Conditions: Type 2 Diabetes
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 159
Healthy volunteers: no

Brief summary:
The main purpose of this study is to evaluate the efficacy and safety of combination therapy with dulaglutide and insulin in Japanese participants with type 2 diabetes.

Detailed description:

Arms:
arm 1: Dulaglutide 0.75 milligram (mg) administered once weekly for 16 weeks. After 16-weeks, dulaglutide administered once weekly for 36 weeks. arm 2: Placebo administered once weekly for 16 weeks. After 16-weeks, dulaglutide 0.75 mg administered once weekly for 36 weeks.

Interventions: intervention 1: Dulaglutide intervention 2: Placebo
Intervention descriptions: intervention 1: Administered subcutaneously (SC) intervention 2: Administered SC

Protocol document:
Prot_000.pdf: 
H9X-JE-GBGF (b) Protocol 
 
 
A Phase 4 Study of Efficacy and Safety of Dulaglutide When Added to Insulin Treatment With 
or Without Oral Antidiabetic Medication in Patients with Type 2 Diabetes 
 
NCT02750410 
Approval Date:  11-Jul-2016    


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Protocol H9X-JE-GBGF(b)
A Phase 4 Study of Efficacy and Safety of Dulaglutide When 
Added to Insulin Treatment With or Without Oral Antidiabetic 
Medication in Patients with Type 2 Diabetes 
Confidential Information
The information contained in this document is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of
dulaglutide (LY2189265), unless such persons are bound by a confidentiality agreement 
with Eli Lilly and Company or its subsidiaries.  
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure. Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release. In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
Dulaglutide (LY2189265)
Study H9X-JE-GBGF is a Phase 4, randomized, placebo-controlled, double-blind 
(16 weeks) and subsequent open-label (36 weeks) study to assess the efficacy and safety 
of dulaglutide 0.75 mg in Japanese patients with type 2 diabetes who have inadequate 
glycemic control on insulin therapy with or without 1 or 2 oral antidiabetic medications.
Eli Lilly Japan K.K.
Kobe, Hyogo Japan
Protocol Electronically Signed and Approved by Lilly: 21-Apr-2016
Amendment (a) Electronically Signed and Approved by Lilly: 09-Jun-2016
Amendment (b) Electronically Signed and Approved by Lilly on date provided below.
Approval Date: 11-Jul-2016 GMT


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Table of Contents
Section
Page
1.
Synopsis .............................................................................................................................8
2.
Schedule of Activities .......................................................................................................11
3.
Introduction ......................................................................................................................15
3.1.
Study Rationale............................................................................................................16
3.2.
Background..................................................................................................................16
3.3.
Benefit/Risk Assessment..............................................................................................16
4.
Objectives and Endpoints..................................................................................................17
5.
Study Design.....................................................................................................................19
5.1.
Overall Design .............................................................................................................19
5.2.
Number of Participants.................................................................................................20
5.3.
End of Study Definition ...............................................................................................20
5.4.
Scientific Rationale for Study Design...........................................................................20
5.5.
Justification for Dose ...................................................................................................21
6.
Study Population...............................................................................................................22
6.1.
Inclusion Criteria..........................................................................................................22
6.2.
Exclusion Criteria ........................................................................................................23
6.3.
Lifestyle Restrictions....................................................................................................25
6.4.
Screen Failures.............................................................................................................25
7.
Treatments........................................................................................................................26
7.1.
Treatments Administered .............................................................................................26
7.1.1.
Packaging and Labeling .......................................................................................26
7.2.
Method of Treatment Assignment ................................................................................27
7.2.1.
Selection and Timing of Doses.............................................................................27
7.2.1.1.
Dulaglutide or Placebo Injections ...................................................................27
7.2.1.2.
Insulin Treatment ...........................................................................................27
7.2.1.3.
Concomitant Oral Antidiabetic Medications ...................................................28
7.3.
Blinding .......................................................................................................................28
7.4.
Dosage Modification....................................................................................................29
7.4.1.
Special Treatment Considerations ........................................................................29
7.4.1.1.
Standards of Medical Care..............................................................................29
7.4.1.2.
Management of Increased Hypoglycemia Risk ...............................................29
7.4.1.3.
Management of Severe, Persistent Hyperglycemia..........................................30
7.5.
Preparation/Handling/Storage/Accountability...............................................................31
7.6.
Treatment Compliance .................................................................................................31


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7.7.
Concomitant Therapy...................................................................................................31
7.7.1.
Oral Antidiabetic Medications..............................................................................32
7.7.2.
Nonstudy Glucagon-Like Peptide-1 Receptor Agonists ........................................32
7.7.3.
Systemic Glucocorticoids.....................................................................................32
7.7.4.
Medications that Promote Weight Loss ................................................................32
7.8.
Treatment after the End of the Study............................................................................32
7.8.1.
Continued Access.................................................................................................32
8.
Discontinuation Criteria ....................................................................................................33
8.1.
Discontinuation from Study Treatment.........................................................................33
8.1.1.
Permanent Discontinuation from Study Treatment and Study...............................33
8.1.2.
Temporary Interruption of Study Treatment .........................................................34
8.1.3.
Discontinuation of Inadvertently Enrolled Patients...............................................34
8.2.
Discontinuation from the Study....................................................................................35
8.3.
Lost to Follow-Up........................................................................................................35
9.
Study Assessments and Procedures ...................................................................................36
9.1.
Efficacy Assessments...................................................................................................36
9.1.1.
Primary Efficacy Assessments .............................................................................36
9.1.2.
Secondary Efficacy Assessments..........................................................................36
9.1.3.
Exploratory Health Outcome/Quality of Life Measures........................................36
9.1.4.
Appropriateness of Assessments ..........................................................................37
9.2.
Adverse Events ............................................................................................................37
9.2.1.
Serious Adverse Events........................................................................................38
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................39
9.2.2.
Adverse Events of Interest....................................................................................39
9.2.2.1.
Hypoglycemia ................................................................................................39
9.2.2.2.
Pancreatitis.....................................................................................................40
9.2.2.3.
C-Cell Hyperplasia and C-Cell Neoplasms .....................................................41
9.2.2.4.
Cardiovascular Events ....................................................................................41
9.2.2.5.
Allergic/Hypersensitivity Reactions................................................................41
9.2.3.
Complaint Handling.............................................................................................42
9.3.
Treatment of Overdose.................................................................................................42
9.4.
Safety...........................................................................................................................42
9.4.1.
Electrocardiograms ..............................................................................................42
9.4.2.
Vital Signs ...........................................................................................................42
9.4.3.
Laboratory Tests ..................................................................................................43
9.4.4.
Body Weight and Body Mass Index .....................................................................43
9.4.5.
Safety Monitoring ................................................................................................43
9.5.
Pharmacokinetics .........................................................................................................43


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9.6.
Pharmacodynamics ......................................................................................................43
9.7.
Pharmacogenomics ......................................................................................................43
9.7.1.
Whole Blood Sample for Pharmacogenetic Research ...........................................43
9.8.
Biomarkers...................................................................................................................44
9.9.
Health Economics ........................................................................................................44
10.
Statistical Considerations ..................................................................................................45
10.1. Sample Size Determination ..........................................................................................45
10.2. Populations for Analyses..............................................................................................45
10.3. Statistical Analyses ......................................................................................................45
10.3.1.
General Statistical Considerations ........................................................................45
10.3.2.
Treatment Group Comparability...........................................................................47
10.3.2.1.
Patient Disposition..........................................................................................47
10.3.2.2.
Patient Characteristics ....................................................................................47
10.3.2.3.
Concomitant Therapy .....................................................................................47
10.3.2.4.
Treatment Compliance....................................................................................47
10.3.3.
Efficacy Analyses ................................................................................................47
10.3.3.1.
Primary Analyses ...........................................................................................47
10.3.3.2.
Secondary Analyses........................................................................................47
10.3.4.
Safety Analyses....................................................................................................48
10.3.4.1.
Study Drug Exposure......................................................................................48
10.3.4.2.
Adverse Events...............................................................................................48
10.3.4.3.
Hypoglycemic Episodes .................................................................................49
10.3.4.4.
Severe, Persistent Hyperglycemia...................................................................49
10.3.4.5.
Special Safety Topics .....................................................................................49
10.3.4.5.1.
Pancreas Safety.........................................................................................49
10.3.4.5.2.
Cardiovascular Safety...............................................................................49
10.3.4.5.3.
Thyroid Safety..........................................................................................49
10.3.4.5.4.
Allergic/Hypersensitivity Reactions..........................................................49
10.3.4.6.
Laboratory Analyses.......................................................................................49
10.3.5.
Health Outcomes Variables..................................................................................50
10.3.6.
Other Exploratory Variables.................................................................................50
10.3.7.
Subgroup Analyses ..............................................................................................50
10.3.8.
Interim Analyses..................................................................................................51
11.
References ........................................................................................................................52
12.
Appendices .......................................................................................................................55


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List of Tables
Table
Page
Table GBGF.4.1. Objectives and Endpoints...............................................................................17
Table GBGF.7.1. Study Treatments and Concomitant Medications............................................26
Table GBGF.7.2. Target Blood Glucose Values ........................................................................28


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List of Figures
Figure
Page
Figure GBGF.1. Illustration of study design for Clinical Protocol H9X-JE-GBGF. ..................20


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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions........................................................................56
Appendix 2.
Clinical Laboratory Tests...............................................................................59
Appendix 3.
Study Governance Considerations..................................................................61
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality....................65
Appendix 5.
Protocol GBGF World Health Organization Classification of Diabetes
and Diagnostic Criteria ..................................................................................66
Appendix 6.
Protocol GBGF World Health Organization Standardized Protocols for 
the Measurement of Height and Weight.........................................................67
Appendix 7.
Protocol H9X-JE-GBGF(b) Amendment Summary 
A Phase 4 Study of Efficacy and Safety of Dulaglutide When Added to 
Insulin Treatment With or Without Oral Antidiabetic Medication in 
Patients with Type 2 Diabetes........................................................................68


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1.
Synopsis
Title of Study:
A Phase 4 Study of Efficacy and Safety of Dulaglutide When Added to Insulin Treatment With or Without Oral 
Antidiabetic Medication in Patients with Type 2 Diabetes 
Rationale: 
Study H9X-JE-GBGF (GBGF) will assess the efficacy and safety of once-weekly dulaglutide added to insulin 
therapy (basal insulin, premixed insulin, or basal/mealtime insulin) with or without 1 or 2 oral antidiabetic (OAD)
medications.
This study will provide data for combination therapy with dulaglutide and insulin in Japanese patients with type 2 
diabetes (T2D).  This study will assess hemoglobin A1c (HbA1c), fasting serum glucose, 7-point self-monitored 
plasma glucose profile, and other aspects of diabetes management, such as hypoglycemia risk and body weight 
changes.  These outcomes will enable appropriate clinical characterization of the combination regimen. 
Objectives/Endpoints:
Objectives
Endpoints
Primary
To show superiority of the addition of once-weekly 
dulaglutide 0.75 mg compared to the addition of 
once-weekly placebo to insulin treatment with or 
without 1 or 2 OADs, on change from baseline in 
HbA1c after 16 weeks of treatment in Japanese patients 
with T2D.

The change in HbA1c from baseline to 
16 weeks
Secondary
For efficacy, to compare dulaglutide 0.75 mg to 
placebo at 16 weeks

Percentage of patients achieving HbA1c 
target values of <7.0% or ≤6.5% at 16 weeks

The change in FSG (central laboratory) from 
baseline to 16 weeks

The change in PG from 7-point SMPG
profiles from baseline to 16 weeks

The change in body weight from baseline to 
16 weeks

The change in insulin dose from baseline to 
16 weeks
For safety, to compare dulaglutide 0.75 mg to placebo 
for 16 weeks

TEAEs

Incidence and rate of hypoglycemic episodes

Adjudicated cardiovascular and pancreatic 
AEs

Thyroid neoplasm AEs

Allergic/hypersensitivity AEs

Laboratory parameters of hematological 
safety and biochemical abnormalities


H9X-JE-GBGF(b) Clinical Protocol
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LY2189265
Objectives
Endpoints
To describe long-term efficacy of dulaglutide 0.75 mg 
in combination with insulin therapy up to 52 weeks.
To describe long-term safety of dulaglutide 0.75 mg in 
combination with insulin therapy up to 56 weeks (to 
include the follow-up period).

