A Randomized, Double-Blind, Parallel Arm Study of the Efficacy and Safety of Investigational Dulaglutide Doses When Added to Metformin in Patients With Type 2 Diabetes Mellitus
Phase: PHASE3
Conditions: Diabetes Mellitus, Type 2
Sponsor: Eli Lilly and Company

Protocol H9X-MC-GBGL 
 
A Randomized, Double-Blind, Parallel Arm Study of the Efficacy and Safety of Investigational 
Dulaglutide Doses When Added to Metformin in Patients with Type 2 Diabetes Mellitus 
 
 
NCT03495102 
 
Approval Date: 05-Feb-2018 

Protocol H9X-MC-GBGL 
Page 1 of 88
LY2189265
Protocol H9X-MC-GBGL
A Randomized, Double-Blind, Parallel Arm Study of the 
Efficacy and Safety of Investigational Dulaglutide Doses 
When Added to Metformin in Patients with Type 2 Diabetes 
Mellitus
(AWARD-11:  Assessment of Weekly AdministRation of 
LY2189265 in Diabetes-11)
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 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) 
Study H9X-MC-GBGL is a Phase 3, randomized, double-blind trial designed to assess the 
efficacy and safety of once weekly investigational dulaglutide doses (4.5 mg or 3.0 mg) 
compared to dulaglutide 1.5 mg in patients with type 2 diabetes mellitus on metformin 
monotherapy.  
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly 
on approval date provided below.
Approval Date: 05-Feb-2018 GMT

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Table of Contents
Section
Page
Protocol H9X-MC-GBGL A Randomized, Double-Blind, Parallel Arm 
Study of the Efficacy and Safety of Investigational Dulaglutide 
Doses When Added to Metformin in Patients with Type 2 Diabetes 
Mellitus...............................................................................................................................1
Table of Contents........................................................................................................................2
1.
Synopsis .............................................................................................................................9
2.
Schedule of Activities .......................................................................................................12
3.
Introduction ......................................................................................................................16
3.1.
Study Rationale............................................................................................................16
3.2.
Background..................................................................................................................16
3.3.
Benefit/Risk Assessment..............................................................................................17
4.
Objectives and Endpoints..................................................................................................18
5.
Study Design.....................................................................................................................21
5.1.
Overall Design .............................................................................................................21
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 Dose and Dose Escalation Regimen ....................................................25
6.
Study Population...............................................................................................................27
6.1.
Inclusion Criteria..........................................................................................................27
6.2.
Exclusion Criteria ........................................................................................................29
6.3.
Lifestyle Restrictions....................................................................................................31
6.4.
Screen Failures.............................................................................................................31
7.
Treatments........................................................................................................................32
7.1.
Treatments Administered .............................................................................................32
7.1.1.
Packaging and Labeling .......................................................................................33
7.1.2.
Medical Devices...................................................................................................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
7.5.
Preparation/Handling/Storage/Accountability...............................................................35
7.6.
Treatment Compliance .................................................................................................35

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7.7.
Concomitant Therapy...................................................................................................36
7.7.1.
Antihyperglycemic Medications...........................................................................37
7.7.1.1.
Required Concomitant Antihyperglycemic Medication:  
Metformin ......................................................................................................38
7.7.1.2.
Initiation of New Antihyperglycemic Medication during 
the Study ........................................................................................................38
7.7.2.
Medications that Promote Weight Loss ................................................................40
7.7.3.
Systemic Glucocorticoids.....................................................................................40
7.7.4.
Antihypertensive Medications..............................................................................40
7.7.5.
Special Treatment Considerations ........................................................................40
7.7.5.1.
Standards of Medical Care..............................................................................40
7.7.5.2.
Management of Increased Hypoglycemia Risk ...............................................41
7.7.5.3.
Management of Patients with Severe, Persistent 
Hyperglycemia during the Treatment Period...................................................41
7.7.5.4.
Management of Patients Permanently Discontinuing 
Study Drug.....................................................................................................42
7.7.5.5.
Management of Patients with GI Symptoms ...................................................42
7.8.
Treatment after the End of the Study............................................................................42
7.8.1.
Continued Access.................................................................................................42
8.
Discontinuation Criteria ....................................................................................................43
8.1.
Discontinuation from Study Treatment.........................................................................43
8.1.1.
Permanent Discontinuation from Study Treatment ...............................................43
8.1.2.
Temporary Interruption of Study Treatment .........................................................44
8.1.3.
Discontinuation of Inadvertently Enrolled Patients...............................................44
8.2.
Discontinuation from the Study....................................................................................44
8.3.
Lost to Follow-Up........................................................................................................45
9.
Study Assessments and Procedures ...................................................................................46
9.1.
Efficacy Assessments...................................................................................................46
9.1.1.
Primary Efficacy Assessment...............................................................................46
9.1.2.
Secondary Efficacy Assessments..........................................................................46
9.1.3.
Exploratory Efficacy Assessments .......................................................................46
9.1.4.
Body Weight, Height, and Body Mass Index........................................................47
9.1.5.
Appropriateness of Assessments ..........................................................................47
9.2.
Adverse Events ............................................................................................................47
9.2.1.
Serious Adverse Events........................................................................................48
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................49
9.2.2.
Adverse Events of Special Interest .......................................................................49
9.2.2.1.
Cardiovascular Events ....................................................................................49
9.2.2.2.
Hypoglycemia and Hyperglycemia .................................................................49

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9.2.2.3.
Pancreatitis.....................................................................................................51
9.2.2.4.
C-Cell Hyperplasia and C-Cell Neoplasms .....................................................52
9.2.2.5.
Hypersensitivity Reactions .............................................................................53
9.2.2.6.
Supraventricular Arrhythmias and Cardiac Conduction 
Disorders........................................................................................................53
9.2.2.7.
Acute Gallbladder Disease..............................................................................53
9.2.2.8.
Acute Renal Events ........................................................................................53
9.2.3.
Complaint Handling.............................................................................................53
9.3.
Treatment of Overdose.................................................................................................54
9.4.
Safety...........................................................................................................................54
9.4.1.
CV Safety ............................................................................................................54
9.4.1.1.
Electrocardiograms.........................................................................................54
9.4.1.2.
Vital Signs......................................................................................................54
9.4.2.
Laboratory Tests ..................................................................................................55
9.4.3.
Safety Monitoring ................................................................................................55
9.4.3.1.
Hepatic Safety Monitoring..............................................................................55
9.4.3.1.1.
Hepatic Safety Data Collection .................................................................55
9.5.
Pharmacokinetics .........................................................................................................56
9.6.
Pharmacodynamics ......................................................................................................56
9.7.
Pharmacogenomics ......................................................................................................56
9.7.1.
Whole Blood Samples for Pharmacogenetic Research..........................................56
9.8.
Biomarkers and Antibodies ..........................................................................................57
9.8.1.
Samples for Immunogenicity Research.................................................................57
9.8.2.
Biomarkers...........................................................................................................57
9.9.
Health Economics ........................................................................................................58
9.9.1.
Diabetes Injection Device Experience Questionnaire (DID-
EQ)......................................................................................................................58
9.9.2.
EQ-5D-5L............................................................................................................58
9.9.3.
Impact of Weight on Self-Perceptions Questionnaire (IW-
SP).......................................................................................................................58
9.9.4.
Ability to Perform Physical Activities of Daily Living 
(APPADL)...........................................................................................................59
10.
Statistical Considerations ..................................................................................................60
10.1. Sample Size Determination ..........................................................................................60
10.2. Populations for Analyses..............................................................................................60
10.3. Statistical Analyses ......................................................................................................61
10.3.1.
General Statistical Considerations ........................................................................61
10.3.2.
Treatment Group Comparability...........................................................................62
10.3.2.1.
Patient Disposition..........................................................................................62

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10.3.2.2.
Patient Characteristics ....................................................................................62
10.3.2.3.
Concomitant Therapy .....................................................................................62
10.3.2.4.
Treatment Compliance....................................................................................63
10.3.3.
Efficacy Analyses ................................................................................................63
10.3.3.1.
Primary Analyses ...........................................................................................63
10.3.3.1.1.
Secondary Analyses for Primary Endpoint................................................63
10.3.3.1.2.
Multiple Imputation for Missing Data.......................................................63
10.3.3.2.
Analyses for Secondary Efficacy Endpoints....................................................64
10.3.3.3.
Multiplicity Adjustments for the Primary and Key 
Secondary Endpoints Analyses .......................................................................64
10.3.3.4.
Tertiary/Exploratory Efficacy Endpoints.........................................................64
10.3.4.
Safety Analyses....................................................................................................64
10.3.4.1.
Study Drug Exposure......................................................................................64
10.3.4.2.
Adverse Events...............................................................................................65
10.3.4.3.
Hypoglycemic Episodes .................................................................................65
10.3.4.4.
Gastrointestinal Safety....................................................................................65
10.3.4.5.
Laboratory Analyses.......................................................................................65
10.3.4.6.
Vital Signs......................................................................................................66
10.3.4.7.
Electrocardiograms.........................................................................................66
10.3.5.
Pharmacokinetic/Pharmacodynamic Analyses......................................................66
10.3.6.
Other Analyses.....................................................................................................66
10.3.6.1.
Health Economics...........................................................................................66
10.3.6.2.
Subgroup Analyses.........................................................................................66
10.3.7.
Evaluation of Immunogenicity .............................................................................67
10.3.8.
Interim Analyses..................................................................................................67
11.
References ........................................................................................................................69
12.
Appendices .......................................................................................................................73

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List of Tables
Table
Page
Table GBGL.1.
Objectives and Endpoints...............................................................................18
Table GBGL.2.
Study Treatments (Weeks 1-52).....................................................................32
Table GBGL.3.
Criteria for Use of Concomitant Medications that May Interfere with 
Efficacy and Safety Assessments...................................................................37
Table GBGL.4.
Populations for Analyses ...............................................................................60

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

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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions........................................................................74
Appendix 2.
Clinical Laboratory Tests...............................................................................79
Appendix 3.
Study Governance Considerations..................................................................81
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality....................85
Appendix 5.
Protocol GBGL World Health Organization Classification of Diabetes 
and Diagnostic Criteria ..................................................................................86
Appendix 6.
Classification of Contraceptive Methods........................................................87
Appendix 7.
Protocol GBGL Standardized Protocols for the Measurement of Height 
and Weight ....................................................................................................88

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LY2189265
1. Synopsis
Title of Study:  A Randomized, Double-Blind, Parallel-Arm Study of the Efficacy and Safety of Investigational 
Dulaglutide Doses When Added to Metformin in Patients with Type 2 Diabetes Mellitus
Rationale:  
Study H9X-MC-GBGL (GBGL) is a Phase 3 trial designed to assess the safety and efficacy of once weekly 
dulaglutide 3.0 mg and 4.5 mg in comparison to dulaglutide 1.5 mg (the highest dose approved by regulatory 
agencies).  The overall goal of the Phase 3 program is to gain regulatory approval for inclusion of at least 1 higher 
dose in the Trulicity label for treatment of patients with type 2 diabetes mellitus (T2D) who require additional 
glucose-lowering to obtain their glycemic target.  The additional dosing option(s) will be administered using the 
same device as that used for currently approved doses of 0.75 mg and 1.5 mg (single-dose pen [SDP]).  
Objectives/Endpoints:
Objectives
Endpoints
Primary
To demonstrate that once weekly dulaglutide 4.5 mg 
and/or 3.0 mg is superior to dulaglutide 1.5 mg for
change from baseline in HbA1c at 36 weeks in patients 
with inadequately controlled T2D on concomitant 
metformin therapy.
Secondary
Efficacy:
To demonstrate that once weekly dulaglutide 4.5 mg 
and/or 3.0 mg is superior to dulaglutide 1.5 mg for 
secondary efficacy parameters at 36 weeks (controlled 
for Type 1 error).
Safety:
To compare each investigational dulaglutide arm 
(4.5 mg, 3.0 mg) to the 1.5 mg arm for selected safety 
parameters through 36 and 52 weeks (unless noted 
otherwise)

The change in HbA1c from baseline 

The change in body weight from baseline

Proportion of patients achieving HbA1c target 
<7.0% (53 mmol/mol) 

The change in fasting serum glucose (FSG) 
from baseline 

Incidence of treatment-emergent adverse events 
(TEAEs) and discontinuation of study drug due 
to adverse events (AEs)

Adjudicated and confirmed cardiovascular and 
pancreatic AEs

Incidence of thyroid neoplasm AEs

Incidence of treatment-emergent (TE) 
dulaglutide anti-drug antibodies (ADA) and 
systemic hypersensitivity reactions

Change from baseline in pulse rate (PR)

Electrocardiogram (ECG) parameters

Occurrence of hypoglycemic episodes 

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Objectives
Endpoints
Pharmacokinetics (PK) and Pharmacodynamics (PD)
To characterize dulaglutide PK and the dose and/or 
exposure-response relationships for key efficacy (eg, 
HbA1c and weight), and safety (eg, heart rate) 
endpoints.

