 to 75 years of age or older (inclusive at the time of Screening) with 
T2DM
Inclusion Criterion 2:
HbA1c ≥7.0% and ≤9.05% at Screening. If the first screening HbA1c does not meet the 
eligibility criterion, the HbA1c value may be checked up to 2 times during Screening, and 
if the average of these determinations meets the criterion, the subject can be randomly 
assigned to treatmentmay be eligible for further participation in the study
Inclusion Criterion 3:
Note: Subject should not have received any other antidiabetic medication within 30 days 
before Screening (e.g., GLP-1R agonist, dipeptidyl peptidase-IV inhibitor, SU, 
meglitinide, sodium-glucose transporter 2 inhibitor, or thiazolidinedione). Subjects 
receiving commercially available premixed basal and prandial insulin are not eligible for 
this study.
Inclusion Criterion 4:
Fasting C-peptide 0.8 ng/mL (0.26 nmol/L). If the fasting C-peptide is <0.8 ng/mL 
(<0.26 nmol/L) but stimulated C-peptide 90 minutes after a standardized mixed 
meal is 1.5 ng/mL (0.5 nmol/L), the subject may be eligible for further 
participation in the study [Jones, 2013; Maldonado, 2005]
Note: Plasma glucose will also be measured 90 minutes after the standardized mixed 
meal; if the concurrent plasma glucose collected 90 minutes after the standardized 


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mixed meal is not 144.0 mg/dL (8.0 mmol/L), the stimulated C-peptide test may 
be repeated during an unscheduled visit.
Inclusion Criterion 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 
the site personnel’s review of the female subject’s medical records, medical examination 
of the subject and/or semen analysis, or interview with the female subject on her male 
partner’s his medical history.
…
Male condom combined with a female diaphragm, either with or without a vaginal 
spermicide (foam, gel, film, cream, or suppository) [Hatcher, 2007]
Inclusion Criterion 8:
Willing and able to comply with all study procedures, including performance of frequent 
SMBG profiles and use of an e-diary, according to the protocol
Inclusion Criterion 9:
Able and willing to provide written informed consent after a thorough explanation of 
the study by the investigator or designee, which will include the opportunity for the 
subjects to ask questions
Inclusion Criterion 10:
Suitable for participation in a treat-to-target study, including intensified basal-bolus 
insulin therapy utilizing the prespecified glycemic targets defined in the protocol
Exclusion Criterion 7:
History of severe hypoglycemia unawareness (i.e., the absence of autonomic warning 
symptoms before the development of neuroglycopenic symptoms such as 
blurred vision, difficulty speaking, feeling faint, difficulty thinking, and 
confusion)
Exclusion Criterion 9:
9. Clinically significant CV and/or cerebrovascular disease within 3 months before 
Screening including, but not limited to, the following:

Stroke or transient ischemic attack

Acute coronary syndrome (myocardial infarction [MI] or unstable angina not 
responsive to nitroglycerin)

Cardiac surgery or percutaneous coronary procedure

Current or history of heart failure (New York Heart Association class III or IV)


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10. Any history of New York Heart Association class III or IV heart failure
Section 4.4, Additional Inclusion Criteria for Randomization:

HbA1c ≥7.0% and 9.0% at Week -1. If the subject does not qualify for 
randomization based on this criterion, the assessment may be repeated on a 
weekly basis for a maximum of 2 additional weeks before randomization. 
The mean of all HbA1c assessments (Week -1 plus the additional HbA1c
assessments) must be ≥7.0% and 9.0% for the subject to be eligible for 
randomization (see Section 4.6). Note: If a subject has confirmed (by a 
central laboratory) HbA1c <7.0% and >9.0% at Week -1 or the subject 
decides not to continue repeat testing, he or she will be considered a 
standardization failure (see Section 4.6)
Section 4.5, Withdrawal Criteria
Every effort should be made to keep subjects in the study. The reasons for subjects not 
completing the study will be recorded.
A subject may be withdrawn from the study for the following reasons:

AE, which, in the opinion of the investigator precludes effective participation of the 
subject or poses a safety concern
The following AEs will require withdrawal from the study:

AE, which, in the opinion of the investigator precludes effective 
participation of the subject or poses a safety concern

Elevation of liver function test results according to meeting any of the liver 
stopping criteria (see Section 6.3.6)

Severe allergic/hypersensitivity reaction that is considered by the investigator to 
be attributable to randomized study medication or without a likely alternative 
etiology (see Section 6.3.9.3)

Confirmed acute or chronic pancreatitis (see Section 6.3.9.4)

Confirmed medullary thyroid cancer (see Section 6.3.9.6)

Severe Recurrent severe hypoglycemia or recurrent nocturnal hypoglycemia 
during the Treatment Period posing a potential risk to the subject, as judged by 
the investigator

Pregnancy or intention of becoming pregnant

Major protocol deviation if withdrawal from the study is mandated by the 
medical monitor (the investigator should discuss the protocol deviation with 
the medical monitor before withdrawing study medication)

GSK-defined Sentinel Event. The medical monitor will advise the 
investigator if an SAE meets the criteria of a true Sentinel Event (e.g., 


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without a clear alternate etiology) for which withdrawal is required (see 
Section 6.3.7.3)
In addition, a subject may be withdrawn from the study for the following reasons:

FPG >270 mg/dL (15.0 mmol/L) at least 8 weeks after randomization on 3 
consecutive days (by blood glucose meter), which is confirmed by a central 
laboratory (to be done within 2 weeks of the home glucose monitoring). 
Continuation of the subject will be at the discretion of the investigator after 
consultation with the medical monitor 

Lost to follow-up

Study closed/terminated or investigator site closed (where subject transfer to 
another site is not possible)

Pregnancy or intention of becoming pregnant

Major protocol deviation (the investigator should discuss the protocol deviation 
with the sponsor before withdrawing study medication)

Subject decision (reason to be documented in the electronic case report form 
[eCRF], if specified by the subject)

Investigator discretion 
Note: Use of a prohibited medication constitutes a protocol deviation. Continuation of the 
subject in the study will be discussed with the medical monitor, and the decision of 
continuation or withdrawal will be documented.
Section 4.6, Screening/Standardization Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
do not meet all inclusion (Section 4.2) and exclusion (Section 4.3) criteria to continue 
in Screening. are never subsequently randomly assigned to treatment. Subjects failing to 
meet eligibility criteria may be rescreened after 2 weeks, as appropriate. In order to 
ensure transparent reporting of screen failure subjects, to meet the Consolidated 
Standards of Reporting Trials publishing requirements, and to respond to queries from 
regulatory authorities, a minimal set of screen failure information will be collected 
including demography, screen failure details, eligibility criteria, and any SAEs.
Standardization failures are defined as subjects who begin the Standardization 
Period but do not complete the Standardization Period or subsequently fail the 
Additional Inclusion Criteria for Randomization criteria (Section 4.4), or subjects 
who decide not to continue repeat testing. Standardization failures may not be 
rescreened. may be rescreened after 2 weeks, as appropriate. Subjects may then be 
randomly assigned provided they now meet the randomization criteria (Section 4.4) and 
still meet all of the inclusion criteria (Section 4.2) and none of the exclusion criteria 
(Section 4.3).


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Section 5.1.1, Dosing Guidance During the Standardization Period
Insulin glargine

If the subject’s prestudy basal insulin is a once-daily regimen, transfer the subject to 
insulin glargine (subcutaneous injection) once daily at bedtime on a unit-per-unit 
basis. Note: At the discretion of the investigator, it is permissible to reduce the 
insulin glargine dose by up to 10% If subject is transferring from insulin detemir, it 
is permissible to reduce the insulin glargine dose by 10% at the discretion of the 
investigator.

If the subject’s prestudy basal insulin is given twice daily, then the subject’s insulin 
glargine should be started once daily at bedtime at a dose that is 20% lower than the 
total daily prestudy basal dose.
During the Standardization Period, insulin glargine may be adjusted to achieve glycemic 
targets as close to normal as possible without untoward hypoglycemia in accordance with 
product labeling in the respective country and standards of care at the study center. The 
treat-to-target titration algorithm for insulin glargine (Section 5.1.3.2, Table 3) is 
intended for use only during the Treatment Period.
Insulin lispro

If the subject’s current regimen of bolus insulin is administered at each of the 3 main 
meals, transfer the subject’s therapy to insulin lispro on a unit-for-unit basis. Note: 
At the discretion of the investigator, it is permissible to reduce the insulin lispro 
dose by up to 10%.

If the subject’s current regimen of bolus insulin is administered more less than 
3 times per day or less more than 3 times per day daily, calculate the total daily 
bolus dose and divide it into 3 equal doses,. Transfer the subject to insulin lispro on a 
unit-for-unit basis based on the calculated dose to be administered with each of the 
3 main meals. Alternatively, at the discretion of the investigator, if felt to be 
clinically preferable, it is permissible to allocate different starting doses of 
insulin lispro to each of the 3 main meals, maintaining the same total daily bolus 
dose.
During the Standardization Period, insulin lispro may be adjusted to achieve glycemic 
targets as close to normal as possible without untoward hypoglycemia in accordance with 
product labeling in the respective country and standards of care at the study center. The 
treat-to-target titration algorithm for insulin glargine (Section 5.1.3.2, Table 3) is 
intended for use only during the Treatment Period.
Section 5.1.3, (title change) Dose Titration During the Treatment Period
Section 5.1.3.1, Albiglutide Titration
New text: Note: In this study, downtitration of albiglutide 50 mg weekly to 30 mg 
weekly is not permitted.


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Section 5.1.3.2, Insulin Titration
The intent of the American Diabetes Association and the European Association for the 
Study of Diabetes consensus statement for the treatment of T2DM is to maintain fasting 
and preprandial glucose values as close to a normal range as possible without untoward 
hypoglycemia or other adverse effects of treatment [Inzucchi, 2015; Inzucchi, 2012;
Nathan, 2008; Nathan, 2006]. Less stringent HbA1c goals are appropriate for other 
subjects, such as those with a history of severe hypoglycemia, limited life 
expectancy, advanced complications, or extensive comorbid conditions.
Insulin Glargine Titration
Both treatment groups will follow the same insulin glargine titration algorithm during the 
Treatment Period.
The main focus for the initial insulin titration should be on the basal insulin given 
before bedtime. Although optimization of insulin glargine should continue 
throughout the Treatment Period, it is expected that the basal insulin dose will have 
been stabilized for all subjects after about 6 weeks.
Prior to each study visit and telephone contact during the Treatment Period, a 
recommended dose of insulin glargine will be based on the mean of the subject’s last 
3 available before breakfast SMBG values (at least 2 of which are consecutive) and 
the titration algorithm for insulin glargine provided in Table 3. It is important that 
the investigator use his or her medical judgment in determining whether or not the 
algorithm recommended dose adjustment is appropriate for a particular subject at 
each time point. Of importance, decisions should be made taking into consideration 
all available information, such as symptoms of hypoglycemia or hyperglycemia, 
current total daily dose of insulin, and previous responses to dose adjustments, as 
well as additional glucose measurements (lowest of the last 3 SMBG values, other 
SMBG values in the week preceding the dose adjustment decision, or FPG [from a 
central laboratory]).
The titration of insulin glargine is based on the mean of the subject’s SMBG values 
measured before breakfast from the last 3 available days (at least 2 of which are 
consecutive) in the week before the next study visit/telephone contact, as shown in Table 
3. 
If measurements from 3 days (at least 2 of which are consecutive) are not available, the 
dose adjustment should be delayed until the next scheduled study visit/telephone contact; 
unless in the investigator’s judgment, a dose adjustment is warranted. The subject should 
be retrained on the importance of SMBG measurements in this treat to target study.


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Table 3, Titration Algorithm for Recommended Insulin Glargine Dose Adjustment
Before Breakfast Blood Glucose1
Adjustment of Insulin Glargine (IU)2
mg/dL
mmol/L
<563
<3.13
-4
For a dose >50 U, consider 10% dose 
reduction
56 – 693
3.1 – 3.83
-2
For a dose >50 U, consider 5% dose 
reduction
70 – 79
3.9 – 4.4
-1
80 – 10999 = Target
4.5 – 5.5 = Target
No adjustment
110 - 139100 – 119
5.6 – 6.6 7.7
+2
140 - 179120 – 139
7.8 – 9.9 6.7 – 7.7
+4
140 – 169180
10.07.8 – 9.4
+6
>170
>9.4
+8
If severe hypoglycemia (requiring assistance) or any other 
clinically significant hypoglycemia (e.g., nocturnal 
hypoglycemia) was documented since the last dose adjustment
Decrease insulin dose 10% to 15%,at the 
investigator’s discretion
1.
Mean of measurements from the last 3 available days (at least 2 of which are consecutive) in the week before 
the next study visit/telephone contact. If measurements from 3 days (at least 2 of which are consecutive) are 
not available, the dose adjustment should be delayed until the next scheduled study visit/telephone contact;
unless in the investigator’s judgment, a dose adjustment is warranted. The subject should be retrained on the 
importance of self-monitored blood glucose measurements.
2. 
Modified based on the insulin titration algorithms in the BEGIN basal-bolus type 2 study [Garber, 2012] and 
other published treat-to-target studies [Rosenstock, 2008; Abrahamson, 2012; Mathieu, 2014; Riddle, 2014].
3.
Investigator may defer adjustment if there is an obvious reason for the low value such as a missed meal.
The algorithm in Table 3 should be followed at all visits and telephone contacts during 
the Treatment Period. However, it is also important that the investigator base the decision 
to adjust the insulin dose on all available information, such as symptoms of 
hypoglycemia or hyperglycemia, previous responses to dose adjustments, as well as 
additional glucose measurements (FPG [from a central laboratory] or SMBG) other than 
the mandatory ones. Any insulin titration that differs deviation from the algorithm 
recommended dose must be commented on by the investigator and the reason 
documented on the appropriate page of the eCRF. If adequate documentation is not 
provided in the eCRF, a protocol deviation will be recorded; any deviation that does 
not have a valid reason, as detailed above, will be recorded as a protocol deviation. 
The main focus for the initial insulin titration should be on the basal insulin given before 
bedtime. After about 6 weeks, it is expected that the basal insulin dose will have been 
optimized for all subjects.
For those subject’s randomly assigned to the albiglutide plus insulin glargine group, the 
optimization of insulin glargine should continue throughout the Treatment Period. If the 
before breakfast glucose target has been achieved, but it is felt that the basal insulin needs 
further optimization, then alternatives (e.g., moving the basal injection to the morning or 
splitting the basal dose into twice daily injections) can be discussed with the medical 
monitor overseeing the titration and documented.


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Insulin Lispro Titration
Insulin titration should start with insulin glargine given before bedtime. After about 
6 weeks, it is expected that the basal insulin glargine dose will have been stabilized 
and the insulin lispro titration may begin.
Following randomization to study medication, insulin lispro will be titrated differently in 
each treatment group.
In the albiglutide plus insulin glargine group, the insulin lispro dose will be downtitrated 
at the Baseline/Randomization visit to half that used at the end of the Standardization 
Period. At Week 4, insulin lispro will be completely discontinued and should remain 
discontinued for the remainder of the Treatment Period; unless the subject meets the 
criteria for insulin lispro re-introduction (see Section 5.1.3.5).
In the insulin glargine plus insulin lispro treatment group, the dose adjustment of insulin 
lispro given in association with a meal is based on the blood glucose measurements 
taken prior to the subsequent meal. Therefore, blood glucose measurements taken 
Prior to Lunch are utilized to adjust the dose of insulin lispro taken with breakfast, 
the blood glucose measurements taken Prior to Dinner are utilized to adjust the 
dose of insulin lispro taken with lunch, and the blood glucose measurements taken 
Prior to Bedtime are utilized to adjust the dose of insulin lispro taken with dinner 
the post-breakfast (prior to lunch), post-lunch (prior to dinner), or post-dinner (i.e., 
bedtime) blood glucose value. Following Baseline/Randomization, tThe main focus 
for the initial insulin titration should be on the basal insulin before considering changes in 
the bolus insulin, unless the investigator finds it absolutely necessary to adjust the bolus 
insulin first.
It is recommended that dose adjustments of insulin lispro be made on the mean of values 
from the last 3 available days (at least 2 of which are consecutive) in the week before the 
next study visit/telephone contact (Table 4). Prior to each study visit and telephone 
contact during the Treatment Period, a recommended dose of insulin lispro for each 
specific meal will be based on the mean of the subject’s last 3 available preprandial 
SMBG values (at least 2 of which are consecutive) and the titration algorithm for 
insulin lispro provided in Table 4. It is important that the investigator use his or her 
medical judgment in determining whether or not the algorithm recommended dose 
adjustment is appropriate for a particular subject at each time point. Of 
importance, decisions should be made taking into consideration all available 
information, such as symptoms of hypoglycemia or hyperglycemia, current total 
daily dose and distribution of insulin lispro doses, and previous responses to dose 
adjustments, as well as additional glucose measurements (lowest of the last 3 SMBG 
values, other SMBG values in the week preceding the dose adjustment decision, or 
FPG [from a central laboratory]) other than the mandatory ones.
If measurements from 3 days (at least 2 of which are consecutive) are not available, the 
dose adjustment should be delayed until the next scheduled study visit/telephone contact, 
unless in the investigator’s judgment, a dose adjustment is warranted at that time. The 
subject should be retrained on the importance of SMBG measurements in this treat to 
target study.


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Table 4, Titration Algorithm for Recommended Insulin Lispro Dose Adjustment
Post-breakfast Prior to Lunch, Post-lunch Prior to Dinner, Prior to 
BedtimePost-dinner Blood Glucose1
Adjustment of Lispro Insulin (U)2
mg/dL
mmol/L
99<70 without obvious 
explanation
5.5<3.9 without obvious explanation
-1 to -23
For a dose >50 U, consider a 5% 
to 10%dose reduction at the 
discretion of the investigator
100 - 11970 – 99 = Target
5.6 – 6.63.9 – 5.5 = Target
No adjustment
120100 – 139
6.7 5.6 – 7.7
+2
140 – 179
7.8 – 9.9
+3
180
10.0
+4
If severe hypoglycemia (requiring assistance) or any other clinically 
significant hypoglycemia was documented since the last dose adjustment
Decrease insulin dose at the 
investigator’s discretion (i.e., 
10% to 15%)
1.
Mean of measurements from the last 3 available days (at least 2 of which are consecutive) in the week before the 
next study visit/telephone contact. If measurements from 3 days (at least 2 of which are consecutive) are not 
available, the dose adjustment should be delayed until the next scheduled study visit/telephone contact, unless in 
the investigator’s judgment, a dose adjustment is warranted at that time. The subject should be retrained on the 
importance of self-monitored blood glucose measurements (SMBG). Note: post-breakfast (prior to lunch), post-
lunch (prior to dinner), post-dinner (i.e., bedtime).
2.
Modified based on the insulin titration algorithms in the BEGIN basal-bolus type 2 study [Garber, 2012] and other 
published treat-to-target studies [Rosenstock, 2008; Abrahamson, 2012; Mathieu, 2014; Riddle, 2014].
3.
For subjects with an SMBG value less than 70 mg/dL without obvious explanation, At the investigator’s 
discretion, insulin lispro may be stopped at the investigator’s discretion.
The algorithm in Table 4 should be followed at all visits and telephone contacts during 
the Treatment Period. However, similar to the titration of insulin glargine, it is also 
important that the investigator base the decision to adjust the insulin dose on all available 
information, such as symptoms of hypoglycemia or hyperglycemia, previous responses to 
dose adjustments, as well as additional glucose measurements (FPG [from a central 
laboratory] or SMBG) other than the mandatory ones. Any deviation from the algorithm 
must be commented on by the investigator and the reason documented on the appropriate 
page of the eCRF; any deviation that does not have a valid reason, as detailed above, will 
be recorded as a protocol deviation. Any insulin titration that differs from the 
algorithm recommended dose must be commented on by the investigator and the 
reason must be documented on the appropriate page of the eCRF. If adequate 
documentation is not provided in the eCRF, a protocol deviation will be recorded.
Section 5.1.3.3, (new section) Intensive Subject Glycemic Surveillance and 
Management
In this treat-to-target study, which includes the discontinuation of prandial insulin 
in subjects randomly allocated to the albiglutide plus insulin glargine treatment arm 
as well as the intensification of basal-bolus insulin in subjects randomly allocated to 
the insulin glargine plus insulin lispro treatment arm, it is important that subjects 
receive adequate diabetic patient education and training and detailed clear 
explanations regarding all required study procedures related to glycemic 
management (see Section 6.2.4 and Section 6.2.5). It is also imperative that study 


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investigators closely monitor available subject information and apply prompt 
medical judgment as necessary to maintain appropriate glycemic control.
To facilitate subject surveillance by the study investigator, the investigator will have 
access to information collected in the subject’s e-diary, such as daily SMBG 
measurements (see Section 6.2.2), daily insulin use (see Section 6.2.5), and 
subject-reported hypoglycemia (see Section 6.3.1). In addition, study investigators 
will receive notification of extreme SMBG measurements (i.e., SMBG measurements 
50 mg/dL [2.8 mmol/L] and SMBG between 50 to 60 mg/dL [2.8 to 3.3 mmol/L]), 
as well as episodes of severe hypoglycemia recorded in the subject’s e-diary. 
Additional details on these tools are provided in the accompanying SPM.
Section 5.1.3.4, (title change) Documentation Surveillance of Insulin Titration
Surveillance of insulin titration and documentation will be performed centrally. Within 
approximately 3 business days 24 hours after a subject’s study visit/telephone contact, 
the investigator must ensure that the following data are available for review by 
GSK/PPD:

Comments on any deviation to the insulin titration algorithms must be entered into 
the eCRFs
The data regarding titration deviations will be reviewed by GSK/PPD. Based on this 
information, an inquiry as to why the investigator chose to deviate from the titration 
algorithm may be made, particularly when details of any SMBG readings, time, and date, 
or hypoglycemic symptoms used in such a decision are not provided or lack clarity
needed. Not all deviations will lead to inquiry. When the investigator receives an inquiry, 
a response with the reasons for not adhering to the titration guideline should be sent to 
GSK/PPD within approximately 3 days. Depending on the response, additional inquiries 
may be sent.


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Figure 2, Re-introduction Algorithm for Insulin Lispro
HbA1c = glycosylated hemoglobin. SMBG = self-monitored blood glucose.
Note: Figure modified with permissions (pending) from [Abrahamson 2012].
1.
Post-breakfast (pPrior to lLunch), post-lunch (pPrior to dDinner), or post-dinner (i.e., Prior to Bbedtime).
2.
Mean of measurements from the last 3 available days (at least 2 of which are consecutive) in week before the 
next study visit/telephone contact. If measurements from 3 days (at least 2 of which are consecutive) are not 
available, the dose adjustment should be delayed until the next scheduled study visit/telephone contact; unless in 
the investigator’s judgment, a dose adjustment is warranted. The subject should be retrained on the importance of 
SMBG measurements.
3.
For insulin lispro dose titration, see Section 5.1.3.2, Table 4.
Section 5.5, Treatment Compliance
Acceptable overall compliance for IP (albiglutide) and other study treatments (insulin 
glargine and insulin lispro) for in this study will be 80%. Site personnel should 
confirm that subjects are taking their doses of albiglutide and insulin glargine and lispro 
insulin, if appropriate, as prescribed by their physician. Adherence will be monitored for 
the duration of the study. 
Section 5.6.2, Prohibited Medications and NondrugTherapies

Any oral antidiabetic medications (e.g., GLP-1R agonist, dipeptidyl peptidase-
IV inhibitor, SU, thiazolidinedione, meglitinide, sodium-glucose transporter 2 


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inhibitor, or commercially available premixed basal and prandial insulin) other 
than the treatment they have been randomly assigned to, insulin glargine, insulin 
lispro, and their current regimen of background metformin, if applicable, being 
taken at Screening.
Section 5.7, (title change) Treatment Between Week 26 (End of Treatment)/Early 
Withdrawal and After the Follow-up Visit End of the Study
Section 5.7.1, (new section) Treatment Between Week 26 (End of Treatment)/Early 
Withdrawal and Follow-up
After completion of the end-of-treatment (Week 26) or Early Withdrawal visits, 
subjects will return to the study center in 4 weeks for the Follow-up visit. During 
this time, subjects will continue insulin glargine or insulin glargine plus insulin 
lispro to maintain adequate glycemic control.
For subjects in the albiglutide plus insulin glargine treatment arm, the last dose of 
once-weekly albiglutide will occur at Week 25. As needed, insulin lispro may also be 
re-introduced during this period according to the re-introduction of insulin lispro 
algorithm provided in Section 5.1.3.5. Insulin glargine alone (in subjects for whom 
insulin lispro has not been re-introduced) or insulin glargine and insulin lispro (in 
subjects for whom insulin lispro has been re-introduced) can be adjusted to achieve 
or maintain glycemic targets as close to normal as possible without untoward 
hypoglycemia in accordance with product labeling in the respective country and 
standards of care at the study center. 
For subjects in the insulin glargine plus insulin lispro treatment arm, both insulin 
glargine and insulin lispro may be adjusted to achieve or maintain glycemic targets 
as close to normal as possible without untoward hypoglycemia in accordance with 
product labeling in the respective country and standards of care at the study center. 
Note: During this time, subjects must not use any prohibited medications or 
nondrug therapies (see Section 5.6.2).
Table 5, Time and Events Table – Study Visits
Dispense home glucose monitoring device and e-diary (title change only)
Collect e-diary from subject: added to Follow-up Visit
Provide advice on diet, exercise, and home glucose monitoring, and hypoglycemia
advise: added to Early Withdrawal Visit
Review glucose monitoring with subject: added to Early Withdrawal Visit
Obtain daily insulin dose information: added to Early Withdrawal Visit
Check visual acuity and funduscopy: added to Early Withdrawal Visit
Obtain chemistry sample: added to Visit 3, Week -1


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Obtain simulated C-peptide sample 90 minutes after administration of a 
mixed-meal: added to Visit 1
Assess investigational product and other study treatment compliance
Footnote 5: Standard diabetic dietary, exercise, and home blood glucose monitoring 
advice to be provided at Visit 2 (Week -4) and reinforced at each study site visit through 
the End-of- Treatment visit. Subjects will monitor their glucose according to instructions. 
The investigator will review the glucose meter readings and adjust insulin glargine and 
insulin lispro doses in accordance with product labeling in the respective country and 
standard of care at the study center during the Standardization Period and per Table 3 and 
Table 4, respectively, during the Treatment Period. At each visit through the end-of-
treatment visit (Visit 9; Week 26), subjects should be trained on the signs and 
symptoms of hypoglycemia, including nocturnal hypoglycemia, as well as the 
common causes of hypoglycemia. Subjects should also be educated on appropriate 
methods to help prevent hypoglycemia. It is also particularly important to advise 
subjects to contact the study site before any potential dietary change, as this may 
necessitate a change in insulin doses to avoid the development of hypoglycemia. 
Subjects should also be educated on how to treat hypoglycemia. For additional 
information, see Section 6.3.1.
Footnote 10 added: For the Screening assessment, a documented examination within 
six months of the Screening visit would also be acceptable but only when there was 
NO clinical change (e.g., decrease in visual acuity/visual field) since the last prior 
funduscopy. The end of treatment/early withdrawal assessment eye exam should be 
carried out by the investigator.
Footnote 24 added: As described in Section 3.1, an optional fasting HbA1c value may 
be determined using a Metrika kit or other finger-stick procedure to provide an 
initial guide of subject eligibility for investigators.
Footnote 25 added: If the HbA1c value at Week -1 is not 7.0% and 9.0%, the 
assessment may be repeated on a weekly basis for a maximum of 2 additional weeks 
before randomization. The mean of all HbA1c assessments (Week -1 plus the 
additional HbA1c assessments) must be 7.0% and 9.0% for the subject to be 
eligible for randomization. Note: If a subject has confirmed (by a central 
laboratory) HbA1c <7.0% and >9.0% at Week -1 or the subject decides not to 
continue repeat testing, he or she will be considered a standardization failure.
Footnote 26 added: Subjects will have both fasting C-peptide and stimulated 
C-peptide testing. If the fasting C-peptide is <0.8 ng/mL (<0.26 nmol/L) but 
stimulated C-peptide 90 minutes after a standardized mixed meal is 1.5 ng/mL 
(0.5 nmol/L), the subject meets the C-peptide inclusion criterion.
Footnote 28 updated: Insulin glargine and insulin lispro will be dispensed during the 
Standardization Period at Visit 2 (Week -4) with additional dispensing at Visit 3 
(Week -1) optional as needed to ensure adequate supply up to Visit 4 (Week 0). Dispense 
albiglutide, insulin glargine, and insulin lispro, as appropriate, according to 


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randomization at Baseline/Randomization. See Section 5.7 for additional information 
regarding insulin usage after Week 26/Early Withdrawal.
Table 6, Time and Events Table – Telephone Calls
A Week 28 telephone call was added.
Section 6.2.2.1, Home Blood Glucose Monitoring
All subjects in the study should be instructed to measure and record blood glucose values 
from their glucose meter a minimum of 4 times per day at the following times (except 
prior to Baseline/Randomization, Week 10, and Week 26 where an 8-point SMBG profile 
will be performed; see Section 6.2.2.2):

Before breakfast (at least 8 hours without food intake)

Post-breakfast (pPrior to Llunch)

Post-lunch (pPrior to Ddinner)

Post-dinner (i.e., aAt bBedtime)
Section 6.3.1, Hypoglycemic Events
Specific criteria for monitoring hypoglycemic events have been designed to ensure 
subject safety and to closely monitor hypoglycemia.
At each visit through the end-of-treatment visit (Visit 9; Week 26), subjects should 
be trained on the signs and symptoms of hypoglycemia (e.g., hunger, confusion, 
dizziness, anxiety, increased heart rate, visual disturbances), including nocturnal 
hypoglycemia (i.e., nightmares; night sweats; tired, irritable, or confused upon 
awakening), as well as the common causes of hypoglycemia. Subjects should also be 
educated on appropriate methods to help prevent hypoglycemia (i.e., strictly 
observe nutritional guidance from the physician or study site staff, consume small 
snacks before intense exercise, promptly communicate with the study site on “ill 
days” for additional guidance). It is also particularly important to advise subjects to 
contact the study site before any potential dietary change, as this may necessitate a 
change in insulin doses to avoid the development of hypoglycemia. Subjects should 
also be educated on how to treat hypoglycemia (e.g., oral glucose treatment with 
simple carbohydrates).
Subjects will be asked to report hypoglycemic events that occur between study visits 
using a diary. Specific criteria for monitoring hypoglycemic events have been designed to 
ensure subject safety and to closely monitor hypoglycemia. In this study, 
hHypoglycemic events are defined according to recommendations by the American 
Diabetes Association and The Endocrine Society Workgroup on Hypoglycemia as 
follows [Seaquist, 2013]:. To aid correct classification and treatment of hypoglycemic 
events, subjects should be instructed to repeat SMBG measurements 70 mg/dL 
(3.9 mmol/L).


