A Randomized, Parallel-Arm, Double-Blind Study of Efficacy and Safety of Dulaglutide When Added to SGLT2 Inhibitors in Patients With Type 2 Diabetes Mellitus
Phase: PHASE3
Conditions: Type 2 Diabetes Mellitus
Sponsor: Eli Lilly and Company

 
 
Protocol H9X-MC-GBGE(a) 
 
 
A Randomized, Parallel-Arm, Double-Blind Study of Efficacy and Safety of Dulaglutide When 
Added to SGLT2 Inhibitors in Patients With Type 2 Diabetes Mellitus 
 
 
NCT02597049 
 
 
Approval Date: 21-Aug-2015 

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LY2189265 
 
 
 
Protocol H9X-MC-GBGE(a) 
A Randomized, Parallel-Arm, Double-Blind Study of Efficacy 
and Safety of Dulaglutide When Added to SGLT2 Inhibitors in 
Patients with Type 2 Diabetes Mellitus 
(AWARD-10: Assessment of Weekly AdministRation of 
LY2189265 in Diabetes – 10) 
 
 
 
 
 
Dulaglutide (LY2189265) 
 
 
 
 
 
Eli Lilly and Company 
Indianapolis, Indiana USA 46285 
 
 
 
Protocol Electronically Signed and Approved by Lilly: 29 July 2015 
Amendment (a) Electronically Signed and Approved by Lilly on date provided below. 
 
 
 
 
Approval Date: 21-Aug-2015 GMT 
Confidential Information 
The information contained in this protocol 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 (LY2189625), 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. 
Study H9X-MC-GBGE is a Phase 3b, randomized, double-blind, placebo-controlled trial that 
investigates the effect of the addition of once-weekly dulaglutide 1.5 mg or 0.75 mg to 
SGLT2 inhibitors, with or without concomitant use of metformin, on change from baseline in 
hemoglobin A1c (HbA1c) at 24 weeks in patients with type 2 diabetes mellitus. 

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Table of Contents 
Section 
Page 
1. Protocol Synopsis .................................................................................................................... 9 
2. Introduction ........................................................................................................................... 12 
2.1. Background ...................................................................................................................... 13 
2.2. Study Rationale ................................................................................................................ 13 
3. Objectives and Endpoints ...................................................................................................... 14 
4. Study Design ......................................................................................................................... 16 
4.1. Overview of Study Design ............................................................................................... 16 
4.2. End of Trial Definition .................................................................................................... 18 
4.3. Scientific Rationale for Study Design .............................................................................. 18 
4.4. Justification for Dose ....................................................................................................... 19 
4.5. Benefit/Risk Assessment ................................................................................................. 19 
5. Study Population ................................................................................................................... 20 
5.1. Inclusion Criteria ............................................................................................................. 20 
5.2. Exclusion Criteria ............................................................................................................ 22 
5.3. Screen Failures ................................................................................................................. 24 
5.4. Lifestyle and/or Dietary Requirements ............................................................................ 24 
6. Treatment .............................................................................................................................. 25 
6.1. Treatments Administered ................................................................................................. 25 
6.2. Method of Treatment Assignment ................................................................................... 25 
6.2.1. Selection and Timing of Doses ................................................................................ 26 
6.2.1.1. 
Dulaglutide or Placebo Injections ..................................................................... 26 
6.3. Blinding ........................................................................................................................... 26 
6.4. Packaging and Labelling .................................................................................................. 27 
6.5. Preparation/Handling/Storage .......................................................................................... 27 
6.6. Dose Modification ........................................................................................................... 28 
6.6.1. Special Treatment Considerations ........................................................................... 28 
6.6.1.1. 
Standards of Medical Care ................................................................................ 28 
6.6.1.2. 
Management of Increased Hypoglycemia Risk ................................................. 28 
6.6.1.3. 
Management of Patients with Severe, Persistent 
Hyperglycemia during the Treatment Period .................................................... 29 
6.7. Treatment Compliance ..................................................................................................... 30 
6.8. Concomitant Therapy ...................................................................................................... 30 
6.8.1. Antihyperglycemia Medications .............................................................................. 31 
6.8.1.1. 
Allowed Concomitant OAMs ............................................................................ 31 
6.8.1.1.1. 
SGLT2 Inhibitors ........................................................................... 32 

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6.8.1.1.2. 
Metformin ....................................................................................... 33 
6.8.2. Medications that Promote Weight Loss ................................................................... 34 
6.8.3. Systemic Glucocorticoids ........................................................................................ 34 
6.8.4. Antihypertensive Medications ................................................................................. 34 
6.9. 
Treatment after Study Completion .................................................................................. 35 
6.9.1. Continued Access .................................................................................................... 35 
7. Discontinuation Criteria ........................................................................................................ 36 
7.1. 
Discontinuation from Study Treatment ........................................................................... 36 
7.1.1. Permanent Discontinuation of Study Treatment ...................................................... 36 
7.1.2. Permanent Discontinuation from the Study ............................................................. 37 
7.1.3. Temporary Interruption of Study Treatment ............................................................ 37 
7.1.4. 
Discontinuation of Inadvertently Enrolled Patients ................................................ 37 
7.1.5. Patients Lost to Follow-Up ...................................................................................... 38 
8. Study Assessments and Procedures ....................................................................................... 39 
8.1. 
Efficacy Assessments ...................................................................................................... 39 
8.1.1. Primary Efficacy Assessments ................................................................................. 39 
8.1.2. Secondary Efficacy Assessments ............................................................................. 39 
8.1.3. Exploratory Assessments ......................................................................................... 39 
8.1.4. Appropriateness of Assessments ............................................................................. 40 
8.2. 
Adverse Events ................................................................................................................ 40 
8.2.1. Serious Adverse Events ........................................................................................... 41 
8.2.1.1. 
Suspected Unexpected Serious Adverse Reactions ........................................... 41 
8.2.2. Adverse Events of Interest ....................................................................................... 42 
8.2.2.1. 
Hypoglycemia and Hyperglycemia ......................................................... 42 
8.2.2.2. 
Pancreatitis .............................................................................................. 42 
8.2.2.3. 
C-Cell Hyperplasia and C-Cell Neoplasms ............................................. 43 
8.2.2.4. 
Cardiovascular Events ............................................................................. 44 
8.2.2.5. 
Renal Events ............................................................................................ 44 
8.2.2.6. 
Allergic/Hypersensitivity Reactions ....................................................... 44 
8.2.3. Complaint Handling ................................................................................................. 44 
8.3. 
Treatment of Overdose .................................................................................................... 44 
8.4. 
Safety Assessments .......................................................................................................... 44 
8.4.1. Electrocardiograms .................................................................................................. 44 
8.4.2. Blood Pressure and Heart Rate ................................................................................ 45 
8.4.3. Laboratory Tests ...................................................................................................... 45 
8.4.4. Body Weight and Body Mass Index ........................................................................ 45 
8.4.5. Safety Monitoring .................................................................................................... 45 
8.5. 
Pharmacokinetics ............................................................................................................. 46 
 

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8.6. 
Pharmacodynamics .......................................................................................................... 46 
8.7. 
Genetics ........................................................................................................................... 46 
8.8. 
Biomarkers ...................................................................................................................... 46 
8.9. 
Health Economics ............................................................................................................ 47 
9. Statistical Considerations and Data Analysis ........................................................................ 48 
9.1. 
Determination of Sample Size ......................................................................................... 48 
9.2. 
General Statistical Considerations ................................................................................... 48 
9.3. 
Treatment Group Comparability ..................................................................................... 49 
9.3.1. Patient Disposition ................................................................................................... 49 
9.3.2. Patient Characteristics ............................................................................................. 50 
9.3.3. Concomitant Therapy .............................................................................................. 50 
9.3.4. Treatment Compliance ............................................................................................. 50 
9.4. 
Primary and Secondary Analyses .................................................................................... 50 
9.4.1. Primary Outcome Measure and Analyses ................................................................ 50 
9.4.1.1. 
Additional Analyses of the Primary Outcome......................................... 50 
9.4.2. Secondary Outcome Measures and Analyses .......................................................... 51 
9.5. 
Safety Analyses ............................................................................................................... 52 
9.5.1. Study Drug Exposure ............................................................................................... 52 
9.5.2. Adverse Events ........................................................................................................ 52 
9.5.3. Hypoglycemic Episodes .......................................................................................... 52 
9.5.4. Hyperglycemic Episodes ......................................................................................... 53 
9.5.5. Special Safety Topics ............................................................................................... 53 
9.5.5.1. 
Pancreas Safety........................................................................................ 53 
9.5.5.2. 
Cardiovascular Safety ............................................................................. 53 
9.5.5.3. 
Thyroid Safety ......................................................................................... 53 
9.5.5.4. 
Renal Safety ............................................................................................ 53 
9.5.5.5. 
Allergic/Hypersensitivity Reactions ....................................................... 53 
9.5.6. Laboratory Analytes................................................................................................. 53 
9.6. 
Pharmacokinetic/Pharmacodynamic Analyses ................................................................ 53 
9.7. 
Other Analyses ................................................................................................................ 54 
9.7.1. Subgroup Analyses .................................................................................................. 54 
9.8. 
Interim Analyses .............................................................................................................. 54 
10. Study Governance Considerations ........................................................................................ 55 
10.1. Regulatory and Ethical Considerations, Including the Informed 
Consent Process ............................................................................................................... 55 
10.1.1. 
Informed Consent ............................................................................................. 55 
10.1.2. 
Ethical Review ................................................................................................. 55 
10.1.3. 
Regulatory Considerations ............................................................................... 55 

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10.1.4. 
Investigator Information.......................................................................................... 56 
10.1.5. 
Protocol Signatures ................................................................................................. 56 
10.1.6. 
Final Report Signature ............................................................................................ 56 
10.2. Data Quality Assurance ................................................................................................... 56 
10.2.1. 
Data Capture System ............................................................................................... 57 
10.3. Study and Site Closure .................................................................................................... 57 
10.3.1. 
Discontinuation of Study Sites ................................................................................ 57 
10.3.2. 
Discontinuation of the Study ................................................................................... 57 
11. References ............................................................................................................................ 58 

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List of Tables 
Table 
Page 
Table GBGE.1. Objectives and Endpoints ................................................................................. 14 
Table GBGE.2. Study Treatments and Concomitant Medications ............................................. 25 
Table GBGE.3. Required Doses of Concomitant SGLT2 Inhibitors and Metformin in 
Study GBGE for Patients Already Using These Agents .................................. 32 

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List of Figures 
Figure 
Page 
Figure GBGE.1.  Illustration of study design for Clinical Protocol H9X-MC-GBGE. ................ 16 

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List of Appendices 
Appendix 
Page 
Appendix 1. 
Abbreviations and Definitions .......................................................................... 61 
Appendix 2. 
Schedule of Activities ....................................................................................... 64 
Appendix 3. 
Clinical Laboratory Tests ................................................................................. 69 
Appendix 4. 
Hepatic Monitoring Tests for Treatment-Emergent Abnormality .................... 71 
Appendix 5. 
Sampling Summary .......................................................................................... 72 
Appendix 6. 
Protocol GBGE World Health Organization Classification of Diabetes 
and Diagnostic Criteria ..................................................................................... 73 
Appendix 7. 
Protocol GBGE World Health Organization Standardized Protocols for 
the Measurement of Height and Weight ........................................................... 74 
Appendix 8. 
Protocol Amendment H9X-MC-GBGE(a) Summary – A Randomized, 
Parallel-Arm, Double-Blind Study of Efficacy and Safety of 
Dulaglutide When Added to SGLT2 Inhibitors in Patients with Type 2 
Diabetes Mellitus .............................................................................................. 75 

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1. Protocol Synopsis 
Title of Study: 
A Randomized, Parallel-Arm, Double-Blind Study of Efficacy and Safety of Dulaglutide When Added to SGLT2 
Inhibitors in Patients with Type 2 Diabetes Mellitus (AWARD-10: Assessment of Weekly AdministRation of 
LY2189265 in Diabetes – 10) 
Rationale: 
Combined use of glucose-lowering pharmacological agents is common in patients with type 2 diabetes (T2D) and 
often includes 2, 3, or more classes of therapeutics. The sodium-glucose co-transporter 2 (SGLT2) inhibitors and 
glucagon-like peptide -1 receptor agonists (GLP-1 RAs) are indicated in similar populations and their combined use 
is of clinical interest; however, clinical data is currently limited. 
An important aspect of the concomitant treatment with these 2 classes of agents is a potential for additive or 
synergistic actions on blood glucose due to their complementary mechanisms of actions; SGLT2 inhibitors lower 
blood glucose by increasing excretion of glucose in the urine, while GLP-1 RAs enhance glucose-mediated insulin 
secretion and also suppress glucagon. Similarly, both may lower body weight and blood pressure; therefore, 
combined use of these agents may provide T2D patients with a treatment regimen that is associated with an 
acceptable safety profile, in addition to clinically relevant glucose-lowering effects. 
It is also of particular interest to assess the overall tolerability of the combination therapy, including hemodynamic 
and renal parameters. SGLT2 inhibitors may cause volume depletion due to their osmotic effect in kidney tubules 
and may be associated with impairment in renal function. GLP-1 RAs may also cause loss of body fluid when 
severe, protracted vomiting occurs. 
Objectives/Endpoints: 
 
Objectives 
Endpoints 
Primary: To demonstrate that once-weekly 
dulaglutide (1.5 mg and/or 0.75 mg) is superior to 
placebo as measured by hemoglobin A1c (HbA1c) at 
24 weeks (change from baseline) in patients with 
inadequately controlled T2D on concomitant SGLT2 
inhibitor therapy. 
 
The change in HbA1c from baseline to 
24 weeks 
Secondary: Key secondary efficacy objectives 
(controlled for type 1 error) are to compare dulaglutide 
1.5 mg and 0.75 mg to placebo at 24 weeks. 
 
Proportion of patients with HbA1c target 
values of <7.0% at 24 weeks 
 
The change in fasting blood glucose (FBG) 
(central laboratory) from baseline to 24 weeks 
 
The change in body weight from baseline to 
24 weeks 

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Summary of Study Design: 
 
Study H9X-MC-GBGE is a randomized, double-blind, placebo-controlled, parallel-arm, multicenter, Phase 3b trial 
that investigates the effect of the addition of once-weekly dulaglutide 1.5 mg or 0.75 mg to SGLT2 inhibitors, with 
or without concomitant use of metformin, on glycemic control and safety over a 24-week treatment period in 
patients with inadequately controlled T2D. 
Treatment Arms and Duration: 
 
After completing screening, a 1-week lead-in period, and if necessary, a 12-week stabilization period, patients will 
be randomized 1:1:1 to a weekly injection of placebo, dulaglutide 0.75 mg, or dulaglutide 1.5 mg, all in combination 
with at least minimum-required doses of SGLT2 inhibitor (± metformin).  Study participants will be treated for 
24 weeks after randomization. 
 
Number of Patients: 
 
The study will need 101completers per arm in order to have 90% probability of achieving statistical significance for 
either dulaglutide 1.5 mg or 0.75 mg versus placebo in change from baseline in mean HbA1c at 24 weeks, assuming 
a standard deviation of 1.2%, a difference between dulaglutide and placebo of 0.6%, and a 2-sided significance level 
of 0.025. Assuming that the dropout rate is 15% for the entire study period, the study will need to enroll at least 119 
patients in each arm for a total of 357 patients enrolled.  Assuming a screen fail rate of 40%, 595 patients will need 
to be screened to meet these enrollment number requirements. 
Statistical Analysis: 
 
Two analysis models will be used for the primary objective. The primary analysis will be mixed-model repeated 
measure (MMRM) analysis using restricted maximum likelihood (REML) with treatment, country, SGLT2 inhibitor 
dose (“low” vs. “high”), metformin use (“yes” vs. “no”), visit and treatment-by-visit as fixed effects, baseline 
value as a covariate, and patient as random effect. An unstructured covariance structure will be used to model the 
within-patient errors. The secondary analysis for the primary objective will be analysis of covariance (ANCOVA) 
using a similar model as described above with treatment, country, SGLT2 inhibitor dose (“low” vs. “high”), and 
metformin use (“yes” vs. “no”) as factors and baseline value as a covariate. Missing endpoints will be imputed with 
the last (post-baseline)-observation-carried-forward (LOCF). For the key secondary continuous measures (body 
weight and FBG), both models (with HbA1c strata included), will also be used. The percent to goal, ie, the 
percentage of patients achieving target HbA1c of <7.0% at 24 weeks, will be analyzed using a longitudinal logistic 
regression with repeated measurements including independent variables for treatment, country, visit, treatment-by- 
visit, and baseline HbA1c as a covariate. 
A graphical testing approach will be used to strongly control for type I error to test for superiority of each of the 
dulaglutide doses versus placebo at 24 weeks for the following measures: (1) change from baseline in HbA1c, (2) 
change from baseline in FBG, (3) percent achieving HbA1c < 7.0%, and (4) change from baseline in body weight. 
The primary analysis population will be the intent-to-treat (ITT) population, defined as all patients randomized who 
have taken at least 1 dose. This is also the safety population. For the primary analysis, all available data up to 24 
weeks will be included except those collected after initiation of glucose-lowering rescue therapy. The primary 
analysis will be repeated with all available data included, including those collected after initiation of rescue therapy. 

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A select number of measurements (HbA1c, percent to goal in HbA1c, FBG, and body weight) will also be evaluated 
in the Per Protocol population. 

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2. Introduction 
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been developed for use as 
monotherapy or in combination with 1 or more oral antihyperglycemia medications (OAMs) 
and/or insulin for treatment of type 2 diabetes mellitus (T2D) (Bydureon® USPI, 2015; Byetta® 
USPI, 2015; Tanzeum™ USPI, 2015; Trulicity™ USPI, 2015; Victoza® USPI, 2015). Expected 
adverse events (AEs) of the GLP-1 RA class are mostly those from the gastrointestinal (GI) 
system organ class. Dulaglutide is a once-weekly GLP-1 RA approved as a monotherapy or in 
combination with OAMs and/or insulin for treatment of T2D (Trulicity USPI, 2015). Based on 
the experience from completed dulaglutide trials, similar to the GLP-1 RA class, GI AEs are the 
most common AEs associated with dulaglutide treatment. These AEs are mostly mild to 
moderate in severity, transient, and their incidence decreases over time. 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). 
Inhibitors of the active sodium-glucose co-transporter 2 (SGLT2) are a new class of glucose- 
lowering agents that act by promoting glucose excretion in the urine. The SGLTs are carrier 
proteins that are located in proximal or distal kidney tubules and are involved in active 
reabsorption of glucose from the tubular fluid back into the bloodstream (Jardiance® USPI, 
2014; Farxiga® USPI, 2015; Invokana® USPI, 2015).  There are two types of SGLTs, SGLT1 
and SGLT2; they differ in their binding capacity and binding affinity for glucose. It has been 
shown that pharmacological inhibition of SGLT2 decreases blood glucose without increasing the 
risk of hypoglycemia, and reduces systolic blood pressure and body weight (Jardiance USPI, 
2014; Farxiga USPI, 2015; Invokana USPI, 2015). The effect of SGLT1 inhibition on urinary 
glucose loss is much smaller, and its contribution to blood glucose lowering is considered to be 
limited. The SGLT2 inhibitors are indicated as monotherapy or in combination with 1 or 2 other 
OAMs and/or insulin for treatment of T2D. The most commonly reported AEs with inhibitors of 
SGLT2 are urinary tract infections and female genital mycotic infections. 
There are no published data from randomized clinical trials on the effects of combined use of 
SGLT2 inhibitors and GLP-1 RAs. Due to their mostly complementary mechanisms of action, 
except for opposing action on glucagon secretion, combined treatment with these agents may 
provide an option for patients with T2D that is effective for glucose lowering without increasing 
hypoglycemia risk, and may decrease body weight and blood pressure. 
Study H9X-MC-GBGE (GBGE; AWARD-10) is designed to assess the efficacy and safety of 
dulaglutide versus placebo, both added to the existing therapy of a stable dose of SGLT2 
inhibitor (with or without a stable dose of metformin) in patients with T2D. The primary 
objective is to show superiority of the dulaglutide 1.5-mg dose and/or dulaglutide 0.75-mg dose 
to placebo for change from baseline in hemoglobin A1c (HbA1c) at 24 weeks. Key secondary 
objectives are to compare both dulaglutide doses to placebo with respect to their effect on the 
proportion of patients reaching HbA1c targets (<7.0%), body weight, and fasting blood glucose 
(FBG) at 24 weeks. The primary objective and all key secondary objectives will be analyzed 
using a family-wise strategy to control for type 1 error. 