Efficacy parameters described above

Safety parameters described above
Abbreviations:  AE = adverse event; FSG = fasting serum glucose; HbA1c = hemoglobin A1c; OAD = oral 
antidiabetic; PG = plasma glucose; SMPG = self-monitored plasma glucose; T2D = type 2 diabetes; TEAE = 
treatment-emergent adverse event.
Summary of Study Design:  
Study GBGF is a Phase 4, randomized, placebo-controlled, double-blind (16 weeks) and subsequent open-label 
(36 weeks, 52 weeks total) study to assess the efficacy and safety of once-weekly dulaglutide 0.75 mg in Japanese 
patients with T2D who have inadequate glycemic control on insulin therapy with or without 1 or 2 OADs.
Treatment Arms and Duration:  
After completing Visit 1, and, if necessary, a 12-week washout period (dipeptidyl peptidase-4 inhibitors, 
sulfonylurea, and glinides will be washed out), patients will be randomized in a 3:1 ratio to a weekly injection of 
dulaglutide 0.75 mg or placebo, in combination with stable doses of insulin (with or without 1 or 2 OADs).  Study 
participants will be treated for 16 weeks after randomization in the double-blind manner, after which all patients will 
be treated with 0.75 mg dulaglutide in combination with insulin for 36 weeks in the open-label extension.
Number of Patients:
A total of approximately 160 patients (dulaglutide:  120 patients; placebo:  40 patients) will be randomized to have 
approximately 136 completers (dulaglutide :  102 patients; placebo:  34 patients) to show dulaglutide is superior to 
placebo with more than 99% power assuming a treatment difference of 1% in HbA1c reduction, standard deviation
= 1.0%, and dropout rate of 15%.  The screen failure rate is estimated as 20%.  Approximately 200 patients will be 
screened.
Statistical Analysis:
The primary analysis model will be mixed-model repeated measure (MMRM) analysis using restricted maximum 
likelihood with treatment, insulin regimen (basal insulin, premixed insulin, or basal/mealtime insulin), visit, and 
treatment-by-visit as fixed effects, a covariate of baseline value, and patient as a random effect.  For analyses of 
variables other than HbA1c, the HbA1c stratum (<8.5%, ≥8.5%) will be included in the model.  An unstructured 
covariance structure will be used to model the within-patient variability and implicitly adjust for missing data.  The 
secondary analysis for the primary endpoint will be analysis of covariance using a similar model as described above 
with treatment, and insulin regimen (basal insulin, premixed insulin, or basal/mealtime insulin) as fixed effects and 
baseline HbA1c as a covariate, with missing endpoints imputed with the last (postbaseline) observation carried 
forward.  All secondary efficacy measures that are continuous variables (changes from baseline) will be analyzed 
using MMRM.  Repeated measures logistic regression with generalized linear mixed model will be used to analyze 
for percentage of patients achieving HbA1c targets of <7.0% or ≤6.5%.  Analyses for other secondary efficacy 
categorical measurements will use the repeated measures logistic regression with generalized linear mixed model, 
unless otherwise noted.


H9X-JE-GBGF(b) Clinical Protocol
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The primary analysis population will be the full analysis set, defined as all patients who received at least 1 dose of 
study treatment and have at least 1 measurement of HbA1c after study treatment.  The safety population will include 
all patients who received at least 1 dose of study treatment.  The primary efficacy measure (HbA1c) will also be 
evaluated in the Per-Protocol population.


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2. Schedule of Activities


H9X-JE-GBGF(b) Clinical Protocol
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Study Schedule, Protocol H9X-JE-GBGF
Screening and
Lead-ina
Primary Treatment
Extension Treatment
ET
Follow-
up
Fixed Insulin Dose
Flexible Insulin Dose
Study Visit
1
2
3
4
5
6
7
8
9
10
11
12
ETb
13c
Week of Treatment
-4 or -14d
-2e
0
4
8
12
16
20
28
36
44
52
―
56
Visit Window (days)
±7
±7
―
±7
±7
±7
±7
±7
±7
±7
±7
±7
―
±7
Informed Consent and Randomization
Informed consent
X
IWRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Randomization
X
Clinical Assessments
Medical history
X
X
Demographics
X
X
Previous diabetes therapy
X
X
Physical exam
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signsf
X
X
X
X
X
X
X
X
X
X
X
X
X
Preexisting conditions and Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hypoglycemic events
X
X
X
X
X
X
X
X
X
X
X
X
X
Single 12-lead ECG g
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Assessments
Serum Pregnancy test h
X
X
Hematology, Chemistry panel
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
Fasting serum glucose i
X
X
X
X
X
X
X
X
X
X
X
Lipid panel i
X
X
X
X
X
X
HbA1c
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pancreatic Enzymes
X
X
X
X
X
X
Calcitonin
X
X
X
X
X
X
Stored Sample
Pharmacogenomics sample(Stored)
X
Patient Education, Supplies, and SMPG
Dispensing of SMPG meter/supplies
X
X
X
X
X
X
X
X
X
X
X
X
SMPG meter training
X


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Study Schedule, Protocol H9X-JE-GBGF
Screening and 
Lead-ina
Primary Treatment
Extension Treatment
ET
Follow-
up
Fixed Insulin Dose
Flexible Insulin Dose
Study Visit
1
2
3
4
5
6
7
8
9
10
11
12
ETb
13c
Week of Treatment
-4 or -14d
-2e
0
4
8
12
16
20
28
36
44
52
―
56
Visit Window (days)
±7
±7
―
±7
±7
±7
±7
±7
±7
±7
±7
±7
―
±7
Patient Education, Supplies and SMPG (cont)
SMPG values review
X
X
X
X
X
X
X
X
X
X
X
X
Daily fasting SMPG measurement j
X
X
X
X
X
X
X
X
X
X
X
X
7-point SMPG measurement k
X
X
X
Dispensing study diary and instruct in use
X
X
X
X
X
X
X
X
X
X
X
X
Study diary review
X
X
X
X
X
X
X
X
X
X
X
X
Dispensing of investigational product and 
injection supplies
X
X
X
X
X
X
X
X
X
Subcutaneous injection training/injection site 
inspection/review of technique
X
X
X
X
X
X
X
X
X
X
X
X
Return of used investigational product 
containers, unused study medication and study 
diary
X
X
X
X
X
X
X
X
X
X
X
Assessment of investigational product
compliance
X
X
X
X
X
X
X
X
X
X
Health Outcome Questionnaires/Other 
Evaluation
DTR-QOL, DTSQs
X
X
X
X
Dietary Evaluation
X
X
X
Questionnaire for device
X
X
X
Abbreviations:  DPP-4 = dipeptidyl peptidase-4; DTR-QOL = Diabetes Therapy-Related Quality of Life Questionnaire; DTSQs = Diabetes Treatment 
Satisfaction Questionnaire status; ECG = electrocardiogram; ET = early termination visit; FSG = fasting serum glucose; HbA1c = hemoglobin A1c; IWRS = 
interactive web response system; SMPG = self-monitored plasma glucose; SU = sulfonylurea.
a
A telephone visit (T/V1; or site visit if preferred) will occur at Week -12 after screening results are available. An optional telephone visit (T/V2; or site visit 
if preferred) may occur between Weeks -8 and 0.
b
Early termination (ET) visit is conducted within 14 days after the decision of discontinuation.
c
Visit 13 should occur 28 days after Visit 12 or the day on which the decision of early termination is made.
d
Visit 1 should occur 4 weeks prior to Visit 3 for patients who have not been receiving DPP-4 inhibitors, SU, or glinides.  Visit 1 should occur 14 weeks prior 
to Visit 3 for patients who have been receiving DPP-4 inhibitors, SU, or glinides (to include 12 weeks of washout).
e
Visit 2 should be 2 weeks prior to Visit 3


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Study Schedule, Protocol H9X-JE-GBGF
f
For each parameter, 3 measurements will be taken 30 seconds apart 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 blood pressure (BP) measurements.  The arm used for the BP measurement should be supported at heart 
level. 
g
A single 12-lead ECG will be performed locally and recorded, after the patient has been lying supine for 5 minutes.  If the subject has a single 12-lead ECG 
record which was performed within 3 months prior to Visit 1, the data can be used as a baseline measurement.
h
Serum pregnancy test to be performed by the central lab at Visits 1 and 3 for women of childbearing potential only. Subsequent pregnancy tests can be 
performed as required at local laboratories.  A local (urine) pregnancy test may additionally be performed at the investigator’s discretion during the study.
i
Fasting laboratory samples must be obtained after a fast of 8 hours or more without eating, drinking (except for water), or performing any significant physical 
activity.
j
Patients are required to measure their fasting (pre-breakfast) plasma glucose (FPG) concentration at least once every 2 to 3 days at approximately the same 
time of day after Visit 3.  By the investigator’s decision, the frequency of measurement of FPG could be increased.
k
7-point SMPG profiles (blood glucose measurements before breakfast, lunch, dinner, and bedtime and 2 hours after breakfast, lunch, and dinner) should be 
performed on 2 days within the 2 weeks prior to Visit 3 (Week 0), Visit 7 (Week 16), and ET visit (only when the patient discontinued before Week 16).


H9X-JE-GBGF(b) Clinical Protocol
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3.
Introduction
It has been approximately 6 years since liraglutide received marketing approval as the first 
glucagon-like peptide-1 (GLP-1) receptor agonist in Japan. Additional GLP-1 receptor agonists 
(exenatide twice daily, exenatide once weekly, and lixisenatide) have been launched since then, 
and these have all become important treatment options for patients with type 2 diabetes (T2D) 
(Japan Diabetes Society 2013; ADA 2015).
Dulaglutide is a long-acting GLP-1 receptor agonist that mimics the effects of endogenous 
GLP-1 (Glaesner et al. 2010). It has been approved and launched in the United States and the 
European Union at once weekly doses of 0.75 mg and 1.5 mg (Trulicity USPI, 2015; Trulicity 
SmPC, 2015) and in Japan at a once weekly dose of 0.75 mg (Trulicity Japan Prescribing 
Information, 2015). In Phase 3 studies in Japanese patients with T2D, once weekly dulaglutide 
0.75 mg has shown superiority to insulin glargine (in a randomized, 26-week, open-label study 
of dulaglutide in combination with sulfonylureas [SU] and/or biguanides) and noninferiority to 
liraglutide 0.9 mg/day (in a randomized monotherapy study in which dulaglutide was compared 
to placebo [double-blind] and to liraglutide 0.9 mg/day [open-label]; the study had a 26-week 
primary endpoint and a 52-week treatment period) in hemoglobin A1c (HbA1c) changes (Araki 
et al. 2015; Miyagawa et al. 2015; Odawara et al. 2016). Also, in a nonrandomized, open-label, 
long-term (52-week) Phase 3 safety study in Japanese patients with T2D, once weekly 
dulaglutide 0.75 mg was well-tolerated overall in combination with a single oral antidiabetic 
(OAD; SU, biguanides, α-glucosidase inhibitors [α-GI], thiazolidinediones [TZD], or glinides) 
(Emoto et al. 2015). 
Glucagon-like peptide-1 receptor agonist is frequently used in combination with insulin and in 
combination with OADs. Beneficial effects of the combination of GLP-1 receptor agonist and 
insulin including greater HbA1c reduction, less weight gain, and lower incidence of 
hypoglycemia associated with a smaller dose of insulin have been reported (Balena et al. 2013; 
Eng et al. 2014). The combination of dulaglutide and insulin has been investigated in global 
studies. Dulaglutide in combination with mealtime insulin was tested in the AWARD-4 study 
(Blonde et al. 2015) and in combination with basal insulin in the AWARD-9 study 
(ClinicalTrials.gov [WWW]).  
It is known that the daily dose of insulin in Japanese diabetic patients is lower than that in 
Western patients because of lean body mass. In clinical studies in Japanese patients, average
insulin doses in patients with T2D were 10 to 15 IU for basal insulin (Kawamori et al. 2003a; 
Inagaki et al. 2012; Odawara et al. 2012) and in patients with type 1 diabetes or T2D, 40 to 50 IU 
for basal/mealtime insulin (Kawamori et al. 2003b; Kobayashi et al. 2007; Iwamoto et al. 2013). 
Because it is difficult to adopt Western data for Japanese patients, efficacy and safety data for the 
combination treatment of dulaglutide and insulin in Japanese patients will be beneficial
information for clinical use of dulaglutide in Japan.
Study H9X-JE-GBGF (GBGF) will assess the efficacy and safety of once weekly dulaglutide in 
combination with insulin therapy (basal insulin, premixed insulin, or basal/mealtime insulin) 
with or without 1 or 2 OADs.  The primary objective is to show superiority of dulaglutide to 


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placebo in HbA1c change from baseline after 16 weeks of treatment, and the secondary 
objectives are to compare the efficacy and safety of the combination to placebo up to 16 weeks 
and to describe the long-term efficacy up to 52 weeks and safety up to 56 weeks (including the 
follow-up period). Dulaglutide will be administered per label in this Phase 4 study.
3.1.
Study Rationale
Study GBGF will provide data for combination therapy with dulaglutide and insulin in Japanese 
patients with T2D.  This study will assess HbA1c, fasting serum glucose (FSG), 7-point self-
monitored plasma glucose (SMPG) profile, and other aspects of diabetes management, such as 
hypoglycemia risk and body weight changes.  These outcomes will enable appropriate clinical 
characterization of the combination regimen in Japanese patients with T2D. 
3.2.
Background
Dulaglutide is a biosynthetic fusion protein molecule produced using mammalian cell cultures, 
and consists of 2 identical, disulphide-linked chain, each containing an N-terminal GLP-1 
analogue sequence covalently linked to a modified human immunoglobulin G4 (IgG4) heavy 
chain by a small peptide linker.  These structural features of the dulaglutide molecule (1) 
decrease the rate of clearance, (2) increase the duration of pharmacologic activity, (3) may 
reduce the immunogenic potential, and (4) may decrease unwanted antibody-mediated effector 
function (Tamaki et al. 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.  
Preclinical and clinical experience to date support the use of dulaglutide as a once-weekly 
injection to improve glycemic control in patients with T2D (Tamaki et al. 2015). Dulaglutide 
received regulatory approval for the treatment of T2D in the United States on 18 September 
2014, in the European Union on 21 November 2014, and in Japan on 3 July 2015.  
3.3.
Benefit/Risk Assessment
More information about the known and expected benefits, risks, serious adverse events (SAEs) 
and reasonably anticipated adverse events (AEs) of dulaglutide are to be found in the Japan 
prescribing information (JPI) and interview form.