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Section 6.3.5, Clinical Laboratory Testing
Other blood tests at time points specified in the Time and Events Table (Table 5):

HbA1c
o
Note: As described in Section 3.1, an optional fasting HbA1c value may 
be determined using a Metrika kit or other finger-stick procedure to 
provide an initial guide of subject eligibility for investigators.

Fasting C-peptide and stimulated C-peptide 90 minutes after a standardized 
mixed meal 

TSH. If TSH is above the ULN, free T4 (reflex) will also be measured

Lipid panel: total cholesterol, low-density lipoprotein cholesterol, high-density 
lipoprotein cholesterol, triglycerides, and free fatty acids 

Hepatitis B surface antigen

Hepatitis C antibody. If hepatitis C antibody positive, an RNA polymerase chain 
reaction should be performed on the same sample to confirm the result
Section 6.7 (new section), Tracking of Albiglutide Pen Injector Failures and User 
Errors
All albiglutide pen injector failures and user errors must be detected, documented, 
and reported by the investigator throughout the study. Detailed information on pen 
injector failures and user errors will be collected on the Injector Pen Failure 
Reporting Form.
NOTE: Pen injector failures and user errors associated with or result in events 
fulfilling the definition of an AE or SAE will follow the processes outlined in 
Section 6.3.7.
Section 8.3.3.1, Primary Comparisons of Interest
…. Further details of the sensitivity analysis, including imputation methods and 
assumptions about the missing data, are described in Section 8.3.5.1will be provided in 
the RAP.
8.3.5.1.1
Impact of Missing Data on Primary Endpoint
Missing data are not explicitly imputed in the primary MMRM analysis; although, 
there is an underlying assumption that data are missing at random, including those 
withdrawn for lack of efficacy. All available scheduled postbaseline assessments up 
to endpoint are utilized and, via modelling of the within subject correlation 
structure, the derived treatment difference at Week 26 is adjusted to take into 
account missing data. The MMRM analysis (using saturated fixed effects and an 
unstructured variance-covariance matrix) is considered appropriate as the primary 


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method of analysis, as it has been shown to give sensible answers to on-treatment 
questions in a range of practical situations [Siddiqui, 2009].
8.3.5.1.2
Extent of Missing Primary Analysis Data
Missing data is expected to arise mainly from subjects missing complete visits. The 
amount of missing data for those baseline covariates included in the statistical 
analysis is expected to be none or at worst minimal. If it should occur, that subject 
will effectively be lost to analysis. Missing data for HbA1c between two nonmissing 
visits will be considered missing at random (intermediate missing data).
In this study, subjects who withdraw from treatment will be withdrawn from the 
study. In the eCRF, the reason for treatment discontinuation and the reason for 
withdrawal from the study are collected separately. Whenever the HbA1c value at 
Week 26 is missing (end of the study), the reason can be determined based on 
available data in these two locations. The reason for missing data can be classified as 
follows:  safety, procedural (including withdrawal of consent), or lack of efficacy.
8.3.5.1.3
Reasons for Withdrawal
Reasons for withdrawal are assumed to fall into three broad categories:

Procedural (e.g., lost to follow-up, withdrew consent, protocol deviation, 
study closed/terminated, and investigator discretion): In this case, it is 
expected that an assumption of Missing at Random (MAR) is appropriate 
for imputation of HbA1c data after withdrawal.  

Safety (e.g., AE, subject reached protocol-defined stopping criteria): It is 
expected that, in most cases, any change in safety related to these reasons 
for withdrawal would have been captured prior to the subject withdrawing 
from the study. In Study GLP108486 (albiglutide versus lispro over 
background glargine), 5% of subjects in the albiglutide group and <1% in 
the lispro group had AEs leading to withdrawal of active treatment through 
Week 26. In the albiglutide group, the most common AE leading to 
withdrawal was injection site reaction (1.1%). Missing HbA1c values after 
withdrawal due to safety concerns will be considered to possibly be missing 
not at random (MNAR).

Lack of efficacy: In this treat-to-target study, a substantial number of cases 
of withdrawal due to lack of efficacy is not expected. Missing HbA1c values 
after withdrawal due to lack of efficacy are considered to possibly be 
MNAR. 
Sensitivity analyses will be performed for data missing due to safety concerns or due 
to lack of efficacy.
8.3.5.1.4
Handling of Missing Data
The impact of missing data will be explored, as outlined below, for the Full Analysis 
Population only.


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Examination of Missing Data Patterns
To examine the nature of missing data, cohorts of subjects will be defined based on 
the scheduled assessments (HbA1c change from Baseline) that were completed at 
Weeks 4, 5, 10, 18, 26. 
1.
Subjects who have week 4 assessment only
2.
Subjects who have assessments up to and including Week 5 only
3.
Subjects who have assessments up to and including Week 10 only
4.
Subjects who have assessments up to and including Week 18 only
5.
Subjects who have assessments up to and including Week 26.
The number and percentage of subjects on each treatment in the 5 cohorts defined 
here will be tabulated. Graphical methods will be used to examine changes from 
Baseline over time to assess the pattern of outcomes prior to withdrawal.
Sensitivity Analyses – Multiple Imputation
Sensitivity analyses using multiple imputation methods will be conducted. Firstly, 
missing data between two nonmissing time points will be considered missing at 
random.  
The following multiple imputation methods are proposed based on whether data are 
missing at random or not at random:
1.
All missing data assumed MAR: Imputation is based on means and 
variances-covariances from subjects in the same treatment group as the 
withdrawn subject and is comparable to MMRM. The main differences are that 
this approach uses separate covariance parameter estimation for each arm, and 
also separate regression parameters are estimated on baseline covariates within 
each arm. This more complex parameterization of the imputation model 
compared with the analysis model is valid. This approach will be used for all 
data missing post withdrawal. Here the estimand is one where after withdrawal 
all subjects progress in a similar way to those who remain in the trial. We 
expect the MMRM and this to give similar answers. If so, then it indicates any 
difference between the primary MMRM analysis and multiple imputation 
sensitivity analysis is due to the assumed effect modification and the assumed 
rates of HbA1c increase after withdrawal, rather than anything to do with going 
from an MMRM approach to a multiple imputation approach.
2.
Missing due to lack of efficacy or due to safety concerns using Last Mean 
Carried Forward (LMCF), that is MNAR: This approach assumes that a 
constant rate of increase in HbA1c change from Baseline is experienced by 
subjects following withdrawal from the study for lack of efficacy or due to 
safety concerns. The MAR approach will be used for missing data due to 
procedural reasons. Sensitivity analyses using the LMCF approach will be 
performed using the following rates of HbA1c increase: 0%/month, 0.1%/month, 
and 0.2%/month to explore the potential impact as in a tipping-point analysis. 


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For each treatment group, these 3 rates will be assumed, resulting in 9 
scenarios. The resulting treatment differences and associated P-values for 
noninferiority will be tabulated against the varying rates of HbA1c increase. 
This estimand is one where those who withdraw for lack of efficacy or safety 
concerns are assumed to revert to an unstable treatment regimen with an 
increasing rate of HbA1c. 
For each imputation data set, an analysis of variance will be carried using Week 26 
data, both actual and imputed, using the same covariates as in the primary analysis. 
Contrasts of interest will be estimated and then combined across imputations using 
standard multiple imputation rules.
Additional scenarios for sensitivity analysis may be added and described in the 
RAP.
Section 9.2, Regulatory and Ethical Considerations, Including the Informed 
Consent Process
The study will be conducted in accordance with ICH GCP, all applicable subject privacy 
requirements, and the guiding ethical principles of the current version of that are 
outlined in the Declaration of Helsinki 2008 (based on the initial version accepted in 
1996), including, but not limited to:

IRB/IEC review and favorable opinion/approval of study protocol and any 
subsequent amendments.

Subject informed consent.

Investigator reporting requirements.
Section 10.0, References
Diamant M, Nauck MA, Shaginian R, Malone JK, Cleall S, Reaney M, et al. 
Glucagon-like peptide 1 receptor agonist or bolus insulin with optimized basal 
insulin in type 2 diabetes. Diabetes Care. 2014;37(10):2763-73.
Food and Drug Administration (FDA). Guidance for Industry. Non-Inferiority 
Clinical Trials. U.S. Department of Health and Human Services. Food and Drug 
Administration. Center for Drug Evaluation and Research (CDER). Center for 
Biologics Evaluation and Research (CBER). March 2010 Clinical/Medical. Available 
from: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/UCM202140.pdf (Accessed 12 Apr 2015).
Garber AJ. Treat-to-target trial: uses, interpretation and review of concepts. 
Diabetes Obes Metab. 2014;16(3):193-205.
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart FH, Kowal D, editors. 
Contraceptive technology. 19th edition. New York: Ardent Media, 2007:28.


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Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycaemia in type 
2 diabetes, 2015: a patient-centred approach. Update to a position statement of the 
American Diabetes Association and the European Association for the Study of 
Diabetes. Diabetologia. 2015;58(3):429-42.
Jones AG, Hattersley AT. The clinical utility of C-peptide measurement in the care 
of patients with diabetes. Diabet Med. 2013;30(7):803-17.
Koivisto V, Cleall S, Pontiroli AE, Giugliano D. Comparison of insulin lispro 
protamine suspension versus insulin glargine once daily in basal-bolus therapies 
with insulin lispro in type 2 diabetes patients: a prospective randomized open-label 
trial. Diabetes Obes Metab. 2011;13(12):1149-57.
Maldonado MR, Otiniano ME, Cheema F, Rodriguez L, Balasubramanyam A. 
Factors associated with insulin discontinuation in subjects with ketosis prone 
diabetes but preserved beta cell function. Diabet Med. 2005;22(12):1744-50.
Siddiqui O, Hung HM, O’Neill R. MMRM vs. LOCF: a comprehensive comparison 
based on simulation study and 25 NDA datasets. J Biopharm Stat. 
2009;19(2):227-46.


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Protocol Amendment Number 02
Protocol Amendment Number 02 is applicable only to clinical study centers in Germany 
who are participating in this study. The rationale for these changes is based on the 
explicit request of a German ethics committee. Protocol changes specified in Amendment 
Number 02 are summarized as follows: 

Inclusion criterion 7 was updated to indicate that progestogen-only pills are 
acceptable only if they have a Pearl Index of less than 1.0

Exclusion criterion 21 was added to exclude persons who have been put in an 
institution because of official or legal order

Exclusion criterion 22 was added to exclude employees (or the employee’s 
relatives) of the sponsor, the contract research organization, or the investigative 
site
Specific Changes in the Text
Section 4.2, Inclusion Criteria
7.
Female subjects of childbearing potential (i.e., not surgically sterile and/or not 
postmenopausal) must be practicing adequate contraception (as defined below) for 
the duration of participation in the study including the 4-week Posttreatment 
Follow-up Period

Abstinence from penile-vaginal intercourse, when this is the female’s preferred 
and usual lifestyle 

Oral contraceptive, either combined or progestogen alone
Note: For subjects participating at sites in Germany, progestogen-only pills 
are only acceptable if they have a Pearl Index of less than 1.0 (e.g., those 
containing 75 g desogestrel)

Injectable progestogen

Implants of etonogestrel or levonorgestrel

Estrogenic vaginal ring

Percutaneous contraceptive patches

Intrauterine device or intrauterine system that has a failure rate of less than 1% 
per year when used consistently and correctly as stated in the product label

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 the site personnel’s review of the female subject’s 
medical records, medical examination of the subject and/or semen analysis, or 
interview with the female subject on her male partner’s medical history.


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
Male condom combined with a female diaphragm, either with or without a 
vaginal spermicide (foam, gel, film, cream, or suppository) [Hatcher, 2007]
Section 4.3, Exclusion Criteria
21. (New) Persons who have been put in an institution because of official or legal 
order.
22. (New) Employees (or the employee’s relatives) of the sponsor, the contract 
research organization, or the investigative site, including the investigator or 
other site staff.


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Protocol Amendment Number 03
Protocol Amendment Number 03 is applicable to all clinical study centers participating in 
this study; where applicable, country-specific requirements have also been incorporated 
into this amendment. The Germany-specific changes outlined in Amendment 2 are 
included, specified for German sites only, and summarized in Section 11.5.1. French-
specific study requirements are summarized in Section 11.5.2. In addition, changes that 
apply to all study centers are shown in Table 3 edits. Table 3 was edited for to correct 
select serum glucose concentrations for the insulin titration algorithm. Previously, 
changes had been made to select glucose concentrations in conventional units
(i.e., mg/dL) but the corresponding changes to select glucose concentrations in SI units
(mmol/L) were inadvertently missed. Therefore, the corrected values have been added for 
the corresponding mmol/L concentrations. 
Protocol changes specified in Amendment Number 03 are summarized as follows:
!
Exclusion Criteria 21 and 22 were noted as being specific to subjects participating 
at German study sites.
!
Table 3 select blood glucose target concentrations (mmol/L) were corrected to the 
appropriate values
!
Section 11.5: Country-specific study requirements were added for Germany and 
France.
!
Incorporated other administrative changes to correct typographical errors and 
defined new abbreviations implemented with this amendment
Specific Changes in the Text:
Title Page
Authors:
 
SPONSOR SIGNATORY
Molly C Carr, Monica Shaw, MD 
Leader, Global Medical Affairs VP Global Specialty 
Franchise Medical Head
GlaxoSmithKline
Date
33'


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List of Abbreviations
ANSM
Agence nationale de sécurité du médicament et des 
produits de santé
CNIL
Commission nationale de l'informatique et des Libertés
CRA
clinical research assistant
CTR
clinical trial registry
IT
Information technology
Section 4.2
Inclusion Criteria #7

Note: For subjects participating at sites in Germany,: progestogen-only pills 
are only acceptable if they have a Pearl Index of less than 1.0 (e.g., those 
containing 75 g desogestrel)

Male partner sterilization prior to the female subject’s entry 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 the site personnel’s review of the 
female subject’s medical records, medical examination of the subject and/or 
semen analysis, or interview with the female subject on her male partner’s 
medical history.

Male condom combined with a female diaphragm combined with a female 
diaphragm, either with or without a vaginal spermicide (foam, gel, film, cream, or 
suppository)
Section 4.3
Exclusion Criteria
The following additional exclusion criteria apply for subjects participating at sites in 
Germany:
21. Persons who have been put in an institution because of official or legal order
22. Employees (or the employee’s relatives) of the sponsor, the contract research 
organization, or the investigative site, including the investigator or other site staff
Section 4.4
Additional Inclusion Criteria for Randomization
If a subject has confirmed (by a central laboratory) HbA1c <7.0% and or >9.0% at Week -
1 or the subject decides not to continue repeat testing, he or she will be considered a 
standardization failure (see Section 4.6)


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Section 5.1.1 Dosing Guidance During the Standardization Period
Insulin lispro

If the subject’s current regimen of bolus insulin is administered at each of the 3 main 
meals, transfer the subject’s therapy to insulin lispro on a unit-for-unit basis. Note: 
At the discretion of the investigator, it is permissible to reduce the total daily insulin 
lispro dose by up to 10%.

If the subject’s current regimen of bolus insulin is administered less than 3 times per 
day or more than 3 times per day, calculate the total daily bolus dose and divide it 
into 3 equal doses, administered with each of the 3 main meals. Alternatively, at the 
discretion of the investigator, if felt to be clinically preferable, it is permissible to 
allocate different starting doses of insulin lispro to each of the 3 main meals, 
maintaining the same total daily bolus dose. Note: As above, at the discretion of 
the investigator, it is permissible to reduce the total daily insulin lispro dose by 
up to 10%.
Section 5.1.3.2
Insulin Titration
Table 3
Titration Algorithm for Recommended Insulin Glargine Dose 
Adjustment
Before Breakfast Blood Glucose1
Adjustment of Insulin Glargine (IU)2
mg/dL
mmol/L
<563
<3.13
-4
For a dose >50 U, consider 10% dose 
reduction
56 – 693
3.1 – 3.83
-2
For a dose >50 U, consider 5% dose 
reduction
70 – 79
3.9 – 4.4
-1
80 – 109 = Target
4.5 – 5.5 6.0 = Target
No adjustment
110 – 139
5.6 6.1 – 7.7
+2
140 – 179
7.8 – 9.9
+4
180
10.0
+6
If severe hypoglycemia (requiring assistance) or any other clinically 
significant hypoglycemia (e.g., nocturnal hypoglycemia) was 
documented since the last dose adjustment
Decrease insulin dose 10% to 15%, at the 
investigator’s discretion
Section 5.1.3.5
Re-introduction of Insulin Lispro in the Albiglutide Treatment 
Group
Additionally, subjects not achieving a predefined threshold for glycemic control 
(confirmed persistent FPG270 mg/dL [15.0 mmol/L]) at any time within at least 
8 weeks after randomization may be considered for study withdrawal based on the 
discretion of the investigator and the medical monitor (see Withdrawal Criteria in 
Section 4.5).


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Section 5.6.2 Prohibited Medications and Nondrug Therapies
Any oral antidiabetic medications (e.g., GLP-1R agonist, dipeptidyl peptidase-IV 
inhibitor, SU, thiazolidinedione, meglitinide, sodium-glucose transporter 2 inhibitor, or 
commercially available premixed basal and prandial insulin) other than the treatment they 
have been randomly assigned to, insulin glargine, insulin lispro, and their current regimen 
of background metformin, if applicable, being taken at Screening.
Section 11.5
Appendix 5: Country-Specific Requirements
No country-specific requirements exist.
Section 11.5.1
German-Specific Eligibility Requirements
Specific eligibility criteria were added for subjects participating at sites in Germany. 
Section 4.2 includes German-specific text for inclusion #7 (bullet 2) stipulating that 
progestogen-only pills are only acceptable if they have a Pearl Index of less than 1.0 
(e.g., those containing 75 g desogestrel) 
Section 4.3 includes German-specific text for exclusion #21 and #22 stipulating 
subjects are not eligible for study participation if they have been put in an 
institution because of official or legal order, or if they are employees (or the 
employee’s relatives) of the sponsor, the contract research organization, or the 
investigative site, including the investigator or other site staff. 
Section 11.5.2
French Administrative Considerations and Specific 
Requirements
This appendix includes all the requirements of the French law (n2004-806 of 9th 
August 2004), and identifies, item per item, the mandatory modifications or 
additional information to the study protocol and includes specifics GSK 
requirements.
1. Concerning the “STUDY POPULATION”

In line with the local regulatory requirements, the following text in section 
“OTHER STUDY ELIGIBILITY CRITERIA CONSIDERATIONS”
(Section 4.4) is added :
A subject will be eligible for inclusion in this study if he /she is either 
affiliated to or beneficiary of a social security category.
It is the investigator’s responsibility to ensure and to document (in source 
document - patient notes) that the patient is either affiliated to or beneficiary 
of a social security category.


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
2. Concerning the “DATA ANALYSIS AND STATISTICAL 
CONSIDERATIONS” and specially in the “SAMPLE SIZE ASSUMPTION”
(Section 8.2.1)
The expected number of patients to be recruited in France is declared to the 
French regulatory authority.

3. Concerning the “STUDY CONDUCT CONSIDERATIONS”

In section “Regulatory and Ethical Considerations, Including the Informed 
Consent Process” (Section 9.2)
Concerning the process for informing the patient or his/her legally 
authorized representative, the following text is added : 
French Patient Informed Consent form is a document which summarizes the 
main features of the study and allows collection of the patient's written 
consent in duplicate. It also contains a reference to the authorisation of 
Agence nationale de sécurité du médicament et des produits de santé 
(ANSM), the French National Agency for Medicines and Health Products 
Safety) and the approval from the French Ethic committee.


In section concerning the “NOTIFICATION TO THE HOSPITAL 
DIRECTOR” (Section 9.2) the following text is added:
In accordance with Article L1123-13 of the Public Health Code, the Hospital 
Director is informed of the commitment to the trial in his establishment. The 
Hospital Director is supplied with the protocol and any information needed 
for the financial disposition, the name of the investigator(s), the number of 
sites involved in his establishment and the estimated time schedule of the trial 
(R.1123-63).


In section concerning the “INFORMATION TO THE HOSPITAL 
PHARMACIST” (Section 9.2) the following text is added:
In accordance with Article R.1123-64 of the Public Health Code, the Hospital 
Pharmacist is informed of the commitment to the trial in his establishment. 
The Pharmacist is supplied with a copy of the protocol (which allows him to 
dispense the drug(s) of the trial according to the trial methodology), all 
information concerning the product(s) of the trial (e.g. included in the IB), 


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the name of the investigator(s), the number of sites involved in his 
establishment and the estimated time schedule of the trial.


In section “DATA MANAGEMENT” (Section 7) the following text is 
added:
Within the framework of this clinical trial, data regarding the identity of the 
investigators and/or co-investigators and/or the pharmacist if applicable, 
involved in this clinical trial, and data regarding the patients recruited in this 
clinical trial (patient number, treatment number, patient status with respect 
to the clinical trial, dates of visit, medical data) will be collected and 
computerized in GSK data bases by GlaxoSmithKline Laboratory or on its 
behalf, for reasons of follow up, clinical trial management and using the 
results of said clinical trial. According to the Act n° 78-17 of 6th January 
1978 further modified, each of these people aforesaid has a right of access, 
correction and opposition on their own data through GlaxoSmithKline 
Laboratory (Clinical Operations Department).

4. Monitoring Visits (Section 9.3)
The Health Institution and the Investigator agree to receive on a regular 
basis a Clinical Research Assistant (CRA) of GLAXOSMITHKLINE or of a 
service provider designated by GLAXOSMITHKLINE. The Health 
Institution and the Investigator agree to be available for any phone call and 
to systematically answer to all correspondence regarding the Study from 
GLAXOSMITHKLINE or from a service provider designated by 
GLAXOSMITHKLINE. In addition, the Health Institution and the 
Investigator agree that the CRA or the service provider designated by 
GLAXOSMITHKLINE have direct access to all the data concerning the 
Study (test results, medical record, etc.). This consultation of the information 
by GLAXOSMITHKLINE is required to validate the data registered in the 
electronic Case Report Form (eCRF), in particular by comparing them 
directly to the source data. In accordance with the legal and regulatory 
requirements, the strictest confidentiality will be respected.

5. Data entry into the eCRF (Section 7)
The Health Institution and the Investigator agree to meet deadlines, terms 
and conditions of the Study’s eCRF use here below:
The Health Institution and the Investigator undertake:


2013N187697_04
CONFIDENTIAL
200977
148
1) That the Investigator and the staff of the investigator center make 
themselves available to attend the training concerning the computer 
system dedicated to the eCRF of the Study provided by 
GLAXOSMITHKLINE or by a company designated by 
GLAXOSMITHKLINE.
2) That the Investigator and the staff of the investigator center use the 
information technology (IT) Equipment loaned and/or the access 
codes only for the purpose of which they are intended and for which 
they have been entrusted to them, namely for the Study achievement, 
to the exclusion of any other use.
3) That the Investigator and the staff of the investigator center use the 
IT Equipment loaned according to the specifications and 
manufacturer’s recommendations which will have been provided by 
GLAXOSMITHKLINE.
4) To keep the IT Equipment and/or access codes in a safe and secure 
place and to only authorize the use of this IT Equipment by 
investigator center staff designated by the principal investigator to 
enter the data of the Study.
5) That the Investigator and the staff of the investigator center enter the 
data of the eCRF related to a patient visit in the 3 days following the 
date of the patient visit or, for the patient test results, in the 3 days 
following the reception of the results of such tests.
6) That the Investigator resolves and returns to GLAXOSMITHKLINE 
the data queries issued by GLAXOSMITHKLINE or a service 
provider designated by GLAXOSMITHKLINE within 7 days after 
the reception of the request of clarification or in a period of one (1) 
day during the final stage of clarification of the data base or in such 
other period as provided by GLAXOSMITHKLINE and/or a 
company designated by GLAXOSMITHKLINE.
7) To be responsible for the installation and payment of the required 
Internet connections needed for the use of the IT Equipment, 
Computer systems and/or access codes.
8) To return at the end of the Study the IT Equipment and/or access 
codes to GLAXOSMITHKLINE or to any company designated by 
GLAXOSMITHKLINE and any training material and 
documentation. The IT Equipment cannot under any circumstances 
be kept by the Health Institution or the Investigator for any reason 
whatsoever.



2013N187697_04
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200977
149
6. CTR Publication (Section 9.7) 
It is expressly specified that GLAXOSMITHKLINE and/or the Sponsor can 
make available to the public the results of the Study by the posting of the said 
results on a website of the GLAXOSMITHKLINE GROUP named Clinical 
Trial Registry (CTR) including the registration of all the clinical trials 
conduct by the GLAXOSMITHKLINE Group and this before or after the 
publication of such results by any other process.
7. Data Protection French Law of 6 January 1987 (CNIL) (Section 9.7)
In accordance with the Data Protection French Law of 6 January 1978 as 
modified, computer files used by GLAXOSMITHKLINE to monitor and 
follow the implementation and the progress of the Study are declared with 
the Commission nationale de l'informatique et des Libertés (CNIL) by 
GLAXOSMITHKLINE. The Investigator has regarding the processing data 
related to him a right of access, of rectification and of opposition with 
GLAXOSMITHKLINE in accordance with the legal provisions. This 
information can be transferred or be accessed to other entities of 
GLAXOSMITHKLINE Group in France, Britain or United States, what the 
Investigator agrees by the signature of the present Protocol.


SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
GSK 200977
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for Study 200977: Albiglutide + 
Insulin Glargine Versus Insulin Lispro + Insulin Glargine in 
the Treatment of Subjects With Type 2 Diabetes Mellitus: 
The Switch Study
Compound Number
:
GSK716155
Effective Date 
:
07-SEP-2017
Version Number           :  Final 1.0
Description:

This reporting and analysis plan describes the statistical analyses that will be 
conducted for protocol 200977.

This RAP is intended to describe the planned efficacy (primary, secondary and 
exploratory) and safety analyses required for the study. 