PK parameters (eg, maximum concentration 
[Cmax], area under the curve [AUC]) at steady 
state

Pharmacodynamic evaluations may include 
changes from baseline in HbA1c, body weight, 
and heart rate at Weeks 36 and 52
Abbreviations:  HbA1c = hemoglobin A1c; T2D = type 2 diabetes mellitus.
Summary of Study Design:  
Study GBGL is a Phase 3, multicenter, randomized, double-blind, parallel-arm study with 3 study periods (Lead-In, 
Treatment, and Safety Follow-Up) in patients with T2D with inadequate glycemic control on metformin only; the 
study will have 52-week treatment duration, with primary endpoint at 36 weeks.
Treatment Arms and Duration:  
At Visit 3 patients will be randomized in a 1:1:1 ratio to weekly injections of dulaglutide 4.5 mg, 3.0 mg, or 1.5 mg, 
in combination with stable doses of metformin.  Patients will be titrated through sequential 4-week treatment 
segments beginning with 0.75 mg once weekly followed by 1.5 mg once weekly.  At Week 8, patients randomized 
to the dulaglutide 1.5 mg group will continue on this dose for the remainder of the Treatment Period.  Patients 
randomized to the dulaglutide 3.0 mg group will be escalated to 3.0 mg once weekly at Week 8 and will continue on 
this dose for the remainder of the Treatment Period.  Patients assigned to the dulaglutide 4.5 mg group will be 
escalated to 3.0 mg once weekly at Week 8 for 4 weeks, followed by escalation to their final dose of 4.5 mg once 
weekly at Week 12. Study participants will be treated for 52 weeks, with the primary objectives assessed at 
Week 36. A 4-week Safety Follow-Up Period will follow the completion of the Treatment Period.  
Number of Patients:  
A sample size of approximately 1800 patients assuming 15% dropout rate will be enrolled (randomized) in order to 
obtain approximately 510 completers per arm at 36 weeks.  This sample size provides at least 80% power for 
demonstrating superiority of at least 1 dulaglutide higher dose to dulaglutide 1.5 mg in glycated hemoglobin 
(HbA1c) change from baseline at Week 36.  This assumes a true treatment difference in HbA1c of -0.22% with a 
standard deviation (SD) of 1.1%.
Statistical Analysis:
Efficacy Analyses:
There will be 2 primary estimands to compare the investigational dulaglutide arms (4.5 mg and 3.0 mg) with 
dulaglutide 1.5 mg in terms of the primary measure of HbA1c change from baseline to 36 weeks. One primary 
estimand will be an efficacy estimand (de jure effect) which will use the data collected before initiation of any 
rescue medication or premature treatment discontinuation to demonstrate the effect of treatment and avoid 
confounding effects of other antihyperglycemic agents; the other primary estimand will be a treatment-regimen
estimand (de facto effect) which will include data collected after initiation of other antihyperglycemic therapy and/or 
after premature treatment discontinuation.  The efficacy estimand measures the benefit of treatment when taken as 

Protocol H9X-MC-GBGL 
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directed, and the treatment-regimen estimand measures the benefit of treatment as actually taken (that is, irrespective 
of adherence to investigational product or introduction of other antihyperglycemic therapy). Both estimands will 
use the same primary analysis model and each will be tested at the full significance level of 0.05.  The treatment-
regimen estimand is included as primary at the request of the US Food and Drug Administration (FDA).  The 
efficacy estimand will be considered primary for all other purposes.  The primary analysis model for HbA1c will be 
a mixed-model for repeated measures (MMRM) using restricted maximum likelihood, with pooled country, 
treatment, visit, and treatment-by-visit as fixed effects, and baseline HbA1c as a covariate. An unstructured 
covariance structure will be used to model the within-patient errors.  The primary analysis model will be repeated 
using all available data from the Per Protocol and Completers populations to check the robustness of the analyses.  
Multiple imputation for missing data within the same treatment arm will be conducted based on data from retrieved 
dropouts. Retrieved dropouts are defined as patients who had their HbA1c value at the Week 36 visit assessed after 
early discontinuation of study drug and/or initiation of rescue  medication. An analysis of covariance (ANCOVA) 
model for the treatment-regimen estimand will be fit to the complete datasets, containing the same covariates as the 
primary analysis, by removing the visit-related terms. 
Analyses of other continuous secondary efficacy measures will be performed using MMRM in the Intent-to-Treat 
(ITT) Population. For percentages of patients achieving target HbA1c <7.0%, longitudinal logistic regression with 
repeated measures will be conducted.
The primary and key secondary analyses will follow a graphical approach for multiple comparisons to strongly 
control the overall Type 1 error rate in the trial at a 2-sided alpha of 0.05.  
Safety Analyses:
Summary statistics will be provided for incidence of treatment-emergent adverse events (TEAEs), serious adverse 
events (SAEs), and study discontinuation due to adverse events (AEs) or death during the Treatment Period. Counts 
and proportions of patients experiencing AEs will be reported for each treatment group, and Fisher’s exact test will 
be used to compare the treatment groups.
For continuous laboratory analytes, the change from baseline to endpoint will be analyzed using an analysis of 
variance (ANOVA) on the rank-transformed data, with treatment as a fixed effect. Last observation carried forward 
(LOCF) will be used to impute missing postbaseline values. For qualitative laboratory analytes, counts and 
percentages of patients with normal and abnormal values will be analyzed using Fisher’s exact test.
Treatment differences in incidence of hypoglycemic episodes will be assessed by Fisher’s exact test. Treatment 
differences in rates of hypoglycemic episodes may be assessed by a likelihood-based approach for repeated 
measures with negative binomial distribution if data warrant; otherwise, the Wilcoxon rank-sum test will be used.

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2. Schedule of Activities
Screening 
and Lead-In
Treatment Period
Safety 
Follow-Up
Visit
1
2
3
4
5
6
7
8
9
10
11
ETa
801
Week of Treatment
-2
-1
1
4
8
12
18
26
36
44
52
56
Allowable Deviation (Days)b
±3
±3
±3
±3
±3
±7
±7
±7
±7
±7
±7
Informed consent
X
Randomizationc
X
Clinical Assessments
Medical History (General)
X
CV risk factor history
X
Gallbladder disease history
X
Physical
X
Height
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs (3 sitting BP and PR measurements)d
X
X
X
X
X
X
X
X
X
X
X
X
Electrocardiogram
X
Xe
X
Xe
Xe
Xe
Xe
Adverse events
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
Review/record hypoglycemic events
X
X
X
X
X
X
X
X
X
X
X
Remind patients about 6-point SMPG
X
X
X
Record 6-point SMPG valuesf                                                      
X
X
X
Xg
Patient summary
X
X
X
Patient Education and Management
Dispense study diary, instruct in use
X
X
X
X
X
X
X
Review study diary
X
X
X
X
X
X
X
X
X
X
X
Return study diary
X
X
X
X
X
X
X
X
Diabetes management educationh
X
Dispense PG meter/supplies
X
X
X
X
X
X
X
X
X
X
PG meter, SMPG trainingh
X
X
Review SMPG values
X
X
X
X
X
X
X
X
X
X
X
Injection trainingh
X
X
Dispense study drugs and/or injection supplies
X
X
X
X
X
X
X
X

Protocol H9X-MC-GBGL 
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Schedule of Activities
Screening 
and Lead-In
Treatment Period
Safety 
Follow-Up
Visit
1
2
3
4
5
6
7
8
9
10
11
ETa
801
Week of Treatment
-2
-1
1
4
8
12
18
26
36
44
52
ET
56
Allowable Deviation (Days)b
±3
±3
±3
±3
±3
±7
±7
±7
±7
±7
±7
Patient Education and Management (concluded)
Observe patient inject study drugi
X
Patient returns study drugs and/or injection supplies
X
X
X
X
X
X
X
X
X
Assess study drug compliance
X
X
X
X
X
X
X
X
X
Laboratory Tests
Serum pregnancy testk
X
Urine pregnancy testl
X
X
X
X
Follicle-stimulating hormone testm
X
Chemistry panel 
X
X
X
X
X
Lipid panel (fasting)n
X
X
X
X
Urinalysis
X
X
X
X
Albumin/creatinine ratio (urine)o
X
X
X
X
eGFR (CKD-EPI)p
X
X
X
X
X
Cystatin C
X
X
X
X
Hematology
X
X
X
X
Immunogenicity
X
X
X
X
X
X
X
Pancreatic amylase, lipase
X
X
X
X
X
X
Calcitonin
X
X
X
X
X
HbA1c
X
X
X
X
X
X
X
X
X
Glucose (fasting)n
X
X
X
X
X
X
X
X
Serum insulin (fasting)n
X
X
X
X
C-peptide
X
X
X
X
Plasma glucagon (fasting)n,q
X
X
X
X
Pharmacogenetic (stored sample)
Xr
Nonpharmacogenetic biomarker (plasma and serum)
(stored sample)
X
X
X
X
PK Samples
PK sampless
X
X
X
X
X
X

Protocol H9X-MC-GBGL 
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Schedule of Activities 
Abbreviations:  BP = blood pressure; CKD-EPI = Chronic Kidney Disease-Epidemiology Collaboration equation; CV = cardiovascular; ECG = 
electrocardiogram; eGFR = estimated glomerular filtration rate; ET = early termination; HbA1c = hemoglobin A1c; OAM = oral antihyperglycemic 
medication; PG = plasma glucose; PK = pharmacokinetic; PR = pulse rate; PRO = Patient-Reported Outcomes; SMPG = self-monitored plasma glucose.
a
Patients who are unable or unwilling to continue in the study for any reason will perform an ET 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 performed as an ET visit.  
Visit 801 (Safety Follow-Up Visit) should be performed 4 weeks after the ET visit as the final study 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
Vital sign measurements should be taken before obtaining an ECG tracing and before collection of blood samples for laboratory testing, at visits where 
required.  The participant should sit quietly for 5 minutes before vital sign measurements are taken.  For each parameter, 3 measurements will be taken using 
the same arm; the recordings should be taken at least 1 minute apart.
e
Electrocardiograms occurring on visits with PK collection should be collected at least 30 minutes prior to obtaining the sample for PK measurement.
f
6-point SMPG consists of measurements before and 2 hours after each of 3 main meals within the same day.  These SMPG profiles will be collected by the 
patient within 1 week prior to the assigned visits.  If 6-point SMPG is not performed, then data from 4-point SMPG can be used.
g If performed prior to visit; if 6-point SMPG is not performed, then data from 4-point SMPG can be used.
h All training should be repeated as needed to ensure patient compliance.
i
Patients should administer their first dose of study drug at the end of this visit, after other study procedures and randomization.  
j
Study drug compliance will be reviewed at every visit between Visit 4 and Visit 11.
k A serum pregnancy test will be performed at Visit 1 for women of childbearing potential only.  
Screening 
and Lead-In
Treatment Period
Safety 
Follow-Up
Visit
1
2
3
4
5
6
7
8
9
10
11
ETa
801
Week of Treatment
-2
-1
1
4
8
12
18
26
36
44
52
ET
56
Allowable Deviation (Days)b
±3
±3
±3
±3
±3
±7
±7
±7
±7
±7
±7
PRO Questionnaires (Health Economics)
Diabetes Injection Device Experience Questionnaire 
(DID-EQ)
X
Xt
EQ-5D-5L
X
X
X
X
Impact of Weight on Self-Perceptions Questionnaire
(IW-SP)
X
X
X
X
Ability to Perform Physical Activities of Daily Living 
Questionnaire (APPADL)
X
X
X
X

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Schedule of Activities
l
A urine pregnancy test will be performed at Visit 3, with the result available prior to randomization and first injection of study drug, and at additional visits as 
shown in the schedule, for women of childbearing potential only.  Additional pregnancy tests may be performed at the investigator’s discretion or if required 
per local regulations and/or institutional guidelines during the study.  
m Follicle-stimulating hormone test will be collected 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 (unless specified otherwise by local regulatory 
requirements).  After Visit 1, additional tests may be performed at the investigator’s discretion during the study.
n For Visit 3, Visit 5, Visit 6, Visit 8, Visit 9, Visit 11, 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).
o Urinary albumin and creatinine will be measured and the ratio will be calculated.
p The CKD-EPI equation will be used by the central laboratory to compute and report eGFR. Values that are <30 mL/min/1.73 m2 at Visit 1 will be required to
be retested at Visit 2. If the highest of the 2 values is lower than <30 mL/min/1.73 m2 (or lower than the cutoff value for discontinuation of metformin per 
country-specific label), the patient will be discontinued from the trial prior to randomization. After randomization (Visit 3), values that would require clinical 
action per protocol or country-specific label must be first confirmed on a retest before any treatment adjustment is implemented.
q Samples should be collected in P800 tube.  Aliquot samples, 1 for glucagon and the remainder for nonpharmacogenetic biomarker.
r
The pharmacogenetic sample should be collected at Visit 3, or at the earliest visit after obtaining local approval.
s
The PK sample should be collected within 30 min after the ECG is obtained on the visits where this procedure is also performed (Visits 6, 9, 11, ET, and 801).  
At Visit 4, the PK sample can be collected at any time during the clinic visit.  The date and time of administration of all dulaglutide doses, and in particular 
the last dulaglutide dose administered prior to each PK sample, together with the date and time of the PK sample, must be clearly recorded.  
t  DID-EQ will be administered at the ET visit only if ET occurs at or before Week 12 (before Visit 6).  