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4.
Objectives and Endpoints
Table GBGF.4.1 shows the objectives and endpoints of the study.
Table GBGF.4.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To show superiority of the addition of once-weekly 
dulaglutide 0.75 mg compared to the addition of 
once-weekly placebo to insulin treatment with or 
without 1 or 2 OADs, on change from baseline in 
HbA1c after 16 weeks of treatment in Japanese patients 
with T2D.

The change in HbA1c from baseline to 
16 weeks
Secondary
For efficacy, to compare dulaglutide 0.75 mg to placebo 
at 16 weeks.

Percentage of patients achieving HbA1c target 
values of <7.0% or ≤6.5% at 16 weeks

The change in FSG (central laboratory) from 
baseline to 16 weeks

The change in PG from 7-point SMPG profiles
from baseline to 16 weeks

The change in body weight from baseline to 
16 weeks

The change in insulin dose from baseline to 16 
weeks
For safety, to compare dulaglutide 0.75 mg to placebo 
for 16 weeks.

TEAEs

Incidence and rate of hypoglycemic episodes

Adjudicated cardiovascular and pancreatic AEs

Thyroid neoplasm AEs

Allergic/hypersensitivity AEs

Laboratory parameters of hematological safety 
and biochemical abnormalities
To describe long-term efficacy of dulaglutide 0.75 mg in 
combination with insulin therapy up to 52 weeks.
To describe long-term safety of dulaglutide 0.75 mg in 
combination with insulin therapy up to 56 weeks (to 
include the follow-up period).

Efficacy parameters described above

Safety parameters described above
Exploratory
Exploratory objectives are to assess the health outcomes 
variables at 16 and 52 weeks.

Diabetes Treatment Satisfaction Questionnaire
status (DTSQs)

Diabetes Therapy Related Quality of Life 
(DTR-QOL)

Device Questionnaire

Dietary Evaluation


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Objectives and Endpoints
Abbreviations:  AE = adverse event; FSG = fasting serum glucose; HbA1c = hemoglobin A1c; OAD = oral 
antidiabetic; PG = plasma glucose; SMPG = self-monitored plasma glucose; T2D = type 2 diabetes; TEAE = 
treatment-emergent adverse event.


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5.
Study Design
5.1.
Overall Design
Study GBGF is a Phase 4, randomized, placebo-controlled, double-blind (16 weeks) and 
subsequent open-label (36 weeks, 52 weeks total) study to assess the efficacy and safety of 
once-weekly dulaglutide 0.75 mg in Japanese patients with T2D who have inadequate glycemic 
control on insulin therapy with or without 1 or 2 OADs. The insulin regimen in this study 
includes basal insulin, premixed insulin, and basal/mealtime insulin for basal-bolus therapy, with 
enrollment target percentages of 60%, 20%, and 20% for the insulin regimens, respectively.  
Also, 20% or more of the patients enrolled in this study will be on insulin therapy without OADs 
(including OAD washout). The sponsor will closely monitor enrollment status to achieve these 
enrollment target percentages.
The study includes a 4- or 14-week screening and lead-in with or without washout period, a 16-
week double-blind primary treatment period, followed by a 36-week open-label extension 
treatment period, and a 4-week safety follow-up visit.  
Laboratory tests will be performed at Visit 1.  A telephone visit (T/V1; or site visit if preferred 
by the patient) at Week -12 will occur after Visit 1 laboratory results are available, and eligible 
patients on dipeptidyl peptidase-4 (DPP-4) inhibitors, SU, or glinides will begin a 12-week 
washout period during which the insulin dose may be uptitrated for up to 4 weeks, with an 
8 week-stabilization (± 20% adjustment) prior to Visit 3.  During Weeks -8 through 0 (the insulin 
dose stabilization period), a second telephone visit (T/V2; or site visit, if preferred) may occur.  
The insulin dose should remain unchanged for the 16-week primary treatment period, unless 
hypoglycemia occurs (see Section 7.4.1.2).  In addition, for patients treated with 1 or 2 OADs
other than DPP-4 inhibitors, SU, or glinide prior to Visit 1, the dosage and administration of 
OADs should not be changed during the 16-week primary treatment period.  Eligible patients not 
on DPP-4 inhibitors, SU, or glinides can proceed to Visit 2.  At Visit 2, HbA1c will be measured 
and eligibility will be reconfirmed.  At Visit 3, approximately 160 patients will be randomized in 
a 3:1 ratio to dulaglutide 0.75 mg or placebo.  After 16 weeks of primary treatment period, 
patients taking placebo will be switched to dulaglutide for an additional 36 weeks of extension
treatment period.  After the extension treatment period, dulaglutide must be discontinued and 
restart is not allowed during the follow-up period.  To preserve the blinding of the study, the 
treatment assignments in the double-blind primary treatment period will be blinded to patients 
and investigators until study completion.
Figure GBGF.1 illustrates the study design.


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Abbreviations:  DPP-4i = dipeptidyl peptidase-4 inhibitors; Dula = dulaglutide; F/U = 
follow-up; IC = informed consent; n = number of patients; OAD = oral antidiabetic; Plc 
= placebo; SU = sulfonylurea; T/V = telephone visit; wks = weeks.
Note:  A telephone visit (T/V1; or site visit if preferred) will occur at Week -12 after 
screening results are available. An optional telephone visit (T/V2; or site visit if 
preferred) may occur between Weeks -8 and 0.  Telephone visits or site visits may 
occur anytime during the study, as needed.
Figure GBGF.1.
Illustration of study design for Clinical Protocol H9X-JE-GBGF.
For each study period and each visit, study procedures are provided in the Schedule of Activities 
(Section 2).
5.2.
Number of Participants
Approximately 200 patients will be screened to achieve approximately 160 randomized
(dulaglutide:  120 patients; placebo:  40 patients) and approximately 136 patients completing the 
study (dulaglutide:  102 patients; placebo:  34 patients).
5.3.
End of Study Definition
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last patient.
5.4.
Scientific Rationale for Study Design
This study was planned based on the Japanese guideline for clinical evaluation of hypoglycemic 
agents (Draft version, Ministry of Health, Labour and Welfare, 2014). This guideline requests 2


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points; the first is to confirm efficacy of study drug compared with placebo in combination with 
stable insulin dose for 12 to 24 weeks, and the second is to confirm long-term (up to 52 weeks) 
efficacy and safety of the combination of study drug and insulin. In this study, we divided
treatment into 16 weeks for the primary treatment period and a 36-week extension treatment 
period. Since HbA1c reduction was stable after 14 weeks in Japanese Phase 3 studies, 16 weeks 
is appropriate to assess efficacy.
For the insulin regimen, this study allows basal insulin, premixed insulin, and basal/mealtime
insulin. These insulin regimens are frequently used in Japanese patients with T2D.
In the screening period, DPP-4 inhibitors, SU, and glinides will be washed out.  Both dulaglutide
and DPP-4 inhibitors decrease blood glucose via the GLP-1 receptor.  Dulaglutide in 
combination with DPP-4 inhibitors has not been investigated for efficacy or safety in clinical 
studies.  Sulfonylureas and glinides will be washed out because these drugs increase the risk of 
hypoglycemia in combination with dulaglutide (Emoto et al. 2015).  
In the 16-week primary treatment period, dulaglutide will be compared with placebo using a 
fixed insulin dose to evaluate the efficacy of dulaglutide only.  In the 36-week extension 
treatment period, the insulin dose will be adjusted to achieve target glucose levels (≤110 mg/dL 
preprandial, and ≤140 mg/dL at bedtime), and efficacy and safety of the combination therapy of 
dulaglutide and insulin will be assessed.
5.5.
Justification for Dose
The approved dosage and administration of dulaglutide in Japan is 0.75 mg once weekly, given 
subcutaneously.  The dosage and administration were established based on Phase 2 and 3 studies 
in Japanese patients with T2D (Terauchi et al. 2014; Araki et al. 2015; Emoto et al. 2015; 
Miyagawa et al. 2015; Odawara et al. 2016). 


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6.
Study Population
The planned patient population includes Japanese adult patients with T2D who have inadequate 
glycemic control with insulin therapy with or without OADs.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as
protocol waivers or exemptions, are not permitted.
6.1.
Inclusion Criteria
Patients are eligible to be included in the study only if they meet all of the following criteria at 
Visit 1 except criterion [4]:
[1]
have T2D (based on the World Health Organization’s [WHO] diagnostic 
criteria [Appendix 5]);
[2]
have been treated with insulin therapy (basal insulin [once or twice daily], 
premixed insulin [twice or 3 times daily], or basal/mealtime insulin [4 or 
5 times daily] regimen) with or without 1 or 2 OADs at stable dose for at least 
3 months prior to Visit 1;
[3]
doses of daily insulin must be stable (±20% versus the most commonly used 
dose for the period) and more than 10 units per day during the 3-month period 
prior to Visit 1;
[4]
have an HbA1c value ≥7.0% and ≤10.5% at Visit 1 if the patient is washing 
out OADs (DPP-4 inhibitors, SU, or glinides) or ≥7.5% and ≤10.5% at Visit 1 
if the patient is not washing out OADs.  At Visit 2, have an HbA1c ≥7.5% and 
≤10.5% (values at Visit 1 and Visit 2 as assessed by the central laboratory);
[5]
have stable weight (±5%) ≥3 months prior to Visit 1;
[6]
have body mass index (BMI) of 18.5 to 35 kg/m2 at Visit 1;
[7]
Japanese men or nonpregnant, nonbreastfeeding Japanese women aged 
≥20 years at Visit 1;
[8]
are females of childbearing potential who must:
[a] test negative for pregnancy at Visit 1;
[b] agree to remain abstinent, use 1 highly effective method of contraception 
(ie, combined oral contraceptive pill and mini-pill, Nuva-Ring, 
implantable contraceptives, injectable contraceptives, intrauterine device, 
contraceptive patch [ONLY women <90 kg], or partner with vasectomy) 
or use a combination of 2 effective methods (ie, condom with spermicide, 
diaphragm with spermicide, female condom with spermicide, cervical 
sponge, cervical cap with spermicide) for the entire study.  Abstinence or 
contraception must continue following completion of investigational 
product administration for 4 weeks following the last dose of 
investigational product.