This document will be provided to the study team members to convey the content 
of the final Statistical Analysis Complete (SAC) Deliverable.
Author’s Name and Functional Area: 
07-SEP-2017
Senior Biostatistician, 
Biostatistics, PPD
Manager, 
Biostatistics, PPD
Approved by: 
07-SEP-2017
Statistics Leader, Clinical Statistics, R&D Projects Clinical 
Platforms & Sciences, GlaxoSmithKline
Copyright 2017 te GlaxoSmithKline group of companies. All rights reserved.  
Unauthorized copying or use of this information is prohibited.
PPD
PPD
PPD


CONFIDENTIAL
GSK 200977
2
TABLE OF CONTENTS
PAGE
1.
REPORTING AND ANALYSIS PLAN SYNOPSIS....................................................6
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................8
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................8
2.2.
Study Objectives and Endpoints ...................................................................8
2.3.
Study Design ..............................................................................................12
2.3.1.
Overview of Study Design and Key Features...............................12
2.3.2.
Study Design ...............................................................................13
2.4.
Statistical Hypotheses.................................................................................14
3.
PLANNED ANALYSES ..........................................................................................14
3.1.
Interim Analyses .........................................................................................14
3.2.
Final Analyses ............................................................................................14
4.
ANALYSIS POPULATIONS ...................................................................................15
4.1.
Deviations from Assigned Treatment ..........................................................15
4.2.
Protocol Deviations.....................................................................................15
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................17
5.1.
Multiple Comparisons and Multiplicity .........................................................17
5.2.
Withdrawal..................................................................................................18
5.3.
Geographic Region.....................................................................................18
5.4.
Baseline and Study Day..............................................................................18
5.5.
Analysis Visit Window and Therapy Periods ...............................................18
5.6.
Multiple Evaluations....................................................................................19
6.
STUDY POPULATION ANALYSES .......................................................................20
6.1.
Overview of Planned Analyses ...................................................................20
6.2.
Disposition of Subjects................................................................................21
6.3.
Protocol Deviations.....................................................................................21
6.4.
Demographic and Baseline Characteristics.................................................21
6.5.
Exposure to Study Drug..............................................................................21
6.6.
Treatment Compliance................................................................................22
6.7.
Dose Titration and Insulin Lispro Re-introduction........................................22
6.8.
Medications ................................................................................................23
6.9.
Medical History ...........................................................................................23
7.
PRIMARY STATISTICAL ANALYSES....................................................................25
7.1.
Efficacy Analyses........................................................................................25
7.1.1.
Overview of Planned Efficacy Analyses .......................................25
7.1.1.1.
Primary Analysis on Primary Efficacy Endpoint ..........25
7.1.1.2.
Supportive Analyses on Primary Efficacy 
Endpoint.....................................................................26
7.1.1.3.
Analyses on Primary Efficacy Endpoint by 
Subgroups..................................................................26
7.1.1.4.
Sensitivity Analysis.....................................................26
7.1.2.
Planned Efficacy Statistical Analyses...........................................27


CONFIDENTIAL
GSK 200977
3
8.
SECONDARY AND EXPLORATORY STATISTICAL ANALYSES..........................28
8.1.
Secondary Efficacy Analyses......................................................................28
8.1.1.
Overview of Planned Secondary Efficacy Analyses .....................28
8.1.2.
Key Secondary Efficacy Endpoints ..............................................29
8.1.2.1.
Proportion of Subjects Who Do Not Meet 
Prespecified Criteria for Severe, Persistent 
Hyperglycemia through Week 26................................29
8.1.2.2.
Percentages of Subjects with Severe or 
Documented Symptomatic Hypoglycemia 
through Week 26........................................................30
8.1.2.3.
Change from Baseline in Body Weight at Week 
26 and over Time .......................................................30
8.1.2.4.
Prescribed Total Daily Insulin Doses and Total 
Number of Weekly Insulin Injections...........................31
8.1.3.
Supportive Secondary Efficacy Endpoints....................................32
8.1.3.1.
HbA1c Change from Baseline over Time .....................32
8.1.3.2.
FPG Change from Baseline at Week 26 and 
over Time ...................................................................32
8.1.3.3.
Proportion of Subjects Achieving HbA1c <7% at 
Week 26 and over Time .............................................32
8.1.3.4.
Proportion of Subjects Achieving HbA1c <6.5% 
at Week 26 and over Time..........................................32
8.1.3.5.
Incidence and Time to Meeting Prespecified 
Criteria for Severe, Persistent Hyperglycemia 
through Week 26........................................................33
8.1.3.6.
Composite Endpoints .................................................33
8.2.
Exploratory Efficacy Analyses.....................................................................33
8.2.1.
Overview of Planned Exploratory Efficacy Analyses ....................33
8.2.2.
TRIM-Diabetes Questionnaire......................................................35
8.2.3.
HFS-II Worry Subscale ................................................................35
8.2.4.
HbA1c Change from Baseline at Week 26 by Baseline FPG 
Tertiles.........................................................................................36
8.2.5.
FPG Change from Baseline at Week 26 by Baseline FPG 
Tertiles.........................................................................................36
8.2.6.
8-Point SMBG Profile and Mean Daily Blood Glucose .................36
8.2.7.
Number and Percentage of Subjects with 1 kg Weight 
Gain at Week 26..........................................................................37
8.2.8.
Percentage of Subjects Achieving HbA1c <7.0% without 
Weight Gain and without Hypoglycemia with Blood 
Glucose <3.1 mmol/L (<56 mg/dL) regardless of 
Symptoms at Week 26.................................................................37
8.2.9.
Proportion of Subjects Treated with Once-Weekly 
Albiglutide That Are Able to Totally Decrease Prandial 
Insulin without Worsening HbA1c Control at Week 26...................37
8.3.
Safety Analyses..........................................................................................38
8.3.1.
Overview of Planned Analyses ....................................................38
8.3.2.
Adverse Events............................................................................39
8.3.2.1.
General Adverse Events Summaries..........................39
8.3.2.2.
Treatment Emergent Adverse Events.........................39
8.3.2.3.
Treatment-Related Adverse Events............................40
8.3.2.4.
Adverse Events by Maximum Intensity .......................40
8.3.2.5.
Most Common Adverse Events ..................................40


CONFIDENTIAL
GSK 200977
4
8.3.3.
Deaths and Serious Adverse Events............................................40
8.3.4.
Adverse Events Leading to Discontinuation of 
Investigational Product and/or Withdrawal from the Study ...........41
8.3.5.
Adverse Events of Special Interest ..............................................41
8.3.5.1.
Hypoglycemic Events .................................................41
8.3.5.2.
Cardiovascular Events................................................42
8.3.5.3.
Pancreatitis and Pancreatic Cancer............................42
8.3.5.4.
Thyroid Adverse Events .............................................42
8.3.5.5.
Gastrointestinal (GI) Events........................................43
8.3.5.6.
Systemic Allergic Reactions .......................................43
8.3.5.7.
Injection Site Reactions..............................................43
8.3.5.8.
Liver Events................................................................44
8.3.5.9.
Atrial Fibrillation/Flutter...............................................44
8.3.5.10.
Pneumonia .................................................................44
8.3.5.11.
Diabetic Retinopathy ..................................................44
8.3.5.12.
Appendicitis................................................................44
8.3.5.13.
Malignant Neoplasm...................................................45
8.3.6.
Pregnancies.................................................................................45
8.3.7.
Clinical Laboratory Evaluations....................................................45
8.3.7.1.
Chemistry, Hematology and Urinalysis .......................45
8.3.7.2.
Albumin/Creatinine Ratio............................................46
8.3.8.
Other Safety Measures................................................................46
8.3.8.1.
Vital Signs ..................................................................46
8.3.8.2.
Electrocardiograms.....................................................46
8.3.8.3.
Physical Exams..........................................................47
8.4.
Biomarker data analyses ............................................................................47
8.5.
Pharmacogenetic data analyses .................................................................47
8.6.
Immunogenicity...........................................................................................47
8.7.
Clinical Pharmacology Data Analysis..........................................................47
9.
OTHER STATISTICAL ANALYSES .......................................................................48
10. REFERENCES.......................................................................................................49
11. APPENDICES........................................................................................................50
11.1.
Appendix 1: Significant Protocol Deviation Plan and Definitions for 
Per-Protocol Population..............................................................................51
11.1.1.
Definitions for Per-Protocol Population ........................................51
11.1.2.
Significant Protocol Deviation Plan and Definitions for Per-
Protocol Population......................................................................51
11.2.
Appendix 2: Time & Events.........................................................................52
11.2.1.
Scheduled Clinic Visits.................................................................52
11.2.2.
Scheduled Telephone Visits ........................................................56
11.3.
Appendix 3: Assessment Windows .............................................................57
11.3.1.
Definitions of Study Day...............................................................57
11.3.2.
Visit Slotting Algorithm.................................................................57
11.3.3.
Early Withdrawal Assessment......................................................57
11.3.4.
Analysis Visit Windows ................................................................58
11.4.
Appendix 4: Treatment Periods...................................................................60
11.5.
Appendix 5: Derived and Transformed Data ...............................................61
11.5.1.
Change from Baseline .................................................................61
11.5.2.
Body Mass Index Calculation.......................................................61


CONFIDENTIAL
GSK 200977
5
11.5.3.
Total Person Time on Treatment .................................................61
11.5.4.
AE (Event) Density and Incidence Rate.......................................61
11.6.
Appendix 6: Premature Withdrawals & Handling of Missing Data ...............62
11.6.1.
Premature Withdrawal .................................................................62
11.6.2.
Missing Date Imputation ..............................................................62
11.6.3.
Sensitivity Analysis on the Primary Efficacy Endpoint ..................63
11.6.3.1.
Extent of Missing Primary Analysis Data 
Endpoint.....................................................................63
11.6.3.2.
Reasons for Withdrawal .............................................63
11.6.3.3.
Handling of Missing Data............................................64
11.6.3.4.
Sensitivity Analysis for Potential Data Integrity 
Issues.........................................................................67
11.7.
Appendix 7: Values of Potential Clinical Importance ...................................68
11.7.1.
Laboratory ...................................................................................68
11.7.2.
Vital Signs....................................................................................70
11.7.3.
ECG.............................................................................................71
11.8.
Appendix 8: Multicenter Studies and Definition of Geographic 
Region for Statistical Analyses....................................................................72
11.9.
Appendix 9: Examination of Covariates, Subgroups & Other Strata............73
11.9.1.
Strata and Covariates ..................................................................73
11.9.2.
Examination of Subgroups...........................................................73
11.10. Appendix 10: Multiple Comparisons & Multiplicity .......................................74
11.11. Appendix 11: Model Checking and Diagnostics for Statistical 
Analyses.....................................................................................................76
11.11.1. Model Checking and Diagnostics for Statistical Analyses ............76
11.12. Appendix 12: Sample Size Considerations .................................................80
11.13. Appendix 13: Abbreviations & Trade Marks ................................................81
11.13.1. Abbreviations & Trade Marks.......................................................81
11.14. Appendix 14: List of Data Displays..............................................................83
11.14.1. Data Display Numbering..............................................................83
11.14.2. Mock Example Numbering...........................................................83
11.14.3. Study Population Tables..............................................................84
11.14.4. Efficacy Tables ............................................................................86
11.14.5. Efficacy Figures ...........................................................................93
11.14.6. Safety Tables...............................................................................96
11.14.7. Safety Figures ...........................................................................103
11.14.8. ICH Listings ...............................................................................105
11.14.9. Non-ICH Listings........................................................................107
11.14.10.Mock Shells for Data Displays ...................................................110


CONFIDENTIAL
GSK 200977
6
1.
REPORTING AND ANALYSIS PLAN SYNOPSIS
Overview
Key Elements of the Reporting and Analysis Plan (RAP)
Purpose

This study will evaluate the efficacy and safety of once-weekly albiglutide 
administered in combination with basal insulin as a replacement for bolus 
insulin in subjects with type 2 diabetes mellitus (T2DM) who are currently 
managed with a basal-bolus insulin regimen but who are not achieving glycemic 
treatment goals. It is expected that subjects switched to albiglutide plus basal 
insulin (with discontinuation of bolus insulin therapy) compared with those
intensifying basal-bolus insulin therapy will be able to maintain glycemic control 
with less hypoglycemia and less weight gain, while also demonstrating a 
reduced total daily insulin requirement and reduced number of weekly injections 
(e.g., 28 injections per week [7 basal insulin and up to 21 bolus insulin 
injections] in basal-bolus-treated subjects compared with potentially 8 injections 
per week [1 weekly albiglutide injection and 7 basal injections] in subjects 
switching to basal insulin plus albiglutide). 
Data from this study will support the concept that albiglutide is a potential 
alternative to bolus insulin that will simplify insulin therapy in subjects with 
T2DM that do not reach adequate control with basal-bolus therapy.
Protocol

This RAP is based on the protocol amendment 3 (Dated: 24-SEP-2015) of 
study GSK200977 (GSK Document No. : 2013N187697_02) and eCRF Version 
6.01.
Primary 
Objective

To evaluate the glycemic effectiveness of once-weekly albiglutide as 
replacement of prandial insulin in subjects with T2DM receiving basal-bolus 
insulin therapy.
Primary 
Endpoint

Change from Baseline in HbA1c at Week 26.
Study 
Design

This Phase IIIb, randomized, open-label, parallel-group, active-control, 
multicenter, treat-to-target study of 26 weeks’ treatment duration will evaluate 
the efficacy and safety of once-weekly albiglutide as replacement of prandial 
insulin in subjects with T2DM.

The study will comprise 4 study periods: Screening (2 weeks), Standardization
(4 weeks), Treatment (26 weeks), and Post-treatment Follow-up (4 weeks). The 
total duration of a subject’s participation will be approximately 36 weeks. 
Subjects will have 10 study center visits and approximately 18 telephone calls 
to monitor insulin titration.

After the Standardization Period, subjects meeting additional criteria for
randomization will be stratified by screening HbA1c value (<8.0% versus 
≥8.0%), age (<65 years versus 65 years), and current background metformin 
(metformin use versus no metformin use). Approximately 794 subjects will be 
randomly assigned to albiglutide + insulin glargine (with or without metformin) or 
intensification of insulin glargine + insulin lispro (with or without metformin) in a 
1:1 ratio. 
Planned 

Final Analysis: After all subjects have completed the planned 26 weeks of 


CONFIDENTIAL
GSK 200977
7
Overview
Key Elements of the Reporting and Analysis Plan (RAP)
Analyses
randomized study treatment and the subsequent follow-up phase, the final 
analysis for the clinical study report will be performed. At this time, the database 
will be frozen. 
Analysis 
Populations

Full Analysis (FA) Population

Per-Protocol (PP) population

Safety Population
Hypothesis

The primary hypothesis to be tested is that albiglutide plus insulin glargine (with 
or without metformin) will provide glycemic control (as measured by HbA1c
change from Baseline) noninferior to insulin lispro plus insulin glargine (with or 
without metformin) after 26 weeks of treatment in subjects with T2DM 
inadequately controlled on their current regimen of basal-bolus insulin therapy.
Primary 
Analyses

The primary endpoint is the change from Baseline in HbA1c at Week 26. The 
primary analysis of the primary endpoint will be conducted using a mixed-effect 
model with repeated measures (MMRM) in the FA Population. The MMRM will 
only include non-missing observations without imputation.
Secondary 
Analyses

Categorical endpoints will be analyzed using CMH test and logistic regression
adjusting for baseline HbA1c category, age category, region and current use of 
metformin. Continuous endpoints will be analyzed using a MMRM model for the 
FA population. Time to event data will be analyzed using a log-rank test with 
Kaplan-Meier method.
Exploratory 
Analyses

Exploratory endpoints will be analysed in a similar manner as described above 
for the secondary endpoints. 
Safety 
Analyses

Adverse events, adverse events of special interest, hypoglycemic events, 
clinical laboratory tests, vital signs and ECG findings will be presented by 
treatment groups.


CONFIDENTIAL
GSK 200977
8
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
Any changes from the originally planned statistical analysis specified in the protocol
amendment 3 (Dated: 24-SEP-2015) are outlined as follows:
Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes

Supportive secondary 
endpoint: Total daily insulin 
dose (24-hour total 
international units [IU] and 
total units/kg body weight) 
over the 3 days preceding the 
Baseline/Randomization and 
Week 4, 10, and 18 visits.

Use prescribed total daily 
insulin dose and 
prescribed total daily 
units/kg body weight for 
analysis. Do not use the 
actual dose taken or the 
doses over the 3 days 
preceding the visits.

The prescribed dose 
reflects the investigator’s 
assessment of what 
would be required to 
maintain or achieve 
glycemic control. The 
‘over the 3 days 
preceding the 
Baseline/Randomization 
and Week 4, 10, and 18 
visits’ text is a carryover 
from earlier protocol.
2.2.
Study Objectives and Endpoints
Objectives
Endpoints
Primary

To evaluate the glycemic 
effectiveness of once-weekly 
albiglutide as replacement of 
prandial insulin in subjects with 
T2DM receiving basal-bolus insulin 
therapy

Change from Baseline in HbA1c at Week 26
Key Secondary

To determine the proportion of 
subjects treated with once-weekly 
albiglutide that are able to replace 
prandial insulin without the need 
for re-introduction of insulin lispro

Proportion of subjects treated with once-weekly 
albiglutide that are able to discontinue insulin lispro 
at Week 4 and do not meet prespecified criteria for 
severe, persistent hyperglycemia through Week 26

To demonstrate a significant 
difference in the frequency of 
hypoglycemic events between 
treatment groups

Percentage of subjects with severe or documented 
symptomatic hypoglycemia through Week 26

To demonstrate a significant 
difference in body weight between 
treatment groups

Change from Baseline in body weight at Week 26 
and over time

To demonstrate a significant 

Prescribed total daily insulin dose at Week 26


CONFIDENTIAL
GSK 200977
9
Objectives
Endpoints
reduction in total daily dose of 
insulin between treatment groups
Supportive Secondary

To assess additional glycemic 
parameters, achievement of HbA1c
treatment goals, body weight, and 
total daily insulin dose

Additional glycemic parameters:
HbA1c change from Baseline over time
FPG change from Baseline at Week 26 and 
over time

Achievement of HbA1c treatment goals:
Proportion of subjects achieving a HbA1c <7.0% 
at Week 26 and over time
Proportion of subjects achieving a HbA1c <6.5% 
at Week 26 and over time

Incidence and time to meeting prespecified criteria 
for severe, persistent hyperglycemia through Week 
26

Additional assessments of daily insulin doses:
Prescribed total daily insulin dose (total units 
and total units/kg body weight) at the
Baseline/Randomization and Week 4, 10, and 
18 visits
Prescribed total daily basal insulin dose (total 
units and total units/kg body weight) at the 
Baseline/Randomization and Week 4, 10, 18, 
and 26 visits
Prescribed total daily bolus insulin dose (total 
units and total units/kg body weight) at the
Baseline/Randomization and Week 4, 10, 18, 
and 26 visits

Total number of weekly insulin injections (7 days) to 
achieve glycemic control to achieve glycemic control 
at Baseline/Randomization and Week 4, 10, 18, and 
26

Composite endpoints (after 26 weeks of treatment):
Percentage of subjects achieving HbA1c <7.0% 
without weight gain
Percentage of subjects achieving HbA1c <7.0% 
without severe or documented symptomatic
hypoglycemia
Percentage of subjects achieving HbA1c <7.0% 
without weight gain and without severe or 
documented Hypoglycemia

To evaluate the safety and 
tolerability of the 2 treatment 
groups

Adverse events (AEs) and serious AEs (SAEs), 
including AEs and SAEs leading to discontinuation of 
randomized study medication

Other AEs of special interest (for example,
cardiovascular [CV] events, GI events, injection site 


CONFIDENTIAL
GSK 200977
10
Objectives
Endpoints
reactions, potential systemic allergic reactions, 
pancreatitis, pancreatic cancer, medullary thyroid 
cancer, malignant neoplasms following treatment 
with insulin, diabetic retinopathy events, appendicitis,
liver events, pneumonia, and atrial fibrillation/flutter)

Assessments of hypoglycemia:
Percentage and number of events of
hypoglycemia with confirmed home blood 
glucose monitoring and/or third-party 
intervention through Week 26 (i.e., severe, 
documented symptomatic, and asymptomatic
hypoglycemic events, see Protocol Section 
6.3.1) in 3-month intervals (i.e., from 
Baseline/Randomization to Week 12, >Week 12 
to Week 26)
Incidence of hypoglycemic events (in total and 
by each category as defined by the American 
Diabetes Association criteria)
Incidence of daytime hypoglycemia (in total and 
by category), defined as hypoglycemic events 
with an onset between 06:00 hours and 00:00 
hours (inclusive), and nocturnal hypoglycemia
(in total and by category), defined as
hypoglycemic events with an onset between 
00:01 hours and 05:59 hours (inclusive)
Incidence of hypoglycemia with blood glucose 
<56 mg/dL (<3.1 mmol/L), regardless of 
symptoms

Assessment of clinical laboratory tests (hematology, 
clinical chemistry, urinalysis, β-human chorionic 
gonadotropin [β-HCG], lipid panel)

Assessment of vital sign measurements (Note: 
Weight is assessed as part of efficacy) and 12-lead 
electrocardiogram (ECG) findings
Exploratory

To compare the effects between 
the 2 treatment groups on patient-
reported outcomes to diabetes 
medication and to further assess 
glycemic parameter, weight, and 
composite endpoints

Patient-reported outcomes to diabetes medication at 
Baseline/Randomization, Week 10, and Week 26:
Treatment-related impact measure for diabetes 
(TRIM-Diabetes) questionnaire
Hypoglycemia fear survey-II (HFS-II) worry 
subscale

Additional glycemic parameter, weight, and
composite endpoints:
HbA1c change from Baseline at Week 26 by 
baseline FPG tertiles
FPG change from Baseline at Week 26 by 


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Objectives
Endpoints
baseline FPG tertiles
24-hour glucose profile: 8-point self-monitored 
blood glucose (SMBG) profile at 
Baseline/Randomization, Week 10, and Week 
26 (before and 120 minutes after the 3 main 
meals, at bedtime, and at 2 AM)
Mean daily blood glucose based on the 8-point 
SMBG profile at Baseline/Randomization, Week 
10, and Week 26
Number (and percentage) of subjects with <=1 
kg weight gain at Week 26
Percentage of subjects achieving HbA1c <7.0% 
without weight gain and without hypoglycemia 
with blood glucose <56 mg/dL (<3.1 mmol/L)
regardless of symptoms at Week 26
Proportion of subjects treated with once-weekly 
albiglutide that are able to totally replace or 
decrease prandial insulin without worsening 
HbA1c control (worsening defined as >0.3% 
increase in HbA1c compared with baseline 
HbA1c) at Week 26

Analysis of genetic sampling may 
also be performed

Genetic sampling

Analysis of novel biomarkers may 
also be performed

Novel biomarker analysis may be performed; a 
decision on whether to analyze novel biomarker 
samples may be made after review of efficacy and 
safety endpoints at the end of the study or other 
emerging information that may become available 
during the study


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2.3.
Study Design
2.3.1.
Overview of Study Design and Key Features
Overview of Study Design and Key Features
SC = subcutaneous; T2DM = type 2 diabetes mellitus; TDD = total daily dose.
Note: Subjects on metformin will continue on the same dose throughout the study, except if the 
subject’s estimated glomerular filtration rate, calculated according to the Modification of Diet in 
Renal Disease formula, decreases during the study to a level where metformin is contraindicated 
according to its label (as appropriate for each participating country), in which case metformin is to 
be stopped.
1. At Baseline/Randomization, albiglutide will be started at 30 mg once weekly with uptitration to 
albiglutide 50 mg once weekly at Week 4. Subjects randomly assigned to this treatment group will 
reduce insulin lispro by 50% at Baseline/Randomization, followed by complete (100%) 
discontinuation of insulin lispro at Week 4.
Design
Features

Randomized, open-label, parallel-group, active-control, multicenter study of 26 
weeks’ treatment duration
Dosing

Albiglutide will be started at 30 mg once weekly with uptitration to Albiglutide 
50 mg once weekly at Week 4. For insulin glargine and insulin lispro, see 
Protocol Section 5.
Treatment 
Assignment

After the Standardization Period, approximately 794 subjects meeting 
additional criteria for randomization will be stratified by screening HbA1c value 
(<8.0% versus ≥8.0%), age (<65 years versus ≥65 years), and current use of 
background metformin (metformin use versus no metformin use) and randomly 
assigned to 1 of the 2 treatment groups in a 1:1 ratio: albiglutide +  insulin 
glargine (metformin) or insulin lispro + insulin glargine (metformin).
Interim 
Analysis

No interim analysis is planned for this study.


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2.3.2.
Study Design
This Phase IIIb, randomized, open-label, parallel-group, active-control, multicenter study 
of 26 weeks’ treatment duration will evaluate the efficacy and safety of once weekly 
albiglutide plus insulin glargine compared with insulin lispro plus insulin glargine in 
subjects with T2DM failing to achieve adequate glycemic control with basal-bolus 
therapy (metformin). 
The study will comprise 4 study periods: Screening (2 weeks), Standardization (4 weeks), 
Treatment (26 weeks), and Post-treatment Follow-up (4 weeks). The total duration of a 
subject’s participation will be approximately 36 weeks.
After Screening, eligible subjects will enter a 4-week Standardization Period to transition 
from their current basal-bolus therapy to insulin glargine/insulin lispro. Subjects already 
on insulin glargine/insulin lispro will also enter the Standardization Period.
After the 4-week Standardization Period, eligible subjects will be stratified by screening 
HbA1c value (<8.0% versus 8.0%), age (<65 years versus 65 years), and current use of 
metformin (metformin use versus no metformin use). Approximately 794 subjects
(Appendix 12: Sample Size Considerations) will be randomized in a 1:1 ratio such that

Approximately 397 subjects are randomly assigned to albiglutide + insulin 
glargine (metformin) 

Approximately 397 subjects are randomly assigned to insulin lispro + insulin 
glargine (metformin)
Following randomization, albiglutide subjects will initiate treatment with once-weekly 
subcutaneous injections of albiglutide 30 mg (with forced uptitration to albiglutide 50 mg 
at Week 4).  
During the treatment period, the study will allow individualization of the insulin dose in 
both treatment arms (i.e., insulin glargine in the albiglutide arm and both insulin glargine 
and insulin lispro in the basal-bolus arm), with a treat-to-target approach and a titration 
regimen based on FPG.
Subjects taking metformin as background antidiabetic medication will remain on their 
current dose for the duration of their participation in the study, unless a decline in kidney 
function results in a contraindication for metformin use. 
The total duration of a subject’s participation will be approximately 36 weeks 
(approximately 2 weeks of Screening, 4 weeks of Standardization, a 26-week Treatment 
Period, and 4 weeks of Post-treatment Follow-up). Subjects who discontinue active 
participation in the study will no longer receive the randomized study medication. 
Immediately upon discontinuation from active participation in this study, these subjects 
should complete the early withdrawal assessments (i.e., safety and laboratory 
assessments) and return 4 weeks later for the follow-up assessments.


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Subject completion is defined as completion of all periods of the study up to and 
including the follow-up visit. For the primary analysis, subject completion is defined as 
completion of all periods of the study up to and including the treatment period.
2.4.
Statistical Hypotheses
The primary hypothesis to be tested is that albiglutide plus insulin glargine (with or 
without metformin) will provide glycemic control (as measured by HbA1c change from 
Baseline) noninferior to insulin lispro plus insulin glargine (with or without metformin) 
after 26 weeks of treatment in subjects with T2DM inadequately controlled on their 
current regimen of basal-bolus insulin therapy. If the null hypothesis of albiglutide 
inferiority is rejected, a test of superiority will be applied.

The null hypothesis is that the difference in the mean change from Baseline to 
Week 26 in HbA1c between albiglutide and insulin lispro is greater than the non-
inferiority margin of 0.3%.

The alternative hypothesis is that the difference in the mean change from Baseline 
to Week 26 in HbA1c between albiglutide and insulin lispro is less than or equal to 
the non-inferiority margin of 0.3%.
The hull hypothesis will be tested based on the upper bound of 1-sided 97.5% confidence 
interval (equivalently, the upper bound of a 2-sided 95% confidence interval) of the least 
squares mean of the treatment difference estimated from a MMRM model. The MMRM 
model will include HbA1c change from Baseline as the dependent variable, treatment, 
region, age category, current use of metformin, visit week, treatment-by-week 
interaction, and baseline HbA1c-by-week interaction as the fixed effects, and baseline 
HbA1c as a continuous covariate. Subject will be included in the model as a random 
effect. If the upper bound of 1-sided 97.5% confidence interval is less than or equal to 
0.3%, non-inferiority will be concluded. If non-inferiority is established, a superiority test 
will be performed and the upper bound of 1-sided 97.5% confidence interval will be 
compared to 0. If it is less than 0, superiority will be claimed. This superiority test with 
respect to HbA1c will be performed after testing the key secondary hypotheses.
3.
PLANNED ANALYSES
3.1.
Interim Analyses
No interim analysis is planned for this study.
3.2.
Final Analyses
After all subjects have completed the planned 26 weeks of randomized study treatment or 
withdrawn from the study and the subsequent follow-up phase, the final analysis for the 
clinical study report will be conducted. At this time, the database will be frozen after all 
required database cleaning activities have been completed.


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4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
Full Analysis (FA) 

Comprise of all subjects randomly assigned to 
treatment.

Randomly assigned subjects who do not 
receive any study treatment will also be 
included.

The subjects in the FA Population will be 
analyzed according to randomized treatment.

Study Population

Efficacy
Per-Protocol (PP)

Comprise of all randomized (FA Population) 
subjects who complete study procedures 
through Week 26 or beyond.

The subjects in the PP Population will be 
analyzed according to randomized treatment.

Supportive Efficacy 
Analysis
Safety

Include all subjects who receive at least 1 dose 
of randomized study medication.

The subjects in the Safety Population will be 
analyzed according to the treatment received.