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3. Introduction
3.1.
Study Rationale
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 type 2 diabetes (T2D).  Treatment of patients with T2D with dulaglutide 
results in significant reductions in glycated hemoglobin (HbA1c) with low risk of hypoglycemia, 
and reductions in body weight. 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 the European Union in 2014 (Trulicity US Package Insert [USPI], Summary of 
Product Characteristics [SmPC]).  
While therapy with currently approved doses of dulaglutide enabled the majority of patients
included in the Phase 3 program to attain their glycemic targets (sometimes with use of other 
concomitant medications for T2D), 30%-50% of patients receiving approved therapies today,
including dulaglutide, are not reaching glycemic control goals (Stark Casagrande et al. 2013; 
Jendle et al. 2016).  Therefore, there remains an important medical need to provide enhanced 
efficacy of pharmaceutical agents while also preserving an overall acceptable benefit/risk profile.
3.2.
Background
Pharmacokinetic (PK)/pharmacodynamics (PD) modeling from original Phase 1-2 dulaglutide 
studies suggested a dose-dependent incremental benefit with dulaglutide versus currently 
approved doses on HbA1c and body weight reduction.  Phase 2 Study H9X-MC-GBGJ (GBGJ) 
was recently conducted to assess the safety and efficacy of once weekly dulaglutide 3.0 mg and 
4.5 mg in comparison to placebo in 317 patients with T2D treated with metformin monotherapy, 
with exploratory comparisons to dulaglutide 1.5 mg (the highest dose approved by regulatory 
agencies).  Data from Study GBGJ provided evidence for incremental efficacy of these higher 
doses of dulaglutide versus 1.5 mg once weekly on glycemic control and body weight reduction, 
particularly at higher baseline HbA1c levels, with an acceptable tolerability and safety profile at 
both higher doses.  The trial results also suggested stepwise titration of dulaglutide dose was 
associated with acceptable tolerability of the 2 higher doses.
Further study of higher doses of dulaglutide also was assessed in context with prior dose-finding 
studies. The currently approved dulaglutide doses (0.75 mg and 1.5 mg once weekly) were 
selected in the Phase 2/3 Study H9X-MC-GBCF (GBCF), which initially included doses up to
3.0 mg once weekly (Skrivanek et al. 2014).  The purpose of the first stage of Study GBCF was 
to identify an optimal dose using prespecified measures of efficacy (HbA1c and weight) and 
safety (diastolic blood pressure [DBP] and heart rate [HR]).  Following a number of interim data 
reviews, the Data Monitoring Committee (DMC) recommended discontinuing the dulaglutide 
3.0 mg dose because of higher incidence in pancreatic enzyme values above upper limit of 
normal (ULN) (with or without abdominal pain or suspected pancreatitis), increases in HR, and 
higher incidence of gastrointestinal (GI) adverse events (AEs) (Skrivanek et al. 2014). 

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Since original dose selection and subsequent approval of dulaglutide, additional data have 
provided a better understanding of the clinical significance of the findings which prompted the 
DMC to terminate the 3.0 mg dose in Study GBCF.  Elevations in pancreatic enzymes associated 
with GLP-1 RA treatment have not been associated with adverse clinical outcomes based on the 
results of adjudication (Nauck et al. 2017; Steinberg et al. 2017a; Steinberg et al. 2017b), and the
risk of adjudicated pancreatitis and investigator-reported pancreatitis in patients treated with 
dulaglutide was similar to the risk observed with nonincretin comparators in dulaglutide 
registration trials (Nauck et al. 2017).  Heart rate elevations are now recognized to be a class 
effect common to all GLP-1 RAs (Lorenz et al. 2017).  Despite increases in HR, completed
cardiovascular (CV) outcome trials for GLP-1 RAs have shown either neutral to favorable 
effects on the risk of major CV events compared to placebo in patients with T2D and high CV 
risk (Pfeffer et al. 2015; Marso et al. 2016a; Marso et al. 2016b; Holman et al. 2017).  Finally, it
is now understood that a slow, stepwise dose titration of weekly GLP-1 RAs upon initiation can 
attenuate the occurrence and severity of GIAEs at higher doses, providing for greater glucose-
lowering effects and more robust body weight reduction (Nauck et al. 2016).  
Thus, based on the limited amount of efficacy data available for higher dulaglutide doses, the 
promising results of Phase 2 Study GBGJ, and considering the updated understanding of the 
benefit/risk profile of GLP-1 RAs as a class, a re-evaluation of the optimal weekly dose of 
dulaglutide for glycemic control was deemed warranted.  The purpose of this Phase 3 study 
(H9X-MC-GBGL [GBGL]) is to assess the safety and efficacy of once weekly dulaglutide 
3.0 mg and 4.5 mg in comparison to dulaglutide 1.5 mg.  The overall goal of the Phase 3 
program is to gain regulatory approval for inclusion of at least 1 higher doses in the Trulicity 
label for treatment of patients with T2D who require additional glucose lowering to obtain 
glycemic targets, to be administered using the same device as that used for currently approved 
doses of 0.75 mg and 1.5 mg (single-dose pen [SDP]).  
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 Investigator’s Brochure (IB).
In addition, detailed information about the known and expected benefits and risks of dulaglutide 
may be found in the Trulicity USPI (2017 [WWW]) and SmPC (2017 [WWW]).

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4.
Objectives and Endpoints
Table GBGL.1 presents the objectives and endpoints of the study.
Table GBGL.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To demonstrate that once weekly dulaglutide 4.5 mg 
and/or 3.0 mg is superior to dulaglutide 1.5 mg for
change from baseline in HbA1c at 36 weeks in patients 
with inadequately controlled T2D on concomitant 
metformin therapy.

The change in HbA1c from baseline 
Secondary
Efficacy:
To demonstrate that once weekly dulaglutide 4.5 mg 
and/or 3.0 mg is superior to dulaglutide 1.5 mg for 
secondary efficacy parameters at 36 weeks (controlled 
for Type 1 error).
Safety:
To compare each investigational dulaglutide arm 
(4.5 mg, 3.0 mg) to the 1.5 mg arm for selected safety 
parameters through 36 and 52 weeks (unless noted 
otherwise)
Pharmacokinetics (PK) and Pharmacodynamics (PD):
To characterize dulaglutide PK and the dose and/or 
exposure-response relationships for key efficacy (eg, 
HbA1c and weight), and safety (eg, heart rate [HR]) 
endpoints.

The change in body weight from baseline

Proportion of patients achieving HbA1c target 
<7.0% (53 mmol/mol) 

The change in fasting serum glucose (FSG) 
from baseline 

Incidence of treatment-emergent adverse events 
(TEAEs) and discontinuation of study drug due 
to adverse events (AEs)

Adjudicated and confirmed cardiovascular and 
pancreatic AEs

Incidence of thyroid neoplasm AEs

Incidence of treatment-emergent (TE) 
dulaglutide anti-drug antibodies (ADA) and 
systemic hypersensitivity reactions

Change from baseline in pulse rate (PR)

Electrocardiogram (ECG) parameters

Occurrence of hypoglycemic episodes 

PK parameters (eg, maximum concentration 
[Cmax], area under the curve [AUC]) at steady 
state

Pharmacodynamic evaluations may include 
changes from baseline in HbA1c, body weight, 
and heart rate at Weeks 36 and 52
Tertiary/Exploratory
To compare once weekly dulaglutide 4.5 mg and 3.0 mg 
to the 1.5 mg arm as measured by the primary and 
secondary outcome measures at 52 weeks.

The change in HbA1c from baseline 

The change in body weight from baseline

Proportion of patients achieving HbA1c target 

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Objectives
Endpoints
To compare once weekly dulaglutide 4.5 mg and 3.0 mg 
to the 1.5 mg arm for exploratory measures through 36 
and 52 weeks (unless noted otherwise).
<7.0% (53 mmol/mol) 

The change in FSG from baseline

Proportion of patients achieving HbA1c target
≤6.5% (48 mmol/mol)

Change from baseline in 6-point self-monitored 
plasma glucose (SMPG) profile

Proportion of patients achieving ≥5% body 
weight loss

Proportion of patients achieving ≥10% body 
weight loss

Proportion of patients meeting the composite 
endpoint of HbA1c <7.0% (53 mmol/mol), no 
weight gain, and no documented symptomatic 
or severe hypoglycemia

Proportion of patients meeting the composite 
endpoint of HbA1c <7.0% (53 mmol/mol), 
body weight loss ≥5%, and no documented 
symptomatic or severe hypoglycemia

Changes from baseline in fasting plasma 
glucagon, HOMA2-%B, HOMA2-IR, and 
C-peptide

Changes from baseline in serum cystatin C and 
cystatin C-based assessment of eGFR

Incidence of initiation of rescue therapy for 
severe, persistent hyperglycemia

Changes from baseline in systolic blood 
pressure (SBP), diastolic blood pressure (DBP), 
and rate pressure product (RPP)

Changes from baseline in serum lipid 
parameters (total cholesterol, high density 
lipoproteins [HDL], low density, lipoproteins 
[LDL], very low density lipoproteins [VLDL], 
and triglycerides)

Diabetes Injection Device Experience 
Questionnaire (DID-EQ) scores at Week 12

Changes from baseline in EQ-5D-5L scores

Changes from baseline in Impact of Weight on 
Self-Perception Questionnaire (IW-SP) scores

Changes from baseline in Ability to Perform 
Physical Activities of Daily Living (APPADL)
scores

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Abbreviations:  eGFR = estimated glomerular filtration rate; HbA1c = glycated hemoglobin A1c; HOMA2-%B = 
-cell function as measured by the Homeostasis Model Assessment-2 method; HOMA2-IR = insulin resistance 
as measured by the HOMA2 method; T2D = type 2 diabetes.

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5. Study Design
5.1.
Overall Design
Study H9X-MC-GBGL (GBGL) is a 52-week, Phase 3, double-blind, multicenter, parallel-arm 
study.  The study is designed to assess the efficacy and safety of once weekly dulaglutide 3.0 mg 
and 4.5 mg in comparison to once weekly dulaglutide 1.5 mg following a primary 36-week 
treatment period and at the end of the 52-week Treatment Period.  The primary objective of this 
trial is to demonstrate that once weekly dulaglutide 4.5 mg and/or 3.0 mg is superior to 
dulaglutide 1.5 mg as measured by change from baseline in HbA1c at Week 36 in patients with 
T2D who are inadequately controlled on concomitant metformin therapy (see Section 4).  
Secondary objectives (controlled for Type 1 error) are to demonstrate superiority of at least 1 of 
the higher dulaglutide doses to dulaglutide 1.5 mg at Week 36 on changes in body weight, 
proportions of patients achieving HbA1c <7.0% (53 mmol/mol), and changes in fasting serum 
glucose (FSG) from baseline at Week 36.
The study will consist of 3 periods:  an approximately 2-week Lead-In Period followed by a
52-week Treatment Period (primary efficacy endpoint at Week 36) and a 4-week Safety 
Follow-Up Period.  
Figure GBGL.1 illustrates the study design.
Abbreviations:  DBL = database lock; dula = once weekly dulaglutide.
Note:  all dulaglutide doses are once weekly.
Figure GBGL.1.
Illustration of study design for Clinical Protocol H9X-MC-GBGL.

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Study Period I (Screening and Lead-In):  
Screening (Visit 1)
The purpose of screening procedures at Visit 1 is to establish initial eligibility 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 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).  If patients develop a condition that is a contraindication for the use of 
metformin or initiate other agents that are prohibited 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.  
Study Period II (Treatment Period):
Randomization (Visit 3)
At Visit 3, patients will perform all required baseline study procedures (including the collection 
of all baseline laboratory measures) prior to randomization and prior to taking the first dose of 
study drug.  Patients who continue to be eligible will then be randomized in a 1:1:1 ratio to 1 of 
the treatment arms:  (1) dulaglutide 4.5 mg, (2) dulaglutide 3.0 mg, or (3) dulaglutide 1.5 mg.  
Immediately after randomization, the patient will inject the first dose of study drug at the study 
site, according to the dose escalation regimen described below.  The date and time of the first 
dose of study drug should be recorded on the electronic case report form (eCRF).
Following randomization, patients will participate in a 52-week Treatment Period.  
Postrandomization Treatment Period (end of Visit 3 to Visit 11)
Beginning at randomization, all patients will receive dulaglutide 0.75 mg once weekly for 
4 weeks (Weeks 1-4), followed by dulaglutide 1.5 mg once weekly for 4 weeks (Weeks 5-8). At 
Week 8 the dosing will diverge based on the randomized treatment arm:

Dulaglutide 1.5 mg arm: Patients will continue to receive dulaglutide 1.5 mg once 
weekly for the remainder of the treatment period.

Dulaglutide 3.0 mg arm:  Patients will receive dulaglutide 3.0 mg once weekly for the 
remainder of the treatment period.

Dulaglutide 4.5 mg arm:  Patients will receive dulaglutide 3.0 mg once weekly for 
4 weeks (Weeks 9-12), and then escalate to dulaglutide 4.5 mg once weekly for the 
remainder of the treatment period.

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Study Period III (Safety Follow-Up Period):
Safety Follow-Up (Visit 801) Visits:  All patients who complete the treatment period are required 
to complete Visit 801, a safety follow-up visit approximately 4 weeks after their last visit.  
Patients discontinuing the study early and performing an early termination (ET) visit will also be 
asked to perform the safety follow-up visit, so that the safety follow-up visit will be their final 
visit. During the Safety Follow-Up Period, patients will not receive study drug.  Patients will be 
treated with another glucose-lowering intervention decided upon by the investigator.  Glucagon-
like peptide-1 RAs (eg, exenatide, liraglutide, or commercial Trulicity) and dipeptidyl peptidase-
4 (DPP-4) inhibitors are not allowed during this period.  Initiation of new antihyperglycemic 
therapy for the Safety Follow-Up Period will not be classified as “rescue therapy” 
(Section 7.7.1.2).  All antihyperglycemic medications will be entered on the eCRF specified for 
this purpose.  Patients are also required to return any remaining study diaries to the study site at 
the end of this period.
Study Procedures
Patients will perform study procedures listed in the Schedule of Activities (Section 2).  
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-monitored plasma glucose (SMPG) measurements (consisting of fasting, 
prelunch, predinner, and bedtime plasma glucose [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.  Data from the 6-point profiles 
will be entered into the eCRF as shown on the Schedule of Activities (Section 2).  In the event 
that a 6-point SMPG profile is not collected as required, then data from the 4-point SMPG 
collected during the week preceding the required visit may be entered in the eCRF instead.
Patients who develop severe, persistent hyperglycemia based on prespecified thresholds (see 
Section 7.7.5.3) will receive a new glucose-lowering intervention (“rescue therapy”) as outlined 
Section 7.7.1.2 and will also continue to administer study drug.  Patients who need 
hyperglycemic rescue therapy will continue in the trial until they complete all study visits.  
Patients who permanently discontinue study drug prior to the Safety Follow-Up Period will also 
be required to continue in the trial and should receive a new glucose-lowering intervention
(Section 7.7.1.2).  