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2.1. Background 
A GLP-1 RA, dulaglutide is a biosynthetic fusion protein molecule produced using mammalian 
cell cultures, and consists of 2 identical, disulphide-linked chains, each containing an N-terminal 
glucagon-like peptide-1 (GLP-1) analogue sequence covalently linked to a modified human 
immunoglobulin G4 (IgG4) heavy chain by a small peptide linker (Trulicity™ USPI, 2015). 
These structural features of the dulaglutide molecule (1) decrease the rate of clearance, (2) 
increase the duration of pharmacologic activity, (3) may reduce immunogenic potential, and (4) 
may decrease unwanted antibody-mediated effect or function (Barrington et al. 2011; Trulicity 
USPI, 2015). 
Dulaglutide exhibits GLP-1 mediated effects, including glucose-dependent potentiation of 
insulin secretion, inhibition of glucagon secretion, delay of gastric emptying, and weight loss 
(Trulicity USPI, 2015). Preclinical and clinical experience to date support the use of dulaglutide 
as a once-weekly injection to improve glycemic control in patients with T2D (Barrington et al. 
2011). Dulaglutide received regulatory approval in the United States on 18 September 2014 and 
in the European Union on 21 November 2014 for use as monotherapy, in combination with 
OAMs or with insulin for treatment of adult patients with T2D. 
2.2. Study Rationale 
Treatment of T2D starts with lifestyle measures followed by stepwise addition of oral and 
injectable glucose-lowering agents. Combined use of pharmacological agents is common and 
often includes 2, 3, or more classes of therapeutics. The SGLT2 inhibitors and GLP-1 RAs are 
indicated in similar populations and their combined use is of clinical interest; however, clinical 
data are currently limited (Inzucchi et al. 2015). 
An important aspect of the concomitant treatment with these 2 classes of agents is a potential for 
additive or synergistic actions on blood glucose due to their complementary mechanisms of 
action; SGLT2 inhibitors lower blood glucose by increasing excretion of glucose in the urine, 
while GLP-1 RAs enhance glucose-mediated insulin secretion and also suppress glucagon 
(Jardiance USPI, 2014; Bydureon USPI, 2015; Byetta USPI, 2015; Farxiga USPI, 2015; 
Invokana USPI, 2015; Tanzeum USPI, 2015; Trulicity USPI, 2015; Victoza USPI, 2015). 
Similarly, both may lower body weight and blood pressure; therefore, combined use of these 
agents may provide T2D patients with a treatment regimen that is associated with an acceptable 
safety profile, in addition to clinically relevant glucose-lowering effects. 
It is also of particular interest to assess the overall tolerability of the combination therapy, 
including hemodynamic and renal parameters. Sodium-glucose co-transporter 2 inhibitors may 
cause volume depletion due to their osmotic effect in kidney tubules and may be associated with 
impairment in renal function. It has been suggested that this excessive water loss in 
insulinopenic T2D patients may increase the risk of ketoacidosis in the absence of severe 
hyperglycemia. In patients taking a GLP-1 RA, the presence of vomiting or decreased appetite 
may be associated with changes to the patient’s volume status. 

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3. Objectives and Endpoints 
Table GBGE.1 shows the objectives and endpoints of the study. 
 
Table GBGE.1. 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
To demonstrate that once-weekly dulaglutide (1.5 mg 
and/or 0.75 mg) is superior to placebo as measured by 
HbA1c at 24 weeks (change from baseline) in patients 
with inadequately controlled T2D on concomitant 
SGLT2 inhibitor therapy. 
 
The change in HbA1c from baseline to 
24 weeks 
Secondary 
Key secondary efficacy objectives (controlled for type 1 
error) are to compare dulaglutide 1.5 mg and 0.75 mg to 
placebo at 24 weeks 
Other secondary efficacy objectives are to compare 
dulaglutide 1.5 mg and 0.75 mg to placebo at 24 weeks 
Secondary safety objectives are to compare dulaglutide 
1.5 mg and 0.75 mg to placebo at 24 weeks 
 
Proportion of patients with HbA1c target values 
of <7.0% at 24 weeks 
 
The change in FBG (central laboratory) from 
baseline to 24 weeks 
 
The change in body weight from baseline to 
24 weeks 
 
Proportion of patients with HbA1c target values 
of ≤6.5% at 24 weeks 
 
The change in 6-point SMPG profile from 
baseline to 24 weeks 
 
The change in fasting glucagon from baseline 
to 24 weeks 
Incidence of: 
 
Treatment-emergent adverse events (TEAEs) 
 
Early discontinuations due to AEs 
 
Adjudicated cardiovascular and pancreatic AEs 
 
Thyroid neoplasms AEs 
 
AEs related to kidney failure, eGFR 
 
Systemic hypersensitivity AEs 
 
Local injection site reactions 
 
The change in systolic and diastolic blood 
pressure, heart rate, and lipids from baseline to 
24 weeks 
 
Incidence and rate of hypoglycemic episodes 
 
Ketoacidosis, and initiation of rescue therapy 
for severe persistent hyperglycemia 

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Objectives and Endpoints 
Objectives 
Endpoints 
Exploratory 
Exploratory efficacy objectives are to compare 
dulaglutide 1.5 mg and 0.75 mg to placebo at 24 weeks 
 
Proportion of patients meeting the composite 
endpoint of HbA1c <7.0%, no weight gain, and 
no documented symptomatic hypoglycemia 
 
Proportion of patients meeting the composite 
endpoint of HbA1c <7.0%, body weight loss 
>5%, and no documented symptomatic 
hypoglycemia 
Abbreviations: AE = adverse event; eGFR = estimated glomerular filtration rate; FBG = fasting blood glucose; 
HbA1c = hemoglobin A1c; SGLT2 = sodium-glucose co-transporter 2; SMPG = self-monitored plasma glucose; 
T2D = type 2 diabetes. 

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24 weeks 
24 week Treatment Period 
Once-weekly  placebo+SGLT2  inhibitor (±metformin) 
Dulaglutide 0.75 mg/week+SGLT2 inhibitor (±metformin) 
Dulaglutide 1.5 mg/week+SGLT2 inhibitor (±metformin) 
1 week 
1 week 
11 weeks 
1 week 
 
4. Study Design 
4.1. Overview of Study Design 
Study GBGE is a randomized, double-blind, placebo-controlled, parallel-arm, multicenter, 
Phase 3b trial that investigates the effects of the addition of once-weekly dulaglutide 1.5 mg or 
0.75 mg to SGLT2 inhibitors, with or without concomitant use of metformin, on glycemic 
control and safety in patients with inadequately controlled T2D. 
Figure GBGE.1 illustrates the study design. 
 
Study 
Period I  Study Period II 
 
Study Period III 
 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
Visit 
1  2 
3 
4 5 
6 
7 
8 
9 
10 
11 
Week 
-(2-14) -(1-13) -12    -1 0 
2 
4 
8 
12 
18 
24 
 
 
 
Randomization 
End of Treatment Period 
Abbreviations: OAM = oral antihyperglycemia medication; SGLT2 = sodium-glucose 
co-transporter 2. 
a Patients who require adjustment of their OAM regimen to meet eligibility criteria will 
implement treatment changes during the lead-in period (between Visit 2 and Visit 3), all 
other patients will continue with their prestudy regimen without changes. 
b Patients who adjust their OAM regimen during lead-in and/or need to stabilize the 
regimen will perform Visit 3 (end of lead-in) as their next visit and will then enter 1 to 
12-weeks stabilization, as needed. All other patients will skip Visit 3 and 4 and will 
perform Visit 5 as their next visit (approximately 1 week after Visit 2). 
 
Figure GBGE.1. 
Illustration of study design for Clinical Protocol H9X-MC-GBGE. 
 
 
Study Periods 
For each study period and each visit, study procedures are provided in the Schedule of Activities 
(Appendix 2). 
Screening 
Lead-Ina 
Stabilizationb 

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Study Period I:  Screening (Visit 1) 
The purpose of Visit 1 is to initiate the assessment of patient eligibility for participation in the 
trial. Patients who meet all applicable inclusion criteria and none of the applicable exclusion 
criteria at Visit 1 (Section 5.1) will proceed to Visit 2 using the same OAMs (type and dose). 
Study Period II:  Lead-in and Stabilization (Visits 2 to 4) 
The purpose of Visit 2 is to confirm patient eligibility, assess the need for stabilization of the 
OAM regimen, and provide trainings on study procedures. The need for stabilization of a 
patient’s OAM regimen should be based on the requirements for minimum required and stable 
doses of SGLT2 inhibitors and metformin (see Section 5.1 and Section 6.8.1). 
Those patients who meet all enrollment requirements for treatment with stable and minimum 
required doses of SGLT2 inhibitor and metformin at Visit 2 will have blood drawn for baseline 
HbA1c at this visit, followed by a 1-week lead-in using the same treatment regimen (same OAM 
type and dose).  They will then proceed to Visit 5 (randomization visit). 
For patients not meeting dose requirements for allowed OAMs at Visit 2, or who require OAM 
regimen adjustments for other reasons, the investigator will advise the patient on how to adjust 
the OAM regimen between Visit 2 and 3 to meet the study requirements (see Section 6.8.1 for 
details). Those patients not accepting required changes will be considered as ineligible and will 
be discontinued immediately from the trial. 
The patients whose OAM regimen has been changed between Visit 2 and 3 or whose doses of 
SGLT2 inhibitor and/or metformin prior to Visit 2 have not been stable long enough to meet 
eligibility requirements at Visit 5 will perform a stabilization that will last 1 to 12 weeks 
(±3 days), that is, until the time these requirements are met. A blood sample for baseline HbA1c 
for patients who need stabilization will be drawn at Visit 4, approximately 1 week prior to 
Visit 5.  They will then proceed to Visit 5 (randomization visit). 
At Visit 2, eligible patients will receive training on study procedures (Schedule of Activities, 
Appendix 2) including the self-monitoring of plasma glucose (SMPG) plan (daily fasting plasma 
glucose and weekly 4-point SMPG profile [consisting of fasting, pre-lunch, pre-dinner, and 
bedtime PG measurements]), 6-point SMPG profile (before and 2 hours after each main meal), 
lifestyle treatment measures (Section 5.4), signs and symptoms and treatment of hyperglycemia 
(Section 6.6.1.3) and hypoglycemia (Section 6.6.1.2), and use of the study diary.  Single-dose 
pen (SDP) injector training will be completed with the demonstrator device, which does not 
include a needle. 
Study Period III:  Randomization and Treatment Period (Visits 5 through 11) 
At Visit 5, investigators will first review the diary and assess patient eligibility. Patients with 
baseline HbA1c <7.0% or >9.5% will be excluded. Those patients who continue to be eligible 
will be randomized to 1 of the following treatment groups in a blinded fashion: (1) once-weekly 
dulaglutide 1.5-mg injection, (2) once-weekly dulaglutide 0.75-mg injection, or (3) once-weekly 
placebo injection (1:1:1 randomization ratio). Patients should inject their first dose of study drug 
while in the clinic for Visit 5. 

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Study participants will be treated for 24 weeks (treatment period). Study procedures for each 
visit are provided in the Schedule of Activities (Appendix 2). 
Participants are required to continue using their concomitant OAMs throughout the treatment 
period. Discontinuation of these medications or changes in their dose is not permitted, except in 
situations where dose adjustment or complete discontinuation is required per country -specific 
label or when allowed per study protocol, for example, in the case of hypoglycemic episodes (see 
Sections 6.6.1.2 and 6.8.1.1). 
Patients who develop persistent, severe hyperglycemia based on pre-specified thresholds (see 
Section 6.6.1.3) will continue administering study drug and will receive a new glucose-lowering 
intervention (rescue) based on the clinical judgment of the investigator. These patients, as well 
as those who receive rescue therapy after discontinuation of study drug due to an AE or any 
other reason, will be asked to perform all study visits to collect planned efficacy and safety 
measurements. 
Those patients who are unable or unwilling to continue in the study because of an AE (see 
Section 7.1.2 for details) or any other reason, will perform an early termination (ET) visit as their 
final study visit (for procedures at the ET visit , see the Schedule of Activities [Appendix 2]). If 
the patient is discontinuing during an unscheduled visit, that visit should be performed as the ET 
visit. If the patient is discontinuing during a scheduled visit, that visit should be considered the 
ET visit. 
4.2. End of Trial Definition 
End of the trial is the date of the last visit at which data for the primary analysis are collected for 
the last patient (Appendix 2). 
4.3. Scientific Rationale for Study Design 
This trial is designed to be consistent with recommendations provided in a position statement of 
the American Diabetes Association and the European Association for the study of Diabetes 
“Management of Hyperglycemia in Type 2 Diabetes: A Patient-Centered Approach” (Inzucchi et 
al. 2015). Placebo comparator was chosen because it will enable characterization of efficacy and 
safety effects of dulaglutide when added to existing therapy with SGLT2 inhibitors, with or 
without metformin. Compared to a design which utilizes active comparator, comparison to 
placebo will allow assessment of the effect attributable to dulaglutide alone, which is of 
importance especially for the safety aspect of the combined use. The results are expected to 
enable physicians to choose patients suitable for the combination therapy in the clinical setting. 
To protect the safety of patients in the placebo arm who will enter Study GBGE with HbA1c 
above the <7% target, several design features are introduced for this purpose: (a) short trial 
duration (24 week-long treatment period), (b) exclusion of patients considered to have 
unacceptably high baseline HbA1c (>9.5%), and (c) additional glucose-lowering intervention 
(rescue) for patients with unacceptably high glycemia during the treatment period. 
Allowed concomitant medications are chosen because the combined use of dulaglutide with 
SGLT2 inhibitors is of significant clinical interest, but available clinical data are very limited. 

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Metformin is an OAM expected to be used in all patients with T2D as the starting OAM, if 
tolerated and no contraindications for its use are present. 
The parallel group design is an appropriate way to compare treatments as it avoids carry-over 
effect that commonly occurs with cross-over designs, while the proposed randomization scheme 
with stratification is included to minimize between -group heterogeneity.  The planned duration 
of treatment (24 weeks) is considered appropriate as the full effect of randomized treatments on 
blood glucose is expected after approximately 12 weeks of therapy, supported by the results of 
the 6 completed Phase 3 AWARD trials (Dungan et al. 2014; Giorgino et al. 2014; Nauck et al. 
2014; Umpierrez et al. 2014; Wysham et al. 2014; Blonde et al. 2015). The additional 12 weeks 
of treatment will allow for stable HbA1c values to be achieved and is needed because of the 
delay in effect on this parameter, the primary endpoint measure in this trial. 
HbA1c is chosen as the primary efficacy measure as it is the most well accepted surrogate of the 
long-term effect of a treatment regimen on blood glucose and has been shown to be a reliable 
predictor of the long-term outcomes of diabetes (DCCT 1993; UKPDS 1998).  Other key 
efficacy measures (proportion of patients with HbA1c <7%, body weight change, and FBG) are 
standard clinical parameters that are relevant for patients and physicians when assessing the 
effects of treatment in the clinical setting. Similarly, other efficacy and safety measures are 
standard for trials that evaluate glucose-lowering agents and are relevant in clinical decision- 
making. 
The statistical plan will include a graphical testing scheme to strongly control for type 1 error 
and will be applied in the analysis of the primary and the key secondary objectives. This 
approach has been well studied in the scientific literature and has been accepted by regulatory 
agencies for labeling (Bretz et al. 2009). 
4.4. Justification for Dose 
The approved Product Information for dulaglutide includes 2 approved doses, 1.5 and 0.75 mg 
once weekly (Trulicity™ Summary of Product Characteristics [SPC], 2014; Trulicity USPI, 
2015). Doses of SGLT2 inhibitors and metformin are chosen based on the approved regulatory 
labeling for these agents. 
4.5. Benefit/Risk Assessment 
More information about the known and expected benefits, risks, SAEs, and reasonably 
anticipated AEs of dulaglutide are to be found in the IB, US prescribing information (USPI), and 
SPC. 

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5. Study Population 
Study participants should be instructed not to donate blood or blood products during the study or 
for 4 weeks following their last study visit. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted. 
 
5.1. 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), and/or, when explicitly indicated below for specific criteria, at other visits 
during the lead-in/stabilization period (Visits 2 -5): 
[1] are men or non-pregnant women aged ≥18 years at screening; 
[2] have T2D (based on the World Health Organization’s [WHO] diagnostic 
criteria [Appendix 6]); 
[3] have been treated with an SGLT2 inhibitor, with or without metformin, for at 
least 3 months prior to study entry (minimum required doses for that period 
for allowed SGLT2 inhibitors: empagliflozin 10 mg, dapagliflozin 5 or 10 mg 
[per country-specific label], canagliflozin 100 mg [see also Table GBGE.3 for 
details]); minimum required dose for metformin, if used, is ≥1500 mg/day and 
must be reached by Visit 3 (or highest tolerated dose which is acceptable with 
documented GI intolerability, see Section 6.8.1.1.2 for further details); 
[4] daily doses of all allowed OAMs must have been stable for at least 12 weeks 
(±3 days) prior to randomization at Visit 5 (study enrollment); daily doses of 
SGLT2 inhibitor and metformin, if used, will be considered stable during this 
period if: 
[a] all prescribed daily doses were in the range between the minimum- 
required dose (see Inclusion Criterion [3]) and maximum-approved dose 
per country-specific label; and 
[b] >90% of prescribed daily doses were equal to the dose at Visit 5; 
[5] have HbA1c ≥7.0% and ≤9.5% at study entry (Visit 1) and at Visit 2 for 
patients without stabilization; HbA1c ≥7.0% and ≤9.5% at study entry 
(Visit 1) and Visit 4 for patients with stabilization; 
[6] have body mass index (BMI) ≤45 kg/m2 and agree to not initiate a diet and/or 
exercise program during the study with the intent of reducing body weight 
other than the lifestyle and dietary measures for diabetes treatment (see 
Section 5.4); 
[7] are able and willing to administer once-weekly injections; 
[8] in the investigator’s opinion, are well motivated, capable, and willing to: 

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[a] perform finger-stick plasma glucose (PG) monitoring including 
scheduled daily PG profile with up to 6 measurements in 1 day; 
[b] learn how to self-inject treatment, as required for this protocol (visually 
impaired persons who are not able to perform the injections must have 
the assistance of a sig hted 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); 
[c] maintain a study diary, as required for this protocol; 
[9] Women of childbearing potential participating must agree to remain abstinent, 
use 1 highly effective method of contraception or use a combination of 2 
effective methods for the entirety of the study. Abstinence or contraception 
must continue following completion of study drug administration until 4 
weeks after the last dose of study drug. 
[a] Women of childbearing potential must test negative for pregnancy prior 
to initiation of treatment as indicated by a negative serum pregnancy test 
at the screening visit (Visit 1) followed by a negative urine pregnancy 
test within 24 hours prior to exposure (Visit 5). 
[b] Either 1 highly effective method of contraception (eg, combined oral 
contraceptive pill and mini-pill, NuvaRing®, implantable contraceptives, 
injectable contraceptives [such as Depo-Provera®], intrauterine devices 
[such as Mirena® and ParaGard®]) or a combination of 2 effective 
methods of contraception (eg, male condom with spermicide, female 
condom with spermicide, diaphragm with spermicide, cervical sponge, 
cervical cap with spermicide) will be used.  The patient may choose to 
use a double-barrier method of contraception. Each barrier method must 
include use of a spermicide (ie, condom with spermicide, diaphragm with 
spermicide, female condom with spermicide). Note: 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. 
Women not of childbearing potential may participate and are defined as: 
[a] infertile due to surgical sterilization (hysterectomy, bilateral 
oophorectomy, or tubal ligation), congenital anomaly such as Mullerian 
agenesis; or 
[b] postmenopausal woman at least 50 years of age with an intact uterus, 
who has not taken hormones or oral contraceptives within 1 year, AND 
i) who has had either cessation of menses for at least 1 year, OR 
ii) 6 months of spontaneous amenorrhea with follicle-stimulating 
hormone >40 mIU/mL (central lab; Appendix 2) 

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Men participating are not required to use contraception during the study. 
Specific local government requirements that require contraception during the 
study are to be complied with to participate. 
[10] have given written and informed consent to participate in this study in 
accordance with local regulations and the ethical review board (ERB) 
governing the study site. 
 
