Conditions: Type 2 Diabetes
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 318
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of investigational doses of dulaglutide in participants with type 2 diabetes on metformin monotherapy.

Detailed description:

Arms:
arm 1: 4.5mg of Dulaglutide administered subcutaneously (SC) arm 2: 3.0mg of Dulaglutide administered SC arm 3: 1.5mg of Dulaglutide administered SC arm 4: Placebo administered SC

Interventions: intervention 1: Dulaglutide intervention 2: Placebo
Intervention descriptions: intervention 1: Administered SC intervention 2: Administered SC

Protocol document:
Prot_001.pdf: 
Protocol H9X-MC-GBGJ (a) 
A Phase 2, Double-Blind, Placebo-Controlled, 18-Week Trial of Investigational Dulaglutide 
Doses versus Placebo in Patients with Type 2 Diabetes on Metformin Monotherapy 
NCT02973100 
Approval Date: 07-Nov-2016 


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Protocol H9X-MC-GBGJ(a)
A Phase 2, Double-Blind, Placebo-Controlled, 18-Week Trial 
of Investigational Dulaglutide Dosesversus Placeboin 
Patients with Type 2 Diabetes on Metformin Monotherapy
Confidential Information
The information contained in this document is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
dulaglutide(LY2189265), unless such persons are bound by a confidentiality agreement 
with Eli Lilly and Company or its subsidiaries.  
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt frompublic disclosure. Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release. In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
[Dulaglutide(LY2189265)]
Study H9X-MC-GBGJ is a Phase 2, randomized, double-blind, placebo-controlled trial 
designed to assess the efficacy and safety of once-weeklyinvestigational dulaglutide doses 
compared to placebo,in patients with type 2 diabetes mellitus on metformin monotherapy. 
Approval Date: 07-Nov-2016 GMT
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly:  19 August 2016
Amendment (a) Electronically Signed and Approved by Lilly
on approval date provided below.


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Table of Contents
Section
Page
1.
Synopsis .............................................................................................................................9
2.
Schedule of Activities .......................................................................................................11
3.
Introduction ......................................................................................................................14
3.1.
Study Rationale............................................................................................................14
3.2.
Background..................................................................................................................14
3.3.
Benefit/Risk Assessment..............................................................................................16
4.
Objectives and Endpoints..................................................................................................17
5.
Study Design.....................................................................................................................20
5.1.
Overall Design .............................................................................................................20
5.2.
Number of Participants.................................................................................................24
5.3.
End of Study Definition ...............................................................................................24
5.4.
Scientific Rationale for Study Design...........................................................................24
5.5.
Justification for Doses..................................................................................................25
6.
Study Population...............................................................................................................27
6.1.
Inclusion Criteria..........................................................................................................27
6.2.
Exclusion Criteria ........................................................................................................29
6.3.
Lifestyle Restrictions....................................................................................................30
6.4.
Screen Failures.............................................................................................................30
7.
Treatments........................................................................................................................31
7.1.
Treatments Administered .............................................................................................31
7.1.1.
Packaging and Labeling .......................................................................................33
7.2.
Method of Treatment Assignment ................................................................................33
7.2.1.
Selection and Timing of Doses.............................................................................33
7.2.2.
Injecting Study Drug............................................................................................34
7.3.
Blinding .......................................................................................................................34
7.4.
Dosage Modification....................................................................................................35
7.4.1.
Special Treatment Considerations ........................................................................35
7.4.1.1.
Standards of Medical Care..............................................................................35
7.4.1.2.
Management of Increased Hypoglycemia Risk ...............................................35
7.4.1.3.
Management of Patients with Severe, Persistent 
Hyperglycemia during the Treatment Period...................................................36
7.5.
Preparation/Handling/Storage/Accountability...............................................................36
7.6.
Treatment Compliance .................................................................................................36
7.7.
Concomitant Therapy...................................................................................................37
7.7.1.
Antihyperglycemia Medications...........................................................................38


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7.7.1.1.
Required Concomitant Antihyperglycemia Medication:  
Metformin ......................................................................................................39
7.7.2.
Medications that Promote Weight Loss ................................................................39
7.7.3.
Systemic Glucocorticoids.....................................................................................40
7.7.4.
Antihypertensive Medications..............................................................................40
7.8.
Treatment after the End of the Study............................................................................40
7.8.1.
Continued Access.................................................................................................40
8.
Discontinuation Criteria ....................................................................................................41
8.1.
Discontinuation from Study Treatment.........................................................................41
8.1.1.
Permanent Discontinuation from Study Treatment ...............................................41
8.1.2.
Temporary Interruption of Study Treatment .........................................................42
8.1.3.
Discontinuation of Inadvertently Enrolled Patients...............................................42
8.2.
Discontinuation from the Study....................................................................................42
8.3.
Lost to Follow-Up........................................................................................................43
9.
Study Assessments and Procedures ...................................................................................44
9.1.
Efficacy Assessments...................................................................................................44
9.1.1.
Primary Efficacy Assessments .............................................................................44
9.1.2.
Secondary Efficacy Assessments..........................................................................44
9.1.3.
Exploratory Efficacy Assessments .......................................................................44
9.1.4.
Appropriateness of Assessments ..........................................................................44
9.1.5.
Body Weight, Height, and Body Mass Index........................................................44
9.2.
Adverse Events ............................................................................................................45
9.2.1.
Serious Adverse Events........................................................................................45
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................46
9.2.2.
Adverse Events of Special Interest .......................................................................46
9.2.2.1.
Hypoglycemia and Hyperglycemia .................................................................46
9.2.2.2.
Pancreatitis.....................................................................................................48
9.2.2.3.
C-Cell Hyperplasia and C-Cell Neoplasms .....................................................49
9.2.2.4.
Allergic/Hypersensitivity Reactions................................................................49
9.2.2.5.
Supraventricular Arrhythmias and Cardiac Conduction 
Disorders........................................................................................................49
9.2.3.
Complaint Handling.............................................................................................50
9.3.
Treatment of Overdose.................................................................................................50
9.4.
Safety...........................................................................................................................50
9.4.1.
CV Safety ............................................................................................................50
9.4.1.1.
Cardiovascular Events ....................................................................................50
9.4.1.2.
Electrocardiograms.........................................................................................50
9.4.1.3.
Vital Signs......................................................................................................51


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9.4.2.
Laboratory Tests ..................................................................................................51
9.4.3.
Safety Monitoring ................................................................................................51
9.5.
Pharmacokinetics .........................................................................................................52
9.6.
Pharmacodynamics ......................................................................................................52
9.7.
Pharmacogenomics ......................................................................................................52
9.7.1.
Whole Blood Samples for Pharmacogenetic Research..........................................52
9.8.
Biomarkers and Antibodies ..........................................................................................53
9.8.1.
Samples for Immunogenicity Research.................................................................53
9.8.2.
Biomarkers...........................................................................................................53
9.9.
Health Economics ........................................................................................................54
10.
Statistical Considerations ..................................................................................................55
10.1. Sample Size Determination ..........................................................................................55
10.2. Populations for Analyses..............................................................................................55
10.3. Statistical Analyses ......................................................................................................55
10.3.1.
General Statistical Considerations ........................................................................55
10.3.2.
Treatment Group Comparability...........................................................................57
10.3.2.1.
Patient Disposition..........................................................................................57
10.3.2.2.
Patient Characteristics ....................................................................................57
10.3.2.3.
Concomitant Therapy .....................................................................................57
10.3.2.4.
Treatment Compliance....................................................................................57
10.3.3.
Efficacy Analyses ................................................................................................58
10.3.3.1.
Primary Analyses ...........................................................................................58
10.3.3.2.
Secondary Analyses........................................................................................58
10.3.3.2.1.
Secondary Analyses for Primary Endpoint................................................58
10.3.3.2.2.
Analyses for Secondary Efficacy Endpoints..............................................58
10.3.3.3.
Tertiary/Exploratory Efficacy Endpoints.........................................................58
10.3.4.
Safety Analyses....................................................................................................59
10.3.4.1.
Study Drug Exposure......................................................................................59
10.3.4.2.
Adverse Events...............................................................................................59
10.3.4.3.
Hypoglycemic Episodes .................................................................................59
10.3.4.4.
Severe, Persistent Hyperglycemia...................................................................59
10.3.4.5.
Pancreas Safety ..............................................................................................59
10.3.4.6.
Cardiovascular Safety.....................................................................................59
10.3.4.7.
Thyroid Safety................................................................................................60
10.3.4.8.
Renal Safety...................................................................................................60
10.3.4.9.
Gastrointestinal Safety....................................................................................60
10.3.4.10. Allergic/Hypersensitivity Reactions................................................................60
10.3.4.11. Immunogenicity..............................................................................................60


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10.3.4.12. Laboratory Analyses.......................................................................................60
10.3.4.13. Vital Signs......................................................................................................60
10.3.4.14. Electrocardiograms.........................................................................................61
10.3.5.
Pharmacokinetic/Pharmacodynamic Analyses......................................................61
10.3.6.
Subgroup Analyses ..............................................................................................61
10.3.7.
Interim Analyses..................................................................................................61
10.3.7.1.
PK/PD Prelock Data Access ...........................................................................62
11.
References ........................................................................................................................63
12.
Appendices .......................................................................................................................65


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List of Tables
Table
Page
Table GBGJ.1.
Objectives and Endpoints...............................................................................17
Table GBGJ.2.
Study Treatments...........................................................................................32
Table GBGJ.3.
Criteria for Use of Concomitant Medications that May Interfere with 
Efficacy and Safety Assessments in Study GBGJ...........................................38
Table GBGJ.4.
Populations for Analyses ...............................................................................55


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List of Figures
Figure
Page
Figure GBGJ.1. Illustration of study design for Clinical Protocol H9X-MC-GBGJ..................21


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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions........................................................................66
Appendix 2.
Clinical Laboratory Tests...............................................................................70
Appendix 3.
Study Governance Considerations..................................................................72
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality....................76
Appendix 5.
Protocol GBGJ World Health Organization Classification of Diabetes 
and Diagnostic Criteria ..................................................................................77
Appendix 6.
Classification of Contraceptive Methods........................................................78
Appendix 7.
Protocol GBGJ World Health Organization Standardized Protocols for 
the Measurement of Height and Weight.........................................................79
Appendix 8.
Protocol Amendment H9X-MC-GBGJ (a) Summary: A Phase 2, 
Double-Blind, Placebo-Controlled, 18-Week Trial of Investigational 
Dulaglutide Doses versus Placebo in Patients with Type 2 Diabetes on 
Metformin Monotherapy................................................................................80


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1.
Synopsis
Title of Study: A Phase 2, Double-Blind, Placebo-Controlled, 18-Week Trial of Investigational Dulaglutide Doses 
versus Placebo in Patients with Type 2 Diabetes on Metformin Monotherapy
Rationale: 
Study H9X-MC-GBGJ (GBGJ) is a Phase 2 trial designed to assess the safety and efficacy of once weekly 
dulaglutide 3.0 mg and 4.5 mg in comparison to placebo in patients with type 2 diabetes mellitus (T2D) treated with 
metformin monotherapy.  The trial will also include exploratory comparisons to dulaglutide 1.5 mg (the highest dose 
approved by regulatory agencies).  The strategic objective is to obtain data to support the development of an 
additional higher dulaglutide dose than the currently approved 0.75 mg and 1.5 mg doses (Trulicity® United States 
Package Insert 2015), that could provide improved clinical benefits, including greater reduction in hemoglobin A1c 
(HbA1c) and greater body weight reduction, with an acceptable safety profile.  
Objectives/Endpoints:
Objectives
Endpoints
Primary
To demonstrate that once weekly dulaglutide (4.5 mg, 
3.0 mg, 1.5 mg) is superior to placebo in HbA1c 
reduction at 18 weeks in patients with T2D on 
concomitant metformin monotherapy.

The change in HbA1c from baseline
Secondary
Efficacy

To compare each dulaglutide arm (4.5 mg, 
3.0 mg, 1.5 mg) to the placebo arm at 18 weeks 
for secondary efficacy parameters

Proportion of patients achieving HbA1c target 
of <7.0%

The change in fasting serum glucose (FSG; 
central laboratory) from baseline

The change in body weight from baseline
Safety

To compare each dulaglutide arm (4.5 mg, 
3.0 mg, 1.5 mg) to the placebo arm for selected 
safety parameters at 18 weeks

Treatment-emergent adverse events (TEAEs) 
and serious adverse events (SAEs)

Discontinuation of study drug due to adverse 
events (AEs)

Incidence and rate of hypoglycemia (severe, 
total, documented symptomatic, and nocturnal)
Pharmacokinetics and Pharmacodynamics

To characterize the pharmacokinetics (PK) of 
dulaglutide and establish the relationships 
between dose/exposure and key safety and 
efficacy measures

PK parameters (eg, Cmax, AUC)

Pharmacodynamic evaluations will include 
HbA1c, FSG, body weight, QTcF interval, and 
heart rate  
Abbreviations:  AUC = area under concentration-time curve; Cmax = maximum concentration; HbA1c = 
hemoglobin A1c; QTcF = Fridericia’s corrected QT interval; T2D = type 2 diabetes mellitus.


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Summary of Study Design:  
Study GBGJ is a Phase 2, multicenter, randomized, double-blind, parallel-arm, placebo-controlled trial with 3 study 
periods (lead-in, treatment, and safety follow-up) in patients who have T2D with inadequate glycemic control on 
metformin only.
Treatment Arms and Duration:  
At Visit 3, patients will be randomized in a 1:1:1:1 ratio to weekly injections of dulaglutide 4.5 mg, 3.0 mg, or
1.5 mg, or placebo, in combination with stable doses of metformin.  Within each of the investigational dulaglutide 
dose (3.0 mg and 4.5 mg) arms, patients will be randomly assigned in a 1:1 ratio to 1 of the dulaglutide dose titration 
algorithms (Algorithm 1 or Algorithm 2).  Study participants will be treated for 18 weeks after randomization in a 
double-blind manner, followed by a 4-week safety evaluation.
Number of Patients:
A total of approximately 300 patients (~75 patients per arm and ~38 per algorithm) will be randomized and 
approximately 240 are expected to complete the treatment period (~60 per arm and ~30 per algorithm) to show that 
each dulaglutide dose arm is superior to placebo with at least 90% power.  This sample size calculation assumes a 
treatment difference of 1.0% in HbA1c reduction, standard deviation of 1.2%, and dropout rate of 20%.  The screen 
failure rate is estimated as 30%.  Approximately 429 patients will be screened.
Statistical Analysis:
The primary analysis for the endpoint of the primary objective, change from baseline in HbA1c at 18 weeks, will be 
mixed-model repeated measures (MMRM) analysis.  In this model, restricted maximum likelihood will be used to 
obtain model estimates with Kenward-Roger option to estimate denominator degrees of freedom.  The 
corresponding baseline value will be used as a covariate, while pooled country, treatment, visit, and treatment-by-
visit interaction will be fixed effects.  The secondary analysis for the primary endpoint will use a Bayesian 
integrated 2-component prediction model (Fu and Manner 2010).  Probabilities based on posterior distributions of 
parameters of interest will be generated from this model.
All secondary efficacy measures that are continuous variables (changes from baseline) will be analyzed using 
MMRM.  Repeated measures logistic regression with generalized linear mixed model will be used to analyze 
percentages of patients achieving HbA1c targets of <7.0% and/or ≤6.5%.  For the analysis of other categorical 
measures, Fisher’s exact test will be used for treatment comparisons, unless 80% of cells have an expected value of 
at least 5, in which case the Chi-square test will be used.  
Population pharmacokinetic (PK) analyses will be conducted using dosing data and dulaglutide concentrations 
obtained from all patients via commonly accepted pharmacostatistical methods (for example, nonlinear mixed-
effects modeling), and covariate screening.  The relationship between dulaglutide doses and/or PK concentrations 
and key safety and efficacy measures will be evaluated in PK/pharmacodynamics analyses.  In addition, any
relationship between dulaglutide PK concentrations and antibody formations will be evaluated for impact on 
dulaglutide clearance and, if applicable, drug effect(s).


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2. Schedule of Activities
Screening 
and Lead-In
Treatment Period
Follow-Up
Visit
1
2
3
4
5
6
7
8
9
10
11
12
801
ET a
Week of Treatment
-2
-1
0
2
4
6
7
8
9
10
14
18
22
ET
Allowable Deviation (Days) b
±3
±3
-3
-3
-3
±3
±3
±3
+4
±7
±7
±3
Informed consent
X
Randomization c
X
Clinical Assessments
Medical History 
X
Physical
X
Height
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs (3 sitting BP and PR measurements)
X
X
X
X
X
X
X
X
X
X
X
X
X
Electrocardiogram d
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Review/record hypoglycemic events
X
X
X
X
X
X
X
X
X
X
X
X
Remind patients about 6-point SMPG
X
X
Record 6-point SMPG values e
X
X
X f
Patient summary
X
X
X
Patient Education and Management
Dispense study diary, instruct in use
X
X
X
X
X
X
Review study diary
X
X
X
X
X
X
X
X
X
X
X
X
Return study diary
X
X
X
X
X
X
X
Diabetes management education g
X
PG meter, SMPG training g
X
X
Review SMPG values
X
X
X
X
X
X
X
X
X
X
X
X
Injection training g
X
X
Dispense PG meter/supplies
X
X
X
X
X
X
X
X
X
X
X
Dispense study drugs and/or injection supplies
X
X
X
X
X
X
Observe patient inject study drug h
X


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Abbreviations:  BP = blood pressure; CKD-EPI = Chronic Kidney Disease-Epidemiology; ECG = electrocardiogram; eGFR = estimated glomerular filtration 
rate; ET = early termination; HbA1c = hemoglobin A1c; OAM = oral antihyperglycemia medication; PG = plasma glucose; PK = pharmacokinetic; PR = 
pulse rate; SMPG = self-monitored plasma glucose.
Screening 
and Lead-In
Treatment Period
Follow-Up
Visit
1
2
3
4
5
6
7
8
9
10
11
12
801
ET a
Week of Treatment
-2
-1
0
2
4
6
7
8
9
10
14
18
22
ET
Allowable Deviation (Days) b
±3
±3
-3
-3
-3
±3
±3
±3
+4
±7
±7
±3
Patient Education and Management (concluded)
Patient returns study drugs and/or injection supplies
X
X
X
X
X
X
X
X
X
X
Assess study drug compliance i
X
X
X
X
X
X
X
X
X
X
Laboratory tests
Serum pregnancy test j
X
Urine pregnancy test k
X
Follicle-stimulating hormone test l
X
Chemistry panel 
X
X
X
Lipid panel (fasting) m
X
X
X
Urinalysis
X
X
X
Albumin/creatinine ratio (urine) n
X
X
X
eGFR (CKD-EPI) o
X
X
X
Hematology
X
X
X
Immunogenicity
X
X
X
X
X
HbA1c
X
X
X
X
X
X
X
Glucose (fasting) m
X
X
X
X
X
X
Pancreatic amylase, lipase
X
X
X
X
X
X
Serum insulin (fasting) m
X
X
X
C-peptide
X
X
X
Plasma glucagon (fasting) m,p
X
X
X
X
Calcitonin
X
X
X
X
Pharmacogenetic
X
Nonpharmacogenetic biomarker (plasma and serum)
X
X
X
X
X
PK samples
PK samples
X q
X r
X q
X s
X t
X u
X u
X u


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a
Patients who are unable or unwilling to continue in the study because of an adverse event or any other reason will perform an ET visit as their final study visit.  
If the patient is discontinuing during an unscheduled visit, that visit should be performed as the ET visit. If the patient is discontinuing during a scheduled 
visit, that visit should be considered the ET visit.  
b
The visit date is determined in relation to the date of the randomization visit (± the allowed visit window).  
c
Baseline assessments must be completed before processing in the interactive web-response system (IWRS).
d
ECGs will be performed in triplicate.  ECGs occurring on visits with PK collection should be measured at least 30 minutes prior to obtaining the sample for 
PK measurement.
e
6-point SMPG consists of measurements before and 2 hours after each of 3 main meals within the same day.  These SMPG profiles are collected by the 
patient within 1 week prior to the assigned visits.
f
If performed prior to visit.
g
All training should be repeated as needed to ensure patient compliance.
h
Patients should administer their first dose of study drug at the end of this visit, after other study procedures and randomization.  Patients will be encouraged to 
administer their weekly dose of study drug in the clinic, when possible, at subsequent visits.
i
Study drug compliance will be reviewed for the time period from Visit 4 to Visit 12 and entered in the eCRFs at Visit 6, Visit 10, Visit 11, and Visit 12 for the 
interval after the previous compliance entry.
j
A serum pregnancy test will be performed at Visit 1 for women of childbearing potential only.
k
A urine pregnancy test will be performed at Visit 3 with the result available prior to randomization and first injection of study drug for women of childbearing 
potential only.  Additional pregnancy tests may be performed at the investigator’s discretion during the study.
l
Follicle-stimulating hormone test performed at Visit 1 for postmenopausal women at least 50 years of age with an intact uterus, not on hormone therapy, and 
who have had spontaneous amenorrhea for more than 6 months and less than 12 months.  After Visit 1, additional tests may be performed at the investigator’s 
discretion during the study.
m For Visit 3, Visit 6, Visit 10, Visit 12, Visit 801, and the ET visit, patients should be reminded to report to the site in a fasting condition, after a period of 
approximately 8 hours without eating, drinking (except water), or any significant physical activity and before taking their OAMs (if used).
n
Urinary albumin and creatinine are measured; the ratio is calculated.
o
The CKD-EPI equation will be used by the central laboratory to estimate and report eGFR. Values that are <60 mL/min/1.73 m2 at Visit 1 must be retested at 
Visit 2. If the highest of the 2 values is lower than the cutoff value for discontinuation of metformin per country-specific label (for example ,
<45 mL/min/1.73 m2 or <60 mL/min/1.73 m2), the patient will be discontinued from the trial prior to randomization.  After randomization (Visit 3), values 
that are <60 mL/min/1.73 m2 must be first confirmed on a retest before any protocol-required treatment adjustment is implemented.
p
Collect sample in P800 tube.  Aliquot samples, 1 for glucagon and the remainder for nonpharmacogenetic biomarker.
q
PK samples at Visit 3 and Visit 5 should be collected 1-24 hours post-injection of study drug.
r
PK sample at Visit 4 should be collected immediately prior to administration of study drug.
s
PK sample at Visit 6 should be collected 5-7 days (120-168 hours) post-injection of Week 5 study drug or just pre-injection of Visit 6 study drug.
t
PK sample at Visit 10 should be collected 1-4 days (24-96 hours) post-injection of Visit 10 study drug.
u
PK samples at Visit 12, Visit 801, and the ET visit can be collected at any time during the visit.


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3.
Introduction
3.1.
Study Rationale
Study H9X-MC-GBGJ (GBGJ) is a Phase 2 trial designed to provide initial safety and efficacy 
data for 2 investigational dulaglutide doses (3.0 mg and 4.5 mg) that are higher than the currently 
approved 0.75 mg and 1.5 mg doses (Trulicity® United States Package Insert [USPI] 2015
[WWW]). The trial objectives are expected to enable a feasibility assessment of further Phase 3 
development of at least 1 of the 2 investigational doses to show improvement in the glycemic 
control efficacy in comparison to the 1.5 mg dose with an acceptable safety profile.
Patients with type 2 diabetes mellitus (T2D) treated with metformin monotherapy will be 
randomized to 1 of the following 4 treatment arms, each dosed once weekly: dulaglutide 3.0 mg 
or 4.5 mg (investigational doses), placebo, or dulaglutide 1.5 mg (the highest dose approved by 
regulatory agencies). The primary objective will compare the 3 dulaglutide doses to placebo in 
change from baseline in hemoglobin A1c (HbA1c) at 18 weeks. The secondary objectives will 
compare the 3 dulaglutide doses to placebo at 18 weeks for additional efficacy measures and for 
safety. The purpose of the primary and secondary objectives is to assess efficacy and safety 
characteristics of the 2 investigational dulaglutide doses. The exploratory objectives will 
compare the efficacy and safety of the 2 investigational dulaglutide doses to the approved 1.5 mg 
dose at 18 weeks. The purpose of these exploratory objectives is to provide scientific support for 
further Phase 3 development of 1 or 2 of the investigational doses. Additional exploratory 
objectives will assess the effect of 2 dulaglutide dose titration algorithms on gastrointestinal (GI)
tolerability with the investigational dulaglutide doses to guide design of the Phase 3 dose titration 
algorithm for dulaglutide.
3.2.
Background
Dulaglutide (Trulicity®) is a once weekly glucagon-like peptide-1 (GLP-1) receptor agonist
(GLP-1 RA) that is approved for use as an adjunct to diet and exercise to improve glycemic 
control in patients with T2D.  It exhibits GLP-1-mediated effects, including glucose-dependent 
potentiation of insulin secretion and inhibition of glucagon secretion, delay of gastric emptying, 
and weight loss. Treatment of patients with T2D with dulaglutide results in significant 
reductions in HbA1c with low risk of hypoglycemia, and reductions in body weight. Clinical 
studies to date support the use of once weekly injection of dulaglutide as monotherapy, in 
combination with oral antihyperglycemia medications (OAMs), or in combination with prandial 
insulin lispro to improve glycemic control in patients with T2D (Investigator’s Brochure [IB]).  
Two once weekly dulaglutide doses, 0.75 mg and 1.5 mg, were studied in the Phase 3 
development program and received regulatory approval in the United States (US) and in the 
European Union in 2014 (Trulicity USPI [WWW], Summary of Product Characteristics [SmPC]
[WWW]). While therapy with these doses of dulaglutide enabled the majority of patients 
included in the Phase 3 program to attain their glycemic targets along with other concomitant 
medications, up to 30% or potentially more of patients receiving approved therapies today,
including dulaglutide, are not reaching glycemic control goals (Stark et al. 2013).  Therefore, 
there remains an important medical need to provide enhanced efficacy of pharmaceutical agents 


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while also preserving an overall acceptable benefit/risk profile.  The overall objective of Study 
GBGJ is to explore higher doses of dulaglutide for treatment of adult patients with T2D in order 
to provide greater glycemic efficacy compared to the currently approved doses with an 
acceptable safety profile.
The currently approved dulaglutide doses were selected in the Phase 2/3 Study H9X-MC-GBCF
(GBCF), which initially included 7 doses in the range between 0.25 mg and 3.0 mg (Skrivanek et 
al. 2014).  Final selection of the 0.75 mg and 1.5 mg doses for development was supported by:
(a) favorable benefit/risk profile of these doses based on a clinical utility index that included 
HbA1c, body weight, pulse rate, and diastolic blood pressure (DBP); and (b) potentially 
concerning, short-term effects on pancreatic enzymes, GI tolerability, and heart rate (HR) 
observed with the 3.0 mg dose, which prompted early discontinuation of this arm (Skrivanek et 
al. 2014; Weinstock et al. 2015). In general, the effects noted with the 3.0 mg dose are now 
understood to be associated also with the GLP-1 RA class and are dose-dependent, occurring 
across the range of doses, and at doses lower than the 3.0 mg dose of dulaglutide. The Phase 3 
dulaglutide development program, which included 0.75 mg and 1.5 mg doses, assessed these 
safety considerations and enabled their better understanding.   
In dulaglutide registration trials, the risk of adjudicated pancreatitis and investigator-reported 
pancreatitis in patients treated with dulaglutide was similar to the risk observed with non-incretin 
comparators (data on file). In addition, the asymptomatic pancreatic enzyme elevations were
observed in patients treated with 0.75 mg or 1.5 mg dulaglutide doses, but also in patients who 
received GLP-1 RA comparators, non-GLP-1 RA comparators or placebo. These elevations 
were not associated with adverse clinical outcomes based on the results of adjudication and do 
not require monitoring in the absence of signs and symptoms of acute pancreatitis (Trulicity 
USPI [WWW]; Umpierrez et al. 2014; Wysham et al. 2014; Blonde et al. 2015; Giorgino et al. 
2015; Weinstock et al. 2015).
With respect to HR elevations, treatment with dulaglutide 0.75 mg or 1.5 mg for 26 weeks 
increases HR in the range between 2 and 4 beats per minute (bpm), with no clinically relevant 
cardiovascular (CV) safety findings (Trulicity USPI [WWW]; Ferdinand et al. 2016). The 
estimated effect of the 3.0 mg dose on HR at 26 weeks, based on a small number of patients with 
mean exposure of approximately 9.2 weeks in Study GBCF, was an increase of approximately 
5 bpm (data on file). No safety data are available after 26 weeks of treatment for doses greater 
than 3.0 mg. Increases in HR with dulaglutide are time-dependent and diminish over time (data 
on file). The ongoing REWIND CV outcome trial (H9X-MC-GBDJ) will provide data on the 
long-term effect of dulaglutide on the CV risk. 
The results from recently reported studies of dulaglutide described above have provided 
understanding of the clinical relevance of the pancreatic enzyme elevations and increases in HR,
which was not available at the time of development of dulaglutide for initial registration (Egan et 
al. 2014).  The additional data did not suggest association between these findings and long-term
safety outcomes, providing support for re-evaluation of a range of once weekly dulaglutide doses 
higher than the currently approved 0.75 mg and 1.5 mg doses to assess whether an additional 
dose with favorable benefit/risk profile compared to the approved doses can be developed.  