Safety

Study Population
NOTES : 

Please refer to Appendix 14: List of Data Displays which details the population to be used for each displays being 
generated.
4.1. Deviations from Assigned Treatment
If subjects do not take treatment according to their randomization, the assignment of 
treatment for summary and analysis will both depend on the extent of the violation and 
the type of data being analyzed. 

If a subject takes non-randomized study treatment for only part of the study, the 
subject will be analyzed based on the randomized treatment assignment for both 
safety and efficacy.

If a subject takes non-randomized study treatment for the entire study, the subject 
will be analyzed based on the treatment actually taken for safety analyses. 
However, the subject will be analyzed according to randomized treatment for 
efficacy per the intent-to-treat principle.
4.2.
Protocol Deviations

Protocol deviations will be tracked by the study team throughout the conduct of the 
study in accordance with the Protocol Deviation Management Plan.  
o
Data will be reviewed prior to freezing the database to ensure all protocol
deviations are identified and documented.
o
This dataset will be the basis for the summary of significant deviations and listing 
of all protocol deviations.


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
A separate summary and listing of all inclusion/exclusion criteria deviations will also 
be provided. This summary will be based on data recorded on the inclusion/exclusion 
page of the eCRF.


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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
The primary analysis in this study is comparison between the treatment groups on the 
primary efficacy endpoint change from baseline in HbA1c with MMRM, where missing 
HbA1c values are assumed to be missing at random. Missing data handling and 
sensitivity analysis for the primary endpoint can be found in Appendix 6: Premature 
Withdrawals & Handling of Missing Data.
In the conduct of the study, specific measures will be put in place to prevent and 
minimize missing data due to treatment withdrawals, noncompliance, etc. Upon study 
completion, the characteristics (frequency, causes) of the missing data, especially as 
related to the key efficacy endpoints, will be examined to inform the sensitivity analysis 
and imputation methods concerning missing data.
Table 1 provides an overview of appendices within the RAP for outlining general 
considerations for data analyses and data handling conventions. 
Table 1
Overview of Appendices
Section
Component
11.1
Appendix 1: Protocol Deviation Management Plan and Definitions for Per-Protocol 
Population
11.2
Appendix 2: Time & Events
11.3
Appendix 3: Assessment Windows
11.4
Appendix 4: Treatment Periods
11.5
Appendix 5: Derived and Transformed Data
11.6
Appendix 6: Premature Withdrawals & Handling of Missing Data
11.7
Appendix 7: Values of Potential Clinical Importance
11.8
Appendix 8: Multicenter Studies and Definition of Geographic Region for Statistical 
Analyses
11.9
Appendix 9: Examination of Covariates, Subgroups & Other Strata
11.10
Appendix 10: Multiple Comparisons & Multiplicity
11.11
Appendix 11: Model Checking and Diagnostics for Statistical Analyses
11.12
Appendix 12: Sample Size Considerations
11.13
Appendix 13: Abbreviations and Trademarks
11.14
Appendix 14: List of Data Displays
5.1.
Multiple Comparisons and Multiplicity
A multiple comparisons adjustment strategy will be implemented for the multiple 
inferential tests among the primary and key secondary endpoints to preserve the family-
wise Type I error rate of 0.05. Testing on other efficacy endpoints will be considered 


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exploratory and no multiplicity adjustment will be applied. Details are provided in
Appendix 10: Multiple Comparisons and Multiplicity.
5.2.
Withdrawal
Subjects withdrawn after not achieving a predefined threshold for glycemic control 
(confirmed FPG ≤270 mg/dL [15.0 mmol/L] at least 8 weeks after randomization) may 
be considered for study withdrawal. Subjects withdrawn for this reason will be 
considered to have completed the efficacy assessments for the primary analysis at the 
time of the assessment that triggers withdrawal. Per the protocol, insulin lispro may be re-
introduced after Week 8 for subjects in the albiglutide treatment group, following a 
standardized, stepwise approach. Efficacy and safety assessments after the re-
introduction of lispro will be included in the statistical analysis as is, without special 
handling.
5.3.
Geographic Region
Clinical sites will be clustered by geographic region since the number of subjects per 
clinical site is expected to be rather small. Geographic regions will be defined based on 
geographic proximity, similarity of medical practice in diabetes, and number of subjects 
per region. Subjects per region will be constrained such that the region with the largest 
sample size is no more than 3 times that of the region with the smallest sample size. The 
classification of region will be determined prior to the database lock and initiation of the 
final analyses, and documented in Appendix 8.
5.4.
Baseline and Study Day
In general, the baseline value for each variable will be defined as the last measurement 
collected prior to the first dose of randomized study medication.
Study day will be defined as the number of days from the first dose of randomized study 
medication. The date when a subject receives the first dose of randomized study 
medication is defined as Day 1. For events after the first dose date, study day is 
calculated as the difference in days between the first dose date and the date of interest, 
plus 1 day. For events that occur before the first dose date, study day is calculated as the 
difference in days between the first dose date and the date of interest. Thus, the day 
before first dose date is defined as Day -1.
5.5.
Analysis Visit Window and Therapy Periods
For all safety and efficacy parameters to be summarized or analyzed by visit, data records 
will be slotted to one of the protocol specified visits using the algorithm defined in 
Appendix 3. 
For classifying AEs (including hypoglycemic events), the therapy periods will be defined 
as pre-therapy, on-therapy and post-therapy. Albiglutide has a half-life of about 5 days in 
human body. Five times the half-life of a drug starting from the last dose of treatment is 
considered as the elimination period after which the drug has practically been eliminated 
from the system. Last dose date plus a period of 5 times of half-life of albiglutide, which 


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is within 25 days after the date of last dose, is defined as on-therapy window for subjects 
in the albiglutide arm. An AE is defined as on-therapy AE if the onset date is on or after 
the start date of randomized study medication and within last dose date plus 25 days in 
the albiglutide arm or within the last dose date in the lispro arm. For other safety
parameters that are assessed prior to administration of randomized study medication on 
dosing days, the assessment date is used to determine the therapy periods. Details on the 
therapy periods of AEs and other safety parameters are provided in Appendix 4.
5.6.
Multiple Evaluations
After all the records have been slotted based on therapy period and study day, if there are 
multiple valid records for an assessment within an assigned analysis visit, only one of 
these records will be used for summary statistics and analyses. The record to be used is 
determined using the following hierarchy (in decreasing order of priority):

the record closest to the target visit day

the record with an original nominal visit that matches the analysis visit

the record earliest in time for postbaseline assessments; for baseline, it is the 
record latest in time


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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Analyses
The study population analyses will be based on the population specified in Section 4.
Table 2 provides an overview of the planned study population analyses with full details 
of data displays being presented in Appendix 14: List of Data Displays.
Table 2
Overview of Planned Study Population Analyses
Display Type
Format
Figure
Table
Listing
Randomization
Randomization
Y
Subject Disposition
Subject Disposition
Y
Y
Reasons for Screening Failures and Standardization 
Failures
Y
Y
Reasons for Withdrawal from Study
Y
Y
Reasons for Discontinuing Study Treatment
Y
Y
Protocol Deviations
Y
Y
Deviations Leading to Exclusions from PP Population
Y
Y
Inclusion and Exclusion Criteria Deviations
Y
Y
Demography
Demographics and Baseline Characteristics
Y
Y
Race & Racial Combinations
Y
Y
Substance use
Y
Y
Study Populations
Y
Y 
Medical Condition & Concomitant  Medications
Medical Conditions (Current/Past)
Y
Y
Concomitant Medication
Y
Y
Exposure and Treatment Compliance
Treatment Compliance
Y
Y
Exposure to Study Drug
Y
Y
Dose Titration
Dose Titration
Y
Note: additional tables, listings and figures will be provided in Appendix 14: List of Data Displays.


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6.2.
Disposition of Subjects
The number of subjects who were randomized and the number of subjects within each 
population (Full Analysis, Safety, Per- Protocol) will be summarized for each treatment 
group. A summary of subjects randomized by geographic region, country, and site will 
also be provided by treatment group. 
The numbers and percentages of subjects who completed the study, discontinued the 
study, and discontinued the study treatment, along with reasons for discontinuation, will 
be summarized by treatment group.
A subject status by visit summary will be provided.
Subject disposition data will be listed as well. All disposition summaries will be based on 
all randomized subjects (i.e., FA Population).
6.3.
Protocol Deviations
As described in Section 4.2, subjects who fail to meet any of the inclusion/exclusion 
criteria will be tabulated and listed by treatment group for FA Population. This will be 
based on data recorded on the inclusion/exclusion page of the eCRF.  A separate listing 
or summary (if applicable) of significant protocol deviations (described in Section 4.2) 
will be generated.
6.4.
Demographic and Baseline Characteristics
Continuous variables such as age, body mass index, weight, and height will be 
summarized using descriptive statistics (n, mean, standard deviation, median, minimum, 
and maximum). Categorical variables including age group (<65, 65 years), sex, race, 
ethnicity, baseline HbA1c category (<8%, 8%), and current metformin use (yes, no) will 
be summarized using numbers and percentages. Summaries will be presented by 
treatment group using the FA Population and Safety Population. 
Summary of substance (alcohol and tobacco) use will be provided, as well as a by-subject 
listing of data on alcohol and tobacco use. All summaries will be performed using the FA
Population.
6.5.
Exposure to Study Drug
Descriptive statistics including the number of subjects, mean, standard deviation, median, 
minimum, and maximum for the duration of study drug exposure to the treatment 
received will be presented by treatment group for the Safety Population. The duration of 
study drug exposure is defined as date of last dose of randomized study drug - date of 
first dose of randomized study drug + 1. The total person time on treatment (in years) as 
defined in Appendix 5 will also be displayed for each treatment group. 
Additionally, the prescribed total daily dose of insulin glargine and insulin lispro will be 
tabulated by visit. 


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A by-subject listing of study drug administration will also be presented.
6.6.
Treatment Compliance
Investigational product accountability will be done for albiglutide at each study visit after 
the baseline visit through the end-of-treatment visit (Visit 9, Week 26). 
Albiglutide treatment compliance will be calculated as total number of doses
administered divided by total number of doses expected based on the last dose date at the 
end of active treatment period. Total number of albiglutide administered during the 
treatment period will be computed as the number of expected dose minus the number of 
missed dose. For the number of expected dose, if subject completes the treatment, it will 
be 26. If subject doesn’t complete the treatment, the number of expected dose will be 
equal to the number of weeks between treatment start date and treatment end date. The 
number of missed dose information, treatment start and end date are captured on the 
albiglutide administration CRF page. Treatment compliance will be summarized for all 
subjects, as well as for subjects who discontinue treatment early and subjects who 
complete active treatment. Summary statistics for treatment compliance percentages, as 
well as the number and percentage of subjects who are <80% and ≥80%compliant will be 
reported for the Safety Population. Individual subject compliance information will also be 
listed.
Treatment compliance of subjects for insulin glargine and insulin lispro will be assessed 
by the investigator at each visit and reported on the eCRFs. At each visit on or after 
baseline, the investigator will answer “yes/no” to the question of “Do you believe the 
subject has been compliant with their insulin regimen at least 80% of the time”. If the 
investigator answered “yes” for all the postbaseline visits for treatment compliance 
assessment (Week 4, 10, 18, and 26), the subject will be considered as being >=80% 
compliant to the treatment during the entire study period. For subjects who discontinued 
the study early, the same rule will apply and the assessment of overall compliance will be 
based on the data from the completed visits. The number and percentage of subjects in 
each compliance category will be summarized overall and by study visit for the safety 
population. Individual subject compliance information will be listed. 
Acceptable overall compliance for IP (albiglutide) and other study treatments (insulin 
glargine and insulin lispro) in this study will be ≥80%.
6.7.
Dose Titration and Insulin Lispro Re-introduction
The albiglutide dose in this study will start at 30 mg weekly and be titrated to 50 mg 
weekly at Week 4. 
Both treatment arms will follow the same insulin glargine titration algorithm during the 
Standardization and Treatment Periods (see Table 3 of the Protocol).
Both treatment arms will follow the same insulin lispro titration algorithm during the 
standardization period. At randomization, the start of the treatment period, the insulin 
lispro titration algorithm will be individualized for each treatment arm (see Table 4 of the 
protocol).


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Insulin lispro may be re-introduced after Week 8 for subjects in the albiglutide treatment 
group. The number of subjects for whom insulin lispro was re-introduced will be 
summarized. For these subjects, the re-introduced insulin lispro will be characterized in 
terms of the number of injections and the total dose over time. The dosing guidance for 
albiglutide, insulin lispro, insulin glargine, and metformin treatment can be found in 
Table 2 of the Protocol.
Individual dose titration information and insulin lispro re-introduction will be listed for 
the safety population.
For lispro re-introduction through Week 26, it will include lispro re-introduced up to 
Week 25 and not include lispro prescribed at Week 26. This is due to that the last 
albiglutide injection is given at Week 25 for subjects in albiglutide arm and at Week 26 
lispro may be prescribed as per standard of care.  
6.8.
Medications
Any prior and concomitant medication used during the study will be recorded and coded 
using GSKDRUG dictionary, which will be updated whenever available throughout the 
life of the study. Summary of all medications by treatment group and preferred term will 
be provided in relation to treatment phase (prior medication, concomitant medication, or 
post-therapy medication). Prior medications are those started and stopped before the first 
dose of randomized study drug. Concomitant medications are those taken at any time on 
or after the day of the first dose of randomized study drug and within last dose date plus 
25 days in the albiglutide arm or within the last dose date in the lispro arm, including 
those medications that started prior to randomization and continued into the treatment
period. Post-therapy medications are those taken after last dose date plus 25 days in the 
albiglutide arm or after the last dose date in the lispro arm.
For this study, insulin glargine, insulin lispro and any other anti-hyperglycemic
medications will be recorded through screening period on the concomitant medications 
eCRF pages. Once subjects enter Visit 2 (Standardization Week -4 visit), the prescribed 
dose for insulin glargine and for insulin lispro are captured in the Insulin Surveillance 
eCRF page.
All prior and concomitant medications will be listed using generic and verbatim terms. 
All summaries will be performed using the safety population.
6.9.
Medical History
Subject data listings and summary tables will be provided for the following current 
and/or past conditions:

cardiovascular medical history

diabetes history

medical/surgical procedure history

gastrointestinal (GI) medical history


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
nephropathy (including microalbuminuria) and kidney injury history

diabetic retinopathy history

cancer history

pneumonia medical history

skin medical conditions

thyroid history, thyroid cancer history

history benign thyroid conditions

thyroid cancer family history

pancreatitis family history

pancreatic cancer family history

other medical history
The number and percentage of subjects with current and/or past cardiovascular medical 
history will be reported by treatment group. Also, the number and percentage of subjects 
with current and/or past diabetes history will be tabulated by treatment group. A
summary of duration of diabetes disease history in years will be provided. The duration 
of diabetes disease history is calculated as the years lapsed between screening visit date 
and T2DM diagnosis date. 
The number and percentages of subjects with current and/or past medical/surgical 
procedure history, gastrointestinal (GI) medical history, nephropathy (including 
microalbuminuria) and kidney injury history, diabetic retinopathy history, cancer history, 
pneumonia medical history, skin medical conditions, thyroid history, thyroid cancer 
history, history benign thyroid conditions, thyroid cancer family history, pancreatitis 
family history, pancreatic cancer family history and other medical history will be 
presented in a similar manner as described for cardiovascular medical history. 
In addition, by subject listings of medical and family history status and all the medical 
conditions listed above will be provided. 
All summaries will be performed using the safety population. In the case of scarce data 
for a medical history and summary is not necessary, only a listing will be provided.


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7.
PRIMARY STATISTICAL ANALYSES
7.1.
Efficacy Analyses
7.1.1.
Overview of Planned Efficacy Analyses
The primary efficacy analyses will be based on the FA population, unless otherwise 
specified.
Table 3 provides an overview of the planned efficacy analyses, with full details of data 
displays being presented in Appendix 14: List of Data Displays.
Table 3
Overview of Planned Efficacy Analyses
Absolute
Change from Baseline
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
HbA1c
Y
Y
Y
Y
Y
Y
Y
Y
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
Following review of the data, additional analyses may be conducted to further support the 
evaluation and interpretation of the data.
7.1.1.1.
Primary Analysis on Primary Efficacy Endpoint
The primary efficacy endpoint is the change from Baseline in HbA1c at Week 26. The 
primary analysis of the primary efficacy endpoint will be conducted using a mixed-effect 
model with repeated measures (MMRM) in the FA population using all available data 
from analysis visits. Missing data will not be imputed.
The model will include HbA1c change from Baseline as the dependent variable; 
treatment, region (defined in Appendix 8: Multicenter Studies and Definition of 
Geographic Region for Statistical Analysis), age category, current metformin use, visit 
week, treatment-by-week interaction, and baseline HbA1c-by-week interaction as fixed 
effects; baseline HbA1c as a continuous covariate; and subject as a random effect (Model 
1). Treatment effects estimates (and associated hypothesis tests) of albiglutide will be 
evaluated within this MMRM model as least squares means contrasts relative to insulin 
lispro. An unstructured covariance matrix will be used for the MMRM analysis, unless 
the model does not converge, in which case the covariance matrix will be decided upon 
model convergence status and the Akaike information criterion (AIC). The MIXED 
procedure in SAS will be used to implement the MMRM analysis. The least squares 
means (and standard errors) of HbA1c at each study visit and least squares means (and 
standard errors) of change from Baseline in HbA1c at each postbaseline study visit will be 
presented. The least squares mean and the associated 1-sided 97.5% confidence interval 
of the treatment difference in change from Baseline in HbA1c at each postbaseline study 
visit will be reported. In addition, the observed HbA1c and change from Baseline HbA1c


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will be summarized descriptively. The least squares means (and standard errors) of 
change from Baseline HbA1c will be plotted by treatment group.
The null hypothesis will be tested based on the 1-sided 97.5% confidence interval of the 
least squares mean of the treatment difference at Week 26 estimated from the MMRM 
model. If the upper bound of the confidence interval is less than or equal to 0.3%, non-
inferiority will be concluded. If non-inferiority is established, key secondary endpoints 
will be tested as described in Appendix 11.10. 
7.1.1.2.
Supportive Analyses on Primary Efficacy Endpoint
The MMRM analysis above assumes that there are no qualitative interactions of 
treatment with the other terms in the model. For the primary endpoint only, the treatment-
by-baseline HbA1c, treatment-by-region, treatment-by-age category, and treatment-by-
current metformin use interactions will be investigated individually at a significance level 
of 0.10. Absence of a significant treatment-by-variable qualitative interaction at the 0.10 
level will be interpreted as supportive of the use of the main-effects model to evaluate the 
treatment efficacy hypotheses. When examining the interaction between the continuous 
variable HbA1c and treatment, the baseline HbA1c category will be used.
The primary endpoint will also be analyzed using Model 1 in the PP population as 
supportive analysis.
7.1.1.3.
Analyses on Primary Efficacy Endpoint by Subgroups
The primary endpoint, HbA1c change from Baseline at Week 26, will also be examined 
by the subgroups of a number of variables, such as baseline HbA1c category, gender, race, 
ethnicity, age category, baseline BMI category, region, duration of diabetes category and 
current use of metformin (see Appendix 9), using a MMRM model that is similar to the 
model for the primary analysis but also includes the subgroup-variable-by-treatment-by-
visit week interaction term (as well as subgroup-variable-by-treatment and subgroup-
variable-by-visit week). The adjusted mean difference and confidence interval for each 
level of the subgroup will be estimated from the MMRM model and the p-values for the 
treatment by subgroup interactions will be reported.
7.1.1.4.
Sensitivity Analysis
Sensitivity analyses will be performed for the primary efficacy endpoint to assess the 
robustness of the primary efficacy analysis results with respect to departures from the 
assumption that missing primary endpoint data are missing at random. Detailed 
methodology is provided in Appendix 6.


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7.1.2.
Planned Efficacy Statistical Analyses
Primary Statistical Analyses
Endpoint(s)

Change from Baseline in HbA1c at Week 26
Model Specification

Change from Baseline in HbA1c = Baseline HbA1c + Treatment + Region + Age Category + 
Current Use of Metformin + Visit Week + Treatment-by-Visit Interaction + Baseline HbA1c-by-
Visit Week Interaction (Model 1)
Model Checking & Diagnostics

Refer to Appendix 11: Model Checking and Diagnostics for Statistical Analyses
Model Results Presentation

The least squares mean of the treatment difference at Week 26 estimated from the MMRM 
model and its 1-sided 97.5% confidence interval

Descriptive statistics for the observed HbA1c and change from Baseline HbA1c

Plot of the least squares means (and standard errors) of change from Baseline HbA1c by 
treatment group

Refer to Appendix 14: List of Data Displays
Supportive Statistical Analysis

The generalizability of the treatment effect will be evaluated within a supportive MMRM model 
that adds terms for treatment-by-variable interaction. The variables include baseline HbA1c, 
region, age category, and current use of metformin. 

The primary endpoint will also be analyzed using Model 1 above in the Per-Protocol Population
Model Specification

Change from Baseline in HbA1c = Baseline HbA1c + Treatment + Region + Age Category + 
Current Use of Metformin + Visit Week + Treatment-by-Visit Interaction + Baseline HbA1c-by-
Visit Week Interaction + Treatment-by-Variable + Visit Week–by-Variable + Treatment-by-Visit
Week-by-Variable.

Refer to Appendix 11: Model Checking and Diagnostics for Statistical Analyses for SAS code
By-Subgroup Statistical Analysis

The subgroup analyses will be performed using MMRM models. The subgroups include
baseline HbA1c category, gender, race, ethnicity, age category, baseline BMI category, region, 
duration of diabetes category and current use of metformin.

Refer to Appendix 9: Examination of Covariates, Subgroups & Other Strata.
Model Specification

Change from Baseline in HbA1c = Baseline HbA1c + Treatment + Region + Age Category + 
Current Use of Metformin + Visit Week + Treatment-by-Visit Interaction + Baseline HbA1c-by-
Visit Week Interaction+ Treatment-by-Visit Week-by-Variable + Treatment-by-Variable + Visit 
Week–by-Variable.

Refer to Appendix 11: Model Checking and Diagnostics for Statistical Analyses for SAS code
Sensitivity Statistical Analysis with Respect to Missing Data MAR Assumption

Refer to Appendix 6, Section 11.6.3: Sensitivity Analysis on the Primary Efficacy Endpoint


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8.
SECONDARY AND EXPLORATORY STATISTICAL 
ANALYSES
8.1.
Secondary Efficacy Analyses
8.1.1.
Overview of Planned Secondary Efficacy Analyses
The secondary efficacy analyses will be based on the Full Analysis (FA) population, 
unless otherwise specified.
Table 4 provides an overview of the planned secondary efficacy analyses, with full
details of data displays being presented in Appendix 14: List of Data Displays.
Table 4
Overview of Planned Secondary Efficacy Analyses
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
Key Secondary Endpoints
Proportion of subjects treated with once-weekly 
albiglutide that are able to discontinue insulin lispro 
at Week 4 and do not meet prespecified criteria for 
severe, persistent hyperglycemia through Week 26
Y
Y
Y
Percentage of subjects with severe or documented 
symptomatic hypoglycemia through Week 26
Y
Y
Y
Change from Baseline in body weight at Week 26 
and over time
Y
Y
Y
Y
Y
Prescribed total daily insulin dose at Week 26
Y
Y
Y
Y
Y
Supportive Secondary Endpoints
HbA1c change from Baseline over time
Y
Y
Y
Y
FPG change from Baseline at Week 26 and over 
time
Y
Y
Y
Y
Y
Proportion of subjects achieving a HbA1c <7.0% at 
Week 26 and over time
Y
Y
Proportion of subjects achieving a HbA1c <6.5% at 
Week 26 and over time
Y
Y
Incidence and time to meeting prespecified criteria 
for severe, persistent hyperglycemia at Week 26
Y
Y
Y
Y
Prescribed total daily insulin dose (total units and 
total units/kg body weight) at the
Baseline/Randomization and Week 4, 10, and 18 
visits
Y
Y
Y
Y
Prescribed total daily basal insulin (insulin glargine) 
(total units and total units/kg body weight) at the 
Baseline/Randomization and Week 4, 10, 18, and 
26 visits
Y
Y
Y
Y


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Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
Prescribed total daily basal insulin (insulin glargine) 
(total units and total units/kg body weight) at the 
Baseline/Randomization and Week 4, 10, 18, and 
26 visits
Y
Y
Y
Y
Prescribed total daily bolus insulin (insulin lispro) 
(total units and total units/kg body weight) at the 
Baseline/Randomization and Week 4, 10, 18, and 
26 visits
Y
Y
Y
Y
Total number of weekly insulin injections (7 
days) to achieve glycemic control at 
Baseline/Randomization and Week 4, 10, 18, and 
26
Y
Y
Y
Y
Composite endpoints (after 26 weeks of treatment): 
Percentage of subjects achieving HbA1c <7.0% 
without weight gain
Y
Y
Composite endpoints (after 26 weeks of treatment): 
Percentage of subjects achieving HbA1c <7.0% 
without severe or documented symptomatic 
hypoglycemia
Y
Y
Composite endpoints (after 26 weeks of treatment): 
Percentage of subjects achieving HbA1c <7.0% 
without weight gain and without severe or 
documented hypoglycemia
Y
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
Following review of the data, additional analyses maybe conducted to further support the 
evaluation and interpretation of the data.
8.1.2.
Key Secondary Efficacy Endpoints
8.1.2.1.
Proportion of Subjects Who Do Not Meet Prespecified Criteria for 
Severe, Persistent Hyperglycemia through Week 26
For this key secondary endpoint, subjects who do not meet prespecified criteria for 
severe, persistent hyperglycemia through Week 26 will be defined operationally as those 
subjects treated with once-weekly albiglutide that are able to replace prandial insulin 
without lispro re-introduction through Week 26. Note: For lispro re-introduction through 
Week 26 the time window is defined up to Week 25. 
Proportion of subjects that are able to discontinue insulin lispro at Week 4 and do not 
meet prespecified criteria for severe, persistent hyperglycemia through Week 26 will be 
summarized descriptively for all the Albiglutide + Insulin Glargine arm subjects and for 


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subgroups of baseline HbA1c category (<8.0%, 8.0%), region, (<65 years versus 65 
years), current use of metformin (Yes, No) in the FA population. The 95% confidence 
interval of the proportions of subjects will be provided.
The insulin lispro that was re-introduced to albiglutide subjects will be characterized.  
Summary statistics for the number of injections, total dose, and time-to-re-introduction 
will be presented.
Additional exploratory analyses to identify potential risk factors for lispro re-introduction 
will be investigated. Potential risk factors include: baseline HbA1c, baseline HbA1c 
category, age, age category, metformin-use, duration of diabetes, weight, BMI, BMI 
category, time in insulin (at baseline), baseline HbA1c, and total insulin dose at baseline.
Time in insulin (at baseline) is defined as the earliest start date of prior insulin
medications taken minus the date of first date of randomized study medication, plus 1. 
8.1.2.2.
Percentages of Subjects with Severe or Documented Symptomatic 
Hypoglycemia through Week 26
The percentage of subjects with severe or documented symptomatic hypoglycemia will 
be summarized descriptively by treatment and analyzed using a Cochran-Mantel-
Haenszel (CMH) test, stratified by baseline HbA1c category, region, age category (<65 
years versus 65 years), current use of metformin (Yes, No) in the FA population.
As supportive analysis, logistic regression models adjusting for baseline HbA1c category, 
region, age category and current use of metformin will be used to quantify the treatment 
effects. Odds ratio for treatment and the associated confidence interval will be used to 
estimate the treatment difference.
8.1.2.3.
Change from Baseline in Body Weight at Week 26 and over Time
Change from Baseline in body weight will be analyzed and summarized analogous to the 
primary efficacy endpoint using a slightly different MMRM model which includes 
change from Baseline in body weight as dependent variable; treatment, region, baseline
HbA1c category, age category, current metformin use, visit week, treatment-by-week 
interaction, and baseline weight-by-week interaction as fixed effects; baseline weight as a 
continuous covariate; and subject as a random effect (Model 2). Treatment difference at 
Week 26 will be tested; p-value and 2-sided 95% confidence interval will be presented. 
The percentage change from baseline in body weight will be analysed using a similar 
MMRM model:
Change from Baseline in Body Weight = Baseline Body Weight + Treatment + Baseline 
HbA1c Category + Region + Age Category + Current Use of Metformin + Visit Week + 
Treatment-by-Visit Interaction + Baseline Body Weight-by-Visit Week Interaction
(Model 2).
The percentage change from Baseline in body weight will be analyzed similarly using 
Model 2 above, with percent change from baseline in body weight as the dependent 
variable.  