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Every attempt will be made to keep patients in the trial irrespective of their adherence to 
treatment with study drug.  An ET visit will be conducted for patients who are to be discontinued 
from the study early (after completing Visit 3 [randomization] and before completing the entire 
52-week treatment period).  If the patient is discontinued during an unscheduled visit, that visit 
should be performed as the ET visit.  If the patient is discontinued during a scheduled visit, that 
visit should be performed as the ET visit.  In either case, ET visit procedures will be performed 
according to the Schedule of Activities (Section 2).  Patients should be instructed to return any 
remaining used or unused study drug supplies and patient diaries to the study site at this visit.  
Study treatment will be terminated at this visit (if not already terminated).  Patients will be asked 
to perform the Safety Follow-Up visit (Visit 801) approximately 30 days after the ET visit, so 
that the Safety Follow-Up visit will be their final visit.  If the patient is not able to perform the 
Safety Follow-Up visit, then the ET visit will be the final study visit.  
Study governance considerations are described in detail in Appendix 3.
5.2.
Number of Participants
Approximately 3000 participants will be screened to achieve approximately 1800 randomized
patients and approximately 1530 patients completing Week 36 (for an estimated total of 
510 patients completing Week 36 per treatment group).
5.3.
End of Study Definition
End of the trial is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last patient.
5.4.
Scientific Rationale for Study Design
Study GBGL utilizes the parallel 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 study is designed to determine the comparative benefits and 
risks of once weekly dulaglutide 3.0 mg or 4.5 mg versus once weekly dulaglutide 1.5 mg in 
patients with T2D who cannot maintain glycemic control with metformin alone. To minimize 
the potential confounding effect of changes to concomitant metformin, patients will be expected 
to maintain metformin throughout the treatment period until the last dose of randomized 
treatment, other than for the situations described in Section 7.7.1.1.
The planned duration of treatment for the primary endpoint at 36 weeks is considered appropriate 
to assess the full effects and benefit/risk of higher doses of dulaglutide compared with the 
dulaglutide 1.5 mg dose on both glycemic control and body weight. While the full effect of 
randomized treatments on PG is expected after approximately 8-12 weeks of therapy and on 
HbA1c after approximately 12-24 weeks (Jendle et al. 2016), a minimum of 26-30 weeks are 
required to assure maximal effects of dulaglutide on the key secondary outcome of body weight
(Davies et al. 2015; Ahrén et al. 2017).  The full treatment duration of 52 weeks will allow for 
collection of additional exposure data to monitor efficacy and safety.  

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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 H9X-MC-
GBCD (GBCD) and GBCF (Barrington et al. 2011; Skrivanek et al. 2014) and evidence for 
incremental increases in efficacy for both glycemic control and body weight reduction, with an 
acceptable safety and tolerability profile, from Study GBGJ.  Further details and the rationale for 
the choice of the doses and dose escalation regimens are provided in Section 5.5.
Dulaglutide 1.5 mg is included as the active comparator because it is the maximum approved 
dose and will enable comparison of efficacy and safety data of higher investigational doses 
collected under similar conditions.  A placebo comparator was not included because it was not 
considered necessary for addressing the primary or secondary objectives of the trial.  Moreover, 
maintaining patients with inadequate glycemic control on metformin monotherapy, particularly
those with relatively poor glycemic control at entry (HbA1c ≥9.0% [75 mmol/mol]), would not 
be consistent with current recommendations provided in a position statement of the American 
Diabetes Association and the European Association for the Study of Diabetes (Inzucchi et al. 
2015).
5.5.
Justification for Dose and Dose Escalation Regimen
The investigational dulaglutide doses (3.0 mg and 4.5 mg) were selected considering adequate 
separation in PK exposure range between the doses and 1.5 mg to enable evaluation of their 
efficacy and adverse effect profiles.  Ratios of mean area under concentration-time curve (AUC)
for 3.0 mg/4.5 mg doses to 1.5 mg dose are 2.26 and 3.10, respectively. The steady-state mean 
AUC and 90% confidence intervals (CIs) for the 1.5 mg, 3.0 mg, and 4.5 mg doses are 11,800 
(5300, 21,300), 26,700 (15,300, 41,400), and 36,600 (21,100, 56,500) ng.h/mL, respectively.
Therefore, the ratio of mean AUC for 4.5 mg to 3.0 mg is anticipated to be 1.37.  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.
Data from Phase 2 Study GBGJ provided evidence for incremental efficacy of dulaglutide 
3.0 mg and 4.5 mg once weekly versus 1.5 mg once weekly on glycemic control and body 
weight reduction.  After 18 weeks of treatment (analysis of on-treatment data without rescue), 
the estimated treatment differences in HbA1c reduction with 3.0 mg and 4.5 mg once weekly 
relative to 1.5 mg once weekly were -0.22% and -0.26%, respectively.  Larger differences were 
observed in subgroups of patients with higher baseline HbA1c (ie, ≥8.5% [69 mmol/mol] vs. 
<8.5% [69 mmol/mol]).  Dulaglutide 3.0 mg and 4.5 mg once weekly also provided for 
additional body weight reduction over the 1.5 mg dose that exceeded 1 kg at Week 18, with 
further weight reduction expected with longer durations of treatment.  Although the effects of
dulaglutide 4.5 mg were generally greater than the effects of the 3.0 mg dose on measures of 
glycemic control and body weight, a larger study is required to fully characterize the benefit/risk 
profile of each higher dulaglutide dose compared with the 1.5 mg dose over a longer duration of 
treatment.

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The dose escalation regimens used for the investigational doses were designed based on 
evaluation of the algorithms tested in Phase 2 Study GBGJ.  While overall tolerability as 
measured by study drug discontinuations due to AE was comparable between the algorithms, 
initiating dose escalation at 0.75 mg once weekly generally resulted in a lower overall incidence 
of GI events.  Pharmacokinetic/PD exposure-response modeling of Study GBGJ data also 
predicted that the daily incidence of nausea and vomiting at higher dulaglutide doses would be 
lowest in algorithms starting at the lower 0.75 mg dose with a slower dose escalation over an 
8-week period, allowing adequate time for tolerance to develop.  Based on these findings, the 
starting dose for all patients in the current study will be 0.75 mg once weekly followed by 1.5 mg 
once weekly, with a 4-week interval for each dose.  Patients will then either remain on 1.5 mg 
once weekly or escalate to their final assigned dose as shown in Figure GBGL.1 and Table 
GBGL.2.

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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 where indicated).  
Type of Patient and Disease Characteristics
[1] Patients with T2D for ≥6 months according to the World Health 
Organization (WHO) classification (Appendix 5) or other locally applicable 
diagnostic standards, treated with stable doses of metformin (as defined in 
[4] below) for at least 3 months.
Patient Characteristics
[2] men or nonpregnant women aged ≥18 years;
[3] have HbA1c ≥7.5% (58 mmol/mol) and ≤11.0% (97 mmol/mol), inclusive, 
as assessed by the central laboratory;
[4] 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 or a documented 
estimated glomerular filtration rate (eGFR; measured by the Chronic 
Kidney Disease-Epidemiology Collaboration equation [CKD-EPI]) or other 
renal function measure which requires lower doses per country-specific 
labeling;
[5] stable body weight for at least 3 months prior to Visit 1 (not changed by 
more than 5% in the past 3 months);
[6] have a body mass index (BMI) ≥25 kg/m2;  
[7] 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 (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 finger stick PG monitoring at least once daily every day and up to 
6 times one day per week at designated times throughout the trial (see 
Schedule of Activities [Section 2]);

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[c] maintain a study diary as required for this protocol;
[8] women of childbearing potential participating must agree to remain 
abstinent (complete abstinence, as their preferred and usual lifestyle) or in a 
same sex relationship without sexual relationships with males (as part of 
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.  Periodic abstinence (eg, calendar, 
ovulation, symptothermal, postovulation methods), declaration of 
abstinence just for the duration of a trial, and withdrawal are not acceptable 
methods of contraception.
[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).  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.
[9] 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 (or longer if required by local regulatory 
requirements) 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

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iii. A woman at least 55 years of age with a diagnosis of menopause prior 
to starting hormone replacement therapy.
[10] no male contraception is required except in compliance with specific local 
government study requirements;
Informed Consent
[11] 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:
Medical Conditions
[12] have type 1 diabetes (T1D);
[13] have a history of ≥1 episode of ketoacidosis or hyperosmolar state/coma;
[14] have had ≥1 episode of severe hypoglycemia and/or ≥1 episode of 
hypoglycemia unawareness within the last 6 months;
[15] have had any of the following CV conditions within 2 months prior to 
Visit 1:  acute myocardial infarction (MI), New York Heart Association 
Class III or Class IV heart failure, or cerebrovascular accident (stroke);
[16] 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®) or chronically take drugs that directly reduce 
gastrointestinal motility;
[17] 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;
[18] have had chronic or acute pancreatitis any time prior to study entry;
[19] have an eGFR <30 mL/min/1.73 m2 (or lower than the country-specific 
threshold for discontinuing metformin therapy per local label), calculated 
by CKD-EPI, as determined by the central laboratory at Visit 1 and 
confirmed at Visit 2;
[20] have a personal or family history of medullary thyroid carcinoma (MTC) 
or personal history of multiple endocrine neoplasia syndrome type 2;

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[21] have serum calcitonin ≥20 ng/L, as determined by the central laboratory at 
study entry;
[22] have evidence of significant, active autoimmune abnormality (eg, lupus, 
rheumatoid arthritis) that, in the opinion of the investigator, is likely to 
require concurrent treatment with systemic glucocorticoids in the next 
12 months;
[23] 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;
[24] 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;
[25] have any hematologic condition that may interfere with HbA1c 
measurement (eg, hemolytic anemias, sickle-cell disease);
[26] known proliferative retinopathy or maculopathy requiring acute treatment
according to the opinion of the investigator;
Prior/Concomitant Therapy
[27] have used any GLP-1 RAs (including investigational agents with GLP-1 
RA activity) or insulin at any time in the past, except for short-term (≤14 
consecutive days) use of insulin for acute conditions;
[28] have used any other glucose-lowering medications other than metformin 
(including insulin) 3 months prior to study entry or during the 
Screening/Lead-In Periods;
[29] have been treated with any other excluded medication (Section 7.7) 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;
[30] 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;
[31] discontinuation of metformin therapy, or change in metformin dose or 
formulation, between Visit 1 and Visit 3;
[32] have been treated with prescription or OTC drugs that promote weight loss 
(Table GBGL.3) within 3 months prior to screening (Visit 1) and/or 
between study entry and randomization (Visit 3); or current (or within the 
last 3 months) participation in, or planned intent to initiate within timeframe 
of the study, an organized diet and/or exercise weight reduction program
other than the lifestyle and dietary measures for diabetes treatment;

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Prior/Concurrent Clinical Trial Experience
[33] are currently enrolled in any other clinical study involving an 
investigational product or any other type of medical research judged not to 
be scientifically or medically compatible with this study;
[34] 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;
[35] have previously completed or withdrawn from this study or any other 
study investigating dulaglutide;
Other Exclusions
[36] 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;
[37] are Lilly employees;
[38] have any other conditions (including known drug or alcohol abuse or 
psychiatric disorder) or circumstances (including known or anticipated 
plans for relocation or extended travel) that may preclude the patient from 
following the protocol and completing the study.
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.  Per Exclusion Criterion [32]
(Section 6.2), patients should not initiate during the study an organized diet and/or exercise 
weight reduction program other than the lifestyle and dietary measures for diabetes treatment.
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
Patients will be randomized in a 1:1:1 ratio to 1 of 3 treatment arms:  dulaglutide 1.5 mg, 
dulaglutide 3.0 mg, or dulaglutide 4.5 mg, each administered once weekly as subcutaneous 
injection in patients with T2D who are already treated with a stable dose of metformin.  
Table GBGL.2 shows the randomized treatments for the entire treatment period.
All patients in the study will initiate treatment with dulaglutide 0.75 mg once weekly for 4 weeks 
(Weeks 1 – 4) and will then receive dulaglutide 1.5 mg once weekly for 4 weeks (Weeks 5 – 8).  
Patients assigned to the dulaglutide 1.5 mg group will receive that dose once weekly from 
Weeks 9 through 52.  Patients assigned to the dulaglutide 3.0 mg group will receive that dose 
once weekly from Weeks 9 through 52.  Patients assigned to the dulaglutide 4.5 mg group will 
receive dulaglutide 3.0 mg once weekly for 4 weeks (Weeks 9 – 12) followed by dulaglutide 
4.5 mg once weekly for the remainder of the treatment period (Weeks 13 – 52).
Single-dose pens will be used to administer randomized dulaglutide doses and the interim doses 
during dose escalation.  No study drug treatment will be administered during the 4-week Safety 
Follow-Up Period.  
Table GBGL.2.
Study Treatments (Weeks 1-52)
Note: All doses will be administered once weekly using single-dose pens.
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
Treatment 
Group
Treatment Period Interval
Weeks 
1 – 4
Weeks 
5 – 8
Weeks
9 - 12
Weeks 
13 – 52
4.5 mg 
Dulaglutide
0.75 mg
1.5 mg
3.0 mg
4.5 mg
3.0 mg 
Dulaglutide
0.75 mg
1.5 mg
3.0 mg
1.5 mg
Dulaglutide
0.75 mg
1.5 mg
1.5 mg

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
maintaining accurate records of study drug dispensing and collection, as well as 
records of interruptions in study drug administration