5.2. Exclusion Criteria 
Patients will be excluded from the study if they meet any of the follo wing criteria at Visit 1 
(study entry), and/or when explicitly indicated below for specific criteria, at other visits during 
the screening and lead-in/stabilization periods (Visits 2-5): 
[11] have type 1 diabetes mellitus; 
[12] have been treated with ANY other OAMs (other than SGLT2 inhibitors and 
metformin), GLP-1 RA, pramlintide or insulin 3 months prior to study entry, 
or between study entry and Visit 5; or initiate metformin between study entry 
and Visit 5; short-term use of insulin for acute care (≤14 days) during the 3- 
month period prior to entry is not exclusionary; 
[13] have any condition that is a contraindication for use of the GLP-1 RA class or 
the SGLT2 inhibitor class (per country-specific labels) at study entry or 
develop such condition between study entry and Visit 5; 
[14] for patients using metformin, if a condition that is a contraindication for its 
use develops between Visit 3 and Visit 5; 
[15] discontinue therapy with SGLT2 inhibitors any time prior to Visit 5 and/or 
metformin, if used, between Visit 3 and Visit 5, based on the Exclusion 
Criteria described under [13] and [14] above, or any other reason; 
[16] have a history of ≥1 episode of ketoacidosis or hyperosmolar state/coma prior 
to study entry; 
[17] have a history of hypoglycemia unawareness within the 6 months prior to 
study entry; 
[18] have been treated with drugs that promote weight loss (eg, Saxenda® 
[liraglutide 3.0 mg], Xenical® [orlistat], Meridia® [sibutramine], Acutrim® 
[phenylpropanolamine], Sanorex® [mazindol], Adipex® [phentermine], 
BELVIQ® [lorcaserin], Qsymia™ [phentermine/topiramate combination], or 
similar over-the-counter [OTC] medications [eg, allī®]) or have received a 
diet and/or exercise program with the intent of reducing body weight  other 
than the lifestyle and dietary measures for diabetes treatment (see Section 5.4) 
within 3 months prior to study entry or between study entry and Visit 5; 

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[19] are receiving chronic (>14 days) systemic glucocorticoid therapy (excluding 
topical, intraocular, intranasal, intra-articular, or inhaled preparations) any 
time between entry and Visit 5 or have received such therapy within 1 month 
prior to study entry; 
[20] have had any of the following cardiovascular (CV) conditions within 
2 months prior to study entry: acute myocardial infarction (MI), New York 
Heart Association (NYHA) Class III or Class IV heart failure, or 
cerebrovascular accident (stroke); 
[21] have a known clinically significant gastric emptying abnormality (eg, severe 
diabetic gastroparesis or gastric outlet obstruction) at study entry, or have 
undergone bariatric surgery (gastric bypass procedure, sleeve gastrectomy, 
adjustable gastric band or biliopancreatic diversion with duodenal switch) in 
the past; 
[22] have acute or chronic hepatitis, signs and symptoms of any other liver disease 
other than nonalcoholic fatty liver disease (NAFLD), or alanine transaminase 
(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; 
[23] had chronic or acute pancreatitis any time prior to study entry; 
[24] have an estimated glomerular filtration rate (eGFR) <45 mL/min/1.73m2, 
calculated by the Chronic Kidney Disease-Epidemiology ( CKD-EPI) 
equation, as determined by the central laboratory at study entry and confirmed 
at Visit 2; 
[25] have evidence of a significant, uncontrolled endocrine abnormality (eg, 
thyrotoxicosis, adrenal crisis) at study entry, in the opinion of the investigator; 
[26] have any self or family history of type 2A or type 2B multiple endocrine 
neoplasia (MEN 2A or 2B) in the absence of known C-cell hyperplasia (this 
exclusion includes patients with a family history of MEN 2A or 2B, whose 
family history for the syndrome is rearranged during transfect [RET]- 
negative; the only exception for this exclusion will be for patients whose 
family members with MEN 2A or 2B have a known RET mutation and the 
potential patient for the study is negative for the RET mutation); 
[27] have any self or family history of medullary C-cell hyperplasia, focal 
hyperplasia, carcinoma (including sporadic, familial, or part of MEN 2A or 
2B syndrome); 
[28] have a serum calcitonin ≥20 pg/mL as determined by the central laboratory at 
study entry; 
[29] have evidence of a significant, active autoimmune abnormality (eg, lupus, 
rheumatoid arthritis) at study entry; 

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[30] have a history of transplanted organ (corneal transplants [keratoplasty] are 
allowed); 
[31] have a history of an active or untreated malignancy, or are in remission from a 
clinically significant malignancy (other than basal or squamous cell skin 
cancer, in situ carcinomas of the cervix, or in situ prostate cancer) during the 
last 5 years prior to study entry; 
[32] have a history of any other condition (eg, known drug or alcohol abuse or 
psychiatric disorder) at study entry, that, in the opinion of the investigator, 
may preclude the patient from following and completing the protocol; 
[33] have any hematologic condition that may interfere with HbA1c measurement 
(eg, hemolytic anemias, sickle-cell disease) at study entry; 
[34] 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; 
[35] are Lilly employees; 
[36] 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; 
[37] are currently enrolled in any other clinical trial involving an investigational 
product or any other type of medical research judged not to be scientifically or 
medically compatible with this study; 
[38] have previously screen failed, withdrawn, discontinued or completed this 
study or been randomized in any other study investigating dulaglutide. 
 
5.3. Screen Failures 
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
re-screened. 
 
5.4. Lifestyle and/or Dietary Requirements 
Per the Schedule of Activities (Appendix 2), qualified medical staff will provide diabetes 
management counseling, which includes diet, 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 stable meal plan (with consistent meal size and time of day) 
throughout the course of the study.  Instruction on how to assess carbohydrate content and 
caloric content of meals may be incorporated into the counseling. Dietary counseling may be 
reviewed throughout the study, as needed. 

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6. Treatment 
6.1. Treatments Administered 
This study involves a comparison of dulaglutide 1.5 mg and dulaglutide 0.75 mg versus placebo, 
given once weekly as a subcutaneous injection in patients with T2D who are already treated with 
a stable dose of SGLT2 with or without stable dose of metformin. Table GBGE.2 shows the 
treatment regimens. 
Table GBGE.2. 
Study Treatments and Concomitant Medications 
Name of Drug 
Dosage 
Frequency 
Drug Formulation 
Route of Administration 
 
Investigational Compound 
Dulaglutide 
1.5 mg 
Once weekly 
Single-dose pen 
Subcutaneous injection 
Dulaglutide 
0.75 mg 
Once weekly 
Single-dose pen 
Subcutaneous injection 
Comparator 
Placebo 
Placebo 
Once weekly 
Single-dose pen 
Subcutaneous injection 
Concomitant SGLT2 inhibitor for all treatment arms 
Canagliflozin 
100 mg or 300 mg 
Once daily 
Tablet 
Oral 
Dapagliflozin 
5 mg or 10 mg 
Once daily 
Tablet 
Oral 
Empagliflozin 
10 mg or 25 mg 
Once daily 
Tablet 
Oral 
Concomitant metformin for all treatment arms 
 
Metformin 
1500 mg to 3000 mga 
Variable 
Tablet/Liquid 
Oral 
Abbreviations:  GI = gastrointestinal; SGLT2 = sodium-glucose co-transporter 2. 
a     Range between minimum required dose of  ≥1500 mg/day (lower [or highest tolerated] dose is acceptable with 
documented GI intolerability) and maximum approved dose for metformin per country-specific label. 
Maximum approved dose may vary across labels. 
 
The investigator or his/her designee is responsible for the following: 
 explaining the correct use of the investigational agent(s) to the patient or patient 
representative, and SDP training with a demonstration device 
 explaining the correct use of concomitant SGLT2 inhibitors and metformin (if 
used) to the patient, including any contraindications and appropriate dosing per 
country-specific labeling 
 verifying that instructions described above are followed properly 
 maintaining accurate records of investigational product dispensing and collection 
Patients should return all unused study drug to the site according to the Schedule of Activities 
(Appendix 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. 
6.2. Method of Treatment Assignment 
Patients who meet all criteria for enrollment will be randomized to double-blind treatment at 
Visit 5.  Assignment to treatment groups will be determined by a computer-generated random 

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sequence using an interactive web-response system (IWRS). The IWRS will be used to assign 
cartons containing double-blind investigational product to each patient. Site personnel will 
confirm that they have located the correct cartons by entering a confirmation number found on 
the carton label into the IWRS. 
Block randomization will be used at the country level. Patients will be randomized in a 1:1:1 
ratio. Stratification for baseline HbA1c (≤8.0%, >8.0%), dose of SGLT2 inhibitor (“low” or 
“high”), and metformin use (“yes” or “no”) will be used to mitigate against baseline 
heterogeneity between treatment groups. For the purpose of patient stratification, low dose of 
SGLT2 inhibitor is defined as the lowest dose approved in any of the participating countries 
(canagliflozin 100 mg, dapagliflozin 5 mg, empagliflozin 10 mg); high dose is defined as any 
dose higher than the low dose. 
6.2.1. Selection and Timing of Doses 
Details of the dosing strategy and administration timing for injectable study drug that are 
provided in this section and the following sections are designed to achieve HbA1c <7.0% 
without hypoglycemia, a standard treatment goal in this population. 
6.2.1.1. Dulaglutide or Placebo Injections 
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. 
Study drug will be administered once weekly. It is recommended that patients inject the study 
drug at approximately the same time of day on the same day each week. If the injection is not 
given on the scheduled day, the missed dose should be given as soon as possible after the 
scheduled day if there are at least 3 days (72 hours) until the next injection. If fewer than 3 days 
remain before the next scheduled injection, the missed dose should be skipped and the next dose 
given at the regularly scheduled time and day. 
6.3. Blinding 
This is a double-blind study. 
To preserve the blinding of the study, a minimum number of Lilly personnel will see the 
randomization table and treatment assignments before the study is complete. 
Emergency unblinding for AEs may be performed through the IWRS, which may supplement or 
take the place of emergency codes generated by a computer drug-labeling system. This option 
may be used ONLY if the patient’s well-being requires knowledge of the patient’s treatment 
assignment.  All calls resulting in an unblinding event are recorded and reported by the IWRS. 
If an investigator, site personnel performing assessments, or patient is unblinded, the patient 
must be discontinued from the study. In cases where there are ethical reasons to have the patient 
remain in the study, the investigator must obtain specific approval from a Lilly clinical research 
physician (CRP) for the patient to continue in the study. 

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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 CRP prior to unblinding 
a patient’s treatment assignment. If a patient’s treatment assignment is unblinded, Lilly must be 
notified immediately. 
6.4. Packaging and Labelling 
The sponsor will provide dulaglutide and placebo in SDPs, which will be dispensed via an 
IWRS. Each SDP (0.75 mg dulaglutide in 0.5 mL OR 1.5 mg dulaglutide in 0.5 mL OR placebo 
in 0.5 mL) is packaged in cartons of 4 pens.  Each carton contains a 4-week supply, as each pen 
is a weekly dose. 
Clinical trial materials will be labeled according to the country’s regulatory requirements. 
 
6.5. Preparation/Handling/Storage 
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 contain ing 4 dulaglutide or placebo SDPs, as required, at 
clinic visits per the Schedule of Activities (Appendix 2). They will receive insulated bags with 
cooling gel packs for use in transporting the SDP carton from the site to home. Investigational 
products in each participating country will be labeled according to the country’s regulatory 
requirements. 
Where appropriate, SGLT2 inhibitors and 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 
case of individual countries, with study team approval, it is acceptable for patients to continue 
obtaining SGLT2 inhibitors by previous prescribing process. In the United States and Puerto 
Rico, a prescription card will be available for patients to obtain these medications, with a 
prescription. 
Clinical trial materials in each participating country will be labeled according to the country’s 
regulatory requirements. 
Dulaglutide demonstration pens will be provided for subcutaneous injection training at the site; 
these pens do not have needles and do not contain study drug. 
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 w hether the patient is correctly administering the assigned 
study drug and storing the study drug according to the provided instructions. 

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6.6. Dose Modification 
No adjustment in injectable study drug dose (dulaglutide or placebo) will be allowed. 
During the 24-week treatment period, participants are required to continue using their 
concomitant OAMs. Discontinuation of these medications or changes in their dose is not 
permitted, except in situations where dose adjustments or complete discontinuation is requir ed 
per country-specific label or when allowed per study protocol, for example, in the case of 
hypoglycemic episodes (Section 6.8.1.1). 
 
6.6.1. Special Treatment Considerations 
6.6.1.1. Standards of Medical Care 
Maintenance of adequate glycemic control in study participants may be enhanced but should not 
be compromised due to trial participation. 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 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 severe, 
persistent hyperglycemia. For effective implementation of measures described here, it is 
important that patients, and their caregivers, if applicable, be well-educated about the signs and 
symptoms of hyperglycemia (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 hyperglycemia or severe 
hypoglycemia between study visits. 
6.6.1.2. Management of Increased Hypoglycemia Risk 
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 should educate and encourage 
patients to measure and record PG values during the symptoms of hypoglycemia and enter the 
results into their study diaries. Patients should be instructed to call the investigative site as soon 
as possible if they experience a hypoglycemic event that requires assistance to administer 
treatment. 
Investigators should use the following definitions and criteria when diagnosing and categorizing 
an episode considered to be related to hypoglycemia: (the PG values in this section refer to 
values determined by a laboratory or International Federation of Clinical Chemistry and 
Laboratory Medicine plasma-equivalent glucose meters and strips) (American Diabetes 
Association 2005): 

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 Documented symptomatic hypoglycemia is defined as any time a patient feels that 
he/she is experiencing symptoms and/or signs associated with hypoglycemia, and has 
a PG level of ≤70 mg/dL (≤3.9 mmol/L). 
 Asymptomatic hypoglycemia is defined as any event not accompanied by typical 
symptoms of hypoglycemia but with a measured PG of ≤70 mg/dL (≤3.9 mmol/L). 
 Probable symptomatic hypoglycemia is defined as an event during which 
symptoms of hypoglycemia are not accompanied by a PG determination (but that was 
presumably caused by a PG concentration of ≤70 mg/dL [≤3.9 mmol/L]). 
 Severe hypoglycemia is defined as an episode requiring the assistance of another 
person to actively administer carbohydrate, glucagon, or other resuscitative actions. 
These episodes may be associated with sufficient neuroglycopenia to induce seizure 
or coma. Plasma glucose measurements may not be available during such an event, 
but neurological recovery attributable to the restoration of PG to normal is considered 
sufficient evidence that the event was induced by a low PG concentration. 
 Nocturnal hypoglycemia is defined as any hypoglycemic event that occurs between 
bedtime and waking. 
Cases of relative hypoglycemia, defined as symptomatic events during which the person reports 
any of the typical symptoms of hypoglycemia and interprets those as indicative of hypoglycemia, 
but a measured PG concentration of >70 mg/dL (>3.9 mmol/L), will also be collected. 
If a hypoglycemic event meets the criteria of severe, it needs to be recorded as serious on the AE 
case report form (CRF) and reported to Lilly as an SAE. 
In each case of suspected or confirmed hypoglycemia, it is important that the event be properly 
categorized, the effect of the intervention be assessed, and the frequency of hypoglycemia be 
evaluated. The role of dietary changes and physical exercise (or any other contributing factor) in 
the development of an event should be established. The patient should receive additional 
education, if deemed appropriate. 
Because of its mechanism of action, no adjustment of dulaglutide dose should be made to 
counteract increased risk of hypoglycemia. If, in the opinion of the investigator, treatment 
regimen requires adjustment because of repeated episodes of hypoglycemia, initial step should 
be dose reduction of metformin, followed by its complete withdrawal, if needed. In the case of 
continuously increased risk of hypoglycemia despite discontinuation of metformin, dose 
reduction or complete withdrawal of the SGLT2 inhibitor is permitted. 
Investigators are responsible for their patients’ management and well-being; therefore, it is their 
responsibility to implement these generally recommended interventions provided above, taking 
into account clinical and other relevant criteria. 
6.6.1.3. Management of Patients with Severe, Persistent Hyperglycemia during 
the Treatment Period 
An additional therapeutic intervention should be considered in patients who develop persistent , 
severe hyperglycemia after randomization based on the following criteria: 

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a) Average daily PG from the 4-point SMPG profile >240 mg/dL over at least a 2-week 
period any time during the first 4 weeks postrandomization; or 
b) Average daily PG >200 mg/dL over a 2-week period at any time after the first 4 weeks 
postrandomization. 
Investigators should first confirm that the patient is fully compliant with the assigned therapeutic 
regimen and that they do not have an acute condition causing severe hyperglycemia. The 
investigator will decide in consultation with the patient on an appropriate glucose-lowering 
intervention (rescue) after considering relevant clinical criteria. Other GLP-1 RAs must not be 
included in the rescue intervention.  Patients who receive a new intervention should also 
continue administering study drug for the remaining period in the trial. 
 
6.7. Treatment Compliance 
The assessment of treatment compliance with study drug (dulaglutide or placebo) will be 
determined by the following: 
 Information about the administration of once weekly study drug injections will be entered 
into the patient diary by the patient and reviewed by the site personnel at each study visit; 
this information will be collected in the eCRF; 
 Study drug accountability will be checked at every visit. For that purpose, patients will 
be instructed to return the study drug carton at the next study visit. They will also be 
instructed to return any unused study drug at the next study visit; 
 In both treatment arms, treatment compliance for once weekly study drug for each visit 
interval is defined as taking at least 75% of the required doses of study drug as assessed 
by site personnel; this information will be entered in the eCRF. 
Other aspects of compliance with the study treatments will also be assessed at each visit based on 
the patient’s adherence to the visit schedule, compliance with the concomitant SGLT2 inhibitor 
and metformin and requirements for non-study glucose-lowering agents, completion of study 
diaries, results of SMPG, and any other parameters the investigator considers necessary. Patients 
considered to be poorly compliant with their  medication and/or the study procedures (for 
example, missed visits or specific diagnostic tests) will receive additional training and 
instructions, as required in the protocol. 
 