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The investigational dulaglutide doses to be studied in Study GBGJ (3.0 mg and 4.5 mg) were 
chosen based on simulations which included data collected in Studies H9X-MC-GBCD (GBCD)
and GBCF (Barrington et al. 2011, Skrivanek et al. 2014). The results of these simulations 
suggest that these doses may provide an incremental, clinically relevant improvement in Hb1Ac
and body weight reduction in comparison to the 1.5 mg dose after 26 weeks.  Further information 
on the rationale for the doses included in this study is provided in Section 5.5.  
Potential poor tolerability due to GI side effects may pose a challenge to achieving the objective 
of development of higher dulaglutide doses, however, the currently approved doses of 
dulaglutide do not require dose-titration at treatment initiation. In 33 patients treated with 
3.0 mg or higher doses in Phase 1 Study GBCD (5 week dosing) and in the dose-finding portion 
of Study GBCF (mean exposure 9.2 weeks), the incidence of GI adverse events (AEs) that are 
commonly related to the treatment with GLP-1 RAs (nausea: 17 patients [52%]; vomiting:  
9 patients [27%]) was higher compared to the incidence reported with approved doses in 
registration trials (Barrington et al. 2011; Skrivanek et al. 2014; Umpierrez et al. 2014; Wysham 
et al. 2014; Blonde et al. 2015; Giorgino et al. 2015; Weinstock et al. 2015). Five out of these 
33 patients (15%) discontinued treatment early due to GI AEs. It has recently been shown that a 
slow, stepwise dose titration upon initiation of GLP-1 RAs can attenuate the occurrence and 
severity of GI AEs, allowing the use of higher doses which provide greater glucose-lowering 
effects and robust body weight reduction.  Simulation results discussed in Section 5.5, showing 
reduction in incidence of GI events with initial titration of dulaglutide, are consistent with these 
reports. In Study GBGJ, different titration options (algorithms) will be included to assess their 
effect on GI tolerability with the 2 investigational dulaglutide doses. Detailed rationale for 
titration algorithms can be found in Section 5.5.
3.3.
Benefit/Risk Assessment
More information about the known and expected benefits, risks, serious adverse events (SAEs) 
and reasonably anticipated AEs of dulaglutide may be found in the IB.
In addition, detailed information about the known and expected benefits and risks of dulaglutide
may be found in the USPI and SmPC.


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4.
Objectives and Endpoints
Table GBGJ.1 shows the objectives and endpoints of the study.
Table GBGJ.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To demonstrate that once weekly dulaglutide (4.5 mg, 
3.0 mg, 1.5 mg) is superior to placebo in HbA1c 
reduction at 18 weeks in patients with T2D on 
concomitant metformin monotherapy.

The change in HbA1c from baseline
Secondary
Efficacy

To compare each dulaglutide arm (4.5 mg, 
3.0 mg, 1.5 mg) to the placebo arm at 18 weeks
for secondary efficacy parameters

Proportion of patients achieving HbA1c target 
of <7.0%

The change in fasting serum glucose (FSG; 
central laboratory) from baseline

The change in body weight from baseline
Safety

To compare each dulaglutide arm (4.5 mg, 
3.0 mg, 1.5 mg) to the placebo arm for selected 
safety parameters at 18 weeks

Treatment-emergent adverse events (TEAEs)
and serious adverse events (SAEs)

Discontinuation of study drug due to adverse 
events (AEs)

Incidence and rate of hypoglycemia (severe, 
total, documented symptomatic, and nocturnal)
Pharmacokinetics and Pharmacodynamics

To characterize the pharmacokinetics (PK) of 
dulaglutide and establish the relationships 
between dose/exposure and key safety and 
efficacy measures

PK parameters (eg, Cmax, AUC)

Pharmacodynamic evaluations will include 
HbA1c, FSG, body weight, QTcF interval, and 
heart rate  
Tertiary/Exploratory
Efficacy

To compare each dulaglutide arm (4.5 mg, 
3.0 mg, 1.5 mg) to the placebo arm for 
additional efficacy measures at 18 weeks

Proportion of patients achieving HbA1c target 
≤6.5%

The change in 6-point self-monitored plasma 
glucose (SMPG) profiles from baseline

The change in fasting plasma glucagon from 
baseline

The change from baseline in insulin resistance 
(HOMA-IR) and -cell function (HOMA-%B) 
as measured by the HOMA2 Method (Caumo et 
al. 2006) 


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Objectives and Endpoints (continued)
Objectives
Endpoints
Tertiary/Exploratory (continued)
Efficacy

To compare the investigational dose dulaglutide 
arms (4.5 mg and 3.0 mg) to the 1.5 mg arm for 
efficacy measures at 18 weeks

Change from baseline in HbA1c

Proportion of patients achieving HbA1c target
<7.0% or ≤6.5%

The change in FSG (by central laboratory) from 
baseline

The change in body weight from baseline

The change in 6-point SMPG profiles from 
baseline

The change in fasting plasma glucagon from 
baseline

The change in HOMA-IR and HOMA-%B
from baseline
Safety

To compare the investigational dose dulaglutide 
arms (4.5 mg and 3.0 mg) to the placebo arm 
for additional safety measures at 18 weeks

Selected gastrointestinal tolerability AEs
(nausea, vomiting, and diarrhea)

Pancreatic safety assessed by incidence of cases 
of adjudicated pancreatitis 

CV safety assessed by the incidence of 
adjudicated deaths and nonfatal major CV 
events

Thyroid-related safety assessed by the 
incidence of cases of thyroid neoplasms

Vital signs (PR, BP)

ECG (HR, QTcF, supraventricular arrhythmias 
and cardiac conduction abnormalities)

Immune system-related safety, including the 
incidence of dulaglutide anti-drug antibodies 
(ADA) and the incidence of allergic and 
hypersensitivity reactions 

Injection site reactions 

Incidence of rescue therapy initiation due to 
severe, persistent hyperglycemia

To compare the investigational dose dulaglutide 
arms (4.5 mg and 3.0 mg) to the 1.5 mg arm for 
safety measures at 18 weeks

TEAEs and SAEs

Discontinuation of study drug due to AEs

Incidence and rate of hypoglycemia (severe, 
total, documented symptomatic, and nocturnal)

Selected gastrointestinal tolerability AEs 
(nausea, vomiting, and diarrhea)

Pancreatic safety assessed by incidence of cases 
of adjudicated pancreatitis 

CV safety assessed by the incidence of 
adjudicated deaths and nonfatal major CV 
events


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Objectives and Endpoints (continued)
Objectives
Endpoints
Tertiary/Exploratory (concluded)

Thyroid-related safety assessed by the 
incidence of cases of thyroid neoplasms

Vital signs (PR, BP)

ECG parameters (HR, QTcF, supraventricular 
arrhythmias and cardiac conduction 
abnormalities)

Immune system-related safety, including the 
incidence of dulaglutide ADA and the 
incidence of allergic and hypersensitivity 
reactions

Injection site reactions

Incidence of rescue therapy initiation due to 
severe, persistent hyperglycemia
Safety

To compare the titration algorithms 
(Algorithm 1 vs. Algorithm 2) within the 
investigational dose dulaglutide arms (4.5 mg 
and 3.0 mg) and across the investigational dose 
arms versus dulaglutide 1.5 mg and placebo at 
6 and 18 weeks

Incidence of selected GI AEs (nausea, 
vomiting, and diarrhea)

Vital signs (PR, BP)
Abbreviations: AUC = area under concentration-time curve; BP = blood pressure; Cmax = maximum concentration; 
CV = cardiovascular; ECG = electrocardiogram; GI = gastrointestinal; HbA1c = hemoglobin A1c; HOMA = 
Homeostasis Model Assessment; HR = heart rate; PR = pulse rate; QTcF = Fridericia’s corrected QT interval; 
T2D = type 2 diabetes mellitus.
.


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5.
Study Design
5.1.
Overall Design
Study GBGJ is a randomized, multicenter, placebo-controlled, double-blind Phase 2 trial in T2D 
patients on metformin monotherapy.  The study is designed to assess the efficacy and safety of 
once weekly dulaglutide 3.0 mg and 4.5 mg in comparison to placebo.  In addition, the trial will 
explore how these dulaglutide doses compare to the approved dulaglutide 1.5 mg dose to support 
dose selection for further development in Phase 3 trials, and to guide design of these additional
trials. Study GBGJ will also explore the effect of 2 dulaglutide dose titration algorithms on GI 
tolerability with investigational doses to guide design of the definitive algorithm to be evaluated 
in Phase 3 trials.  The primary objective of this trial is to show superiority of the 3 dulaglutide 
doses (4.5 mg, 3.0 mg, 1.5 mg) to placebo in change in HbA1c at 18 weeks (see Section 4).
During the trial, an unblinded internal assessment committee (AC) will review data on safety and 
tolerability in study participants according to a prespecified schedule in order to assure the safety 
of randomized patients.
The study will consist of 3 periods:  an approximately 2-week lead-in period, followed by an 
18-week treatment period, and a 4-week safety follow-up period.  
Figure GBGJ.1 illustrates the study design.


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a   Patients will administer 1 injection per week in the first 4 weeks of the titration 
phase, and 2 injections per week in the remainder of the titration phase (see Section 7.1
and Table GBGJ.2).
b   During the maintenance phase, the assigned dose will require 3 injections (see 
Section 7.1 and Table GBGJ.2). 
Figure GBGJ.1.
Illustration of study design for Clinical Protocol H9X-MC-GBGJ.
Study Period I (Screening and Lead-In): 
Screening (Visit 1)
The purpose of screening procedures at Visit 1 is to establish initial eligibility (see Sections 6.1
and 6.2) and to obtain blood samples for laboratory assessments needed to confirm eligibility at 
Visit 2. Patients who meet all applicable inclusion criteria and none of the applicable exclusion 
criteria at Visit 1 will continue on their prestudy therapy (see Section 7.7.1.1) until Visit 2.
Lead-In (Visit 2 to Visit 3)
At Visit 2, the screening laboratory results will be reviewed and definite patient eligibility will be 
established. During the lead-in period, eligible patients should continue their prestudy therapy,
metformin (same formulation and dose), in order to allow reliable assessment of HbA1c at 
baseline (Visit 3); see Section 7.7.1.1.  If patients develop a condition that is a contraindication 
for the use of metformin or initiate other agents that are prohibited (see Table GBGJ.3 and


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Sections 6.1 and 6.2 for further details) between entry (Visit 1) and randomization, they will be 
considered ineligible and will be discontinued from the trial before randomization.  During this 
period, patients will be trained on disease monitoring and disease management procedures, study 
diaries, and study procedures. They will also receive education and training on how to perform 
subcutaneous injections; this should be reviewed as necessary throughout the study.  The training 
should include information on appropriate injection site locations, injection technique, and the 
signs and symptoms of local adverse reactions, should that occur. Patients will receive 
instructions on timing of doses (Table GBGJ.2 and Section 7.2.1), and will be instructed to 
record the date and time of all injections administered throughout the study in their study diaries.  
Study site staff will observe each patient self-injecting for training purposes. 
Visit-specific subject diaries will be dispensed at Visit 2 and at prespecified visits thereafter, 
until the last study visit (see Schedule of Activities, Section 2).
Study Period II (Treatment Period):
Randomization (Visit 3)
At Visit 3, patients will perform study procedures that are required prior to randomization.
Patients who continue to be eligible will then be randomized in a 1:1:1:1 ratio to 1 of the 
treatment arms: (1) dulaglutide 4.5 mg, (2) dulaglutide 3.0 mg, (3) dulaglutide 1.5 mg, or (4) 
placebo.  Within each of the investigational dulaglutide dose (3.0 mg and 4.5 mg) arms, patients 
will be randomly assigned in a 1:1 ratio to 1 of the titration algorithms (Algorithm 1 or 
Algorithm 2). Immediately after randomization, the patient will inject the first dose of study 
drug at the study site.  The Visit 3 pharmacokinetics (PK) sample must be collected 1-24 hours 
after the patient has injected study drug for the first time.
Following randomization, patients will participate in an 18-week treatment period that consists 
of a 6-week titration phase followed by a 12-week maintenance treatment phase at the final 
dosage. 
Titration Phase (end of Visit 3 to Visit 6)
During the titration phase in the investigational dose dulaglutide arms, the dose of dulaglutide 
will be escalated according to 1 of 2 algorithms:  

Algorithm 1: patients will receive dulaglutide 1.5 mg once weekly for the first 
4 weeks followed by dulaglutide 3.0 mg once weekly for the next 2 weeks, or 

Algorithm 2: patients will receive dulaglutide 0.75 mg once weekly for the first 
2 weeks followed by dulaglutide 1.5 mg once weekly for the next 4 weeks.
Maintenance Phase (end of Visit 6 to Visit 12)
During the maintenance phase, patients will administer study drug at their final assigned dose 
once weekly for approximately 12 weeks. 


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General considerations
Patients will perform study procedures listed in the Schedule of Activities (Section 2).  
In order to allow timely sampling for PK assessments, visits when collection of the PK samples
are required will be scheduled within the required time windows for PK sampling provided in the 
Schedule of Activities (Section 2 and Section 9.5). Therefore, the scheduling of visits when 
these samples are to be collected should take into account visit intervals/windows, timing of 
study drug injections and PK sampling windows. The sponsor will provide appropriate training 
on these requirements to avoid protocol deviations. 
Patients will continue to use concomitant metformin throughout the treatment period:  
discontinuation or changes to dose are not permitted, except in the situations where dose 
adjustment or complete discontinuation is required per country-specific label or when allowed 
per study protocol (for further details see Section 7.7.1.1).
Patients will be instructed to perform fasting plasma glucose (FPG) measurements once daily 
and 4-point self-monitoring plasma glucose (SMPG) measurements (consisting of fasting, 
pre-lunch, pre-dinner, and bedtime PG measurements) once weekly and to record all results in 
diaries; these results will be used for glucose management only.  In addition, 6-point SMPG 
(prior to and 2 hours after the morning, midday, and evening meals) will be collected during the 
week preceding prespecified clinic visits as shown in the Schedule of Activities (Section 2) and 
will be used for efficacy analyses.  During the weeks when the 6-point SMPG profiles are to be 
collected, patients will not be required to collect 4-point SMPG profiles, and the 6-point profiles 
will be used for glucose management instead. 
Patients who develop severe, persistent hyperglycemia based on prespecified thresholds (see 
Section 7.4.1.3) will receive a new glucose-lowering intervention (or rescue therapy) based on 
clinical judgment of the investigator (see Table GBGJ.3) and will also continue to administer 
study drug.  Patients who need rescue therapy for this reason will continue in the trial until they 
complete all study visits.  Patients who discontinue study drug due to AEs will also be required 
to continue in the trial and will receive an appropriate rescue glucose-lowering regimen.  
Table GBGJ.3 provides details on the use of glucose-lowering medications for rescue and for 
treatment of acute conditions as well as other medication classes that may interfere with efficacy 
and safety assessments in this trial. Patients who are unable or unwilling to continue in the study 
because of an AE or any other reason will perform an early termination (ET) visit as their final 
study visit.  If the patient is discontinuing during an unscheduled visit, that visit should be 
performed as the ET visit.  If the patient is discontinuing during a scheduled visit, that visit 
should be considered the ET visit. At this visit, patients will perform procedures listed in the 
Schedule of Activities (Section 2).
Study Period III (Safety Follow-Up, Visit 801):
All randomized patients who complete the treatment period will complete the safety follow-up 
visit at 22 weeks, approximately 4 weeks after their last visit on treatment.  During the safety 
follow-up study period, patients will be treated with the appropriate glucose-lowering regimen 
decided on by the investigator and the patient.  Glucagon-like peptide-1 receptor agonists and 


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dipeptidyl peptidase-4 (DPP-4) inhibitors will not be allowed during this period.  Patients will 
also be required to return any remaining study diaries to the investigative site.
5.2.
Number of Participants
Approximately 429 patients will be screened to achieve a total of approximately 300 randomized 
patients.
5.3.
End of Study Definition
End of the trial is the date of the last visit or last scheduled procedure (ie, the end of the 4-week 
safety follow-up period) shown in the Schedule of Activities (Section 2) for the last patient.
5.4.
Scientific Rationale for Study Design
Study GBGJ utilizes the parallel arm design as an appropriate option to collect data attributable 
to a specific randomized therapy without potential interference from other randomized 
treatments or the randomization sequence.
The 2 investigational dulaglutide doses (once weekly 3.0 mg and 4.5 mg) to be studied in this 
trial were chosen based on simulations which included data collected in Studies GBCD and 
GBCF (Barrington et al. 2011; Skrivanek et al. 2014), among other studies. Further details and 
the rationale for the choice of the doses are provided in Sections 3.2 and 5.5. The placebo 
comparator is considered appropriate for this trial to establish effects of the investigational doses 
on efficacy and safety measures that are attributable to dulaglutide. The active comparator 
dulaglutide 1.5 mg dose has been chosen to enable comparison of data collected under similar 
conditions to the investigational doses. Due to small sample size, the comparison between 
investigational doses and the dulaglutide 1.5 mg dose will use exploratory assessments with 
Bayesian-based methods to guide dose selection for Phase 3 development and design of 
confirmatory trials.
The 2 titration algorithms to be used in the dulaglutide 3.0 mg and 4.5 mg arms have been
chosen based on simulations that included data from several Phase 2 and Phase 3 trials to assess 
the potential mitigating effect of doubling increases in titrated doses (ie, Algorithm 1) versus 
longer exposure at lower titration doses (ie, Algorithm 2). They differ with respect to the initial 
dose (0.75 mg or 1.5 mg) corresponding to the recommended starting doses in different country-
specific labels, number of dose steps (2 or 3), and duration of exposure at the initiation dose (2 or 
4 weeks). The exposure-response information for GI tolerability collected from this study will
be combined with information from previous studies to guide design of the final algorithm to 
determine the starting dose(s), titration step(s), and duration of titration, to be taken into Phase 3 
development if data suggests dose titration is necessary.
The study population, patients with T2D treated with metformin, is considered adequate since 
these patients have been shown in Phase 3 trials to respond well to dulaglutide due to preserved 
beta cell function, a key prerequisite for assessment of response to the GLP-1 RA class of agents. 
Metformin is a required concomitant OAM in this study since patients with T2D are treated with 
metformin from the very early stages of the disease. Due to its predominant mechanism of 


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action (suppression of hepatic glucose output), metformin is not expected to interfere with 
planned assessments in this trial, if used in stable doses over a longer time period, as required per 
study protocol.
The planned efficacy measures are accepted for assessment of the short- and long-term effects of 
glucose-lowering therapies on glycemic control. The safety measures included in the trial are 
considered suitable for a trial that investigates GLP-1 RAs, since they allow for assessment of 
general safety, as well as for assessment of safety issues that are of special interest with this class 
of medication (for example, pancreatic and thyroid safety). The schedule of electrocardiograms 
(ECGs) includes important time points with respect to dulaglutide dose increases or duration of 
exposure to the investigational doses to enable characterizations of the effects on 
electrocardiographic parameters, including HR. As explained in Section 3.2, monitoring of 
asymptomatic elevations in pancreatic enzymes does not predict clinical outcomes; multiple 
assessments of pancreatic enzymes are planned during the study to better understand the changes 
in enzyme concentrations with the 2 investigational doses.    
The primary and secondary objectives are expected to provide initial benefit/risk profiles for the 
2 investigational dulaglutide doses versus placebo. The exploratory objectives are included to 
guide dose selection and trial design for Phase 3 development (if the feasibility of further 
development is confirmed). For this purpose, the choice of Bayesian-based methods is 
considered suitable since the sample size is not large enough to allow the use of frequentist 
approaches.  The treatment period duration of 18 weeks will allow patients to be treated with
their randomized dose (for example, 3.0 mg or 4.5 mg) for at least 12 weeks, which is considered 
sufficient time to assess the effect of dulaglutide on HbA1c due to the short time needed to 
achieve maximum glucose-lowering effect (approximately 2 weeks after initiation [Weinstock et 
al. 2015]). 
Taken together, the evidence provided supports the design and objectives of Study GBGJ, which 
aims to further explore the safety and efficacy of once weekly dulaglutide doses higher than 
1.5 mg, and to guide further development of an additional dose with an improved glycemic 
efficacy versus the highest approved dulaglutide dose, with an acceptable safety profile.
5.5.
Justification for Doses
The rationale for dulaglutide dose selection in this study was based on PK/pharmacodynamic 
(PD) model projections centered on identifying 1 or more doses higher than 1.5 mg that may
yield up to or greater than 0.2% additional HbA1c reduction and up to or greater than 1.0 kg 
additional weight loss at the Week 18 endpoint, with an acceptable safety and tolerability profile 
compared to placebo and the 1.5 mg dose.  The chosen higher dulaglutide doses (3.0 mg and 
4.5 mg) were selected considering adequate separation in PK exposure range between the doses 
to enable evaluation of their efficacy and adverse effect profiles.  Based on predicted plasma 
exposures in patients with T2D receiving the highest investigational dulaglutide dose of 4.5 mg, 
the margins of safety (ie, plasma exposure multiples at the no-observed-adverse-effect level 
[NOAEL]) in chronic toxicology studies in monkeys and rats were 162-fold and 55-fold, 
respectively.


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The 2 titration algorithms for the investigational doses were designed based on PK/PD modeling, 
with the goal of alleviating GI AEs.  The current predicted daily incidence of nausea and 
vomiting, together with observed data showing onset of such events diminishing by 4 to 6 weeks 
of treatment, suggest that utilizing a 4- to 6-week titration phase to reach the targeted dose will 
reduce the risk of new events with further uptitration by inducing tachyphylaxis. The titration 
algorithms will be initiated using 1 of the approved doses of dulaglutide (0.75 mg and 1.5 mg), 
because these doses do not require titration at initiation (see Figure GBGJ.1 and also Section 5.4
for further details). 
Study GBGJ is expected to inform the design of Phase 3 studies to further develop at least 1
higher dulaglutide dose by improving understanding of the effects of the 2 investigational 
dulaglutide doses on patient safety and tolerability, such as nausea and vomiting and the effect of 
an optimized dose-titration approach on these outcomes.


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6.
Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
6.1.
Inclusion Criteria
Patients are eligible to be included in the study only if they meet all of the following criteria at 
study entry (Visit 1), or at other visits, only when indicated:
[1]
are men or nonpregnant women aged ≥18 years;
[2]
have had T2D for ≥6 months according to the World Health Organization 
(WHO) classification (Appendix 5);
[3]
have HbA1c of 7.0% to 10.0%, inclusive, as assessed by the central 
laboratory;
[4]
have been treated with stable doses of metformin for at least 3 months prior to 
Visit 1 and between Visit 1 and Visit 3; the metformin dose will be considered 
stable for this period if all prescribed daily doses were in the range between 
the minimum required dose (≥1500 mg/day) and the maximum approved dose 
per country-specific label; lower doses will be allowed only with documented 
GI intolerability in the required dose range;
[5]
have had stable body weight for at least 3 months prior to Visit 1; body weight 
will be considered stable if it has not changed more than 5% in the past 
3 months;
[6]
agree not to initiate a diet and/or exercise program during the study with the 
intent of reducing body weight other than the lifestyle and dietary measures 
for diabetes treatment;
[7]
have a body mass index (BMI) ≥25 kg/m2;  
[8]
in the investigator’s opinion, are well-motivated, capable, and willing to:
[a] self-inject treatment as required for this protocol or come into the clinic 
for injections, up to 3 injections per week on the same day and within 
30 minutes (visually impaired persons who are not able to perform the 
injections must have the assistance of a sighted individual trained to inject 
the study drug; persons with physical limitations who are not able to 
perform the injections must have the assistance of an individual trained to 
inject the study drug);
[b] perform fingerstick PG monitoring at least once daily and up to 6 times 
per day once weekly (per Schedule of Activities [Section 2]) throughout 
the trial;
[c] maintain a study diary as required for this protocol;


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[9]
women of childbearing potential participating must agree to remain abstinent
(if this is their preferred and usual lifestyle), use 1 highly effective method of 
contraception, or a combination of 2 effective methods of contraception (see 
Appendix 6) starting at screening and continuing until 4 weeks after the last 
dose of the randomized therapy to allow for the plasma concentration to fall to 
≤365 ng/mL level (average concentration [Cave] at the NOAEL from Study 
WIL-353116).  
[a] Women of childbearing potential participating must test negative for 
pregnancy as indicated by negative serum pregnancy test at screening 
(Visit 1) followed by a negative urine pregnancy test within 24 hours prior 
to exposure (Visit 3).
[b] The patient may choose to use a double-barrier method of contraception.  
Barrier protection methods without concomitant use of a spermicide are 
not a reliable or acceptable method.  Thus, each barrier method must 
include use of a spermicide (ie, condom with spermicide, diaphragm with 
spermicide, female condom with spermicide) (Appendix 6).  It should be 
noted that the use of male and female condoms as a double-barrier method 
is not considered acceptable due to the high failure rate when these 
methods are combined.
[c] Women must not be breastfeeding.
[10] women not of childbearing potential may participate and include those who 
are:
[a] infertile due to surgical sterilization (hysterectomy, bilateral 
oophorectomy, or tubal ligation), congenital anomaly such as Müllerian 
agenesis; or
[b] postmenopausal – defined as either
i. A woman ≥50 years of age with an intact uterus, not on hormone 
therapy who has had either
a) cessation of menses for at least 1 year, or
b) at least 6 months of spontaneous amenorrhea with a follicle-
stimulating hormone >40 mIU/mL (central laboratory, see 
Schedule of Activities [Section 2]); or
ii. A woman 55 or older not on hormone therapy, who has had at least 6 
months of spontaneous amenorrhea; or
iii. A woman at least 55 years of age with a diagnosis of menopause prior 
to starting hormone replacement therapy.
[11] no male contraception is required except in compliance with specific local 
government study requirements;


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[12] have given written consent to participate in this study in accordance with local 
regulations and the Ethics Review Board (ERB) governing the study site
6.2.
Exclusion Criteria
Patients will be excluded from study enrollment if they meet any of the following criteria at 
study entry (Visit 1), or at other visits, only when indicated:
[13] have type 1 diabetes (T1D);
[14] have used any glucose-lowering medication other than metformin 3 months 
prior to study entry or during screening/lead-in period or have used any GLP-
1 RAs at any time in the past.  Short-term use of insulin for acute conditions is 
allowed (≤14 days);
[15] have been treated with any other excluded medication (Table GBGJ.3) within 
3 months prior to screening (Visit 1) and/or between study entry and 
randomization (Visit 3); excluded glucocorticoids must not have been used for 
>14 days within 1 month prior to Visit 1 or between Visits 1 and 3;
[16] have a condition that is a contraindication for use of the GLP-1 RA class or 
metformin (per country-specific labels) at Visit 1 or develop such condition 
between Visit 1 and Visit 3;
[17] have a history of ≥1 episode of ketoacidosis or hyperosmolar state/coma;
[18] have had ≥1 episode of severe hypoglycemia and/or ≥1 episode of 
hypoglycemia unawareness within the 6 months;
[19] have had any of the following CV conditions:  acute myocardial infarction 
(MI), New York Heart Association Class III or Class IV heart failure, or 
cerebrovascular accident (stroke);
[20] have a known clinically significant gastric emptying abnormality (eg, severe 
diabetic gastroparesis or gastric outlet obstruction) or have undergone gastric 
bypass (bariatric) surgery or restrictive bariatric surgery (eg, Lap-Band®);
[21] have acute or chronic hepatitis, signs and symptoms of any other liver disease 
other than nonalcoholic fatty liver disease (NAFLD), or alanine 
aminotransferase (ALT) level >2.5 times the upper limit of the reference 
range, as determined by the central laboratory at study entry; patients with 
NAFLD are eligible for participation in this trial;
[22] have had chronic or acute pancreatitis any time prior to study entry;
[23] have an estimated glomerular filtration rate (eGFR) <45 mL/min/1.73m2, 
calculated by the Chronic Kidney Disease-Epidemiology (CKD-EPI) 
equation, as determined by the central laboratory at Visit 1 and confirmed at 
Visit 2; if any country-specific label for countries involved in this trial 
requires discontinuation of metformin for eGFR cut-off ≥45 mL/min/1.73 m2,
then that requirement must be followed in that country;


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[24] have a personal or family history of medullary thyroid carcinoma (MTC) or 
personal history of multiple endocrine neoplasia syndrome type 2;
[25] have serum calcitonin ≥20 pg/mL, as determined by the central laboratory at 
study entry;
[26] have evidence of significant, active autoimmune abnormality (eg, lupus, 
rheumatoid arthritis);
[27] have active or untreated malignancy, or have been in remission from clinically 
significant malignancy (other than basal cell or squamous cell skin cancer) for 
less than 5 years;
[28] any serious disease or other condition (eg, known drug or alcohol abuse) 
which, in the opinion of the investigator, would pose a significant risk to the 
patient or interfere with the interpretation of safety, efficacy, or PD data;
[29] have any hematologic condition that may interfere with HbA1c measurement 
(eg, hemolytic anemias, sickle-cell disease);
[30] are investigator site personnel directly affiliated with this study and/or their 
immediate families (immediate family is defined as a spouse, parent, child, or 
sibling, whether biological or legally adopted);
[31] are currently enrolled in any other clinical trial involving an investigational 
product or any other type of medical research judged not to be scientifically or 
medically compatible with this study;
[32] are Lilly employees;
[33] have participated, within the last 30 days in a clinical trial involving an 
investigational product.  If the previous investigational product has a long 
half-life, 3 months or 5 half-lives (whichever is longer) should have passed;
[34] have previously completed or withdrawn from this study or any other study 
investigating dulaglutide
6.3.
Lifestyle Restrictions
Per the Schedule of Activities (Section 2), qualified medical staff will provide diabetes
management counseling, which will include instructions on diet and exercise and education 
about the signs, symptoms, and treatment of hypoglycemia, should it occur. Patients should 
continue their usual exercise habits and generally follow a healthy meal plan (with consistent 
meal size and time of day) throughout the course of the study. Dietary counseling may be
reviewed throughout the study, as needed.
Study participants should be instructed not to donate blood or blood products during the study.
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) must not
be rescreened.  