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[c] 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 ≥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.
[9]
have given written informed consent to participate in the study in accordance 
with local regulations and the ethical review board (ERB) governing the study 
site.
6.2.
Exclusion Criteria
Patients will be excluded from study enrollment if they meet any of the following criteria at 
Visit 1:
[10] have type 1 diabetes (based on WHO diagnostic criteria);
[11] have previously received therapy with a GLP-1 receptor agonist within 
3 months prior to Visit 1;
[12] have been previously treated with dulaglutide prior to Visit 1;
[13] have been treated with 2 of the following at Visit 1:  DPP-4 inhibitor, SU, and 
glinide (ie, DPP-4 inhibitor and SU, or DPP-4 inhibitor and glinide);
[14] have been treated with continuous subcutaneous insulin infusion at Visit 1;
[15] have been treated with drugs that promote weight loss within the 3 months 
prior to Visit 1;
[16] are receiving chronic (>14 days) systemic glucocorticoid therapy (excluding 
topical, intraocular, or intranasal preparations) or have received such therapy 
within the 4 weeks prior to Visit 1;
[17] have 1 or more episodes of severe hypoglycemia within the 6 months prior to 
Visit 1;
[18] have 1 or more episodes of diabetic ketoacidosis within the 6 months prior to 
Visit 1;
[19] have had any of the following cardiovascular conditions within the 3 months 
prior to Visit 1:  acute myocardial infarction (MI), New York Heart 
Association (NYHA) Class III or Class IV heart failure, or cerebrovascular 
accident (stroke);


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[20] have a known clinically significant gastric emptying abnormality or have 
undergone gastric bypass surgery or restrictive bariatric surgery;
[21] have acute or chronic hepatitis, signs and symptoms of any other liver disease, 
or alanine aminotransferase (ALT) level >2.5 times the upper limit of the 
reference range, as determined by the central laboratory at Visit 1;
[22] have a history of chronic pancreatitis or acute idiopathic pancreatitis, or were 
diagnosed with any type of acute pancreatitis within the 3 months prior to 
Visit 1;
[23] have an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2, 
calculated by the Japanese Society of Nephrology equation, as determined by 
the central laboratory; for participants on metformin, have moderate renal 
disease or renal dysfunction (for example, eGFR <60 mL/min/1.73 m2) at 
Visit 1;
[24] 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;
[25] have any self or family history of medullary C-cell hyperplasia, focal 
hyperplasia, or carcinoma (including sporadic, familial, or part of MEN 2A or 
2B syndrome);
[26] have serum calcitonin ≥20 pg/mL, as determined by the central laboratory at 
Visit 1;
[27] have evidence of a significant, active uncontrolled endocrine or autoimmune 
abnormality, as judged by the investigator at Visit 1;
[28] have a history of transplanted organ;
[29] have a history of active or untreated malignancy, or are in remission from a 
clinically significant malignancy during the 5 years prior to Visit 1;
[30] have a history of any other condition which, in the opinion of the investigator, 
may preclude the participant from following and completing the protocol;
[31] have any hematologic condition that may interfere with HbA1c measurement 
(for example, hemolytic anemias, sickle-cell disease);
[32] 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
[33] have participated, within the last 30 days in a clinical trial involving an 
investigational product. If the previous investigational product has a long 
half-life, 3 months or 5 half-lives (whichever is longer) should have passed;
[34] have previously completed or withdrawn from this study or any other study 
investigating dulaglutide;  


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[35] 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;
[36] are Lilly employees;
[37] are unable and/or unwilling to provide written informed consent, make 
themselves available for the duration of the study, or abide by study 
procedures and restrictions.
6.3.
Lifestyle Restrictions
Study participants should be instructed not to donate blood or blood products during the study or 
for 4 weeks following the study.
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
rescreened.


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7. Treatments
7.1.
Treatments Administered
This study involves a comparison of dulaglutide 0.75 mg versus placebo administered once 
weekly as a subcutaneous injection by single-dose pen (SDP) in patients with T2D who are 
already treated with insulin with or without 1 or 2 OADs.  Table GBGF.7.1 summarizes study 
treatments and concomitant medications during the primary treatment period, and the extension
treatment period.
Table GBGF.7.1.
Study Treatments and Concomitant Medications
Name of Drug
Dosea
Frequencya
Drug Formulation
Route of Administration
16-Week Primary Treatment Period
Investigational Compound
Dulaglutide
0.75 mg
Once weekly
Single-dose pen
Subcutaneous injection
Comparator
Placebo
Placebo
Once weekly
Single-dose pen
Subcutaneous injection
Concomitant Insulin for Both Treatment Arms
Basal, mixed, or 
mealtime insulin
Fixed
Fixed
Pen type device/Vial 
and syringe
Subcutaneous injection
Oral Antidiabetic Medications for Both Treatment Arms
Biguanides, TZD, 
α-GI, SGLT2i
Fixed
Fixed
Tablet
Oral
36-Week Extension Treatment Period
Dulaglutide
0.75 mg
Once weekly
Single-dose pen
Subcutaneous injection
Basal, mixed, or 
mealtime insulin
Flexible
Fixed
Pen type device/Vial 
and syringe
Subcutaneous injection
Biguanides, TZD, 
α-GI, SGLT2i
Fixedb
Fixedb
Tablet
Oral
Abbreviations:  α-GI = alpha-glucosidase inhibitor; CRP = clinical research physician; CRS = clinical research 
scientist; OAD = oral antidiabetic; SGLT2i = sodium-glucose co-transporter 2 inhibitor; TZD = 
thiazolidinedione.
a
Dose and frequency refer to investigational compound and concomitant medications within a patient.
b
The investigator is to consult with the Lilly CRP or CRS if the dosage of OADs is changed.
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

verifying that instructions are followed properly

maintaining accurate records of investigational product dispensing and collection
7.1.1. Packaging and Labeling
The sponsor will provide dulaglutide and placebo in SDPs, which will be dispensed via an 
interactive web-response system (IWRS).  Each SDP (0.75 mg dulaglutide in 0.5 mL OR 


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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.
Investigational products will be labeled according to the country’s regulatory requirements.
7.2.
Method of Treatment Assignment
Patients who meet all criteria for enrollment will be randomized to double-blind treatment at
Visit 3.  Assignment to treatment groups will be determined by a computer-generated random 
sequence using an 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.
Randomization will be stratified by insulin regimen (basal insulin, premixed insulin, or 
basal/mealtime insulin) and HbA1c at Visit 2 (<8.5%, ≥8.5%) to achieve between-group 
comparability.
7.2.1. Selection and Timing of Doses
Details of the dosing strategy and administration timing for injectable investigational product,
insulin, and concomitant OADs are provided in the following sections.
7.2.1.1.
Dulaglutide or Placebo Injections
All patients will inject investigational product 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.
Investigational product will be administered once weekly.  It is recommended that patients inject 
the investigational product 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.
7.2.1.2.
Insulin Treatment
During the screening period, eligible patients on DPP-4 inhibitor, SU, or glinide will begin a 
12-week washout of those medications; these patients may uptitrate their insulin dose for up to
4 weeks, followed by an 8-week stabilization (±20% adjustment) of insulin dose prior to Visit 3.  
For the patients who do not need to wash out, the insulin dose will remain unchanged during the 
screening and lead-in period. 
After completion of the screening and lead-in period, the insulin dose at randomization will be 
fixed for the 16-week primary treatment period, except for patients who experience repeated or 
severe hypoglycemia (Section 7.4.1.2).  During the 36-week extension treatment period in which 
all patients will be on dulaglutide and insulin therapy, the investigator will adjust the patient’s 
insulin dose to achieve target blood glucose values (Table GBGF.7.2).


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During the whole study period (16-week primary treatment period and 36-week extension
treatment period), if repeated hypoglycemia (SMPG ≤70 mg/dL or symptomatic hypoglycemia) 
occurs, and it is considered to be related to the pharmacological therapy, the investigator can 
decrease the dose of insulin any time.  If at least 1 episode meets the criteria for severe 
hypoglycemia (events requiring assistance to administer therapy) or is associated with SMPG 
<54 mg/dL recorded during the assessment period, the investigator should decrease the dose of 
insulin.
Table GBGF.7.2.
Target Blood Glucose Values
Insulin Therapy
Assess Blood Glucose Value
Target Blood Glucose
Adjust Insulin Dose
Basal Insulin
Pre-Morning Meal
>70 and ≤110 mg/dL
Basal Insulin
Mixed Insulin
Pre-Morning Meal
>70 and ≤110 mg/dL
Mixed Insulin (Pre-Evening Meal)
Pre-Evening Meal
>70 and ≤110 mg/dL
Mixed Insulin (Pre-Morning Meal)
Mealtime Insulin
Pre-Midday Meal
>70 and ≤110 mg/dL
Mealtime Insulin (Pre-Morning Meal)
Pre-Evening Meal
>70 and ≤110 mg/dL
Mealtime Insulin (Pre-Midday Meal)
Pre-Bedtime
>70 and ≤140 mg/dL
Mealtime Insulin (Pre-Evening Meal)
7.2.1.3.
Concomitant Oral Antidiabetic Medications
The use of 1 or 2 of the OADs (biguanides, TZD, -GI, and sodium-glucose co-transporter 2 
inhibitors [SGLT2i]) is permitted during the study, provided the dose is stable for at least 3 
months prior to Visit 1. These drugs must be used based on label information.  Patients should 
remain on their prestudy OAD regimen for the screening and lead-in, and treatment periods.  
Patients who are taking concomitant OADs and who develop a condition that is a 
contraindication will be considered ineligible and must be discontinued from the study before 
randomization.  No change in dosage or administration of OADs is allowed during the 16-week 
primary treatment period.  During the 36-week extension treatment period, the investigator is to 
consult with the Lilly Clinical Research Physician (CRP) or Clinical Research Scientist (CRS) if 
the dosage or administration of OADs is changed.
7.3.
Blinding
This study includes a 16-week double-blind (dulaglutide versus placebo) primary treatment 
period, and a 36-week open-label extension treatment period.
To preserve the blinding of the study, the treatment assignments in the double-blind period will 
be blinded to patients and investigators until study completion.
Emergency unblinding for AEs may be performed through the IWRS, which may supplement or 
take the place of emergency codes generated by a computer drug-labeling system.  This option 
may be used ONLY if the patient’s well-being requires knowledge of the patient’s treatment 
assignment.  All actions resulting in an unblinding event are recorded and reported by the IWRS.


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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 CRP or CRS for 
the patient to continue in the study.
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 or CRS prior to 
unblinding a patient’s treatment assignment unless this could delay emergency treatment of the 
patient.  If a patient’s treatment assignment is unblinded, Lilly must be notified immediately.
7.4.
Dosage Modification
The dosage of investigational product (dulaglutide or placebo) cannot be adjusted (see Section 
7.2.1.1).
During the 16-week primary treatment period, the patient’s insulin dose is to remain fixed.  The 
insulin dose may be adjusted to maintain target glucose values during the 36-week extension
treatment period (Section 7.2.1.2).  For patients treated with 1 or 2 OADs prior to Visit 1, no 
change is allowed during the 16-week primary treatment period; during the 36-week extension
treatment period, the investigator is to consult with the Lilly CRP or CRS if the dosage or 
administration of OADs is changed (7.2.1.3).
7.4.1. Special Treatment Considerations
7.4.1.1.
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 standard of care for diabetes 
management (Japan Diabetes Society, 2013), except where that treatment would be in conflict 
with the protocol-provided treatment requirements.
This section provides guidance on management of hypoglycemic events and episodes of severe, 
persistent hyperglycemia. For effective implementation of measures described here, it is 
important that patients, and their caregivers, if applicable, be well-educated about the signs and 
symptoms of hypoglycemia (for example, intense hunger, sweating, tremor, restlessness, 
irritability, depression, headaches, disturbed sleep, or transient neurological disorders) and 
hyperglycemia (for example, severe thirst, dry mouth, frequent micturition, or dry skin). Patients 
should be instructed to contact the investigative site in the event of severe hypoglycemia or 
severe, persistent hyperglycemia (Section 7.4.1.3) between study visits.
7.4.1.2.
Management of Increased Hypoglycemia Risk
If a hypoglycemic event occurs, the patient should record in the study diary the plasma glucose 
(PG) level measured during the episode and, prior to administration of treatment (if taken), 
associated symptoms, and treatment administered.  Site personnel should educate and encourage 


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patients to measure and record PG values during the symptoms of hypoglycemia in 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) (ADA 2005):

Documented symptomatic hypoglycemia is defined as any time a patient feels that 
he/she is experiencing symptoms and/or signs associated with hypoglycemia, and has a 
PG level of ≤70 mg/dL (≤3.9 mmol/L).

Asymptomatic hypoglycemia is defined as an 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 with 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. 
7.4.1.3.
Management of Severe, Persistent Hyperglycemia
During the 16-week primary treatment period, if a patient experiences severe, persistent 
hyperglycemia, the patient must discontinue from study. Severe, persistent hyperglycemia is 
defined as follows; the patient’s fasting SMPG concentrations are consistently above the fasting 
plasma glucose threshold (see below) for at least 2 weeks.
Week of Study Treatment
Weeks 0-4
Weeks 5-16
Average Fasting Plasma 
Glucose for 2 weeks
>15.0 mmol/L
>13.3 mmol/L
>270 mg/dL
>240 mg/dL


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7.5.
Preparation/Handling/Storage/Accountability
The study site must store the SDP cartons in a locked and secure environment.  The SDPs must 
be refrigerated (not frozen) at 2°C to 8°C until use.  Dry ice should not be used for cooling.  
Patients will be provided with cartons containing 4 dulaglutide or placebo SDPs, as required, at 
clinical visits per the Schedule of Activities (Section 2).  They will receive insulated bags with 
cooling gel packs for use in transporting the SDP carton from the site to home.  Investigational 
products will be labeled according to Japan’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 investigational product.
Patients will also be provided with a commercially available PG meter and test strips to use 
during the study.  Sufficient investigational product and glucose testing supplies will be 
dispensed, as needed, at each visit.
Study site staff must regularly assess whether the patient is correctly administering the assigned 
investigational product and storing the investigational product according to the provided 
instructions.
7.6.
Treatment Compliance
Patient compliance with study medication will be assessed at each visit by the investigator, based 
on the patient’s adherence to the visit schedule and compliance with the study medication 
assessed by study diaries. Initially, patients considered as poorly compliant with their 
medication and/or the study procedures will receive additional training and instruction, as 
required, and be reminded of the importance of complying with the protocol. 
Overall treatment compliance is defined as taking at least 75% of the required doses of 
investigational product. Compliance is further defined as not missing more than 2 consecutive 
weekly injections of dulaglutide or >14 consecutive daily injections of insulin. Similarly, a 
patient will be considered significantly noncompliant if he/she is judged by the investigator to 
have intentionally or repeatedly taken more than the prescribed amount of medication.
7.7.
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 investigational product. 
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 over-the-counter [OTC] drugs, such as paracetamol or 
aspirin) must be documented, and the name of the drug, the dosage (OADs only), and the date(s)
of administration must be recorded in the patient’s diary and on the “Concomitant Medications” 
section of the eCRF.