6.8. Concomitant Therapy 
Patients are 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 drug. 
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, 
except when initiated for treatment of medical emergencies. Any additional medication initiated 
during the course of the study (including OTC drugs, such as paracetamol or aspirin) must be 
documented, and the name of the drug and the date(s) of administration must be recorded in the 
patient’s diary and on the “Concomitant Medications” section of the eCRF. In addition, for 

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allowed concomitant glucose-lowering agents, the dosage will also be documented and collected 
(SGLT2 inhibitors and metformin). 
Nonstudy medications taken by patients who are screened but not randomized wil l not be 
reported to Lilly unless an SAE or AE occurs that the investigator believes may have been 
caused by a study procedure. 
6.8.1. Antihyperglycemia Medications 
The only glucose-lowering agents that are allowed 3-months prior to study entry and during the 
study are study drug and concomitant SGLT2 inhibitors and metformin. In addition, short-term 
insulin use for management of medical emergencies is allowed prior to study entry and after 
randomization (Visit 5), but not during screening and lead-in/stabilization (Sections 5.1 and 5.2). 
Rescue therapy with other glucose-lowering agents, including insulin, may be medically 
indicated in certain situations after randomization. These situations are described in Section 
6.6.1.3 (severe, persistent hyperglycemia) and in Section 7.1.1 (early discontinuation of study 
drug). If any such situation occurs, the patient may be treated with any locally-approved 
glucose-lowering agent, except other GLP-1 RAs. If insulin is prescribed as a rescue therapy, it 
must be differentiated from short-term use of insulin therapy for medical emergencies when 
reported in the eCRF. 
Patients who receive any glucose-lowering agents 3 months prior to entry or during the screening 
or lead-in/stabilization periods, other than those allowed, will not be eligible for further 
participation in the trial. The patients not using metformin prior to study entry (Visit 1) are not 
allowed to initiate this therapy between study entry and Visit 5 . Patients who violate this 
requirement will be considered as ineligible and will be discontinued from further participation 
in this trial. 
If any new glucose-lowering medication is initiated after randomization at Visit 5, other than 
rescue therapy or short-term use of insulin for medical emergencies, the patient will be required 
to immediately discontinue the medication and the appropriate study deviation report will be 
generated. Any such violation of the protocol that lasted longer than 14 days will exclude the 
patient from the Per Protocol (PP) population. Patients who receive insulin therapy for 
management of medical emergencies >14 days as well as those who receive rescue therapy, will 
also be excluded from the PP population. 
6.8.1.1. Allowed Concomitant OAMs 
The key requirements for use of SGLT2 inhibitors and metformin, the allowed OAMs in 
Study GBGE, are provided in Section 5.1 and Section 5.2.  Table GBGE.3 provides minimum 
required and maximum approved doses for these agents (Note: for SGLT2 inhibitors, these are 
the only approved doses per country-specific labels [“low” and “high” dose]; therefore, no other 
doses should be used during this study). The minimum required doses correspond to the lowest 
recommended dose per country-specific label and may not be the same dose in all participating 
countries. All prescribed doses to the study participants must comply with country-specific 
labels for these medications. 

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Table GBGE.3. 
Required Doses of Concomitant SGLT2 Inhibitors and Metformin in 
Study GBGE for Patients Already Using These Agents 
 
Drug Class 
Minimum-Required Dosea 
Maximum Dosea 
Canagliflozin 
eGFR >60 mL/min/1.73 m2 
100 mg QD 
300 mg QD 
eGFR 45-60 mL/min/1.73 m2 
100 mg QD 
100 mg QD 
eGFR <45 mL/min/1.73 m2 
Contraindicated 
Contraindicated 
Dapagliflozin 
eGFR ≥60 mL/min/1.73 m2 
5 or 10 mg QDb 
10 mg QD 
eGFR <60 mL/min/1.73 m2 
Contraindicated 
Contraindicated 
Empagliflozin 
eGFR >60 mL/min/1.73 m2 
10 mg QD 
25 mg QD 
eGFR 45-60 mL/min/1.73 m2 
10 mg QD 
10 or 25 mg QDb 
eGFR <45 mL/min/1.73 m2 
Contraindicated 
Contraindicated 
Metformin 
eGFR ≥60 mL/min/1.73 m2 
1500 mgc 
2550 mg or 3000 mgb 
eGFR <60 mL/min/1.73 m2 
Contraindicated 
Contraindicated 
Abbreviations: eGFR = estimated glomerular filtration rate; QD = once-daily; SGLT2 = sodium-glucose co- 
transporter 2. 
a Based on the labels approved in participating countries. 
b These doses may differ in different countries, and country-specific labels are required to be followed to reach 
decisions appropriate for individual patients. 
c Lower dose allowed in the case of documented intolerability. 
Note: eGFR calculated by the Chronic Kidney Disease-Epidemiology (CKD-EPI) equation and will be provided by 
the central laboratory. 
 
 
6.8.1.1.1. SGLT2 Inhibitors 
Patients in this study are required to be treated with an SGLT2 inhibitor for at least 3 months 
prior to Visit 1. The dose during this time must be at least the minimum required dose, per 
country-specific label. The dose may be adjusted between Visit 2 and Visit 3, if required per 
label and to comply with the protocol requirements. Dose adjustment may be considered in the 
following situations: 
a) For patients who are on the minimum-required doses of SGLT2 inhibitors that is lower 
than the maximum approved dose at study entry (Visit 1); no further dose increase for 
these patients is required; however, if judged by the investigator as clinically appropriate 
and if allowed per label, dose increase is not prohibited; 
b) For patients with a confirmed eGFR 45 to 59 mL/min/1.73 m2 (see Appendix 2 for 
further details on handling of low eGFR): dapagliflozin, if used, should be immediately 
discontinued when required per label; for these patients, they could either be discontinued 
from the study, or if the local label allows, patients could be prescribed another SGLT2 
inhibitor to maintain eligibility; the dose of canagliflozin and empagliflozin, if used, 
would need to be reduced if required per local label (see Table GBGE.3). 
For patients who adjust their SGLT2 inhibitor regimen between Visit 2 and Visit 3 for reasons 
described under a) and b), or for any other reason per product label, they will be required to 

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undergo stabilization. The type and dose of SGLT2 inhibitor should remain unchanged during 
stabilization. For all randomized patients, the type and dose of the SGLT2 inhibitor should 
remain unchanged during the treatment period other than as described below. 
Those patients who discontinue therapy with SGLT2 inhibitors prior to randomization at Visit 5 
will be discontinued from the trial. 
After randomization, dose adjustment or discontinuation of SGLT2 inhibitors is allowed under 
the following circumstances: 
 in situations that require short-term treatment interruption consistent 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 6.6.1.2). 
Dose reduction/discontinuation of SGLT2 inhibitors during the trial should be properly 
documented. 
In patients who require rescue therapy, dose increase of SGLT2 inhibitors is allowed, but the 
dose and the reason for change must be properly documented in the eCRF. 
6.8.1.1.2. Metformin 
Patients in this study are not required to be treated with metformin to be eligible for 
participation, but if used for at least 3 months prior to study entry, metformin therapy should be 
continued during the entire trial. Those patients not using metformin prior to study are not 
allowed to initiate this medication after entry. Patients who use metformin should have been on 
at least the minimum-required dose for at least 12 weeks prior to randomization at Visit 5. If 
metformin therapy adjustment is required at Visit 2 per label and/or to meet protocol dosing 
requirements, the site personnel will instruct the patient on the changes needed prior to Visit 3. 
Metformin treatment adjustments may be considered in the following situations: 
a) If the dose of metformin is less than the minimum-required (≥1500 mg/day) at Visit 1; 
the dose should be up-titrated based on efficacy and safety parameters per label; 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 (that is, the highest 
tolerated dose) prior to Visit 1 or between Visit 2 and Visit 3; 
b) For patients who are on the minimum-required doses of metformin that is lower than the 
maximum approved dose at study entry (Visit 1), no further dose increase is required; 
however, if judged by the investigator as clinically appropriate and if allowed per label, 
dose increase is not prohibited; 
c) For patients with a confirmed eGFR 45 to 59 mL/min/1.73 m2 (see Appendix 2 for 
further details on the handling of low eGFR); metformin should be immediately 
discontinued when required per country-specific label (see Table GBGE.3); 

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For patients who change their metformin regimen between Visit 2 and Visit 3 for reasons 
described under a), b) and c), or for any other reason per product label, the patient will be 
required to undergo stabilization and the dose should remain unchanged during stabilization. For 
all randomized patients, the dose of metformin should remain unchanged during the entire study 
other than as described below. 
Those patients who discontinue metformin between Visit 3 and Visit 5 will be discontinued from 
the trial. Discontinuation of metformin, if required per label, is allowed prior to Visit 3, in which 
case, the patient will perform stabilization. 
Dose adjustment or discontinuation of metformin is allowed after randomization 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 6.6.1.2). 
Dose reduction/discontinuation of metformin during the trial should be properly documented. 
In patients who require rescue therapy, dose increase or initiation of metformin is allowed, but 
the dose and the reason for change/initiation must be properly documented in the eCRF. 
6.8.2. Medications that Promote Weight Loss 
Prescription or OTC medications that promote weight loss are exclusionary if used 3 months 
prior to study entry, or between study entry and randomization at Visit 5 (see Section 5.2). 
These medications are also not allowed at any time during the treatment period. If started, they 
should be immediately withdrawn. Patients who use any medication from these groups during 
the treatment period will not be included in the PP analysis if the duration of use is >14 days 
(cumulative). In addition, patients should not receive a 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 5.4). 
 
6.8.3. Systemic Glucocorticoids 
Chronic systemic glucocorticoid therapy (with the exception of topical, intraocular, intra- 
articular, or intranasal preparations) is exclusionary if used >14 consecutive days during the 
1-month period before study entry or between study entry and randomization at V isit 5. This 
therapy is not allowed during the treatment period and patients who require >14 days of therapy 
with these medications will not be included in the PP analysis. 
 
6.8.4. 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. If initiation of any new blood pressure 

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lowering agent is required at any time during the study, the type and dose of medication must be 
documented in the eCRF. 
6.9. Treatment after Study Completion 
6.9.1. Continued Access 
After study treatment is discontinued, an appropriate diabetes treatment regimen will be initiated 
by the investigator. 

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7. Discontinuation Criteria 
7.1. Discontinuation from Study Treatment 
Study drug may be interrupted temporarily or discontinued permanently. 
 
7.1.1. Permanent Discontinuation of Study Treatment 
Patients will be permanently discontinued from study drug in the following circumstances: 
 For inadvertently enrolled patients for whom it was determined that continued treatment 
with study drug would not be medically appropriate (see Section 7.1.4); 
 Exclusion Criteria [31] and [38] develop(s), after randomization (see Section 5.2); 
 The patient is diagnosed by the investigator with an AE of acute or chronic pancreatitis; 
 A patient is diagnosed with C-cell hyperplasia or medullary thyroid carcinoma after 
randomization; 
 If a patient develops an eGFR <30 mL/min/1.73m2 as calculated by CKD-EPI; 
 If the patient or the patient’s designee, for example, legal guardian, requests to be 
withdrawn from study drug; 
 If the investigator or sponsor decides that the patient should be withdrawn from study 
drug; if the sponsor decides to permanently discontinue study treatment because of an 
SAE or a clinically significant laboratory value, Lilly or its designee should be alerted 
immediately [see Section 8.2.1]); 
 Discontinuation of the investigational product for abnormal liver tests should be 
considered by the investigator when a patient meets one of the following conditions after 
consultation with the Lilly designated medical monitor: 
o ALT or aspartate aminotransferase (AST) >8X upper limit of normal (ULN) 
o ALT or AST >5X ULN for more than 2 weeks 
o ALT or AST >3X ULN and total bilirubin level (TBL) >2X ULN or prothrombin 
time >1.5X ULN 
o ALT or AST >3X ULN with the appearance of fatigue, nausea, vomiting, right 
upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
o Alkaline phosphatase (ALP) >3X ULN 
o ALP >2.5X ULN and TBL >2X ULN 
o ALP >2.5 ULN with the appearance of fatigue, nausea, vomiting, right upper- 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
Those patients who stop the study drug permanently will receive another glucose-lowering 
intervention (rescue) and will continue participation in the trial according to the protocol, to 
collect all planned efficacy and safety measurements. The rescue intervention must not include 
another GLP-1 RA. 

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7.1.2. Permanent Discontinuation from the Study 
Every attempt should be made to keep patients in the trial irrespective of their adherence to 
treatment with study drug in order to minimize the amount of missing data and to enable 
assessment of study objectives as planned by the study protocol. Patient discontinuation from 
the study early may be warranted in the following situations for ethical or legal reasons: 
 Exclusion Criterion [11] 
 When a female patient becomes pregnant; 
 When a patient is enrolled in another clinical trial involving an investigational product or 
is enrolled in any other type of medical research judged not to be scientifically or 
medically compatible with this study. 
Patients may also discontinue from the study due to: 
 Sponsor or Investigator Decision 
o If Lilly or its designee stops the study or if Lilly or the investigator stops the 
patient’s participation in the study for medical, safety, regulatory, or other reasons 
consistent with applicable laws, regulations, and good clinical practice (GCP) 
 Patient Decision 
o 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 (Appendix 2). 
During the ET visit the patient will be prescribed an appropriate glucose-lowering regimen and 
glucose self-monitoring plan. 
 
7.1.3. Temporary Interruption of Study Treatment 
In certain situations after randomization, the investigator may need to temporarily discontinue 
(interrupt) study drug (for example, due to an AE or a clinically significant laboratory value). If 
study drug interruption is due to an AE, the event is to be documented and followed according to 
the procedures in Section 8.2 of this protocol. Investigators should inform the Sponsor that study 
drug has been temporarily interrupted. Every effort should be made by the investigator to 
maintain patients on study drug and to restart study drug after any temporary interruption, as 
soon as it is safe to do so. The data related to temporary interruption of study treatment will be 
documented in source documents and entered in the eCRF. 
7.1.4. Discontinuation of Inadvertently Enrolled Patients 
If the sponsor or investigator identifies a patient who did not meet enrollment criteria and was 
inadvertently enrolled, a discussion must occur between the sponsor CRP and the investigator to 
determine if the patient may continue in th e 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. An inadvertently enrolled patient may be allowed to continue treatment 

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with study drug only if the principal investigator and Lilly study physician responsible for 
medical monitoring of this trial agree that it is safe for the patient to do so. 
7.1.5. Patients Lost to Follow-Up 
A patient will be considered lost to follow -up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Site personnel are expected to make 
diligent attempts to contact patients who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the site. 

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8. Study Assessments and Procedures 
Appendix 2 lists the Schedule of Activities, with the study procedures and their timing (including 
tolerance limits for timing). 
Appendix 3 lists the laboratory tests that will be performed for this study. 
Appendix 5 provides a summary of the maximum number and volume of invasive samples, for 
all sampling, during the 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 (Sections 8.7 and 8.8). 
8.1. Efficacy Assessments 
8.1.1. Primary Efficacy Assessments 
The primary efficacy measure is change in HbA1c from baseline at 24 weeks. 
 
8.1.2. Secondary Efficacy Assessments 
The following key secondary efficacy measures will be evaluated at 24 weeks: 
 Proportion of patients achieving HbA1c target of <7.0% 
 Changes in FBG from baseline measured at the central laboratory 
 Changes in body weight from baseline 
Other secondary efficacy measures will also be evaluated at 24 weeks: 
 Proportion of patients achieving HbA1c target of ≤6.5% 
 Changes from baseline in PG from 6-point SMPG profile 
 Changes in fasting glucagon from baseline 
 
8.1.3. Exploratory Assessments 
The following exploratory measures will be evaluated at 24 weeks: 
 Percentage of patients achieving HbA1c target <7.0%, with no weight gain and no 
documented symptomatic hypoglycemia 
 Percentage of patients achieving HbA1c target <7.0%, with body weight loss >5%, and 
no documented symptomatic hypoglycemia 

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8.1.4. Appropriateness of Assessments 
Efficacy and safety assessments included in this study are generally regarded as reliable and 
accurate with respect to the efficacy and safety assessments in individuals and populations with 
T2D. 
8.2. Adverse Events 
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the patient. 
The investigator is responsible for the appropriate medical care of patients during the study. 
Investigators must document their review of each laboratory safety report. 
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the investigational 
product or the study, or that caused the patient to discontinue the investigational product before 
completing the study. The patient should be followed until the event resolves, stabilizes with 
appropriate diagnostic evaluation, or is reasonably explained. The frequency of follow-up 
evaluations of the AE is left to the discretion of the investigator. 
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
establish treatment effect. 
After the informed consent form (ICF) is signed, study site personnel will record via eCRF the 
occurrence and nature of each patient’s preexisting conditions, including clinically significant 
signs and symptoms of the disease under treatment in the study. In addition, site personnel will 
record via eCRF 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 decides whether he or she interprets the observed AEs as reasonably possibly 
related to disease, to the investigational product, study device, study procedure, or other 
concomitant treatment or pathologies. To assess the relationship of the AEs, the following is 
defined: 
Reasonably Possibly Related: Reasonable possibility 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. 

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8.2.1. Serious Adverse Events 
An SAE is any AE from this study that results in one 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 after signing the ICF are recorded in the eCRF, SAE reporting begins after the 
patient has signed the ICF and has received investigational product. However, if an SAE occurs 
after signing the ICF, but prior to receiving investigational product, it needs to be reported 
ONLY if it is considered reasonably possibly related to study procedure. 
Study site personnel must alert Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a sponsor-approved method. If alerts are issued via telephone, they 
are to be immediately followed with official notification on study-specific SAE forms. This 
24-hour notification requirement refers to the initial SAE information and all follow -up SAE 
information. 
Pregnancy (during maternal or paternal exposure to investigational product) does not meet the 
definition of an AE. However, to fulfill regulatory requirements any pregnancy should be 
reported following the SAE process to collect data on the outcome for both mother and fetus. 
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued and/or completed the study (the patient summary CRF has been completed). 
However, if the investigator learns of any SAE, including a death, at any time after a subject has 
been discharged from the study, and he/she considers the event reasonably possibly related to the 
study treatment or study participation, the investigator must promptly notify Lilly. 
Requirements for the reporting of severe hypoglycemia episodes, AEs of pancreatitis, and AEs 
of systemic hypersensitivity as SAEs are found in Section 8.2.2. 
8.2.1.1. 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 guidances 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 guidances. 