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7. Treatments
7.1.
Treatments Administered
In this study patients will receive treatment with 1 of the 3 doses of dulaglutide (4.5 mg, 3.0 mg, 
and 1.5 mg) or with placebo, each administered once weekly as subcutaneous injection(s) in 
patients with T2D who are already treated with a stable dose of metformin.  Prefilled syringes 
(PFS) in 1 of 2 strengths (dulaglutide 0.75 mg; dulaglutide 1.5 mg) will be used to administer 
randomized dulaglutide doses and the interim doses required by the titration algorithms during 
the titration phase for the investigational dulaglutide doses only.  
Table GBGJ.2 shows the randomized treatments for the entire treatment period (titration phase
and maintenance phase).
For doses requiring multiple injections, the entire dose (all injections for that week) should be 
administered within 30 minutes.  


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Table GBGJ.2.
Study Treatments 
Treatment 
Arm
Titration Phase Dosea
Maintenance 
Phase Doseb
Titration
Algorithm
Total dose/
Administered as
6-week Titration Phase
12-week Dosing
Week 0 and 
Week 1
Week 2 and
Week 3
Week 4 and
Week 5
Week 6 through
Week 17
4.5 mg 
Dulaglutide
1
Total dose
1.5 mg QW
1.5 mg QW
3.0 mg QW
4.5 mg QW
Administered as
1 × 1.5 mg PFS
1 × 1.5 mg PFS
2 ×1.5 mg PFS
3 × 1.5 mg PFS
2
Total dose
0.75 mg QW
1.5 mg QW
1.5 mg QW
4.5 mg QW
Administered as
1 × 0.75 mg PFS
1 × 1.5 mg PFS
2 × 0.75 mg PFS
3 × 1.5 mg PFS
3.0 mg 
Dulaglutide
1
Total dose
1.5 mg QW
1.5 mg QW
3.0 mg QW
3.0 mg QW
Administered as
1 × 1.5 mg PFS
1 × 1.5 mg PFS
2 × 1.5 mg PFS
2 × 1.5 mg PFS +
1 × Placebo PFS
2
Total dose
0.75 mg QW
1.5 mg QW
1.5 mg QW
3.0 mg QW
Administered as
1 × 0.75 mg PFS
1 × 1.5 mg PFS
2 × 0.75 mg PFS
2 × 1.5 mg PFS +
1 × Placebo PFS
1.5 mg 
Dulaglutide
—
Total dose
1.5 mg QW
1.5 mg QW
1.5 mg QW
1.5 mg QW
Administered as
1 × 1.5 mg PFS
1 × 1.5 mg PFS
2 × 0.75 mg PFS
1 × 1.5 mg PFS +
2 × Placebo PFS
Placebo
—
Total dose
Placebo
Placebo
Placebo
Placebo
Administered as
1 × Placebo PFS
1 × Placebo PFS
2 × Placebo PFS
3 × Placebo PFS
Abbreviations:  PFS = prefilled syringe; QW = once weekly.
a
Patients will administer 1 injection per week at the assigned dose for the first 4 weeks of the titration phase (Weeks 0, 1, 2, and 3), and 2 injections per week 
for the final 2 weeks of the titration phase (Weeks 4 and 5), totaling the assigned dose. 
b
During the maintenance phase, patients (Weeks 6 through 17) will administer 3 injections per week (different combinations of dulaglutide and placebo 
totaling the assigned dose).


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The investigator or his/her designee is responsible for the following:

explaining the correct use of the study drug to the patient or patient representative 

explaining the correct use of metformin to the patient, including any 
contraindications and appropriate dosing per country-specific labeling

verifying that treatment instructions described above are followed properly

maintaining accurate records of study drug dispensing and collection

Patients should return all unused study drug to the site according to the Schedule of 
Activities (Section 2).  The patients should be instructed to discard all used PFSs in a 
closeable, puncture-resistant container, and dispose according to local regulations.  Sites 
may be authorized to destroy used and unused PFSs locally per applicable local or 
national requirements.
7.1.1. Packaging and Labeling
The sponsor will provide dulaglutide and injectable placebo in PFSs, which will be dispensed via 
an interactive web-response system (IWRS).  Each PFS (0.75 mg dulaglutide in 0.5 mL OR 
1.5 mg dulaglutide in 0.5 mL OR placebo in 0.5 mL) will be packaged in cartons to be 
dispensed.   Titration cartons will contain 2 PFSs, and cartons for the maintenance phase will 
contain 3 PFSs.  Injections are to be administered as described in Table GBGJ.2 and Sections 
7.2.1 and 7.2.2.    
Clinical trial materials in each participating country will be labeled according to the country’s 
regulatory requirements.
7.2.
Method of Treatment Assignment
Patients who meet all criteria for enrollment will be randomized to 1 of the study treatment arms
at Visit 3.  Assignment to treatment arms will be determined by a computer-generated random 
sequence using an IWRS.  The IWRS will be used to assign cartons containing double-blind 
study drug to each patient.  Site personnel will confirm that they have located the correct cartons
by entering a confirmation number found on the label into the IWRS.
Block randomization will be used at the country level.  Patients will be randomized in a 1:1:1:1 
ratio (dulaglutide 4.5 mg, dulaglutide 3.0 mg, dulaglutide 1.5 mg, placebo).  Within the 
dulaglutide 4.5 mg and 3.0 mg arms, patients will be randomly assigned (1:1) to Algorithm 1 or 
Algorithm 2.  Randomization will be stratified by HbA1c (<8%, ≥8%).
7.2.1. Selection and Timing of Doses
Patients will be allocated to 1 of the 3 dulaglutide doses (4.5 mg, 3.0 mg, or 1.5 mg) or placebo, 
each administered once weekly as subcutaneous injection(s). Rationale for the choice of the 2 
investigational doses (4.5 mg and 3.0 mg) is provided in Section 5.5. The dulaglutide 1.5 mg 
dose was chosen as the active comparator since this is the highest dose approved by regulatory 
agencies. The randomization strategy is described in Section 7.2. 


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During the titration phase (end of Visit 3 to Visit 6 [Weeks 0 to 5]), patients assigned to 
investigational-dose dulaglutide (3.0 mg or 4.5 mg) will begin treatment using Algorithm 1 or 
Algorithm 2 (Table GBGJ.2).  Patients assigned to dulaglutide 1.5 mg or placebo will begin 
administering treatment as assigned at Visit 3, without titration.  During the maintenance phase 
(end of Visit 6 to Visit 12 [Weeks 6 to 17]), all patients will administer study drug at their final 
assigned dose. The assigned doses during the titration and maintenance periods may not be 
downtitrated.  Patients with poor tolerability of the study treatments will be allowed to 
discontinue dosing temporarily (Section 8.1.2). Patients who discontinue study treatment 
temporarily and are then unable to tolerate it upon rechallenge will be discontinued from study 
drug and will be initiated on glycemic rescue therapy (Section 8.1.1).
It is recommended that patients inject the study drug at approximately the same time of day on 
the same day each week.  For doses requiring multiple injections, the entire dose (all injections 
for that week) should be administered on the same day, within 30 minutes.  The day and time of 
all dose administrations are to be recorded in diaries by the patients.  If 1 or more injections are
not given on the scheduled day, the missed injection(s) should be given as soon as possible after 
the scheduled day if there are at least 3 days (72 hours) until the next dose.  If fewer than 3 days 
remain before the next scheduled dose, the missed injection(s) should be skipped and the next 
dose given at the regularly scheduled day and time.   
7.2.2. Injecting Study Drug 
All patients will inject study drug subcutaneously in the abdomen or thigh using the injection 
supplies provided; a caregiver may administer the injection(s) in the patient’s upper arm.  A new 
PFS will be used for each injection. For each individual dose, all injections should be 
administered at the same region.  Different doses can be injected in different regions (rotation is 
encouraged).
7.3.
Blinding
This is a double-blind study.
To preserve the blinding of the study, a minimum number of Lilly personnel will have access to
the randomization table and treatment assignments before the study is complete.
Emergency unblinding for AEs may be performed through the IWRS, which may supplement or 
take the place of emergency codes generated by a computer drug-labeling system.  This option 
may be used ONLY if the patient’s well-being requires knowledge of the patient’s treatment 
assignment.  All actions resulting in an unblinding event are recorded and reported by the IWRS.
If an investigator, site personnel performing assessments, or patient is unblinded, the patient will 
continue on the assigned therapy through the end of the study, if medically appropriate.  Study 
site personnel and the sponsor will document any unblinding events.
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a patient’s treatment assignment is warranted.  Patient safety must always be the first 
consideration in making such a determination.  If the investigator decides that unblinding is 


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warranted, the investigator should make every effort to contact the Lilly clinical research 
physician (CRP) prior to unblinding a patient’s treatment assignment unless this could delay 
emergency treatment of the patient.  If a patient’s treatment assignment is unblinded, Lilly must 
be notified immediately.
7.4.
Dosage Modification
No adjustment in study drug doses (dulaglutide or placebo) will be allowed. Dosing of required 
concomitant metformin is discussed in Section 7.7.1.1.
7.4.1. Special Treatment Considerations
7.4.1.1.
Standards of Medical Care
Investigators and other study team members are expected to treat patients according to the 
nationally established standards of care for diabetes management in respective participating 
countries, except where that treatment would be in conflict with the protocol-provided treatment 
requirements. If there are no local standards of care for diabetes, the investigators should follow 
current published standards of care from the American Diabetes Association (American Diabetes 
Association 2016) and the European Association for Study of Diabetes (Inzucchi et al. 2015) 
during their patients’ participation in this study. 
This section provides guidance on management of episodes of hypoglycemic events and events 
of severe, persistent hyperglycemia. For effective implementation of measures described here, it 
is important that patients, and their caregivers, if applicable, be well-educated about the signs 
and symptoms of hyperglycemia (for example, severe thirst, dry mouth, frequent micturition, or 
dry skin) and hypoglycemia (for example, intense hunger, sweating, tremor, restlessness, 
irritability, depression, headaches, disturbed sleep, or transient neurological disorders). Patients 
should be instructed to contact the investigative site in the event of severe, persistent 
hyperglycemia or severe hypoglycemia between study visits.
7.4.1.2.
Management of Increased Hypoglycemia Risk
Dulaglutide and metformin are non-secretagogues; therefore, clinically relevant increases in the 
risk of hypoglycemia are not expected in this trial (Trulicity USPI [WWW]).  
In this study, increased risk of hypoglycemia is defined as having a single episode of severe 
hypoglycemia or having more than 1 episode of documented symptomatic hypoglycemia within 
a 1-week period at any time during the treatment period. 
In cases where a patient experiences hypoglycemia as described above, to confirm the increased 
risk, the study sites must ensure that the patient has been fully compliant with the assigned 
therapeutic regimen and also that there is no evidence of other possible causes of hypoglycemia 
(for example, omission of meal, unexpected increase in exercise).
Patients fulfilling the definition of increased risk of hypoglycemia should first decrease the 
metformin dose, followed by discontinuation of metformin, if needed.  If the patient continues to 
experience hypoglycemic events after the discontinuation of metformin, the investigator should
discontinue the patient from study drug.  No adjustment of the dulaglutide dose should be made.


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7.4.1.3.
Management of Patients with Severe, Persistent Hyperglycemia during 
the Treatment Period
An additional therapeutic intervention should be considered in patients who develop severe, 
persistent hyperglycemia after randomization based on the following criteria:
a) average FPG >240 mg/dL (>13.3 mmol/L) over any 2-week period or longer during the 
first 6 weeks postrandomization; or
b) average FPG >200 mg/dL (>11.1 mmol/L) over any 2-week period or longer after the 
first 6 weeks postrandomization.
Investigators should first confirm that the patient is fully compliant with the assigned therapeutic 
regimen and that he/she does not have an acute condition causing severe hyperglycemia.  The 
investigator will decide in consultation with the patient on an appropriate glucose-lowering 
intervention (rescue intervention) after considering relevant clinical criteria.  Other GLP-1 RAs 
or DPP-4 inhibitors must not be included in the rescue intervention (see Table GBGJ.3 for 
allowed medications).  Patients who receive a new intervention for hyperglycemia management 
should also continue administering study drug for the remaining period in the trial.
7.5.
Preparation/Handling/Storage/Accountability
The study site must store the PFS cartons in a locked and secure environment.  The PFSs must be 
refrigerated (not frozen) at 2°C to 8°C until use.  Dry ice should not be used for cooling.  Patients 
will be provided with cartons containing the required number of dulaglutide and/or placebo PFSs
at clinic visits per the Schedule of Activities (Section 2).  They will receive insulated bags with 
cooling gel packs for use in transporting the PFS cartons from the site to home.  Investigational 
products in each participating country will be labeled according to the country’s regulatory 
requirements.
Patients will also be provided with a commercially available PG meter and test strips to use 
during the study.  Sufficient study drug material and glucose testing supplies will be dispensed, 
as needed, at each visit.
Study site staff must regularly assess whether the patient is correctly administering the assigned 
study drug and storing the study drug according to the provided instructions.  
7.6.
Treatment Compliance
The assessment of treatment compliance with study drug (dulaglutide or placebo) will be 
determined by the following:

Information about the once weekly study drug injections will be entered into the patient 
diary by the patient and reviewed by the site personnel at each study visit; this 
information will be collected in the electronic case report form (eCRF);

Study drug accountability will be checked at every visit.  For that purpose, patients will 
be instructed to return the study drug carton(s) at the next visit.  They will also be 
instructed to return any unused study drug at the next study visit;

In all treatment arms, treatment compliance for once weekly study drug for prespecified 
intervals (for titration phase and every 4 weeks thereafter) is defined as taking at least 


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75% of the required injections of study drug as assessed by site personnel; this 
information will be entered in the eCRF.
Other aspects of compliance will also be assessed at each visit, including the patient’s adherence 
to the visit schedule, compliance with the concomitant metformin requirements and other 
medication guidances (Section 7.7), completion of study diaries, results of SMPG, and any other 
parameters the investigator considers necessary.  Patients considered to be poorly compliant with 
their medications and/or study procedures (for example, missed visits or specific diagnostic tests) 
will receive additional training and instructions, as required (see Section 7.6).
7.7.
Concomitant Therapy
Patients will be permitted to use concomitant medications that they require during the study, 
except certain medications that may interfere with the assessment of efficacy and safety 
characteristics of the study treatments (Section 6.2).
Investigative site staff will inform patients that they must consult with the investigator or a 
designated site staff member upon being prescribed any new medications during the study. This 
may not be possible when initiated for treatment of medical emergencies, in which case the 
patient will inform the investigator or a designated site staff member as soon as possible.  Any 
additional medication initiated during the course of the study (including over-the-counter [OTC]
drugs, such as paracetamol or aspirin) must be documented, and the name of the drug and the 
date(s) of administration must be recorded in the patient’s diary and on the “Concomitant 
Medications” section of the eCRF. In addition, for required concomitant glucose-lowering 
agents (ie, metformin), the dosage will also be documented and collected.
Non-study medications taken by patients who are screened but not randomized will not be 
reported to Lilly unless an SAE or AE occurs that the investigator believes may have been 
caused by a study procedure.
Table GBGJ.3 provides a summary of criteria for use of concomitant medications that may 
interfere with planned assessments during the study.


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Table GBGJ.3.
Criteria for Use of Concomitant Medications that May Interfere with 
Efficacy and Safety Assessments in Study GBGJ
Abbreviations: DPP-4 = dipeptidyl peptidase-4; GLP-1 RA = glucagon-like peptide-1 receptor agonist; N = no; N/A 
= not applicable; SGLT2 = sodium-glucose co-transporter 2; Y = yes.
a
Acute therapy = treatment for up to 14 days.
b
Includes Saxenda® (liraglutide 3.0 mg), Xenical® (orlistat), Meridia® (sibutramine), Sanorex® (mazindol), 
Apidex® (phentermine), BELVIQ® (lorcaserin), Qsymia® (phentermine/topiramate combination), Contrave®
(naltrexone/buproprion), or similar other body weight loss medications including over-the-counter medications 
(eg, allī®) within 3 months prior to Visit 1 or any time during the trial. 
c
From 1 month prior to Visit 1 or between Visits 1 and 3; does not apply to topical, intraocular, intranasal, 
intra-articular, or inhaled preparations.
d
Switching metformin manufacturers is allowed as long as the dosage is the same.  Changing to a metformin 
formulation with a different action profile (ie, from short-acting to long-acting metformin) is not permitted.
e
For rescue therapy, metformin dose can be increased if the dose is below maximum approved dose per country-
specific label.
7.7.1. Antihyperglycemia Medications
The only glucose-lowering agent allowed 3 months prior to study entry and during the study is 
the required concomitant metformin.  In addition, short-term insulin use (up to 14 days) for
management of medical emergencies is allowed prior to study entry and during the study.  
Rescue therapy with other glucose-lowering agents, including insulin, may be medically 
indicated in certain situations after randomization (Table GBGJ.3).  These situations are 
described in Section 7.4.1.3 (severe, persistent hyperglycemia) and in Section 8.1.1 (early 
discontinuation of study drug).  If any such situation occurs, the patient may be treated with any 
locally approved glucose-lowering agent, except other GLP-1 RAs and DPP-4 inhibitors.  If 
insulin is prescribed as a rescue therapy, it must be differentiated from short-term use of insulin 
therapy for medical emergencies when reported in the eCRF.
Drug Class
Use During 
Screening/Lead-In
Conditions for Use after Randomization
Acute 
therapya
Rescue 
therapy 
During Safety 
Follow-Up Period
Drugs with approved weight loss 
indicationb
Excluded
N
N/A
Y
Systemic glucocorticoid therapyc
Excluded except for 
acute therapya
Y
N/A
Y
Antihyperglycemia medications
Other GLP-1 RAs
Excluded
N
N
N
DPP-4 inhibitors
Excluded
N
N
N
SGLT2 inhibitors
Excluded
N
Y
Y
Insulins and insulin mixtures
Excluded except for 
acute therapya
Y
Y
Y
Meglitinides
Excluded
N
Y
Y
Alpha-glucosidase inhibitors
Excluded
N
Y
Y
Sulphonylureas
Excluded
N
Y
Y
Thiazolidinediones
Excluded
N
Y
Y
Metformind
Required
N/A
Ye
Y


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Patients who receive any glucose-lowering agents 3 months prior to entry or during the screening 
or lead-in/stabilization periods, other than metformin, will not be eligible for further participation 
in the trial.
If any new glucose-lowering medication is initiated after randomization at Visit 3 and prior to 
safety follow-up period, other than study drug, rescue therapy, or short-term use of insulin for 
medical emergencies, the patient will be required to immediately discontinue the medication and 
the appropriate study deviation report will be generated. Any such violation of the protocol that 
lasts longer than 14 days will exclude the patient from the per-protocol (PP) population for 
analyses. 
7.7.1.1.
Required Concomitant Antihyperglycemia Medication:  Metformin
The key requirements for the use of metformin, the required OAM in Study GBGJ, are provided 
in Section 6.1 and Section 6.2.  
Patients in this study must be treated with metformin for at least 3 months prior to Visit 1; the 
minimum required dose during this time is 1500 mg/day; a lower dose will be acceptable only in 
the case of documented (ie, recorded in the patient’s medical file) poor GI tolerability of the 
minimum required dose.  The prescreening dose and formulation (short-acting or long-acting) 
should be maintained during the screening and lead-in periods, through randomization at Visit 3.
Metformin dose adjustment or discontinuation is allowed after randomization (during the 
treatment period) under the following circumstances:

in situations that require short-term treatment interruption in line with the product 
labeling for each respective country;

in situations that require dose adjustment or discontinuation per country-specific label, 
for example, in the case of reduced eGFR;

in the case of increased hypoglycemia risk during the treatment period (as described in 
Section 7.4.1.2).
Dose reduction/discontinuation of metformin during the trial should be properly documented.
In patients who require rescue therapy, dose increase of metformin is allowed, but the dose and 
the reason for change must be properly documented in the eCRF.
Guidance for treatment during the safety follow-up period is provided in Section 5.1
(Study Period III: Safety Follow-Up, Visit 801).
Where appropriate, metformin may be obtained locally by the Lilly affiliate in the participating 
country from local commercial supplies and distributed to sites.  It is acceptable for patients to 
continue obtaining metformin by previous prescribing process.  In the US and Puerto Rico, a 
prescription card will be available for patients to obtain metformin, with a prescription.
7.7.2. Medications that Promote Weight Loss
Prescription or OTC medications that promote weight loss are exclusionary if used within the 
3 months prior to Visit 1 (study entry), or between study entry and randomization at Visit 3 


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(see Section 6.2).  These medications are also not allowed at any time during the treatment 
period.  If started after randomization, these medications should be immediately withdrawn.  In 
addition, patients should not receive an intensive diet/exercise program with the intent of 
reducing body weight at any time during the study, other than the lifestyle and dietary measures 
for diabetes treatment (see Section 6.3).
Patients who use any medication from these groups during the treatment period will not be 
included in the PP analysis if the duration of use is >14 days (cumulative).  
7.7.3. Systemic Glucocorticoids
Chronic systemic glucocorticoid therapy (excluding topical, intraocular, intranasal, intra-
articular, or inhaled preparations) is exclusionary if used >14 consecutive days during the 
1-month period before study entry (Visit 1) or between study entry (Visit 1) and randomization 
at Visit 3. Patients who require >14 consecutive days of therapy with these medications after 
randomization will be excluded from the PP population for analyses.
7.7.4. Antihypertensive Medications
If used, antihypertensive therapy should be kept stable throughout the trial to allow assessments
of the effect of randomized therapies on blood pressure (BP). If initiation, discontinuation, or 
dose adjustment of any BP-lowering agent is medically required at any time during the study, the 
type and dose of medication must be documented in the eCRF.
7.8.
Treatment after the End of the Study
7.8.1. Continued Access
After study treatment is discontinued, an appropriate diabetes treatment regimen will be initiated 
by the investigator.


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8.
Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
8.1.1. Permanent Discontinuation from Study Treatment
Patients will be permanently discontinued from study drug in the following circumstances:

if a patient is inadvertently enrolled and it is determined that continued treatment with 
study drug would not be medically appropriate (see Section 8.1.3)

if a patient is diagnosed with an active or untreated malignancy (other than basal or 
squamous cell skin cancer, in situ carcinomas of the cervix, or in situ prostate cancer) 
after randomization

if a patient is diagnosed by the investigator with acute or chronic pancreatitis

if a patient is diagnosed with C-cell hyperplasia or MTC after randomization

if a patient develops an eGFR <30 mL/min/1.73m2 as calculated by CKD-EPI

if the patient or the patient’s designee, for example, legal guardian, requests that the 
patient be withdrawn from study drug

if the investigator or sponsor decides that the patient should be withdrawn from study 
drug; if the investigator decides to permanently discontinue study treatment because of an 
SAE or a clinically significant laboratory value, Lilly or its designee should be alerted 
immediately

if the sponsor decides that a treatment arm and patients in that arm should be withdrawn 
from study drug
Discontinuation of the investigational product for abnormal liver tests should be considered by 
the investigator when a patient meets one of the following conditions after consultation with the 
Lilly designated medical monitor:

ALT or aspartate aminotransferase (AST) >8 × upper limit of normal (ULN)

ALT or AST >5 × ULN for more than 2 weeks

ALT or AST >3 × ULN and total bilirubin level >2 × ULN or prothrombin time 
>1.5 × ULN

ALT or AST >3 × ULN with the appearance of fatigue, nausea, vomiting, right 
upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)

Alkaline phosphatase >3 × ULN

Alkaline phosphatase >2.5 × ULN and total bilirubin >2 × ULN


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
Alkaline phosphatase >2.5 × ULN with the appearance of fatigue, nausea, 
vomiting, right quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
Patients who stop the study drug permanently will receive another glucose-lowering intervention 
(rescue) and will continue participating in the trial according to the protocol to collect all planned 
efficacy and safety measurements.
8.1.2. Temporary Interruption of Study Treatment
In certain situations after randomization, the investigator may need to temporarily discontinue 
(interrupt) study drug (for example, due to an AE or a clinically significant laboratory value).  If 
study drug interruption is due to an AE, the event is to be documented and followed according to 
the procedures in Section 9.2 of this protocol.  Investigators should inform the sponsor that study 
drug has been temporarily interrupted.  Every effort should be made by the investigator to 
maintain patients on study drug and to restart study drug after any temporary interruption, as 
soon as it is safe to do so.  The data related to temporary interruption of study treatment will be 
documented in source documents and entered in the eCRF.   
8.1.3. Discontinuation of Inadvertently Enrolled Patients
If the sponsor or investigator identify a patient who did not meet enrollment criteria and was 
inadvertently enrolled, a discussion must occur between the sponsor CRP and the investigator to 
determine if the patient may continue in the study.  If both agree it is medically appropriate to 
continue, the investigator must obtain documented approval from the sponsor CRP to allow the 
inadvertently enrolled patient to continue in the study with or without treatment with 
investigational product. Any inadvertently enrolled patient in whom continuous administration 
of study drug may result in possible or definite safety risk should be discontinued from study 
drug (see Section 8.1.1). 
8.2.
Discontinuation from the Study
Every attempt should be made to keep patients in the trial irrespective of their adherence to 
treatment with study drug in order to minimize the amount of missing data and to enable 
assessment of study objectives as planned by the study protocol.  Patient discontinuation from 
the study early may be warranted in the following situations for ethical or legal reasons:

If a patient is diagnosed with T1D

If a female patient becomes pregnant

Enrollment in any other clinical trial involving an investigational product or enrollment in 
any other type of medical research judged not to be scientifically or medically compatible 
with this study
Patients may also discontinue from the study due to:

Sponsor or investigator decision when participation in the study needs to be stopped for 
medical, safety, regulatory, or other reasons consistent with applicable laws, regulations, 
and good clinical practice (GCP)


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
Patient decision when the patient or the patient’s designee, for example, legal guardian, 
requests to be withdrawn from the study
Prior to early study discontinuation, the patient will discontinue study drug and will have end-of-
study procedures (ET visit) performed as shown in the Schedule of Activities (Section 2). 
During the ET visit, the patient will be prescribed an appropriate glucose-lowering regimen and 
glucose self-monitoring plan.
8.3.
Lost to Follow-Up
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Site personnel are expected to make 
diligent attempts to contact patients who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the site.


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9.
Study Assessments and Procedures
Section 2 lists the Schedule of Activities, with the study procedures and their timing (including 
tolerance limits for timing).
Appendix 2 lists the laboratory tests that will be performed for this study.
Unless otherwise stated in the subsections below, all samples collected for specified laboratory 
tests will be destroyed within 60 days of receipt of confirmed test results.  Certain samples may 
be retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards.  
9.1.
Efficacy Assessments
9.1.1. Primary Efficacy Assessments
The primary efficacy measure is change in HbA1c from baseline at 18 weeks.
9.1.2. Secondary Efficacy Assessments
The following secondary efficacy measures will be evaluated at 18 weeks:

proportion of patients achieving HbA1c target <7.0% 

change in body weight from baseline

change in fasting serum glucose (central laboratory) from baseline
9.1.3. Exploratory Efficacy Assessments
The following exploratory efficacy measures will be evaluated at 18 weeks:

proportion of patients achieving HbA1c target ≤6.5%

change in 6-point SMPG profile from baseline

change in fasting plasma glucagon from baseline

change in HOMA-IR and HOMA-%B from baseline
9.1.4. Appropriateness of Assessments
Efficacy and safety assessments included in this study are generally regarded as reliable and 
accurate with respect to the efficacy and safety assessments in individuals and populations with 
T2D.
9.1.5. Body Weight, Height, and Body Mass Index
Body weight will be measured at prespecified time points (see Schedule of Activities, Section 2).  
Each patient’s weight should be measured according to a standardized protocol (Appendix 7).  
Body mass index will be computed from the patient’s weight and height.