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The observed body weight values and change and percent change from baseline body 
weight will be summarized descriptively and presented graphically. The least squares 
means (and standard errors) of change from baseline body weight will be plotted by 
treatment group.
The analyses will be performed on FA population and all data will be listed.
8.1.2.4.
Prescribed Total Daily Insulin Doses and Total Number of Weekly 
Insulin Injections
Prescribed total daily insulin doses at Baseline, Week 4, 5, 10, 18 and 26 will be assessed 
from several aspects: 

Total daily insulin dose (IU)

Body weight adjusted total daily insulin dose (IU/kg)

Total daily basal insulin (insulin glargine) dose (IU)

Body weight adjusted total daily basal insulin (insulin glargine) dose

Total daily bolus insulin (insulin lispro) dose (IU)

Body weight adjusted total daily bolus insulin (insulin lispro) dose
The absolute value in each of the above variables by visit will be analyzed using an 
MMRM model similar to Model 2 where the specific insulin dose replaces weight
(Section 8.1.2.3). The prescribed total daily insulin doses will be summarized 
descriptively and presented graphically by treatment group. The least squares means (and 
standard errors) of the prescribed total daily insulin doses will be plotted by treatment 
group.
In addition, total number of weekly insulin injections (7 days) to achieve glycemic 
control at Baseline, Week 4, 5, 10, 18 and 26 will also be assessed and summarized using 
descriptive statistics; the value for this analysis is derived based on the number of 
prescribed insulin injections as follows:

Albiglutide: 1 injection per week

Insulin Glargine: 1 injection per day (7 injections per week)

Insulin Lispro: 3 injections per day (21 injections per week)
For subjects who was randomized to the albiglutide arm and required re-introduction of 
insulin lispro, the number of injections for insulin lispro should be based on data 
collected in the Surveillance eCRF page. These subjects could have once-daily, twice-
daily or three times daily insulin lispro injections.
Definitions for insulin dose and number of injections at Week 26 for albiglutide arm:

Both glargine and lispro dose at Week 26 will be defined operationally as the 
prescribed dose at Week 25.

For lispro number of injections at Week 26 will be defined operationally as the 
prescribed number of injections at Week 25. For glargine number of injections at 
Week 26 will be considered 1 per day. 


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8.1.3.
Supportive Secondary Efficacy Endpoints
8.1.3.1.
HbA1c Change from Baseline over Time
HbA1c change from Baseline by visit will be analyzed analogous to the primary efficacy 
endpoint using the same MMRM model (Model 1) in the FA population. The observed 
HbA1c and change from Baseline HbA1c will be summarized descriptively and presented 
graphically. The least squares means (and standard errors) of change from Baseline 
HbA1c will be plotted by treatment group.
8.1.3.2.
FPG Change from Baseline at Week 26 and over Time
FPG change from Baseline by visit will be analyzed and summarized similarly to weight 
change from Baseline using Model 2 with FPG replacing weight in the model (Section 
8.1.2.3). The analyses will be performed on FA population and all data will be listed.
Due to administrative error in the Time and Events table in the protocol, fasting plasma 
glucose (FPG) was not collected at Week 26 and will be imputed with fasting serum 
glucose (FSG) value. Correlation analyses of FPG and FSG values using data from this 
trial at earlier visit as data allows will be performed to provide an assessment of the 
validity of this imputation.
8.1.3.3.
Proportion of Subjects Achieving HbA1c <7% at Week 26 and over Time
The proportion of subjects achieving HbA1c target values of <7.0% at Week 26 and over 
time will be summarized by treatment and visit for the FA population. The treatment 
comparison will be carried out using the CMH test and logistic regression model 
described in Section 8.1.2.2. The proportion of subjects who responded over time will 
also be plotted using a bar chart.
If a subject has a missing HbA1c value at week 26 and the reason why value is missing is 
not related to efficacy or safety (e.g., procedural) and could be assumed that value is
missing at random, then the value will be left as missing for calculations; if the reason 
why value is missing is lack of efficacy or due to safety, then this missing value will be 
imputed as ‘not meeting target’ and included in the denominator in the calculation of the 
proportion of subjects achieving target HbA1c <7%. 
The results with the observed data and with imputed data will be both presented as part of 
sensitivity analysis.    
8.1.3.4.
Proportion of Subjects Achieving HbA1c <6.5% at Week 26 and over 
Time
Proportion of subjects achieving HbA1c target values of <6.5% at Week 26 and over time 
will be analyzed and summarized in a similar manner as specified in Section 8.1.3.3.   


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8.1.3.5.
Incidence and Time to Meeting Prespecified Criteria for Severe, 
Persistent Hyperglycemia through Week 26
In this treat-to-target study design, subjects may be withdrawn if they have severe and
persistent hyperglycemia. Meeting prespecified criteria for severe, persistent 
hyperglycemia at week 26 will be defined operationally as being withdrawn due to lack 
of efficacy as recorded on the Treatment Discontinuation and Study Conclusion eCRF 
pages. Proportion of subjects who meet prespecified criteria for severe, persistent 
hyperglycemia at Week 26 will be summarized and analyzed in a same manner as 
described in Section 8.1.2.2.
The time to meeting prespecified criteria for severe, persistent hyperglycemia through
Week 26 will be calculated as the number of days between the date of first dose of 
randomized study medication and the date of meeting prespecified criteria, persistent 
hyperglycemia, plus 1. Subjects who do not meet the criteria will be censored at the date 
of the Week 26 visit or the date of the early termination visit if the subject terminated the 
study early. Kaplan-Meier estimates of the median time to meeting the criteria and 95% 
confidence interval for each treatment group will be presented. The treatment difference
will be assessed using a log-rank test. The proportion of subjects meeting the criteria up 
to Week 26 (Day 182) based on Kaplan-Meier estimates will be displayed in the 
summary table. Kaplan-Meier curves of the times to meeting the criteria for each 
treatment group will be presented. 
The analysis will be performed on FA population and all data will be listed. 
8.1.3.6.
Composite Endpoints
The following composite endpoints (after 26 weeks of treatment) will be analyzed as 
secondary efficacy endpoints:   

Percentage of subjects achieving HbA1c <7.0% without weight gain 

Percentage of subjects achieving HbA1c <7.0% without severe or documented 
symptomatic hypoglycemia

Percentage of subjects achieving HbA1c <7.0% without weight gain and without 
severe or documented symptomatic hypoglycemia
No weight gain is defined as ≤1 kg increase from baseline in body weight. These 
composite endpoints will be analyzed and summarized in a similar manner as specified in 
Section 8.1.2.2.
8.2.
Exploratory Efficacy Analyses
8.2.1.
Overview of Planned Exploratory Efficacy Analyses
The exploratory efficacy analyses will be based on the FA population, unless otherwise 
specified.
Table 5 provides an overview of the planned exploratory efficacy analyses, with full
details of data displays being presented in Appendix 14: List of Data Displays.


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Table 5
Overview of Planned Exploratory Efficacy Analyses
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
Exploratory Endpoints
Patient-reported outcomes to diabetes medication at 
Baseline/Randomization, Week 10, and Week 26: 
Treatment-related impact measure for diabetes 
(TRIM-Diabetes) questionnaire
Y
Y
Y
Patient-reported outcomes to diabetes medication at 
Baseline/Randomization, Week 10, and Week 26: 
Hypoglycemia fear survey-II (HFS-II) worry subscale
Y
Y
Y
HbA1c change from Baseline at Week 26 by baseline 
FPG tertiles
Y
Y
Y
FPG change from Baseline at Week 26 by baseline 
FPG tertiles
Y
Y
Y
24-hour glucose profile: 8-point self-monitored blood 
glucose (SMBG) profile at Baseline/Randomization, 
Week 10, and Week 26 (before and 120 minutes 
after the 3 main meals, at bedtime, and at 2 AM)
Y
Y
Y
Y
Mean daily blood glucose based on the 8-point 
SMBG profile at Baseline/Randomization, Week 10, 
and Week 26
Y
Y
Y
Number (and percentage) of subjects with <=1 kg 
weight gain at Week 26
Y
Y
Y
Percentage of subjects achieving HbA1c <7.0% 
without weight gain and without hypoglycemia with 
blood glucose <56 mg/dL (<3.1 mmol/L) regardless 
of symptoms at Week 26
Y
Y
Y
Proportion of subjects treated with once-weekly 
albiglutide that are able to totally replace or 
decrease prandial insulin without worsening HbA1c
control (worsening defined as >0.3% increase in 
HbA1c compared with baseline HbA1c) at Week 26
Y
Y
Y
Genetic sampling
Novel biomarker analysis
TBD
TBD
TBD
TBD
TBD
TBD
TBD
NOTES :
T = Table, F = Figure, L = Listing, Y = Yes display generated.
Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.
Summary = Represents TF related to any summaries (i.e. descriptive statistics) of the observed raw data.
Individual = Represents FL related to any displays of individual subject observed raw data. 
TBD = to be determined after review of efficacy and safety data at the end of the study or other emerging information 
that may become available during the study
Following review of the data, additional analyses maybe conducted to further support the 
evaluation and interpretation of the data.


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8.2.2.
TRIM-Diabetes Questionnaire
The TRIM-Diabetes questionnaire is a 28-item treatment satisfaction measure with 
5 domains assessing treatment burden, daily life, diabetes management, compliance, and 
psychological health. Measures can be scored independently for each domain or as a total 
score. Higher scores indicate a better health state.
The TRIM-Diabetes will be administered in this study at baseline, Week 10, and Week 
26 to assess treatment satisfaction within each treatment group of the study.
There are three steps for the calculation of TRIM- Diabetes scores. The first step is to 
reverse the coded value for questions in daily life, compliance, and psychological health
domains, so that a higher score indicates better health for all domains. In the second step, 
raw scale scores are computed by summing across items in the same domain (raw domain 
scores). A total raw score can also be calculated. In last step, raw scale scores are 
transformed to a 0-100 scale (transformed scale scores) using the following: Domain= 
[(raw score - lowest possible raw score) / possible raw score range] x 100.
Change from baseline in TRIM-Diabetes total score and individual domain scores will be 
summarized descriptively by visit and treatment group, and analyzed using a similar
MMRM model as Model 2 where TRIM-Diabetes scores replace weight.
Every effort will be made to minimize the amount of missing data and therefore 
maximize the quality of the data collected. If a patient answers at least half of the items in 
a multi-item domain (or half plus one in the case of domains with an odd number of 
items) then a domain score should be calculated. The average score (across completed 
items in the same domain) for that patient will be used to estimate any missing item in 
that domain. For example, if a patient leaves a blank item in the 5-item Diabetes 
Management domain, substitute the patient’s average score (across the four answered 
Diabetes Management items) for the score for that item.
If more than one answer is ticked off by the patient (adjacent answers or not) the item 
should be coded as missing.
8.2.3.
HFS-II Worry Subscale
The HFS-II questionnaire is a 33-item questionnaire with 2 subscales that measure: 
1) behavior to avoid hypoglycemia and its negative consequences and 2) worries about 
hypoglycemia and its negative consequences. This study will include the worry subscale 
only (18 items, score range 0 to 72). Responses use a 5-point Likert scale ranging from 
Never to Always. The HFS-II has a 6-month recall period.
The HFS-II will be administered in this study at baseline, Week 10, and Week 26 to 
assess within each treatment group worries about hypoglycemia. 
The continuous endpoint of HFS-II worry subscale score change from Baseline by visit 
will be analyzed using an MMRM model similar to Model 2 where HFS-II worry 
subscale score replaces weight.


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If a subject missed one or more items, or ticked multiple items, the data will be handled 
in the same as for TRIM-Diabetes questionnaire items.
8.2.4.
HbA1c Change from Baseline at Week 26 by Baseline FPG Tertiles
The minimum, 33% percentile, 66% percentile and the maximum values of baseline FPG 
concentration will be obtained from the valid FPG values at baseline. The subjects will be 
stratified into 3 groups with their baseline FPG concentration <33% percentile (1st FPG 
Tertile), ≤33% to <67% percentile (2nd FPG Tertile), and the rest (3rd FPG Tertile). HbA1c
values will be summarized descriptively by baseline FPG tertiles, by visit and treatment. 
The MMRM model for the subgroup analysis on the primary efficacy endpoint (Section 
7.1.1.3) will be used in the FA population for this analysis.
8.2.5.
FPG Change from Baseline at Week 26 by Baseline FPG Tertiles
This endpoint will be summarized descriptively and analyzed using a similar model as 
used for the analysis in Section 8.2.4, with FPG change from baseline as the response 
variable and adding baseline FPG tertile as covariate (Refer to Appendix 11 for model 
specification and SAS code). 
8.2.6.
8-Point SMBG Profile and Mean Daily Blood Glucose
An 8-point blood glucose profile will be performed by the subject 3 times in the week 
prior to Baseline, Week 10 and Week 26. Subjects will be instructed to measure and 
record glucose values from their glucose meter at the following times:

Before breakfast (at least 8 hours without food intake)

2 hours after breakfast

Before lunch

2 hours after lunch

Before dinner

2 hours after dinner

At bedtime

At 2 AM
Glucose concentrations at each of the 8 time points will be averaged over three days with 
the largest count of 8-point SMBG data points within the visit window to derive the mean 
glucose concentrations at each time point. If there are ties for these counts within the visit 
window, select the one closest to the actual visit day. If subject only had 1 or 2 days of 8-
point SMBG within the visit window, use 1 day 8-point SMBG or average of 2 days of 8-
point SMBG data. The daily average of glucose concentrations will be calculated as the 
average over the glucose concentrations at the 8 time points. The daily average data will 
be calculated only if at least one pair of preprandial and postprandial glucose values is 
available. Only complete pairs of preprandial and postprandial glucose values will be 
used for the calculation.


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Visit window will be defined for the purpose of SMBG calculation. It will be defined by 
study day according to following table.
Table - Visit Window for SMBG Calculation
Visit
Target Study Day 
Range of Study Day
Baseline
1
Study day <= 1
Week 10
71
43 <= study day <= 99
Week 26
183
155 <= study day <= 211
The absolute glucose concentrations and change from Baseline at each time point will be 
summarized descriptively by treatment and visit for the FA population. The daily average 
glucose concentration and change from Baseline will be summarized similarly. The 
absolute glucose concentrations will also be plotted by visit, time points and treatment.
Daily average glucose concentrations will be analyzed similarly to weight, with a 
MMRM model (Model 2) with daily average glucose replacing weight in the model 
(Section 8.1.2.3). The analyses will be performed on FA population and all data will be 
listed.  
8.2.7.
Number and Percentage of Subjects with 1 kg Weight Gain at 
Week 26
Number and percent of subjects with <=1 kg weight gain at Week 26 will be analyzed in 
the same manner as specified in Section 8.1.2.2.   
8.2.8.
Percentage of Subjects Achieving HbA1c <7.0% without Weight 
Gain and without Hypoglycemia with Blood Glucose <3.1 mmol/L 
(<56 mg/dL) regardless of Symptoms at Week 26
This composite endpoint will be analyzed in the same manner as specified in Section 
8.1.2.2.
8.2.9.
Proportion of Subjects Treated with Once-Weekly Albiglutide 
That Are Able to Totally Decrease Prandial Insulin without 
Worsening HbA1c Control at Week 26
Worsening HbA1c is defined as >0.3% increase in HbA1c compared to baseline at Week 
26. This exploratory endpoint will be analyzed in the same manner as specified in Section 
8.1.2.1. 


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8.3.
Safety Analyses
8.3.1.
Overview of Planned Analyses
The safety analyses will be based on the Safety population.
Table 6 provides an overview of the planned analyses with further details of data displays 
being presented in Appendix 14: List of Data Displays.
Table 6
Overview of Planned Safety Analyses
Endpoints
Observed
Change from 
Baseline
Summary
Individual
Summary
Individual
T
F
F
L
T
F
F
L
Adverse Events
  All AEs
Y
Y
Treatment-Emergent AEs
Y
Y
  Relationship of AEs to Study Drug
Y
Y
  AEs by Maximum Intensity
Y
Y
  Most Common AEs
Y
Y
  Serious AEs
Y
Y
  AEs and SAEs Leading to Treatment Discontinuation
Y
Y
Fatal AEs and non-fatal SAEs
Y
Y
  AEs of special interest 
Y
Y
Severe, documented symptomatic, and asymptomatic 
hypoglycemic events in 3-month
Y
Incidence of hypoglycemic events (in total and by each 
category as defined by the American Diabetes 
Association criteria)
Y
Incidence of daytime hypoglycemia (in total and by 
category), and nocturnal hypoglycemia (in total and by 
category)
Y
Incidence of hypoglycemia with blood glucose <56 mg/dL 
(<3.1 mmol/L), regardless of symptoms
Y
Clinical Laboratory
Y
Y
Y
Y
Y
Y
Vital Signs
Y
Y
Y
Y
Y
Y
Electrocardiogram (ECG)
Y
Y
Y
Y
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.


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Following review of the data, additional analyses maybe conducted to further support the 
evaluation and interpretation of the data.
8.3.2.
Adverse Events
All AEs will be coded using MedDRA which will be updated whenever available 
throughout the life of the study. Adverse events will be categorized by their occurrence in 
regard to therapeutic phase (pre-therapy, on-therapy, or post-therapy) as defined in 
Appendix 4. Adverse events will be summarized in various subsets by treatment group. 
An overview summary of the number and percentage of subjects with any AE, the total 
number of AEs recorded, and the overall AE density and incidence rate for on-therapy 
AEs will be provided by treatment group. The overview will also summarize SAEs, 
treatment-related AEs, AEs by maximum intensity, and AEs by therapy phase. 
Summaries of the number and percentage of subjects with any treatment-emergent AEs
(TEAEs), related AEs, AEs leading to treatment discontinuation or withdrawal from 
study, SAES, fatal AEs etc, will be provided. Adverse events will also be summarized by 
maximum intensity (mild, moderate, and severe).
Except summaries for serious AEs, AEs leading to withdrawal from treatment or pre-
therapy AEs, all other AE summaries do not include hypoglycemic events, unless 
otherwise specified.
All AEs will be listed in a subject data listing.
8.3.2.1.
General Adverse Events Summaries
Summaries of the number and percentage of subjects with AEs and the total number of 
AEs will be provided by treatment group overall and at the SOC and PT level for the 
following time periods:
1) On-therapy and post-therapy combined period
2) Pre-therapy (includes hypoglycemia events)
3) On-therapy
4) Post-therapy 
In addition, on-therapy Adverse events will be presented by time intervals of onset (<=12 
weeks, >12 - <=26 weeks) and by treatment group; the on-therapy non-serious AEs will 
be summarized by treatment group.
An additional on-therapy AE summary will also be provided following government 
clinical register format; these summaries will include the AEs of hypoglycemia event.
A by-subject listing of all AEs will also be presented.
8.3.2.2.
Treatment Emergent Adverse Events
TEAEs are defined as any AEs, regardless of relationship to the, randomized study drug 
(i.e., albiglutide or other study treatments), that occur after the first dose of the 


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randomized study medication, which is equivalent to on-therapy and post-therapy AEs 
combined. Summaries of the number and percentage of subjects with TEAEs will be 
provided by treatment group overall at the SOC and PT level. TEAES will also be further 
defined as on-therapy or post-therapy AEs for summary purposes.
A by-subject listing of all TEAEs will also be presented.
8.3.2.3.
Treatment-Related Adverse Events
Treatment-related AEs will be defined as any AEs that are considered by the investigator 
to have a reasonable possibility to be related to the study treatment. If a relationship to 
the study treatment is missing or unknown after the start of treatment it will be assumed, 
for the purpose of analyses, to be treatment-related.
A summary of the number and percentage of subjects with treatment-related AEs will be 
displayed. The treatment-related AE data will be categorized and presented in a manner 
similar to that described above for the general AE summaries for both the on-therapy and 
post-therapy therapeutic phases.
8.3.2.4.
Adverse Events by Maximum Intensity
A summary of the number and percentage of subjects with on-therapy and post-therapy 
adverse events by intensity (mild, moderate, and severe) will be produced. The data will 
be sorted and categorized using the method and format described previously. 
Subjects who experience the same event several times with different intensity will only 
be counted once according to the maximum intensity experienced (for that therapeutic 
phase). AEs with missing intensity will be considered to be severe for the purposes of 
summarization.
8.3.2.5.
Most Common Adverse Events
A summary of most common on-therapy adverse events (>2% total incidence in any 
treatment arm) by treatment will be produced.
In addition, on-therapy non-serious AEs with proportion of subjects experiencing the AE 
>=5% among any of the active arms will be summarized by treatment group following 
government clinical register format; this summary will include AEs of hypoglycemia 
event.
8.3.3.
Deaths and Serious Adverse Events
Serious adverse events (SAEs) will be summarized in a manner similar to that described 
above for the general AE summaries by treatment group for pre-therapy, on-therapy, and 
post-therapy therapeutic phases. Treatment-related SAEs will also be summarized 
separately by treatment group for both the on-therapy and post-therapy therapeutic 
phases.


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SAE, fatal SAE and serious non-fatal AEs will also be summarized following 
government clinical register format; these summaries will include SAEs of hypoglycemia 
event.
Summaries and by subject listings of fatal AEs and serious non-fatal AEs will be 
presented. 
8.3.4.
Adverse Events Leading to Discontinuation of Investigational 
Product and/or Withdrawal from the Study
A summary of the number and percentage of subjects with adverse events leading to 
permanent discontinuation of the randomized study drug (that is, withdrawal of active 
treatment) will be presented by treatment group for the on-therapy phase. 
A by-subject listing of all adverse events leading to permanent discontinuation of study 
drug/withdrawal from the study will be produced.
8.3.5.
Adverse Events of Special Interest
For selected AEs of special interest such as hypoglycemia, the exposure-adjusted event
rate, i.e., AE density, will be calculated as the number of events in a given period divided 
by the total person time on treatment of subjects at risk within the same period; the 
exposure-adjusted incidence rate will also be calculated as the number of subjects in a 
given period divided by the total person time on treatment of subjects at risk within the 
same period. The exposure-adjusted event rate and incidence rate will be expressed as an 
annualized rate (expected number of events or subjects per 100 person-years).
For any AEs of special interest, if the number of events is limited and does not warrant 
summary tables, by subject data listings will be provided instead.
8.3.5.1.
Hypoglycemic Events
Hypoglycemic events merit special attention in the development and study of drugs for 
the treatment of T2DM since they are often related to the efficacy of a compound. In 
order to accomplish this, hypoglycemic event data including supplemental hypoglycemic 
event information not collected on AE eCRF page are reported on a separate 
hypoglycemic event eCRF page. However, any hypoglycemic event that meets the 
criteria for a serious AE will also be included in the serious AE summaries.
Analysis of on-therapy hypoglycemic events will include all AEs coded to the preferred 
term of ‘Hypoglycemia’. For on-therapy hypoglycemic events the number and percentage 
of subjects with events, the number of events, the incidence rate (per 100 person-years) 
and AE density (per 100 person-years) by the severity of the event defined by American 
Diabetes Association [ADA], SAE status, relationship to the investigational product, and 
withdrawal status will be summarized by treatment group. The events will also be 
summarized according to intervention provided, action taken with regard to background 
and anti-hyperglycemic medications and onset week and glucose levels. All 
hypoglycemic events will be classified as severe, documented symptomatic, 


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asymptomatic, probable symptomatic, or pseudohypoglycemia per the American 
Diabetes Association criteria) criteria. 
The number of events of hypoglycemia with confirmed home blood glucose monitoring < 
3.9 mmol/L and/or requiring third party intervention (i.e., severe, documented 
symptomatic and asymptomatic hypoglycemic events) in 3 monthly intervals (i.e., from 
Baseline to Week 12, >Week 12 to Week 26) will be summarized by treatment group. 
The exposure-adjusted event rate will be compared between treatment groups using a 
Poisson regression model with offset for the person-year, which will include HbA1c
stratum, age (<65 years versus 65 years), current use of metformin (metformin use 
versus no metformin use), and region as covariates.
Incidence (in total and by each category) of hypoglycemia, daytime hypoglycemia, and 
nocturnal hypoglycemia will be summarized by treatment group. Daytime hypoglycemia 
is defined as hypoglycemic events with an onset between 06:00 hours and 00.00 hours 
(inclusive). Nocturnal hypoglycemia is defined as hypoglycemic events with an onset 
between 00:01 hour and 05:59 hours (inclusive). The incidence of hypoglycemia with 
blood glucose <56 mg/dL (<3.1 mmol/L), regardless of symptoms, will also be 
summarized by treatment group.
On-therapy hypoglycemic events over time will be summarized by onset week and 
plotted for each treatment group.
A by-subject listing of all hypoglycemic events will be produced.
8.3.5.2.
Cardiovascular Events
A summary of the number and percentage of subjects with cardiovascular events will be 
reported by treatment group and therapeutic phase.
A by-subject listing of all the data elements collected on the eCRF page will be presented 
for subjects who experience cardiovascular events.
8.3.5.3.
Pancreatitis and Pancreatic Cancer
The number and percent of subjects with pancreatitis and pancreatic cancer will be 
reported by treatment group. A by-subject listing of all the data elements collected on 
pancreatitis event page of the eCRF will be presented for subjects who experienced 
pancreatitis and pancreatic cancer. This listing of the pancreatitis events will also include 
the adjudication results as determined by the independent pancreatitis adjudication 
committee.
8.3.5.4.
Thyroid Adverse Events
The number and percent of subjects with thyroid AEs will be reported by treatment 
group. Additionally thyroid adverse events identified by a customized MedDRA query 
will be presented by treatment group. 
A by-subject listing of all the data elements captured in the thyroid tumor eCRF page will 
be produced.


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8.3.5.5.
Gastrointestinal (GI) Events
A summary of the number and percentage of subjects with GI events (specifically, AEs 
coded to the MedDRA SOC of gastrointestinal disorders) will be reported by treatment 
group and therapeutic phase (pre-, on-, or post-therapy). Also, summaries of on-therapy 
GI events that lead to withdrawal of active treatment, treatment-related and serious GI 
events (including those that do not necessarily lead to withdrawal of active treatment) 
will be presented separately by treatment group.
For each subject, the time to first occurrence of a GI event is calculated as the number of 
days between the randomization date and the date of onset of the first on-therapy GI 
event plus 1. Subjects who do not experience any GI events will be censored at the last 
dose date plus 25 days in the albiglutide arm or within the last dose date in the lispro arm. 
The median time to first occurrence of a GI event as well as the Kaplan-Meier probability 
of first occurrence of a GI event at various time points will be presented for each 
treatment group. Kaplan-Meier curves for the time to first occurrence of a GI event for 
each treatment group will also be presented.
The prevalence of GI events will be reported and plotted by treatment group. 
The number and percentage of subjects reporting nausea at each study week will be 
presented by treatment group. Each week will include those subjects with onset of nausea 
during that particular week and also those subjects with nausea that started during a 
previous week but has not resolved. The prevalence of nausea will also be plotted over 
time. Similar summaries and plots will be presented for subjects reporting events of 
diarrhea and also separately for subjects reporting events of vomiting. In addition, a 
combined summary and accompanying plot of the number and percentage of subjects 
reporting events of nausea and/or vomiting will be presented.
8.3.5.6.
Systemic Allergic Reactions
Systemic allergic reactions are reported by the investigators on the eCRF. The number 
and percentage of subjects with suspected systemic allergic reactions will be presented by 
treatment group. In addition, the time to first occurrence of a systemic allergic reaction 
will be analyzed and presented in a manner identical to that described above for first 
occurrence of a GI event.
A summary of systemic allergic reactions based on customized MedDRA query (CMQ) 
list identified by GSK will also be presented. Analyses will be repeated for this data.
8.3.5.7.
Injection Site Reactions
Injection site reactions are reported by the investigators on the eCRF. The number and 
percentage of subjects with injection site reactions will be presented. In addition, the time 
to first occurrence of an injection site reaction will be analyzed and presented in a manner 
identical to that described above for first occurrence of a GI event.
The number and percentage of subjects reporting injection site reactions at each study 
week will be presented by treatment group. Each week will include those subjects with 


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the onset of an injection site reaction during that particular week as well as those subjects 
with injection site reactions from previous weeks that have not resolved. The incidence of 
injection site reactions will be plotted over time. Various characteristics of injection site 
reactions at the event level and subject level will be summarized.
A by-subject listing of injection site reactions will also be produced.
8.3.5.8.
Liver Events
The number and percentage of subjects with liver events that have been identified by 
investigators on the liver events eCRF page will be presented by treatment group. 
Additionally, liver events identified by a customized MedDRA query will also be 
presented by treatment group. By-subject listings of all the data elements collected on the 
eCRF page will be presented for subjects who experience adverse liver events, as 
identified by the investigators.
8.3.5.9.
Atrial Fibrillation/Flutter
The number and percentage of subjects with Atrial Fibrillation/Flutter events will be 
presented by treatment group for Atrial Fibrillation and Atrial Flutter. By-subject listings 
of all the data elements collected on the Atrial Fibrillation and Atrial Flutter event eCRF 
page will be presented for subjects who experience atrial fibrillation/flutter events, as 
reported by the investigators.
8.3.5.10.
Pneumonia
The number and percentage of subjects with Pneumonia events will be presented by 
treatment group for Pneumonia event reported by the investigator on the eCRF. Summary 
of Pneumonia events identified by a selected list of preferred terms will also be provided. 
By-subject listings of all the data elements collected on the Pneumonia event eCRF page 
will be presented for subjects who experience pneumonia events, as reported by the 
investigators.
8.3.5.11.
Diabetic Retinopathy
The number and percentage of subjects with diabetic retinopathy events will be presented 
by treatment group. A by-subject listing of all the data elements collected on the diabetic 
retinopathy eCRF page will be presented for subjects who experience diabetic 
retinopathy, as reported by the investigators.
8.3.5.12.
Appendicitis
The preferred terms containing the word “appendicitis” will be identified as Appendicitis 
events. The number and percentage of subjects with appendicitis will be presented by 
treatment group and a by-subject listing will be presented. 