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8.2.2. Adverse Events of Interest 
8.2.2.1. Hypoglycemia and Hyperglycemia 
Patients will collect information on episodes of hypoglycemia between Visit 2 and the last study 
visit (Visit 11 or ET visit).  For that purpose, patients will be trained about signs and symptoms 
of hypoglycemia, how to treat hypoglycemia, and how to collect appropriate information for 
each episode of hypoglycemia in the study diary (see Section 6.6.1.2) according to the Schedule 
of Activities (Appendix 2). Site personnel will enter this information into the eCRF at each visit 
after Visit. 
Events of interest related to hyperglycemia (rescue therapy for severe, persistent hyperglycemia, 
per criteria specified in Section 6.6.1.3, and ketoacidosis) will be collected during the trial to 
assess the risk of extreme disbalance in glycemic control. 
8.2.2.2. Pancreatitis 
Acute pancreatitis is defined as an AE of interest in all trials with dulaglutide, including this trial. 
Acute pancreatitis is an acute inflammatory process of the pancreas that may also involve 
peripancreatic tissues and/or remote organ systems (Banks and Freeman 2006). The diagnosis of 
acute pancreatitis requires 2 of the following 3 features: 
1. 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); 
2. Serum amylase (total and/or pancreatic) and/or lipase ≥3×ULN; or 
3. 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 supports 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 6.8.1 and 
Section 7.1.1 for details on rescue intervention). The most appropriate diabetes therapeutic 
regimen will be decided by the investigator, based on the patient’s clinical status. A review of 
the patient’s concomitant medications should be conducted to assess any potential causal 
relationship with pancreatitis . 
Each case of AE of pancreatitis must be reported.  If typical signs and/or symptoms of 
pancreatitis are present and confirmed by laboratory values (lipase or amylase [total and/or 
pancreatic]) and imaging studies, the event must be reported as an SAE.  For a potential case that 

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does not meet all of these criteria, it is up to the investigator to determine the seriousness of the 
case (AE or SAE) and the relatedness of the event to study drug. 
In addition to the diagnostic assessment in patients who develop symptoms of acute pancreatitis, 
each patient will have measurements of pancreatic amylase and lipase at screening, baseline, and 
the last study visit (Visit  11 [Week 24] or ET visit), to assess any potential effects of dulaglutide 
on the exocrine pancreas (refer to the Schedule of Activities, Appendix 2). Further diagnostic 
assessment per Lilly algorithm for assessment of asymptomatic pancreatic hyperenzymemia will 
be required whenever lipase and/or pancreatic amylase are ≥3×ULN at any time during the study. 
If this situation occurs at Visit 11 (Week 24), the patient will be required to undergo this 
additional work-up, and the data will be collected in the clinical trial database. 
All AEs of acute or chronic pancreatitis, as well as cases of confirmed lipase or pancreatic 
amylase values ≥3×ULN, will be adjudicated by an independent committee of expert physicians. 
In addition, AEs of severe or serious abdominal pain of unknown etiology will also be submitted 
to the adjudication committee to assess for possible pancreatitis or other pancreatic dis ease. 
Relevant data from patients with acute or chronic pancreatitis, those with severe or serious 
abdominal pain, and those that undergo additional assessments due to confirmed 
hyperenzymemia will be entered into a specifically designed eCRF page by study site or Lilly 
staff. The adjudication committee representative will enter the results of adjudication in a 
corresponding eCRF page. 
8.2.2.3. C-Cell Hyperplasia and C-Cell Neoplasms 
Individuals with personal or family history of certain thyroid or nonthyroid endo crine 
abnormalities or certain preexisting laboratory and genetic characteristics will be excluded from 
the study (see Section 5.2).  The assessment of thyroid safety during the trial will include 
reporting of thyroid treatment-emergent adverse events (TEAEs) and measurements of calcitonin 
according to the Schedule of Activities (Appendix 2) at screening, baseline, and Visit 11 
(Week 24). The purpose of calcitonin measurements is to assess the potential of dulaglutide 
versus placebo to affect the thyroid C-cell function, which may indicate development of C-cell 
hyperplasia and neoplasms. 
Patients who develop serum calcitonin increases ≥50% of the mean of the baseline and screening 
values AND an absolute value ≥20 pg/mL and <35 pg/mL at Visit 11 (Week 24) will be asked to 
repeat the measurement within 1 month. If this repeat value is increasing (≥10% increase), the 
patient will be recommended that he or she undergo additional endocrine assessment and longer- 
term follow-up by an endocrinologist to exclude a serious adverse effect on the gland. 
Patients with an increase in serum calcitonin ≥50% of the mean of the baseline and screening 
values AND an absolute value ≥35 pg/mL at Visit 11 (Week 24) will be recommended to 
immediately undergo additional endocrine assessments and longer term follow-up by an 
endocrinologist. 

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For patients who require additional endocrine assessment because of increased calcitonin 
concentration per criteria provided in this section, data from the follow-up assessment will be 
collected in the specific section of the eCRF. 
8.2.2.4. Cardiovascular Events 
Deaths and nonfatal CV AEs will be adjudicated by a committee of physicians external to Lilly 
with cardiology expertise. The nonfatal CV AEs to be adjudicated include: MI; hospitalization 
for unstable angina; hospitalization for heart failure; coronary interventions (such as coronary 
artery bypass graft or percutaneous coronary intervention); and cerebrovascular events, including 
cerebrovascular accident (stroke) and transient ischemic attack (TIA). 
8.2.2.5. 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. 
8.2.2.6. Allergic/Hypersensitivity Reactions 
All allergic or hypersensitivity reactions will be reported by the investigator as either AEs or, if 
any serious criterion is met, as SAEs. Additional data, such as type of reaction and treatment 
received, will be collected on any AEs or SAEs that the investigator deems related to study drug 
via a CRF created for this purpose. Study drug should be temporarily interrupted in any 
individual suspected of having a severe or serious allergic reaction to study drug (Section 7.1.3). 
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, the patient will receive another glucose-lowering treatment, 
judged by the investigator to be appropriate based on the patient’s clinical status, and will 
continue in the trial to collect all planed efficacy and safety measurements (see Section 6.8.1 and 
Section 7.1.1). 
 
8.2.3. 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. 
 
8.3. Treatment of Overdose 
Study drug overdose will be reported as an AE. In the event of overdose, refer to the IB and/or 
Product Label. 
 
8.4. Safety Assessments 
8.4.1. Electrocardiograms 
Episodes of symptomatic hypotension have been reported in patients treated with SGLT2 
inhibitors, while treatment with dulaglutide increases the mean heart rate (HR) (2 to 4 beats/min) 
and the mean duration of the PR interval (2 to 3 msec). To assess the effect of their combined 

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use on cardiac electrophysiology in Study GBGE , electrocardiograms (ECGs) will be collected 
according to the Schedule of Activities (Appendix 2) and centrally overread. Electrocardiograms 
should be recorded according to the study-specific recommendations included in the Manual of 
Operations for the study, using standardized equipment provided by the Sponsor. 
Each ECG tracing will be assessed by the investigator immediately upon recording for clinical 
management purposes. Any clinically significant findings from ECGs that result in a diagnosis 
and that occur after the patient receives the first dose of the investigational treatment should be 
reported to Lilly or its designee as an AE via eCRF. Results of the central overread will be 
entered into the clinical trial database and will be used for the statistical analysis of the effects of 
the randomized treatments. In addition, once the overread ECG is returned from the centralized 
ECG vendor, the investigator, or qualified designee, is responsible for determining if any change 
to the patient management is needed. The investigator, or qualified designee, must document 
his/her review of the ECG printed at the time of evaluation, the final overread ECG report issued 
by the central ECG laboratory, and any alert reports. 
 
8.4.2. Blood Pressure and Heart Rate 
Sitting blood pressure (BP) and HR will be measured according to the Schedule of Activities 
(Appendix 2), using standardized equipment provided by the Sponsor. Vital sign measurements 
should be taken before obtaining an ECG tracing, at visits where required (see Schedule of 
Activities, Appendix 2), and before collection of blood samples for laboratory testing. For each 
parameter, 2 measurements will be taken using the same arm. 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. Each 
measurement of sitting HR and BP is to be recorded in the eCRF. Any AE related to changes in 
BP and HR should be reported, per requirements provided in Section 8.2. 
8.4.3. Laboratory Tests 
For each patient, laboratory tests detailed in Appendix 3 should be conducted according to the 
Schedule of Activities (Appendix 2). 
Any clinically significant findings from laboratory tests that result in a diagnosis and that occur 
after the patient receives the first dose of investigational product should be reported to Lilly or its 
designee as an AE via eCRF. 
 
8.4.4. Body Weight and Body Mass Index 
Body weight will be measured at prespecified time points (see Schedule of Activities,  Appendix 
2). Each patient’s weight should be measured according to a standardized protocol ( Appendix 7). 
Body mass index will be computed from the patient’s weight and height. 
 
8.4.5. 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. Lilly will also 
review SAEs within time frames mandated by company procedures. The Lilly study physician 

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will, as appropriate, consult with the functionally independent Global Patient Safety therapeutic 
area physician or clinical scientist. 
In addition, specific safety measures are included in the protocol to ensure appropriate 
monitoring of pancreatic, thyroid, and liver safety. Laboratory findings that trigger pancreatic 
and thyroid safety monitoring per Lilly standards are provided in Section 8.2.2.2 and 8.2.2.3. 
Details of the liver safety monitoring are provided in Appendix 4. If a study patient experiences 
elevated ALT ≥3X ULN, ALP ≥2X ULN, or elevated TBL ≥2X ULN, clinical and laboratory 
monitoring should be initiated by the investigator. Details for hepatic monitoring depend upon 
the severity and persistence of observed laboratory test abnormalities. To ensure patient/subject 
safety and comply with regulatory guidance, the investigator is to consult with the Lilly CRP 
regarding collection of specific recommended clinical information a nd follow-up laboratory 
tests. 
 
8.5. Pharmacokinetics 
Not applicable. 
 
8.6. Pharmacodynamics 
Not applicable. 
 
8.7. Genetics 
A blood sample will be collected for pharmacogenetic analysis where local regulations and 
ERBs allow (Appendix 2). These samples are not being collected to create a biobank for 
conducting unspecified disease or population genetic research either now or in the future. 
Samples may be used to investigate variable response to dulaglutide, and to investigate genetic 
variants thought to play a role in diabetes and diabetes-related complications. Assessment of 
variable response may include evaluation of AEs or differences in efficacy. These studies may 
include but are not limited to the genetic variants in drug target pathway (glucagon-like peptide 1 
receptor [GLP1R]) genes and genes associated with diabetes and related complications (eg, 
transcription factor 7-like 2 [TCF7L2]).  Samples will be retained for a maximum of 15 years 
after the last subject visit, or as local regulations and ERBs allow, for the study at a facility 
selected by the sponsor. 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 drug development or when the drug is commercially available. Molecular technologies are 
expected to improve during the 15 year storage period and therefore cannot be specifically 
named.  However, existing approaches include whole genome or exome sequencing, genome 
wide association studies, candidate gene studies, a nd epigenetic analyses. Regardless of the 
technology utilized, genotyping data generated will be used only for the specific research scope 
described here. 
8.8. Biomarkers 
Serum and plasma samples for non-genetic biomarker research will be collected at the times 
specified in the Schedule of Activities (Appendix 2) where local regulations and ERBs allow. 

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Samples will be used for research on the drug target, disease process, pathways associated with 
T2D, mechanism of action of dulaglutide, and/or research method or in validating diagnostic 
tools or assay(s) related to T2D. 
All biomarker 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. Samples will 
be destroyed according to a process consistent with local regulations. 
Samples will be retained for a maximum 15 years after the last patient visit for the study, or for a 
shorter period if local regulations and ERBs impose shorter time limits, at a facility selected by 
the sponsor. This retention period enables use of new technologies, response to regu latory 
questions, and investigation of variable response that may not be observed until later in drug 
development or when the drug is commercially available. 
8.9. Health Economics 
Not applicable. 

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9. Statistical Considerations and Data Analysis 
9.1. Determination of Sample Size 
The study will need 101 completers per arm in order to have 90% probability of achieving 
statistical significance for either dulaglutide 1.5 mg or 0.75 mg versus placebo in change from 
baseline in mean HbA1c at 24 weeks, assuming a standard deviation (SD) of 1.2%, a difference 
between dulaglutide and placebo of 0.6%, and a 2-sided significance level of 0.025. Assuming 
that the dropout rate is 15% for the entire study period, the study will need to enroll at least 
119 patients in each arm for a total of 357 patients enrolled. Assuming a screen fail rate of 40%, 
a total of 595 patients will be screened to meet these enrollment number requirements. 
9.2. 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 will be conducted as deemed appropriate. 
The primary analysis population will be the intent -to-treat (ITT) population, defined as all 
patients randomized who have received at least 1 dose. This is also the safety population. A 
select number of measurements (HbA1c, percent to goal in HbA1c, FBG, and body weight) will 
also be evaluated in the PP population. The PP population will be based on patients who were 
compliant with study medication, took no concomitant medications that would confound the 
interpretation of results (such as systemic steroids or non-study glucose-lowering agents used 
>14 days), and have an HbA1c measurement at the primary visit endpoint. 
Analyses of certain efficacy outcomes (HbA1c, percent to goal in HbA1c, FBG, body weight) 
and hypoglycemia will be performed on the full dataset with censoring as primary (ie, to exclude 
data collected after initiation of rescue with glucose-lowering therapy for reasons described in 
Section 6.6.1.3, Section 6.8.1, and Section 7.1.1). These same analyses will also be performed 
without censoring post rescue data as sensitivity analyses. 
Unless otherwise noted, all tests of treatment effects will be conducted at a 2-sided alpha level of 
0.05, and confidence intervals (CIs) will be calculated at 95%, 2-sided. All tests of interactions 
between treatment groups and other factors will be conducted at a 2-sided alpha level of 0.10. 
The baseline will be Visit 5, except for HbA1c. Patients who do not need stabilization will have 
blood drawn for baseline HbA1c at Visit 2, and those who need stabilization at Visit 4. For all 
variables except HbA1c, if baseline data are missing, the last nonmissing measurement taken 
prior to Visit 5 will be used for the baseline measurement. For HbA1c, if baseline data are 
missing, the imputation will be conducted only if an additional value between Visit 2 and 
randomization (patients not needing stabilization) or Visit 4 and randomization (patients needing 
stabilization) is collected. The endpoint for the primary analysis is defined as the change from 
baseline in HbA1c at 24 weeks (Visit 11). Key secondary endpoints are percent to goal in 

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HbA1c (<7.0%) at 24 weeks and change from baseline in FBG (central laboratory) and body 
weight at 24 weeks. 
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) (Section 9.4.1). An unstructured covariance structure 
will be used to model the within-patient errors. If this model fails to converge, the following 
covariance structures will be tested in order: 
 Toeplitz with heterogeneity 
 autoregressive with heterogeneity, by visit 
 compound symmetry with heterogeneous variances by visit, 
 Toeplitz, autoregressive 
 compound symmetry without heterogeneous variances, by visit 
The first covariance structure that converges will be used. 
The secondary analysis for the primary and key secondary continuous endpoints will be analysis 
of covariance (ANCOVA) (Section 9.4.2). Missing endpoints will be imputed with the last 
(postbaseline) observation carried forward (LOCF). The percentage of patients achieving the 
target HbA1c of <7.0% at 24 weeks will be analyzed using a longitudinal logistic regression with 
repeated measurements (Section 9.4.2). 
A graphical testing approach will be used to strongly control for type 1 error to test for 
superiority of each of the dulaglutide doses versus placebo at 24 weeks for the following 
measures: (1) change from baseline in HbA1c, (2) change from baseline in FBG (central 
laboratory), (3) percent achieving HbA1c <7.0%, and (4) change from baseline in body weight. 
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 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 (dulaglutide – 
placebo), along with the p-values for the treatment comparisons. 
For categorical measures, summary statistics will include sample size, frequency, and 
percentages. Fisher’s exact test will be used for treatment comparisons, unless 80% of cells have 
an expected value of at least 5, in which case the chi-square test will be used. 
9.3. Treatment Group Comparability 
9.3.1. Patient Disposition 
A detailed description of patient disposition will be provided at the end of the study. 
Frequency counts and percentages of all patients entered, randomized/enrolled, completing, 
discontinuing from the study drug early, and discontinuing from the study early will be presented 
for each of the treatment groups. The reasons for discontinuation from the study and/or study 

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drug will be summarized by treatment group. A summary of discontinuations will also be 
presented by visit. 
The overall percent discontinued comparisons among the treatment groups will be performed 
using a chi-square test. 
 
9.3.2. Patient Characteristics 
Demographic and baseline characteristics will be summarized for both treatment arms. 
 
9.3.3. Concomitant Therapy 
Glucose lowering agents will be summarized by treatment at entry, baseline (Visit 5), and for the 
entire 24-week treatment period. Doses of SGLT2 inhibitors and metformin will be summarized 
at baseline (Visit 5). Other prespecified concomitant medications of interest will be summarized 
by treatment at baseline (Visit 5). Frequency of use of non-study glucose-lowering medications 
will be summarized at baseline (Visit 5) and for the entire 24-week treatment period by treatment 
group. 
9.3.4. Treatment Compliance 
Treatment compliance for each visit interval is defined as taking at least 75% of required 
injections. Overall compliance is defined as being at least 75% compliant with study drug for at 
least 75% of the visits. The investigator will advise the patient that injections should be given at 
approximately the same time of the day, on the same day of the week. Compliance will be 
summarized by all treatment arms, by visits and overall. Listings will also be produced. 
9.4. Primary and Secondary Analyses 
9.4.1. Primary Outcome Measure and Analyses 
The primary outcome is an efficacy estimand defined as the difference in HbA1c mean change 
from baseline to 24 weeks in the ITT population with post-rescue data censored (excluded). The 
primary hypothesis of interest in this placebo-controlled study is whether dulaglutide has 
superior efficacy compared to placebo, in patients already treated with SGLT2 inhibitors, without 
confounding with rescue therapy. 
The primary analysis model will be an MMRM for HbA1c change from baseline to 24 weeks in 
the ITT population (Visit 11) with treatment, country, SGLT2 inhibitor dose (“low” vs. “high”; 
see Section 6.2), metformin use (“yes” vs. “no”), visit and treatment-by-visit as fixed effects, 
baseline HbA1c as a covariate, and patient as a random effect. 
9.4.1.1. Additional Analyses of the Primary Outcome 
The primary analysis model, MMRM, will be repeated using the PP population to check the 
sensitivity of the analys is. If the conclusion differs from that of the ITT population, the data and 
analyses will be further investigated. The secondary analysis model will be an ANCOVA for 
HbA1c change from baseline to 24 weeks (Visit 11), using a similar model as described above 
with treatment, country, SGLT2 inhibitor dose (“low” versus “high”), and metformin use (“yes” 

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versus “no”) as factors and baseline HbA1c as a covariate. Missing endpoints will be imputed 
with the LOCF using postbaseline data only. 
To investigate departure from the Missing At Random (MAR) assumption for the primary 
analysis that excludes post-rescue data, a sensitivity analysis using a particular missing not at 
random (MNAR) assumption will be performed. Specifically, a placebo multiple imputation 
(pMI) will be performed (Ayele et al. 2014), which assumes that the drug effect in missing data 
and post-rescue data in both the placebo arm and dulaglutide arm was like the observed effect in 
the placebo arm (excluding post-rescue data). This is essentially the “copy reference” approach 
as described in Carpenter et al. 2013. This approach is in essence assuming that the drug effect 
will decay over time, in accordance with the correlation structure implied by the data. Data 
imputed this way will be analyzed with the same MMRM model as the primary analysis. This 
particular MNAR assumption can be viewed as a “worst reasonable case” assess ment of the 
efficacy estimand, or as an effectiveness estimand that assumes patients with missing data or 
rescued patients received no drug benefit after dropout or rescue. 
Also of interest is the effectiveness/treatment regimen estimand that evaluates the difference in 
mean HbA1c change from baseline to 24 weeks in the ITT population regardless of treatment 
discontinuation or use of rescue therapy (ITT estimand). Therefore as a supportive analysis, 
MMRM will be performed on the ITT population with all post-rescue data up to the primary 
endpoint of 24 weeks included. 
For both the efficacy estimand (missing data and post-rescue data both considered as missing), 
and the ITT estimand (post-rescue data not treated as missing), a tipping point analysis will be 
performed in which the missing data are imputed with a MAR assumption. However, prior to 
analysis, in the dulaglutide arm the imputed values will be replaced by the imputed value plus 
delta. Multiple values of delta will be tried until the value at which the conclusion from the 
MMRM analysis changes. 
9.4.2. Secondary Outcome Measures and Analyses 
The key secondary continuous efficacy measures will also be analyzed using both models, the 
MMRM and the ANCOVA with LOCF models described above (with and without censoring 
data collected after initiation of rescue intervention). Analysis of other secondary efficacy 
measures that are continuous variables, except glucagon (for glucagon, see Section 9.5.6), will be 
performed using MMRM on the ITT population. There will be no multiplicity adjustment for 
pairwise comparisons.  The MMRM and ANCOVA models will include the model terms given 
for the previously described primary analysis model with the addition of the HbA1c strata 
(≤8.0%, >8.0%). 
For percentages of patients achieving target HbA1c of <7.0% (including exploratory composite 
endpoints with body weight and hypoglycemia) or ≤6.5% at 24 weeks, longitudinal logistic 
regression with repeated measurements will be used. The model will include independent 
variables treatment, country, visit, treatment-by-visit, and baseline HbA1c as a covariate. These 
analyses will be performed with post-rescue data excluded (considered missing), and separately 
with all post-rescue data included. In addition, an analysis of percentage of patients on HbA1c 

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targets will be performed where patients who have been rescued or have no post-baseline data 
being considered (imputed) as not having achieved the target. 
9.5. Safety Analyses 
The safety analysis will include measurements of AEs, SAEs, hypoglycemic and hyperglycemic 
episodes, and laboratory analytes. Unless otherwise specified, the ITT population will be used 
for analyses of safety measures. 
9.5.1. Study Drug Exposure 
Exposure to each study treatment will be calculated for each patient and summarized by 
treatment group. The time points for exposure summaries will be defined in the SAP. 
9.5.2. Adverse Events 
Adverse events will be coded from the actual term using the Medical Dictionary for Regulatory 
Activities (MedDRA) and reported in preferred term and system organ class (SOC). Selected 
notable AEs of interest may be reported using high-level terms. All AEs and TEAEs, defined as 
postbaseline events that are new events or preexisting conditions that worsened in severity after 
randomization, will be listed by patient and visit.  Information on treatment, actual term, 
preferred term, severity, seriousness, and relationship to study drug will also be reported. 
Summary statistics will be provided of TEAEs, SAEs, and study discontinuation due to AEs or 
death during the treatment period. Counts and proportions of patients experiencing AEs will be 
reported for each treatment group, and chi-square tests will be used to compare the treatment 
groups. 
Listings of patients experiencing allergic and hypersensitivity reactions, as well as those 
discontinuing the study due to AEs, will be produced. 
 