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9.2.
Adverse Events
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the patient.
The investigator is responsible for the appropriate medical care of patients during the study.
Investigators must document their review of each laboratory safety report.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the investigational 
product or the study, or that caused the patient to discontinue the investigational product before 
completing the study.  The patient should be followed until the event resolves, stabilizes with 
appropriate diagnostic evaluation, or is reasonably explained.  The frequency of follow-up 
evaluations of the AE is left to the discretion of the investigator.
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
establish treatment effect.
After the informed consent form (ICF) is signed, study site personnel will record via eCRF the 
occurrence and nature of each patient’s preexisting conditions, including clinically significant 
signs and symptoms of the disease under treatment in the study.  In addition, site personnel will 
record any change in the condition(s) and any new conditions as AEs. Investigators should 
record their assessment of the potential relatedness of each AE to study procedure, 
investigational product, and study device via eCRF.
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, study device, or a study procedure, taking into account the 
disease, concomitant treatment or pathologies.
Planned surgeries and nonsurgical interventions should not be reported as AEs unless the 
underlying medical condition has worsened during the course of the study.
If a patient’s investigational product is discontinued as a result of an AE, study site personnel 
must report this to Lilly or its designee via eCRF, clarifying if possible, the circumstances 
leading to any dosage modifications, or discontinuations of treatment. 
9.2.1. Serious Adverse Events
An SAE is any AE from this study that results in 1 of the following outcomes:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect


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
considered significant by the investigator for any other reason:  important medical 
events that may not result in death, be life-threatening, or require hospitalization 
may be considered serious, based upon appropriate medical judgment.
Although all AEs occurring after signing the ICF are recorded in the eCRF, SAE reporting 
begins after the patient has signed the ICF and has received investigational product.  However, if 
an SAE occurs after signing the ICF, but prior to receiving investigational product, it needs to be 
reported ONLY if it is considered reasonably possibly related to study procedure.
Study site personnel must alert Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a sponsor-approved method.  If alerts are issued via telephone, they 
are to be immediately followed with official notification on study-specific SAE forms.  This 
24-hour notification requirement refers to the initial SAE information and all follow-up SAE 
information.
Pregnancy (during maternal or paternal exposure to investigational product) does not meet the 
definition of an AE.  However, to fulfill regulatory requirements, any pregnancy should be 
reported following the SAE process to collect data on the outcome for both mother and fetus.
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued and/or completed the study (the patient summary CRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a subject has 
been discharged from the study, and he/she considers the event reasonably possibly related to the 
study treatment or study participation, the investigator must promptly notify Lilly.
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator identifies as related to investigational product or procedure.  
United States 21 CFR 312.32 and European Union Clinical Trial Directive 2001/20/EC and the 
associated detailed guidance or national regulatory requirements in participating countries 
require the reporting of SUSARs.  Lilly has procedures that will be followed for the recording 
and expedited reporting of SUSARs that are consistent with global regulations and the associated 
detailed guidance.
9.2.2. Adverse Events of Special Interest
9.2.2.1.
Hypoglycemia and Hyperglycemia
Patients will collect information on episodes of hypoglycemia starting from Visit 2 until the last 
study visit (Visit 801 or ET visit).  For that purpose, patients will be trained about signs and 
symptoms of hypoglycemia, how to treat hypoglycemia, and how to collect in the study diary 
appropriate information for each episode of hypoglycemia according to the Schedule of 
Activities (Section 2).  Site personnel will enter this information into the eCRF at each visit.


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Investigators should use the following definitions and criteria when diagnosing and categorizing 
an episode considered to be related to hypoglycemia (the PG values in this section refer to values 
determined by a laboratory or International Federation of Clinical Chemistry and Laboratory 
Medicine plasma-equivalent glucose meters and strips) (American Diabetes Association 2005):

Documented symptomatic hypoglycemia is defined as any time a patient feels 
that he/she is experiencing symptoms and/or signs associated with hypoglycemia, 
and has a PG level of ≤70 mg/dL (≤3.9 mmol/L).

Asymptomatic hypoglycemia is defined as any event not accompanied by typical 
symptoms of hypoglycemia, but with a measured PG ≤70 mg/dL (≤3.9 mmol/L).

Probable symptomatic hypoglycemia is defined as an event during which 
symptoms of hypoglycemia are not accompanied by a PG determination (but that 
was presumably caused by a PG concentration ≤70 mg/dL [≤3.9 mmol/L]).

Severe hypoglycemia is defined as an episode requiring the assistance of another 
person to actively administer carbohydrate, glucagon, or other resuscitative 
actions.  These episodes may be associated with sufficient neuroglycopenia to 
induce seizure or coma.  Plasma glucose measurements may not be available 
during such an event, but neurological recovery attributable to the restoration of 
PG to normal is considered sufficient evidence that the event was induced by a 
low PG concentration.

Nocturnal hypoglycemia is defined as any hypoglycemic event that occurs 
between bedtime and waking.
For additional analysis, hypoglycemia defined as glucose <54 mg/dL (<3.0 mmol/L) will also be 
considered.
Cases of relative hypoglycemia are defined as symptomatic events during which the person 
reports any of the typical symptoms of hypoglycemia and interprets those as indicative of 
hypoglycemia, but a measured PG concentration >70 mg/dL (>3.9 mmol/L) is collected.
If a hypoglycemic event meets the criteria of severe, it needs to be recorded as serious on the AE
CRF and reported to Lilly as an SAE.
In each case of suspected or confirmed hypoglycemia, it is important that the event be properly 
categorized, the effect of the intervention be assessed, and the frequency of hypoglycemia be 
evaluated.  The role of dietary changes and physical exercise (or any other contributing factor) in 
the development of an event should be established.  The patient should receive additional 
education, if deemed appropriate.  Management of increased risk of hypoglycemia is described 
in Section 7.4.1.2.
Severe, persistent hyperglycemia will be collected during the trial to assess the risk of extreme 
imbalance in glycemic control. Events of interest related to hyperglycemia include rescue 
therapy for severe, persistent hyperglycemia, per criteria specified in Section 7.4.1.3.


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9.2.2.2.
Pancreatitis
Acute pancreatitis is defined as an AE of interest in all trials with dulaglutide, including this trial. 
Acute pancreatitis is an acute inflammatory process of the pancreas that may also involve 
peripancreatic tissues and/or remote organ systems (Banks and Freeman 2006). The diagnosis of 
acute pancreatitis requires 2 of the following 3 features:

abdominal pain, characteristic of acute pancreatitis (generally located in the 
epigastrium and radiates to the back in approximately half the cases [Banks 
and Freeman 2006; Koizumi et al. 2006]; the pain is often associated with 
nausea and vomiting);

serum amylase (total and/or pancreatic) and/or lipase ≥3 × ULN

characteristic findings of acute pancreatitis on computed tomography (CT) 
scan or magnetic resonance imaging (MRI).
If acute pancreatitis is suspected, appropriate laboratory tests (including levels of pancreatic 
amylase and lipase) should be obtained via the central laboratory (and locally, if needed). 
Imaging studies, such as abdominal CT scan with or without contrast, MRI, or gallbladder 
ultrasound, should be performed.  If laboratory values and/or abdominal imaging support the 
diagnosis of acute pancreatitis, the patient must discontinue therapy with investigational product,
but will continue in the study on another glucose-lowering regimen (see Sections 7.7.1 and 8.1.1
for details on rescue intervention).  The most appropriate diabetes therapeutic regimen will be 
decided by the investigator, based on the patient’s clinical status.  A review of the patient’s 
concomitant medications should be conducted to assess any potential causal relationship with 
pancreatitis.
Each case of AE of pancreatitis must be reported. If typical signs and/or symptoms of 
pancreatitis are present and confirmed by laboratory values (lipase or amylase [total and/or 
pancreatic]) and imaging studies, the event must be reported as an SAE. For a potential case that 
does not meet all of these criteria, it is up to the investigator to determine the seriousness of the 
case (AE or SAE) and the relatedness of the event to study drug.
In addition to the diagnostic assessment in patients who develop symptoms of acute pancreatitis, 
each patient will have measurements of pancreatic amylase and lipase at screening, baseline, 
Visit 6 (Week 6), Visit 12 (Week 18), and the last study visit (Visit 801 [Week 22] or ET visit), 
to assess any potential effects of dulaglutide on the exocrine pancreas (refer to the Schedule of 
Activities, Section 2).  Further diagnostic assessment per Lilly algorithm for assessment of 
asymptomatic pancreatic hyperenzymemia will be required whenever lipase and/or pancreatic 
amylase are ≥3 × ULN at any time during the study.  If this situation occurs at Visit 801
(Week 22), the patient will be required to undergo this additional work-up, and the data will be 
collected in the clinical trial database.
All suspected cases of acute or chronic pancreatitis, as well as cases of confirmed lipase or 
pancreatic amylase values ≥3 × ULN, will be adjudicated by an independent committee of expert 
physicians. In addition, AEs of severe or serious abdominal pain of unknown etiology will also 
be submitted to the adjudication committee to assess for possible pancreatitis or other pancreatic 


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disease. Relevant data from patients with acute or chronic pancreatitis, those with severe or 
serious abdominal pain, and those that undergo additional assessments due to confirmed 
hyperenzymemia will be entered into a specifically designed eCRF page by study site or Lilly 
staff. The adjudication committee representative will enter the results of adjudication in a 
corresponding eCRF page.
9.2.2.3.
C-Cell Hyperplasia and C-Cell Neoplasms
Individuals with personal or family history of certain thyroid or nonthyroid endocrine 
abnormalities or certain preexisting laboratory and genetic characteristics will be excluded from 
the study (see Section 6.2).  The assessment of thyroid safety during the trial will include 
reporting of thyroid treatment-emergent AEs (TEAEs) and measurements of calcitonin according 
to the Schedule of Activities (Section 2) at screening, baseline, and Visit 12 (Week 18) or ET 
visit.  The purpose of calcitonin measurements is to assess the potential of dulaglutide to affect 
thyroid C-cell function, which may indicate development of C-cell hyperplasia and neoplasms.  
Patients who develop serum calcitonin increases ≥50% of the mean of the baseline and screening 
values AND an absolute value ≥20 pg/mL and <35 pg/mL at Visit 12 (Week 18) will be asked to 
repeat the measurement within 1 month.  If this repeat value is increasing (≥10% increase), the 
patient will be encouraged to undergo additional endocrine assessment and longer-term follow-
up by an endocrinologist to exclude a serious adverse effect on the gland.  
Patients with an increase in serum calcitonin ≥50% of the mean of the baseline and screening 
values AND an absolute value ≥35 pg/mL at Visit 12 (Week 18) will be recommended to 
immediately undergo additional endocrine assessments and longer-term follow-up by an 
endocrinologist.
For patients who require additional endocrine assessment because of increased calcitonin 
concentration per criteria provided in this section, data from the follow-up assessment will be 
collected in the specific section of the eCRF.
9.2.2.4.
Allergic/Hypersensitivity Reactions
All allergic or hypersensitivity reactions will be reported by the investigator as either AEs or, if 
any serious criterion is met, as SAEs.  Additional data, such as type of reaction and treatment 
received, will be collected on any AEs or SAEs that the investigator deems related to study drug 
via an eCRF created for this purpose.  At the time of AE occurrence, a sample will be collected 
for measurement of dulaglutide anti-drug antibodies (ADA). Study drug should be temporarily 
interrupted in any individual suspected of having a severe or serious allergic reaction to study 
drug (Section 8.1.2).  Study drug may be restarted when/if it is safe to do so, in the opinion of the 
investigator.  If study drug is permanently discontinued, see Section 8.1.1 for procedures
required in this situation.
9.2.2.5.
Supraventricular Arrhythmias and Cardiac Conduction Disorders
All events of treatment-emergent supraventricular arrhythmias and cardiac conduction disorders 
will be fully evaluated. Patients who develop any event from these groups of disorders should 
undergo an ECG which should be submitted to the central reading center.  Additional diagnostic 
tests to determine exact diagnosis should be performed, as needed.  The specific diagnosis will 


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be recorded as an AE.  Events that meet criteria for serious conditions as described in 
Section 9.2.1 must be reported as SAEs.  Study drug should be temporarily discontinued in any 
patient with signs and symptoms of serious cardiac arrhythmias or conduction disorders.  Study 
drug may be restarted when/if it is safe to do so, in the opinion of the investigator.
9.2.3. Complaint Handling
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical studies in order to ensure the safety of study participants, monitor quality, and to 
facilitate process and product improvements.
Patients will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed.
9.3.
Treatment of Overdose
Study drug overdose (more than the specified number of injections, whether for placebo or 
dulaglutide treatment) will be reported as an AE.  In the event of overdose, refer to the IB and or 
Product Label.
9.4.
Safety
9.4.1. CV Safety
9.4.1.1.
Cardiovascular Events
Deaths and nonfatal CV AEs will be adjudicated by a committee of physicians external to Lilly 
with cardiology expertise. The nonfatal CV AEs to be adjudicated include: MI; hospitalization 
for unstable angina; hospitalization for heart failure; coronary interventions (such as coronary 
artery bypass graft or percutaneous coronary intervention); and cerebrovascular events, including 
cerebrovascular accident (stroke) and transient ischemic attack.
9.4.1.2.
Electrocardiograms
To assess the effect of higher doses on cardiac electrophysiology, ECGs will be collected 
according to the Schedule of Activities (Section 2) and centrally overread.  Electrocardiograms 
should be recorded in triplicate according to study-specific recommendations included in the 
Manual of Operations for the study, using standardized equipment provided by the sponsor.  
Each ECG tracing will be assessed by the investigator immediately upon recording for clinical 
management purposes.  Any clinically significant findings from ECGs that result in a diagnosis 
and that occur after the patient receives the first dose of the investigational treatment should be 
reported to Lilly or its designee as an AE via eCRF.  Results of the central overread will be 
entered into the clinical trial database and will be used for the statistical analysis of the effects of 
the randomized treatments.  In addition, once the overread ECG is returned from the centralized 
ECG vendor, the investigator, or qualified designee, is responsible for determining if any change 
to the patient management is needed. The investigator, or qualified designee, must document 
his/her review of the ECG printed at the time of evaluation, the final overread ECG report issued 
by the central ECG laboratory, and any alert reports.


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9.4.1.3.
Vital Signs
Sitting BP and pulse rate (PR) will be measured using standardized equipment provided by the 
sponsor according to the Schedule of Activities (Section 2). Vital sign measurements should be 
taken before obtaining an ECG tracing and before collection of blood samples for laboratory 
testing, at visits where required (see Schedule of Activities, Section 2). The participant should 
be required to sit quietly for 5 minutes before vital sign measurements are taken. An 
appropriately sized cuff (cuff bladder encircling at least 80% of the arm) should be used to 
ensure the accuracy of BP measurements.  The arm used for the BP measurement should be 
supported at heart level. At Visit 1 (screening), to determine which arm should be used to collect 
BP and PR throughout the study, BP and PR will be measured once in each arm, and the arm that 
had the higher systolic BP should be used to collect all 3 measurements of both BP and PR at all 
study visits.  For each parameter (PR, systolic blood pressure [SBP], and DBP), 3 measurements 
will be taken using the same arm; the recordings should be taken at least 1 minute apart, and 
each measurement of sitting PR and BP will be recorded in the eCRF.  Any AE related to 
changes in BP and PR should be reported.
9.4.2. Laboratory Tests
For each patient, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities (Section 2). 
Any clinically significant findings from laboratory tests that result in a diagnosis and that occur 
after the patient receives the first dose of investigational product should be reported to Lilly or its 
designee as an AE via eCRF.
9.4.3. Safety Monitoring
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods, including trends in safety variables, laboratory analytes, and AEs.  An AC will review 
prespecified safety reports in an unblinded fashion.  In addition, the study team will review 
safety reports in a blinded fashion according to the schedule provided in the Trial-Level Safety 
Review plan.  Lilly will also review SAEs within time frames mandated by company procedures.  
The Lilly CRP will, as appropriate, consult with the functionally independent Global Patient 
Safety therapeutic area physician or clinical scientist.
In addition, specific safety measures are included in the protocol to ensure appropriate 
monitoring of pancreatic, thyroid, and liver safety.  Laboratory findings that trigger pancreatic 
and thyroid safety monitoring per Lilly standards are provided in Sections 9.2.2.2 and 9.2.2.3, 
respectively.  Details of liver safety monitoring are provided in Appendix 4.  If a study patient 
experiences elevated ALT ≥3 × ULN, alkaline phosphatase ≥2 × ULN, or elevated total bilirubin
≥2 × ULN, clinical and laboratory monitoring should be initiated by the investigator per Lilly
Hepatic Safety Monitoring Algorithm.  Details for hepatic monitoring depend upon the severity 
and persistence of observed laboratory test abnormalities.  To ensure patient safety and comply 
with regulatory guidance, the investigator is to consult with the Lilly CRP regarding collection of 
specific recommended clinical information and follow-up laboratory tests.  See Appendix 4.


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9.5.
Pharmacokinetics
Blood samples for determining plasma concentrations of dulaglutide, associated with time from 
dose, will be obtained at selected visits from all patients in accordance with the Study Schedule 
and at ET (see Schedule of Activities [Section 2]). However, only samples from patients 
assigned to treatment with dulaglutide will be analyzed for drug concentrations.
Timing of PK blood draws have been optimized for sparse sampling using a standard PK optimal 
sampling approach. Pharmacokinetic samples will be drawn to include a range of sampling time 
windows (predose, and 1-24 hours, 24-96 hours, and 120-168 hours postdose) spread over 
several clinic visits.  For the ET visit, a sample may be drawn at any time during the visit. The 
study has been designed so that, where possible, each immunogenicity sample will be 
accompanied by a PK sample in the same visit.  At visits where ECG measurements are taken, 
these should be accompanied by a time-matched PK sample within 30 minutes (before or after), 
during the same visit.
At the visits and times specified in the Schedule of Activities (Section 2), venous blood samples 
of approximately 4 mL each will be collected to determine the plasma concentrations of 
dulaglutide.
Instructions for the collection and handling of blood samples will be provided by the sponsor.  
The actual date and time (24-hour clock time) of each sampling and all study drug doses must be 
clearly recorded.
Drug concentration information that would unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded.
Bioanalytical samples collected to measure investigational product concentration will be retained 
for a maximum of 1 year following last patient visit for the study.
9.6.
Pharmacodynamics
Pharmacodynamic parameters will include safety and efficacy endpoints as described in 
Section 4. Analysis methods are described in Section 10.3.5.
9.7.
Pharmacogenomics
9.7.1. Whole Blood Samples for Pharmacogenetic Research
A whole blood sample will be collected for pharmacogenetic analysis as specified in the 
Schedule of Activities (Section 2) where local regulations allow.  
Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future.  Samples will be used to investigate variable response to dulaglutide and to 
investigate genetic variants thought to play a role in T2D and related complications.  Assessment 
of variable response may include evaluation of AEs or differences in efficacy.  
All samples will be coded with the patient number.  These samples and any data generated can 
be linked back to the patient only by the investigator site personnel.  


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Samples will be retained for a maximum of 15 years after the last patient visit for the study, or 
for a shorter period if local regulations and/or ERBs/investigational review boards impose 
shorter time limits, at a facility selected by Lilly or its designee.  This retention period enables
use of new technologies, response to regulatory questions, and investigation of variable response 
that may not be observed until later in the development of dulaglutide or when dulaglutide is 
widely commercially available.
Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named.  However, existing approaches include whole genome or exome 
sequencing, genome-wide association studies, and candidate gene studies, and epigenetic 
analyses.  Regardless of technology utilized, genotyping data generated will be used only for the 
specific research scope described in this section. 
9.8.
Biomarkers and Antibodies
9.8.1. Samples for Immunogenicity Research
Samples from patients in each treatment arm will be tested for the development of treatment-
emergent dulaglutide ADA, defined as 4-fold increase in titer from baseline.  A blood sample 
will be collected at specific study visits according to the Schedule of Activities (Section 2).
Treatment-emergent positive dulaglutide ADA samples will be evaluated for their ability to 
neutralize the activity of assigned treatment (dulaglutide-neutralizing antibodies).  Positive
dulaglutide ADA samples may also be tested for cross-reactivity with native GLP-1, and if 
positive, then for neutralizing antibodies against native GLP-1.
Samples will be retained for a maximum of 15 years after the last patient visit for the study, or 
for a shorter period if regulations and ERBs impose shorter time limits, at a facility selected by 
Lilly or its designee.  The duration allows the sponsor to respond to future regulatory requests 
related to dulaglutide.
9.8.2. Biomarkers
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, PD, mechanism of action, variability of subject response (including safety), and 
clinical outcome.  Sample collection is incorporated into clinical studies to enable examination of 
these questions through measurement of biomolecules including DNA, RNA, proteins, lipids, 
and other cellular elements.
Serum and plasma samples (ethylenediaminetetraacetic acid [EDTA] and remaining P800 
plasma from glucagon collection) for nonpharmacogenetic biomarker research will be collected 
at the times specified in the Schedule of Activities (Section 2) where local regulations allow.
Samples will be used for research on the drug target, disease process, variable response to 
dulaglutide, pathways associated with diabetes mellitus, mechanism of action of dulaglutide, 
and/or research method, or for validating diagnostic tools or assay(s) related to diabetes mellitus.


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All samples will be coded with the subject number.  These samples and any data generated can 
be linked back to the subject only by the investigative site personnel.
Samples will be retained for a maximum of 15 years after the last subject visit, or for a shorter 
period if local regulations and/or ERBs impose shorter time limits, at a facility selected by Lilly.  
This retention period enables use of new technologies, response to regulatory questions, and 
investigation of variable response that may be not observed until later in the development of 
dulaglutide or after dulaglutide is commercially available.
9.9.
Health Economics
Not applicable.  


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10. Statistical Considerations
10.1. Sample Size Determination
Assuming a screen failure rate of 30%, approximately 429 patients will need to be screened to 
attain approximately 300 patients randomized to the 4 treatment arms in a 1:1:1:1 ratio for
4.5 mg, 3.0 mg, 1.5 mg dulaglutide, or placebo weekly (~75 patients per arm).  For the 
investigational dulaglutide dose arms (4.5 mg and 3.0 mg), approximately 38 patients will be 
assigned to each titration algorithm (Algorithms 1 and 2).  Assuming a 20% dropout, this will 
result in approximately 60 patients per arm and 30 patients per algorithm (in each of the 
investigational-dose dulaglutide arms) completing the study. 
The aforementioned sample size provides ≥90% power to demonstrate superiority for the
dulaglutide doses (4.5 mg, 3.0 mg, and 1.5 mg) to placebo with respect to HbA1c change from 
baseline to 18 weeks. This assumes a true glycemic effect difference of -1% HbA1c for each 
dulaglutide dose versus placebo, and a standard deviation (SD) of 1.2% with a 2-sided alpha of 
0.05.
10.2. Populations for Analyses
Table GBGJ.4 defines the populations to be used for analyses.
Table GBGJ.4.
Populations for Analyses
Population
Description
Entered
All participants who sign informed consent
Intent-to-treat (ITT)
All participants who are randomized and take at least 1 dose of study medication 
for an assigned treatment arm
All randomized population
All patients who are randomized 
Per protocol
All ITT patients who meet all of the following criteria:

Have no important protocol deviation that could impact the assessment 
of the primary endpoint*

At least 75% compliant with study drug administration

Complete the treatment period (18 weeks) 

Have a value of the primary efficacy measure (HbA1c) at 18 weeks
Completer set
All ITT patients who complete 18 weeks of study drug treatment without rescue 
therapy
Abbreviation:  HbA1c = hemoglobin A1c.
*Full list will defined in the Statistical Analysis Plan.
10.3. Statistical Analyses
10.3.1. General Statistical Considerations
Statistical analysis of this study will be the responsibility of Lilly or its designee. Any change to 
the data analysis methods described in the protocol will require an amendment ONLY if it 
changes a principal feature of the protocol.  Any other change to the data analysis methods 
described in the protocol, and the justification for making the change, will be described in the 


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clinical study report (CSR).  Additional exploratory analyses of the data will be conducted as 
deemed appropriate.
Unless otherwise specified, listings will include all randomized patients.  Efficacy and safety 
analyses will be conducted in the intent-to-treat (ITT) population.  The primary efficacy measure 
(change from baseline in HbA1c) will also be evaluated in the PP population and Completer sets.  
In all efficacy and hypoglycemia analyses, all data after rescue therapy will be censored.
Analyses of safety parameters, except for hypoglycemia events, will be conducted in the ITT 
population including the post-rescue therapy data.  
Countries with fewer than 10 randomized patients will be pooled for statistical analyses. Pooled 
country will be employed for all formal statistical model-based analyses.
Unless otherwise specified, all tests of treatment effects will be conducted at a 2-sided alpha 
level of 0.05, and confidence intervals (CIs) will be calculated at 95%, 2-sided.  All tests of 
interactions between treatments and factors of interest will be conducted at a 2-sided alpha level 
of 0.10. 
The baseline visit will be Visit 3.  For all variables, including HbA1c, if baseline data are not 
available or are missing, the last nonmissing measurement taken prior to this visit will be used 
for the baseline measurement.  The measurement for the primary analysis is defined as the 
change from baseline in HbA1c to Week 18 (Visit 12).
For all statistical analyses, missing data will be treated as missing at random; therefore, no 
imputation is needed unless otherwise stated. 
A mixed-model repeated measures (MMRM) analysis will be used to analyze continuous 
longitudinal variables.  In this model, restricted maximum likelihood will be used to obtain 
model estimates with Kenward-Roger option to estimate denominator degrees of freedom.  The 
corresponding baseline value will be used as a covariate, and the stratification factor (HbA1c 
<8% or ≥8%), pooled country, treatment, visit, and treatment-by-visit interaction will be fixed 
effects.  For HbA1c change from baseline analysis, stratification factor will be removed from the 
aforementioned model.  An unstructured covariance structure will be used to model the within-
patient errors.  If this model fails to converge, the following covariance structures will be tested 
in order:

Toeplitz with heterogeneity

autoregressive with heterogeneity, by visit

compound symmetry with heterogeneous variances by visit 

Toeplitz

autoregressive

compound symmetry without heterogeneous variances, by visit.
The first covariance structure that converges will be used.
For continuous laboratory measurements for safety, an analysis of variance (ANOVA) on ranks 
will be used with treatment as a fixed effect.


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For all continuous measures, summary statistics will include number of patients, mean, SD, 
median, minimum, and maximum for both the actual and change from baseline measurements at 
each scheduled visit for each treatment.  Least-squares mean (LS mean) and standard errors 
(SEs) derived from the model will also be displayed for the change from baseline measurements
at each scheduled visit for each treatment.  Treatment comparisons will be displayed showing the 
treatment difference LS mean and the 95% CIs between each dose and placebo, and between 
each investigational dose and 1.5 mg at the same visit, along with the corresponding p-values.
Summary statistics for categorical measures will include number of subjects and percentages.
The percentage of patients achieving target HbA1c <7.0% at Week 18 will be analyzed using a 
longitudinal logistic regression with repeated measurements with treatment, visit, treatment-by-
visit interaction, and baseline HbA1c-by-visit interaction as fixed effects and baseline HbA1c as 
a covariate.  For the analysis of other categorical measures, Fisher’s exact test will be used for 
treatment comparisons, unless 80% of cells have an expected value of at least 5, in which case 
the Chi-square test will be used unless otherwise stated.
No adjustments for multiplicity will be performed.
10.3.2. Treatment Group Comparability
10.3.2.1. Patient Disposition
A detailed description of patient disposition will be provided at the end of the study. 
Frequency counts and percentages of all patients entered, randomized/enrolled, completing, 
and/or discontinuing from the study early will be presented for each treatment.  The reasons for 
discontinuation from the study will be summarized by treatment group.  A summary of 
discontinuations will also be presented by visit.
10.3.2.2. Patient Characteristics
Demographic and baseline characteristics will be summarized by treatment.  For continuous 
measures, summary statistics will include sample size, mean, median, maximum, minimum, and 
SDs along with ANOVA’s p-value to test overall treatment effect.  For categorical measures, 
summary statistics will include sample size, frequency, and percent.  
10.3.2.3. Concomitant Therapy 
The prespecified concomitant medications of interest will be summarized by treatment.  
10.3.2.4. Treatment Compliance
Treatment compliance is defined as taking at least 75% of required injections for the prespecified 
time intervals (see Section 7.6).  Overall compliance is defined as being at least 75% compliant 
with investigational product across the treatment period.  Compliance will be summarized by 
each treatment and time interval, and overall.  Listings will also be produced.


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10.3.3. Efficacy Analyses
10.3.3.1. Primary Analyses
The primary analysis for the primary endpoint, change from baseline in HbA1c at 18 weeks, will 
employ MMRM described in Section 10.3.1 in ITT population by censoring all post rescue data. 
10.3.3.2. Secondary Analyses
10.3.3.2.1.Secondary Analyses for Primary Endpoint
A Bayesian integrated 2-component prediction (ITP) model (Fu and Manner 2010) will be 
applied as a supportive analysis for the primary endpoint, change from baseline in HbA1c at 18 
weeks, in ITT population by censoring all post-rescue data. Probabilities based on posterior 
distributions of the parameter of interest will be generated from this model. Non-informative 
priors will be used in this model. In addition, the informative priors from the posterior for 
placebo and posterior for dulaglutide 1.5 mg obtained from Studies GBCF and H9X-MC-GBDE
(GBDE) will be evaluated in this model to check the robustness of the analysis. The primary 
analysis model, MMRM, will be repeated using the PP and Completers populations for the 
primary endpoint only to check the sensitivity of the analysis.  If the conclusions differ from that 
of the ITT population, the data and analyses may be further explored using selected pattern 
mixture models for missing data (Kenward and Rosenkranz 2011). As a sensitivity analysis, the 
primary endpoint will be analyzed with MMRM and Bayesian ITP model in the ITT population 
including post-rescue therapy data.
10.3.3.2.2.Analyses for Secondary Efficacy Endpoints
The ITT population without post-rescue data is the analysis population for secondary efficacy 
endpoints. The MMRM described in Section 10.3.1 will be used for the secondary continuous 
efficacy endpoints.  For percentages of patients achieving HbA1c target <7.0%, repeated 
measures logistic regression with generalized linear mixed model described in Section 10.3.1
will be fitted.
A Bayesian ITP model will be fitted to analyze body weight change from baseline as a 
supportive analysis.  
10.3.3.3. Tertiary/Exploratory Efficacy Endpoints
The analysis of patients reaching HbA1c target ≤6.5% will use the same model as that for 
HbA1c target <7.0% described in Section 10.3.3.2.2. 
Longitudinal continuous variables such as fasting glucagon will be analyzed using MMRM 
described in Section 10.3.1.  If the normality assumption is violated, appropriate transformation 
is needed prior to analysis.
Non-longitudinal continuous variables such as 6-point SMPG, HOMA-IR, and HOMA-%B will 
be analyzed using last observation carried forward (LOCF) by fitting a linear model with pooled
country, treatment, baseline HbA1c strata as fixed effect, and corresponding baseline value as a 
covariate.  Data transformation may be applied if data are not normally distributed.  