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8.3.5.13.
Malignant Neoplasm
Malignant neoplasm will be captured in the AE eCRF pages. The number and 
percentages of subjects with malignant neoplasm identified by a customized MedDRA 
query will be presented by treatment group and a by-subject listing will be presented.
8.3.6.
Pregnancies
A listing of subject pregnancies will be provided.
8.3.7.
Clinical Laboratory Evaluations
Laboratory results that are beyond the limits of quantification will have the inequality 
sign dropped (<, ≤, >, or ≥) and the quantification limit will be used as the numeric result 
for summarization.  
8.3.7.1.
Chemistry, Hematology and Urinalysis
Laboratory parameters include the following tests: hematology, chemistry and urinalysis. 
Established or generally acknowledged methods, normal ranges, and quality control 
procedures will be supplied by Quest Diagnostics Clinical Laboratory for the study 
records.
Hematology parameters used in summaries include complete blood count with red blood 
cell indices, white blood cell count differential, and platelet count. Chemistry parameters 
(including lipids) used in summaries include glucose, blood urea nitrogen, creatinine, 
sodium, potassium, chloride, carbon dioxide, calcium, total protein, albumin, total 
bilirubin, direct bilirubin, alkaline phosphatase (ALP), ALT, aspartate aminotransferase 
(AST), gamma-glutamyltransferase, uric acid, magnesium, phosphorus, eGFR, total 
cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, 
triglycerides. Urinalysis parameters used in summaries include specific gravity, pH, 
glucose, ketones, microalbumin, creatinine, blood, leukocyte esterase, and nitrites.
All laboratory parameters will be summarized, for each treatment group, at every 
scheduled assessment time point using descriptive statistics and presented graphically. In 
addition, for hematology and chemistry laboratory parameters, change from Baseline in 
these quantitative tests will be summarized by treatment group and at every scheduled 
assessment postbaseline time point. Shift tables providing the number and percentage of 
subjects with indicated shifts (normal, abnormal not of clinical concern, abnormal of 
clinical concern) in their results from baseline to each scheduled postbaseline assessment 
will also be presented for all hematology and chemistry parameters.
Additionally, the number of subjects with laboratory values of potential clinical concern 
will be summarized by treatment group and scheduled assessment time point for 
hematology and chemistry. The criteria for laboratory values of potential clinical concern 
are detailed in Appendix 7: Values of Potential Clinical Importance.
A summary of laboratory values of potential clinical concern will be provided for liver 
function tests, including ALT, AST, and total bilirubin. The criteria for liver function 


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tests of potential clinical concern are detailed in Appendix 7: Values of Potential Clinical 
Importance.
All summaries will be done for the safety population and all laboratory data will be listed 
including hepatitis B, hepatitis C, fasting C-peptide, TSH, and urine pregnancy test 
results.
8.3.7.2.
Albumin/Creatinine Ratio
The pattern of urine albumin to creatinine ratio (UACR) over time and change from 
Baseline over time will be evaluated descriptively using summary statistics and 
graphically at each scheduled visit. Change from Baseline of each of the ratios will be 
calculated as postbaseline value divided by baseline value. A value less than 1 represents 
a decrease from baseline and a value greater than one represents an increase from 
baseline. Shift tables providing the number and percentage of subjects with indicated 
shifts (normal, abnormal not of clinical concern, abnormal of clinical concern) in their 
results from baseline to each scheduled postbaseline assessment will also be presented.
The analysis will be performed on safety population and all data will be listed.
8.3.8.
Other Safety Measures
8.3.8.1.
Vital Signs
The vital sign summary and analysis will include systolic blood pressure (mmHg), 
diastolic blood pressure (mmHg), and heart rate (bpm).
Each vital sign parameter at every scheduled assessment time point will be summarized 
using descriptive statistics and presented graphically. Change from Baseline will also be 
summarized using descriptive statistics and presented graphically. Additionally, the 
number of subjects with vital signs of potential clinical concern will also be summarized. 
Shift tables providing the number and percentage of subjects with indicated shifts 
(normal, low value of clinical concern, high value of clinical concern) in their results 
from baseline to each scheduled postbaseline assessment will also be presented. The 
criteria for vital signs of potential clinical concern are detailed in Appendix 7: Values of 
Potential Clinical Importance. 
All summaries will be done for the safety population and all vital sign data will be listed. 
8.3.8.2.
Electrocardiograms
ECG parameters collected at each scheduled assessment time point include heart rate, 
QRS interval, QT interval, QT interval – Bazett correction (QTcB), QT interval –
Fridericia correction (QTcF), RR interval and PR interval. 
Each ECG parameter at each scheduled assessment time point will be summarized by 
treatment group using descriptive statistics and presented graphically. Change from 
Baseline will also be summarized using descriptive statistics. A summary of the number 
and percentage of subjects in overall ECG interpretation and abnormal findings will be 
displayed by treatment group. The number of subjects with ECG values of potential 


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clinical concern will also be summarized. Shift tables providing the number and 
percentage of subjects with indicated shifts (normal, low value of clinical concern, high 
value of clinical concern) in their results from baseline to each scheduled postbaseline 
assessment will also be presented. The criteria for ECG values of potential clinical 
concern are detailed in Appendix 7: Values of Potential Clinical Importance. 
Additionally, categorical summaries for QTcB and QTcF values (>450, >480, and >500 
msec) and QTcB and QTcF change from Baseline values (>30, and >60 msec) will be 
presented by visit and treatment group.
All summaries will be done for the safety population and all ECG data will be listed.
8.3.8.3.
Physical Exams
In this study, findings from physical exams will be recorded in the AE eCRF page or 
medical history CRF page by the investigator as deemed appropriate. No separate 
summary of physical exams will be provided.
8.4.
Biomarker data analyses
After completion of the clinical trial, if biomarker investigations are performed on 
samples collected during the study, the results will be reported separately from the main 
clinical study report. 
8.5.
Pharmacogenetic data analyses
Additional blood samples drawn for pharmacogenetic (PGx) analysis will be stored and 
may be analyzed in the future for exploratory study of variability in drug response 
because of hereditary factors in different populations. Whenever applicable, the details of 
these analyses will be described in a separate document. See the protocol for details about 
the Pharmacogenetics Analysis Plan.
8.6.
Immunogenicity 
In the case of severe systemic allergic reactions that include anaphylaxis, angioedema, or
other severe potential hypersensitivity reactions that cannot reasonably be attributed to
another cause, five 1-mL serum samples should be obtained for immunogenicity testing
(within 24 hours of the event if possible) and sent to the central laboratory (see details in
the SPM) for immediate distribution to contracted testing facility for specific
immunological testing (albiglutide-specific immunoglobulin E and other tests, as
appropriate). A follow-up serum sample will be taken 8 weeks after final dose of study
treatment in these subjects. If data is available, a listing will be created to display 
immunogenicity testing.
8.7.
Clinical Pharmacology Data Analysis
Not applicable.


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9.
OTHER STATISTICAL ANALYSES
Not Applicable.


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10.
REFERENCES
American Diabetes Association. Standards of Medical Care in Diabetes—2010. 
Diabetes Care. 2010;33;S11-S61. 
Gail M, Simon R. Testing for qualitative interactions between treatment effects 
and patient subsets. Biometrics. 1985; 41:361-72. 
Koch GG, Gansky SA. Statistical considerations for multiplicity in confirmatory 
protocols. Drug Inf J. 1996;30:523-33.
Carpenter J.R., Kenward M.G. 2013. Multiple Imputation and its Application.
Chichester: John Wiley & Sons.
Rubin D.B. 1987. Multiple Imputation for Nonresponse in Surveys. Ner York: John 
Wiley & Sons.


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11.
APPENDICES
Section
Appendix
RAP Section 4 : Analysis Populations
Section 11.1
Appendix 1: Protocol Deviation Management and Definitions for Per-Protocol 
Population
RAP Section 5 : General Considerations for Data Analyses & Data Handling Conventions
Section 11.2
Appendix 2: Time and Events
Section 11.3
Appendix 3: Assessment Windows
Section 11.4
Appendix 4: Treatment Periods
Section 11.5
Appendix 5: Derived and Transformed Data
Section 11.6
Appendix 6: Premature Withdrawals & Handling of Missing Data
Section 11.7
Appendix 7: Values of Potential Clinical Importance
Section 11.8
Appendix 8: Multicentre Studies and Definition of Geographic Region for 
Statistical Analyses
Section 11.9
Appendix 9: Examination of Covariates and Subgroups
Section 11.10
Appendix 10: Multiple Comparisons and Multiplicity
Section 11.11
Appendix 11: Model Checking and Diagnostics for Statistical Analyses
Other RAP Appendices
Section 11.12
Appendix 12: Sample Size Considerations
Section 11.13
Appendix 13: Abbreviations & Trade Marks
Section 11.14
Appendix 14: List of Data Displays


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11.1.
Appendix 1: Significant Protocol Deviation Plan and 
Definitions for Per-Protocol Population
11.1.1.
Definitions for Per-Protocol Population
The per-protocol population is a subset of the full analysis population including all 
subjects who were randomized, have completed Week 26 treatment, and overall 
compliance greater than or equal to 80%.
11.1.2.
Significant Protocol Deviation Plan and Definitions for Per-
Protocol Population
The Significant Protocol Deviation Plan Version 1, dated 18 Sep 2015 will be used to 
identify the significant protocol deviations. It is intended to categorize significant 
protocol deviations that are anticipated to occur in a study and to document study-specific 
requirements for cross-functional team review of these significant protocol deviations and 
other deviations that may occur in the study. 
Part A of the Significant Protocol Deviation Plan is a list of the frequency that all 
deviations (protocol and GCP) will undergo review by a cross-functional team. (Review 
should assess trending and appropriate categorization (both deviation type and 
significance)).
Part B is a list of each significant protocol deviation in the appropriate category and 
indicates the criterion that makes the deviation significant. Non-significant deviations 
should not be included.
This Significant PD Rules document should be updated when changes are identified (e.g., 
new deviation, re-classification of significance of a deviation). The revised document 
should describe changes in the Change History and appropriate version control should be 
applied.  
The executed Protocol Deviation Plan will be maintained in the PPD electronic Trial 
Master File (eTMF).  GSK and PPD team members will have access to the Plan, 
including any amendments.  


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11.2.
Appendix 2: Time & Events
11.2.1.
Scheduled Clinic Visits
Table 5 and Table 6 of the protocol (Note: the tables and sections referred there are also from the protocol, not from this RAP)


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11.2.2.
Scheduled Telephone Visits


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11.3.
Appendix 3: Assessment Windows
11.3.1.
Definitions of Study Day
When study day is used for display or in comparisons the following algorithm will be 
used:

study day = date of assessment - date of first dose +1, if date of assessment 
first dose date

study day = date of assessment - date of first dose, if date of assessment < first 
dose date.
Note that the date of first dose is Day 1 and the day before the date of first dose is Day -1 
(there is no Day 0).
11.3.2.
Visit Slotting Algorithm
For all safety and efficacy parameters to be summarized or analyzed by visit, data records 
will be slotted to one of the protocol specified visits using the following algorithm: 
a) Determine the therapy period and study day for all records using the algorithms from 
Appendix 4: Treatment Periods.
b) For all records (including unscheduled visit records, early withdrawal records and 
repeat visit records), use the therapy period and study day determined above with the 
slotting intervals in the Table Analysis Visit Windows below to slot the record to the 
appropriate analysis visit.

For records determined to be in the pre-therapy period, the Week -6 and Week 
-4 analysis visits will be based on the nominal visits recorded on the eCRF. 
The Week -1 and Baseline analysis visits will be assigned based on the study 
day slotting intervals as shown in the table below. 

For records determined to be in the on-therapy period, use the study day with 
the slotting intervals in the table below to assign the records to the appropriate 
on-therapy analysis visit (Week 1 through Week 26).

For records determined to be in the post-therapy period, the study day will not 
be used for assigning the analysis visit. Instead, all post-therapy period 
records for subjects who complete randomized study treatment according to 
protocol will be assigned to the Week 30 post-therapy analysis visit. For 
subjects who terminate study treatment early, the follow-up analysis visit will 
be based on the nominal visit recorded on the eCRF. All other post-therapy 
period records for subjects who terminate study treatment early will be 
assigned to the 4 Week Follow-up analysis visit.
11.3.3.
Early Withdrawal Assessment
For subjects who are withdrawn early, handling of efficacy endpoint results from end-
of- treatment (EOT) visit will be based on the elapsed time between the EOT visit and 
the recorded last dose date in the study per CRF.  Specifically:


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
If the EOT visit is > 14 days since last dose, and the visit falls in the follow-up 
visits window, the results will be treated as follow-up results. 

If the EOT visit is >14 days since last dose, but the visit does not fall in the 
follow-up visit window, the results will not be used for analysis purposes, but 
will be listed in the data listing. 

If the EOT visit is at ≤ 14 days since last dose, the assessment is a valid 
assessment for efficacy analysis. The EOT result will be assigned to a 
scheduled visit based on the slotting algorithm. If an assessment already exists 
for the scheduled visit where the EOT is assigned, the assessment closest to 
the target study day for the visit will be used for analysis. 
For safety endpoints, the EOT result will be assigned to a scheduled visit based on 
the slotting algorithm.
11.3.4.
Analysis Visit Windows
Table - Analysis Visit Windows
Scheduled Visit
Target Study Day of 
Visit
Slotting Intervals
Week -6 
-42
Visit = ” SCREENING”
Week -4
-28
Visit = ” STANDARDIZATION 1”
Week -1
-7
Visit = ” STANDARDIZATION 4”
Baseline (Week 0)
1
Visit = ” BASELINE”
Week 4
29
2 to 32 days
Week 5
36
33 to 53 days
Week 10
71
54 to 99 days
Week 18
127
100 to 155 days
Week 26 (End of Treatment 
Visit)*
183
Albiglutide arm: 156  to (last dose date + 25 days)
Lispro arm: 156  to last dose date 
Week 30**
211
For subjects completed study
Albiglutide arm: >Last dose date + 25 days
Lispro arm: >Last dose date
4 Week Follow-up Visit**
Last dose date + 35 
days***
For subjects didn’t complete study
Albiglutide arm: >Last dose date + 25 days
Lispro arm: >Last dose date
* Week 26 is the end of treatment visit for those subjects completing the study per-protocol. For subjects who withdraw early from 
active treatment, the end of treatment visit will be assigned to an analysis visit based on the visit slotting algorithm using study day and 
therapy phase.
** Week 30 is the 4 week post-treatment follow-up visit for those subjects completing the study per-protocol. The 4 Week Follow-up 
Visit is the 4 week post-treatment follow-up visit for those subjects who withdraw early from active treatment. Both visits will be 
assigned based on the visit slotting algorithm using therapy phase.
*** The target study day for the 4 Week Follow-up Visit for subjects who withdraw early from active treatment is set to be 5 weeks (35 
days) after last dose to correspond with the timing of the 4 week post-treatment follow-up for subjects completing the study per-
protocol (where last dose is at Week 25 and the follow-up visit is at Week 30).
For parameters which were not scheduled to be collected at all visits, the all-
inclusive visit intervals defined for all visits (that is, the visit window table above) 
will still be used to slot records. However, if a value is slotted to a visit 
unscheduled for a parameter, it will not be summarized (and not be included in the 
efficacy datasets) but will be included in data listings.


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For analyses on the prescribed insulin dose, the total number of weekly insulin injections
and SMBG profile, visit and visit dates recorded on the eCRF are used for analysis
because a specific visit date is needed to calculate the analysis values.


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11.4.
Appendix 4: Treatment Periods
For classifying AEs (including hypoglycemic events), the therapy periods will be defined 
as: 

Pre-therapy: The onset date of the AE is before the start date of randomized 
study medication. If the onset date of the AE is on the start date of randomized 
study medication, the AE will be considered as on-therapy.

On-therapy: The onset date of the AE is on or after the start date of randomized 
study medication, and within last dose date plus 25 days in the albiglutide arm or 
within the last dose date in the lispro arm.

Post-therapy: The onset date of the AE is more than 25 days after the last dose 
date in the albiglutide arm or after the last dose date in the lispro arm.
For immunogenicity data and other safety parameters that are assessed prior to 
administration of randomized study medication on dosing days, the therapy periods will
be defined as:   

Pre-therapy: The assessment date is on or before the start date of randomized 
study medication. 

On-therapy: The assessment date is after the start date of randomized study 
medication, and within last dose date plus 25 days in the albiglutide arm or within 
the last dose date in the lispro arm.

Post-therapy: The assessment date is more than 25 days after the last dose date in 
the albiglutide arm or after the last dose date in the lispro arm.
For an AE with an incomplete start date where the year and month are present while the 
day is missing, or where the year is present while both month and day are missing, the 
date is imputed in a dynamic way consistent with the partial date information so that the 
resulting AE therapy period assignment based on the imputed date is the most 
conservative possible, where the order from the most to the least conservative is: on-
therapy phase > post-therapy phase > pre-therapy. Note that if the AE stop date is 
present, the imputed start date will always be on or prior to the stop date.
For the subjects in the insulin lispro + insulin glargine arm, the first drug dispense date 
recorded on eCRF after randomization is considered the starting date of treatment period. 
For the last dose date, it will be derived based on the last visit date. The last dose date 
will be Week 30 follow-up visit date for subject who completed the study, or the 4-week 
follow-up visit/end of study visit date for subjects who withdrew early.
For the subjects in the albiglutide + insulin glargine arm, the starting and last dose date 
will be derived based on the actual dose date of albiglutide in the exposure data set.


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11.5.
Appendix 5: Derived and Transformed Data
11.5.1.
Change from Baseline
The baseline value for an assessment is defined as the last available non-missing value 
prior to the first dose of the randomized treatment. Change from Baseline is defined as 
the postbaseline value minus the baseline value for the given assessment.
11.5.2.
Body Mass Index Calculation
Body mass index (BMI) will be calculated as follows:
BMI = weight (kg)
[height (m)]2
11.5.3.
Total Person Time on Treatment
The total person time on albiglutide treatment (in years) is defined as the total time on 
study medication between the time of the last dose date and the first dose date plus 26
days (to account for the long half-life of albiglutide) day and then divided by 365.25 
days/year. For insulin lispro, it defined as the duration of study drug exposure (defined as 
the total time between the last dispensed dose date of randomized treatment and the first 
dose date of randomized treatment plus 1 day) divided by 365.25 days/year.
11.5.4.
AE (Event) Density and Incidence Rate
AE density, also referred to as event density, will be calculated as the number of events in 
a given period divided by the total person time on treatment (in years) of subjects at risk 
at the beginning of the same period. The incidence rate for an AE will be calculated as 
the number of subjects experiencing that AE within a given period divided by the total 
person time on treatment (in years) of subjects at risk at the beginning of the same period.
To enhance the data presentation and to aid comparison between treatment groupings, all
AE densities and all incidence rates of AEs will be presented per 100 person-years (by 
multiplying the above defined statistics by 100).


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11.6.
Appendix 6: Premature Withdrawals & Handling of Missing 
Data
11.6.1.
Premature Withdrawal 
The reasons for subjects not completing the treatment period will be recorded as detailed 
in Section 4.5 of the protocol. Subjects who discontinue active participation in the study 
will no longer receive the randomized study medication. Immediately upon 
discontinuation from active participation in this study, these subjects should complete the 
early withdrawal assessments and return 4 weeks later for the follow-up assessments.
The reasons for subjects not completing the study will be recorded. Subjects who are 
withdrawn will not be replaced.
Per the protocol, insulin lispro may be re-introduced after Week 8 for subjects in the 
albiglutide treatment group, following a standardized, stepwise approach. Efficacy and 
safety assessments after the re-introduction of lispro will be included in the statistical 
analysis as is, without special handling.
11.6.2.
Missing Date Imputation
In general, partial dates will be imputed as follows:
A partial event start date, partial start dates of prior and concomitant medications or 
partial diagnosis date will be assumed to be the earliest possible date consistent with the 
partial date. 
o
If year is missing, the year will be assumed to be the year part of informed 
consent date of that subject; 
o
If month is missing, the month will be assumed to be January; 
o
If day is missing, it will be assumed to be the first day of the month. 
o
In the case of a completely missing start date, the start date will be assumed to be 
prior to date of the first administration of study drug. 
Partial event or medication stop dates will be assumed to be the latest possible date 
consistent with the partial date.
o
If month is missing, it will be assumed to be December; 
o
If day is missing, it will be assumed to be the last day of the month. 
o
In the case of completely missing stop date, the stop date will be assumed to be 
after the date of the last study visit; the event or medication are considered as 
ongoing.
For AE date imputation this rule will be followed but will be more conservative in nature 
consistent with the therapy phase (see Appendix 4: Treatment Periods for details).


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Since only the year of birth is recorded for subjects in this study, the age of the subjects 
for analysis purposes is calculated using June 30 of the birth year as the imputed subject 
birth date.
11.6.3.
Sensitivity Analysis on the Primary Efficacy Endpoint
Missing data are not explicitly imputed in the primary MMRM analysis; although there is 
an underlying assumption that data are missing at random, including those withdrawn for 
lack of efficacy. The MMRM method will produce an unbiased estimate of treatment 
effect under the missing at random (MAR) assumption. 
The sensitivity of the results of analysis to the method of handling missing values will be 
investigated, especially if the number of missing values is substantial or if the 
characteristics of missing values differ between treatment groups. 
11.6.3.1.
Extent of Missing Primary Analysis Data Endpoint
Missing data is expected to arise mainly from subjects missing complete visits. The 
amount of missing data for those baseline covariates included in the statistical analysis is 
expected to be none or at worst minimal. If it should occur, that subject will effectively 
be lost to analysis. Missing data for HbA1c between two non-missing visits will be 
considered missing at random (intermediate missing data).
In this study, subjects who withdraw from treatment will be withdrawn from the study. In 
the eCRF, the reason for treatment discontinuation and the reason for withdrawal from 
the study are collected separately. Whenever the HbA1c value at Week 26 is missing (end 
of the study), the reason can be determined based on available data in these two locations. 
The reason for missing data can be classified as follows: safety, procedural (including 
withdrawal of consent), or lack of efficacy.
11.6.3.2.
Reasons for Withdrawal
Reasons for withdrawal are assumed to fall into three broad categories:

Procedural (i.e. lost to follow-up, investigator site closed, withdrew consent, 
protocol deviation, and investigator discretion that are not related to study 
treatment): In this case, it is expected that an assumption of missing at random 
(MAR) is appropriate for imputation of HbA1c data after withdrawal.

Safety (i.e. AE; subject reached protocol-defined stopping criteria; withdrew 
consent, protocol deviation, and investigator discretion that are related to study 
treatment): It is expected that, in most cases, any change in safety related to these 
reasons for withdrawal would have been captured prior to the subject withdrawing 
from the study. In Study GLP108486 (albiglutide versus lispro over background 
glargine), 5% of subjects in the albiglutide group and <1% in the lispro group had 
AEs leading to withdrawal of active treatment through Week 26. In the albiglutide 
group, the most common AE leading to withdrawal was injection site reaction 
(1.1%). Missing HbA1c values after withdrawal due to safety concerns will be 
considered to possibly be missing not at random (MNAR).


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
Lack of efficacy: In this treat-to-target study, a substantial number of cases of 
withdrawal due to lack of efficacy is not expected. Missing HbA1c values after 
withdrawal due to lack of efficacy are considered to possibly be MNAR. 
Sensitivity analyses will be performed for data missing due to safety concerns or due to 
lack of efficacy.
11.6.3.3.
Handling of Missing Data
The impact of missing data will be explored, as outlined below, for the Full Analysis 
Population only.
Examination of Missing Data Patterns
To examine the nature of missing data, cohorts of subjects will be defined based on the 
scheduled assessments (HbA1c change from Baseline) that were completed at Weeks 4, 5, 
10, 18 and 26.
1.
Subjects who have Week 4 assessment only
2.
Subjects who have assessments up to and including Week 5 only
3.
Subjects who have assessments up to and including Week 10 only
4.
Subjects who have assessments up to and including Week 18 only
5.
Subjects who have assessments up to and including Week 26.
The number and percentage of subjects on each treatment in the 5 cohorts defined here 
will be tabulated. Graphical methods will be used to examine changes from Baseline over 
time to assess the pattern of outcomes prior to withdrawal.
Sensitivity Analyses – Multiple Imputation
Sensitivity analyses using multiple imputation methods will be conducted. Firstly, 
missing data between two non-missing time points will be considered missing at random.
The following multiple imputation methods are proposed based on whether data are 
missing at random or not at random:

All missing data assumed MAR: Imputation is based on means and
variances-covariances from subjects in the same treatment group as the withdrawn 
subject and is comparable to MMRM. The main differences are that this approach 
uses separate covariance parameter estimation for each arm, and also separate 
regression parameters are estimated on baseline covariates within each arm. This 
more complex parameterization of the imputation model compared with the 
analysis model is valid. This approach will be used for all data missing post 
withdrawal. Here the estimand is one where after withdrawal all subjects progress 
in a similar way to those who remain in the trial. We expect the MMRM and this 
to give similar answers. If so, then it indicates any difference between the primary 
MMRM analysis and multiple imputation sensitivity analysis is due to the 
assumed effect modification and the assumed rates of HbA1c increase after
withdrawal, rather than anything to do with going from an MMRM approach to a 
multiple imputation approach.

Missing due to lack of efficacy or due to safety concerns using last mean carried 
forward (LMCF), which is MNAR (Carpenter and Kenward (2013)) (Step 2 


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below). The imputed values based on LMCF will be then updated with an added 
delta using a constant rate of increase in HbA1c change from Baseline is 
experienced by subjects following withdrawal from the study for lack of efficacy 
or due to safety concerns (Step 3 below). The MAR approach will be used for 
missing data due to procedural reasons. Sensitivity analyses using the LMCF 
approach will be performed using the following rates of HbA1c increase: 
0%/month, 0.1%/month, and 0.2%/month to explore the potential impact as in a 
tipping-point analysis. For each treatment group, these 3 rates will be assumed, 
resulting in 9 scenarios. The resulting treatment differences and associated P-
values for non-inferiority will be tabulated against the varying rates of HbA1c
increase. This estimand is one where those who withdraw for lack of efficacy or 
for safety concerns are assumed to revert to an unstable treatment regimen with an 
increasing rate of HbA1c.
For each imputation data set, an analysis of variance will be carried using Week 26 data, 
both actual and imputed, using the same covariates as in the primary analysis. Contrasts 
of interest will be estimated and then combined across imputations using standard 
multiple imputation rules.
The details of implementing the multiple imputation assuming MAR and the multiple 
imputation using the LMCF approach are the following:

Step 1: Multiple Imputation under MAR (K=100 times)
o
Run PROC MI for all subjects BY treatment group (specifying the options 
chain=multiple in the MCMC statement). 
o
As a result 100 sets of mean vectors (µ) and variance-covariance matrices 
(∑) for each treatment group are simulated from the posterior distribution.
o
Each of the above 100 simulated parameter sets leads to a separate 
imputed dataset, in which the missing values (Y2) for each subject are 
replaced by values drawn randomly from their conditional distribution 
given the observed values (Y1). This condition distribution (Y2/Y1) is 
multinomial with mean µ2 + ∑21 ∑11-1 (Y1 - µ1) and variance-covariance 
matrix ∑22 - ∑21 ∑11-1 ∑12. So, 100 imputed datasets are generated.

Step 2: Multiple Imputation using LMCF (K=100 times)
o
For each imputed dataset from Step 1, update the imputed values (post-last 
observation) for only subjects who whtidraw due to lack of efficacy and 
safety concern as follows:

For each subject per treatment group, if there are any imputed 
values after the last observation (Yp, imp), first split the simulated 
mean vector (µ) into three parts: µb (prior to last obs), µlast (last 
obs) and µp (post last obs) and then update these imputed values as 
Y*p, imp=( Yp, imp - µp + µlast). Repeat for all subjects and for both 
treatment groups.
o
Repeat for the 100 imputed datasets from Step 1.

Step 3: Multiple Imputation using added delta value (K=100 times)
o
Calculate delta value for each subject at each visit post-last observation


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
Let 1  and 2 be the rates of HbA1c increase per month after the 
last observation for the Albiglutide and Insulin Lispro treatment 
group, respectively.

Let be the length of time between visits. Also, consider 1 
month=4 weeks and determine using the visit week values. For 
example, time between visits Week 16 and Week 20 is 4 weeks 
(i.e. 1 month) and time between visits Week 16 and Week 26 is 10 
weeks (i.e. 10/4=2.5 months). 