9.5.3. Hypoglycemic Episodes 
Section 6.6.1.2 contains definitions of categories of hypoglycemia. A listing of individual 
hypoglycemic episodes by patient will be presented. Summary reports will include both 
incidence and rates of hypoglycemia for the ITT population (with post-rescue data censored, and 
without post-rescue data censored). Hypoglycemia will be categorized as “documented 
symptomatic,” “asymptomatic,” “probable,” “severe,” or “nocturnal,” and for all events 
combined, “total hypoglycemia.” Only “documented symptomatic” and “total hypoglycemia” 
will be analyzed inferentially. 
Baseline hypoglycemia risk will be established based on hypoglycemia events recorded between 
Visit 2 and Visit 5. The incidence of hypoglycemic episodes will be summarized by frequencies 
and percentages for each treatment group, by visit as well as overall. Treatment differences in 
the incidence of hypoglycemic episodes will be assessed using a logistic regression. Treatment 
differences in rates of hypoglycemic episodes (episodes/patient/30 days; episodes/patient/year) 
will be assessed by the likelihood-based model for repeated measures. The model will include 
the same terms as in the primary analysis model with baseline hypoglycemia as a covariate 

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instead of baseline HbA1c. The logarithm of days between visit s will be adjusted as an offset to 
account for possible unequal duration between visits and between patients. Certain categories of 
hypoglycemia may also be evaluated using a PG cutoff <54 mg/dL (<3.0 mmol/L). 
9.5.4. Hyperglycemic Episodes 
Listings and summaries (if appropriate) will be provided for events of severe, persistent 
hyperglycemia resulting in initiation of rescue therapy, as well as events of ketoacidosis. 
9.5.5. Special Safety Topics 
9.5.5.1. Pancreas Safety 
Listings and summaries of adjudicated pancreatic events will be provided. 
9.5.5.2. Cardiovascular Safety 
Listings and summaries of adjudicated CV events will be provided. Heart rate and systolic and 
diastolic blood pressure from vital signs will be summarized as well as ECG data. Adverse 
events suggestive of hypotension will be provided. 
9.5.5.3. Thyroid Safety 
Listings of AEs of interest associated with the thyroid gland (benign and malignant neoplasms) 
will be produced, as well as a listing of biopsy reports. 
9.5.5.4. Renal Safety 
To assess renal safety, summary and analyses will be provided for eGFR, as well as shift tables. 
Listing of AEs suggestive of acute and chronic kidney failure will also be provided. Other 
reports may also be generated if deemed appropriate. 
9.5.5.5. Allergic/Hypersensitivity Reactions 
Summaries and listings of allergic and other hypersensitivity AEs will be provided. 
 
9.5.6. Laboratory Analytes 
Laboratory measurements will be listed by patient and visit. An additional listing will be 
presented for laboratory measurements that are outside the normal range. 
Laboratory measurements will also be summarized. For continuous (numeric) laboratory 
analytes, including glucagon, the change from baseline to endpoint will be analyzed using an 
analysis of variance (ANOVA) on the rank-transformed data, with treatment as fixed effects. 
Last observation carried forward will be used to impute missing postbaseline values. 
For subjective (qualitative) laboratory analytes, counts and percentages of patients with normal 
and abnormal values will be analyzed using chi-square tests. 
 
9.6. Pharmacokinetic/Pharmacodynamic Analyses 
Not applicable. 

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9.7. Other Analyses 
9.7.1. Subgroup Analyses 
A subgroup analysis will be performed on the primary endpoint using the efficacy estimand and 
the same model as the primary analysis model with an added term for the 3 -way interaction visit - 
by-treatment-by- [subgroup]. The 2-way interaction of treatment-by-[subgroup] at the primary 
time point of 24 weeks will be evaluated to assess an interaction in the treatment effect with the 
subgroup levels. Significance will be evaluated at alpha=0.10. The following are candidate 
subgroups that might be analyzed.  This list is not necessarily all-inclusive: 
 baseline age group (<65 years, ≥65 years) 
 race 
 ethnicity 
 country 
 duration of diabetes at baseline (<median duration and ≥median duration) 
 BMI (<median and ≥median) 
 concomitant metformin 
 baseline HbA1c (≤8.0%, >8.0%) 
 baseline glucagon (<median and ≥median) 
When analyzing baseline HbA1c as a subgroup, the baseline HbA1c will not be included as a 
covariate to avoid confounding. 
A subgroup analysis will also be performed for the change from baseline in body weight by 
baseline glucagon only, using a similar approach as described for HbA1c above. Other 
subgroups may be assessed when considered appropriate. 
For all subgroup analyses, if the MMRM fails to converge, then the corresponding ANCOVA 
model (LOCF) will be used. 
 
9.8. Interim Analyses 
No interim analyses 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. 

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10. Study Governance Considerations 
10.1. Regulatory and Ethical Considerations, Including the Informed 
Consent Process 
10.1.1. 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. 
 
10.1.2. Ethical Review 
The investigator 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 site’s ERB(s) should be provided with the following: 
 the current IB or package labeling  and updates during the course of the study 
 ICF 
 relevant curricula vitae 
 study diary 
10.1.3. Regulatory Considerations 
This study will be conducted in accordance with: 
 consensus ethics principles derived from international ethics guidelines, including 
the Declaration of Helsinki and Council for International Organizations of 
Medical Sciences (CIOMS) International Ethical Guidelines 
 applicable ICH GCP Guidelines 
 applicable laws and regulations 

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Some of the obligations of the sponsor will be assigned to a third-party organization (TPO). 
 
10.1.4. Investigator Information 
Physicians with a specialty in diabetes/endocrinology internal medicine, family medicine, or 
general medicine with clinical research experience will participate as investigators in this clinical 
trial. 
 
10.1.5. Protocol Signatures 
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study. 
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative. 
10.1.6. 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. 
 
10.2. Data Quality Assurance 
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following: 
 provide instructional material to the study sites, as appropriate 
 sponsor start-up training to instruct the investigators and study coordinators. This 
training will give instruction on the protocol, the completion of the CRFs, and 
study procedures. 
 make periodic visits to the study site 
 be available for consultation and stay in contact with the study site personnel by 
mail, telephone, and/or fax 
 review and evaluate CRF data and use standard computer edits to detect errors in 
data collection 
 conduct a quality review of the database 
In addition, Lilly or its representatives will periodically check a sample of the patient data 
recorded against source documents at the study site. The study may be audited by Lilly or its 
representatives, and/or regulatory agencies at any time. Investigators will be given notice before 
an audit occurs. 

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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. 
10.2.1. Data Capture System 
An electronic data capture system will be used in this study. The site maintains 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 generic labs system. 
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 may include, for example, a paper diary to collect patient - 
reported outcome measures (for example, a rating scale), a daily dosing schedule, or an event 
diary. 
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system. 
10.3. Study and Site Closure 
10.3.1. Discontinuation of Study Sites 
Study site participation may be discontinued if Lilly, 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. 
 
10.3.2. Discontinuation of the Study 
The study will be discontinued if Lilly judges it necessary for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations, and GCP. 

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11. References 
American Diabetes Association. Defining and reporting hypoglycemia in diabetes: a report from 
the American Diabetes Association Workgroup on Hypoglycemia. Diabetes Care. 
2005;28(5):1245-1249. 
Ayele BT, Lipkovich I, Molenberghs G, Mallinckrodt CH. A multiple-imputation-based 
approach to sensitivity analyses and effectiveness assessment s in longitudinal clinical trials. J 
Biopharm Stat. 2014;24(2):211-228. 
Banks PA, Freeman ML; Practice Parameters Committee of the American College of 
Gastroenterology. Practice guidelines in acute pancreatitis. Am J Gastroenterol. 
2006;101(10):2379-2400. 
Barrington P, Chien JY, Tibaldi F, Showalter HD, Schneck K, Ellis B. LY2189265, a long- 
acting glucagon-like peptide-1 analogue, showed a dose-dependent effect on insulin secretion 
in healthy subjects. Diabetes Obes Metab. 2011;13(5):434-438. 
Blonde L, Jendle J, Gross J, Woo V, Jiang H, Fahrbach JL, Milicevic Z. Once-weekly 
dulaglutide versus bedtime insulin glargine, both in combination with prandial insulin lispro, 
in patients with type 2 diabetes (AWARD-4): a randomised, open-label, phase 3, non- 
inferiority study. Lancet. 2015;385(9982):2057-2066. 
Bretz F, Maurer W, Brannath W, Posch M. A graphical approach to sequentially rejective 
multiple test procedures. Stat Med. 2009;28(4):586-604. 
Bydureon [US package insert (USPI)]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2015. 
Available at: http://www.azpicentral.com/bydureon/pi_bydureon.pdf#page=1. Accessed July 
14, 2015. 
Byetta [US package insert (USPI)]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2015. 
Available at: http://www.azpicentral.com/byetta/pi_byetta.pdf#page=1. Accessed July 14, 
2015. 
Carpenter JR, Roger JH, Kenward MG. Analysis of longitudinal trials with protocol deviation: a 
framework for relevant, accessible assumptions, and inference via multiple imputation. J 
Biopharm Stat. 2013;23(6):1352-1371. 
[DCCT] The Diabetes Control and Complications Trial Research Group. The effect of intensive 
treatment of diabetes on the development and progression of long-term complications in 
insulin-dependent diabetes mellitus. N Engl J Med.1993;329(14):977-986. 
Dungan KM, Povedano ST, Forst T, Gonzalez JG, Atisso C, Sealls W, Fahrbach JL. Once- 
weekly dulaglutide versus once-daily liraglutide in metformin-treated patients with type 2 
diabetes (AWARD-6): a randomised, open-label, phase 3, non-inferiority trial. Lancet. 
2014;384(9951):1349-1357. 
Farxiga [US package insert (USPI)]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2015. 
Available at: http://www.azpicentral.com/farxiga/pi_farxiga.pdf#page=1. Accessed July 14, 
2015. 

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Giorgino F, Benroubi M, Sun JH, Zimmermann AG, Pechtner V. Efficacy and safety of once 
weekly dulaglutide vs. insulin glargine in combination with metformin and glimepiride in type 
2 diabetes patients (AWARD-2). Can J Diabetes. 2014;38(5):S4. 
Invokana [US package insert (USPI)]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2015. 
Available at:  http://www.invokana.com/prescribing-information.pdf. Accessed July 14, 2015. 
Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, Peters AL, Tsapas 
A, Wender R, Matthews DR. Management of hyperglycemia in type 2 diabetes, 2015: a 
patient-centred approach. Update to a position statement of the American Diabetes Association 
and the European Association for the Study of Diabetes. Diabetologia. 2015;58(3):429-442. 
Jardiance [US package insert (USPI)]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, 
Inc.; 2014. Available at: 
http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt&fol 
derPath=/Prescribing+Information/PIs/Jardiance/jardiance.pdf. Accessed July14, 2015. 
Koizumi M, Takada T, Kawarada Y, Hirata K, Mayumi T, Yoshida M, Sekimoto M, Hirota M, 
Kimura Y, Takeda K, Isaji S, Otsuki M, Matsuno S; JPN. JPN Guidelines for the management 
of acute pancreatitis: diagnostic criteria for acute pancreatitis. J Hepatobiliary Pancreat Surg. 
2006;13(1):25-32. 
Nauck M, Weinstock RS, Umpierrez GE, Guerci B, Skrivanek Z, Milicevic Z. Efficacy and 
safety of dulaglutide versus sitagliptin after 52 weeks in type 2 diabetes in a randomized 
controlled trial (AWARD-5). [erratum in Diabetes Care 2015 Mar;38(3):538]. Diabetes Care. 
2014;37(8):2149-2158. 
Tanzeum [US package insert (USPI)]. Wilmington, DE: GlaxoSmithKline LLC; 2015. Available 
at: 
https://www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Inform 
ation/Tanzeum/pdf/TANZEUM-PI-MG-IFU-COMBINED.PDF. Accessed July 14, 2015. 
Trulicity [summary of product characteristics (SPC)]. Houten, The Netherlands; 2014. Available 
at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_- 
_Product_Information/human/002825/WC500179470.pdf. Accessed July 14, 2015. 
Trulicity [US package insert (USPI)]. Indianapolis, IN: Eli Lilly and Company; 2015 . Available 
at:  http://pi.lilly.com/us/trulicity-uspi.pdf. Accessed July 14, 2015. 
[UKPDS] UK Prospective Diabetes Study Group. Intensive blood-glucose control with 
sulphonylureas or insulin compared with conventional treatment and risk of complications in 
patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352(9131):837-853. 
Umpierrez G, Povedano ST, Manghi FP, Shurzinske L, Pechtner V. Efficacy and safety of 
dulaglutide monotherapy vs metformin in type 2 diabetes in a randomized controlled trial 
(AWARD-3). Diabetes Care. 2014; 37(8):2168-2176. 
Victoza [US package insert (USPI)]. Bagsvaerd, Denmark: Novo Nordisk A/S; 2015. Available 
at:  http://www.novo-pi.com/victoza.pdf. Accessed July 14, 2015. 

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Wysham C, Blevins T, Arakaki R, Colon P, Atisso C, Kuhstoss D, Lakshmanan M. Efficacy and 
safety of dulaglutide added on to pioglit azone and metformin versus exenatide in type 2 
diabetes in a randomized controlled trial (AWARD-1). [erratum in Diabetes Care 2014 
Oct;37(10):2895]. Diabetes Care. 2014;37:2159-2167. 

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Appendix 1. 
Abbreviations and Definitions 
 
 
 
 
Term 
Definition 
 
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. 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
ANOVA 
analysis of variance 
AST 
aspartate aminotransferase 
blinding/masking 
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 
CIOMS 
Council for International Organizations of Medical Sciences 
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. 
CI 
confidence interval 
CRF/eCRF 
case report form/electronic case report form 
CRP 
clinical research physician:  Individual responsible for the medical conduct of the study. 
Responsibilities of the CRP may be performed by a physician, clinical research 
scientist, global safety physician or other medical officer. 
CSR 
clinical study report 
CT 
computed tomography 
CV 
cardiovascular 
ECG 
electrocardiogram 
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. 

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enter 
Patients entered into a trial are those who sign the informed consent form directly or 
through their legally acceptable representatives. 
ERB 
ethical review board 
ET 
early termination 
fasting 
abstaining from food and drink (except water) for approximately 8 hours (typically, 
overnight), no significant physical activity and no administration of glucose-lowering 
agents during this period 
FBG 
fasting blood glucose 
GCP 
good clinical practice 
GI 
gastrointestinal 
GLP-1 
glucagon-like peptide-1 
GLP-1 RA 
glucagon-like peptide-1 receptor agonist 
HbA1c 
hemoglobin A1c 
HR 
heart rate 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
 
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. 
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 
MEN 
multiple endocrine neoplasia 
MI 
myocardial infarction 
MMRM 
mixed-model repeated measures 

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MNAR 
missing not at random 
MRI 
magnetic resonance imaging 
NAFLD 
nonalcoholic fatty liver disease 
OAM 
oral antihyperglycemia agent 
OTC 
over the counter 
PG 
plasma glucose 
PP 
per protocol: 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. 
QD 
once daily 
REML 
restricted maximum likelihood 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
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 
SGLT1/SGLT2 
sodium-glucose co-transporter 1/sodium-glucose co-transporter 2 
SMPG 
self-monitored plasma glucose 
SPC 
summary of product characteristics 
SUSARs 
suspected unexpected serious adverse reactions 
T2D 
type 2 diabetes 
TBL 
total bilirubin level 
TEAE 
treatment-emergent adverse event:  Any untoward medical occurrence that either occurs 
or worsens at any time after treatment baseline and that does not necessarily have to 
have a causal relationship with this treatment. 
ULN 
upper limit of normal 
USPI 
United States prescribing information 

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Appendix 2. 
Schedule of Activities 
 

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Schedule of Activities, Protocol H9X-MC-GBGE 
Perform procedure as indicated. 
 
Study 
Period I 
Study Period II 
Study Period III 
Screening Lead in 
Stabilizationa 
Treatment Period 
Visit 
1 
2a 
3 
4 
5b 
6 
7 
8 
9 
10 
11 
ET 
Week of Treatment 
-(2-14) 
-(1-13) 
-12 
-1 
0 
2 
4 
8 
12 
18 
24 
Allowable Deviation (Days) 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
Informed consent 
X 
Randomizationc 
X 
Clinical Assessments 
Medical History 
X 
Physical 
X 
X 
X 
Heightd 
X 
Weightd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Electrocardiograme 
X 
X 
X 
X 
Vital Signs (BP and HR 
measurements)f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Preexisting conditions/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 
Review/record hypoglycemic 
events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient summary 
X 
X 

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Schedule of Activities, Protocol H9X-MC-GBGE 
Study 
Period I 
Study Period II 
Study Period III 
Screen 
ing 
Lead 
in 
Stabilizationa 
Treatment Period 
Visit 
1 
2a 
3 
4 
5b 
6 
7 
8 
9 
10 
11 
ET 
Week of Treatment 
-(2-14) 
-(1-13) 
-12 
-1 
0 
2 
4 
8 
12 
18 
24 
Allowable Deviation (Days) 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
Patient Education and Management 
Diet and exercise and SMPG trainings 
X 
PG meter training 
X 
Subcutaneous injection training 
X 
X 
Review of subcutaneous injection 
training 
X 
Dispense PG meter/suppliesg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense study diary, instruct in use 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review/return study diary 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review/record 6-point SMPG valuesh 
X 
X 
X 
Xi 
Dispense study drug and/or injection 
supplies 
X 
X 
X 
X 
X 
X 
Observe patient inject study drug 
X 
Patient returns study drug and injection 
supplies 
X 
X 
X 
X 
X 
X 
X 
Assess study drug compliance 
X 
X 
X 
X 
X 
X 
X 

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Schedule of Activities, Protocol H9X-MC-GBGE 
Study 
Period I 
Study Period II 
Study Period III 
Screening Lead in 
Stabilizationa 
Treatment period 
Visit 
1 
2a 
3 
4 
5b 
6 
7 
8 
9 
10 
11 
ET 
Week of Treatment 
-(2-14) 
-(1-13) 
-12 
-1 
0 
2 
4 
8 
12 
18 
24 
Allowable Deviation (Days) 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
Laboratory Tests j 
Pregnancy testk 
X 
X 
Chemistry panel 
X 
X 
X 
X 
Urinalysis panel 
X 
X 
X 
Urinary albumin/creatinine ratio 
X 
X 
X 
eGFR (CKD-EPI)l 
X 
X 
X 
X 
Calcitonin 
X 
X 
X 
X 
Hematology 
X 
X 
X 
X 
Lipid panel 
X 
X 
X 
HbA1c 
X 
Xm 
Xn 
X 
X 
X 
X 
Pancreatic amylase, lipase 
X 
X 
X 
X 
Fasting glucagon 
X 
X 
X 
Follicle-stimulating hormone testo 
X 
Stored Samples: 
Pharmacogenetic 
X 
Nonpharmacogenetic 
X 
X 
X 
X 
X 
Abbreviations: BP = blood pressure; CKD-EPI = Chronic Kidney Disease-Epidemiology; CRF = case report form; CV = cardiovascular; eGFR = estimated 
glomerular filtration rate; ET = early termination; HbA1c = hemoglobin A1c; HR = heart rate; OAM = oral antihyperglycemia medication; PG = plasma 
glucose; SMPG = self-monitored plasma glucose. 
a Visit 2:  Lead-in 
 
Patients who require adjustment of their OAM regimen will implement treatment changes between Visits 2 and 3 (the lead-in period), all other patients 
will continue with their prestudy regimen without changes; 
 
Patients who adjust their OAM regimen during lead-in and/or need to stabilize the regimen will perform Visit 3 (end of lead-in) as their next visit and 
will then run 1 to 12-week stabilization. All other patients will skip Visit 3 and Visit 4 and will perform Visit 5 as their next visit. 
b The final visit window is determined by the dates of the previous visit(s). The visit calculator should be used to determine the exact visit window for all 
subsequent visits. 
c Baseline assessments must be completed before processing in the interactive web-response system (IWRS). 