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Nonstudy medications taken by patients who are screened but not randomized will not be
reported to Lilly unless the medication is associated with an SAE or AE that the investigator
believes may have been caused by a study procedure.
If the following prohibited drugs are used by a patient, the patient must discontinue from the 
study.
7.7.1. Oral Antidiabetic Medications
In the screening and lead-in period, DPP-4 inhibitors, SU, and glinides will be washed out, and 
are not permitted during the treatment period.  Dulaglutide and DPP-4 inhibitors decrease blood 
glucose via the GLP-1 receptor; this combination has not been investigated for efficacy and 
safety in clinical studies.  Sulfonylureas and glinides increase the risk of hypoglycemia in 
combination with dulaglutide (Emoto et al. 2015).
7.7.2. Nonstudy Glucagon-Like Peptide-1 Receptor Agonists
Nonstudy GLP-1 receptor agonists (for example, liraglutide or exenatide) are not allowed at any 
time during the study.  
7.7.3. Systemic Glucocorticoids
Systemic glucocorticoid therapy for >14 consecutive days (with the exception of topical, 
intraocular, or intranasal preparations) within 4 weeks prior to Visit 1 is exclusionary, and is not 
allowed at any time during the study.  Patients who require >14 days of therapy with these 
medications at any time during the treatment period must immediately be discontinued from the 
study.
7.7.4. Medications that Promote Weight Loss
Medications that promote weight loss are not allowed at any time during the study.
7.8.
Treatment after the End of the Study
7.8.1. Continued Access
Dulaglutide will not be made available after conclusion of the study to patients.


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8.
Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
Investigational product may be interrupted temporarily or discontinued permanently.  Those 
patients who stop the investigational product permanently will also be immediately discontinued 
from the study.
8.1.1. Permanent Discontinuation from Study Treatment and Study
Patients will be permanently discontinued from investigational product and from the study in the 
following circumstances:

For inadvertently enrolled patients for whom it was determined that continued treatment 
with investigational product would not be medically appropriate (see Section 8.1.3);

The patient misses more than 2 consecutive weekly injections of investigational product 
or more than 14 consecutive daily injections of insulin;

The patient’s fasting SMPG concentrations are consistently above the fasting plasma 
glucose threshold for at least 2 weeks (see Section 7.4.1.3)

The patient becomes pregnant during the study, in which case, the patient must 
discontinue the study immediately and Lilly or its designee is to be informed 
immediately;

The patient is diagnosed with acute pancreatitis or acute hepatitis;

The patient develops Exclusion Criterion [23] (eGFR <30 mg/min/1.73m2);

The patient is diagnosed with C-cell hyperplasia or medullary thyroid carcinoma;

The patient uses or needs to use additional antidiabetic medication or prohibited 
medication (for example, weight loss medication; see Section 7.7);

The patient requires >14 days of therapy with systemic glucocorticoids;

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;

Sponsor decision
o
Sponsor 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)

Investigator decision
o
The investigator decides that the patient should be discontinued from the study


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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 requests to be withdrawn from the study
Discontinuation of the investigational product for abnormal liver tests should be considered by 
the investigator when a patient meets 1 of the following conditions after consultation with the 
Lilly CRP or CRS:

ALT or aspartate aminotransferase (AST) >8X upper limit of normal (ULN)

ALT or AST >5X ULN for more than 2 weeks

ALT or AST >3X ULN and total bilirubin level (TBL) >2X ULN or prothrombin 
time >1.5X ULN

ALT or AST >3X ULN with the appearance of fatigue, nausea, vomiting, right 
upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)

alkaline phosphatase (ALP) >3X ULN

ALP >2.5X ULN and TBL >2X ULN

ALP >2.5 ULN with the appearance of fatigue, nausea, vomiting, right-quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (>5%)
Patients who discontinue investigational product and the study early will complete the early 
termination (ET) visit and safety follow-up visit as shown in the Schedule of Activities (Section 
2), unless the patient withdraws consent.  At the ET visit, the investigator will prescribe an 
appropriate antihyperglycemia regimen and SMPG monitoring plan to be followed after 
completion of the study.
8.1.2. Temporary Interruption of Study Treatment
In certain situations after randomization, the investigator may need to temporarily discontinue 
(interrupt) investigational product (for example, due to an AE or a clinically significant 
laboratory value).  If investigational product discontinuation is due to an AE, the event is to be 
documented and followed according to the procedures in Section 9.2 of this protocol.  
8.1.3. Discontinuation of Inadvertently Enrolled Patients
If the sponsor or investigator identify a patient who did not meet enrollment criteria and was 
inadvertently enrolled, a discussion must occur between the sponsor CRP or CRS 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
or CRS to allow the inadvertently enrolled patient to continue in the study with or without 
treatment with investigational product.


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8.2.
Discontinuation from the Study
Patients who discontinue investigational product must discontinue from the study (see Section 
8.1.1).
8.3.
Lost to Follow-Up
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Site personnel are expected to make 
diligent attempts to contact patients who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the site.


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9.
Study Assessments and Procedures
Section 2 lists the Schedule of Activities, with the study procedures and their timing (including 
tolerance limits for timing).
Appendix 2 lists the laboratory tests that will be performed for this study.
Unless otherwise stated in the subsections below, all samples collected for specified laboratory 
tests will be destroyed within 60 days of receipt of confirmed test results.  Certain samples may 
be retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards.
9.1.
Efficacy Assessments
9.1.1. Primary Efficacy Assessments
The primary efficacy measure is change in HbA1c from baseline at 16 weeks.
9.1.2. Secondary Efficacy Assessments
The following secondary efficacy measures will be evaluated at 16 and 52 weeks:

Change from baseline in HbA1c (52 weeks)

Percentage of patients achieving HbA1c targets of <7.0% or ≤6.5%, as measured at the 
central laboratory

Changes from baseline in FSG measured at the central laboratory

Changes from baseline in PG from 7-point SMPG profiles

Changes from baseline in body weight

Changes from baseline in insulin dose
9.1.3. Exploratory Health Outcome/Quality of Life Measures
The following health outcomes and dietary measures listed below will be assessed according to 
the Schedule of Activities (Section 2); these are considered exploratory objectives of the study.  
The questionnaires will be given to the patient by the investigator or site staff and self-completed 
by the patient during the visit.  The investigator or site staff will be responsible for checking for 
missing responses before the patient leaves the site.  The questionnaires should be completed 
before any other study procedures, if the patient is not adversely affected by the fasting 
condition, or completed after the patient has sufficiently recovered from the visit procedures.

The Diabetes Therapy Related-Quality of Life (DTR-QOL) is a disease-specific, self-
administered questionnaire to assess the influence of diabetes treatment on patient quality 
of life, regardless of treatment method.  The DTR-QOL consists of “burden on social 
activities and daily activities” (13 items), “anxiety and dissatisfaction with treatment” (8 
items), “hypoglycemia” (4 items), and “satisfaction with treatment” (4 items).  Each 


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question is rated on a 7-point scale, with higher scores indicating higher quality of life 
(4 scores in “satisfaction with treatment” must be reversed).

The Diabetes Treatment Satisfaction Questionnaire status (DTSQs) is a patient-reported 
assessment of treatment satisfaction (6 questions) and perceived frequency of severe 
hypoglycemia and hyperglycemia (2 questions).  Each question is rated on a 7-point scale
from 0 to 6, with higher scores indicating either greater treatment satisfaction or greater 
perceived frequency of hypoglycemic or hyperglycemic events.

The Device Questionnaire is a self-administered questionnaire to assess the usability and 
preference of Ateos (the name of device for Trulicity in Japan) compared to the insulin 
device the patient has been using so far.  The questionnaire consists of 2 sections.  In the 
first section, patients will respond to 12 items about usability and preference using a 
5-point scale (from “Strongly Agree” to “Agree” in insulin device, both devices are the 
same, and from “Strongly Agree” to “Agree” in Ateos). In the second section, patients 
are asked whether each procedure to prepare and inject was cumbersome or not for Ateos
(3 procedures) and insulin device (6 items). The patients’ response is chosen from rarely, 
sometimes, or always cumbersome in each procedure. This questionnaire was developed 
by the study team based on the previous research (Bailey et al. 2011; Oyer et al. 2011).

The Dietary Evaluation will explore the relationship between meal preference and 
efficacy of dulaglutide in Japanese patients with T2D.  Patients are required to complete a 
meal record (picture and record sheet) on 2 days during the 2-week period immediately 
before:  Visit 3 (Week 0), Visit 7 (Week 16), or Visit 12 (Week 52). The timing of the 
meal record should be on the same date as 7-point SMPG measurements (except for 52 
weeks). The Lilly designated vendor will calculate the total fats, total carbohydrates, 
total protein, and caloric intake amount based on the meal record. 
9.1.4. Appropriateness of Assessments
Efficacy and safety assessments included in this study are generally regarded as reliable and 
accurate with respect to the efficacy and safety assessments in individuals and populations with 
T2D.
9.2.
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 


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appropriate diagnostic evaluation, or is reasonably explained.  The frequency of follow-up 
evaluations of the AE is left to the discretion of the investigator.
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
establish treatment effect.
After the informed consent form (ICF) is signed, study site personnel will record via eCRF the 
occurrence and nature of each patient’s preexisting conditions, including clinically significant 
signs and symptoms of the disease under treatment in the study.  In addition, site personnel will 
record any change in the condition(s) and any new conditions as AEs. Investigators should 
record their assessment of the potential relatedness of each AE to study procedure, 
investigational product, and study device via eCRF.
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, study device, or a study procedure, taking into account the 
disease, concomitant treatment, or pathologies.
A “reasonable possibility” means that there is a cause and effect relationship between the 
investigational product, study device, and/or study procedure and the AE.
The investigator answers yes/no when making this assessment.
Planned surgeries and nonsurgical interventions should not be reported as AEs unless the 
underlying medical condition has worsened during the course of the study.
If a patient’s investigational product is discontinued as a result of an AE, study site personnel 
must report this to Lilly or its designee via eCRF, clarifying if possible, the circumstances 
leading to any dosage modifications, or discontinuations of treatment.
9.2.1. Serious Adverse Events
An SAE is any AE from this study that results in 1 of the following outcomes:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

considered significant by the investigator for any other reason:  important medical 
events that may not result in death, be life-threatening, or require hospitalization 
may be considered serious, based upon appropriate medical judgment.
Although all AEs occurring after signing the ICF are recorded in the eCRF, SAE reporting 
begins after the patient has signed the ICF and has received investigational product.  However, if 
an SAE occurs after signing the ICF, but prior to receiving investigational product, it needs to be 
reported ONLY if it is considered reasonably possibly related to study procedure.


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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 patients 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 patient 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 9.2.2.
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the package insert 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.
9.2.2. Adverse Events of Interest
9.2.2.1.
Hypoglycemia
Patients will collect information on episodes of hypoglycemia between Visit 2 and the last study 
visit (Visit 13 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 7.4.1.2) according to the Schedule 
of Activities (Section 2).  Site personnel will enter this information into the eCRF at each visit 
after Visit 1.