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10.3.4. Safety Analyses
The safety analyses will include AEs, SAEs, and TEAEs, defined as postbaseline events that are 
new events or preexisting conditions that worsened in severity after randomization, 
hypoglycemic and hyperglycemic episodes, and laboratory analytes.  Unless otherwise specified, 
the ITT population will be used for analyses of safety measures.
10.3.4.1. Study Drug Exposure
Exposure will be calculated for each patient and summarized by each treatment group.
10.3.4.2. Adverse Events
Adverse events will be coded from the actual term using the Medical Dictionary for Regulatory 
Activities (MedDRA) and reported with preferred terms and system organ class.  Selected 
notable AEs of interest may be reported using high-level terms.   
Summary statistics will be provided for overall AE, TEAEs, SAEs, and study discontinuation 
due to AEs or death during the treatment period.  Counts and proportions of patients 
experiencing AEs will be reported for each treatment.  Adverse events will be analyzed as 
described in Section 10.3.1.
Listings of patients experiencing SAEs, allergic and hypersensitivity reactions, ADA as well as 
those discontinuing the study, or study medication due to AEs, will be generated.
10.3.4.3. Hypoglycemic Episodes
Section 9.2.2.1 contains definitions of categories of hypoglycemia. A listing of individual 
hypoglycemic episodes by patient will be presented.  Summary reports will include both 
incidence and rates of hypoglycemia.  Hypoglycemia will be analyzed as documented 
symptomatic, asymptomatic, probable, severe, or nocturnal and for all events combined as total 
hypoglycemia.  Other categories, including the categories above defined with different glucose 
thresholds, may also be included in these analyses when deemed appropriate.  
The incidence will be analyzed using the categorical methods described in Section 10.3.1 and 
rate of hypoglycemic episodes will be analyzed using a generalized linear mixed-effects model
assuming negative binomial distribution for hypoglycemic episodes.  Incidence and rates will be 
summarized for each treatment arm and entire treatment period.  
10.3.4.4. Severe, Persistent Hyperglycemia
Listings and summaries (if appropriate) will be provided for events of severe, persistent 
hyperglycemia resulting in initiation of rescue therapy.
10.3.4.5. Pancreas Safety
Listings and summaries of adjudicated pancreatic events will be provided.
10.3.4.6. Cardiovascular Safety
Listings and summaries of adjudicated CV events will be provided.  Summaries and listings of 
supraventricular arrhythmias and cardiac conduction disorders will be provided.


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10.3.4.7. Thyroid Safety
Listings and summaries of AEs of interest associated with the thyroid gland (benign and 
malignant neoplasms) will be produced, as well as a listing of biopsy reports.
10.3.4.8. Renal Safety
To assess renal safety, summary and analyses, including shift tables, will be provided for renal 
functional laboratory variables.  Listing of AEs suggestive of acute and chronic kidney failure 
will also be provided. Other reports may also be generated if deemed appropriate.  
10.3.4.9. Gastrointestinal Safety
Because GI AEs, including nausea, vomiting, and diarrhea, are among the most common events 
reported in patients treated with dulaglutide, summaries and analyses for incidence, time to 
onset, duration, and severity of nausea and vomiting will be provided for each treatment during 
the 18-week treatment period and during the first 6 weeks (titration phase), overall and by visit,
to compare the effects of the 4 different dose escalations (2 algorithms for each of the 2 
investigational doses) and effects of the 2 titration algorithms on GI tolerability, as well as the 
overall effects of randomized therapies.  The planned reports will be further described in the 
statistical analysis plan (SAP).
10.3.4.10.
Allergic/Hypersensitivity Reactions
Summaries and listings of allergic and other hypersensitivity AEs including injection site
reaction will be provided.
10.3.4.11.
Immunogenicity
Summaries and listings of dulaglutide ADA will be generated.
10.3.4.12.
Laboratory Analyses
Laboratory measurements will be listed by patient.  Additional listings will be presented for 
laboratory measurements that are outside the normal range and for measurements outside certain 
prespecified clinically relevant thresholds.
Laboratory safety measurements will be summarized.  For continuous (numeric) laboratory 
analytes, the change from baseline to endpoint (Week 18) will be analyzed as detailed in Section 
10.3.1.
For subjective (qualitative) laboratory analytes, counts and percentages of patients with normal 
and abnormal values will be analyzed using Chi-square tests or Fisher’s exact test.
Shift tables of the change from baseline value to the most extreme postbaseline value, and from 
baseline to Week 18 for selected analytes using clinically meaningful thresholds will be 
summarized separately using generalized McNemar’s test for within-treatment comparison and 
using likelihood ratio test for between-treatment comparisons. 
10.3.4.13.
Vital Signs
Vital signs will be listed for all randomized patients.
Descriptive statistics for the actual measurements and changes from baseline for SBP and DBP, 
and PR will be presented by treatment and visit.  


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Vital signs will be analyzed using a similar MMRM-based model as that described in 
Section 10.3.1 for continuous variable analysis.
10.3.4.14.
Electrocardiograms
Descriptive statistics for the absolute measurements, outliers, and changes from baseline for 
selected ECG parameters defined in the SAP, including  QT corrected for heart rate using 
Fridericia’s formula (QTcF) will be presented by treatment and visit.  These parameters will be 
analyzed using a similar MMRM-based model as that described in Section 10.3.1 for continuous 
variable analysis.
10.3.5. Pharmacokinetic/Pharmacodynamic Analyses
Population PK analyses will be conducted using dosing data and dulaglutide concentrations 
obtained from all patients via commonly accepted pharmacostatistical methods (for example, 
nonlinear mixed-effects modeling), and covariate screening. 
The relationship between dulaglutide doses and/or concentrations and key safety measures (such 
as QT intervals, BP and HR, nausea, vomiting), and efficacy measures (such as fasting glucose, 
HbA1c, and weight) will be assessed in PK/PD analyses.  Endpoints may include but are not 
necessarily limited to those listed above.
In addition, if positive antibody titers to dulaglutide are observed, the relationship between 
dulaglutide PK concentrations and antibody formations will be evaluated for impact on 
dulaglutide clearance and, if applicable, drug effect(s).
10.3.6. Subgroup Analyses
Subgroup analyses of treatment interaction for important factors, including age, race, gender, 
country, duration of diabetes, baseline HbA1c (<8%, ≥8%), and BMI may be conducted for the 
primary endpoint of HbA1c.
These will be conducted using the MMRM with treatment, visit, subgroup, treatment-by-visit, 
treatment-by-subgroup, visit-by-subgroup, and treatment-by-visit-by-subgroup as fixed effects, 
and baseline as covariate. If the MMRM fails to converge, the corresponding analysis of 
covariance (ANCOVA) or ANOVA model (LOCF) will be used.
When analyzing baseline HbA1c as a subgroup, the baseline HbA1c will not be included as a 
covariate to avoid colinearity.
Other exploratory subgroup analyses may be performed as deemed appropriate.
10.3.7. Interim Analyses
There will be at least 3 interim safety analyses for this study.  The purpose of these analyses will 
be to monitor the safety and tolerability of the 2 investigational dulaglutide doses.  An additional 
interim efficacy/safety analysis may be conducted for sponsor planning purposes.  An AC will be 
formed to review the interim analyses in an unblinded fashion.  The first interim safety analysis 
will occur after approximately 15 patients have completed 8 weeks of treatment.  The AC will 
continue to evaluate safety when approximately 30 and 60 patients have exposure to therapy for 


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at least 8 weeks (interim safety analyses 2, and 3, respectively).  The efficacy/safety interim 
analysis will be conducted after approximately 120 patients have completed the 18-week 
therapy. The AC proceedings will be described in a separate AC charter. Any change to the 
proceedings will be included in the AC charter and will not require a protocol amendment.   
Only the AC and Statistical Analysis Center will be authorized to evaluate unblinded interim 
analyses.  Study sites will receive information about interim results ONLY if they need to know 
for the safety of their patients. 
Unblinding details are specified in the unblinding plan section of the statistical analysis plan 
(SAP).
10.3.7.1. PK/PD Prelock Data Access
A limited number of preidentified individuals will require access to the unblinded PK and PD 
(safety and efficacy) data, as specified in the unblinding plan, prior to final database lock. This 
is necessary in order to initiate population PK/PD model development for final analyses.  
Information that may unblind the study during the analyses will not be reported to study sites or 
to the blinded study team until the study data lock occurs.


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trial (AWARD-3). Diabetes Care. 2014;37(8):2168-2176.
Weinstock RS, Guerci B, Umpierrez G, Nauck MA, Skrivanek Z, Milicevic Z. Safety and 
efficacy of once-weekly dulaglutide versus sitagliptin after 2 years in metformin-treated 
patients with type 2 diabetes (AWARD-5): a randomized, phase III study. Diabetes Obes 
Metab. 2015;17(9): 849-858.
Wysham C, Blevins T, Arakaki R, Colon G, Garcia P, Atisso C, Kuhstoss D, Lakshmanan M. 
Efficacy and safety of dulaglutide added onto pioglitazone and metformin versus exenatide in 
type 2 diabetes in a randomized controlled trial (AWARD-1). Diabetes Care. 
2014;37(8):2159-2167.


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12.
Appendices


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Appendix 1.
Abbreviations and Definitions
Term
Definition
AC
Assessment Committee
ADA
anti-drug antibodies
AE
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product.
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ANOVA
analysis of variance
AST
aspartate aminotransferase
blinding/masking
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the patient is not, or vice versa, or when the sponsor is aware of the 
treatment but the investigator and/his staff and the patient are not.
A double-blind study is one in which neither the patient nor any of the investigator or 
sponsor staff who are involved in the treatment or clinical evaluation of the patients are 
aware of the treatment received.
BMI
body mass index
BP
blood pressure
bpm
beats per minute
CI
confidence interval
CKD-EPI
Chronic Kidney Disease-Epidemiology
Complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
CRP
clinical research physician: Individual responsible for the medical conduct of the study.  
Responsibilities of the CRP may be performed by a physician, clinical research 
scientist, global safety physician, or other medical officer.
CSR
clinical study report


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CT
computed tomography
CV
cardiovascular
DBP
diastolic blood pressure
DPP-4
dipeptidyl peptidase-4
ECG
electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
Enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the trial are 
those who have been assigned to a treatment.
Enter
Patients entered into a trial are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ERB
Ethics Review Board
ET
early termination
FPG
fasting plasma glucose
GCP
good clinical practice
GI
gastrointestinal
GLP-1
glucagon-like peptide-1
GLP-1 RA
glucagon-like peptide-1 receptor agonist
HbA1c
hemoglobin A1c
HOMA
Homeostasis Model Assessment
HOMA-%B
-cell function as measured by the HOMA2 method
HOMA-IR
insulin resistance as measured by the HOMA2 method
HR
heart rate
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.


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investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form.
ITP
integrated 2-component prediction
ITT
intention to treat: The principle that asserts that the effect of a treatment policy can be 
best assessed by evaluating on the basis of the intention to treat a patient (that is, the 
planned treatment regimen) rather than the actual treatment given.  It has the 
consequence that patients allocated to a treatment group should be followed up, 
assessed, and analyzed as members of that group irrespective of their compliance to the 
planned course of treatment.
IWRS
interactive web-response system
LOCF
last observation carried forward
LS mean
least-squares mean
MedDRA
Medical Dictionary for Regulatory Activities
MI
myocardial infarction
MMRM
mixed-model repeated measures
MRI
magnetic resonance imaging
MTC
medullary thyroid carcinoma
NAFLD
nonalcoholic fatty liver disease
NOAEL
no adverse effect level
OAM
oral antihyperglycemia medications
OTC
over-the-counter
PD
pharmacodynamic
PFS
prefilled syringe
PG
plasma glucose
PK
pharmacokinetics
PP
per-protocol set: The set of data generated by the subset of patients who sufficiently 
complied with the protocol to ensure that these data would be likely to exhibit the 
effects of treatment, according to the underlying scientific model.
PR
pulse rate
QTc
corrected QT interval


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SAE
serious adverse event
SAP
statistical analysis plan
SBP
systolic blood pressure
Screen
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study. 
SD
standard deviation
SE
standard error
SmPC
Summary of Product Characteristics
SMPG
self-monitored plasma glucose
SUSARs
suspected unexpected serious adverse reactions
T1D
type 1 diabetes
T2D
type 2 diabetes 
TEAE
treatment-emergent adverse event:  An untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens relative 
to the pretreatment state, and does not necessarily have to have a causal relationship 
with this treatment.
ULN
upper limit of normal
US
United States
USPI
United States Package Insert
WHO
World Health Organization


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Appendix 2.
Clinical Laboratory Tests 
Clinical Laboratory Testsa
Hematology
Clinical Chemistry
Hemoglobin
Serum Concentrations of:
Hematocrit
Sodium
Erythrocyte count (RBC)
Potassium
Mean cell volume (MCV)
Total bilirubin
Mean cell hemoglobin concentration (MCHC)
Direct bilirubin
Leukocytes (WBC)
Alkaline phosphatase
Neutrophils, segmented
Alanine aminotransferase (ALT)
Lymphocytes
Aspartate aminotransferase (AST)
Monocytes
Blood urea nitrogen (BUN)
Eosinophils
Creatinine
Basophils
Creatine kinase (creatine phosphokinase; CPKd)
Platelets
Uric acid
Calcium
Urinalysis
Albumin
Specific gravity
Glucosee
pH
Protein
Glucose
eGFR (calculated by CKD-EPI equation)f
Ketones
Blood
Pancreas (Exocrine)
Urine leukocyte esterase
   Serum pancreatic amylase
Creatinine
Serum lipase
Lipid Panel (fasting)
Albumin/creatinine ratio (urine)b
Total cholesterol
LDLg
HbA1c
HDL
VLDL
Endocrine
Triglycerides
Fasting plasma glucagonc
Fasting serum insulin
Glucose (fasting)
Calcitonin
Follicle-stimulating hormone
Pregnancy test serum and urineh
C-peptide
Samples for PK analysis
Immunogenicity
Dulaglutide anti-drug antibody
Stored Samples
Dulaglutide neutralizing antibody
Pharmacogenomics sample
Native GLP-1 crossreactive antibody
Non-pharmacogenomic biomarker sample
Native GLP-1 neutralizing antibody
(serum, plasma EDTA/P800c)


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Clinical Laboratory Tests
Abbreviations:  CKD-EPI = Chronic Kidney Disease-Epidemiology; CK-MB = creatine kinase-MB; EDTA = 
ethylenediaminetetraacetic acid; eGFR = estimated glomerular filtration rate; GLP-1 = glucagon-like peptide-1; 
HbA1c = hemoglobin A1c; HDL = high density lipoprotein cholesterol; LDL = low density lipoprotein 
cholesterol; PK = pharmacokinetics; RBC = red blood cells; VLDL = very low density lipoprotein cholesterol;
WBC = white blood cells.
a
All tests will be performed by a Lilly-designated central laboratory, unless otherwise noted.
b
Urinary albumin and creatinine are measured; the ratio is calculated.
c
Remaining P800 plasma from glucagon collection for non-pharmacogenomic biomarker sample.
d
CK-MB is to be assayed if the creatine kinase result is >1000 IU/L.
e
For those visits when fasting glucose is required, glucose will not be included in the chemistry panel.
f
CKD-EPI equation described in Levey et al. 2009.
g
This value will be calculated.  If triglycerides >400 ng/mL, then direct LDL will be assayed.
h
Serum pregnancy test will be performed by central laboratory at Visit 1 for women of childbearing potential; 
urine pregnancy test will be  performed at the site at Visit 3 for women of childbearing potential.  Additional
pregnancy tests may be performed at the investigator’s discretion during the study.


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Appendix 3.
Study Governance Considerations


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Appendix 3.1. Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Appendix 3.1.1.
Informed Consent
The investigator is responsible for ensuring:

that the patient understands the potential risks and benefits of participating in 
the study

that informed consent is given by each patient or legal representative.  This 
includes obtaining the appropriate signatures and dates on the informed 
consent form (ICF) prior to the performance of any protocol procedures and 
prior to the administration of investigational product.

answering any questions the patient may have throughout the study and 
sharing in a timely manner any new information that may be relevant to the 
patient’s willingness to continue his or her participation in the trial.
Appendix 3.1.2.
Ethical Review
The investigator or an appropriate local representative must give assurance that the ethical 
review board (ERB) was properly constituted and convened as required by International 
Conference on Harmonisation (ICH) guidelines and other applicable laws and regulations.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site(s).  Lilly or its representatives must approve the ICF, 
including any changes made by the ERBs, before it is used at the investigative site(s).  All ICFs 
must be compliant with the ICH guideline on Good Clinical Practice (GCP).
The study site’s ERB(s) should be provided with the following:

the current Investigator Brochure (IB) and updates during the course of the 
study

informed consent form

relevant curricula vitae
Appendix 3.1.3.
Regulatory Considerations
This study will be conducted in accordance with:

consensus ethics principles derived from international ethics guidelines, including 
the Declaration of Helsinki and Council for International Organizations of
Medical Sciences (CIOMS) International Ethical Guidelines

applicable ICH GCP Guidelines

applicable laws and regulations
Some of the obligations of the sponsor will be assigned to a third-party.


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Appendix 3.1.4.
Investigator Information
Physicians with a specialty in diabetes/endocrinology, internal medicine, family medicine, or 
general medicine with clinical research experience will participate as investigators in this clinical 
trial.
Appendix 3.1.5.
Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
Appendix 3.1.6.
Final Report Signature
The CSR coordinating investigator will sign the final CSR for this study, indicating agreement 
that, to the best of his or her knowledge, the report accurately describes the conduct and results 
of the study.
The sponsor’s responsible medical officer and statistician will approve the final CSR for this 
study, confirming that, to the best of his or her knowledge, the report accurately describes the 
conduct and results of the study.
Appendix 3.2.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate

sponsor start-up training to instruct the investigators and study coordinators.  This 
training will give instruction on the protocol, the completion of the CRFs, and 
study procedures.

make periodic visits to the study site

be available for consultation and stay in contact with the study site personnel by 
mail, telephone, and/or fax

review and evaluate CRF data and use standard computer edits to detect errors in 
data collection

conduct a quality review of the database
In addition, Lilly or its representatives will periodically check a sample of the patient data 
recorded against source documents at the study site.  The study may be audited by Lilly or its 
representatives, and/or regulatory agencies at any time.  Investigators will be given notice before 
an audit occurs.
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide the sponsor, 


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applicable regulatory agencies, and applicable ERBs with direct access to original source 
documents.
Appendix 3.2.1.
Data Capture System
An electronic data capture system will be used in this study.  The sites will maintain a separate 
source for the data entered by the site into the sponsor-provided electronic data capture system.
Case report form data will be encoded and stored in a clinical trial database.  Data managed by a 
central vendor, such as laboratory test data or ECG data, will be stored electronically in the 
central vendor’s database system.  Data will subsequently be transferred from the central vendor 
to the Lilly data warehouse.
Any data for which paper documentation provided by the patient will serve as the source 
document will be identified and documented by each site in that site’s study file.  Paper 
documentation provided by the patient will include diaries and dosing records.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.
Appendix 3.3.
Study and Site Closure
Appendix 3.3.1.
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly or its designee, the investigator, or the ERB 
of the study site judges it necessary for medical, safety, regulatory, or other reasons consistent 
with applicable laws, regulations, and GCP.
Appendix 3.3.2.
Discontinuation of the Study
The study will be discontinued if Lilly or its designee judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP.


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Appendix 4.
Hepatic Monitoring Tests for Treatment-
Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with patients in consultation with the Lilly, or its designee, clinical 
research physician.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin Time
WBC
Prothrombin Time, INR
Neutrophils, segmented
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B Core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear antibodya
AST
GGT
Alkaline Phosphatase Isoenzymesa
CPK
Anti-smooth muscle antibody (or anti-actin 
antibody)a
Abbreviations:  ALT = alanine aminotransferase; AST = aspirate aminotransferase; CPK = creatinine 
phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalized 
ratio; RBC = red blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.


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Appendix 5.
Protocol GBGJ World Health Organization 
Classification of Diabetes and Diagnostic Criteria
Type 1 Diabetes: Type 1 diabetes is judged to be present when the classical symptoms of 
diabetes (thirst, polyuria, wasting and stupor, or coma) are associated with readily detectable 
concentrations of glucose and ketone bodies in the blood and urine. Insulin treatment is 
necessary not only to control hyperglycemia but also to prevent spontaneous ketosis and death.
Type 2 Diabetes: Type 2 diabetes, although often asymptomatic, may also present with 
classical hyperglycemic symptoms (thirst, polyuria, weight loss), but despite hyperglycemia, 
ketone bodies are present in only low concentrations in the blood and urine. Coma is rare in type 
2 diabetes but may result from extreme hyperglycemia and hyperosmolarity; lactic acidosis or 
ketoacidosis can also occur in fulminating illness (for example, severe infection or mesenteric 
artery thrombosis) due to an acute increase in insulin requirements, but spontaneous ketosis does 
not occur. Some patients with type 2 diabetes later progress to a state of absolute insulin 
deficiency (Alberti and Zimmet 1998).


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Appendix 6.
Classification of Contraceptive Methods
Highly Effective Methods of Contraception:

Combined oral contraceptive pill and mini pill

NuvaRing

Implantable contraceptives

Injectable contraceptives (such as Depo-Provera®)

Intrauterine device (such as Mirena® and ParaGard®)

Contraceptive patch – ONLY women <198 pounds or 90 kg

Total abstinence

Vasectomy – for men in clinical trials
Effective methods of contraception (must use combination of 2 methods)

Male condom with spermicide

Female condom with spermicide

Diaphragm with spermicide

Cervical sponge

Cervical cap with spermicide


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Appendix 7.
Protocol GBGJ World Health Organization 
Standardized Protocols for the Measurement of Height 
and Weight
The following information has been adapted from standardized physical measurement protocols 
for the World Health Organization’s STEPwise approach to Surveillance (STEPS) (WHO 2008)
(Available at: http://www.who.int/chp/steps/Part3_Section3.pdf), accessed: August 16, 2016.
Measuring Height
Step 1 Ask the patient to remove their footwear and any headgear (light headgear worn for 
religious reasons can remain, but this should be worn by the patient at every clinic visit when 
their weight is measured).
Step 2 Ask the patient to stand on the calibrated height measuring board (stadiometer) or against 
a wall with their feet together and their knees straight with their heels against the back board or 
the stadiometer or the wall.
Step 3 Ask the patient to look straight ahead without tilting their head up.
Step 4 Ask the patient to breathe in and stand tall. If using a stadiometer or fixed measuring 
device, move the device’s measurement arm gently down onto the top of the patient’s head. 
Record the patient’s height in centimeters (cm).
Measuring Weight
Body weight measurements should be done in a consistent manner using a calibrated scale 
(mechanical or digital scales are acceptable). All weights for a given patient should be measured 
using the same scale, whenever possible, after the patient has emptied their bladder. Patients 
should be lightly clothed but not wearing shoes while their weight is measured.
Step 1 Ask the patient to remove their footwear and any headgear (light headgear worn for 
religious reasons can remain, but this should be worn by the patient at every clinic visit when 
their weight is measured).
Step 2 Make sure the scale is placed on a firm, flat, even surface (not on carpet or on a sloping 
surface or a rough uneven surface).
Step 3 Ask the patient to step onto the scale with one foot on each side of the scale.
Step 4 Ask the patient to stand still with their arms by their sides and then record their weight in 
kilograms (kg).


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Appendix 8.
Protocol Amendment H9X-MC-GBGJ (a)
Summary: A Phase 2, Double-Blind, Placebo-Controlled, 
18-Week Trial of Investigational Dulaglutide Doses 
versus Placebo in Patients with Type 2 Diabetes on 
Metformin Monotherapy
Overview
Protocol H9X-MC-GBGJ [A Phase 2, Double-Blind, Placebo-Controlled, 18-Week Trial of 
Investigational Dulaglutide Doses versus Placebo in Patients with Type 2 Diabetes on Metformin 
Monotherapy] has been amended.  The new protocol is indicated by amendment (a) and will be 
used to conduct the study in place of any preceding version of the protocol.
The overall changes and rationale for the changes made to this protocol are as follows:

Section 4 Objectives, Section 9.2.2.5 Supraventricular Arrhythmias and Cardiac 
Conduction Disorders, and 10.3.4.6. Cardiovascular Safety: Based on a request from
the US Food and Drug Administration (FDA) on 21 October 2016, supraventricular 
arrhythmias and cardiac conduction disorders were added as adverse events of special 
interest.  

Section 8.1.1 Permanent Discontinuation from Study Treatment: A criterion was 
added to allow for discontinuation of a treatment arm if decided by sponsor.  This is to 
ensure the safety of patients at investigational doses of dulaglutide. 

Minor editorial changes were made throughout the protocol to improve clarity and/or 
correct typographical errors.


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Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
Global Changes

Page headers:  H9X-MC-GBGJ (a) Clinical Protocol

The terms “HOMA_B%” and “HOMA_IR%” have been changed to “HOMA-%B” and 
“HOMA-IR” throughout.
1. Synopsis
Treatment Arms and Duration:  
At Visit 3, patients will be randomized in a 1:1:1:1 ratio to weekly injections of dulaglutide 4.5 mg, 3.0 mg, or 
1.5 mg, or placebo, in combination with stable doses of metformin.  Within each of the investigational dulaglutide 
dose (3.0 mg and 4.5 mg) arms, patients will be randomly assigned in a 1:1 ratio to 1 of the dulaglutide dose titration 
algorithms (Algorithm 1 and or Algorithm 2).  Study participants will be treated for 18 weeks after randomization in 
a double-blind manner, followed by a 4-week safety evaluation.
4. Objectives
Table GBGJ.1.
Objectives and Endpoints
Objectives
Endpoints
Tertiary/Exploratory
Safety

To compare the investigational dose dulaglutide 
arms (4.5 mg and 3.0 mg) to the placebo arm 
for additional safety measures at 18 weeks

Selected gastrointestinal tolerability AEs
(nausea, vomiting, and diarrhea)

Pancreatic safety assessed by incidence of cases 
of adjudicated pancreatitis 

CV safety assessed by the incidence of 
adjudicated deaths and nonfatal major CV 
events

Thyroid-related safety assessed by the 
incidence of cases of thyroid neoplasms

Vital signs (PR, BP)

ECG (HR, QTcF, supraventricular arrhythmias 
and cardiac conduction abnormalities)

Immune system-related safety, including the 
incidence of dulaglutide anti-drug antibodies 
(ADA) and the incidence of allergic and 
hypersensitivity reactions 


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Objectives and Endpoints (continued)
Objectives
Endpoints
Tertiary/Exploratory (concluded)

Thyroid-related safety assessed by the 
incidence of cases of thyroid neoplasms

Vital signs (PR, BP)

ECG parameters (HR, QTcF, supraventricular 
arrhythmias and cardiac conduction 
abnormalities)

Immune system-related safety, including the 
incidence of dulaglutide ADA and the 
incidence of allergic and hypersensitivity 
reactions

Injection site reactions

Incidence of rescue therapy initiation due to 
severe, persistent hyperglycemia
5.1. Overall Design
Randomization (Visit 3)
At Visit 3, patients will perform study procedures that are required prior to randomization.
Patients who continue to be eligible will then be randomized in a 1:1:1:1 ratio to 1 of the 
treatment arms:  (1) dulaglutide 4.5 mg, (2) dulaglutide 3.0 mg, (3) dulaglutide 1.5 mg, or (4) 
placebo.  Within each of the investigational dulaglutide dose (3.0 mg and 4.5 mg) arms, patients 
will be randomly assigned in a 1:1 ratio to 1 of the titration algorithms (Algorithm 1 and or 
Algorithm 2).  Immediately after randomization, the patient will inject the first dose of study 
drug at the study site.  The Visit 3 pharmacokinetics (PK) sample must be collected 1-24 hours 
after the patient has injected study drug for the first time.
6.2. Exclusion Criteria
[15] have been treated with any other excluded medication (Table GBGJ.3) within 
3 months prior to screening (Visit 1) and/or between study entry and 
randomization (Visit 3); excluded glucocorticoids must not have been used for 
≥>14 days within 1 month prior to Visit 1 or between Visits 1 and 3;
8.1.1. Permanent Discontinuation from Study Treatment
Patients will be permanently discontinued from study drug in the following circumstances:

if a patient is inadvertently enrolled and it is determined that continued treatment with 
study drug would not be medically appropriate (see Section 8.1.3)

if a patient is diagnosed with an active or untreated malignancy (other than basal or 
squamous cell skin cancer, in situ carcinomas of the cervix, or in situ prostate cancer) 
after randomization

if a patient is diagnosed by the investigator with acute or chronic pancreatitis

if a patient is diagnosed with C-cell hyperplasia or MTC after randomization


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
if a patient develops an eGFR <30 mL/min/1.73m2 as calculated by CKD-EPI

if the patient or the patient’s designee, for example, legal guardian, requests that the 
patient be withdrawn from study drug

if the investigator or sponsor decides that the patient should be withdrawn from study 
drug; if the investigator decides to permanently discontinue study treatment because of an 
SAE or a clinically significant laboratory value, Lilly or its designee should be alerted 
immediately

if the sponsor decides that a treatment arm and patients in that arm should be withdrawn 
from study drug
9.2.2.5. Supraventricular Arrhythmias and Cardiac Conduction Disorders
All events of treatment-emergent supraventricular arrhythmias and cardiac conduction disorders 
will be fully evaluated.  Patients who develop any event from these groups of disorders should 
undergo an ECG which should be submitted to the central reading center.  Additional diagnostic 
tests to determine exact diagnosis should be performed, as needed.  The specific diagnosis will 
be recorded as an AE.  Events that meet criteria for serious conditions as described in 
Section 9.2.1 must be reported as SAEs.  Study drug should be temporarily discontinued in any 
patient with signs and symptoms of serious cardiac arrhythmias or conduction disorders.  Study 
drug may be restarted when/if it is safe to do so, in the opinion of the investigator.
9.4.1.3. Vital Signs
Sitting BP and pulse rate (PR) will be measured using standardized equipment provided by the 
sponsor according to the Schedule of Activities (Section 2).  Vital sign measurements should be 
taken before obtaining an ECG tracing and before collection of blood samples for laboratory 
testing, at visits where required (see Schedule of Activities, Section 2). The participant should 
be required to sit quietly for 5 minutes before vital sign measurements are taken.  An 
appropriately sized cuff (cuff bladder encircling at least 80% of the arm) should be used to 
ensure the accuracy of BP measurements.  The arm used for the BP measurement should be 
supported at heart level.  At Visit 1 (screening), to determine which arm should be used to collect 
BP and PR throughout the study, BP and PR will be measured once in each arm, and the arm that 
had the higher systolic BP should be used to collect all 3 measurements of both BP and PR at all 
study visits.  For each parameter (PR, systolic blood pressure [SBP], and DBP), 3 measurements 
will be taken using the same arm; the recordings should be taken at least 1 minute apart, and 
each measurement of sitting PR and BP will be recorded in the eCRF.  Any AE related to 
changes in BP and PR should be reported.