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 
SDPs in a closeable, puncture-resistant container, and dispose according to local 
regulations.  Sites may be authorized to destroy used and unused SDPs locally per 
applicable local or national requirements.
7.1.1. Packaging and Labeling
The sponsor will provide dulaglutide in SDPs, which will be dispensed via an interactive web-
response system (IWRS).  Each SDP will be packaged in cartons to be dispensed. Injections are 
to be administered as described in Section 7.2.2.  
Clinical study materials will be labeled according to the country’s regulatory requirements.
7.1.2. Medical Devices
The manufactured medical devices provided for use in the study will be SDPs containing
dulaglutide 0.75 mg (0.5 mL at 1.5 mg/mL), dulaglutide 1.5 mg (0.5 mL at 3.0 mg/mL), 
dulaglutide 3.0 mg (0.5 mL at 6.0 mg/mL), and dulaglutide 4.5 mg (0.5 mL at 9.0 mg/mL).
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 
ratio (dulaglutide 4.5 mg, dulaglutide 3.0 mg, dulaglutide 1.5 mg).  Randomization will be 
stratified by HbA1c (<8.5% [69 mmol/mol], ≥8.5% [69 mmol/mol]).
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), each 
administered once weekly as subcutaneous injection.  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.  Patients will be escalated to their final assigned dose using the regimens outlined in 
Table GBGL.2.  The randomization strategy is described in Section 7.2.  
The assigned doses will not be downtitrated.  Patients with poor tolerability of the study 
treatments will be allowed to discontinue dosing temporarily (Section 8.1.2).  Investigators 
should inform the Sponsor any time study drug is interrupted.  If interruption occurs after 
Week 12, then study drug should be resumed as soon as it is safe to do so.  If interruption occurs 
prior to Week 12 (that is, prior to when the final assigned dose may have been initiated), then the 

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investigator should consult with Lilly on the schedule and method for the resumption of study 
drug, and the approach will be documented.  Patients who interrupt study treatment temporarily 
and are then unable to tolerate it upon rechallenge will be discontinued from study drug and 
should be initiated on new antihyperglycemic medication in accordance with Section 7.7.1.2; 
they should remain in the study and complete all study procedures.
After the administration of study drug in the clinic at Visit 3 (randomization), the patient should 
determine the most convenient day of the week and time of day for subsequent dosing 
throughout the study.  Once determined, it is recommended that patients inject the study drug at 
approximately the same time of day on the same day each week.  The date and time of all study
drug administrations are to be recorded in diaries by the patients.  If the injection is not given on 
the scheduled day, the missed injection 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 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 in the patient’s upper arm.  A new 
SDP will be used for each injection. Subsequent doses should be injected in different regions 
(eg, arm, abdomen, thigh; rotation is encouraged).  If study drug is to always be injected in the 
same body region, patients should be advised to use a different injection site each week.
7.3.
Blinding
This is a double-blind study.  Investigators, site staff, clinical monitors and patients will remain 
blinded to the treatment assignments until the study is complete.  To preserve the blinding of the 
study, the Sponsor will be blinded to treatment assignments until after the primary endpoint 
(Week 36) database lock. The primary endpoint database lock is planned to occur after all 
patients have completed or discontinued the study prior to Visit 9 (Week 36).  
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.
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 
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.

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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.
7.4.
Dosage Modification
No adjustment in study drug doses will be allowed.  Further details about dose administration 
during the study are described in Section 7.2.1 and Section 8.1.2.  
Dosing of required concomitant metformin is discussed in Section 7.7.1.1.
7.5.
Preparation/Handling/Storage/Accountability
The study site must store the SDP cartons in a locked and secure environment.  The SDPs 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 SDPs at 
clinic visits per the Schedule of Activities (Section 2).  They will receive insulated bags with 
cooling gel packs for use in transporting the SDP 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 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 entered in the 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 each visit
interval is defined as taking at least 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) 

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will receive additional training and instructions, as required, but should not be discontinued from 
the study.
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.  Certain categories of medications will be collected with more 
detailed information on specific eCRF pages:

Antihyperglycemic medications used during the study.  This includes:
o
Details on metformin use at screening and any subsequent changes to dose or 
formulation during the study, and
o
Any additional antihyperglycemic medications initiated during the study (eg, for 
hyperglycemic rescue, after permanent study drug discontinuation, or during the 
Safety Follow-Up Period)

Antihypertensive medications (regardless of the specific indication for use)

Glucocorticoid medications
Nonstudy 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 GBGL.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 GBGL.3.
Criteria for Use of Concomitant Medications that May Interfere with 
Efficacy and Safety Assessments 
Abbreviations:  DPP-4 = dipeptidyl peptidase-4; GLP-1 RA = glucagon-like peptide-1 receptor agonist; IP = 
investigational product; 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
Metformin prescreening dose and formulation (short-acting or long-acting) should be maintained throughout the 
study, except as specified in Section 7.7.1.1.  Increasing the metformin dose should not be used as the sole 
intervention for antiglycemic rescue or after premature study drug discontinuation.
7.7.1. Antihyperglycemic Medications
The only glucose-lowering agent allowed 3 months prior to study entry and during the study
(excluding the Safety Follow-Up Period) 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; otherwise, eligible patients must be insulin- and GLP-1 
RA-naive. Patients who receive any glucose-lowering agents other than metformin within the 
3 months prior to entry or during the screening or lead-in/stabilization periods will not be eligible 
for further participation in the trial.
Drug Class
Use during 
Screening/Lead-In
Conditions for Use after Randomization
Acute 
Therapya
Rescue Therapy or Post-IP 
Discontinuation Therapy
Drugs with approved weight loss 
indicationb
Excluded
N
N/A
Systemic glucocorticoid therapyc
Excluded except for 
acute therapya
Y
N/A
Antihyperglycemic medications
Other GLP-1 RAs
Excluded
N
N
DPP-4 inhibitors
Excluded
N
N
SGLT2 inhibitors
Excluded
N
See Section 7.7.1.2
Insulins and insulin mixtures
Excluded except for 
acute therapya
Y
See Section 7.7.1.2
Meglitinides
Excluded
N
See Section 7.7.1.2
Alpha-glucosidase inhibitors
Excluded
N
See Section 7.7.1.2
Sulfonylureas
Excluded
N
See Section 7.7.1.2
Thiazolidinediones
Excluded
N
See Section 7.7.1.2
Metformind
Required
N/A
Ye

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7.7.1.1.
Required Concomitant Antihyperglycemic Medication:  Metformin
The key requirements for the use of metformin, the required oral antihyperglycemic medication
(OAM) in the study, 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, or in cases where lower doses are recommended per country-specific 
labeling due to reduced renal function (for example, eGFR 30 to 45 mL/min/1.73 m2).  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 7.7.5.2.
Dose reduction/discontinuation of metformin during the trial should be properly documented and
recorded on the appropriate eCRF.
Guidance for treatment following the end of the study is provided in Section 7.8.1.
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.  
7.7.1.2.
Initiation of New Antihyperglycemic Medication during the Study  
The introduction of new antihyperglycemic medication is expected during the study only in the
following situations:

As an antihyperglycemic intervention for severe, persistent hyperglycemia (“rescue 
therapy”), as defined in Section 7.7.5.3.

In those patients who require permanent discontinuation of study drug, but remain in the 
study (Section 8.1.1).

During the Safety Follow-Up Period (between Visit 11 [Week 52] or ET and Visit 801).
If a new antihyperglycemic medication is introduced during the Treatment Period (that is, prior 
to Visit 11), the patient should be treated with a locally approved glucose-lowering agent (except 
other GLP-1 RAs including commercial Trulicity and DPP-4 inhibitors) according to the 
following order of preference:

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1. Sodium-glucose co-transporter 2 (SGLT2) inhibitors should be initiated first, unless a 
contraindication is present;
2. If a contraindication to SGLT2 inhibitor is present, then a sulfonylurea or 
thiazolidinedione can be considered;
3. If glycemic control remains inadequate despite introduction of new antihyperglycemic 
medication (eg, after 3 months or within a timeframe determined by the investigator), 
then addition of basal insulin therapy should be considered; if insulin is prescribed as a 
rescue therapy for hyperglycemia or as a new antiglycemic intervention in patients 
requiring study drug discontinuation, it must be differentiated from short-term use of 
insulin therapy for medical emergencies when reported in the eCRF;
4. Initiation of insulin as first rescue intervention for hyperglycemia should be reserved for 
patients with severe, persistent hyperglycemia (Section 7.7.5.3) with an average 
FPG ≥300 mg/dL (16.6 mmol/L), in patients with symptoms of hyperglycemia, or in 
other clinical situations where the investigator believes more rapid glycemic control is 
warranted.
Initiation of other classes of antihyperglycemic medications (for example, meglitinides, alpha-
glucosidase inhibitors) for hyperglycemic rescue or after premature discontinuation of study drug 
is discouraged.  Since patients should already be taking maximally or near maximally tolerated 
doses of metformin, increases in metformin dose should not be used as the sole intervention for 
antiglycemic rescue or after premature study drug discontinuation.
While investigators are strongly encouraged to follow the above guidance for managing patients 
requiring the initiation of new antihyperglycemic medications during the Treatment Period, 
management of these patients is ultimately up to the judgment of the investigator and may be 
dependent on a number of patient- and disease-related factors, patient glycemic response, or 
other clinical factors.  At a minimum, management of these patients should be consistent with 
local standards of care or current guidelines from the American Diabetes Association (2017) and 
the European Association for Study of Diabetes (Inzucchi et al. 2015).
The type of antihyperglycemic medication initiated during the Safety Follow-Up Period (at or 
after Visit 11) (excluding other GLP-1 RAs or DPP-4 inhibitors) can be at the discretion of the 
investigator and does not need to follow the order of preference outlined above.
Initiation of antihyperglycemic medication during the Safety Follow-Up Period (at or after 
Visit 11) or after premature discontinuation of study drug for any reason other than severe, 
persistent hyperglycemia will not be considered rescue therapy.
If any new glucose-lowering medication is initiated after randomization at Visit 3 and prior to 
Visit 11 (end of Treatment Period), other than study drug, rescue therapy, post study drug
discontinuation, 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 consecutive days will 
exclude the patient from the Per-Protocol (PP) Population for analyses.  

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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 
(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 Population 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.
7.7.5. Special Treatment Considerations
7.7.5.1.
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 (2017) 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, and management of patients who permanently discontinue 
study drug prior to Visit 11 and continue in the study. 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 (eg, severe thirst, dry mouth, frequent 
micturition, or dry skin) and hypoglycemia (eg, 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 

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hyperglycemia or severe hypoglycemia between study visits, or in the event that a patient intends 
to permanently discontinue study drug.
7.7.5.2.
Management of Increased Hypoglycemia Risk
Dulaglutide and metformin are nonsecretagogues; 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 
(eg, 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.
7.7.5.3.
Management of Patients with Severe, Persistent Hyperglycemia during 
the Treatment Period
Investigators will be trained on the application of criteria for deciding when and how to intervene 
in patients who do not reach glycemic targets.  An additional therapeutic intervention should be 
considered in patients who develop severe, persistent hyperglycemia after randomization based 
on the following criteria:
a) During the first 8 weeks postrandomization (up to Visit 5):  An average FPG above 
270 mg/dL (15.0 mmol/L) over at least a 2-week period (at least 4 values/week must be 
available)
OR
b) Between Week 8 and Week 18 (between Visits 5 and 7):  An average FPG above 
240 mg/dL (13.3 mmol/L) over at least a 2-week period (at least 4 values/week must be 
available)
OR
c) Between Week 18 and Week 26 (between Visits 7 and 8):  An average FPG above 
200 mg/dL (11.1 mmol/L) over at least a 2-week period (at least 4 values/week must be 
available) or HbA1c above 8.0% (64 mmol/mol)
OR
d) Beginning at Week 26 (Visits 8 through 11):  HbA1c above 8.0% (64.0 mmol/mol) which 
is not at least 0.3% less than the HbA1c at the previous scheduled measurement  
Persistent hyperglycemia considered of severe intensity by the investigator should be reported on 
the AE eCRF whenever any of the above criteria are met.  

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In considering whether initiation of rescue therapy is warranted, 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.  If confirmed, the investigator 
will initiate an appropriate glucose-lowering intervention (rescue intervention) according to the 
guidance outlined in Section 7.7.1, and it will be recorded on the eCRF specified for collecting 
antihyperglycemic medications.  Other GLP-1 RAs (including commercial Trulicity) or DPP-4 
inhibitors must not be used as the rescue intervention.  Patients who receive rescue intervention 
for hyperglycemia management should also continue administering study drug for the remaining 
period in the trial.  
7.7.5.4.
Management of Patients Permanently Discontinuing Study Drug
Circumstances under which patients may be required to prematurely discontinue study drug are 
outlined in Section 8.1.  Patients who stop the study drug permanently will continue participating 
in the trial according to the protocol to collect all planned efficacy and safety measurements and 
should receive another glucose-lowering intervention (Section 7.7.1).  The new glucose-lowering 
intervention will be recorded on the eCRF specified for collecting antihyperglycemic 
medications.
To assure timely initiation of another antihyperglycemic medication after permanent 
discontinuation of study drug, patients should be advised to promptly notify the site when this 
situation occurs.  The investigator should evaluate the need for additional antihyperglycemic
medication at this time (as outlined in Section 7.7.1) and initiate the additional intervention 
accordingly.  An unscheduled visit should be used as needed for more timely initiation if
warranted based on the investigator’s clinical judgment.
7.7.5.5.
Management of Patients with GI Symptoms
Patients will be guided on dietary behaviors that may help mitigate nausea symptoms and 
vomiting; for example, eating smaller meals, splitting 3 daily meals into 4 or more smaller ones, 
and stopping eating when they feel full.  For patients experiencing intolerable GI symptoms, the
investigator may temporarily discontinue (interrupt) study drug and then restart study drug as 
soon as it is safe to do so (Section 8.1.2).  Investigators may consider the use of oral antiemetic 
or antidiarrheal medication as needed in patients who experience intolerable GI symptoms, per 
local country availability and individual patient needs.  In cases where study drug is temporarily 
interrupted due to nausea or vomiting, use of oral antiemetic medication may be considered prior 
to restarting study drug to mitigate the reoccurrence of symptoms.  
7.8.
Treatment after the End of the Study
7.8.1. Continued Access
After completion of the study (defined as completion of Visit 801 or ET visit), an appropriate 
diabetes treatment regimen should 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
Following randomization, it is expected that patients will remain on study medication for the 
duration of the Treatment Period (through Visit 11). Patients will be required to permanently 
discontinue from study drug only 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 <15 mL/min/1.73 m2 (confirmed on retest) 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 1 of the following conditions after consultation with the 
Lilly designated medical monitor:

ALT or aspartate aminotransferase (AST) >8×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

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
Alkaline phosphatase >2.5×ULN and total bilirubin >2×ULN

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 
(Section 7.7.1) 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 (eg, 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.  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. See Section 7.2.1 for dosing details when resuming study drug after a 
temporary interruption.  Investigators should inform the sponsor that study drug has been
temporarily interrupted.  The data related to temporary interruption of study treatment will be 
documented in source documents and entered on an 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 will 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.
8.2.
Discontinuation from the Study
Every attempt will 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 in 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

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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)

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. Visit 801 (Safety Follow-Up Visit) should be performed 
approximately 4 weeks after the ET visit as the final study visit.  
Patients discontinuing from the study prematurely for any reason should complete AE and other 
safety follow-up per Schedule of Activities (Section 2), Section 9.2 (Adverse Events), and 
Section 9.4 (Safety) of this protocol.
8.3.
Lost to Follow-Up
Every attempt will be made to minimize the number of patients considered lost to follow-up at 
the end of the study.  Patients will be informed about the importance of completing the study and 
providing updated contact information to the study site when necessary.  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.  Attempts to contact the patient should be documented in the study source 
documents.