For each subject and each visit post-last observation, a delta value 
will be derived according to the treatment group the subject was 
randomized to and time between the last observation visit and the 
present visit (). If the subject belongs to the Albiglutide treatment 
group, the delta value = 1 x /4; if the subject belongs to the 
Insulin Lispro treatment group, the delta value = 2 x /4.
o
For each updated imputed dataset from Step 2 increase the imputed values 
post-last observation by the corresponding delta values (per subject per 
visit post-last observation).
o
Repeat for the 100 imputed datasets from Step 2

Step 4: 
o
Perform Step 1 only for one scenario under MAR with 100 imputed 
datasets generated
o
Repeat Step 1, Step 2 and Step 3 for additional 9 scenarios using 
LMCF/delta method  based on different rates of HbA1c increase for each 
treatment group 

1=0/month , 2=0/month

1=0/month , 2=0.1/month

1=0/month , 2=0.2/month

1=0.1/month , 2=0/month

1=0.1/month , 2=0.1/month

1=0.1/month , 2=0.2/month

1=0.2/month , 2=0/month

1=0.2/month , 2=0.1/month

1=0.2/month , 2=0.2/month

Step 5: For each of the above 10 scenarios, apply ANCOVA analysis at Week 26 
for each of the 100 imputed datasets and save the difference in LSmeans between 
treatment group  and the associated standard error from each of the 100 analyses.

Step 6: For each of the above 10 scenarios, combine the 100 set of analysis results 
using Rubin's rules (Rubin, 1987) via SAS PROC MIANALYZE. The treatment 
differences, confidence intervals and p-values will be estimated by 
MODELEFFECTS and STDERR statement. Use the degrees of freedom (EDF) 
you would have if the dataset were complete.


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11.6.3.4.
Sensitivity Analysis for Potential Data Integrity Issues
In case where there are data integrity issues, that could potentially impact the primary 
analysis outcome of the trial, we will perform a sensitivity analysis by excluding certain 
sites from the primary analysis.
One site in Poland (site ID = 
has been stopped due to significant GCP concerns.
A sensitivity analysis, with data from this site excluded, will be performed.  For this, the 
planned primary analysis will be generated without data from this site.  The results will 
be used to assess potential impact of data from this particular site on the primary analysis 
results.
PPD


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11.7.
Appendix 7: Values of Potential Clinical Importance
11.7.1.
Laboratory
Hematology
Laboratory 
Test
Units
Change from Baseline of 
Potential Clinical Concern 
Potential Clinical Concern 
Value 
Basophils
GI/L
None
None
Eosinophils
GI/L
None
None
Hematocrit
1
>0.1 decrease
>0.05 below LLN
>0.04 above ULN
Hemoglobin
g/L
>25 g/L decrease
>20 g/L below LLN 
>10 g/L above ULN
Lymphocytes
GI/L
None
<0.5 x LLN
Monocytes
GI/L
None
None
Neutrophils
GI/L
None
<1 GI/L
Neutrophil 
Bands
GI/L
None
None
Platelets
GI/L
None
<80 GI/L
>500 GI/L
Red Blood Cell 
Count
TI/L
None
None
Segmented  
Neutrophils
GI/L
None
<0.5 x LLN
White Blood Cell 
Count
GI/L
None
>1 GI/L below LLN 
>5 GI/L above ULN
Chemistry
Laboratory 
Test
Units
Change from Baseline of 
Potential Clinical Concern  
Potential Clinical Concern 
Value 
Albumin
g/L
None
>5 g/L above ULN or below LLN
Alkaline 
Phosphatase 
U/L
None
>3 x ULN
ALT
U/L
None
>3 x ULN
AST
U/L
None
>3 x ULN
Bicarbonate 
(Carbon Dioxide 
Content)
mmol/L
None
<16 mmol/L
> 40 mmol/L
Blood Urea 
Nitrogen
mmol/L
None
>2 x ULN
Calcitonin
pmol/L
None
>100
Calcium
mmol/L
None
<1.8 mmol/L


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Chemistry
Laboratory 
Test
Units
Change from Baseline of 
Potential Clinical Concern  
Potential Clinical Concern 
Value 
>3.0 mmol/L
Chloride
mmol/L
None
None
Creatinine 
umol/L
None
>159 umol/L
Direct Bilirubin
umol/L
None
>1.35 x ULN
Gamma 
Glutamyl 
Transferase
U/L
None
>3 x ULN
Glucose 
(fasting) 
mmol/L
None
<3 mmol/L
>22 mmol/L
Magnesium
mmol/L
None
<0.411 mmol/L
>1.644 mmol/L
Phosphorus
mmol/L
None
0.323 mmol/L above ULN or 
below LLN
Potassium
mmol/L
None
>0.5 mmol/L below LLN 
>1.0 mmol/L above ULN
Sodium
mmol/L
None
>5 mmol/L above ULN or below 
LLN
Total Bilirubin 
umol/L
None
>1.5 x ULN
Total Protein
g/L
None
>15 g/L above ULN or below 
LLN
Uric acid
umol/L
None
>654 umol/L
Free Fatty Acids
mmol/L
None
None
HDL Cholesterol
mmol/L
None
None
LDL Cholesterol
mmol/L
None
None
Triglycerides
mmol/L
None
> 9.04 mmol/L
Total 
Cholesterol
mmol/L
None
None
Urinalysis
Laboratory Test
Potential Clinical Concern Value     
Urinalysis 
Albumin/Creatinine 
Ratio
>29 mg/g  (>3.4 mg/mmol in SI units)


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Liver Function Tests
Laboratory Test
Potential Clinical Concern Value     
ALT
≥ 2 x ULN
≥ 3 x ULN
≥ 5 x ULN
≥ 8 x ULN
≥ 10 x ULN
≥ 3 x ULN and Total Bilirubin ≥ 2 x ULN
AST
≥ 2 x ULN
≥ 3 x ULN
≥ 5 x ULN
≥ 8 x ULN
≥ 10 x ULN
≥ 3 x ULN and Total Bilirubin ≥ 2 x ULN
Total Bilirubin
≥ 1.5 x ULN
≥ 2 x ULN
≥ 3 x ULN
≥ 5 x ULN
≥ 8 x ULN
≥ 10 x ULN
11.7.2.
Vital Signs
Parameter
Units
Change from Baseline of 
Potential Clinical Concern  
Potential Clinical 
Concern Value 
Systolic BP
mmHg
Decrease >30 mmHg 
Increase >30 mmHg
<100 mmHg
>170 mmHg
Diastolic BP
mmHg
Decrease >30 mmHg 
Increase >30 mmHg
<50 mmHg
>110 mmHg 
Heart rate
bpm
Decrease >30 bpm 
Increase >30 bpm 
<50 bpm
> 120 bpm


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11.7.3.
ECG
Parameter
Units
Change from Baseline of Potential Clinical 
Concern  
Potential Clinical 
Concern Value 
Heart Rate
bpm
None
Supine: < 50 or > 120
QRS interval
msec
Increase of > 25% when baseline QRS >100 msec 
Increase of > 50% when baseline QRS 100 msec
>200 msec 
QTcF 
msec
≥ 60 msec
≥500 msec
PR Interval
msec
Increase of > 25% when baseline PR >200 msec
Increase of > 50% when baseline PR 200 msec
>300 msec


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11.8.
Appendix 8: Multicenter Studies and Definition of 
Geographic Region for Statistical Analyses
Clinical sites will be clustered by geographic region since the number of subjects per 
clinical site is expected to be rather small. Geographic regions will be defined based on 
geographic proximity, similarity of medical practice in diabetes, and number of subjects 
per region. Subjects per region will be constrained such that the region with the largest 
sample size is no more than 3 times that of the region with the smallest sample size. The 
clustering will be finalized after clinical site selection and randomization are complete. 
Final classification of Geographic region for clinical sites:

Region 1: United States and Canada; 

Region 2: Mexico; 

Region 3: Brazil; 

Region 4: Poland and Hungary; 

Region 5: Germany, France, Spain, Italy and United Kingdom; 

Region 6: Philippines, South Africa and Korea.


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11.9.
Appendix 9: Examination of Covariates, Subgroups & Other 
Strata
11.9.1.
Strata and Covariates
The randomization for this study is stratified by the following baseline characteristics:

HbA1c at Screening (<8.0% versus ≥8.0%)

Age at randomization (<65 years versus ≥65 years)

Current use of metformin (metformin use versus no metformin use)
The primary analysis of HbA1c change from Baseline will use a mixed-effect model with 
repeated measures (MMRM), which includes HbA1c change from Baseline at all 
postbaseline visits as dependent variables; treatment, region, age category, current use of 
metformin, visit week, treatment-by-week interaction, and baseline HbA1c-by-week 
interaction as fixed effects; baseline HbA1c as a continuous covariate; and subject as a 
random effect. MMRM will only include non-missing observations therefore imputation 
will not be performed.
11.9.2.
Examination of Subgroups
The primary efficacy endpoint will be analyzed for the following subgroups using a
MMRM model described in Section 7.

Baseline HbA1c (<8.0%, ≥8.0%)

Gender (male, female)

Race (white, non-white)

Ethnicity (Hispanic, non-Hispanic)

Age at randomization (<65 years, ≥65 years) 

Baseline BMI (<25 kg/m2, ≥25 to <30 kg/m2, ≥30 to <35 kg/m2, ≥35 kg/m2)

Region (Region 1, Region 2, Region 3, Region4, Region5, Region 6)

Duration of Type II diabetes (< 8 years, >= 8 - <= 13 years, > 13 years)

Current use of metformin (metformin use, no metformin use)

Baseline FPG tertiles


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11.10.
Appendix 10: Multiple Comparisons & Multiplicity
A closed testing strategy will be implemented for the multiple inferential tests among the 
primary and key secondary endpoints to preserve overall family-wise Type I error rate of 
0.05. The strategy involves pre-specification of test order [Koch, 1996].
The first test to be conducted is the primary efficacy analysis of HbA1c change from 
Baseline at Week 26 on treatment comparison of albiglutide versus insulin lispro using 
non-inferiority testing. The comparison will be evaluated inferentially at the 1-sided
0.025 criterion significance level. If the non-inferiority of albiglutide is established,
testing of superiority for the key secondary endpoints and the primary endpoint will 
proceed sequentially in a step-down manner at a 2-sided significance level of 0.05 in the 
following order:
1) Change from Baseline in body weight at Week 26
2) Prescribed total daily insulin dose at Week 26
3) Change from baseline in HbA1c at Week 26
If a test for higher order endpoints above does not reach statistical significance, the 
results of statistical tests for lower order endpoints will not be interpreted.
Note that for one of the key secondary endpoints listed in the protocol, proportion of 
subjects treated with once-weekly albiglutide that are able to discontinue insulin lispro at 
Week 4 and do not meet prespecified criteria for severe, persistent hyperglycemia 
through Week 26, treatment comparison is not applicable as it is only defined for the 
Albiglutide + Insulin Glargine arm.
This is a treat-to-target study with the primary efficacy endpoint HbA1c as the 
measurement. By the study design of treat-to-target, change from baseline in HbA1c
values in both treatment groups (Albiglutide + Insulin Glargine versus Insulin Lispro + 
Insulin Glargine), is expected to reach the target, and thus not expected to show a
significant difference. Thus, testing of superiority for change from Baseline in HbA1c at 
Week 26 is considered lowest priority in the hierarchy of the multiple testing procedure.
Testing on other efficacy or exploratory endpoints, if applicable, will be considered 
exploratory and no multiplicity adjustment will be applied. Any secondary and 
exploratory endpoints that do not qualify for formal statistical testing will be analyzed 
and have results presented with confidence intervals and nominal p-values, if applicable.
The order of the testing strategy is shown in the diagram below.
Albiglutide + Insulin Glargine versus Insulin Lispro + Insulin Glargine


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Primary Efficacy Endpoint -
HbA1c Change from Baseline at
Primary Efficacy Endpoint -
HbA1c Change from Baseline at
Key Secondary Efficacy Endpoint 
1 - Percentage of subjects with 
Key Secondary Efficacy Endpoint 
2 - Change from Baseline in body 
Key Secondary Efficacy Endpoint 
3 - Total daily insulin dose at


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11.11.
Appendix 11: Model Checking and Diagnostics for 
Statistical Analyses
11.11.1.
Model Checking and Diagnostics for Statistical Analyses
1. Example SAS code for the primary efficacy analysis of the primary endpoint 
(Model 1)
ODS OUTPUT LSMeans= OUTLIBNAME.LSMeans SLICES= OUTLIBNAME.Diffs; 
PROC MIXED DATA= INDATA; 
   CLASS USUBJID TRT01PN REGION METFORMIN AGEGR1 AVISITN; 
   MODEL CHG = BASE TRT01PN REGION METFORMIN AGEGR1 AVISITN  
TRT01PN*AVISITN BASE*AVISITN /DDFM =KR ; 
   REPEATED AVISITN/SUB=USUBJID TYPE=UN;
   LSMEANS TRT01PN*AVISITN/SLICE=AVISITN CL DIFF;
   ESTIMATE 'Treatment difference at Week 26' 
   TRT01PN 1 -1
   TRT01PN*AVISITN  0 0  0 0 1
                    0 0  0 0 -1 /CL ;
RUN;
2. Example SAS code for the supportive analysis – interaction terms- of the primary 
endpoint
For HbA1c (Baseline HbA1c category: HBGR1): 
ODS OUTPUT LSMeans= OUTLIBNAME.LSMeans SLICES= OUTLIBNAME.Diffs; 
PROC MIXED DATA= INDATA; 
   CLASS USUBJID TRT01PN REGION METFORMIN AGEGR1 AVISITN HBGR1; 
   MODEL CHG = HBGR1 TRT01PN REGION METFORMIN AGEGR1 AVISITN  
TRT01PN*AVISITN HBGR1*AVISITN TRT01PN*HBGR1  
TRT01PN*HBGR1*AVISITN /DDFM =KR ; 
   REPEATED AVISITN/SUB=USUBJID TYPE=UN;
   LSMEANS TRT01PN*HBGR1*AVISITN/SLICE=AVISITN CL  DIFF;
   ESTIMATE 'Treatment difference at Week 26 for Baseline HbA1c 
Category < 8.0%' 
   TRT01PN 1 -1
   TRT01PN*AVISITN  0 0  0 0 1
0 0  0 0  -1
  TRT01PN*HBGR1*AVISITN   0 0 0 0 0 0 0 0  1  0
          0 0 0 0 0 0 0 0 -1  0 /CL ;
RUN;


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(or use the following statement to replace the ‘LSMEANS’ AND 
‘ESTIMATE’ statements above: 
SLICE HBR1*TRT01PN*AVISITN/SLICEBY(AVISITN=’26’) DIFF; and ODS 
table SLICETESTS to obtain p-value for the interaction at Week 26 
(AVISITN=26).
For Age category, Metformin use or Region: 
ODS OUTPUT LSMeans= OUTLIBNAME.LSMeans SLICES= OUTLIBNAME.Diffs; 
PROC MIXED DATA= INDATA; 
   CLASS USUBJID TRT01PN REGION METFORMIN AGEGR1 AVISITN; 
   MODEL CHG = BASE TRT01PN REGION METFORMIN AGEGR1 AVISITN  
TRT01PN*AVISITN BASE*AVISITN  TRT01PN*AGEGR1  
AVISITN*AGEGR1  TRT01PN*AGEGR1*AVISITN /DDFM =KR ; 
   REPEATED AVISITN/SUB=USUBJID TYPE=UN;
   LSMEANS TRT01PN*AGEGR1*AVISITN /SLICE=AVISITN CL DIFF;
   ESTIMATE 'Treatment difference at Week 26 for Age category < 65' 
   TRT01PN 1 -1
   TRT01PN*AVISITN       0 0  0 0 1
0 0  0 0  -1
  TRT01PN*AGEGR1*AVISITN  0
0 0 0
1 0 0 0  0  0
          0
0 0 0 -1 0 0 0
0  0 /CL ;
RUN;
Note: The contrasts may need to be adjusted for a different factor.
(or use the following statement to replace the ‘LSMEANS’ AND 
‘ESTIMATE’ statements above: 
SLICE HBR1*TRT01PN*AVISITN/SLICEBY(AVISITN=’26’) DIFF; and ODS 
table SLICETESTS to obtain p-value for the interaction at Week 26 
(AVISITN=26).
3. Example SAS code for the by-subgroup analysis of the primary endpoint
Take by-FPG Tertiles as an example
ODS OUTPUT LSMeans= OUTLIBNAME.LSMeans SLICES= OUTLIBNAME.Diffs; 
PROC MIXED DATA= INDATA; 
   CLASS USUBJID TRT01PN REGION METFORMIN AGEGR1 FPG_TTL AVISITN; 
   MODEL CHG= BASE TRT01PN REGION METFORMIN AGEGR1 FPG_TTL
AVISITN  TRT01PN*AVISITN BASE*AVISITN
TRT01PN*FPG_TTL FPG_TTL*AVISITN 
TRT01PN*FPG_TTL*AVISITN /DDFM =KR ; 
   REPEATED AVISITN/SUB=USUBJID TYPE=UN;
   LSMEANS TRT01PN*FPG_TTL*AVISITN/SLICE=AVISITN CL DIFF;
ESTIMATE 'Treatment difference at Week 26 for 1st Baseline FPG 
Tertile' 
TRT01PN -1 1
TRT01PN*AVISITN       
0 0 0 0  1 0 0 0 0 -1
   TRT01PN*FPG_TTL*AVISITN  0 0 0 0 1 0 0 0 0  0
0 0 0 0  0 0 0 0 0 -1
0 0 0 0  0 0 0 0 0  0 /CL ;
RUN;
For Age category


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Use the same SAS code for the supportive analysis on 
interaction terms.
For Baseline HbA1c category
ODS OUTPUT LSMeans= OUTLIBNAME.LSMeans SLICES= OUTLIBNAME.Diffs; 
PROC MIXED DATA= INDATA; 
   CLASS USUBJID TRT01PN REGION METFORMIN AGEGR1 HBGR1 AVISITN; 
   MODEL CHG= HBGR1 TRT01PN REGION METFORMIN AGEGR1 AVISITN  
TRT01PN*AVISITN HBGR1*AVISITN 
TRT01PN*HBGR1*AVISITN/DDFM =KR ; 
   REPEATED AVISITN/SUB=USUBJID TYPE=UN;
   LSMEANS TRT01PN*AVISITN/SLICE=AVISITN CL DIFF;
   ESTIMATE 'Treatment difference at Week 26 for Baseline HbA1c 
<8.0%' 
   TRT01PN -1 1
   TRT01PN*AVISITN       0 0 0 0 1 0 0 0 0 -1
   TRT01PN*HBGR1*AVISITN 0
0 0 0  1 0 0 0  0  0
                    
0  0 0 0 -1 0 0 0
0  0 /CL ;
RUN;
4. Example SAS code for key secondary efficacy endpoints Weight, Insulin dose etc 
(Model 2)
ODS OUTPUT LSMeans= OUTLIBNAME.LSMeans SLICES= OUTLIBNAME.Diffs; 
PROC MIXED DATA= INDATA; 
   CLASS USUBJID TRT01PN REGION METFORMIN AGEGR1 AVISITN HBGR1; 
   MODEL CHG= BASE TRT01PN HBGR1 REGION METFORMIN AGEGR1 AVISITN  
TRT01PN*AVISITN BASE*AVISITN /DDFM =KR ; 
   REPEATED AVISITN/SUB=USUBJID TYPE=UN;
   LSMEANS TRT01PN*AVISITN/SLICE=AVISITN CL DIFF;
   ESTIMATE 'Treatment difference at Week 26' 
   TRT01PN -1 1
   TRT01PN*AVISITN  0 0  0 0 -1
                    0 0  0 0  1 /CL ;
RUN;
Note: The contrasts may need to be adjusted for an endpoint that has a different 
visit scheme from that of HbA1c.
5. Example SAS code for analysis on FPG change from baseline by baseline FPG 
tertiles
ODS OUTPUT LSMeans= OUTLIBNAME.LSMeans SLICES= OUTLIBNAME.Diffs; 
PROC MIXED DATA= INDATA; 
CLASS USUBJID TRT01PN REGION METFORMIN AGEGR1 HBGR1 FPG_TTL
AVISITN; 
   MODEL CHG= FPG_TTL HBGR1 TRT01PN REGION METFORMIN AGEGR1
AVISITN TRT01PN*AVISITN TRT01PN*FPG_TTL
FPG_TTL*AVISITN TRT01PN*FPG_TTL*AVISITN /DDFM =KR; 
   REPEATED AVISITN/SUB=USUBJID TYPE=UN;
   LSMEANS TRT01PN*FPG_TTL*AVISITN/SLICE=AVISITN CL DIFF;
ESTIMATE 'Treatment difference at Week 26 for 1st Baseline FPG 
Tertile' 
TRT01PN -1 1
TRT01PN*AVISITN       
0 0 0 0  1 0 0 0 0 -1


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   TRT01PN*FPG_TTL*AVISITN  0 0 0 0 1 0 0 0 0  0
0 0 0 0  0 0 0 0 0 -1
0 0 0 0  0 0 0 0 0  0 /CL ;
RUN;
5. Example SAS code for analysis on exposure-adjusted event rate with Poisson 
regression model
ODS OUTPUT LSMeans= Lsmeans Diffs=Diffs; 
proc genmod data=INDATA;
   class USUBJID TRT01AN MCRIT2ML HBGR1 AGEGR1 METFMN CTRYGR1;
   model NUMEVT1=TRT01AN MCRIT2ML HBGR1 AGEGR1 METFMN CTRYGR1/ 
d=poisson offset=PYOFFSET;
   repeated SUBJECT=USUBJID /corrw covb type=exch;
   LSMEANS TRT01AN/ EXP ILINK E CL DIFF;
run;


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11.12.
Appendix 12: Sample Size Considerations
The primary hypothesis to be tested is that albiglutide plus insulin glargine (with or 
without metformin) will provide glycemic control (as measured by HbA1c change from 
Baseline) noninferior to insulin lispro plus insulin glargine (with or without metformin) 
after 26 weeks of treatment in subjects with T2DM inadequately controlled on their 
current regimen of basal-bolus insulin therapy. If the null hypothesis of albiglutide 
inferiority is rejected, a test of superiority will be applied.
Approximately 794 subjects will be randomly assigned in a 1:1 ratio to 2 treatment 
groups. Eligible subjects will be stratified by screening HbA1c value (<8.0% versus 
≥8.0%), age (<65 years versus ≥65 years), and use of metformin (metformin use versus 
no metformin use). Assuming that 15% of subjects will be withdrawn early or will be lost 
to follow-up, approximately 337 subjects in each treatment group will complete 26 weeks 
of study assessments.
With 337 completed subjects in each of the 2 treatment groups, the study will have at 
least 90% power to reject the null hypothesis of inferiority for HbA1c change from 
Baseline, assuming a non-inferiority margin of 0.3%, an expected treatment group 
difference of 0.0%, and a standard deviation of 1.2%, using a 2-sample, 1-sided t test 
with a test-wise significance level of 0.025.
If non-inferiority of albiglutide is established, superiority of albiglutide versus insulin 
lispro will be tested. Given the sample size of 337 completed subjects per treatment 
group and assuming a common standard deviation of 1.2, the minimum detectable 
difference in means between albiglutide and insulin lispro resulting in a significant test is 
0.18, with a power of 50% and a type I error rate of 0.05.


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11.13.
Appendix 13: Abbreviations & Trade Marks
11.13.1.
Abbreviations & Trade Marks
List of Abbreviations
AE 
Adverse Event
AIC                             Akaike information criterion
ALP 
alkaline phosphatase
ALT 
alanine aminotransferase
AST 
aspartate aminotransferase
β-HCG 
β-human chorionic gonadotropin
CMH test                    Cochran-Mantel-Haenszel test
CV 
cardiovascular
dL 
deciliter
ECG 
electrocardiogram
eCRF 
electronic case report form
eGFR 
estimated glomerular filtration rate
FA 
full analysis
FPG 
fasting plasma glucose
FSG
fasting serum glucose
g 
gram
GCP
Good clinical practice
GI 
gastrointestinal
GSK 
GlaxoSmithKline
HbA1c
glycosylated hemoglobin
HFS-II 
hypoglycemia fear survey-II
ICH 
International Conference on Harmonisation
IU 
international unit
kg 
kilogram
L 
liter
LMCF 
last mean carried forward
m 
meter
MAR 
missing at random
MedDRA 
Medical Dictionary for Regulatory Activities
mg 
milligram
MI 
myocardial infarction
min 
minute
mL 
milliliter
mmol 
millimole
MMRM 
mixed-effect model with repeated measures
MNAR 
missing not at random
PK 
pharmacokinetic
PP 
per-protocol
PT                               Preferred Term
RAP 
reporting and analysis plan
SAC                            Statistical Analysis Complete
SAE 
serious adverse event


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SMBG 
self-monitored blood glucose
SOC                            System Organ Class
SU 
sulfonylurea
T2DM 
type 2 diabetes mellitus
TEAE                         Treatment Emergent Adverse Event
TRIM-Diabetes 
treatment-related impact measure for diabetes
TSH 
thyroid-stimulating hormone
ULN 
upper limit of normal
Trademark Information
Trademarks of the GlaxoSmithKline
group of companies
None
Trademarks not owned by the
GlaxoSmithKline group of companies
HFS-II
Humalog
Lantus
MedDRA
TRIM-Diabetes


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11.14.
Appendix 14: List of Data Displays
11.14.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.01 to 1.46
N/A
Efficacy
2.01 to 2.701
2.01 to 2.92
Safety
3.01 to 3.348
3.01 to 3.71
Other Analysis
Section
Listings
ICH Listings
1 to 44
Other Listings
101 to 170
11.14.2.
Mock Example Numbering
Non IDSL specifications will be referred as detailed below and where appropriate an 
example mock-up table is provided in a separate shell document:
Section
Figure
Table
Listing
Study Population
Efficacy
Safety
Other Analysis
NOTE:

Non-Standard displays are indicated in the IDSL / TST ID / Example Shell’ or Programming Notes’ column as 
‘[Non-Standard] + Reference.’