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10.3.4. Safety Analyses
10.3.4.5.
Special Safety Topics
10.3.4.5.1. 10.3.4.5. Pancreas Safety
Listings and summaries of adjudicated pancreatic events will be provided.
10.3.4.5.2. 10.3.4.6. Cardiovascular Safety
Listings and summaries of adjudicated CV events will be provided.  Summaries and listings of 
supraventricular arrhythmias and cardiac conduction disorders will be provided.
10.3.4.5.3. 10.3.4.7. Thyroid Safety
Listings and summaries of AEs of interest associated with the thyroid gland (benign and 
malignant neoplasms) will be produced, as well as a listing of biopsy reports.
10.3.4.5.4. 10.3.4.8. Renal Safety
To assess renal safety, summary and analyses, including shift tables, will be provided for renal 
functional laboratory variables.  Listing of AEs suggestive of acute and chronic kidney failure 
will also be provided.  Other reports may also be generated if deemed appropriate.  
10.3.4.5.5. 10.3.4.9. Gastrointestinal Safety
Because GI AEs, including nausea, vomiting, and diarrhea, are among the most common events 
reported in patients treated with dulaglutide, summaries and analyses for incidence, time to 
onset, duration, and severity of nausea and vomiting will be provided for each treatment during 
the 18-week treatment period and during the first 6 weeks (titration phase), overall and by visit, 
to compare the effects of the 4 different dose escalations (2 algorithms for each of the 2 
investigational doses) and effects of the 2 titration algorithms on GI tolerability, as well as the 
overall effects of randomized therapies.  The planned reports will be further described in the 
statistical analysis plan (SAP).  
10.3.4.5.6. 10.3.4.10. Allergic/Hypersensitivity Reactions
Summaries and listings of allergic and other hypersensitivity AEs including injection site 
reaction will be provided.
10.3.4.6. 10.3.4.11. Immunogenicity
Summaries and listings of dulaglutide ADA will be generated.
10.3.4.7. 10.3.4.12. Laboratory Analyses
Laboratory measurements will be listed by patient.  Additional listings will be presented for 
laboratory measurements that are outside the normal range and for measurements outside certain 
prespecified clinically relevant thresholds.
10.3.4.8. 10.3.4.13. Vital Signs
Vital signs will be listed for all randomized patients.
10.3.4.9. 10.3.4.14. Electrocardiograms
Descriptive statistics for the absolute measurements, outliers, and changes from baseline for 
selected ECG parameters defined in the SAP, including  QT corrected for heart rate using 


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Fridericia’s formula (QTcF) will be presented by treatment and visit.  These parameters will be 
analyzed using a similar MMRM-based model as that described in Section 10.3.1 for continuous 
variable analysis.


PPD
Leo Document ID = 0c4771e4-5f04-410d-ba2c-aa0e2ac98b02
Approver:
Approval Date & Time: 04-Nov-2016 21:07:21 GMT
Signature meaning: Approved
Approver:
Approval Date & Time: 07-Nov-2016 13:52:15 GMT
Signature meaning: Approved
PPD

SAP_000.pdf: 
H9X-MC-GBGJ Statistical Analysis Plan Version 1
A Phase 2, Double-Blind, Placebo-Controlled, 18-Week Trial of Investigational Dulaglutide 
Doses versus Placebo in Patients with Type 2 Diabetes on Metformin Monotherapy 
NCT02973100 
Approval Date: 08-Dec-2016 


H9X-MC-GBGJ Statistical Analysis PlanVersion 1
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1. Statistical Analysis Plan: 
H9X-MC-GBGJ: A Phase 2, Double-Blind, Placebo-
Controlled, 18-Week Trial of Investigational Dulaglutide
Doses versus Placebo in Patients with Type 2 Diabetes 
on Metformin Monotherapy
Confidential Information
The information contained in thisdocumentis confidential and the information contained 
within it may not be reproduced or otherwise disseminated without the approval of Eli Lilly 
and Company or its subsidiaries.  
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure. Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release. In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
Dulaglutide(LY2189265)T2D
Study H9X-MC-GBGJ is a Phase 2, randomized, double-blind, placebo-controlled trial 
designed to assess the efficacy and safety of once-weekly investigational dulaglutidedoses 
compared to placeboat 18 weeks in patients with type 2 diabetes mellitus on metformin 
monotherapy.  
Approval Date: 08-Dec-2016 GMT
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol H9X-MC-GBGJ
Phase2
Statistical Analysis Planelectronically signed and approvedby Lilly on date provided 
below.


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2.
Table of Contents
1.
Statistical Analysis Plan:  H9X-MC-GBGJ: A Phase 2, Double-
Blind, Placebo-Controlled, 18-Week Trial of Investigational 
Dulaglutide Doses versus Placebo in Patients with Type 2 Diabetes 
on Metformin Monotherapy ................................................................................................1
2.
Table of Contents................................................................................................................2
3.
Revision History .................................................................................................................8
4.
Study Objectives and Endpoints..........................................................................................9
5.
Study Design.....................................................................................................................12
5.1.
Summary of Study Design............................................................................................12
5.2.
Determination of Sample Size ......................................................................................13
5.3.
Method of Assignment to Treatment ............................................................................13
6.
A Priori Statistical Methods ..............................................................................................15
6.1.
General Considerations ................................................................................................15
6.2.
Adjustments for Covariates ..........................................................................................17
6.3.
Handling of Dropouts or Missing Data.........................................................................17
6.4.
Multicenter Studies ......................................................................................................18
6.5.
Multiple Comparisons/Multiplicity...............................................................................18
6.6.
Patient Population ........................................................................................................18
6.7.
Patient Disposition .......................................................................................................19
6.8.
Patient Characteristics ..................................................................................................19
6.9.
Treatment Compliance .................................................................................................20
6.10. Concomitant Therapy...................................................................................................20
6.11. Efficacy Analyses ........................................................................................................21
6.11.1.
Primary Outcome and Methodology.....................................................................21
6.11.2.
Additional Analyses of the Primary Outcome.......................................................21
6.11.2.1.
MMRM in different populations .....................................................................21
6.11.2.2.
Missing data imputation..................................................................................21
6.11.2.3.
Bayesian Analyses For Exploratory Objectives...............................................21
6.11.3.
Secondary Efficacy Analyses ...............................................................................22
6.11.3.1.
The Primary Analyses for Secondary Efficacy Endpoints ...............................22
6.11.3.2.
Supporting Analyses For Secondary Efficacy Endpoints.................................23
6.11.3.3.
Bayesian Analyses For Exploratory Objectives...............................................23
6.12. Pharmacokinetic/Pharmacodynamic (PK/PD) Methods ................................................23
6.13. Safety Analyses............................................................................................................23
6.13.1.
Extent of Exposure...............................................................................................24
6.13.2.
Adverse Events ....................................................................................................24


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6.13.3.
Deaths, Other Serious Adverse Events, and Other Notable 
Adverse Events ....................................................................................................25
6.13.4.
Adverse Events of Special Interest .......................................................................25
6.13.4.1.
Hypoglycemic Episodes .................................................................................25
6.13.4.2.
Severe, Persistent Hyperglycemia...................................................................27
6.13.4.3.
Pancreatitis.....................................................................................................27
6.13.4.4.
C-cell hyperplasia and C-cell Neoplasms........................................................28
6.13.4.5.
Allergic/Hypersensitivity Reactions................................................................28
6.13.4.6.
Supraventricular Arrhythmias and Cardiac Conduction 
Disorders........................................................................................................28
6.13.5.
Gastrointestinal Safety .........................................................................................28
6.13.6.
Treatment of Overdose.........................................................................................29
6.13.7.
Cardiovascular Safety ..........................................................................................29
6.13.7.1.
Cardiovascular Events ....................................................................................29
6.13.7.2.
Electrocardiograms.........................................................................................29
6.13.7.3.
Vital Signs......................................................................................................31
6.13.8.
Renal Safety.........................................................................................................32
6.13.9.
Immunogenicity...................................................................................................33
6.13.10. Clinical Laboratory Evaluation.............................................................................33
6.14. Subgroup Analyses.......................................................................................................33
6.15. Important Protocol Deviations......................................................................................34
6.16. Interim Analyses and Assessment Committee ..............................................................35
6.16.1.
Assessment Committee ........................................................................................35
6.16.2.
Interim Analyses..................................................................................................35
6.16.2.1.
Timing of the Interim Analysis.......................................................................35
6.16.2.2.
Evaluation Criteria..........................................................................................35
6.17. Planned Exploratory Analyses......................................................................................36
6.18. Annual Report Analyses...............................................................................................36
6.19. Clinical Trial Registry Analyses...................................................................................37
7.
Unblinding Plan................................................................................................................38
7.1.
Operational Procedures ................................................................................................38
7.2.
Site Level Unblinding ..................................................................................................39
7.3.
Trial Level Safety Reviews ..........................................................................................40
7.4.
Assessment Committee Reports ...................................................................................40
7.4.1.
Safety Only Reports.............................................................................................41
7.4.2.
Efficacy/Safety Interim Report.............................................................................41
7.4.2.1.
Model Development .......................................................................................41
7.4.2.2.
Reports Delivery.............................................................................................41


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7.5.
Clinical Study Report...................................................................................................42
7.5.1.
Prelock Unblinding ..............................................................................................42
7.5.2.
End of Study Unblinding......................................................................................42
8.
References ........................................................................................................................43
9.
Appendices .......................................................................................................................44


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List of Tables
Table
Page
Table GBGJ.1.
Objectives and Endpoints ................................................................................9
Table GBGJ.2.
Populations for Analyses ...............................................................................19
Table GBGJ.3.
Heart Rate, PR-Interval, and QTcF Abnormal Data .......................................31
Table GBGJ.4.
Abnormality Data for Heart Rate, Systolic Blood Pressure and Diastolic 
Blood Pressure...............................................................................................32
Table GBGJ.5.
Study H9X-MC-GBGJ Group Name and Membership...................................39


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List of Figures
Figure
Page
Figure GBGJ.1. Illustration of study design for Clinical Protocol H9X-MC-GBGJ..................13


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List of Appendices
Appendix
Page
Appendix 1.
Analysis Windows for the Selected Parameters..............................................45


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3.
Revision History
Statistical analysis plan (SAP) Version 1 was approved prior to unblinding (or the first visit 
when a subject receives study drug or any other protocol intervention if the clinical trial is open-
label).


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4.
Study Objectives and Endpoints
Table GBGJ.1 shows the objectives and endpoints of the study.
Table GBGJ.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To demonstrate that once weekly dulaglutide (4.5 mg, 
3.0 mg, 1.5 mg) is superior to placebo in HbA1c 
reduction at 18 weeks in patients with T2D on 
concomitant metformin monotherapy.

The change in HbA1c from baseline
Secondary
Efficacy

To compare each dulaglutide arm (4.5 mg, 
3.0 mg, 1.5 mg) to the placebo arm at 18 weeks 
for secondary efficacy parameters

Proportion of patients achieving HbA1c target 
of <7.0% 

The change in fasting serum glucose (FSG; 
central laboratory) from baseline

The change in body weight from baseline
Safety

To compare each dulaglutide arm (4.5 mg, 
3.0 mg, 1.5 mg) to the placebo arm for selected 
safety parameters at 18 weeks

Treatment-emergent adverse events (TEAEs) 
and serious adverse events (SAEs)

Discontinuation of study drug due to adverse 
events (AEs)

Incidence and rate of hypoglycemia (severe, 
total, documented symptomatic, and nocturnal)
Pharmacokinetics and Pharmacodynamics

To characterize the pharmacokinetics (PK) of 
dulaglutide and establish the relationships 
between dose/exposure and key safety and 
efficacy measures

PK parameters (eg, Cmax, AUC)

Pharmacodynamic evaluations will include 
HbA1c, FSG, body weight, QTcF interval, and 
heart rate
Tertiary/Exploratory
Efficacy

To compare each dulaglutide arm (4.5 mg, 
3.0 mg, 1.5 mg) to the placebo arm for 
additional efficacy measures at 18 weeks

Proportion of patients achieving HbA1c target 
≤6.5%

The change in 6-point self-monitored plasma 
glucose (SMPG) profiles from baseline

The change in fasting plasma glucagon from 
baseline

The change from baseline in insulin resistance 
(HOMA-IR) and -cell function (HOMA-%B) 
as measured by the HOMA2 Method (Caumo et 
al. 2006) 


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Objectives and Endpoints
Objectives
Endpoints
Tertiary/Exploratory (continued)
Efficacy

To compare the investigational dose dulaglutide
arms (4.5 mg and 3.0 mg) to the 1.5 mg arm for 
efficacy measures at 18 weeks

Change from baseline in HbA1c

Proportion of patients achieving HbA1c target
<7.0% or ≤6.5% 

The change in FSG (by central laboratory) from 
baseline

The change in body weight from baseline

The change in 6-point SMPG profiles from 
baseline

The change in fasting plasma glucagon from 
baseline

The change in HOMA-IR and HOMA-%B
from baseline
Safety

To compare the investigational dose dulaglutide
arms (4.5 mg and 3.0 mg) to the placebo arm 
for additional safety measures at 18 weeks

Selected gastrointestinal tolerability AEs
(nausea, vomiting, and diarrhea)

Pancreatic safety assessed by incidence of cases 
of adjudicated pancreatitis

CV safety assessed by the incidence of 
adjudicated deaths and nonfatal major CV 
events

Thyroid-related safety assessed by the 
incidence of cases of thyroid neoplasms

Vital signs (PR, BP)

ECG (HR, QTcF, supraventricular arrhythmias 
and cardiac conduction abnormalities)

Immune system-related safety, including the 
incidence of dulaglutide antidrug antibodies 
(ADA) and the incidence of allergic and 
hypersensitivity reactions

Injection site reactions

Incidence of rescue therapy initiation due to 
severe, persistent hyperglycemia

To compare the investigational dose dulaglutide
arms (4.5 mg and 3.0 mg) to the 1.5 mg arm for 
safety measures at 18 weeks

TEAEs and SAEs

Discontinuation of study drug due to AEs

Incidence and rate of hypoglycemia (severe, 
total, documented symptomatic, and nocturnal)

Selected gastrointestinal tolerability AEs 
(nausea, vomiting, and diarrhea)

Pancreatic safety assessed by incidence of cases 
of adjudicated pancreatitis

CV safety assessed by the incidence of 
adjudicated deaths and nonfatal major CV 
events


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Objectives and Endpoints 
Objectives
Endpoints
Tertiary/Exploratory (concluded)

Thyroid-related safety assessed by the 
incidence of cases of thyroid neoplasms

Vital signs (PR, BP)

ECG parameters (HR, QTcF, supraventricular 
arrhythmias and cardiac conduction 
abnormalities)

Immune system-related safety, including the 
incidence of dulaglutide ADA and the 
incidence of allergic and hypersensitivity 
reactions

Injection site reactions

Incidence of rescue therapy initiation due to 
severe, persistent hyperglycemia
Safety

To compare the titration algorithms 
(Algorithm 1 vs. Algorithm 2) within the 
investigational dose dulaglutide arms (4.5 mg 
and 3.0 mg) and across the investigational dose 
arms versus dulaglutide 1.5 mg and placebo at 
6 and 18 weeks

Incidence of selected GI AEs (nausea, 
vomiting, and diarrhea)

Vital signs (PR, BP)
Abbreviations: ADA = antidrug antibodies; AE = adverse event; AUC = area under concentration-time curve; BP = 
blood pressure; Cmax = maximum concentration; CV = cardiovascular; ECG = electrocardiogram; FSG = fasting 
serum glucose; GI = gastrointestinal; HbA1c = hemoglobin A1c; HOMA = Homeostasis Model Assessment; HR 
= heart rate; PR = pulse rate; QTcF = Fridericia’s corrected QT interval; T2D = type 2 diabetes mellitus; SAEs = 
serious adverse events; SMPG = self-monitored plasma glucose; TEAS = treatment emergent adverse events.


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5.
Study Design
5.1.
Summary of Study Design
Study H9X-MC-GBGJ (GBGJ) is a randomized, multicenter, placebo-controlled, double-blind 
Phase 2 trial in T2D patients on metformin monotherapy. The study is designed to assess the 
efficacy and safety of once weekly dulaglutide 3.0 mg and 4.5 mg in comparison to placebo. In 
addition, the trial will explore how these dulaglutide doses compare to the approved dulaglutide
1.5 mg dose to support dose selection for further development in Phase 3 trials, and to guide 
design of these additional trials. Study GBGJ will also explore the effect of 2 dulaglutide dose 
titration algorithms on gastrointestinal (GI) tolerability with investigational doses to guide design 
of the definitive algorithm to be evaluated in Phase 3 trials. The primary objective of this trial is 
to show superiority of the 3 dulaglutide doses (4.5 mg, 3.0 mg, 1.5 mg) to placebo in change in
hemoglobin A1c (HbA1c) at 18 weeks.
During the trial, an unblinded internal assessment committee (AC) will review data on safety and
tolerability in study participants according to a prespecified schedule in order to assure the safety
of randomized patients.  An efficacy/safety interim analysis will be conducted after 
approximately 120 patients have completed the 18-week therapy.
The study will consist of 3 periods: an approximately 2-week lead-in period, followed by an 18-
week treatment period, and a 4-week safety follow-up period.
Figure GBGJ.1 illustrates the study design.


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a
Patients will administer 1 injection per week in the first 4 weeks of the titration
phase, and 2 injections per week in the remainder of the titration phase.
b
During the maintenance phase, the assigned dose will require 3 injections.
Figure GBGJ.1.
Illustration of study design for Clinical Protocol H9X-MC-GBGJ.
5.2.
Determination of Sample Size
Assuming a screen failure rate of 30%, approximately 429 patients will need to be screened to
attain approximately 300 patients randomized to the 4 treatment arms in a 1:1:1:1 ratio for
4.5 mg, 3.0 mg, 1.5 mg dulaglutide, or placebo weekly (~75 patients per arm). For the
investigational dulaglutide dose arms (4.5 mg and 3.0 mg), approximately 38 patients will be
assigned to each titration algorithm (Algorithms 1 and 2). Assuming a 20% dropout, this will
result in approximately 60 patients per arm and 30 patients per algorithm (in each of the
investigational-dose dulaglutide arms) completing the study.
The aforementioned sample size provides ≥90% power to demonstrate superiority for the
dulaglutide doses (4.5 mg, 3.0 mg, and 1.5 mg) to placebo with respect to HbA1c change from
baseline to 18 weeks. This assumes a true glycemic effect difference of -1% HbA1c for each
dulaglutide dose versus placebo, and a standard deviation (SD) of 1.2% with a 2-sided alpha of
0.05.
5.3.
Method of Assignment to Treatment
Patients who meet all criteria for enrollment will be randomized to one of the study treatment 
arms at Visit 3. Assignment to treatment arms will be determined by a computer-generated 
random sequence using an Interactive Web Response System (IWRS). The IWRS will be used 


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to assign cartons containing double-blinded study drug to each patient. Site personnel will 
confirm that they have located the correct cartons by entering a confirmation number found on 
the label into the IWRS.
Block randomization will be used at the country level. Patients will be randomized in a 1:1:1:1
ratio (dulaglutide 4.5 mg, dulaglutide 3.0 mg, dulaglutide 1.5 mg, placebo). Within the
dulaglutide 4.5 mg and 3.0 mg arms, patients will be randomly assigned (1:1) to Algorithm 1 or
Algorithm 2. Randomization will be stratified by HbA1c (<8%, ≥8%).


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6.
A Priori Statistical Methods
6.1.
General Considerations
Statistical analysis of this study will be the responsibility of Eli Lilly and Company or its 
designee. Any change to the data analysis methods described in the protocol will require an 
amendment ONLY if it changes a principal feature of the protocol. Any other change to the data 
analysis methods described in the protocol, and the justification for making the change, will be 
described in the statistical analysis plan (SAP) or the clinical study report (CSR). Additional 
exploratory analyses of the data may be conducted as deemed appropriate without further 
changes made to the protocol or SAP even after the datalock.
Countries with fewer than 10 randomized patients will be pooled for statistical analyses. Pooled
country will be employed for all formal statistical model-based analyses as a block factor unless 
otherwise denoted.
Unless otherwise specified, all tests of treatment effects will be conducted at a 2-sided alpha
level of 0.05, and confidence intervals (CIs) will be calculated at 95%, 2-sided. All tests of
interactions between treatments and factors of interest will be conducted at a 2-sided alpha level
of 0.10.  No adjustments for multiplicity will be performed.
The baseline visit will be Visit 3. For all variables, including HbA1c, if baseline data are not
available or are missing, the last nonmissing measurement taken prior to this visit will be used
for the baseline measurement. The efficacy measure for the primary analysis is defined as the
change from baseline in HbA1c to Week 18 (Visit 12).
For all statistical analyses, missing data will be treated as missing at random unless otherwise 
specified; therefore, no imputation is needed unless otherwise stated.
The treatment groups mentioned in this document are based on the randomized treatment groups: 
dulaglutide 4.5 mg, dulaglutide 3.0 mg, dulaglutide 1.5 mg, placebo. For the purposes of tables, 
figures, the treatment groups will be: Dula 4.5, Dula 3.0, Dula 1.5, and Placebo. For data 
listings, the treatment groups will be presented as Placebo, Dula 1.5, Dula 3.0/A1 representing 
dulaglutide 3.0 mg/algorithm 1, Dula 3.0/A2 representing dulaglutide 3.0 mg/algorithm 2, Dula 
4.5/A1 representing dulaglutide 4.5 mg/algorithm 1, Dula 4.5/A2 representing dulaglutide
4.5 mg/algorithm 2.
Incidence of nausea, vomiting, and diarrhea, vital signs (pulse rate, blood pressure [PR, BP]), 
electrocardiogram (ECG) variables (heart rate [HR], PR interval, and Fridericia’s corrected QT 
interval [QTcF]), and pancreatic enzyme (amylase and lipase) will be summarized by the 
randomized treatments, and by algorithm within the same investigational dulaglutide dose, and 
by algorithm across the investigational dulaglutide doses.
Placebo will serve as the reference treatment for each dulaglutide dose, while dulaglutide 1.5 mg 
as the active comparator for each investigational dulaglutide dose. 
All efficacy and safety data will be summarized by each treatment group at each scheduled visit
unless otherwise indicated. A scheduled visit is based on the analysis window for the selected


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parameters of interest (Appendix 1, Table APP1.1) not the actual visit number reported by the 
site. For the other measures, the actual scheduled visit reported by the sites will be used.
A mixed-model repeated measures (MMRM) analysis will be used to analyze continuous 
longitudinal variables.  In this model, restricted maximum likelihood will be used to obtain 
model estimates with Kenward-Roger (KR) option to estimate denominator degrees of freedom.
The corresponding baseline value will be used as a covariate, and the stratification factors 
(pooled country, HbA1c strata [screening HbA1c at Visit 1: <8.0%, ≥8.0%]),treatment 
(dulaglutide 4.5 mg, dulaglutide 3.0 mg, dulaglutide 1.5 mg, placebo), visit, and treatment-by-
visit interaction will be fixed effects.  For HbA1c change from baseline analysis or HbA1c target 
analysis,  HbA1c strata will be replaced with continuous baseline HbA1c as a covariate from the 
aforementioned model.  An unstructured covariance structure will be used to model the within-
patient errors. If this model fails to converge, the following covariance structures will be tested 
in order:

toeplitz with heterogeneity

autoregressive with heterogeneity, by visit

compound symmetry with heterogeneous variances by visit 

toeplitz

autoregressive

compound symmetry without heterogeneous variances, by visit

compound symmetry
The first covariance structure that converges will be used.
The analysis of covariance (ANCOVA) as a sensitivity analysis for the primary and secondary 
continuous efficacy endpoints using the last observation carried forward (LOCF) described in 
Section 10.3.1 of the protocol H9X-MC-GBGJ(a) will not be used for analyses of secondary 
continuous efficacy endpoints as the analysis was shown to produce biased results (Lachin 2016)
with little inferential value. 
For continuous laboratory measurements for safety, an analysis of variance (ANOVA) on ranks 
will be used with treatment as a fixed effect.
For all continuous measures, summary statistics will include number of patients, mean, SD, 
median, minimum, and maximum for both the actual and change from baseline values at each 
scheduled visit for each treatment unless otherwise specified.  Least-squares mean (LS mean) 
and standard errors (SEs) derived from the model will also be displayed for the change from 
baseline values at each scheduled visit for each treatment.  Treatment comparisons will be 
displayed showing the treatment difference LS mean and the 95% CIs between each dose and 
placebo, and between each investigational dulaglutide dose and 1.5 mg at the same visit, along 
with the corresponding p-values.


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Summary statistics for categorical measures will include number of subjects and percentages.
The percentage of patients achieving target HbA1c <7.0% at Week 18 will be analyzed using a 
longitudinal logistic regression with repeated measurements with treatment, visit, treatment-by-
visit interaction, and baseline HbA1c-by-visit interaction as fixed effects and baseline HbA1c as 
a covariate.  For the analysis of other categorical measures, Fisher’s exact test will be used for 
treatment comparisons, unless 80% of cells have an expected value of at least 5, in which case 
the Chi-square test will be used unless otherwise stated. Unless otherwise stated, categorical 
variables will be summarized by sample size, the number of patients and percentages for each 
treatment group at each visit. 
Imputed data may be applied in model-based data analysis, but will not be used in data listing.
The latter will only present the non-imputed raw data including site reported scheduled, site
reported unscheduled, or early termination visit data; however, only scheduled visits for the
measure of interest (Appendix 1, Table APP1.1) will be included in the summary table and
statistical inference unless otherwise stated.
Additional analyses may be performed even after datalock if deemed needed.
All statistical analyses will be conducted with Statistical Analysis System (SAS) Version 9.4® or 
higher unless otherwise stated.
6.2.
Adjustments for Covariates
The study is stratified by baseline HbA1c with country as a block factor; therefore, both 
stratification factors will be fitted in the corresponding statistical model as fixed effects for the 
non-HbA1c measurements unless otherwise stated.  For HbA1c analysis, the strata of baseline 
HbA1c will be replaced with the covariate of baseline HbA1c. For other continuous variables 
other than some safety laboratory measures, a corresponding baseline measure will be added as a 
covariate.
6.3.
Handling of Dropouts or Missing Data
Missing data will be imputed as a sensitivity analysis for the primary and key secondary 
continuous endpoints using a tipping point approach, and copy reference approach.  The 
reference is from those patients on the same treatment who received rescue medication and/or 
stopped study medication, but had the measurement for the corresponding endpoints.
For HbA1c target of <7.0% and ≤6.5%, those who have missing data at Week 18 (Visit 12) or 
who receive rescue therapy prior to the Week 18 visit will be imputed as not reaching HbA1c 
target.
Last observation carried forward (LOCF) to impute the missing endpoint data will be used for 
the non-longitudinal continuous variables such as 6-point self-monitored plasma glucose 
(SMPG), Homeostasis Model Assessment (HOMA-IR), and HOMA-%B, c-peptide, fasting 
insulin, and the selected safety laboratory measures.


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Any missing component of date and/or time will be imputed following Lilly or dulaglutide
compound level standards. For example, the missing day or month could be imputed with the 
first day of the month, or first month of the year.
If the first dosing date/time is missing, the non-missing randomization date will be used to 
impute the first dosing date and the time will be placed with 0800 hours. The 0800 hours is the 
most common first injection time per historical dulaglutide studies. This imputation is only 
applicable for PK related exposure analysis.
Other imputation may be applied if deemed necessary even after this document is approved. This 
addition or even change does not require an SAP revision. Rather, those detailed imputation 
rules will be documented in a separated file such as statistical decision log or track change log.
6.4.
Multicenter Studies
No planned analysis related to site will be conducted. This will be only performed upon request 
after datalock. 
6.5.
Multiple Comparisons/Multiplicity
This is an exploratory Phase 2 study; thus, multiplicity adjustment will not be performed.
6.6.
Patient Population
Five patient populations are defined for the analyses in this study with detailed information listed 
in Table GBGJ.2.  Unless otherwise specified, listings will include all randomized patients. 
Efficacy and safety analyses will be conducted in the intent-to-treat (ITT) population. The 
primary efficacy measure (change from baseline in HbA1c) will also be evaluated in the per 
protocol (PP) population and Completer set (CS) population.
In all efficacy and hypoglycemia analyses, all data after rescue therapy will be censored unless 
otherwise stated.
Analyses of safety parameters, except for hypoglycemia events, will be conducted in the ITT
population including the post-rescue therapy data.