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9.
Study Assessments and Procedures
Section 2 presents the Schedule of Activities, with the study procedures and their timing 
(including number of days for allowable visit deviations [visit windows]).
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 Assessment
The primary efficacy measure is change from baseline in HbA1c at 36 weeks.
9.1.2. Secondary Efficacy Assessments
The following secondary efficacy measures (controlled for Type 1 error) will be evaluated at 
36 weeks:

change in body weight from baseline

proportion of patients achieving HbA1c target <7.0% (53 mmol/mol) 

change in FSG (central laboratory) from baseline
9.1.3. Exploratory Efficacy Assessments
The primary (Section 9.1.1) and secondary efficacy measures (Section 9.1.2) will also be 
evaluated at 52 weeks as an exploratory efficacy assessment.
The following exploratory efficacy measures will be evaluated at 36 and 52 weeks (unless noted 
otherwise):

proportion of patients achieving HbA1c target ≤6.5% (48 mmol/mol)

proportion of patients achieving ≥5% body weight loss

proportion of patients achieving ≥10% body weight loss

change in 6-point SMPG profile from baseline

proportion of patients meeting the composite endpoint of HbA1c <7.0% (53 mmol/mol),
no weight gain, and no documented symptomatic hypoglycemia

proportion of patients meeting the composite endpoint of HbA1c <7.0% (53 mmol/mol),
body weight loss ≥5%, and no documented symptomatic hypoglycemia or severe 
hypoglycemia

changes in systolic blood pressure (SBP) and DBP from baseline

changes from baseline in serum lipid parameters (total cholesterol, high density 
lipoproteins [HDL], low density, lipoproteins [LDL], very low density lipoproteins 
[VLDL], and triglycerides)

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
changes in insulin resistance as measured by the Homeostasis Model Assessment-2 
(HOMA2) method (HOMA2-IR) (Caumo et al. 2006)

-cell function as measured by the HOMA2 method (HOMA2-%B), changes in fasting 
plasma glucagon, changes in fasting plasma glucagon adjusted for fasting glucose, 
changes in fasting insulin, and changes in C-peptide

Diabetes Injection Device Experience Questionnaire (DID-EQ) scores at Week 12

changes in EQ-5D-5L scores from baseline

changes in Impact of Weight on Self-Perceptions Questionnaire (IW-SP) scores from 
baseline

changes in Ability to Perform Physical Activities of Daily Living (APPADL) score from 
baseline
9.1.4. 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 and recorded on 
the eCRF to the nearest one-tenth kg (Appendix 7).  
Body mass index will be computed from the patient’s weight and height.  Body mass index 
should be rounded to the nearest whole number for purposes of Inclusion Criterion [6] 
(Section 6.1).  
9.1.5. 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.
9.2.
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.

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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.  
A “reasonable possibility” means that there is a cause and effect relationship between the 
investigational product, study device, and/or study procedure and the AE.
The investigator answers yes/no when making this assessment.
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

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.  

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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 eCRF 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.
Cardiovascular Events
Information on CV risk factors will be collected on an eCRF at Visit 2. In addition to 
monitoring of vital signs (PR, SBP, DBP) and 12-lead electrocardiograms (ECGs) throughout the 
study, data on any new CV event will be prospectively collected using a CV event eCRF.
Deaths and nonfatal CV AEs will be adjudicated by a committee of physicians external to Lilly 
with cardiology expertise (Clinical Endpoint Committee [CEC]). The nonfatal CV AEs to be 
adjudicated are: 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.
9.2.2.2.
Hypoglycemia and Hyperglycemia
Patients will collect information on episodes of hypoglycemia starting from Visit 2 until the last 
study visit (ET visit or Visit 801).  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).  If a hypoglycemic event occurs, the patient should record in the study diary the PG 
level measured during the episode and prior to administration of treatment (if taken), as well as 
associated symptoms and treatment administered. Site personnel will enter this information into 
the hypoglycemia eCRF at each visit.
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 

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Medicine plasma-equivalent glucose meters and strips) in accordance with the 2017 American 
Diabetes Association position statement on glycemic targets:
Glucose Alert Value (Level 1):

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).

Documented 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).

Documented unspecified hypoglycemia is defined as any event with no information 
about symptoms of hypoglycemia available, but with a measured PG ≤70 mg/dL 
(≤3.9 mmol/L).
Clinically Significant Hypoglycemia (Level 2):

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 <54 mg/dL (<3.0 mmol/L).

Documented asymptomatic hypoglycemia is defined as any event not accompanied 
by typical symptoms of hypoglycemia, but with a measured PG <54 mg/dL 
(<3.0 mmol/L).

Documented unspecified hypoglycemia is defined as any event with no information 
about symptoms of hypoglycemia available, but with a measured PG <54 mg/dL 
(<3.0 mmol/L).
Severe hypoglycemia (Level 3):

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.
Other hypoglycemia categories:

Nocturnal hypoglycemia is defined as any hypoglycemic event that occurs between 
bedtime and waking.

Relative hypoglycemia is defined as any symptomatic event 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.

Probable symptomatic hypoglycemia is defined as symptoms of hypoglycemia but PG 
measurement was not reported.

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All reported cases of hypoglycemia will be reported on the hypoglycemia eCRF.  
To avoid duplicate reporting, all consecutive PG values ≤70 mg/dL (3.9 mmol/L) occurring 
within a 1-hour period may be considered to be a single hypoglycemic event (Weinberg et al. 
2010; Danne et al. 2013).  
In each case of suspected or confirmed hypoglycemia, it is important that details for each event 
be recorded on the eCRF as completely and accurately as possible, including information on the
date, time, PG value, symptoms, and the nature and outcome of any interventions.  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 7.7.1 and 
Section 8.1.1.
It is important that each case of suspected or confirmed hypoglycemia be properly categorized 
with respect to severity.  If a hypoglycemic event meets the criteria of severe, it also needs to 
be recorded on the AE eCRF as serious and reported to Lilly as an SAE.
Severe, persistent hyperglycemia will be collected as an AE during the trial to assess the risk of 
extreme imbalance in glycemic control, as defined in Section 7.7.5.3. Details of 
antihyperglycemic medication initiated as rescue therapy for severe, persistent hyperglycemia
per these criteria will be collected on the antihyperglycemic concomitant therapy eCRF.
9.2.2.3.
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 Section 7.7.1 and 
Section 8.1.1 for details on the introduction of new antihyperglycemic interventions).  A review 

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of the patient’s concomitant medications should be conducted to assess any potential causal 
relationship with pancreatitis.
Each suspected 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.
Each patient will have measurements of p-amylase and lipase (assessed at the central laboratory) 
as shown on the Schedule of Activities (Section 2) to assess the effects of the investigational 
doses of dulaglutide on pancreatic enzyme levels.  Serial measures of pancreatic enzymes have
limited clinical value for predicting episodes of acute pancreatitis in asymptomatic patients 
(Nauck et al. 2017; Steinberg et al. 2017a; Steinberg et al. 2017b).  Thus, further diagnostic
follow-up of cases of asymptomatic pancreatic hyperenzymemia (lipase and/or pancreatic 
amylase ≥3×ULN) is not mandated, but may be performed based on the investigator’s clinical 
judgement and assessment of the patient’s overall clinical condition.  Only cases of pancreatic 
hyperenzymemia that undergo additional diagnostic follow-up and/or are accompanied by 
symptoms suggestive of pancreatitis will be submitted for adjudication.  
All suspected cases of acute or chronic pancreatitis will be adjudicated by an independent CEC. 
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 disease. 
Relevant data from patients with acute or chronic pancreatitis and those with severe or serious 
abdominal pain 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.
9.2.2.4.
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).  Patients with a personal or family history of MTC or personal 
history of multiple endocrine neoplasia syndrome type 2, or who have serum calcitonin ≥20 ng/L
at study entry as determined by the central laboratory will be excluded.  The assessment of 
thyroid safety during the trial will include reporting of thyroid treatment-emergent (TE) AEs 
(TEAEs) and measurements of calcitonin according to the Schedule of Activities (Section 2).
Patients who develop serum calcitonin increases ≥50% of the screening value AND an absolute 
value ≥20 ng/L and <35 ng/L at a postrandomization visit will be asked to repeat the 
measurement within 1 month.  If this repeat value is increasing (≥10% increase from the initial 
elevated value), the patient will be encouraged to undergo additional endocrine assessment and 
longer-term follow-up by an endocrinologist to rule out a serious adverse effect on the gland.  
Patients with an increase in serum calcitonin ≥50% of the screening value AND an absolute 
value ≥35 ng/L at a postrandomization visit will be asked to immediately undergo additional 
endocrine assessments and longer-term follow-up by an endocrinologist.

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For patients who require additional endocrine assessments due to increased calcitonin 
concentration per the criteria provided in this section or for thyroid-related TEAEs, data from the 
follow-up assessments will be collected on a specific eCRF.
9.2.2.5.
Hypersensitivity Reactions 
All hypersensitivity reactions will be reported by the investigator as either AEs or, if any serious 
criterion is met, as SAEs.  Additional data about these events, such as type of reaction and 
treatment received, will be collected on an eCRF created for this purpose.  Injection site 
reactions will be collected on an eCRF separate from the hypersensitivity reaction eCRF.  At the 
time of AE occurrence, samples will be collected for measurement of dulaglutide anti-drug 
antibodies (ADA) and dulaglutide concentration.  Study drug should be temporarily interrupted 
in any individual suspected of having a severe or serious hypersensitivity 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.
9.2.2.6.
Supraventricular Arrhythmias and Cardiac Conduction Disorders
All events of TE 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.
9.2.2.7.
Acute Gallbladder Disease
Information on the patient’s history of gallbladder disease (prior cholecystectomy, history of 
acute cholecystitis or cholelithiasis) will be recorded on an eCRF at Visit 2.  All events of TE
biliary colic, cholecystitis, or other suspected events related to gallbladder disease should be
evaluated and additional diagnostic tests performed, as needed.  
9.2.2.8.
Acute Renal Events
Renal safety will be assessed based on repeated renal functional assessment, as well as 
assessment of AEs suggestive of acute and chronic renal failure.
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, and a 
product complaint form should be completed.

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9.3.
Treatment of Overdose
Study drug overdose (more than the specified number of injections) 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.
Electrocardiograms
Electrocardiograms will be collected according to the Schedule of Activities (Section 2) and 
centrally overread.  Electrocardiograms should be recorded 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 relevant findings from ECGs obtained before the first 
dose of study drug that result in a diagnosis should be reported as a preexisting condition and 
medical history.  Any clinically relevant 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.
9.4.1.2.
Vital Signs
Sitting BP and 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 SBP 
should be used to collect all 3 measurements of both BP and PR at all study visits.  For each
parameter (PR, SBP, and DBP), 3 measurements will be taken for each patient at each visit 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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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).  
Specific laboratory measures to be analyzed as exploratory endpoints are listed in Section 4.
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.
With the exception of laboratory test results that may unblind the study, Lilly or its designee will 
provide the investigator with the results of laboratory tests analyzed by a central vendor.  
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.  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.  
Specific safety measures are included in the protocol to ensure appropriate monitoring of 
pancreatic (Section 9.2.2.3), thyroid (Section 9.2.2.4), and liver safety (Section 9.4.3.1).  
In the event that safety monitoring uncovers an issue that needs to be addressed by unblinding at 
the group level, only members of the DMC (an advisory group for this study formed to protect 
the safety of the patients and the integrity of data; refer to Section 10.3.8) will be allowed to
conduct additional analyses of the safety data.
9.4.3.1.
Hepatic Safety Monitoring
If a study patient experiences elevated ALT ≥3×ULN, alkaline phosphatase ≥2×ULN, or 
elevated total bilirubin ≥2×ULN, liver testing (Appendix 4) should be repeated within 3 to 5 days 
including ALT, AST, alkaline phosphatase, total bilirubin, direct bilirubin, gamma-glutamyl 
transferase (GGT), and creatine kinase to confirm the abnormality and to determine if it is 
increasing or decreasing.  If the abnormality persists or worsens, clinical and laboratory 
monitoring should be initiated by the investigator and in consultation with the study medical 
monitor.  Monitoring of ALT, AST, alkaline phosphatase, and total bilirubin should continue 
until levels normalize or return to approximate baseline levels.  
9.4.3.1.1. Hepatic Safety Data Collection
Additional safety data should be collected via the eCRF if 1 or more of the following conditions 
occur:  

elevation of serum ALT to ≥5×ULN on 2 or more consecutive blood tests

elevated serum total bilirubin to ≥2×ULN (except for cases of known 
Gilbert’s syndrome)

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
elevation of serum alkaline phosphatase to ≥2×ULN on 2 or more consecutive 
blood tests

patient discontinued from treatment due to a hepatic event or abnormality of 
liver tests

hepatic event considered to be a SAE
9.5.
Pharmacokinetics
Venous blood samples of approximately 4 mL 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 (Section 2). 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.
A PK sample can be collected at any time during those clinic visits at which an immunogenicity 
sample is to be taken, and at ET visits.  
The study has been designed so that, where possible, each immunogenicity sample will be 
accompanied by a PK sample in the same visit (except for Visit 3 [baseline]).  At visits where 
ECG measurements are also taken, these should be accompanied by a time-matched PK sample 
within 30 minutes after the ECG measurement, during the same visit.
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 at a facility selected by Lilly or its designee 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 
impose shorter time limits.  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.
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 dulaglutide 
ADA.  A blood sample will be collected at specific study visits according to the Schedule of 
Activities (Section 2), along with a simultaneous drug concentration sample.
Samples with dulaglutide ADA detected will be titered and evaluated for their ability to 
neutralize the activity of assigned treatment (dulaglutide-neutralizing antibodies).  Samples with 
dulaglutide ADA detected will also be tested for cross-reactive-binding to native GLP-1, and if 
such is detected, 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 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.
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.