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11.14.3.
Study Population Tables
Study Population Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subjection Disposition, Demographics and Baseline Characteristics
1.01
FA
Subject Disposition
1.02
Summary of Study Enrollment and Reasons for Screening 
Failures and Standardization Failures
1.03
FA
Reasons for Withdrawal from Study
1.04
FA
Reasons for Discontinuing Study Treatment
1.05
FA
Subject Status by Visit
1.06
FA
Subjects Randomized across Sites
1.07
FA
Inclusion/Exclusion Criteria Deviations
1.08
FA
Significant Protocol Deviations
1.09
FA
Demographics and Baseline Characteristics
1.10
FA
Geographic Ancestry
1.11
FA
Substance Use
Medical History
1.21
Safety
Medical and Family History Status
1.22
Safety
Current and/or Past Cardiovascular Medical History
1.23
Safety
Current and/or Past Diabetes Related Conditions
1.24
Safety
Duration of Diabetes Disease History
1.25
Safety
Current and/or Past Medical/Surgical Procedure History
1.26
Safety
Current and/or Past Gastrointestinal Medical Conditions
1.27
Safety
Current and/or Past Nephropathy (Including 
Microalbuminuria) and Kidney Injury History


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Study Population Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.28
Safety
Current and/or Past Cancer History
1.29
Safety
Current and/or Past Pneumonia Medical History
1.30
Safety
Current and/or Past Skin Medical Conditions
1.31
Safety
Current and/or Past Thyroid Medical History
1.32
Safety
Current and/or Past Other Medical History
Medications and Non-drug Therapies
1.41
Safety
Prior Medications
1.42
Safety
Concomitant Medications
1.43
Safety
Post-therapy Medications


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11.14.4.
Efficacy Tables
Efficacy: Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Change from Baseline in HbA1c
2.01
FA
Analysis of Change from Baseline in HbA1c (%) at Week 
26
2.02
FA
Statistical Output Supporting the Analysis of Change from 
Baseline in HbA1c (%) at Week 26
2.03
FA
Analysis of Selected Interaction Terms in MMRM Model 
for Change from Baseline in HbA1c (%) at Week 26
2.04
FA
Statistical Output Analysis of Selected Interaction Terms 
in MMRM Model for Change from Baseline in HbA1c (%) at 
Week 26
2.05
Per-
Protocol
Analysis of Change from Baseline in HbA1c (%) at Week 
26 for Per-Protocol Population
2.06
FA
Analysis of Change from Baseline in HbA1c (%) at Week 
26 by Baseline HbA1c Category
2.07
FA
Analysis of Change from Baseline in HbA1c (%) at Week 
26 by Age Category at Randomization
2.08
FA
Analysis of Change from Baseline in HbA1c (%) at Week 
26 by Region
2.09
FA
Analysis of Change from Baseline in HbA1c (%) at Week 
26 by Current Use of Metformin
2.10
FA
Analysis of Change from Baseline in HbA1c (%) at Week 
26 by Gender
2.11
FA
Analysis of Change from Baseline in HbA1c (%) at Week 
26 by Race


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Efficacy: Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.12
FA
Analysis of Change from Baseline in HbA1c (%) at Week 
26 by Ethnicity
2.13
FA
Analysis of Change from Baseline in HbA1c (%) at Week 
26 by Baseline BMI Category
2.14
FA
Analysis of Change from Baseline in HbA1c (%) at Week 
26 by Duration of Type II Diabetes Category
2.15
FA
Sensitivity Analysis of Change from Baseline in HbA1c 
(%) at Week 26
2.16
FA
Examination of the Pattern of Missing HbA1c Values
2.17
FA
Summary Statistics for HbA1c (%) by Visit
2.18
FA
Analysis of Change from Baseline in HbA1c (%) over 
Time
2.19
FA
Summary Statistics for HbA1c (%) by Visit and Baseline 
Fasting Plasma Glucose Tertiles
2.20
FA
Analysis of Change from Baseline in HbA1c (%) at Week 
26 by Baseline Fasting Plasma Glucose Tertiles
2.21
FA
Sensitivity Analysis of Change from Baseline in HbA1c 
(%) at Week 26 Excluding All Data from One Site in 
Poland Closed Due to Significant GCP Concerns
Subjects Treated with Once-Weekly Albiglutide That Are Able to Discontinue Insulin Lispro at Week 4 and Do Not Meet Prespecified Criteria for Severe, 
Persistent Hyperglycemia through Week 26
2.31
FA
Proportion of Subjects Treated with Once-weekly 
Albiglutide That Are Able to Totally Replace Prandial 
Insulin without Re-introduction of Inuslin Lispro through 
Week 26


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Efficacy: Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.32
FA
Summary Characteristics of Albiglutide-treated Subjects 
by Prescribed Lispro Re-introduction Status (Albiglutide-
treated Subjects Only)
2.33
FA
Summary Statistics of Prescribed Total Lispro Daily Dose 
for Subjects Taking Re-introduced Lispro by Visit 
(Albiglutide-treated Subjects Only)
2.34
FA
Summary of Number of Lispro (Prescribed) Injections per 
Day by Visit (Albiglutide-treated Subjects Only)
Severe or Documented Symptomatic Hypoglycemia
2.41
FA
Summary of Subjects with Severe or Documented 
Symptomatic Hypoglycemia through Week 26 by Baseline 
HbA1c Category, Age Category, Region, and Current Use 
of Metformin
2.42
FA
Percentages of Subjects with Severe or Documented 
Symptomatic Hypoglycemia through Week 26
2.43
FA
Percentages of Subjects with Severe or Documented 
Symptomatic Hypoglycemia through Week 26 – Excluding 
Early Withdrawals
Change and Percent Change from Baseline in Body Weight
2.51
FA
Analysis of Change from Baseline in Body Weight (Kg) by 
Visit
2.52
FA
Analysis of Percent Change from Baseline in Body Weight 
(Kg) by Visit
2.53
FA
Summary Statistics for Body Weight (Kg) by Visit
2.54
FA
Summary Statistics for Percent Change from Baseline in 
Body Weight (Kg) by Visit
Prescribed Insulin Dose and Number of Injections


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Efficacy: Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.61
FA
Analysis of Prescribed Total Daily Insulin Dose (IU) at 
Baseline, Week 4, Week 5, Week 10, Week 18 and Week 
26
2.62
FA
Analysis of Body Weight Adjusted Prescribed Total Daily 
Insulin Dose (IU/Kg) at Baseline, Week 4, Week 5, Week 
10, Week 18 and Week 26
2.63
FA
Analysis of Prescribed Total Daily Basal Insulin (Insulin 
Glargine) Dose (IU) at Baseline, Week 4, Week 5, Week 
10, Week 18 and Week 26
2.64
FA
Analysis of Body Weight Adjusted Prescribed Total Daily 
Basal Insulin (Insulin Glargine) Dose (IU/Kg) at Baseline, 
Week 4, Week 5, Week 10, Week 18 and Week 26
2.65
FA
Analysis of Prescribed Total Daily Bolus Insulin (Insulin 
Lispro) Dose (IU) at Baseline, Week 4, Week 5, Week 10, 
Week 18 and Week 26
2.66
FA
Analysis of Body Weight Adjusted Prescribed Total Daily 
Bolus Insulin (Insulin Lispro) Dose (IU/Kg) at Baseline, 
Week 4, Week 5, Week 10, Week 18 and Week 26
2.67
FA
Summary Statistics for Prescribed Insulin Dose
2.68
FA
Summary Statistics for Total Number of Weekly Insulin 
Injections
Change from Baseline in Fasting Plasma Glucose
2.75
FA
Summary Statistics for Fasting Plasma Glucose (mmol/L) 
by Visit
2.76
FA
Analysis of Change from Baseline in Fasting Plasma 
Glucose (mmol/L) by Visit


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Efficacy: Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.77
FA
Summary Statistics for Change from Baseline in Fasting 
Plasma Glucose (mmol/L) by Visit and Baseline Fasting 
Plasma Tertiles
2.78
FA
Analysis of Change from Baseline in Fasting Plasma 
Glucose (mmol/L) at Week 26 by Baseline Fasting Plasma 
Tertiles
2.79
FA
Statistical Output for the Analysis of Correlation between 
Fasting Plasma Glucose (mmol/L) and Fasting Serum 
Glucose (mmol/L) at Screening Visit
Subjects Achieving HbA1c Target Response
2.81
FA
Analysis of Proportion of Subjects Achieving HbA1c < 
6.5% Response by Visit
2.82
FA
Analysis of Proportion of Subjects Achieving HbA1c < 
7.0% Response by Visit
2.83
FA
Analysis of Proportion of Subjects Achieving HbA1c < 
7.0% Response without Weight Gain at Week 26
2.84
FA
Analysis of Proportion of Subjects Achieving HbA1c < 
7.0% Response without Severe or Documented 
Symptomatic Hypoglycemia at Week 26
2.85
FA
Analysis of Proportion of Subjects Achieving HbA1c < 
7.0% Response without Weight Gain and without Severe 
or Documented Symptomatic Hypoglycemia at Week 26
2.86
FA
Analysis of Proportion of Subjects Achieving HbA1c < 
6.5% Response by Visit, Considering Missing HbA1c 
Values
2.87
FA
Analysis of Proportion of Subjects Achieving HbA1c < 
7.0% Response by Visit, Considering Missing HbA1c 
Values


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Efficacy: Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subjects Who Meet Prespecified Criteria for Severe, Persistent Hyperglycemia
2.101
FA
Analysis of Proportion of Subjects Who Meet Prespecified 
Criteria for Severe, Persistent Hyperglycemia at Week 26
2.102
FA
Kaplan-Meier Analysis of Time to Meeting Prespecified 
Criteria for Severe, Persistent Hyperglycemia
2.103
FA
Summary Statistics for Proportion of Subjects Meeting 
Prespecified Criteria for Severe, Persistent Hyperglycemia
Other Exploratory Endpoints
2.201
FA
Summary Statistics for TRIM-Diabetes Questionnaire 
Total and Individual Domain Scores by Visit
2.202
FA
Analysis of Change from Baseline in TRIM-Diabetes 
Questionnaire Total Score over Time
2.203
FA
Analysis of Change from Baseline in TRIM-Diabetes 
Questionnaire Treatment Burden Score Over Time
2.204
FA
Analysis of Change from Baseline in TRIM-Diabetes 
Questionnaire Daily Life Score over Time
2.205
FA
Analysis of Change from Baseline in TRIM-Diabetes 
Questionnaire Diabetes Management Score over Time
2.206
FA
Analysis of Change from Baseline in TRIM-Diabetes 
Questionnaire Compliance Score over Time
2.207
FA
Analysis of Change from Baseline in TRIM-Diabetes 
Questionnaire Psychological Health Score over Time
2.301
FA
Summary Statistics for HFS-II Questionnaire Worry 
Subscale Total Score by Visit
2.302
FA
Analysis of Change from Baseline in HFS-II Questionnaire 
Worry Subscale Total Score over Time


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Efficacy: Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.401
FA
Summary Statistics for 8-Point Self-Monitored Blood 
Glucose (mmol/L) Profile by Visit
2.402
FA
Summary Statistics for Daily Average Glucose 
Concentration from 8-Point Self-Monitored Blood Glucose 
(mmol/L) Profile by Visit
2.403
FA
Analysis of Change from Baseline in Daily Average 
Glucose Concentration from 8-Point Self-Monitored Blood 
Glucose Concentration (mmol/L) Over Time
2.501
FA
Analysis of Proportion of Subjects with <= 1 Kg Weight 
Gain at Week 26
2.601
FA
Analysis of Proportion of Subjects Achieving HbA1c < 
7.0% without Weight Gain and Without Hypoglycemia with 
Plasma Glucose <3.1 mmol/L (<56 mg/dL) Regardless of 
Symptoms at Week 26
2.701
FA
Proportion of Subjects Treated with Once-weekly 
Albiglutide That Are Able to Totally Replace Prandial 
Insulin without Re-introduction of Inuslin Lispro and 
without Worsening HbA1c Control at Week 26


CONFIDENTIAL
GSK 200977
93
11.14.5.
Efficacy Figures
Efficacy: Figures
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Change from Baseline in HbA1c
2.01
FA
Line Graph of Mean (+/- SE) of HbA1c (%) by Visit
2.02
FA
Line Graph of Mean (+/- SE) of Change from Baseline in 
HbA1c (%) by Visit
2.03
FA
Line Graph of LS Mean (+/- SE) of Change from Baseline 
in HbA1c (%) by Visit
2.04
FA
Model-adjusted Change from Baseline in HbA1c (%) for 
Albiglutide vs. Insulin Lispro and 95% CI at Week 26
2.05
FA
Line Graph of Mean of Change from Baseline in HbA1c 
(%) by Missing Data Patterns and Treatment
Change and Percent Change from Baseline in Body Weight
2.21
FA
Line Graph of Mean (+/- SE) of Body Weight (Kg) by Visit
2.22
FA
Line Graph of Mean (+/- SE) of Change from Baseline in 
Body Weight (Kg) by Visit
2.23
FA
Line Graph of LS Mean (+/- SE) of Change from Baseline 
in Body Weight (Kg)
2.24
FA
Model-adjusted Change from Baseline in Body Weight 
(Kg) for Albiglutide vs. Insulin Lispro and 95% CI at Week 
26
2.25
FA
Line Graph of Mean (+/- SE) of Percent Change from 
Baseline in Body Weight (%) by Visit
2.26
FA
Line Graph of LS Mean (+/- SE) of Percent Change from 
Baseline in Body Weight (%)


CONFIDENTIAL
GSK 200977
94
Efficacy: Figures
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.27
FA
Model-adjusted Percent Change from Baseline in Body 
Weight (%) for Albiglutide vs. Insulin Lispro and 95% CI at 
Week 26
Prescribed Insulin Dose and Number of Injections
2.41
FA
Line Graph of Mean (+/- SE) of Prescribed Daily Insulin 
Dose (IU) by Visit
2.42
FA
Line Graph of Mean (+/- SE) of Body Weight Adjusted 
Prescribed Daily Insulin Dose (IU/Kg) by Visit
2.43
FA
Line Graph of LS Mean (+/- SE) of Prescribed Daily 
Insulin Dose (IU) by Visit
2.44
FA
Line Graph of LS Mean (+/- SE) of Body Weight Adjusted 
Prescribed Daily Insulin Dose (IU/Kg) by Visit
2.45
FA
Model-adjusted Prescribed Total Daily Insulin Dose (IU) 
for Albiglutide vs. Insulin Lispro and 95% CI at Week 26
Change from Baseline in Fasting Plasma Glucose
2.61
FA
Line Graph of Mean (+/- SE) of Fasting Plasma Glucose 
(mmol/L) by Visit
2.62
FA
Line Graph of Mean (+/- SE) of Change from Baseline in 
Fasting Plasma Glucose (mmol/L) by Visit
2.63
FA
Line Graph of LS Mean (+/- SE) of Change from Baseline 
in Fasting Plasma Glucose (mmol/L) by Visit
2.64
FA
Model-adjusted Change from Baseline in Fasting Plasma 
Glucose (mmol/L) for Albiglutide vs. Insulin Lispro and 
95% CI at Week 26
Meeting Prespecified Criteria for Severe, Persistent Hyperglycemia
2.71
FA
Kaplan-Meier Plot of Time to Meeting Prespecified Criteria 
for Severe, Persistent Hyperglycemia


CONFIDENTIAL
GSK 200977
95
Efficacy: Figures
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Other Endpoints
2.81
FA
Line Graph of Mean (+/- SE) of Glucose Concentration 
from 8-Point Self-Monitored Blood Glucose (mmol/L) 
Profile by Visit and Time Points
2.91
FA
Bar Plot for Proportion of Subjects Achieving HbA1c < 
7.0% Response by Visit
2.92
FA
Bar Plot for Proportion of Subjects Achieving HbA1c < 
6.5% Response by Visit


CONFIDENTIAL
GSK 200977
96
11.14.6.
Safety Tables
Safety : Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Exposure to Treatment
3.01
Safety
Exposure to Treatment
Treatment Compliance
3.02
Safety
Treatment Compliance
Adverse Events
3.11
Safety
Overview of Adverse Events
3.12
Safety
All On-therapy and Post-therapy Adverse Events
3.13
Safety
Pre-therapy Adverse Events
3.14
Safety
On-therapy Adverse Events
3.15
Safety
Most Common On-therapy Adverse Events
3.16
Safety
Post-therapy Adverse Events
3.17
Safety
On-Therapy Adverse Events and the Information on 
Relation to Treatment
3.18
Safety
On-therapy Adverse Events by Time of Onset With 12-
Weeks Intervals
3.19
Safety
On-therapy Non-serious Adverse Events
3.20
Safety
On-Therapy Non-serious Adverse Events with Incidence 
of Preferred Term >=5% in Any Treatment Group and the 
Information on Relation to Treatment
3.21
Safety
On-therapy and Post-therapy Adverse Events Related to 
Individual Study Treatment
3.22
Safety
On-therapy Treatment-related Adverse Events  


CONFIDENTIAL
GSK 200977
97
Safety : Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.23
Safety
Post-therapy Treatment-related Adverse Events
3.24
Safety
On-therapy and Post-therapy Treatment-related Adverse 
Events
3.31
Safety
On-therapy and Post-therapy Adverse Events by 
Maximum Intensity
3.32
Safety
On-therapy Adverse Events by Maximum Intensity
3.33
Safety
Post-therapy Adverse Events by Maximum Intensity
3.34
Safety
On-therapy and Post-therapy Adverse Events by 
Maximum Intensity
3.41
Safety
Pre-therapy Serious Adverse Events  
3.42
Safety
On-therapy Serious Adverse Events
3.43
Safety
On-Therapy Serious Adverse Events and the Information 
on Relation to Treatment
3.44
Safety
Post-therapy Serious Adverse Events
3.45
Safety
On-therapy Treatment-related Serious Adverse Events
3.46
Safety
Post-therapy Treatment-related Serious Adverse Events
3.47
Safety
On-Therapy Fatal Serious Adverse Events and the 
Information on Relation to Treatment
3.48
Safety
On-Therapy Non-fatal Serious Adverse Events and the 
Information on Relation to Treatment
3.51
Safety
On-therapy Adverse Events Leading to Permanent 
Discontinuation of the Randomized Study Drug
3.52
Safety
On-therapy Adverse Events Leading to Withdrawal from 
Study
AE of Special Interest


CONFIDENTIAL
GSK 200977
98
Safety : Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.61
Safety
Overview of On-therapy Adverse Events of Special 
Interest
3.71
Safety
On-therapy Hypoglycemic Events by SAE Status, 
Relationship to Study Medication, and Withdrawal Status
3.72
Safety
On-therapy Hypoglycemic Events by Treatment, 
Symptom, Severity, Intervention and Action Taken
3.73
Safety
On-therapy Hypoglycemic Events by Blood Glucose Level
3.74
Safety
On-therapy Daytime and Nocturnal Hypoglycemic Events
3.75
Safety
On-therapy Hypoglycemic Events with Confirmed Home 
Plasma Glucose Monitoring <3.9 mmol/L and/or Requiring
Third Party Intervention by Intervals for Time of Onset
3.76
Safety
Analysis of Exposure-adjusted Incidence Rate of On-
therapy Severe, Documented Symptomatic or 
Asymptomatic Hypoglycemic Events
3.77
Safety
Analysis of Exposure-adjusted Incidence Rate of On-
therapy Severe Hypoglycemic Events
3.78
Safety
Analysis of Exposure-adjusted Incidence Rate of On-
therapy Documented Symptomatic Hypoglycemic Events
3.79
Safety
Analysis of Exposure-adjusted Incidence Rate of On-
therapy Asymptomatic Hypoglycemic Events
3.80
Safety
On-therapy Hypoglycemic Events Over Time by Onset 
Week
3.91
Safety
On-therapy and Post-therapy Cardiovascular Adverse 
Events
3.101
Safety
On-therapy and Post-therapy Thyroid Adverse Events 
Reported by the Investigator


CONFIDENTIAL
GSK 200977
99
Safety : Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.102
Safety
On-therapy and Post-therapy Thyroid Adverse Events 
Identified by a Customized MedDRA Query
3.111
Safety
Summary of Gastrointestinal Adverse Events
3.112
Safety
On-therapy Gastrointestinal Adverse Events
3.113
Safety
On-therapy Serious Gastrointestinal Adverse Events
3.114
Safety
On-therapy Treatment-related Gastrointestinal Adverse 
Events
3.115
Safety
On-therapy Gastrointestinal Adverse Events Leading to 
Permanent Discontinuation of Study Treatment before 
Scheduled End of Treatment Period
3.116
Safety
On-therapy Gastrointestinal Adverse Events Over Time
3.117
Safety
On-therapy Gastrointestinal Adverse Events by Onset 
Week
3.118
Safety
Kaplan-Meier Analysis of Time to First Occurrence of On-
therapy Gastrointestinal Adverse Event
3.119
Safety
On-therapy Nausea Over Time
3.120
Safety
On-therapy Diarrhea Over Time
3.121
Safety
On-therapy Vomiting Over Time
3.122
Safety
On-therapy Nausea or Vomiting Over Time
3.131
Safety
On-therapy and Post-therapy Potential System Allergic 
Reactions Identified by the Investigator
3.132
Safety
On-therapy and Post-therapy System Allergic Reactions 
Identified by a Customized MedDRA Query
3.133
Safety
Kaplan-Meier Analysis of Time to First Occurrence of On-
therapy Systemic Allergic Reaction Reported by the 
Investigator


CONFIDENTIAL
GSK 200977
100
Safety : Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.134
Safety
Kaplan-Meier Analysis of Time to First Occurrence of On-
therapy Systemic Allergic Reaction Identified by a 
Customized MedDRA Query
3.141
Safety
On-therapy and Post-therapy Injection Site Reactions
3.142
Safety
Kaplan-Meier Analysis of Time to First Occurrence of On-
therapy Injection Site Reaction
3.143
Safety
On-therapy Injection Site Reaction Over Time
3.144
Safety
Summary Characteristics of On-therapy Injection Site 
Reactions Identified by the Investigator
3.151
Safety
On-therapy and Post-therapy Liver Events Identified by a 
Customized MedDRA Query
3.161
Safety
On-therapy and Post-therapy Pancreatitis and Pancreatic 
Cancer
3.162
Safety
On-therapy and Post-therapy Adjudicated Pancreatitis 
Events
3.171
Safety
On-therapy and Post-therapy Atrial Fibrillation and Atrial 
Flutter Adverse Events
3.181
Safety
On-therapy and Post-therapy Pneumonia Adverse Events 
Reported by the Investigator
3.182
Safety
On-therapy and Post-therapy Pneumonia Adverse Events 
Identified by a Customized MedDRA Query
3.191
Safety
On-therapy and Post-therapy Diabetic Retinopathy 
Adverse Events
3.201
Safety
On-therapy and Post-therapy Appendicitis Adverse Events
3.211
Safety
On-therapy and Post-therapy Malignant Neoplasm 
Adverse Events Identified by a Customized MedDRA 
Query


CONFIDENTIAL
GSK 200977
101
Safety : Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Labs
3.221
Safety
Change from Baseline in Hematology by Visit
3.222
Safety
Change from Baseline in Chemistry by Visit
3.223
Safety
Hematology Values of Clinical Concern by Visit
3.224
Safety
Chemistry Values of Clinical Concern by Visit
3.225
Safety
Liver Function Tests of Clinical Concern by Visit
3.226
Safety
Shift in Hematology by Visit
3.227
Safety
Shift in Chemistry by Visit
3.228
Safety
Urinalysis by Visit
3.229
Safety
Change from Baseline to Week 26 in Urine 
Albumin/Creatinine Ratio (mg/mmol)
3.230
Safety
Shift in Urine Albumin/Creatinine Ratio From Baseline to 
Week 26
Vital Signs
3.231
Safety
Change from Baseline in Vital Signs by Visit
3.232
Safety
Vital Signs of Clinical Concern by Visit
3.233
Safety
Shift in Vital Signs of Clinical Concern by Visit
ECGs
3.341
Safety
Change from Baseline in ECG Values by Visit
3.342
Safety
ECG Values of Clinical Concern by Visit
3.343
Safety
Overall ECG Interpretations by Visit
3.344
Safety
Shift in ECG Values of Clinical Concern from Baseline to 
Week 26


CONFIDENTIAL
GSK 200977
102
Safety : Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.345
Safety
ECG QTcF and QTcB Results by Category
3.346
Safety
ECG QTcF and QTcB Change from Baseline by Category


CONFIDENTIAL
GSK 200977
103
11.14.7.
Safety Figures
Safety : Figures
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events
3.01
Safety
On-therapy Hypoglycemic Events Over Time
3.11
Safety
On-therapy Gastrointestinal Adverse Events Over Time
3.12
Safety
Kaplan-Meier Plot of Time to First Occurrence of a 
Gastrointestinal Adverse Event over Time
3.13
Safety
On-therapy Nausea Over Time
3.14
Safety
On-therapy Diarrhea Over Time
3.15
Safety
On-therapy Vomiting Over Time
3.16
Safety
On-therapy Nausea or Vomiting Over Time
3.31
Safety
Kaplan-Meier Plot of Time to First Occurrence of a 
Systemic Allergic Reaction Reported by the Investigator
3.32
Safety
Kaplan-Meier Plot of Time to First Occurrence of a 
Systemic Allergic Reaction Identified by a Customized
MedDRA Query
3.41
Safety
Kaplan-Meier Plot of Time to First Occurrence of an 
Injection Site Reaction
3.42
Safety
On-therapy Injection Site Reaction Over Time
Labs
3.51
Safety
Line Graph of Mean (+/- SE) Results for Hematology 
Parameters
3.52
Safety
Line Graph of Mean (+/- SE) Results for Chemistry 
Parameters


CONFIDENTIAL
GSK 200977
104
Safety : Figures
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.53
Safety
Line Graph of Mean (+/- SE) Change from Baseline 
Results for Hematology Parameters
3.54
Safety
Line Graph of Mean (+/- SE) Change from Baseline 
Results for Chemistry Parameters
3.55
Safety
Line Graph of Mean (+/- SE) Urine Albumin/Creatinine 
Ratio
3.56
Safety
Scatter Plot of Urine Albumin/Creatinine Ratio
Vital Signs
3.61
Safety
Line Graph of Mean (+/- SE) of Vital Sign Parameters
3.62
Safety
Line Graph of Mean (+/- SE) Change from Baseline in 
Vital Sign Parameters
ECGs
3.71
Safety
Line Graph of Mean (+/- SE) ECG Results over Time


CONFIDENTIAL
GSK 200977
105
11.14.8.
ICH Listings
ICH : Listings
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1
FA
Vital Signs of Clinical Concern
2
FA
ECG Values of Clinical Concern
3
FA
Serious Adverse Events
4
FA
Fatal Adverse Events
5
FA
Serious Non-fatal Adverse Events
6
FA
Adverse Events Leading to Withdrawal from Study
7
FA
Adverse Events Leading to Permanent Discontinuation of 
Study Drug
8
FA
Hypoglycemic Events
10
FA
Cardiovascular Events - Deep Vein 
Thrombosis/Pulmonary Embolism
11
FA
Cardiovascular Events - Arrhythmias
12
FA
Cardiovascular Events - Myocardial Infarction 
(MI)/Unstable Angina (UA)
13
FA
Cardiovascular Events - Cerebrovascular Events/Stroke 
(CVA) and Transient Ischemic Attack (TIA)
14
FA
Cardiovascular Events - Congestive Heart Failure
15
FA
Cardiovascular Events - Peripheral Arterial 
Thromboembolism
16
FA
Cardiovascular Events - Pulmonary Hypertension
17
FA
Cardiovascular Events - Coronary Revascularization
18
FA
Cardiovascular Events - Peripheral Revascularization


CONFIDENTIAL
GSK 200977
106
ICH : Listings
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
19
FA
Cardiovascular Events - Valvulopathy
20
FA
Pancreatitis Events
26
FA
Thyroid Cancer/Nodules/Goiter
30
FA
Customized MedDRA Query Identified Thyroid Adverse 
Events
31
FA
Systemic Allergic Reactions Reported by the Investigator
32
FA
Systemic Allergic Reactions Identified by Customized
MedDRA Query
33
FA
Injection Site Reactions
35
FA
Liver Events Identified by a Customized MedDRA Query
36
FA
Atrial Fibrillation/Flutter
37
FA
Pneumonia Reported by the Investigator
38
FA
Pneumonia Reported Identified by a Customized MedDRA 
Query
39
FA
Diabetic Retinopathy
40
FA
Appendicitis
41
FA
Malignant Neoplasm
42
FA
Hematology Values of Clinical Concern
43
FA
Chemistry Values of Clinical Concern
44
FA
Liver Function Test Results of Clinical Concern


CONFIDENTIAL
GSK 200977
107
11.14.9.
Non-ICH Listings
Non-ICH : Listings
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
101
FA
Randomized Allocation to Treatment
102
FA
Subject Disposition
103
FA
Reasons for Withdrawal from Study
104
FA
Reasons for Discontinuing Study Treatment
105
Reasons for Screening Failures and Standardization 
Failures
106
FA
Subject Visits 
107
FA
Inclusion/Exclusion Criteria Deviations
108
FA
Protocol Deviations
109
FA
Major Protocol Deviations
110
FA
Analysis Populations
111
FA
Demographics and Baseline Characteristics
112
FA
Geographic Ancestry
113
FA
Substance Use
115
FA
Cardiovascular Medical History
116
FA
Diabetes Related Conditions
117
FA
Diabetes Disease History
118
FA
Medical/Surgical Procedure History
119
FA
Gastrointestinal Medical Conditions
120
FA
Nephropathy (Including Microalbuminuria) and Kidney 
Injury History


CONFIDENTIAL
GSK 200977
108
Non-ICH : Listings
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
121
FA
Diabetic Retinopathy History
123
FA
Cancer History
124
FA
Pneumonia Medical History
125
FA
Skin Medical Conditions
126
FA
Thyroid Medical History
127
FA
Thyroid Cancer History
129
FA
History Benign Thyroid Conditions
131
FA
Thyroid Cancer Family History 
132
FA
Pancreatitis Family History
133
FA
Pancreatitis Cancer Family History 
134
FA
Other Medical History
135
FA
Hypersensitivity - Past Medical Conditions
136
FA
Prior and Concomitant Medications
137
FA
Albiglutide Administration and Compliance 
138
FA
Albiglutide Accountability
139
FA
Insulin Glargine Accountability and Compliance
140
FA
Insulin Lispro Accountability and Compliance
145
FA
HbA1c (%) 
146
FA
Stratifying Factors Used in MMRM Models
147
FA
Subgroup Values Used in Subgroup Analyses
149
FA
Weight (Kg)
150
FA
Insulin Surveillance


CONFIDENTIAL
GSK 200977
109
Non-ICH : Listings
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
151
FA
Fasting Plasma Glucose (mmol/L)
152
FA
TRIM-Diabetes (TRIM-D) Questionnaire Scores
153
FA
Hypoglycemia Fear Survey-II (HFS-II) Questionnaire 
Worry Subscale Scores
154
FA
8-Point Self-Monitored Blood Glucose (SMBG) Profile
155
FA
Adverse Events
156
FA
Treatment Emergent Adverse Events
157
FA
Hematology Laboratory Evaluations
158
FA
Chemistry Laboratory Evaluations
159
FA
Urinalysis Laboratory Evaluations
160
FA
Urine Albumin/Creatinine Ratio
161
FA
Vital Signs
162
FA
ECG Values
163
FA
Overall ECG Interpretations
164
FA
Pregnancies
165
FA
Liver Events Information
166
FA
Liver Biopsy
167
FA
Liver Imaging
168
FA
Other Medical/Surgical Procedures
170
FA
Other Lab Results at Screening


CONFIDENTIAL
GSK 200977
110
11.14.10. Mock Shells for Data Displays