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9.2.2.2.
Pancreatitis
Acute pancreatitis is defined as an AE of interest in all trials with dulaglutide, including this trial.  
Acute pancreatitis is an acute inflammatory process of the pancreas that may also involve 
peripancreatic tissues and/or remote organ systems (Banks and Freeman 2006).  The diagnosis of 
acute pancreatitis requires 2 of the following 3 features:
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 amylase [total 
and pancreatic] 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 
and will also be discontinued from the study.  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) and imaging 
studies, the event must be reported as an SAE.  For a potential case that does not meet all of 
these criteria, it is up to the investigator to determine the seriousness of the case (AE or SAE) 
and the relatedness of the event to investigational product.
In addition to the diagnostic assessment in patients who develop symptoms of acute pancreatitis, 
each patient will have measurements of total amylase, lipase, and trypsin at Visit 3 (Week 0), 
Visit 7 (Week 16), Visit 10 (Week 36), Visit 12 (Week 52), and the 4-week safety follow-up visit
to assess any potential effects of dulaglutide on the exocrine pancreas (refer to the Schedule of 
Activities, Section 2).  Further diagnostic assessment per Lilly algorithm for assessment of 
asymptomatic pancreatic hyperenzymemia will be required whenever lipase and/or amylase 
(pancreatic and/or total) are ≥3×ULN at any time during the study.  If this situation occurs at 
Visit 12 (Week 52), the patient will 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 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 origin will also be submitted to the 


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adjudication committee to assess for possible pancreatitis or other pancreatic disease.  Relevant 
data from patients with acute or chronic pancreatitis, those with severe or serious abdominal pain, 
and those that undergo additional assessments due to confirmed hyperenzymemia will be entered 
into a specifically designed eCRF page by study site or Lilly staff.  The adjudication committee 
representative will enter the results of adjudication in a corresponding eCRF page.
9.2.2.3.
C-Cell Hyperplasia and C-Cell Neoplasms
Individuals with personal or family history of certain thyroid or nonthyroid endocrine 
abnormalities or certain preexisting laboratory and genetic characteristics will be excluded from 
the study (see Section 6.2).  The assessment of thyroid safety during the trial will include 
reporting of thyroid treatment-emergent adverse events (TEAEs) and measurements of calcitonin 
according to the Schedule of Activities (Section 2) at Visit 1, Visit 3 (Week 0), Visit 7 (Week 
16), Visit 10 (Week 36), and Visit 12 (Week 52).  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 12 (Week 52) will be asked to 
repeat the measurement within 1 month.  If this repeat value is increasing (≥10% increase), it 
will be recommended that the patient undergo additional endocrine assessment and longer-term 
follow-up by an endocrinologist to exclude a serious adverse effect on the gland.  
Patients with an increase in serum calcitonin ≥50% of the mean of the baseline and screening 
values AND an absolute value ≥35 pg/mL at Visit 12 (Week 52) will be recommended to 
immediately undergo additional endocrine assessments and longer-term follow-up by an 
endocrinologist.
9.2.2.4.
Cardiovascular Events
Deaths and nonfatal cardiovascular (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).
9.2.2.5.
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 
investigational product via a CRF created for this purpose.  Investigational product should be 
temporarily interrupted in any individual suspected of having a severe or serious allergic reaction 
to investigational product (Section 8.1.2).  Investigational product may be restarted when/if it is 
safe to do so, in the opinion of the investigator.  If investigational product is permanently 
discontinued, the patient will be discontinued from the trial (Section 8.1.1).


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9.2.3. Complaint Handling
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical studies in order to ensure the safety of study participants, monitor quality, and to 
facilitate process and product improvements.
Patients will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed.
9.3.
Treatment of Overdose
Investigational product overdose will be reported as an AE.  In the event of overdose, refer to the
Product Label.
9.4.
Safety
9.4.1. Electrocardiograms
For each patient, a single 12-lead electrocardiogram (ECG) will be obtained according to the 
Schedule of Activities (Section 2). The patient must be supine for approximately 5 minutes 
before ECG collection and remain supine but awake during ECG collection. Electrocardiograms 
must be recorded before collecting any blood for safety tests. Electrocardiograms may be 
obtained at additional times, when deemed clinically necessary. All ECGs recorded should be 
stored at the investigational site.
Electrocardiograms will be interpreted by a qualified physician (the investigator or qualified 
designee) at the site as soon after the time of ECG collection as possible, and ideally while the 
patient is still present, to determine whether the patient meets entry criteria and for immediate
patient management, should any clinically relevant findings be identified.
After enrollment, if a clinically significant finding is identified (including but not limited to
changes in QT/QTc interval from baseline), the investigator will determine if the patient can 
continue in the study. The investigator or qualified designee is responsible for determining if 
any change in patient management is needed and must document his/her review of the ECG 
printed at the time of collection. Any new clinically relevant finding should be reported as an 
AE.
9.4.2. Vital Signs
Sitting blood pressure (BP) and pulse rate (PR) will be measured according to the Schedule of 
Activities (Section 2), using the site’s existing equipment.  Vital sign measurements should be 
taken before obtaining an ECG tracing, at visits where required (see Schedule of Activities, 
Section 2), and before collection of blood samples for laboratory testing.  For each parameter, 
3 measurements will be taken 30 seconds apart 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 


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measurement of sitting BP and PR is to be recorded in the eCRF. Any AE related to changes in 
BP and PR should be reported, per requirements provided in Section 9.2.
9.4.3. Laboratory Tests
For each patient, laboratory tests detailed in (Appendix 2) should be conducted according to the 
Schedule of Activities (Section 2). 
Any clinically significant findings from laboratory tests that result in a diagnosis and that occur 
after the patient receives the first dose of investigational product should be reported to Lilly or its 
designee as an AE via eCRF.
9.4.4. Body Weight and Body Mass Index
Body weight will be measured at prespecified time points (see Schedule of Activities, Section 2).  
Each patient’s weight should be measured according to a standardized protocol (Appendix 6).  
Body mass index will be computed from the patient’s weight and height.
9.4.5. Safety Monitoring
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods.
In addition, specific safety measures are included in the protocol to ensure appropriate 
monitoring of pancreatic, thyroid, and liver safety.  Laboratory findings that trigger pancreatic 
and thyroid safety monitoring per Lilly standards are provided in Sections 9.2.2.2 and 9.2.2.3, 
respectively.  If a study patient/subject 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 safety and to comply with regulatory 
guidance, the investigator is to consult with the Lilly CRP or CRS regarding collection of 
specific recommended clinical information and follow-up laboratory tests (see Appendix 4).
9.5.
Pharmacokinetics
Not applicable.
9.6.
Pharmacodynamics
Not applicable.
9.7.
Pharmacogenomics
9.7.1. Whole Blood Sample for Pharmacogenetic Research
A whole blood sample will be collected for pharmacogenetic analysis as specified in the 
Schedule of Activities (Section 2) where local regulations allow.  
Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future.  Samples will be used to investigate variable response to dulaglutide and to 


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investigate genetic variants thought to play a role in T2D and related complications.  Assessment 
of variable response may include evaluation of AEs or differences in efficacy.  
All samples will be coded with the patient number.  These samples and any data generated can 
be linked back to the patient only by the investigator site personnel.  
Samples will be retained for a maximum of 15 years after the last patient visit for the study, or 
for a shorter period if local regulations and/or ethical review boards (ERBs)/investigational 
review boards (IRBs) impose shorter time limits, at a facility selected by Lilly or its designee.  
This retention period enables use of new technologies, response to regulatory questions, and 
investigation of variable response that may not be observed until later in the development of 
dulaglutide.
Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named.  However, existing approaches include whole genome or exome 
sequencing, genome wide association studies, and candidate gene studies.  Regardless of 
technology utilized genotyping data generated will be used only for the specific research scope 
described in this section.
9.8.
Biomarkers
Not applicable.
9.9.
Health Economics
Not applicable.


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10. Statistical Considerations
10.1. Sample Size Determination
A total of approximately 160 patients (dulaglutide:  120 patients; placebo:  40 patients) will be 
randomized to have approximately 136 completers (dulaglutide :  102 patients; placebo:  
34 patients) to show dulaglutide is superior to placebo with more than 99% power assuming a 
treatment difference of 1% in HbA1c reduction, standard deviation (SD) = 1.0%, and dropout 
rate of 15%.  The screen failure rate is estimated as 20%.  Approximately 200 patients will be 
screened.
10.2. Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
All Randomized Patients
All patients randomized to 1 of the 2 treatments
Full Analysis Set (FAS)
All patients who received at least 1 dose of study treatment and have at least 1 
measurement of HbA1c after study treatment
Per Protocol
All patients in the FAS who meet the following criteria:

Have no important protocol deviations that could impact the 
assessment of the primary objective (see SAP)

At least 75% compliant with investigational product

Complete the treatment phase (16 weeks [Visit 7]) for primary 
endpoint

Not missing more than 2 consecutive weekly injections of 
investigational product or more than 14 consecutive daily injections of 
insulin
Safety Population
All patients who received at least 1 dose of study treatment
Abbreviations:  HbA1c = hemoglobin A1c; SAP = Statistical Analysis Plan.
10.3. Statistical Analyses
10.3.1. General Statistical Considerations
Statistical analysis of this study will be the responsibility of Lilly or its designee.  Any change to 
the data analysis methods described in the protocol will require an amendment ONLY if it 
changes a principal feature of the protocol.  Any other change to the data analysis methods 
described in the protocol, and the justification for making the change, will be described in the 
clinical study report (CSR).  Additional exploratory analyses of the data will be conducted as 
deemed appropriate.
Statistical tests will only be conducted for the 16-week primary treatment period.  Summary 
statistics will be provided for the observed value and change from baseline value based on 
mixed-model for repeated measures (MMRM) (note: statistical comparison will not be 
conducted) during the entire study period for each arm. 
Unless otherwise specified, listings will include all randomized patients.  Efficacy analyses will 
be conducted using the full analysis set (FAS) which is defined as all patients who received at 


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least 1 dose of study treatment and have at least 1 measurement of HbA1c after study treatment.  
The primary efficacy measure (HbA1c) will also be evaluated in the Per Protocol (PP)
population.  Also, safety analyses will be conducted on the safety population which is defined as 
all patients who received at least 1 dose of study treatment.
Unless otherwise specified, all tests of treatment effects will be conducted at a 2-sided alpha 
level of 0.05, and confidence intervals (CIs) will be calculated at 95%, 2-sided.  All tests of 
interactions between treatment groups and other factors will be conducted at a 2-sided alpha 
level of 0.10.
The baseline will be Visit 3.  For all variables, including HbA1c, if baseline data are missing, the 
last nonmissing measurement taken prior to this visit will be used for the baseline measurement.  
The measurement for the primary analysis is defined as the change from baseline in HbA1c to 
Week 16 (Visit 7).
The primary analysis model will be MMRM analysis using restricted maximum likelihood 
(REML) (Section 10.3.3.1).  An unstructured covariance structure will be used to model the 
within-patient variability and implicitly adjust for missing data.  If this analysis 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 Kenward-Roger approximation 
will be used to estimate denominator degrees of freedom.  Significance tests will be based on least 
squares (LS) means using Type III sum of squares.
The secondary analysis for the primary endpoint will be analysis of covariance (ANCOVA) 
(Section 10.3.3.2).  Missing endpoints will be imputed with the last observation carried forward 
(LOCF), using only postbaseline data.  If there are no data after the date of randomization, the 
endpoint will be considered missing.
For continuous measures, summary statistics will include sample size, mean, SD, median, 
minimum, and maximum for both the actual and the change from baseline measurements.  Least-
squares 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 means 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.  Multiplicity will 
not be adjusted for efficacy and health outcome endpoints in this study.


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10.3.2. Treatment Group Comparability
10.3.2.1. Patient Disposition
A detailed description of patient disposition will be provided at the end of the study. 
Frequency counts and percentages of all patients entered, randomized/enrolled, completing, 
and/or discontinuing from the study early will be presented for each of the treatment groups.  
The reasons for discontinuation from the study will be summarized by treatment group.  A 
summary of discontinuations will also be presented by visit.
10.3.2.2. Patient Characteristics
Patients’ age, sex, weight, height, and other demographic characteristics will be recorded.
Demographic and baseline characteristics will be summarized for both treatment arms.  For 
continuous measures, summary statistics will include sample size, mean, median, maximum, 
minimum, and SDs.  Means will be displayed. For categorical measures, summary statistics will 
include sample size, frequency, and percent.  
10.3.2.3. Concomitant Therapy 
Concomitant medications, including previous therapy for diabetes, will be summarized by 
treatment.  
10.3.2.4. Treatment Compliance 
Overall treatment compliance is defined as taking at least 75% of the required doses of 
investigational product. Compliance is further defined as not missing more than 2 consecutive 
weekly injections of dulaglutide or >14 consecutive daily injections of insulin. Similarly, a 
patient will be considered significantly non-compliant if he/she is judged by the investigator to 
have intentionally or repeatedly taken more than the prescribed amount of medication.
Compliance will be summarized by treatment arm, by visit, and overall.  Listings will also be 
produced.
10.3.3. Efficacy Analyses
10.3.3.1. Primary Analyses
The primary analysis model will be an MMRM for HbA1c change from baseline to 16 weeks 
(Visit 7) using REML with treatment, insulin regimen (basal insulin, premixed insulin, or 
basal/mealtime insulin), visit, and treatment-by-visit as fixed effects, baseline HbA1c as a 
covariate, and patient as a random effect. 
10.3.3.2. Secondary 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 FAS, the data and analyses 
will be further investigated.  The secondary analysis for the primary endpoint will be an 
ANCOVA for HbA1c change from baseline to the Week 16 endpoint with treatment, and insulin 
regimen (basal insulin, premixed insulin, or basal/mealtime insulin) as fixed effects and baseline 
HbA1c as a covariate, with missing endpoints imputed with LOCF using postbaseline data only.