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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 not be observed until later in the development of 
dulaglutide or after dulaglutide is commercially available.
9.9.
Health Economics
9.9.1. Diabetes Injection Device Experience Questionnaire (DID-EQ)
The Diabetes Injection Device Experience Questionnaire is a newly developed questionnaire to 
specifically evaluate newer diabetes injection devices (Matza et al. 2016, Matza et al. 2017).  
This questionnaire has been developed because all validated device questionnaires were 
developed specifically for evaluating devices for insulin injections; no validated device 
experience questionnaire was available that could be used to evaluate devices for injections of 
GLP-1 RAs.  
The DID-EQ will be administered at Week 12 (Visit 6) only, or at the ET visit if early 
termination occurs prior to Visit 6.
9.9.2. EQ-5D-5L
Generic health-related quality of life will be assessed using the EQ-5D (EQ-5D; EuroQoL Group 
2015).  The EQ-5D is a standardized 5-item instrument for use as a measure of health outcomes.  
It provides a simple descriptive profile and a single index value for health status that can be used 
in the clinical and economic evaluation of healthcare as well as population health surveys.  The 
EQ-5D comprises 5 dimensions of health (mobility, self-care, usual activities, pain/discomfort, 
and anxiety/depression).  The 5L version, introduced in 2005, scores each dimension at 5 levels 
(no, slight, moderate, severe problems, extreme problems), for a total of 3251 possible health 
states.  In addition, the EQ Visual Analog Scale (VAS) records the respondents’ self-rated health 
status on a vertical graduated (0 to 100) VAS.  In conjunction with the health state data it 
provides a composite picture of the respondents’ health status.  
The EQ-5D is used worldwide and is available in more than 170 languages.  Details on the 
instrument, and scoring, organizing, and presenting the data collected can be found in the EQ-5D 
User Guide (EuroQoL Group 2015).  
The EQ-5D-5L will be administered at Weeks 0, 36, and 52, and at ET (Visits 3, 9, 11, and ET).  
9.9.3. Impact of Weight on Self-Perceptions Questionnaire (IW-SP)
Patients’ self-perception related to their body weight will be assessed using the IW-SP (Hayes
and DeLozier 2015).  The IW-SP is a 3-item questionnaire that has demonstrated validity, 
reliability, and responsiveness in individuals with T2D and obesity, thereby making it an 
appropriate tool for the evaluation of weight-loss interventions targeted toward patients with 
T2D (Hayes and DeLozier 2015).  Each item is rated on a 5-point scale ranging from “always” to 
“never.”  Total scores for the IW-SP are derived by summing the item scores and dividing by the 

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number of items.  The score can also be transformed to a range from 0 to 100.  Higher IW-SP 
scores correspond to better self-perception (Hayes and DeLozier 2015).
The IW-SP will be administered at Weeks 0, 36, and 52, and at ET (Visits 3, 9, 11, and ET).  
9.9.4. Ability to Perform Physical Activities of Daily Living (APPADL)
The APPADL questionnaire contains 7 items that assess how difficult it is for patients to engage 
in various physical activities considered to be integral to normal daily life, such as walking, 
standing, and climbing stairs (Hayes et al. 2011; Hayes et al. 2012).  Items are scored on a 
5-point numeric rating scale, where 5=“not at all difficult” and 1=“unable to do.”  A raw overall 
score is calculated by simply summing the scores of the 7 items, and a transformed overall score 
is obtained by linearly transforming the raw overall score to a 0 to 100 scale.  A higher raw 
overall score and a lower transformed overall score are indicative of better ability to perform 
activities of daily living.  
The APPADL will be administered at Weeks 0, 36, and 52, and at ET (Visits 3, 9, 11, and ET).

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10.
Statistical Considerations
10.1. Sample Size Determination
Assuming a screen failure rate of 40%, approximately 3000 patients will need to be screened to 
attain approximately 1800 patients randomized to the 3 treatment groups (600 patients/groups) in 
a 1:1:1 ratio for dulaglutide 4.5 mg, 3.0 mg, and 1.5 mg. Assuming 15% dropout, this will result 
in approximately 510 patients per arm completing 36 weeks of treatment (the primary time 
point).  
The aforementioned sample size provides ≥80% power to demonstrate superiority of at least 1 of 
the investigational dulaglutide doses (4.5 mg or 3.0 mg) to dulaglutide 1.5 mg with respect to the 
primary endpoint (change from baseline in HbA1c) at Week 36.  This sample size is calculated 
based on the assumption that there is a treatment difference (for either investigational dose) in 
HbA1c change from baseline of approximately -0.22%, a standard deviation (SD) of 1.1%, and a
2-sided alpha of 0.05.  
10.2. Populations for Analyses
Table GBGL.4 defines the populations to be used for analyses.
Table GBGL.4.
Populations for Analyses
Population
Description
Entered
All participants who sign informed consent
All randomized
All patients who are randomized 
Intent to treat (ITT)
All participants who are randomized and take at least 1 dose of 
study medication for an assigned treatment arm
Completers
All ITT patients who have an HbA1c measure at Visit 9 
(Week 36) regardless of compliance with the protocol, rescue 
medication, or treatment discontinuation. However, data 
postrescue and/or posttreatment discontinuation will be excluded
Per protocol (PP) 
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 
through Week 36 

Complete the treatment period through 36 weeks (Visit 9) 

Have a value of the primary efficacy measure (HbA1c) at 
Visit 9 (Week 36)

Excluding data collected postrescue and/or posttreatment 
discontinuation
Abbreviation:  HbA1c = hemoglobin A1c.
Note:  The full list will be defined in the Statistical Analysis Plan.

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10.3. Statistical Analyses
10.3.1. General Statistical 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.
Table GBGL.4 defines the populations to be used for analyses.
Efficacy and safety analyses will be conducted in the Intent to Treat (ITT) Population. There 
will be 2 primary estimands to compare treatment groups in terms of the primary measure of 
HbA1c change from baseline to Week 36.
One primary estimand will be an efficacy estimand (de jure effect) which will use the data 
collected before initiation of any rescue medication or premature treatment discontinuation to 
demonstrate the effect of treatment and avoid confounding effects of other antihyperglycemic 
agents (Little and Kang, 2014).  The other primary estimand will be a treatment-regimen 
estimand (de facto effect) which will include data collected after initiation of other 
antihyperglycemic therapy and/or after premature treatment discontinuation.  
The treatment-regimen (de facto) estimand is included as primary at the request of the US Food 
and Drug Administration (FDA). The efficacy (de jure) estimand will be considered primary for 
all other purposes, and will be applied to all efficacy outcomes unless otherwise specified to 
demonstrate effect of treatment and avoid confounding effects with other antihyperglycemic 
agents.  
Both estimands will be tested at the full significance level of 0.05.
Analyses of safety parameters, except for hypoglycemia events, will be conducted in the ITT 
Population unless otherwise specified.  
Unless otherwise noted, all tests of treatment effects will be conducted at a 2-sided alpha level of 
0.05, and CIs will be calculated at 95%, 2-sided.  All tests of interactions between treatment 
groups and other factors will be conducted at a 2-sided alpha level of 0.10.  
The baseline will be at the randomization visit (Visit 3). If baseline data are missing, the last 
nonmissing measurement taken prior to Visit 3 will be used.  
Two analysis models will be used for the primary and key secondary continuous efficacy 
measures.  The primary analysis will be mixed-model repeated measure (MMRM) analysis using 
restricted maximum likelihood (REML).  The model will include factors for treatment, pooled 
country, visit, treatment-by-visit interaction and the baseline as a covariate. For analyses of body 
weight and FSG, the baseline HbA1c stratification (≥8.5% [69 mmol/mol] and <8.5%) will be 
added in this model as a fixed effect. An unstructured covariance structure will be used to model 

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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.
The secondary analysis for the primary and key secondary continuous endpoints will be analysis
of covariance (ANCOVA).  Missing endpoints will be imputed with the last (postbaseline) 
observation carried forward (LOCF) unless otherwise specified.  The percentage of patients 
achieving target HbA1c <7.0% (53 mmol/mol) will be analyzed using a longitudinal logistic 
regression with repeated measurements.
For continuous measures, summary statistics will include sample size, mean, SD, median, 
minimum, and maximum for both the actual and change from baseline measurements.  
Least-squares mean (LS mean) and standard errors (SEs) derived from the model will also be 
displayed for the change from baseline measurements.  Treatment comparisons will be displayed 
showing the treatment difference LS mean and the 95% CIs for the treatment differences, along 
with the p-values for the treatment comparisons.
For categorical measures, summary statistics will include sample size, frequency, and 
percentages.  A Fisher’s exact test will be used for treatment comparisons.
10.3.2. Treatment Group Comparability
10.3.2.1. Patient Disposition
Frequency counts and percentages of all patients entered, randomized/enrolled, completing
Weeks 36 and/or 52, and/or discontinuing from the study and/or study treatment early will be 
presented for each treatment.  The reasons for discontinuation from the study will be summarized 
by treatment group.  Patient disposition will be listed.
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 an analysis of variance (ANOVA) p-value to test overall treatment effect.  For 
categorical measures, summary statistics will include sample size, frequency, and percent.  
Demographics will be summarized for the ITT, Completers, and PP populations.
10.3.2.3. Concomitant Therapy 
The prespecified concomitant medications of interest will be summarized by treatment.  

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Incidence of initiation of rescue therapy for severe, persistent hyperglycemia will be analyzed as 
an exploratory safety endpoint.
10.3.2.4. Treatment Compliance
Treatment compliance is defined as taking at least 75% of required injections for the visit
intervals (see Section 7.6).  Overall compliance is defined as being at least 75% compliant with 
investigational product for at least 75% of visits across the Treatment Period.  Compliance will 
be summarized by each treatment, and overall.  
10.3.3. Efficacy Analyses
10.3.3.1. Primary Analyses
There will be 2 primary estimands to compare each investigational dulaglutide dose and 
dulaglutide 1.5 mg in terms of the primary measure of HbA1c change from baseline to Week 36. 
See Section 10.3.1.
Both estimands will use the same primary analysis model by employing the MMRM described in 
Section  10.3.1 in the ITT Population, and each will be tested at the full significance level of 0.05.  
For each type of estimand, the 2 investigational doses will each be tested versus dulaglutide 1.5 
mg simultaneously, controlling the 2-sided alpha of 0.05.
10.3.3.1.1.Secondary Analyses for Primary Endpoint
The primary analysis model, MMRM, will be repeated using the PP Population and the 
Completers Population to check the sensitivity of the analysis.  If the conclusion differs from that 
of the primary analysis, the data and analyses may be further investigated.
10.3.3.1.2.Multiple Imputation for Missing Data 
To investigate departure from the missing at random (MAR) assumption for the primary analysis 
(MMRM) and check the robustness of the conclusions drawn from the primary analysis, a
pattern-mixture model (PMM) coupled with multiple imputation, recommended by National 
Research Council ([NRC]; 2010), will be performed.  
All data including those collected after rescue and/or treatment discontinuation will be included 
in the analyses. The missing data will be imputed based on measurements from patients in the 
same treatment arm who discontinued treatment but still had their measurements taken at the 
primary endpoint visit (Week 36) if there are an adequate number of observations for imputation.  
An ANCOVA model will be fit to the complete datasets at Week 36, containing effects for 
treatment, pooled country, and the baseline as a covariate.  
Inference based on PMM does not involve directly making the assumption of MAR. Instead, 
PMM involves making other types of (untestable) identifiability assumptions for the 
unobservable distributions. This assumption cannot be validated from the observed data. The 
PMM model depends on the probability mass function of possible missing data patterns, which 
would not be known a priori. The proposed multiple imputation may require posthoc changes 
after database lock to resolve any convergence issues.