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Table GBGJ.2.
Populations for Analyses
Population
Description
Entered
All participants who sign informed consent
Intent-to-treat
All participants who are randomized and take at least 1 dose of study medication 
for an assigned treatment arm
All randomized population
All patients who are randomized 
Per protocol
All ITT patients who meet all of the following criteria:

Have no important protocol deviation that could impact the assessment 
of the primary endpoint; the list of specific criteria is provided in 
Section 6.15

At least 75% compliant with study drug administration

Complete the treatment period (18 weeks) 

Have a value of the primary efficacy measure at 18 weeks
Note: the final criteria will be documented in electronic Trial Master 
File (eTMF).  
Completer set
All ITT patients who complete 18 weeks of study drug treatment without rescue 
therapy
Abbreviation:  HbA1c = hemoglobin A1c; ITT = intent to treat.
6.7.
Patient Disposition
The reasons for patient discontinuations from study medication and from the study will be 
summarized for all randomized subjects by each randomized treatment, by visit, and overall. An 
additional report will be provide to provide combined disposition report for early discontinuation 
of study drug and early discontinuation of study, by visit, cumulative and overall. The latter 
report is need to account for patients who permanently discontinue study drug but continued in 
the trial, as allowed by the study protocol.
The p-value to test the overall treatment effect among all randomized treatments and the p-value 
will be presented using Fisher’s exact test or Chi-square test detailed in Section 6.1.
Kaplan-Meier curves by treatment for time to study discontinuation due to any reason will be 
presented. The log-rank p-value will be presented.
In addition, all entered patients will be summarized including, but not limited to, the total
number of patients screened (entered) and the number of patients excluded due to screen failure.
Patient disposition will be listed for all randomized population.
6.8.
Patient Characteristics
Demographic and baseline clinical characteristics will be summarized by treatment for ITT 
population detailed in Section 6.1. For continuous measures, summary statistics will include 
sample size, mean, median, maximum, minimum, and SD along with the ANOVA p-value to test 
for difference among all randomized treatment groups. For categorical measures, summary 
statistics will include sample size, the number and percentage of patients for each category with 
Fisher’s or Chi-square p-value. In the summary report, each algorithm arm will be included.


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Similar summary reports will be generated separately for PP ad CS population.
The patient characteristics will be listed for all randomized population.
6.9.
Treatment Compliance
Treatment compliance in GBGJ is defined as taking at least 75% of the required injections for 
the prespecified time intervals: titration phase from the first dose to the sixth dose, and every 
4 weeks thereafter: from the seventh dose to the 10th dose, from the 11th dose to the 14th dose, 
from the 15th dose to the 18th dose. Overall compliance is defined as being at least 75% 
compliant with investigational product across the treatment period. Compliance source data is 
from the site reported case report form (CRF) data.
Compliance will be summarized using ITT population by each randomized treatment and time 
interval, and overall.  Listings will also be produced from all randomized population.
6.10. Concomitant Therapy
The prespecified concomitant medications of interest will be summarized (detailed in 
Section 6.1) by all randomized treatments groups for baseline and after randomization, for the
ITT population. In addition, antihyperglycemia medications will be also summarized at 
screening and for the last 3 months prior to study enrollment by each randomized treatment 
group.  The concomitant therapies will be mapped using the World Health Organization (WHO)
DRUG dictionary in the clinical trial database and will be further classified using Anatomic-
Therapeutic-Chemical (ATC) codes for reporting purposes.
The agents of interest for the summary report include the following groups of medication:

anthihyperglycemia agents
o
background metformin therapy
o
agents used for short term therapy for acute condition
o
rescue therapy (only applicable for after randomization)
o
agents used for other reasons

weight loss medications

systemic glucocorticoids

antihypertensive agents

lipid lowering agents

anticoagulant agents

anti-inflammatory agents

cardiac therapy
Concomitant therapy will be listed for the all-randomized population.


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6.11. Efficacy Analyses
6.11.1. Primary Outcome and Methodology
The primary analysis for the primary outcome, change from baseline in HbA1c at Week 18 
(Visit 12), will employ MMRM described in Section 6.1 in ITT population by censoring all post 
rescue data.
The report from this analysis includes LS means and corresponding 95% CIs for each 
randomized treatment at each scheduled visit, and the difference in LS means, corresponding 
95% CI along with p-value compared to placebo and to dulaglutide 1.5 mg at the same visit.
6.11.2. Additional Analyses of the Primary Outcome
6.11.2.1. MMRM in different populations
Different populations including ITT regardless of rescue therapy or adherence to study drug, PP, 
CS population will be evaluated separately using the same model as described in Section 6.1  
The goal for these analyses is to assess the robustness of the primary outcome.
The output will be generated as that listed in Section 6.11.1.  
6.11.2.2. Missing data imputation
If the conclusions differ among the four populations listed in Section 6.11.1 and Section 6.11.2.1, 
additional analyses may be further explored using selected pattern mixture models for missing 
data (Kenward and Rosenkranz 2011) in the ITT population regardless of rescue therapy or 
compliance to the study treatment. In this case, imputed 18-week HbA1c response for the 
missing data along with the non-missing 18-week data will be employed using an ANCOVA 
model by removing all visit related terms. The missing data will be imputed from the non-
missing subjects who took rescue therapy or continued on the study but discontinued study 
medication. Depending on the missing data status, the non-missing data used for imputation may 
be altered from what is described in this section.
The tipping-point approach is like a progressive stress-test to assess how severe departures from 
missing at random (MAR) need to be in order to overturn conclusions from the primary analysis.  
In the dulaglutide arms, the imputed values will be replaced by the imputed value plus a shift 
parameter beginning from 0 with the increment of 0.05. Each value of the shift parameter will 
be tested sequentially until the value is reached at which the conclusion from the MMRM 
analysis is reversed. That value is the tipping point indicating that the conclusion under MAR is 
questionable if this shift parameter value is plausible.  If implausible departures from MAR are 
required to change the results from statistically significant (p≤0.05) to not statistically significant
(p>0.05), the results will be said to be robust to the departure from MAR assumption and provide 
more confidence in the results obtained based on statistical methods with the MAR assumptions.
6.11.2.3. Bayesian Analyses For Exploratory Objectives
A Bayesian integrated 2-component prediction (ITP) model (Fu and Manner 2010) will be fitted 
for the primary endpoint separately in ITT population by censoring all post rescue therapy data, 


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and in ITT population including all available data regardless of rescue medication or adherence 
to the study drug. Non-informative priors will be used in this model. In addition, the informative 
priors from the posterior for placebo and posterior for dulaglutide 1.5 mg obtained from Study
H9X-MC-GBCF (GBCF) and Study H9X-MC-GBDE (GBDE) will be evaluated in this model to 
check the robustness of the analysis.
)
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ijt
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ijt
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Prior information: θi, α ~N (0, 3); Sij, εijk, ~uniform (0.01, 3); ki~uniform (-1, 1) where Yijt 
represents HbA1c change from baseline from dose i, subject j at time t. Parameter θi is the 
predicted drug effect of dose i at 18-week therapy. The parameter Sij is a random between-
subject SD, and εijt is the within subject SD. The Bij is baseline HbA1c for subject j at dose i and 
_
B is the overall arithmetic mean baseline HbA1c from all subjects. ki is the parameter to 
represent how fast to reach the effect for dose i at Week 18.
Probabilities based on posterior distributions of the parameter of interest: change from baseline 
to Week 18, and Week 26 will be generated from this model using 10000 MCMC samples with 
thin=10 and burn-in=10000:
                       pr(Δi-Δdula1.5mg < threshold)
                       i stands for dulaglutide 3.0 mg or 4.5 mg.
            The threshold of -.15, -.2, and -.3% will be used, separately.
If this model fails to converge, an alternative Bayesian model will be fitted:
                   
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Where β[i,t] is the effect for dose i at time t.  Ωis the variance-covariance matrix.
The priors for each parameters are:  α ~ N(0,3), β[i,t] ~ N (0,3), Ω~wishart(t, t-demension 
Identitiy matrix).
The probability for Week 26 will be assumed to be the same as Week 18 from this model.
6.11.3. Secondary Efficacy Analyses
6.11.3.1. The Primary Analyses for Secondary Efficacy Endpoints
The ITT population by censoring the post-rescue data is the analysis population for secondary 
efficacy endpoints. Data for secondary endpoints will be summarized as described in 
Section 6.1. The MMRM described in Section 6.1 will be used to analyze each secondary 


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continuous efficacy endpoint: change from baseline in FSG and body weight. The result will be 
reported as detailed in Section 6.11.1.
The proportion of patients achieving HbA1c target <7.0% will be analyzed using repeated
measures logistic regression mixed model described in Section 6.1 as the primary analysis. 
Pooled country, treatment, visit, treatment-by-visit interaction will be fitted as fixed effects, 
baseline HbA1c as a covariate. This model will be fitted to leverage all available data without 
imputation.
6.11.3.2. Supporting Analyses For Secondary Efficacy Endpoints
As a sensitivity analysis for proportion of patients on HbA1c targets, a logistic regression model 
will be fitted with pooled country and treatment as fixed effect, baseline HbA1c as a covariate to 
analyze the endpoint data. Prior to this analysis, the missing data or the patients rescued up to 
Week 18 will be imputed as not achieving HbA1c target.
The analyses listed in Section 6.11.3.1 will be repeated for the ITT population without censoring 
the post rescue data as a sensitivity analysis to FSG and body weight change from baseline.
6.11.3.3. Bayesian Analyses For Exploratory Objectives
A similar Bayesian ITP model listed in Section 6.11.2.3will be fitted to analyze body weight 
change from baseline as a supportive analysis by only changing the prior information with θi, 
α~N(0,100).
Probabilities based on posterior distributions of the parameter of interest: change from baseline 
in body weight at Week 18, and Week 26 will be generated from this model using 10000 MCMC 
samples with thin=10 and burn-in=10000:
                       pr(Δi-Δdula1.5mg < threshold) 
                       i stands for dulaglutide 3.0 mg or 4.5 mg.
The threshold for this analysis will be -1 kg and -2 kg.
If this model doesn’t converge, the similar alternative Bayesian model in Section 6.11.2.3 will be 
adopted with the priors: α, β[i,t]~N(0,100).
The probability for Week 26 will be assumed to be the same as Week 18 from this model.
The imputed data along with non-missing 18-week data will be analyzed using an ANCOVA 
model following the same method listed in Section 6.11.2.2.
6.12. Pharmacokinetic/Pharmacodynamic (PK/PD) Methods
All PK/PD analyses will be performed by Lilly and details will be documented in a separate
analysis plan.
6.13. Safety Analyses
The safety analyses will include adverse events (AEs), serious adverse events (SAEs), AEs of 
special interest (AESIs), and treatment emergent adverse events (TEAEs), safety laboratory 


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analytes, vital signs, ECG. Adverse events of special interest include hypoglycemic and 
hyperglycemic episodes, pancreatitis, thyroid C-cell hyperplasia and C-cell neoplasms, 
allergic/hypersensitivity reactions, supraventricular arrhythmias and cardiac conduction 
disorders.
An AE will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).
TEAEs are defined as postbaseline events that are new events or preexisting conditions that 
worsened in severity after randomization using MedDRA low level term (LLT).  The maximum
severity level for baseline and post baseline for each same LLT term will be used as a criterion to 
determine TEAEs. If an AE occurs on the same date as the first dosing date with missing event 
occurring time, that event will be counted as post baseline event.
Unless otherwise specified, the ITT population will be used for analyses of safety measures, and 
all randomized population for data listing.
6.13.1. Extent of Exposure
Treatment exposure is defined as the time from when the patient took his/her first dose until the
last dosing date. If that first dosing date is missing, it will be imputed with the date of 
randomization. If the last dosing date is missing, it will be imputed with the date the patient 
discontinued treatment or completed the treatment period, whichever is earlier.
Exposure will be calculated for each patient. It will be summarized for ITT population by 
treatment with mean, SD, minimum, maximum, the first quartile and the third quartile. The 
mean exposure duration in days among treatment groups will be compared with ANOVA model 
using treatment as a fixed effect.  The p-value to compare the overall randomized treatment 
effect will be presented.  The total patient-years of study drug exposure will be added at the end 
of the summary. Duration of exposure was categorized into the following groups: ≤28 days, >28 
to ≤42 days, >42 to ≤56 days, >56 to ≤70 days, >70 to ≤98 days, >98 and 126 days, >126 days. 
These categories were summarized as frequency by treatment.  
Similar summary reports will be generated separately for PP ad CS population.  Each subject’s 
detailed dose information at each post dose week (first dosing week will be coded as week 1) 
will be calculated based on the CRF sourced from the study drug administration log. For the 
maintenance phase, the dose information will use the package information for the missed 
injection(s). For the titration phase, the package information is not needed. For the first four 
weeks, missed injection means the entire dose is missed. For each of the last 2 titration week 
doses, missed 0, 1, and 2 injections means full dose, half dose, or no dose injected, respectively.  
This dose information along with the actual dosing date/time will be used for patient narratives, 
and PK analysis.  The actual dosing information calculated in this section will be summarized by 
randomized treatment group. The exposure data will be listed for ITT population.
6.13.2. Adverse Events
Unless otherwise specified, AEs will be reported using the MedDRA system organ class (SOC) 
and preferred term (PT). Selected AEs may be reported using MedDRA high-level terms (HLT), 
in addition to the SOC and PT, for consistency with other dulaglutide studies. Treatment-


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emergent AEs are defined as events that are newly reported after the first dosing or reported to 
worsen in severity from the first dosing.
Summary statistics will be provided for the following data: medical history and/or pre-existing 
condition AEs, TEAEs, SAEs, TEAESIs, and study discontinuations due to death or AEs. For 
TEAEs, SAE and TEAESIs will be reported separately from baseline to the end of the treatment 
period, and to the end of the study including safety follow-up. The number and proportions of
patients experiencing each corresponding AEs will be reported for each randomized treatment 
group. Chi-square or Fisher’s exact tests will be used to compare the randomized treatment 
groups detailed in Section 6.1.
The incidence of patients with at least one TEAE will be reported, and the proportion of patients
experiencing each reported TEAE will be presented by PT (descending order) and by 
randomized treatment group, and also by the SOC (alphabetical order) and by descending PT
order within the SOC. The proportion of patients experiencing each reported TEAE that are 
assessed as related to the study disease, study drug device, or procedures will be summarized.
Note, drug device is coded as concomitant device. Additionally, a summary of TEAEs by 
maximum severity will be presented descriptively by randomized treatment group.
Separate summary reports will be provided for the number and percentage of patients who 
discontinued from the study and for patients who discontinue study treatment due to AE or death 
by descending frequency PT and within SOC by the randomized treatments.  If deemed 
necessary, a Bayesian model may be fitted to evaluate if the probability of the incidence of 
discontinuation due to AEs for any investigational dose being ≤10%, ≤15%.
Listings will be provided for SAEs, TEAEs, and discontinuations due to AE or death.
Additional analyses will be performed for the purpose of fulfilling the clinical trial registry
(CTR) requirements (Section 6.19).
6.13.3. Deaths, Other Serious Adverse Events, and Other Notable 
Adverse Events
All SAEs will be summarized by treatment by PT term using descending frequency order, and by 
SOC and PT (descending frequency order within SOC). Death will be listed including both 
adjudicated and investigator reported. Patient listings for the patient narratives will be generated
for further processing. The criteria for patient narratives will be provided by the trial medical 
team and will be documented in eTMF.
6.13.4. Adverse Events of Special Interest
6.13.4.1. Hypoglycemic Episodes
Summary reports will include both incidence and rates of hypoglycemia in the ITT population by 
censoring the post rescue data. Hypoglycemia will be analyzed as documented symptomatic, 
asymptomatic, probable, severe, total, and nocturnal hypoglycemia with the definition (American
Diabetes Association 2005) below:


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
Documented symptomatic hypoglycemia: any time a patient feels that he/she is 
experiencing symptoms and/or signs associated with hypoglycemia, and has a PG 
level of ≤70 mg/dL (≤3.9 mmol/L).

Asymptomatic hypoglycemia: any event not accompanied by typical symptoms 
of hypoglycemia, but with a measured PG ≤70 mg/dL (≤3.9 mmol/L).

Probable symptomatic hypoglycemia: an event during which symptoms of 
hypoglycemia are not accompanied by a PG determination (but that was 
presumably caused by a PG concentration ≤70 mg/dL [≤3.9 mmol/L]).

Severe hypoglycemia: an episode requiring the assistance of another person to 
actively administer carbohydrate, glucagon, or other resuscitative actions.  These 
episodes may be associated with sufficient neuroglycopenia to induce seizure or 
coma.  Plasma glucose measurements may not be available during such an event, 
but neurological recovery attributable to the restoration of PG to normal is 
considered sufficient evidence that the event was induced by a low PG 
concentration.

Total hypoglycemia: any event of documented symptomatic, asymptomatic, 
probable, unspecified, severe hypoglycemia.  Unspecified hypoglycemia is 
defined as an event during which PG ≤ 70 mg/dl (3.9 mmol/l) but no information 
relative to symptoms of hypoglycemia was recorded.

Nocturnal hypoglycemia: any total hypoglycemic event that occurs between 
bedtime and waking.
A different glucose threshold of <54 mg/dL (<3 mmol/l) may also be included in these analyses 
when deemed appropriate.
For each category of the aforementioned hypoglycemia categories, the incidence will be 
analyzed using the methods for analyses of categorical data described in Section 6.1, by visit and 
by randomized treatment; the rate of hypoglycemic episodes will be analyzed using a generalized 
linear mixed-effects model assuming negative binomial distribution for hypoglycemic episodes 
with pooled country, treatment, visit, and treatment-by-visit interaction as fixed effects and
baseline HbA1c and baseline rate as covariates. The logarithm of days between visits will be 
adjusted as an offset to account for possible unequal duration between visits and between 
patients. This model will be implemented using SAS® procedure GLIMMIX using the log link 
function. The predicted hypoglycemia rate per 1-year by treatment and by visit will also
presented. An unstructured covariance structure will be used to model the within-patient errors. 
If this analysis fails to converge, the following covariance structures will be tested in this order:
compound symmetry, then autoregressive. For rare hypoglycemic episodes such as severe 
hypoglycemia, stratified Wilcoxon rank sum test will be used to test 1-year corresponding 
hypoglycemia rate between each dulaglutide dose and placebo, and between each 2 higher dose 
and dulaglutide 1.5 mg.
A listing of individual hypoglycemic episodes by patient will be presented.


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6.13.4.2. Severe, Persistent Hyperglycemia
Summaries (if appropriate ) will be provided for events of severe, persistent hyperglycemia
(Protocol Section 7.4.1.3) resulting in initiation of rescue therapy by each randomized treatment.  
The time to the first rescue therapy use will be analyzed using PROC LIFETEST to generate 
Kaplan-Meier (KM) curves for each treatment. The summary reports will be only generated if 
more than 3% patients receive rescue intervention.
The patients who experienced severe, persistent hyperglycemia will be listed.
6.13.4.3. Pancreatitis
Summaries of adjudicated and investigator-reported pancreatic events will be provided by each 
randomized treatment. However, the summary report will only be generated if more than 3% 
patients have pancreatic event(s). Determination of investigator-reported events will be through 
the “Acute pancreatitis” Standardized MedDRA Queries (SMQ) and a “Chronic pancreatitis”
Lilly Search Categories (LSC) of the AE database, while adjudication-confirmed pancreatitis
will be found from adjudication CRF.
The patients developing pancreatitis will be listed separately for the investigator-reported and the 
adjudicated events.
Each pancreatic enzyme at Week 6 and Week 18, and the maximum post-dose value will be 
summarized by each randomized treatment, dulaglutide 3.0 mg/algorithm 1, dulaglutide 
3.0 mg/algorithm 2, dulaglutide 4.5 mg/algorithm 1, dulaglutide 4.5 mg/algorithm 2, algorithm 1, 
and algorithm 2 in a shift table using >1 upper limit normal (ULN), and ≥3 ULN separately for 
the ITT population, ITT population with normal baseline, ITT population with baseline value > 
ULN.
A MMRM with pooled country, baseline HbA1c strata, treatment, visit, and treatment-by-visit 
interaction as fixed effects will be fitted to analyze each pancreatic enzyme (p-amylase and 
lipase). In this model, the log transformed ratio (post first dose measure/baseline measure) will 
be the response variable and log transformed baseline measure instead of baseline measure will 
be a covariate.  The variance-covariance structure selection is detailed in Section 6.1. The 
treatment in the model will include placebo, dulaglutide 1.5 mg, dulaglutide 3.0 mg/algorithm 1, 
dulaglutide 3.0 mg/algorithm 2, dulaglutide 4.5 mg/algorithm 1, dulaglutide 4.5 mg/algorithm 2.  
The report from this analysis will include:
1) Geometric LS means and corresponding 95% CIs for each randomized treatment at each 
scheduled visit, and the ratio in geometric LS means, corresponding 95% CI along with 
p-value compared relative to placebo and to dulaglutide 1.5 mg at the same visit.
2) Geometric LS means and corresponding 95% CIs of pancreatic enzyme for algorithm 1, 
algorithm 2 after adjusting for baseline, and the ratio between algorithm 2 and algorithm 
1 (using algorithm 1 as reference) at Week 6 (Visit 6).  These results won’t be acquired
directly from the MMRM model. Rather, they will be obtained from the same model by 
forming appropriate estimate statements with the same algorithm across dulaglutide
3.0 mg and dulaglutide 4.5 mg.


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3) Geometric LS means and corresponding 95% CIs of pancreatic enzyme for dulaglutide
3.0, dulaglutide 4.5 after adjusting for baseline, and the ratio between each combined 
treatment across algorithms and placebo, and the difference between each combined 
treatment to Dulaglutide1.5 at the same Week (Visit):  Week 6 (Visit 6), Week 18 
(Visit 12).  These results will be obtained through the same model by forming appropriate 
estimate statements for the same dose across different algorithms.
4) The ratio of geometric LS means and the corresponding 95% CIs along with the p-value 
between each maintenance visit (Week 18/Visit 12) and the end of titration (Week 6/Visit 
6) within the same treatment including the dulaglutide 3.0 mg, and 4.5 mg, and within the 
same algorithm will be presented.  Any result related to combined treatment across 
algorithms and each algorithm at Visit 6 (Week 6) will be formed by constructing an 
appropriate estimate statement.
6.13.4.4. C-cell hyperplasia and C-cell Neoplasms
Listings of AEs of interest using a LSC will be provided by high level terms thyroid neoplasms, 
thyroid neoplasms malignant and thyroid disorders, as well as a listing of biopsy reports. The 
summary report for these AESIs by each randomized treatment will be reported if there are more 
than 3% patients with these AESIs.
Calcitonin data will be summarized using an ANCOVA model with treatment as a fixed effect 
by using LOCF. The response variable will be the rank on the change from baseline.
Calcitonin values will be listed for those patients with a post first dose serum calcitonin increase 
from (mean of the screening and baseline measures) ≥ 50% and the absolute value ≥20 pg/ml.
These patients will be classified by their absolute calcitonin values into the following categories: 
≥20 and <25 pg/ml; ≥35and <50 pg/ml; and ≥50 pg/ml. A shift table using these categories will 
be generated if the proportion of patients with these changes is 3% or more.
6.13.4.5. Allergic/Hypersensitivity Reactions
Listings of allergic/hypersensitivity AEs will be generated. If the number of patients with these 
events is 3% or more, then, a summary report will also be generated by each randomized 
treatment group.
A similar summary and listing will be generated for patients with injection site reactions.
6.13.4.6. Supraventricular Arrhythmias and Cardiac Conduction Disorders
Summaries of these AESIs will be produced by PT with decreased frequency and by each 
randomized treatment using SMQ.  The data listing will be generated.  The qualitative ECG data 
including conduction and arrhythmia will be summarized by each randomized treatment and 
listed by treatment and patient.
6.13.5. Gastrointestinal Safety
Because certain GI AEs, including nausea, vomiting, and diarrhea, are among the most common 
events reported in patients treated with dulaglutide, summaries and analyses for incidence will be 
provided for each randomized treatment, dulaglutide 3.0 mg/algorithm 1, dulaglutide 3.0 


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mg/algorithm 2, dulaglutide 4.5 mg/algorithm 1, dulaglutide 4.5 mg/algorithm 2, algorithm 1, 
algorithm 2 during the 18-week treatment period and during the first 6 weeks (titration phase), 
overall, and by visit, to compare the effects of the 4 different dose escalations (2 algorithms for 
each of the 2 investigational doses) and effects of the 2 titration algorithms on GI tolerability, as 
well as the overall effects of randomized treatments.
The prevalence of GIs, as well as the incidence of the first occurrence of nausea and/or vomiting 
will be summarized separately by the treatment and the time interval of interest mentioned in the 
first paragraph.
The maximum severity and duration from baseline to Week 18 of nausea and/or vomiting 
TEAEs will be summarized by the aforementioned treatments.
The time course plot on the initiation of nausea regardless of severity (prevalence) will be 
generated for each treatment.  The y-axis is the % subjects with nausea and the x-axis is the time 
since the first dose.
If data warrant, a negative binomial model similar to the rate of hypoglycemia analysis may be 
implemented for each of the aforementioned parameters.
A listing with treatment-emergent GI AEs of interest will be provided.
6.13.6. Treatment of Overdose
A study drug overdose (more than the specified number of injections, whether for placebo or 
dulaglutide treatment) will be reported as an AE.  This AE will be summarized only if it occurs 
with more than 3% of patients. Otherwise, only a data listing will be generated including the 
actual dose data (Section 6.13.1) along with treatment overdose AE reported date.
6.13.7. Cardiovascular Safety
6.13.7.1. Cardiovascular Events
Listings and summaries of adjudicated and investigator-reported CV events will be provided.
The summary report for adjudicated and investigator-reported CV events will only be generated 
if more than 3% patients have the events. The test statistics are detailed in Section 6.1.
6.13.7.2. Electrocardiograms
Heart rate (HR), PR interval (PR), and QT corrected for heart rate using QTcF are collected in 
triplicates. Prior to any analysis, the arithmetic mean from the three measures for the same 
parameter at the same visit will be calculated and use for all subsequent analysis.  MMRM model 
detailed in Section 6.1. for continuous variable analysis will be used to analyze each parameter in 
change from baseline. The treatment in the model will be placebo, dulaglutide 1.5 mg, 
dulaglutide 3.0 mg/algorithm 1, dulaglutide 3.0 mg/algorithm 2, dulaglutide 4.5 mg/algorithm 1, 
dulaglutide 4.5 mg/algorithm 2.
The reports for these analyses will include:


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
LS means and corresponding 95% CIs for each randomized treatment at each 
scheduled visit, and the difference in LS means, corresponding 95% CI along with 
p-value compared to placebo and to dulaglutide 1.5 mg at the same visit.

LS means and corresponding 95% CIs of each parameter’s effect for algorithm 1, 
algorithm 2, and the difference between algorithm 2 and algorithm 1 (using 
algorithm 1 as reference) at Week 6 (Visit 6).  These results will not be acquired
directly from the MMRM model. Rather, they will be obtained from the same 
model by forming appropriate estimate statements with the same algorithm across 
dulaglutide 3.0 mg and dulaglutide 4.5 mg.

LS means and corresponding 95% CIs of each parameter’s effect for dulaglutide
3.0, dulaglutide 4.5, and the difference between each combined treatment across 
algorithms and Placebo, and the difference between each combined treatment to 
Dula 1.5 at the same Week (Visit):  Week 8 (Visit 8), Week 10 (Visit 10) and 
Week 18 (Visit 12).  These results will be obtained through the same model by 
forming appropriate estimate statements for the same dose across different 
algorithms.

The difference in LS means and the corresponding 95% CIs along with the p-
value between each maintenance visit (Week 8/Visit 8, Week 10/Visit 10, Week 
18/Visit 12) and the end of titration (Week 6/Visit 6) within the same treatment 
including the combined dulaglutide 3.0 mg and 4.5 mg, and within the same 
algorithm will be presented.  Any result related to combined treatment across 
algorithms and each algorithm at Visit 6 (Week 6) will be formed by constructing 
an appropriate estimate statement.
The threshold analysis will only include HR, PR by visit and by randomized treatment, 
dulaglutide 3.0, and dulaglutide 4.5 mg.  The threshold is defined in Table GBGJ.3.