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All secondary efficacy measures that are continuous variables (changes from baseline) other than 
HbA1c will be analyzed using MMRM on the FAS.  There will be no multiplicity adjustment for 
pairwise treatment comparisons.  The MMRM and ANCOVA models will include treatment, 
baseline HbA1c (<8.5%, ≥8.5%), and insulin regimen (basal insulin, premixed insulin, or 
basal/mealtime insulin) as fixed effects and a covariate of baseline value.
Repeated measures logistic regression with generalized linear mixed model will be used to 
analyze for percentage of patients achieving HbA1c targets of <7.0% or ≤6.5%. 
10.3.4. Safety Analyses
The safety analyses will include measurements of AEs, SAEs, hypoglycemic episodes,
laboratory analytes, vital signs, and ECGs.  The safety analyses will be conducted by treatment
for 2 periods; primary treatment period and entire study period (including primary, extension,
and follow-up periods). Unless otherwise specified, the Safety Population will be used for 
analyses of safety measurements.  P-values provided from all safety analyses will be used for 
guidance purposes only.
10.3.4.1. Study Drug Exposure
Exposure to each study treatment will be calculated for each patient and summarized by 
treatment group.  
10.3.4.2. Adverse Events
Adverse events will be coded from the actual term using the Medical Dictionary for Regulatory 
Activities (MedDRA) and reported 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 
events that are newly reported after the first dose of investigational product or reported to worsen
in severity from baseline, will be listed by patient and visit.  Information on treatment, actual 
term, preferred term, severity, seriousness, and relationship to investigational product will also 
be reported.  
Summary statistics will be provided for 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.  
Because gastrointestinal AEs, such as nausea and vomiting, are among the most common events 
reported in patients treated with dulaglutide, summaries and analyses for time to onset, duration, 
and severity of nausea and vomiting will be provided.  The planned reports will be further 
described in the Statistical Analysis Plan (SAP).
Listings of patients experiencing allergic and hypersensitivity reactions, as well as those 
discontinuing the study due to AEs, will be produced.


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10.3.4.3. Hypoglycemic Episodes
Section 7.4.1.2 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 Safety Population. Hypoglycemia will be analyzed 
as “documented symptomatic,” “asymptomatic,” “probable,” “severe,” or “nocturnal” and for all 
events combined, “total hypoglycemia.”  Other categories, including the categories above 
defined with differing PG thresholds, may also be included in these analyses when deemed 
appropriate.  
Hypoglycemia rates will be summarized for periods of 1 year, 30 days, and 100 years (severe 
hypoglycemia only).  The rate of severe hypoglycemia per 100 years will be compared between 
treatment groups using the empirical method (details will be described in the SAP). For each of 
the other categories of hypoglycemia, the number of hypoglycemia events during a specific 
period (rate) after randomization (for example, 0-16 weeks of treatment period) will be analyzed 
by using a negative binomial regression model.  The model will include treatment and the 
baseline hypoglycemia rate (measured during lead-in) as a covariate.  An offset defined as the 
log transformation of treatment exposure in the specific period (days)/365.25 days (or 30 days) 
will be included in the model to estimate the rate of hypoglycemia per year (or per 30 days).  The 
proportion of subjects with at least 1 hypoglycemic event in each category (incidence) during a 
specific period after randomization will be analyzed using a logistic regression model including 
treatment and baseline hypoglycemia rate value in the model.
10.3.4.4. Severe, Persistent Hyperglycemia
Time to study discontinuation due to severe, persistent hyperglycemia will be analyzed.  The 
incidence and percentage of patients discontinuing the study due to severe, persistent 
hyperglycemia will be analyzed using Fisher’s exact test.  A listing of patients who discontinue 
the study due to severe, persistent hyperglycemia will be provided.
10.3.4.5. Special Safety Topics
10.3.4.5.1.Pancreas Safety
Listings and summaries of adjudicated pancreatic events will be provided.
10.3.4.5.2.Cardiovascular Safety
Listings and summaries and adjudicated CV events will be provided.  Pulse rate and systolic and 
diastolic BP from vital signs will also be summarized.  
10.3.4.5.3.Thyroid Safety
Listings of AEs of interest associated with the thyroid gland (benign and malignant neoplasms) 
will be produced.
10.3.4.5.4.Allergic/Hypersensitivity Reactions
Summaries and listings of allergic and other hypersensitivity AEs will be provided.
10.3.4.6. Laboratory Analyses
Laboratory measurements will be listed by patient and visit.  An additional listing will be 
presented for laboratory measurements that are outside the normal range.


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Laboratory measurements and vital signs will also be summarized.  
For subjective (qualitative) laboratory analytes, counts and percentages of patients with normal 
and abnormal values will be analyzed using chi-square tests.
10.3.5. Health Outcomes Variables

DTR-QOL (Diabetes Therapy Related-Quality of Life) 
Summary statistics for each dimension and total score by visit and change from baseline 
values will be provided.

DTSQs (Diabetes Treatment Satisfaction Questionnaire status) 
Summary statistics for each dimension and total score by visit and change from baseline 
values will be provided.

Device Questionnaire
In the first section, frequency and percentage of sum of “Strongly Agree” and “Agree” 
for Ateos, sum of “Strongly Agree” and “Agree” for Insulin Device, and “Both Devices 
are the same” will be presented. Also, the overall preference for Ateos versus Insulin 
Device, which was evaluated by a percentage of sum of “Strongly Agree” and “Agree” 
for Ateos will be presented. This was tested by the use of a one-sample binomial test 
using an exact method at each visit. The null hypothesis was that the preference for 
Ateos was equal to 50%, against the hypothesis that it was different from 50%.
In the second section, the frequency and percentage of each category (ie, “Rarely,”
“Sometimes,” and “Always”) will be presented by device at each scheduled visit.
10.3.6. Other Exploratory Variables

Dietary Evaluation
Summary statistics for total fats, total carbohydrates, total protein, and caloric intake 
amount (actual) by visit and change from baseline values will be provided.
10.3.7. Subgroup Analyses 
Population subgroups of interest will be analyzed for the variable of HbA1c, body weight, and 
hypoglycemia rate.  Other variables may also be evaluated.
The following are candidate subgroups that might be analyzed.  This list is not necessarily all-
inclusive:

Baseline HbA1c (<8.5%, ≥8.5%)

Insulin regimen (basal insulin, premixed insulin, or basal/mealtime insulin).
For the subgroup analysis of insulin regimen, an analysis will be performed using an MMRM 
model that includes the same effects given for primary or secondary efficacy measures plus
subgroup, subgroup-by-treatment interaction, subgroup-by-visit interaction, and subgroup-by-
treatment-by-visit interaction. For the subgroup analysis of baseline HbA1c strata (<8.5%, 
≥8.5%), baseline HbA1c will not be included as a covariate. The interaction effect will be 
evaluated using a significance level of 0.10, unadjusted.


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10.3.8. Interim Analyses
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the appropriate Lilly CRP or CRS, or designee, will be consulted to determine 
whether it is necessary to amend the protocol.


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11.
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[ADA] American Diabetes Association. Approaches to glycemic treatment. Diabetes Care.
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Tamaki C, Takeuchi M, Iwamoto N, Glaesner W. Pharmacological profile and clinical trial 
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agonist dulaglutide for 12 weeks in Japanese patients with type 2 diabetes: dose-dependent 
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12.
Appendices


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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 AE 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.
α-GI
alpha-glucosidase inhibitor
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
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.
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.
CRS
clinical research scientist
CSR
clinical study report
CT
computed tomography
CV
cardiovascular
DPP-4
dipeptidyl peptidase-4


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DTR-QOL
Diabetes Therapy Related-Quality of Life
DTSQs
Diabetes Treatment Satisfaction Questionnaire status
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.
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
FAS
full analysis set
FSG
fasting serum glucose
GCP
good clinical practice
GLP-1
glucagon-like peptide-1
HbA1c
hemoglobin A1c
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.
IWRS
interactive web-response system
LOCF
last observation carried forward
LS mean
least-squares mean
MEN
multiple endocrine neoplasia
MI
myocardial infarction
MMRM
mixed-model repeated measures
MRI
magnetic resonance imaging
OAD
oral antidiabetic


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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.
PR
pulse rate
QTc
corrected QT interval
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
SGLT2i
sodium-glucose co-transporter 2 inhibitor
SMPG
self-monitored plasma glucose
SmPC
summary of product characteristics
SU
sulfonylurea
SUSARs
suspected unexpected serious adverse reactions
T2D
type 2 diabetes
TBL
total bilirubin level
TEAE
treatment-emergent adverse event:  An untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens relative 
to the pretreatment state, which and does not necessarily have to have a causal 
relationship with this treatment.
T/V
telephone visit
TZD
thiazolidinedione 
ULN
upper limit of normal
USPI
United States prescribing information 
WHO
World Health Organization


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Appendix 2.
Clinical Laboratory Tests 
Clinical Laboratory Tests (to be collected centrally)a
Hematology
Clinical Chemistry
Hemoglobin
Sodium
Hematocrit
Potassium
Erythrocyte count (RBC)
Chloride
Mean cell volume (MCV)
Bicarbonate
Mean cell hemoglobin concentration (MCHC)
Total bilirubin
Leukocytes (WBC)
Direct bilirubin
Neutrophils
Alkaline phosphatase (ALP)
Lymphocytes
Alanine aminotransferase (ALT/SGPT)
Monocytes
Aspartate aminotransferase (AST/SGOT)
Eosinophils
Gamma-glutamyl transferase (GGT)
Basophils
Blood urea nitrogen (BUN)
Platelets
Creatininee
Creatine kinase (creatine phosphokinase)f
Urinalysis
Uric acid
Protein
Calcium
Glucose
Albumin
Ketones
Blood
Pregnancy test (serum)g
Urine leukocyte esterase
HbA1c
Microscopicb
Glucose, fasting
Calcitonin
Albumin/creatinine ratio (urine)c
Pancreas (exocrine)
Lipid panel
Total amylase
Total cholesterol
Lipase
High-density lipoprotein-cholesterol (HDL-C)
Trypsin
Low-density lipoprotein-cholesterol (LDL-C)d
Triglycerides
Stored Samples
Pharmacogenomics sample
Abbreviations:  CK-MB = creatine kinase-MB; eGFR = estimated glomerular filtration rate; HbA1c = hemoglobin 
A1c; RBC = red blood cells; SGOT = serum glutamic oxaloacetic transaminase; SGPT = serum glutamic pyruvic 
transaminase; WBC = white blood cells.
a
All tests will be performed by the Lilly-designated central laboratory.
b
Microscopic evaluation to be performed if any of the listed analytes are positive.
c
Urinary albumin and creatinine are measured; ratio is calculated.
d
Direct LDL-C is measured.
e
Japanese eGFR equation defined by the Japanese Society of Nephrology is used to estimate glomerular filtration 
rate.
f
CK-MB is to be assayed if creatine kinase result >1000 IU/L.


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g
A serum pregnancy test will be performed at Visit 1 and Visit 3 for women of childbearing potential only and 
will be analyzed at a central laboratory.  Pregnancy tests may be repeated at any time during the study and 
analyzed locally at the investigator’s discretion.


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Appendix 3.
Study Governance Considerations 


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


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Appendix 3.1.4.
Investigator Information
Physicians with a specialty in diabetes/endocrinology, internal medicine, or family medicine will 
participate as investigators in this clinical trial.
Appendix 3.1.5.
Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
Appendix 3.1.6.
Final Report Signature
The Clinical Study Report (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 investigator with the most enrolled patients will serve as the CSR coordinating investigator.  
If this investigator is unable to fulfill this function, another investigator will be chosen by Lilly to 
serve as the CSR coordinating investigator.
The sponsor’s responsible medical officer and statistician will approve the final CSR for this 
study, confirming that, to the best of his or her knowledge, the report accurately describes the 
conduct and results of the study.
Appendix 3.2.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate

sponsor start-up training to instruct the investigators and study coordinators.  This 
training will give instruction on the protocol, the completion of the case report 
forms (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 ethical review boards (ERBs) with direct access to 
original source documents.
Appendix 3.2.1.
Data Capture System
An electronic data capture system will be used in this study.  The 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, will be stored electronically in the central vendor’s 
database system.  Data will subsequently be transferred from the central vendor to the Lilly data 
warehouse.
Any data for which paper documentation provided by the patient will serve as the source 
document will be identified and documented by each site in that site’s study file.  Paper 
documentation provided by the patient may include, for example, a paper diary to collect patient-
reported outcome (PRO) measures (for example, health outcome measures), dosing information, 
or an event diary.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.
Appendix 3.3.
Study and Site Closure
Appendix 3.3.1.
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, the investigator, or the ERB of the study 
site judges it necessary for medical, safety, regulatory, or other reasons consistent with 
applicable laws, regulations, and GCP.
Appendix 3.3.2.
Discontinuation of the Study
The study will be discontinued if Lilly judges it necessary for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations, and GCP.


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


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Appendix 5.
Protocol GBGF 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 6.
Protocol GBGF 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 7.
Protocol H9X-JE-GBGF(b) Amendment 
Summary 
A Phase 4 Study of Efficacy and Safety of Dulaglutide 
When Added to Insulin Treatment With or Without Oral 
Antidiabetic Medication in Patients with Type 2 Diabetes
Overview
Protocol H9X-JE-GBGF, A Phase 4 Study of Efficacy and Safety of Dulaglutide When Added to 
Insulin Treatment With or Without Oral Antidiabetic Medication in Patients with Type 2 
Diabetes, has been amended.  The new protocol is indicated by amendment (b) and will be used 
to conduct the study in place of any preceding version of the protocol.
Lilly has made a change as follows:

Section 6.2: Changed eGFR exclusion threshold for metformin users to comply with 
metformin package insert.