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10.3.3.2. Analyses for Secondary Efficacy Endpoints
The key secondary measures change from baseline to 36 weeks in body weight and FSG, will be 
analyzed using both models, the MMRM and the ANCOVA, described in Section 10.3.1.  
For percentages of patients achieving target HbA1c of <7.0% (53 mmol/mol), longitudinal 
logistic regression with repeated measurements will be used.  The model will include 
independent variables treatment, pooled country, visit, treatment-by-visit, and baseline HbA1c as 
a covariate.  
Treatment-regimen estimands using an ANCOVA model coupled with a PMM may be 
conducted for each key secondary continuous endpoint.
10.3.3.3. Multiplicity Adjustments for the Primary and Key Secondary Endpoints 
Analyses
Superiority for the primary and secondary endpoints for each type of estimand will be assessed 
in a graphical approach (Bretz et al. 2009; Bretz et al. 2011) to control the overall Type 1 error 
rate. The tested hypotheses are superiority of each of the investigational dulaglutide doses 
versus dulaglutide 1.5 mg at Week 36 for the following measures:  (1) change from baseline in 
HbA1c, (2) change from baseline in body weight, (3) percent to target HbA1c <7.0% (53 
mmol/mol), and (4) change from baseline in FSG.  
Each estimand will be tested at the full significance level of 0.05 (2-sided).
10.3.3.4. Tertiary/Exploratory Efficacy Endpoints
The analysis of patients reaching HbA1c target ≤6.5% and other binary outcomes will use the 
same model as that for HbA1c target <7.0% (53 mmol/mol) described in Section 10.3.3.2.  
Longitudinal continuous variables will be analyzed using MMRM described in Section 10.3.1. 
The analysis will be conducted for on-treatment without rescue medication data. Log-normal-
distributed data such as fasting glucagon may be analyzed using log scale.
Nonlongitudinal continuous variables such as 6-point SMPG, 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 corresponding baseline value as a covariate.  Data 
transformation may be applied if data are not normally distributed.  
10.3.4. Safety Analyses
The safety endpoints will include incidence of AEs, adjudicated AEs, discontinuations due to 
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.

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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 (SOC).  Selected 
notable AEs of interest may be reported using high-level terms.  
Summary statistics will be provided for overall AE, TEAEs, SAEs, study discontinuation due to 
AEs or death, and study drug discontinuation due to AEs.  Counts and proportions of patients 
experiencing AEs will be reported for each treatment.  
Summaries (if appropriate) of adverse events of special interest (AESI) defined in Section 9.2.2
will be generated.  
10.3.4.3. Hypoglycemic Episodes
Section 9.2.2.2 contains definitions of categories of hypoglycemia. Summary reports on-
treatment without rescue medication will include both incidence and rates of hypoglycemia.  
Hypoglycemia will be analyzed as documented symptomatic, asymptomatic, nocturnal 
documented symptomatic, or severe.  
Hypoglycemic episodes will be analyzed using 2 hypoglycemic thresholds:  Level 1 (glucose 
alert level, ≤70 mg/dL [3.9 mmol/L]) and Level 2 (clinically significant hypoglycemia level, 
<54 mg/dL [3.0 mmol/L]).  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 (events/patient/1 year) will be analyzed using a generalized linear 
mixed-effects model assuming negative binomial distribution for hypoglycemic episodes if data 
warrants. Otherwise, the rate will be analyzed using Wilcoxon rank-sum test. Incidence and 
rates will be summarized for each treatment arm and entire Treatment Period.  
10.3.4.4. 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 may be provided for each treatment during 
the weeks of dose escalation, during the period on the final assigned dose, and overall, to 
compare the effects of the 3 different doses on GI tolerability, as well as the overall effects of 
randomized therapies.  
10.3.4.5. Laboratory Analyses
Laboratory safety measurements will be summarized.  For continuous (numeric) laboratory 
analytes, the change from baseline by visit will be summarized as detailed in Section 10.3.1.
Change from baseline to endpoint (LOCF) will be analyzed using an ANOVA on the ranks with 
treatment as a fixed effect unless otherwise specified.  For subjective (qualitative) laboratory 
analytes, counts and percentages of patients with normal and abnormal values will be analyzed 
using Fisher’s exact test.

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Shift tables of the change from baseline value to the most extreme postbaseline value and from 
baseline to Week 52 for selected analytes using clinically meaningful thresholds will be 
summarized.  
10.3.4.6. Vital Signs
Descriptive statistics for the actual measurements and changes from baseline for SBP and DBP, 
PR, and rate-pressure product (RPP; SBP×PR/1000) will be presented by treatment and visit.  
Vital signs will be analyzed using a similar MMRM-based model as that described in 
Section 10.3.1 for continuous variable analyses.
10.3.4.7. Electrocardiograms
Descriptive statistics for the absolute measurements, changes from baseline, and clinically
relevant changes for selected ECG parameters defined in the SAP, including QT corrected for 
heart rate (HR) using Fridericia’s formula (QTcF), will be presented by treatment and visit.  
These parameters will be analyzed using a similar MMRM as that described in Section 10.3.1 for 
continuous variable analyses.
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. If necessary, data from this study 
may be combined with data from previous study/studies for analysis, or prior population PK or 
PK/PD model information from previous studies may be utilized to initiate analysis.  
The relationships between dulaglutide doses and/or concentrations and key safety measures 
(such as QT interval, PR interval, and HR), tolerability measure (such as nausea and vomiting),
and efficacy measures (such as fasting glucose, HbA1c, and weight) will be assessed either 
graphically or through modeling. Endpoints may include but are not necessarily limited to those 
listed above.
In addition, if positive antibody titers to dulaglutide are observed, the impact of antibody 
formation on PK exposures, dulaglutide clearance, and if applicable, drug effect(s) will be 
evaluated.  
10.3.6. Other Analyses
10.3.6.1. Health Economics 
Continuous measures from the patient reported outcomes (PRO) instruments will be analyzed 
using the MMRM model specified in Section 10.3.1, using on-treatment without rescue data.
Categorical measures from the PRO instruments will be summarized for each treatment.  
10.3.6.2. Subgroup Analyses
Subgroup analyses of treatment interaction with important factors, including age (<65 years, 
≥65), race, gender, country, duration of diabetes, baseline HbA1c (<8.5% [69 mmol/mol], ≥8.5%
[69 mmol/mol]), body weight, and BMI may be conducted for the primary endpoint of HbA1c.

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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 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. Evaluation of Immunogenicity 
The frequency and percentages of patients with preexisting (baseline) ADA and with TE ADA to 
dulaglutide will be tabulated. For patients with ADA detected at baseline, TE ADA are defined 
as those with a 4-fold (2 dilutions) increase in titer compared to baseline.  The frequency of 
neutralizing antibodies with specificity for dulaglutide and with specificity for native-sequence 
GLP-1 will also be tabulated in patients with TE ADA detected.
The relationship between the presence of antibodies and the PK parameters and PD response
including safety and efficacy to dulaglutide may be assessed.
10.3.8. Interim Analyses
No interim analyses of efficacy are planned for this study.  If an unplanned interim analysis is 
deemed necessary, the appropriate Lilly medical director, or designee, will be consulted to 
determine whether it is necessary to amend the protocol.
An independent DMC will have the responsibility to review unblinded interim analysis results in 
order to monitor the safety of the patients in the study up until the last patient completes the 
Week 36 visit (Visit 9). The detailed analysis and communication plan for the interim analyses
will be defined in a separate DMC charter. An internal Statistical Analysis Center (SAC)
external to the study team will perform the data analysis for the DMC. As no efficacy analyses 
are planned by the DMC, the Family-Wise Error Rate will not be affected by any of these interim 
analyses; hence, no alpha spending is necessary.  
Only the DMC will be authorized to evaluate unblinded interim safety analyses. Study sites will 
receive information about interim results ONLY if deemed necessary for the safety of their 
patients.
The DMC will perform the first safety analysis after approximately 900 patients (50% of the 
planned sample size) have the opportunity to complete Visit 7 (Week 18) or approximately 
7 months after the first patient is randomized (whichever comes first).  A second safety review 
will be planned after approximately 900 patients have the opportunity to complete Visit 9 
(Week 36), or approximately 12 months after the first patient is randomized (whichever comes 
first). The number and timing of the DMC interim analyses may be adjusted by the actual 
enrollment rate. This adjustment will not require a protocol amendment.  

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There may be 2 database locks for this study. A primary database lock may be conducted for all
data accumulated through the time when all randomized patients have completed 36 weeks of 
treatment (Visit 9, primary objective endpoint). The final database lock will be conducted for all
data accumulated through the time when all patients have completed the 4-week Safety 
Follow-Up Period (through Visit 801). For the primary database lock, all efficacy analyses will 
be conducted based on Week 36 (Visit 9). If a decision is made to only conduct the final 
database lock and not the primary lock, it will be documented without an amendment to the 
protocol.
A limited number of pre-identified individuals may gain access to unblinded data, as specified in 
the unblinding plan prior to the primary lock, in order to initiate the population PK/PD model 
development processes. Following the primary database lock, the Sponsor will be unblinded to 
analyze and report the data. Unblinded data and results will not be shared with the study sites in 
order to maintain blinding at the site while the study is still ongoing.  
Unblinding details are specified in the unblinding plan.

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11.
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Hayes RP, Nelson DR, Meldahl ML, Curtis BH. Ability to perform daily physical activities in 
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A, Wender R, Matthews DR. Management of hyperglycemia in type 2 diabetes, 2015: a 
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Trulicity [summary of product characteristics (SmPC)]. Houten, The Netherlands; 2017. 
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12.
Appendices

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Appendix 1.
Abbreviations and Definitions
Term
Definition
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.
AESI
adverse event of special interest
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ANOVA
analysis of variance
APPADL
Ability to Perform Physical Activities of Daily Living
AST
aspartate aminotransferase
AUC
area under concentration-time curve
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
CEC
Clinical Endpoint Committee
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.

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CSR
clinical study report
CT
computed tomography
CV
cardiovascular
DBP
diastolic blood pressure
DID-EQ
Diabetes Injection Device Experience Questionnaire
DMC
Data Monitoring Committee
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
ESRD
end-stage renal disease
ET
early termination
FDA
Food and Drug Administration
FPG
fasting plasma glucose
FSG
fasting serum glucose
GCP
good clinical practice
GGT
gamma glutamyl-transferase
GI
gastrointestinal
GLP-1
glucagon-like peptide-1
GLP-1 RA
glucagon-like peptide-1 receptor agonist
HbA1c
hemoglobin A1c
HOMA2
Homeostasis Model Assessment-2
HOMA2-%B
-cell function as measured by the HOMA2 method

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HOMA2-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 complete reporting database is created/locked for the 
primary endpoint.
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.
ITT
intent 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.
IW-SP
Impact of Weight on Self-Perceptions Questionnaire
IWRS
interactive web-response system
LOCF
last observation carried forward
LS mean
least-squares mean
MAR
missing at random
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
NRC
National Research Council
OAM
oral antihyperglycemic medication

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OTC
over-the-counter
PD
pharmacodynamic
PG
plasma glucose
PK
pharmacokinetics
PMM
pattern-mixture model
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
PRO
patient reported outcome
QTcF
QT corrected for heart rate using Fridericia’s formula
REML
restricted maximum likelihood
RPP
rate-pressure product
SAC
Statistical Analysis Center
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
SDP
single-dose pen
SGLT2
sodium-glucose co-transporter 2
SmPC
Summary of Product Characteristics
SMPG
self-monitored plasma glucose
SOC
system organ class
SUSARs
suspected unexpected serious adverse reactions
T1D
type 1 diabetes
T2D
type 2 diabetes mellitus
TE
treatment-emergent

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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
VAS
Visual Analog Scale
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
Cystatin C
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 cross-reactive antibody
Non-pharmacogenomic biomarker sample
Native GLP-1 neutralizing antibody
(serum, plasma EDTA/P800c)

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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 will be measured; the ratio will be calculated.
c
Remaining P800 plasma from glucagon collection for nonpharmacogenomic biomarker sample.
d
CK-MB will 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 or if required per local regulations and/or 
institutional guidelines 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 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.

that a copy of the ICF is provided to the participant or the participant’s legal 
representative and is kept on file.

that the medical record includes a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the 
written consent was obtained.  The authorized person obtaining the informed 
consent must also sign the ICF.
Appendix 3.1.2.
Recruitment
Lilly or its designee is responsible for the central recruitment strategy for patients.  Individual 
investigators may have additional local requirements or processes.
Appendix 3.1.3.
Ethical Review
The investigator or an appropriate local representative must give assurance that the 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 GCP.
The study sites’ ERB(s) should be provided with the following:

the protocol and related amendments and addenda, current Investigator 
Brochure (IB), and updates during the course of the study

ICF

other relevant documents

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Appendix 3.1.4.
Regulatory Considerations
This study will be conducted in accordance with the protocol and with the:

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.
Appendix 3.1.5.
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 3.1.6.
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

provide sponsor start-up training to instruct the investigators and study 
coordinators.  This training will give instruction on the protocol, the completion 
of the eCRFs, 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

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
review and evaluate eCRF 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, 
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.
Appendix 3.4.
Publication Policy
The publication policy for Study H9X-MC-GBGL is described in the Clinical Trial Agreement.

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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 = aspartate 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 GBGL World Health Organization 
Classification of Diabetes and Diagnostic Criteria
 
 
 
 
 
 
 
 
 
CCI

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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 (if this is their preferred and usual lifestyle) or in a same-sex relationship
with no sexual relationship with males (as part of their preferred and usual lifestyle).  
Note:  periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation 
methods), declaration of abstinence just for the duration of a trial, and withdrawal are not 
acceptable methods of contraception

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 GBGL 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/Section%204%20Step%202%20Physical%20Measurements.pdf), 
accessed: January 24, 2018.
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 height 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 
electronic scale capable of measuring weight in kilograms. 

All weights for a given patient should be measured using the same scale, whenever possible, 
at approximately the same time in the morning after evacuation of bladder contents. 

Patients should be lightly clothed but not wearing shoes while their weight is measured.
Step 1 Ask the patient to remove their footwear, outerwear (coat, jacket, etc), and any headgear 
(light headgear worn for religious reasons can remain, but this should be worn by the patient at 
every clinic visit when 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 arms by sides and then record weight in kilograms (kg)
to the nearest one-tenth kg.

Leo Document ID = 3692d6d5-9b4f-4e1a-9296-465107a18616
Approver: 
Approval Date & Time: 05-Feb-2018 19:19:45 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 05-Feb-2018 20:10:39 GMT
Signature meaning: Approved