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Schedule of Activities, Protocol H9X-MC-GBGE 
d Refer to Protocol Appendix 7 for standardized procedure.  
e     Refer to Protocol Section 8.4.1 for standardized procedure. 
f 
Refer to Protocol Section 8.4.2 for standardized procedure. 
g    Dispense only as needed. 
h One 6-point SMPG profile should be performed by patient during the week prior to this visit. 
i 
If performed prior to the visit. 
j 
For Visits 5 and 11, 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. 
k A serum pregnancy test will be performed at Visit 1 for women of childbearing potential only. A urine pregnancy test must be performed at Visit 5 with the 
result available prior to randomization and first injection of study drug for women of childbearing potential only. Additional urine pregnancy tests may be 
performed at the investigator’s discretion during the study. 
l 
The CKD-EPI equation will be used by the central lab to estimate and report eGFR. Values that are below important thresholds (60 mL/min/1.73 m2 or 
45 mL/min/1.73 m2) must be first confirmed at the next visit before any protocol-required treatment adjustment or other protocol-required action is 
implemented.  The higher of the 2 available values should be used when making clinical decisions.  For example, if a patient’s eGFR value is 
<45 mL/min/1.73 m2 at Visit 1 but the value at Visit 2 is ≥45 mL/min/1.73 m2, the patient will be allowed to continue in the trial. 
m HbA1c blood draw only for patients who do NOT require stabilization of the OAM regimen. 
n HbA1c blood draw only for patients whose OAM regimen needs to be stabilized due to changes made between Visit 2 and Visit 3 and/or to meet requirements 
for stable doses of OAMs. 
o  Follicle-stimulating hormone test performed at Visit 1 for postmenopausal woman at least 50 years of age with an intact uterus, who has not taken hormones 
or oral contraceptives within 1 year and has had  6 to 12 months of spontaneous amenorrhea. 

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Appendix 3. 
Clinical Laboratory Tests 
 

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Clinical Laboratory Testsa 
 
Hematology 
Clinical Chemistry 
Hemoglobin 
Sodium 
Hematocrit 
Potassium 
Erythrocyte count (RBC) 
Total bilirubin 
Mean cell volume (MCV) 
Direct bilirubin 
Mean cell hemoglobin concentration (MCHC) 
Alkaline phosphatase 
Leukocytes (WBC) 
Alanine aminotransaminase (ALT/SGPT) 
Neutrophils 
Aspartate aminotransaminase (AST/SGOT) 
Lymphocytes 
Gamma-glutamyl transferase (GGT) 
Monocytes 
Blood urea nitrogen (BUN) 
Eosinophils 
Creatinine 
Basophils 
Creatine kinase (creatine phosphokinase; CPKb) 
Platelets 
Uric acid 
Calcium 
Urinalysis 
Albumin 
Specific gravity 
Glucose 
pH 
Protein 
Pancreas (Exocrine)c 
Glucose 
Serum pancreatic amylase 
Ketones 
Serum lipase 
Bilirubin 
Urobilinogen 
HbA1c 
Blood 
Nitrite 
Pregnancy test serum and urined 
Leukocyte esterase 
 
Albumin/creatinine ratio (urine)e 
Follicle-stimulating hormone 
 
Lipid Panel 
Endocrine 
Total cholesterol 
Calcitoninc 
LDLf 
Fasting glucagon 
HDL 
VLDL 
Stored Samples 
Triglycerides 
Pharmacogenetic stored sample 
Biomarker stored sample 
 
Abbreviations: CK-MB = creatine kinase-MB; HbA1c = hemoglobin A1c; HDL = high-density lipoprotein 
cholesterol; LDL = low-density lipoprotein cholesterol; RBC = red blood cells; WBC = white blood cells; VLDL 
= very low density lipoprotein cholesterol. 
a All tests will be performed by a Lilly-designated central laboratory, unless otherwise noted. 
b CK-MB is to be assayed if the creatine kinase result is >1000 IU/L. 
c Additional samples may be collected based on the investigator’s judgment. 
d A serum screening pregnancy test will be performed at Visit 1 for women of childbearing potential only by a 
Lilly-designated laboratory. A urine pregnancy test must be performed at Visit 5 for women of childbearing 
potential with the result available prior to randomization and first injection of study drug. A local urine 
pregnancy test may be performed at the investigator’s discretion during the study. 
e Urinary albumin and creatinine are measured; the ratio is calculated. 
f 
This value will be calculated.  If triglycerides >400 ng/mL, then direct LDL will be assayed. 

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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, CRP. 
Hepatic Monitoring Testsa 
 
Hematologyb 
Haptoglobinb 
Hemoglobin 
Hematocrit 
Hepatic Coagulationb 
Erythrocyte count (RBC) 
Prothrombin Time 
Leukocytes (WBC) 
Prothrombin Time, INR 
Neutrophils, segmented 
Lymphocytes 
Hepatic Serologiesb 
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 Chemistryb 
Hepatitis C antibody 
Total bilirubin 
Hepatitis E antibody, IgG 
Direct bilirubin 
Hepatitis E antibody, IgM 
Alkaline phosphatase 
Alanine transaminase (ALT/SGPT) 
Anti-nuclear antibodyb 
Aspartate transaminase (AST/SGOT) 
Gamma-glutamyl transferase (GGT) 
Alkaline Phosphatase Isoenzymesb 
Creatine phosphokinase (CPK) 
Anti-smooth muscle antibody (or anti-actin 
antibody)b 
Abbreviations: IgG = immunoglobulin G; IgM = immunoglobulin M; INR = international normalised ratio (for 
blood clotting time); RBC = red blood cells; WBC = white blood cells. 
a Hepatic safety will be assessed and monitored throughout the study, based on clinical and laboratory parameters. 
Any patient who develops abnormalities that meet standard criteria for hepatic assessment will be referred for 
clinical assessment in accordance with Lilly standards. Hepatic assessment may include the tests listed above, or 
others as clinically indicated, as part of patient follow-up, in consultation with Lilly-designated Medical Monitor. 
b Assayed by Lilly-designated or local laboratory. 

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Appendix 5. 
Sampling Summary 
 
 
 
 
This table summarizes the approximate number of samples (venipunctures) and volumes for all 
sampling (screening, standard laboratory, pharmacogenetic, biomarker, and exploratory) and 
tests during the study. Fewer samples may actually be taken, but this will not require a protocol 
amendment. 
Protocol H9X-MC-GBGE Sampling Summary 
Purpose 
Sample 
Type 
Maximum Amount 
per Sample 
Maximum 
Number Samples 
Maximum 
Total Amount 
Screening testsa 
Blood 
10 mL 
1 
10 mL 
Standard laboratory testsa 
Blood 
20 mL 
6 
120 mL 
Pharmacogenetic samples 
Blood 
10 mL 
1 
10 mL 
Other exploratory 
Nonpharmacogenetic samples 
Blood 
20 mL 
4 
80 mL 
Total Blood 
220 mL 
Hepatic Monitoringb 
Blood 
3-30 mL 
- 
- 
a Additional samples may be drawn if needed for safety purposes. 
b Based on laboratory safety values, unscheduled hepatic monitoring testing may be performed as part of patient 
follow-up, in consultation with Lilly-designated Medical Monitor. 

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Appendix 6. 
Protocol GBGE World Health Organization 
Classification of Diabetes and Diagnostic Criteria 
 
 
 
Type 1 Diabetes Mellitus (T1DM): Type 1 diabetes mellitus is judged to be present when the 
classical symptoms of diabetes (thirst, polyuria, wasting and stupor, or coma) are associated with 
readily detectable concentrations of glucose and ketone bodies in the blood and urine. Insulin 
treatment is necessary not only to control hyperglycemia but also to prevent spontaneous ketosis 
and death. 
Type 2 Diabetes Mellitus (T2DM): Type 2 diabetes mellitus, although often asymptomatic, 
may also present with classical hyperglycemic symptoms (thirst, polyuria, weight loss), but 
despite hyperglycemia, ketone bodies are present in only low concentrations in the blood and 
urine. Coma is rare in type 2 diabetes but may result from extreme hyperglycemia and 
hyperosmolarity; lactic acidosis or ketoacidosis can also occur in fulminating illness (for 
example, severe infection or mesenteric artery thrombosis) due to an acute increase in insulin 
requirements, but spontaneous ketosis does not occur. Some patients with type 2 diabetes later 
progress to a state of absolute insulin deficiency (Alberti and Zimmet 1998). 

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

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Appendix 8. Protocol Amendment H9X-MC-GBGE(a) 
Summary – A Randomized, Parallel-Arm, Double-Blind 
Study of Efficacy and Safety of Dulaglutide When Added 
to SGLT2 Inhibitors in Patients with Type 2 Diabetes 
Mellitus 
 
 
 
Overview 
Protocol H9X-MC-GBGE, A Randomized, Parallel-Arm, Double-Blind Study of Efficacy and 
Safety of Dulaglutide When Added to SGLT2 Inhibitors in Patients with Type 2 Diabetes 
Mellitus has been amended. The new protocol is indicated by amendment (a) and will be used to 
conduct the study in place of any preceding version of the protocol. 
Based on regulatory guidance, changes were made to the protocol to include additional 
provisions to minimize the risk of early patient discontinuations from the study, and to continue 
to measure key endpoints at key time points in all randomized patients regardless of adherence to 
therapy or study protocol. This regulatory guidance also requested that additional statistical 
reports be included to provide data for incidence of early treatment discontinuation separate from 
the incidence of early study discontinuation and to assess the primary objective without and with 
data censored at the time point of rescue therapy initiation. The overall changes made to this 
protocol are as follows: 
 Added text in Section 1 stating that for the primary analysis, all available data up to 24 
weeks will be included except those collected after initiation of glucose-lowering rescue 
therapy. The primary analysis will also be repeated with all available data included. 
 Modified text in Section 3 and Section 9.5.4 to state that patients will initiate rescue 
therapy for severe, persistent hyperglycemia, rather than discontinue. 
 Added text in Section 4.1 to instruct that patients developing persistent, severe 
hyperglycemia will continue administering study drug and receive a new glucose- 
lowering intervention (rescue). These patients, as well as those who receive rescue 
therapy after discontinuation of study drug early, will remain in the study and will be 
asked to perform all study visits to collect planned efficacy and safety measurements. 
 Added text in Section 4.3 describe that patients in the placebo arm with unacceptably 
high glycemia during the treatment period will be offered additional glucose-lowering 
intervention (rescue), rather than discontinuation. 
 Added text in Section 6.6.1.3 to instruct that for patients with severe, persistent 
hyperglycemia, the investigator will decide in consultation with the patient on an 
appropriate glucose-lowering intervention (rescue), and these patients should also 
continue administering study drug for the remaining period in the trial. Other GLP-1 
RAs must not be included in the rescue intervention. 

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 Added text in Section 6.8.1 to advise that rescue therapy with other glucose lowering 
agents, including insulin, may be medically indicated in certain situations after 
randomization (severe, persistent hyperglycemia; early discontinuation of study drug); 
treatment with other GLP-1 RAs is not allowed. Glucose-lowering medications other 
than rescue therapy or short-term use of insulin for medical emergencies must be 
discontinued immediately. Clarified that patients receiving insulin >14 days for 
management of medical emergencies, as well as those receiving rescue therapy will be 
excluded from the PP analysis. 
 Added text in Sections 6.8.1.1.1 and 6.8.1.1.2 that dose increase of SGLT2 inhibitors, or 
dose increase or initiation of metformin are allowed as rescue interventions, but the dose 
and reason for change must be properly documented in the eCRF. 
 Added text in Section 6.8.3 to clarify that patients using chronic systemic glucocorticoid 
therapy for >14 days during the treatment period will be excluded from the PP analysis 
and these patients will not be discontinued from the trial. 
 Deleted text in Section 7.1 that patients stopping study drug permanently will be 
discontinued from the study. 
 Deleted select criteria in Section 7.1.1 that would be cause for permanent discontinuation 
of study drug. Added criteria that would be cause for permanent discontinuation of study 
drug. Clarified that in the case of early discontinuation of study drug, patients will receive 
another glucose-lowering intervention and will continue in the study, to collect all 
planned efficacy and safety measurements. The rescue intervention must not include 
another GLP-1 RA. 
 Added Section 7.1.2, Permanent Discontinuation from the Study, to Section 7, 
Discontinuation Criteria, to help separate criteria for discontinuation of study drug versus 
discontinuation of study. Clarified that prior to study discontinuation, patient will 
discontinue study drug and will perform end-of-study procedures at an ET visit; during 
the ET visit, the patient will be prescribed an appropriate glucose-lowering regimen and 
glucose self-monitoring plan. 
 Clarified in Section 7.1.4 that an inadvertently enrolled patient may be allowed to 
continue treatment with study drug if the investigator and Lilly study physician agree that 
it is safe for the patient to do so. 
 Added text in Section 8.2.2.1 to include rescue therapy for severe, persistent 
hyperglycemia as an event of interest related to hyperglycemia. 
 Added text in Section 8.2.2.2 instructing that in patients diagnosed with acute 
pancreatitis, the patient must discontinue therapy with study drug, but will continue in the 
study on another glucose-lowering regimen. 

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 Added text in Section 8.2.2.6 instructing that if study drug is permanently discontinued in 
a patient with a severe or serious allergic reaction, the patient will continue in the study 
on another glucose-lowering regimen. 
 Added text in Section 9.2 stating that analyses of certain outcomes will be performed on 
the full dataset with censoring (to exclude data collected after initiation of rescue with 
glucose lowering therapy for any reason), and also without censoring as sensitivity 
analyses. 
 Added text in Section 9.3.1 describing that patient disposition will include patients 
entered, randomized/enrolled, completing, discontinuing from study drug early, and 
discontinuing from study early. Reasons for discontinuation from the study and/or study 
drug will be summarized. 
 Added the definitions for Efficacy Estimand and ITT Estimand in Section 9.4.1 and 
clarified the population for the primary analysis of the primary outcome measure. 
 Added a new section, Section 9.4.1.1 to describe the additional analyses for the primary 
outcome measure. 
 Clarified additional analyses of the key secondary efficacy measures in Section 9.4.2. 
 Clarified in Section 9.5.3 that hypoglycemia will be analyzed with post-rescue data 
censored, and without post-rescue data censored. 
 Clarified in Section 9.7.1 that the subgroup analysis will be performed using the efficacy 
estimand described in Section 9.4.1. 
 Statistical references were added to Section 11. 
 The list of abbreviations was updated in Appendix 1. 
 Minor editorial changes to the text were made to correct typographical errors. 

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Revised Protocol Sections 
 
1. 
Synopsis 
 
Statistical Analysis: 
 
The primary analysis population will be the intent-to-treat (ITT) population, defined as all patients randomized who 
have taken at least 1 dose. This is also the safety population. For the primary analysis, all available data up to 24 
weeks will be included except those collected after initiation of glucose-lowering rescue therapy. The primary 
analysis will be repeated with all available data included, including those collected after initiation of rescue therapy. 
A select number of measurements (HbA1c, percent to goal in HbA1c, FBG, and body weight) will also be evaluated 
in the Per Protocol population. 
3. 
Objectives and Endpoints 
 
Secondary 
Key secondary efficacy objectives (controlled for type 1 
error) are to compare dulaglutide 1.5 mg and 0.75 mg to 
placebo at 24 weeks 
Other secondary efficacy objectives are to compare 
dulaglutide 1.5 mg and 0.75 mg to placebo at 24 weeks 
Secondary safety objectives are to compare dulaglutide 
1.5 mg and 0.75 mg to placebo at 24 weeks 
 
Proportion of patients with HbA1c target values 
of <7.0% at 24 weeks 
 
The change in FBG (central laboratory) from 
baseline to 24 weeks 
 
The change in body weight from baseline to 
24 weeks 
 
Proportion of patients with HbA1c target values 
of ≤6.5% at 24 weeks 
 
The change in 6-point SMPG profile from 
baseline to 24 weeks 
 
The change in fasting glucagon from baseline 
to 24 weeks 
Incidence of: 
 
Treatment-emergent adverse events (TEAEs) 
 
Early discontinuations due to AEs 
 
Adjudicated cardiovascular and pancreatic AEs 
 
Thyroid neoplasms AEs 
 
AEs related to kidney failure, eGFR 
 
Systemic hypersensitivity AEs 
 
Local injection site reactions 
 
The change in systolic and diastolic blood 
pressure, heart rate, and lipids from baseline to 
24 weeks 
 
Incidence and rate of hypoglycemic episodes 
 
Ketoacidosis, and discontinuation due to 
initiation of rescue therapy for severe persistent 
hyperglycemia 
 Note: Deletions have been identified by strikethroughs. 
Additions have been identified by the use of underscore. 