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Table GBGJ.3.
Heart Rate, PR-Interval, and QTcF Abnormal Data
Parameter (Unit)
Visit 
Threshold definition
HR (bpm)
Baseline (Visit 1)
>100, ≥130
Post baseline 
>100 and CFB >15
PR (msec)
Baseline (Visit 1)
≥220
Post baseline
≥220
≥220 and (%CFB >0 and ≤25%)
≥220 and (%CFB >25%)
QTcF
Baseline (Visit 1)
> 450 (Male) or > 470 (Female)
> 480   
> 500
Post baseline 
> 450 (Male) or > 470 (Female)
> 480   
> 500
>30 CFB
>60 CFB
Abbreviations:  QTcF = Fridericia’s corrected QT interval.
Note: CFB means change from baseline; and %CFB is the percentage change from baseline.
The qualitative summary related to the treatment-emergent cardiac conduction and rhythm 
abnormalities will be reported by treatment. The abnormal ECG outcomes will be listed by 
treatment and patient.
A non-ITP Bayesian model will be fitted detailed in Section 6.11.2.3 with the priors: 
α,β[i,t]~N(0,100) using 10000 MCMC samples with thin=10 and burn-in=10000. The 
probability of the posterior distribution of the parameter of interest on heart rate increase from 
baseline of each investigational dulaglutide dose compared to Dula 1.5 mg at Week 18.
                       pr(Δi-Δdula1.5mg < threshold) 
                       i stands for dulaglutide 3.0 mg/algorithm 1, dulaglutide 3.0 mg/algorithm 2, 
dulaglutide 4.5 mg/algorithm 1, and dulaglutide 4.5 mg/algorithm 2.
The threshold for this analysis will be 3bpm, 5 bpm, 7 bpm, 10 bpm.
The probability for Week 26 will be assumed to be the same as Week 18 from this model. The 
algorithm comparison at Week 6 will be evaluated.
6.13.7.3. Vital Signs
Vital signs will be listed for all randomized patients. Prior to any analysis, the arithmetic mean 
from the triplicates for the same parameter at the same visit will be calculated and used for all 
subsequent analysis. The change from baseline in pulse rate, systolic blood pressure, diastolic 
blood pressure (SBP, DBP) will be analyzed using a similar MMRM-based model as that 
described in Section 6.13.7.2. The result will be reported in the same manner as that for heart 
rate listed in Section 6.13.7.2. The threshold analyses will be summarized with the threshold 
definition is listed in Table GBGJ.4.


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Table GBGJ.4.
Abnormality Data for Heart Rate, Systolic Blood Pressure and 
Diastolic Blood Pressure
Parameter (unit)
Visit
Threshold definition
Pulse rate (bpm)
Baseline (Visit 1)
>100, ≥130 
Post baseline 
>100 and CFB > 15
SBP (mmHg)
Baseline (Visit 1)
≥160, ≤90
Post baseline
≥160 and  CFB ≥20
≤90 and CFB ≤-20
DBP (mmHg)
Baseline (Visit 1)
≥100, ≤50
Post baseline
≥100 and CFB≥10
≤50 and CFB≤-10
Abbreviations: bpm = beats per minute; CFB = change from baseline; DBP = diastolic blood pressure; SBP = 
systolic blood pressure
A non-ITP Bayesian model will be fitted detailed in Section 6.11.2.3with the priors: 
α,β[i,t]~N(0,100) using 10000 MCMC samples with thin=10 and burn-in=10000. The 
probability of the posterior distribution of the parameter of interest on heart rate increase from 
baseline of each investigational dulaglutide dose compared to dulaglutide 1.5 mg at Week 18.
                       pr(Δi-Δdula1.5mg < threshold) 
i stands for dulaglutide 3.0 mg/algorithm 1, dulaglutide 3.0 mg/algorithm 2, dulaglutide 
4.5 mg/algorithm 1, and dulaglutide 4.5 mg/algorithm 2.
The threshold for this analysis will be 3 bpm, 5 bpm, 7 bpm, 10 bpm.
The probability at Week 26 will be assumed to be the same as Week 18 from this model. The 
algorithm comparison at Week 6 will be evaluated. 
6.13.8. Renal Safety
To assess renal safety, a summary and analyses using LOCF will be provided for renal functional 
laboratory measures: estimated glomerular filtration rate (eGFR), Chronic Kidney Disease-
Epidemiology Collaboration (CKD-EPI), creatinine, urine albumin/creatinine ratio (ACR), by
treatment. The ANOVA model will be fitted with treatment as a fixed effect on the ranked 
LOCF change from baseline data.
An ANCOVA model will be fitted with treatment as a fixed effect. The change from baseline in 
rank for each parameter will be the response variable.
The minimum eGFR value and the maximum creatinine, urine ACR will be used for baseline and 
post baseline calculation to generate the shift table. Within treatment comparison will be tested 
using generalized McNemar’s test.  The shift table will use eGFR cutoff (<30, 30-<60, 60-<90, 
and ≥90 mL/min/1.73m2), creatinine (≤1ULN, >1 and ≤2 ULN, 2 and ≤4ULN, and >4ULN), 
and UACR (<30, (≥30 and ≤300), and 300 mg/g).  The overall randomized treatment 
comparison will be tested using a likelihood-ratio Chi-square test.The shift table for minimum 
eGFR for both baseline and post-first dose at Week 18 will be classifiedusing the 


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To examine AE indicating decrease in renal function, the SMQ for acute renal failure and a LSC 
for chronic renal failure events will be used to search the clinical trial data base for events of 
interest. A listing will be provided with all detected TEAE from these categories. 
6.13.9. Immunogenicity
Summaries dulaglutide anti-drug-antibodies (ADA) will be generated separately for treatment-
emergent ADA, for detected ADA by each dulaglutide treatment if more than 3% patients
developed an ADA.
The patient treatment-emergent ADA data will be listed.
6.13.10.
Clinical Laboratory Evaluation
Amylase, lipase, calcitonin, eGFR, creatinine, urine ACR are included in Section 6.13.4.3, 
Section 6.13.4.4, and Section 6.13.8. For other laboratory safety measurements summaries will 
be provided in this Section. For continuous (numeric) laboratory analytes, the rank on the change 
from baseline to endpoint (Week 18) will be analyzed as detailed in Section 6.1. For qualitative 
laboratory analytes, the number and percentages of patients with normal and abnormal values 
will be analyzed using Chi-square tests or Fisher’s exact test.
A summary report and analysis for treatment-emergent abnormal laboratory values (outside the 
reference ranges as appropriate) will be provided for each continuous analyte by treatment. Shift 
tables of the change from baseline value to the maximum post baseline value to Week 18 for 
selected analytes using clinically meaningful thresholds will be summarized separately using 
generalized McNemar’s test for within-treatment comparison and using likelihood ratio test for 
between-treatment (randomized) comparisons. A shift table for ALT, AST, ALP, GGT, total 
bilirubin, and direct bilirubin will be generated using cutoff ≤1ULN, (> 1 ULN and <3 ULN), 
(≥3ULN and <5ULN), (≥5ULN and <8 ULN), ≥8ULN.
Laboratory measurements will be listed by patient. Additional listings will be presented for 
laboratory measurements that are outside the normal range and for measurements outside certain
prespecified clinically relevant thresholds if deemed appropriate. A listing of patients with either 
AST or ALT ≥3xULN, and total bilirubin ≥2X ULN will also be provided.
6.14. Subgroup Analyses
Subgroup analyses of the treatment interaction for important factors, including age group, race, 
gender, country, duration of diabetes (< median, ≥median), baseline HbA1c (<8%, ≥8%), and 
BMI (< median, ≥median), may be conducted for the primary endpoint of HbA1c.  Country will
use the pooled country.
These will be conducted using the MMRM with treatment, visit, subgroup, treatment-by-visit,
treatment-by-subgroup, visit-by-subgroup, and treatment-by-visit-by-subgroup as fixed effects,
and baseline as a covariate. If the MMRM fails to converge, the corresponding analysis of
covariance (ANCOVA) or ANOVA model (LOCF) will be used.


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When analyzing baseline HbA1c as a subgroup, the baseline HbA1c will not be included as a
covariate to avoid colinearity.
TEAE exceeding 5% will be summarized descriptively for the patients with the top quartile of 
the body weight reduction from baseline by treatment group.
Other exploratory subgroup analyses may be performed as deemed appropriate.
6.15. Important Protocol Deviations
Important protocol deviations will be listed for all randomized patients and summarized by 
treatment group.  All important deviations related to study inclusion or exclusion criteria, 
conduct of the trial, patient managements or patient assessment will be described. The important
rotocol deviations will be prospectively defined in the study-specific monitoring requirements. 
Some of the protocol deviations that may not be prospectively identified may later be considered 
important by the Lilly study team, in which case will be also reported. The important protocol 
deviations will be captured from the clinical trial database as well as an excel file managed by 
the study clinical trial manager (CTM). The excel file generated by the CTM will be converted in 
a domain of the study data tabulation model (STDM) as a source in addition to other necessary 
SDTM domains to define the PP population.  The rationale for choosing certain important 
protocol deviations as exclusionary from the PP population will be based on their potential effect 
on the primary efficacy measures.  The decision and rationale for not reporting certain protocol 
deviations as important ones will be documented in the eTMF.  The following protocol 
conditions will result in exclusion from the PP population:

informed consent was never obtained

patients were randomized but the informed consent date is missing.

age <18 years old at randomization

patients have known type 1 diabetes

patients who had any hematologic condition that may have interfered with 
HbA1c measurement (eg, hemolytic anemias, sickle-cell disease)

excluded medicine use prior to safety follow-up
o
weight loss agents,
o
prohibited glucose-lowering agents (>14 days of use during the treatment 
period or any time during the screening/lead-in period of sulfonylureas, 
thiazolidinediones, alpha-glucosidase inhibitors, SGLT2 inhibitors, 
meglitinides, other GLP receptor agonists or DPP4 inhibitors, etc.)
o
>14 days use of systemic glucocorticoid

patients have an HbA1c <7% or >10% at Visit 1.

patients have a missing HbA1c at baseline (both Visit 1 and Visit 3) or at 18 
weeks (Visit 12).

patients do not have an overall compliance with study drug of at least 75% up 
to 18 weeks.
A complete list and summary report of important protocol deviations will be generated.


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6.16. Interim Analyses and Assessment Committee
At least three safety interim analyses and one efficacy/safety interim analysis will be conducted 
according to the specifications included in the protocol. The purpose of the safety analyses will
be to monitor the safety and tolerability of the 2 investigational dulaglutide doses. The interim 
efficacy/safety analysis will be conducted for internal clinical development planning purposes to 
enable preliminary dose-selection for Phase 3 planning.  The study will not be stopped based on 
the efficacy results at this interim analysis. 
6.16.1. Assessment Committee
The interim analyses will be conducted under the auspices of an Assessment Committee (AC). 
The AC is authorized to review unblinded interim analyses.  Before any interim analysis is 
performed, an AC will be established to control the dissemination of the findings. Lilly 
representatives having direct contact with the investigative sites will not be part of the AC unless 
they stop contact with the sites from the time of their inclusion into the study AC. Statistical 
Analysis Center (SAC) will be authorized to evaluate unblinded interim analyses and prepare the 
reports for the AC to review. Study sites may receive information about interim results ONLY if 
these results may have an impact on the safety of patients in this trial.
The AC proceedings will be described in an AC charter. Any change to the proceedings will be 
included in the AC charter and will not require a protocol or SAP amendment. The AC Charter 
describes the precise plan of the unblinded safety monitoring and interim statistical analyses.
6.16.2. Interim Analyses
6.16.2.1. Timing of the Interim Analysis
The first safety only interim analysis will occur after approximately 15 patients have completed 8
weeks of treatment. The AC will continue to evaluate patient safety and tolerability when 
approximately 30 patients and 60 patients complete 8weeks of treatment.
The efficacy/safety interim analysis will be conducted after approximately 120 patients have 
completed the 18-week treatment period.
6.16.2.2. Evaluation Criteria
For safety only interim analyses, the totality of the safety data on AEs, SAEs, TEAEs, and 
AESIs, disposition, discontinuation due to AEs, ECG, vital signs, ADA, GI AEs, cardiovascular 
events, and safety laboratory analytes will be evaluated. The analysis for each mentioned 
parameter will be analyzed in the same way as defined in this SAP.
For efficacy/safety analysis, the AC will base their decision on the following criteria in addition 
to the safety parameters listed in the preceding paragraph:
HbA1c Criterion:
At least 80% probability that at least one dose of dulaglutide 3.0 or dulaglutide 4.5 mg 
reduces HbA1c by at least 0.2% compared to dulaglutide 1.5 mg at Week 18, that is, 


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Pr(∆dula3.0 or dula4.5 - ∆dula1.5 < -0.2%) ≥80%]. The other thresholds of -0.15% and -0.3% 
will be also be evaluated.  The probability will be at least 55% at the end of the study.
Other efficacy endpoint at week 18:  change from baseline in body weight, will also be 
assessed relative to 1.5 mg as, Pr(∆dula3.0 or dula4.5 - ∆dula1.5 < threshold of -1 and -2 kg. 
Safety Parameters:
Heart rate from ECG, pulse rate from vital signs using change from baseline  to be 
assessed relative to placebo as , Pr(∆dula3.0 or dula4.5 - ∆placebo < threshold of 3, 5, 7, 10 bpm.
MMRM analysis results will be reported for change from baseline in HbA1c, body 
weight, selected ECG, vital signs, and pancreatic enzymes , too.
PK/PD exposure-response results will be generated based on a separate PK/PD analysis 
plan by PK/PD group.
6.17. Planned Exploratory Analyses
Some of the planned exploratory analyses are described in Section 6.1. The remaining 
exploratory exploratory analyses are described in this Section.
The analysis of patients reaching HbA1c target ≤6.5% will use the same model as that for 
HbA1c target <7.0% described in Section 6.11.3. 
Longitudinal continuous variables such as fasting glucagon will be analyzed using MMRM 
described in Section 6.1.  If the normality assumption is violated, appropriate data transformation 
is needed prior to analysis.
Non-longitudinal continuous variables such as 6-point SMPG, c-peptide, fasting insulin,  
HOMA2-IR, and HOMA2-%B will be analyzed using LOCF by fitting a linear model with 
pooled country, treatment, baseline HbA1c strata as fixed effects and the corresponding baseline 
value as a covariate.  A data transformation may be applied if data are not normally distributed.
The 6-point SMPG consists of measurements before and 2 hours after each of 3 main meals 
within the same day. Each of the time point of the 6-point SMPG will be analyzed separated.
6.18. Annual Report Analyses
The following reports are needed for the Development Safety Update Report (DSUR): (1)
Estimated cumulative subject exposure, (2) Cumulative exposure to investigational drug, by 
demographic characteristics for ongoing unblinded clinical trials and completed clinical trials, 
(3) Exposure information for ongoing clinical trials and clinical trials that completed during the 
reporting period, (4) Listing of subjects who died during the DSUR period, (5) Discontinuations
from the study due to adverse event, (6) Discontinuations from the study treatment due to 
adverse event during the DSUR Period.


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6.19. Clinical Trial Registry Analyses
Additional analyses will be performed for the purpose of fulfilling the Clinical Trial Registry 
(CTR) requirements.
Analyses provided for the CTR requirements include the following:
Summary of adverse events, provided as a dataset which will be converted to an XML file.  
Both SAE and ‘Other’ AE are summarized: by treatment group, by MedDRA preferred term.

An adverse event is considered ‘Serious’ whether it is a treatment emergent 
adverse event (TEAE).

An adverse event is considered in the ‘Other’ category if it is a TEAE but not 
serious.  For each Serious AE and ‘Other’ AE, for each term and treatment 
group, the following are provided:
o
the number of participants at risk of an event
o
the number of participants who experienced each event term
o
the number of events experienced

Consistent with www.ClinicalTrials.gov requirements, ‘Other’ AEs that occur 
in fewer than 5% of patients/subjects in every treatment group may not be 
included if a 5% threshold is chosen (5% is the minimum threshold).

AE reporting is consistent with other document disclosures for example, the 
CSR, manuscripts, and so forth.


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7.
Unblinding Plan
The purpose of the unblinding plan is to detail the procedures that are in place to minimize bias 
while preparing for or conducting any summary or analysis of the data for AC reports, data 
reviews, dose selection (interim efficacy/safety only), and developing/refining exposure 
analyses.  Additionally, this plan identifies personnel who will be unblinded during the study, 
including unblinding for the AC safety only analyses, and safety/efficacy interim analyses in 
support of the AC meetings.
The access to subject treatment assignments will not be provided to the following personnel until 
datalock is authorized for the planned final analysis at the completion of the blinded study:

investigator and site personnel

Lilly personnel with direct site contact

Lilly personnel responsible for data entry and data validation

Lilly study team not in the AC and/or SAC
After datalock, the study team will be unblinded to the study data to prepare for the analyses for 
CSR. Investigators can be provided treatment assignments for their subjects when unblinding 
has occurred and the information will not impact scientific integrity or introduce bias.
7.1.
Operational Procedures
The randomization code (treatment assignment) will be stored in the Lilly interactive web 
response system (IWRS) and will not be accessible to the blinded Lilly study team, except for 
those pre-specified in the unblinding plan to be unblinded, until the final database lock (DBL). 
Members from the SAC, AC, and the study global patient safety (GPS) scientist may be 
unblinded to data prior to the DBL. The SAC, composed of Lilly unblinded statistics personnel,
PK/PD scientists and the PK/PD analysts (for efficacy/safety interim analysis only) will form a 
separate team from the Lilly blinded team.  The SAC will obtain the randomization code from 
the unblinded inVentiv data movement group in order to generate unblinded TFLs for the AC.  
Membership is listed in Table GBGJ.5 for each of the groups mentioned above.
More specifically, the inVentiv data movement group will load CRF data, clinical laboratory 
results, ECG, and IWRS data into the designed blinded and unblinded locations.  The blinded 
version of the data will then be provided to the blinded Lilly study team.  The unblinded data
will be provided to the SAC.  The inVentiv data movement group is not blinded, but is not 
involved in study-level activities.


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Table GBGJ.5.
Study H9X-MC-GBGJ Group Name and Membership
Abbreviations: GPS = global patient safety; PD = pharmacodynamics; PK = pharmacokinetics; SAE = significant
adverse events.
Periodically throughout the trial until the DBL, blinded data will be transferred by inVentiv data 
movement per the data transfer plan to the blinded Lilly study team members including the 
blinded Lilly statistics group for the purpose of preparing Study Data Tabulation Model (SDTM) 
and Analysis Data Model (ADaM) dataset, AC reports, trial level safety review reports, blinded 
AC reviews, TFL reviews, and CSR preparation.  To minimize bias during statistical planning 
and data review, these transfers will be provided under the guidelines described in the following 
sections.
By setting up appropriate access privileges, the Lilly system will only allow unblinded personnel 
(unblinded statistician and/or programmers) to access data that contains unblinding information.
7.2.
Site Level Unblinding
The procedure for site personnel to unblind an individual patient’s treatment assignment for an 
emergency is described in the protocol Section 7.3. Emergency unblinding for adverse events 
may be performed by accessing the IWRS at the site level. When an IWRS Clinical Trial Study 
Management System (CT-SMS) is used to unblind a patient’s treatment assignment, the 
computer application will maintain the date, reason for unblinding, and the identification of the 
person unblinding the treatment assignment.  All calls resulting in an unblinding event are
recorded and reported by the IWRS.
Group Name
Group Members
Blinded Lilly Study Team
Lilly clinical study team personnel who work on the 
study and have direct site contact including the clinical 
research physician, clinical trial manager , data sciences 
and solutions, global patient safety personnel, and study 
monitors, etc., and non site direct contact regulatory 
scientist, statistician(s). However, per Lilly procedure, 
for patient safety, the study GPS scientist will be 
unblinded to SAE patient level data for patient safety.
Blinded Lilly statistics group
Lilly statisticians and statistical analyst(s)
Statistical Analysis Center (Unblinded)
Lilly statisticians and statistical analyst(s)
Unblinded PK/PD team scientists (part of the SAC)
Lilly study team pharmacokinetic/pharmacodynamics 
(PK/PD) scientists and analyst(s), etc.
Assessment Committee
Lilly Physicians, Statisticians, and GPS personnel
external to the study team
inVentiv data movement group
inVentiv data movement representative
The program senior management 
Lilly dulaglutide senior medical director or above 


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The site monitor is responsible for verifying compliance with the blinding procedures at the 
investigative site and verifying that access to the patients’ treatment assignments remains
restricted from the investigator and site personnel in direct contact with patients.
The investigator and site personnel are instructed to make every attempt to contact Lilly 
personnel when a patient’s treatment assignment is unblinded at the site.  The affiliate personnel 
document the unblinding records and inform the designated study team member, CTM, who 
documents the overall unblinding records for the entire study. The documentation is filed in the 
study files. A final Study Unblinding Summary will be prepared at the end of the study (at the 
study closeout).
7.3.
Trial Level Safety Reviews
Periodic Trial Level Safety Review (TLSR) summaries and listings will be produced by the 
blinded Lilly statistics group and delivered to the blinded Lilly study teams per TLSR plan.
These summaries will be blinded until after the DBL.  They will contain neither randomization 
assignments nor post randomization primary endpoint HbA1c, dose information, or PK data with 
the potential to unblind.  Blinding flags will be created in the central laboratory database, based 
upon the Alert and Blinding Criteria document maintained by the Clinical Laboratory Operations 
(CLO) group.  These flags will blind specific report data to the site and investigators.  Data 
transferred to and exported from the clinical laboratory results will not be blinded to the Lilly 
team or to the data management of third party organization performing the labs.
The complete list of TLSR variables include overall AEs, serious adverse events (SAEs), TEAEs
AEs of special interest, laboratory data, vital signs, ECG, discontinuations, concomitant 
medications, and historical/pre-existing medical conditions.
7.4.
Assessment Committee Reports
The blinded Lilly study team will remain blinded to randomization assignments and potentially 
unblinding results until after the DBL.
The SAC statistician is responsible for authorizing the access of Lilly personnel to unblinded 
data.  Every attempt should be made to contact the statistician and document the authorization 
before access is given to unblinded data.  A designated Interactive Web Response System 
(IWRS) representative, inVentiv data movement team or the replacement or their designee, will 
provide all data transfers to the Lilly statistics group based on the data transfer plan.
The study project statistician will be responsible for keeping a running log of individuals given 
access to any unblinded study data.  This log will include the person’s name, title, date of 
unblinding, level of unblinding (that is, group or patient), and purpose of unblinding. This record 
will be stored in a secure area and will be stored in eTFM via the study CTM after DBL.
Two types of interim analyses will be performed for this study:


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7.4.1. Safety Only Reports
There are at least 3 unblinded safety only reviews. The following personnel will be unblinded to 
the safety data (efficacy measures will NOT be unblinded), in order to perform the safety data 
analysis, prepare the AC safety reports, and review/discuss the safety results:
The AC (determined in AC Charter)
Internal SAC (Lilly study personnel)
Computational Statisticians
Others:  No, but can be added upon AC Chair’s request
7.4.2. Efficacy/Safety Interim Report
7.4.2.1.
Model Development
For the interim analysis of efficacy, safety and pharmacokinetics, the following personnel will be 
unblinded to the pharmacokinetics related data about 4 to 6 weeks after approximately 
80 subjects complete 18weeks of treatment in order to develop the PK/PD modeling and/or 
TFLs:
Internal SAC (Lilly study personnel)
Computational Statisticians
Internal Pharmacokinetic Analysis Group (Lilly study personnel, part of the SAC)
Pharmacokineticist and Pharmacokinetics Analysts
7.4.2.2.
Reports Delivery
The following personnel will be unblinded to the efficacy, safety, and pharmacokinetics data 
after approximately 120 subjects complete 18-week treatment, in order to perform data analysis, 
prepare the interim reports, review the results, and discuss business related matters:
AC (determined in AC Charter)
Internal SAC (Lilly personnel) or its delegate
Computational Statisticians
Internal Pharmacokinetic Analysis Group (Lilly personnel, part of SAC) or its 
delegate
Pharmacokineticist and Pharmacokinetics Analysts
Others:  No, but can be added per the request from AC Chair and/or the program 
senior management
If PK reports needs more time to be generated, this interim review can be proceeded without PK 
data. A subsequent PK results review can be formed later after the results are available.
In addition, in order to perform the critical business development and the regulatory interactions, 
some personnel need to be unblinded to the related summary (group) level data, and possibly 
limited patient-level data after the interim safety/efficacy analysis.  This unblinding requires 


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approval from AC and signature for Confidentiality Responsibilities Agreement. The SAC 
statistician should be informed by AC Chair for documentation purpose.
7.5.
Clinical Study Report
Prior to the final DBL, SDTM/ADaM datasets and draft TFLs will be produced by blinded team 
members and delivered to the blinded Lilly study team to review as appropriate.
7.5.1. Prelock Unblinding
Lilly PK/PD scientists along with the SAC statistician(s) who generate the data for PK/PD 
scientists will access randomization codes prior to the final DBL.  Lilly PK/PD scientists will 
obtain unblinding information about 1 to 2 months before the DBL in order to perform PK/PD 
model-based analysis if deemed necessary.
7.5.2. End of Study Unblinding
After the final DBL, all transfers of SDTM/ADaM files and TFLs to Lilly will be unblinded and 
will contain unblinded results for all laboratory parameters, PK data, and CRF data.
Immunogenicity data will be obtained about 1 or 2 months after the final DBL in a separate 
transfer without overwriting the already locked database.


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8.
References
Fu H, Manner D. Bayesian adaptive dose-finding studies with delayed responses. J Biopharm
Stat. 2010;20(5):1055-1070.
Kenward MG, Rosenkranz GK. Joint modeling of outcome, observation time, and missingness. J
Biopharm Stat. 2011;21(2):252-262.
Lachin JM. Fallacies of last observation carried forward analyses. Clin Trials. 2016;13(2):161-
168.
Caumo A, Perseghin G, Brunani A, Luzi L. New insights on the simultaneous assessment of 
insulin sensitivity and beta-cell function with the HOMA2 method. Diabetes Care. 2006;
29(12): 2733-2734.
American Diabetes Association Workgroup on Hypoglycemia. Defining and reporting 
hypoglycemia in diabetes: a report from the American Diabetes Association Workgroup on 
Hypoglycemia. Diabetes Care. 2005;28(5):1245–1249.


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9.
Appendices


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Appendix 1.
Analysis Windows for the Selected Parameters
In clinical trials, visits do not always occur as scheduled in the protocol, and a certain visit may 
actually occur closer to the protocol-specified time of a different scheduled visit. When there is
interest in the effect of the drug over time, using the visit number for analysis may not provide 
the best representation of time. For that reason, analysis windows will be used to define ranges 
of days relative to the date of first dose in order to associate collected data with scheduled time 
points of interest. These analysis windows will be implemented in ADaM, and they will not be 
used to overwrite or change the actual visit number that was reported by the site. Furthermore, 
these analysis windows are separate from the allowable range of days in the protocol’s schedule 
of events for visits; they are not intended to be provided to sites so that there is no confusion 
regarding the acceptable timing of patient visits.
There will be cases where a patient has more than 1 measurement in the same analysis window. 
If multiple measurements fall within the same window but were collected on different days, the 
measurement closest to the target time will be used. If multiple measurements within the same 
window are equidistant from the target, the earlier measurement will be used to be conservative 
with regard to the drug effect. If more than 1 measurement was collected on the same day for a 
patient, the last measurement on that day will be used for that patient because there may have 
been an error with the test itself that caused the investigator to repeat it on the same day.


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Table APP1.1.
Analysis Windows for the Selected Parameters
Screening and 
Lead-in
Treamtent Period
Safety Follow-
up
Visit
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V801
Week
-2
-1
0
2
4
6
7
8
9
10
14
18
22
Day
-14 
-7
1
15
29
43
50
57
64
71
99
127
155
Vital signs, Height, 
Weight, BMI
(-∞,-4)
(-10, -4)
(-3,1)
(2,22)
(23, 36)
(37, A) (A+1, 53)
(54, 60)
(61,67)
(68,85)
(86,113)
(114,B)
(B+1, C)
ECG
(-∞,1)
(2,A)
(A+1, 64)
(65, 99)
(100,B)
(B+1, C)
6-point SMPG, Lipids 
panel (fasting), c-
peptide, fasting insulin
(-∞,1)
(2,B)
Chemistry panel, 
urinary analysis, ACR, 
eGFR, Hematology
(-∞,1)
(2,B)
HbA1c, fasting glucose
(-∞,-7)
(-6,1)
(2, A)
(A+1,99)
(100,B)
(B+1, C)
(p) amylase, lipase, 
Serum calcitonin
(-∞,-7)
(-6,1)
(2,A)
(A+1,B)
(B+1,C)
Fasting plasma 
glucagon
(-∞,1)
(2,A)
(A+1,B)
Calcitonin
(-∞,-7)
(-6,1)
(2,B)
Immunogenicity
(-∞,1)
(2, A) 
(A+1,B)
(B+1, C)
Abbreviations:  ACR = albumin/creatinine ratio; BMI = body mass index; ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; HbA1c = 
hemoglobin A1c; SMPG = self-monitored plasma glucose; V = visit.
Windows represent the range of days, relative to the date of the first dose, associated with a particular time point.
Note: (day1, day2), are inclusive.
      A, B, C: actual day on which each patient individually ends the titration phase, maintenance phase, or safety follow-up. If the actual day is missing, the
planned day of 46, 141, and  158 will be used to represent the end of the titration phase, maintenance phase, or safety follow-up.
Day 1: The day of the first dosing date or the day of the randomization date if first dosing date is missing
* When creating windows for the baseline, use the last non-missing pre-first dosing value.
The above analysis windows will not be used for analysis of hypoglycemia or compliance over time.
Any other parameters not listed in this table will use the site or investigator reported visit measurement directly without applying the visit window.


PPD
Leo Document ID = fd7b28a3-2e71-452d-9516-82fbf127c4af
Approver: 
Approval Date & Time: 08-Dec-2016 20:45:48 GMT
Signature meaning: Approved