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4.1. 
Overview of Study Design 
Study Period III:  Randomization and Treatment Period (Visits 5 through 11) 
Patients who develop persistent, severe hyperglycemia based on pre-specified thresholds (see 
Section 6.6.1.3) will continue administeringdiscontinue study drug and study and will receive a 
new glucose-lowering intervention (rescue) based on the clinical judgment of the investigator. 
These patients, as well as those who receive rescue therapy after discontinuation ofe study drug 
due to an AE or any other reasons, will be asked to perform all study visits to collect planned 
efficacy and safety measurements. 
Those patients who are unable or unwilling to continue in the study because of an AE (see 
Section 7.1.2 for details) or any other reason, will perform an early termination (ET) visit as their 
final study visit (for procedures at the ET visit, see the Schedule of Activities [Appendix 2]). If 
the patient is discontinuing during an unscheduled visit, that visit should be performed as the ET 
visit.  If the patient is discontinuing during a scheduled visit, that visit should be considered the 
ET visit. 
4.3. 
Scientific Rationale for Study Design 
This trial is designed to be consistent with recommendations provided in a position statement of 
the American Diabetes Association and the European Association for the study of Diabetes 
“Management of Hyperglycemia in Type 2 Diabetes: A Patient-Centered Approach” (Inzucchi et 
al. 2015). Placebo comparator was chosen because it will enable characterization of efficacy and 
safety effects of dulaglutide when added to existing therapy with SGLT2 inhibitors, with or 
without metformin. Compared to a design which utilizes active comparator, comparison to 
placebo will allow assessment of the effect attributable to dulaglutide alone, which is of 
importance especially for the safety aspect of the combined use. The results are expected to 
enable physicians to choose patients suitable for the combination therapy in the clinical setting. 
To protect the safety of patients in the placebo arm who will enter Study GBGE with HbA1c 
above the <7% target, several design features are introduced for this purpose: (a) short trial 
duration (24 week-long treatment period), (b) exclusion of patients considered to have 
unacceptably high baseline HbA1c (>9.5%), and (c) additional glucose-lowering intervention 
(rescue) discontinuation offor patients with unacceptably high glycemia during the treatment 
period. 
5.2. 
Exclusion Criteria 
[12] have been treated with ANY other OAMs (other than SGLT2 inhibitors and 
metformin), GLP-1 RA, pramlintide or insulin 3 months prior to study entry, 
or between study entry and Visit 5; or initiate metformin between study entry 
and Visit 5; short-term use of insulin for acute care (≤14 days) during the 3- 
month period prior to entry is not exclusionary; 

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6.6.1.3. 
Management of Patients with Severe, Persistent Hyperglycemia during the 
Treatment Period 
An additional therapeutic intervention should be considered in patients who develop persistent, 
severe hyperglycemia after randomization based on the following criteria: 
a) Average daily PG from the 4-point SMPG profile >240 mg/dL over at least a 2-week 
period any time during the first 4 weeks postrandomization; or 
b) Average daily PG >200 mg/dL over a 2-week period at any time after the first 4 weeks 
postrandomization. 
Investigators should first confirm that the patient is fully compliant with the assigned therapeutic 
regimen and that they do not have an acute condition causing severe hyperglycemia. The 
investigator will decide in consultation with the patient on an appropriate glucose-lowering 
intervention (rescue) after considering relevant clinical criteria. Other GLP-1 RAs must not be 
included in the rescue intervention. Patients who require receive a new intervention will should 
also stop thecontinue administering study drug for the remaining period in the trial and will be 
discontinued from the study. The investigator will decide in consultation with the patient on an 
appropriate glucose-lowering regimen to be used after the study completion. 
6.8.1.   Antihyperglycemia Medications 
The only glucose-lowering agents that are allowed 3-months prior to study entry and during the 
study are study drug and concomitant SGLT2 inhibitors and metformin. In addition, short-term 
insulin use for management of medical emergencies is allowed prior to study entry and after 
randomization (Visit 5), but not during screening and lead-in/stabilization (Sections 5.1 and 5.2). 
Rescue therapy with other glucose-lowering agents, including insulin, may be medically 
indicated in certain situations after randomization. These situations are described in Section 
6.6.1.3 (severe, persistent hyperglycemia) and in Section 7.1.1 (early discontinuation of study 
drug).  If any such situation occurs, the patient may be treated with any locally-approved 
glucose-lowering agent, except other GLP-1 RAs. If insulin is prescribed as a rescue therapy, it 
must be differentiated from short-term use of insulin therapy for medical emergencies when 
reported in the eCRF. 
Patients who receive any glucose-lowering agents 3 months prior to entry or during the screening 
or lead-in/stabilization periods, other than those allowed, will not be eligible for further 
participation in the trial. The patients not using metformin prior to study entry (Visit 1) are not 
allowed to initiate this therapy between study entry and Visit 5. Patients who violate this 
requirement will be considered as ineligible and will be discontinued from further participation 
in this trial. 
If any new glucose-lowering medication is initiated after randomization at Visit 5, other than 
rescue therapy or short-term use of insulin for medical emergencies, the patient will be required 
to immediately discontinue the medication and the appropriate study deviation report will be 
generated. Any such violation of the protocol that lasted longer than 14 days will exclude the 
patient from the Per Protocol (PP) population. Patients who refuse to discontinue non-study 

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medications initiated during the treatment period will be immediately discontinued from the trial. 
Patients who receive insulin therapy for management of medical emergencies >14 days as well 
as those who receive rescue therapy, will also be excluded from the PP population. 
6.8.1.1.1. 
SGLT2 Inhibitors 
After randomization, dose adjustment or discontinuation of SGLT2 inhibitors is allowed under 
the following circumstances: 
 in situations that require short-term treatment interruption consistent with the product 
labeling for each respective country; 
 in situations that require dose adjustment or discontinuation due to contraindications 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 6.6.1.2). 
Dose reduction/discontinuation of SGLT2 inhibitors during the trial should be properly 
documented. 
In patients who require rescue therapy, dose increase of SGLT2 inhibitors is allowed, but the 
dose and the reason for change must be properly documented in the eCRF. 
6.8.1.1.2. 
Metformin 
Dose adjustment or discontinuation of metformin is allowed after randomization 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 due to contraindications 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 6.6.1.2). 
Dose reduction/discontinuation of metformin during the trial should be properly documented. 
In patients who require rescue therapy, dose increase or initiation of metformin is allowed, but 
the dose and the reason for change/initiation must be properly documented in the eCRF. 
6.8.3.   Systemic Glucocorticoids 
Chronic systemic glucocorticoid therapy (with the exception of topical, intraocular, intra- 
articular, or intranasal preparations) is exclusionary if used >14 consecutive days during the 
1-month period before study entry or between study entry and randomization at Visit 5. This 
therapy is not allowed during the treatment period and patients who require >14 days of therapy 
with these medications must immediatelywill not be included in the PP analysis be discontinued. 

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7.1. 
Discontinuation from Study Treatment 
Study drug may be interrupted temporarily or discontinued permanently. Those patients who 
stop the study drug permanently will also be immediately discontinued from the study. 
7.1.1. Permanent Discontinuation from of Study Treatment and Study 
Patients will be permanently discontinued from study drug and from the study in the following 
circumstances: 
 For inadvertently enrolled patients for whom it was determined that continued treatment 
with study drug would not be medically appropriate (see Section 7.1.3); 
 Exclusion Criterion Criteria [11], [31], [32], or [34] throughand [38] develop(s), after 
randomization (see Section 5.2); 
 The patient requires a new intervention due to severe, persistent hyperglycemia (Section 
6.6.1); 
 The patient is diagnosed by the investigator with an AE of acute or chronic pancreatitis; 
 A patient is diagnosed with C-cell hyperplasia or medullary thyroid carcinoma after 
randomization; 
 If a patient develops an eGFR <30 mL/min/1.73m2 as calculated by CKD-EPI; 
 If the patient or the patient’s designee, for example, legal guardian, requests to be 
withdrawn from study drug; 
 If the investigator or sponsor decides that the patient should be withdrawn from study 
drug; if the sponsor decides to permanently discontinue study treatment because of an 
SAE or a clinically significant laboratory value, Lilly or its designee should be alerted 
immediately [see Section 8.2.1]); 
 The patient requires >14 days of therapy with systemic glucocorticoids; 
 A non-study glucose lowering agent is initiated, except for short-term insulin therapy for 
medical emergencies, and the patient refuses to discontinue this medication; 
 A female patient becomes pregnant; 
 An investigator, site personnel performing assessments, or patient is unblinded; 
 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. 
 Investigator Decision 
o the investigator decides that the patient should be discontinued from the study 
o if the patient, for any reason, requires treatment with another therapeutic agent 
that has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study occurs prior to introduction of the new agent 
 Patient Decision 
o The patient or the patient’s designee, for example, parents or legal guardian, 
requests to be withdrawn from the study 
 Sponsor Decision 

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o Lilly or its designee stops the study or stops the patient’s participation in the study 
for medical, safety, regulatory, or other reasons consistent with applicable laws, 
regulations, and good clinical practice (GCP) 
 Adverse Event 
o If the investigator decides that the patient should be withdrawn because of an 
SAE (other than those listed above) or a clinically significant laboratory value, the 
investigational product is to be discontinued and appropriate measures are to be 
taken. Lilly or its designee is to be alerted immediately. Refer to Adverse Events 
(Section 8.2). 
 Discontinuation of the investigational product for abnormal liver tests should be 
considered by the investigator when a patient meets one of the following conditions 
after consultation with the Lilly designated medical monitor: 
o ALT or aspartate aminotransferase (AST) >8X upper limit of normal (ULN) 
o ALT or AST >5X ULN for more than 2 weeks 
o ALT or AST >3X ULN and total bilirubin level (TBL) >2X ULN or prothrombin 
time >1.5X ULN 
o ALT or AST >3X ULN with the appearance of fatigue, nausea, vomiting, right 
upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
o Alkaline phosphatase (ALP) >3X ULN 
o ALP >2.5X ULN and TBL >2X ULN 
o ALP >2.5 ULN with the appearance of fatigue, nausea, vomiting, right upper- 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
Patients who discontinue the study early will have end-of-study procedures performed (ET visit) 
as shown in the Schedule of Activities (Appendix 2). At the ET visit, the investigator will 
prescribe an appropriate antihyperglycemia regimen and SMPG monitoring plan to be followed 
after completion of the study. 
Those patients who stop the study drug permanently will receive another glucose-lowering 
intervention (rescue) and will continue participation in the trial according to the protocol, to 
collect all planned efficacy and safety measurements. The rescue intervention must not include 
another GLP-1 RA. 
7.1.2. Permanent Discontinuation from the Study 
Every attempt should be made to keep patients in the trial irrespective of their adherence to 
treatment with study drug in order to minimize the amount of missing data and to enable 
assessment of study objectives as planned by the study protocol. Patient discontinuation from 
the study early may be warranted in the following situations for ethical or legal reasons: 
 Exclusion Criterion [11] 
 When a female patient becomes pregnant; 

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 When a patient is enrolled in another clinical trial involving an investigational product or 
is enrolled in any other type of medical research judged not to be scientifically or 
medically compatible with this study. 
Patients may also discontinue from the study due to: 
 Sponsor or Investigator Decision 
o If Lilly or its designee stops the study or if Lilly or the investigator stops the 
patient’s participation in the study for medical, safety, regulatory, or other reasons 
consistent with applicable laws, regulations, and good clinical practice (GCP) 
 Patient Decision 
o 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 (Appendix 2). 
During the ET visit the patient will be prescribed an appropriate glucose-lowering regimen and 
glucose self-monitoring plan. 
7.1.4. Discontinuation of Inadvertently Enrolled Patients 
If the sponsor or investigator identifies a patient who did not meet enrollment criteria and was 
inadvertently enrolled, a discussion must occur between the sponsor CRP and the investigator to 
determine if the patient may continue in the study. If both agree it is medically appropriate to 
continue, the investigator must obtain documented approval from the sponsor CRP to allow the 
inadvertently enrolled patient to continue in the study with or without treatment with 
investigational product. An inadvertently enrolled patient may be allowed to continue treatment 
with study drug only if the principal investigator and Lilly study physician responsible for 
medical monitoring of this trial agree that it is safe for the patient to do so. 
8.2.2.1. 
Hypoglycemia and Hyperglycemia 
Events of interest related to hyperglycemia (rescue therapy for severe, persistent hyperglycemia, 
per criteria specified in Section 6.6.1.3, and ketoacidosis) will be collected during the trial to 
assess the risk of extreme disbalance in glycemic control. 
8.2.2.2. 
Pancreatitis 
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 supports 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 6.8.1 and 
Section 7.1.1 for details on rescue intervention).and will also be discontinued from the study. 
The most appropriate diabetes therapeutic regimen will be decided by the investigator, based on 

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the patient’s clinical status. A review of the patient’s concomitant medications should be 
conducted to assess any potential causal relationship with pancreatitis. 
8.2.2.6. 
Allergic/Hypersensitivity Reactions 
All allergic or hypersensitivity reactions will be reported by the investigator as either AEs or, if 
any serious criterion is met, as SAEs. Additional data, such as type of reaction and treatment 
received, will be collected on any AEs or SAEs that the investigator deems related to study drug 
via a CRF created for this purpose.  Study drug should be temporarily interrupted in any 
individual suspected of having a severe or serious allergic reaction to study drug (Section 7.1.2). 
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, the patient will receive another glucose-lowering treatment, 
judged by the investigator to be appropriate based on the patient’s clinical status, and will 
continue in the trial to collect all planed efficacy and safety measurementsbe discontinued from 
the trial (see Section 6.8.1 and Section 7.1.1). 
9.2. 
General Statistical Considerations 
Analyses of certain efficacy outcomes (HbA1c, percent to goal in HbA1c, FBG, body weight) 
and hypoglycemia will be performed on the full dataset with censoring as primary (ie, to exclude 
data collected after initiation of rescue with glucose-lowering therapy for reasons described in 
Section 6.6.1.3, Section 6.8.1, and Section 7.1.1). These same analyses will also be performed 
without censoring post rescue data as sensitivity analyses. 
9.3.1.   Patient Disposition 
Frequency counts and percentages of all patients entered, randomized/enrolled, completing, 
and/or discontinuing from the study drug early, and discontinuing from the study early will be 
presented for each of the treatment groups. The reasons for discontinuation from the study 
and/or study drug will be summarized by treatment group. A summary of discontinuations will 
also be presented by visit. 
9.4.1. Primary Outcome Measure and Analyses 
The primary outcome is an efficacy estimand defined as the difference in HbA1c mean change 
from baseline to 24 weeks in the ITT population with post-rescue data censored (excluded). The 
primary hypothesis of interest in this placebo-controlled study is whether dulaglutide has 
superior efficacy compared to placebo, in patients already treated with SGLT2 inhibitors, 
without confounding with rescue therapy. 
9.4.1.1. 
Additional Analyses of the Primary Outcome 
The primary analysis model, MMRM, will be repeated using the PP population to check the 
sensitivity of the analysis. If the conclusion differs from that of the ITT population, the data and 
analyses will be further investigated. The secondary analysis model will be an ANCOVA for 
HbA1c change from baseline to 24 weeks (Visit 11), using a similar model as described above 
with treatment, country, SGLT2 inhibitor dose (“low” versus “high”), and metformin use (“yes” 

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versus “no”) as factors and baseline HbA1c as a covariate. Missing endpoints will be imputed 
with the LOCF using postbaseline data only. 
To investigate departure from the Missing At Random (MAR) assumption for the primary 
analysis that excludes post-rescue data, a sensitivity analysis using a particular missing not at 
random (MNAR) assumption will be performed. Specifically, a placebo multiple imputation 
(pMI) will be performed (Ayele et al. 2014), which assumes that the drug effect in missing data 
and post-rescue data in both the placebo arm and dulaglutide arm was like the observed effect in 
the placebo arm (excluding post-rescue data). This is essentially the “copy reference” approach 
as described in Carpenter et al. 2013. This approach is in essence assuming that the drug effect 
will decay over time, in accordance with the correlation structure implied by the data. Data 
imputed this way will be analyzed with the same MMRM model as the primary analysis. This 
particular MNAR assumption can be viewed as a “worst reasonable case” assessment of the 
efficacy estimand, or as an effectiveness estimand that assumes patients with missing data or 
rescued patients received no drug benefit after dropout or rescue. 
Also of interest is the effectiveness/treatment regimen estimand that evaluates the difference in 
mean HbA1c change from baseline to 24 weeks in the ITT population regardless of treatment 
discontinuation or use of rescue therapy (ITT estimand). Therefore as a supportive analysis, 
MMRM will be performed on the ITT population with all post-rescue data up to the primary 
endpoint of 24 weeks included. 
For both the efficacy estimand (missing data and post-rescue data both considered as missing), 
and the ITT estimand (post-rescue data not treated as missing), a tipping point analysis will be 
performed in which the missing data are imputed with a MAR assumption. However, prior to 
analysis, in the dulaglutide arm the imputed values will be replaced by the imputed value plus 
delta. Multiple values of delta will be tried until the value at which the conclusion from the 
MMRM analysis changes. 
9.4.2. Secondary Outcome Measures and Analyses 
The primary analysis model, MMRM, will be repeated using the PP population to check the 
sensitivity of the analysis. If the conclusion differs from that of the ITT population, the data and 
analyses will be further investigated. The secondary analysis model will be an ANCOVA for 
HbA1c change from baseline to 24 weeks (Visit 11), using a similar model as described above 
with treatment, country, SGLT2 inhibitor dose (“low” vs. “high”), and metformin use (“yes” vs. 
“no”) as factors and baseline HbA1c as a covariate. Missing endpoints will be imputed with the 
LOCF using postbaseline data only. 
The key secondary continuous efficacy measures will also be analyzed using both models, the 
MMRM and the ANCOVA with LOCF models described above (with and without censoring 
data collected after initiation of rescue intervention). Analysis of other secondary efficacy 
measures that are continuous variables, except glucagon (for glucagon, see Section 9.5.6), will be 
performed using MMRM on the ITT population. There will be no multiplicity adjustment for 
pairwise comparisons.  The MMRM and ANCOVA models will include the model terms given 

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for the previously described primary analysis model with the addition of the HbA1c strata 
(≤8.0%, >8.0%). 
For percentages of patients achieving target HbA1c of <7.0% (including exploratory composite 
endpoints with body weight and hypoglycemia) or ≤6.5% at 24 weeks, longitudinal logistic 
regression with repeated measurements will be used. The model will include independent 
variables treatment, country, visit, treatment-by-visit, and baseline HbA1c as a covariate. These 
analyses will be performed with post-rescue data excluded (considered missing), and separately 
with all post-rescue data included. In addition, an analysis of percentage of patients on HbA1c 
targets will be performed where patients who have been rescued or have no post-baseline data 
being considered (imputed) as not having achieved the target. 
9.5.3. Hypoglycemic Episodes 
Section 6.6.1.2 contains definitions of categories of hypoglycemia. A listing of individual 
hypoglycemic episodes by patient will be presented. Summary reports will include both 
incidence and rates of hypoglycemia for the ITT population (with post-rescue data censored, and 
without post-rescue data censored). Hypoglycemia will be categorized as “documented 
symptomatic,” “asymptomatic,” “probable,” “severe,” or “nocturnal,” and for all events 
combined, “total hypoglycemia.” Only “documented symptomatic” and “total hypoglycemia” 
will be analyzed inferentially. 
9.5.4. Hyperglycemic Episodes 
Listings and summaries (if appropriate) will be provided for events of severe, persistent 
hyperglycemia resulting in discontinuationinitiation of rescue therapy, as well as events of 
ketoacidosis. 
9.7.1.   Subgroup Analyses 
A subgroup analysis will be performed on the primary endpoint using the efficacy estimand and 
the same model as the primary analysis model with an added term for the 3-way interaction visit- 
by-treatment-by- [subgroup]. 
11. 
References 
Ayele BT, Lipkovich I, Molenberghs G, Mallinckrodt CH. A multiple-imputation-based 
approach to sensitivity analyses and effectiveness assessments in longitudinal clinical trials. J 
Biopharm Stat. 2014;24(2):211-228. 
Carpenter JR, Roger JH, Kenward MG. Analysis of longitudinal trials with protocol deviation: a 
framework for relevant, accessible assumptions, and inference via multiple imputation. J 
Biopharm Stat. 2013;23(6):1352-1371. doi: 10.1080/10543406.2013.834911. 

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Appendix 1.   Abbreviations and Definitions 
 
Term 
Definition 
 
LS mean 
least-squares mean 
MAR 
missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEN 
multiple endocrine neoplasia 
MI 
myocardial infarction 
MMRM 
mixed-model repeated measures 
MNAR 
missing not at random 
 
 
Appendix 2.   Schedule of Activities 
c Baseline assessments must be completed before processing in the interactive interactive voiceweb-response 
system (IWRS). 

 
 
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