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Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
6.2.
Exclusion Criteria
[23] have an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2, 
calculated by the Japanese Society of Nephrology equation, as determined by 
the central laboratory; for participants on metformin, have moderate renal 
disease or renal dysfunction (for example, eGFR <45 60 mL/min/1.73 m2) at 
Visit 1;

SAP_001.pdf: 
H9X-JE-GBGF Statistical Analysis Plan 
 
A Phase 4 Study of Efficacy and Safety of Dulaglutide When Added to Insulin Treatment With 
or Without Oral Antidiabetic Medication in Patients with Type 2 Diabetes 
 
NCT027504 
Approval Date:   12-Sep-2018 


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1.
Statistical Analysis Plan for Clinical Studies:  
H9X-JE-GBGF:  A Phase 4 Study of Efficacy and Safety of 
Dulaglutide When Added to Insulin Treatment With or 
Without Oral Antidiabetic Medication in Patients with 
Type 2 Diabetes
Confidential Information
The information contained in this document is confidential and the information contained 
within it may not be reproduced or otherwise disseminated without the approval of Eli Lilly 
and Company or its subsidiaries.  
Note to Regulatory Authorities: this document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure. Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release. In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
Dulaglutide (LY2189265) Type 2 Diabetes
Study H9X-JE-GBGF is a Phase 4, randomized, placebo-controlled, double-blind (16 
weeks) and subsequent open-label (36 weeks) study to assess the efficacy and safety of 
dulaglutide 0.75 mg in Japanese patients with type 2 diabetes who have inadequate 
glycemic control on insulin therapy with or without 1 or 2 oral antidiabetic medications.
Eli Lilly Japan K.K.
Kobe, Hyogo Japan
Protocol H9X-JE-GBGF
Phase 4
Statistical Analysis Plan electronically signed and approved by Lilly on date provided 
below.
Approval Date: 12-Sep-2018 GMT


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2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan for Clinical Studies:   H9X-JE-GBGF:  A 
Phase 4 Study of Efficacy and Safety of Dulaglutide When Added to 
Insulin Treatment With or Without Oral Antidiabetic Medication in 
Patients with Type 2 Diabetes .............................................................................................1
2.
Table of Contents................................................................................................................2
3.
Revision History .................................................................................................................6
4.
Study Objectives.................................................................................................................7
4.1.
Primary Objective ..........................................................................................................7
4.2.
Secondary Objectives.....................................................................................................7
4.3.
Exploratory Objectives...................................................................................................7
5.
A Priori Statistical Methods ................................................................................................8
5.1.
Determination of Sample Size ........................................................................................8
5.2.
General Considerations ..................................................................................................8
5.2.1.
Analysis Populations..............................................................................................9
5.2.2.
Baseline Definition ..............................................................................................10
5.3.
Patient Disposition .......................................................................................................10
5.4.
Protocol deviations.......................................................................................................10
5.5.
Patient Characteristics ..................................................................................................10
5.6.
Concomitant Therapy...................................................................................................10
5.7.
Historical Illness ..........................................................................................................10
5.8.
Treatment Compliance .................................................................................................10
5.9.
Treatment Exposure .....................................................................................................11
5.10. Efficacy Analysis .........................................................................................................11
5.10.1.
Primary Efficacy Analysis....................................................................................11
5.10.2.
Secondary Efficacy Analysis................................................................................12
5.11. Insulin Dose.................................................................................................................14
5.12. Health Outcome Analyses ............................................................................................15
5.12.1.
DTSQs (Diabetes Treatment Satisfaction Questionnaire 
status) ..................................................................................................................15
5.12.2.
DTR-QOL (Diabetes Therapy Related-Quality of Life)........................................15
5.12.3.
Device Questionnaire ...........................................................................................15
5.13. Other Exploratory Variables.........................................................................................15
5.13.1.
Dietary Evaluation ...............................................................................................15
5.14. Safety Analyses............................................................................................................16


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5.14.1.
Adverse Events ....................................................................................................16
5.14.2.
Adverse Events of Special Interest (AESI) ...........................................................16
5.14.3.
Hypoglycemic Episodes.......................................................................................16
5.14.4.
Laboratory Analyses ............................................................................................17
5.14.5.
Physical Characteristics and Vital Signs...............................................................19
5.14.6.
Adjudication of safety events ...............................................................................19
5.14.7.
Renal safety .........................................................................................................19
5.15. Subgroup Analyses.......................................................................................................21
6.
Unblinding Plan................................................................................................................23
6.1.
Interim Analyses ..........................................................................................................23
6.2.
Site Level Unblinding ..................................................................................................23
6.3.
Sponsor/Trial Level Unblinding ...................................................................................23
7.
References ........................................................................................................................25
8.
Appendices .......................................................................................................................26
Appendix 1.
Empirical method for the rate of severe hypoglycemia....................................27


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Table of Contents
Table
Page
Table GBGF 5.1.
Treatment Groups for Each Treatment Period .............................................9
Table GBGF 5.2.
Analysis Population for Study H9X-JE-GBGF............................................9
Table GBGF 5.3.
Vitals Threshold for Study H9X-JE-GBGF...............................................19
Table GBGF 5.4.
CKD Stage based on eGFR for Study H9X-JE-GBGF ..............................21
Table GBGF 5.5.
CKD Stage based on UACR for Study H9X-JE-GBGF.............................21


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Table of Contents
Appendix
Page
Appendix 1.
Empirical method for the rate of severe hypoglycemia....................................27


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3.
Revision History
SAP Version 1 was approved prior to First Patient Visit (FPV).
SAP Version 2:  Unblinding Plan Section was added to clarify the unblinding plan and blinding 
strategy throughout the study conduct. Summary of concomitant medication and plot of SMPG 
during follow-up period have been added.
SAP Version 3: Some post hoc analyses were added: Statistical tests were added for DTSQs and 
DTR-QOL.


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4.
Study Objectives
4.1.
Primary Objective
The primary objective of this study is to show superiority of the addition of once-weekly 
dulaglutide 0.75 mg compared to the addition of once weekly placebo to insulin treatment with 
or without 1 or 2 OADs, on change from baseline in HbA1c after 16 weeks of treatment in 
Japanese patients with T2D.
4.2.
Secondary Objectives
The secondary objectives of this study are as follows:

For efficacy, to compare dulaglutide 0.75 mg to placebo at 16 weeks;

For safety, to compare dulaglutide 0.75 mg to placebo for 16 weeks;

To describe long-term efficacy of dulaglutide 0.75 mg in combination with insulin 
therapy up to 52 weeks;

To describe long-term safety of dulaglutide 0.75 mg in combination with insulin 
therapy up to 56 weeks (to include the follow-up period).
4.3.
Exploratory Objectives
The exploratory objective of this study is as follows:

To assess the health outcomes variables at 16 and 52 weeks.


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5.
A Priori Statistical Methods
5.1.
Determination of Sample Size
A total of approximately 160 patients (dulaglutide:  120 patients; placebo:  40 patients) will be 
randomized to have approximately 136 completers (dulaglutide :  102 patients; placebo:  
34 patients) to show dulaglutide is superior to placebo with more than 99% power assuming a 
treatment difference of 1.0% in HbA1c reduction, standard deviation (SD) = 1.0%, and dropout 
rate of 15%.  The screen failure rate is estimated as 20%. Approximately 200 patients will be 
screened.
5.2.
General Considerations
Statistical analysis of this study will be the responsibility of Lilly or its designee.  Any change to 
the data analysis methods described in the protocol will require an amendment ONLY if it 
changes a principal feature of the protocol.  Any other change to the data analysis methods 
described in the protocol, and the justification for making the change, will be described in the 
clinical study report (CSR).  Additional exploratory analyses of the data will be conducted as 
deemed appropriate.
All analyses will be implemented using Version 9.1.3 SAS or higher.
Continuous data will be summarized in terms of the number of observations (n), mean, standard 
deviation (SD) and/or standard error of the mean (SEM), median, minimum (Min), and 
maximum (Max). 
Categorical data will be summarized in terms of the number of observations (n), frequency count, 
and percentages. Percentages will be rounded to one decimal place. Percentages will not be 
presented for zero counts. Unless noted otherwise, percentages will be calculated using n (the 
number of observations with non-missing values) as denominator.
For efficacy analysis based on mixed-model for repeated measures (MMRM), summary statistics 
will be provided for the observed value and change from baseline value for each arm based on 
MMRM. Also, for efficacy analysis, statistical tests (including MMRM and ANCOVA) will only 
be conducted during the double-blind primary treatment period at each visit (i.e. Visit 4, 5, 6 and 
7) and will not be conducted for time point  after Visit 7.
For safety analysis, summary statistics will be provided for each arm during the both double-
blind primary treatment period (i.e. Visit 3 to 7) and entire study period (i.e. Visit 3 to 13). Table 
GBGF 5.1 gives the treatment groups to be displayed for each treatment period. 
Unless otherwise specified, all tests of treatment effects will be conducted at a 2-sided alpha 
level of 0.05, and confidence intervals (CIs) will be calculated at 95%, 2-sided.  All tests of 
interactions between treatment groups and other factors will be conducted at a 2-sided alpha 
level of 0.10. There will be no multiplicity adjustment for pairwise treatment comparisons.  
List of analysis (LOA) will contain the list of all tables, figures and listings (TFLs), and will be 
provided separately.


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Table GBGF 5.1.
Treatment Groups for Each Treatment Period
Treatment Period
Treatment Groups
Abbreviation
Between-Group 
Comparison When 
Applicable
Double-blind 
primary treatment 
period (i.e. Visit 3 
to 7)
Placebo
Dulaglutide
Total
Plc
Dula
Total
Dula vs Plc
Treatment period
(i.e. Visit 3 to 12)
Placebo/ Dulaglutide
Dulaglutide/ Dulaglutide
Total
Plc/Dula
Dula/Dula
Total
No Between-Group 
Comparisons
Entire study period
(i.e. Visit 3 to 13)
Placebo/ Dulaglutide
Dulaglutide/ Dulaglutide
Total
Plc/Dula
Dula/Dula
Total
No Between-Group 
Comparisons
5.2.1. Analysis Populations
The analysis populations used in the study are described below (Table GBGF 5.2).
Table GBGF 5.2.
Analysis Population for Study H9X-JE-GBGF
Population
Definition
All Entered
All patients who signed informed consents
All Randomized
All patients who were randomized to a treatment arm
Non-randomized
All patients entered but not randomized to a treatment arm
Full Analysis Set (FAS)
All patients who received at least one dose of study treatment and 
have at least one measurement of HbA1c after study treatment
Per-Protocol Set (PPS)
All patients in the FAS who meet the following criteria:

Have no important protocol deviations that could impact the 
assessment of the primary objective (see section 5.4)

At least 75% compliant with the required doses of 
investigational product

Complete the treatment period (16 weeks [Visit 7]) for primary 
endpoint

Not missing more than 2 consecutive weekly injections of 
investigational product or more than 14 consecutive daily 
injections of insulin
Safety Analysis Set
All patients who received at least one dose of study treatment


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5.2.2. Baseline Definition
The baseline will be Visit 3.  For all variables, including HbA1c, if baseline data are missing, the 
last nonmissing measurement taken prior to this visit will be used for the baseline measurement.  
Change from baseline will be calculated as the post-baseline value minus the baseline value. If 
all baseline values are missing for a particular variable, the change from baseline will not be 
calculated.
5.3.
Patient Disposition
For summary tables, frequency counts and percentages of all patients entered, randomized, 
completed, and/or discontinued from the study will be presented, and the reasons for 
discontinuation from the study will be summarized. Listing will also be made.
5.4.
Protocol deviations
Important protocol deviation will only be summarized and listed. For the protocol deviations 
resulting in exclusion of the patient from the PPS, see the Protocol Deviation Pre-defined List
separately provided.
5.5.
Patient Characteristics
Demographic (gender, age, etc.) and baseline variables (body weight, height, baseline HbA1c, 
etc.) will be summarized using both FAS and PPS. Listing will also be made using FAS.
5.6.
Concomitant Therapy
Concomitant therapy and type of insulin will be summarized and listed using FAS. Oral 
antidiabetic medicine will be summarized separately.  WHO drug generic name will be used. The 
definition of each type of insulin regimen is as follows.

Basal insulin regimen is defined as the regimen using only basal insulin;

Premixed insulin regimen is defined as the regimen using only premixed insulin;

Basal/mealtime insulin regimen is defined as the regimen using only both basal insulin
and mealtime insulin.
5.7.
Historical Illness
Historical illnesses will be listed using all randomized patients. No summaries will be created for 
this measurement. Pre-existing condition will also be summarized and listed using safety 
analysis set.
5.8.
Treatment Compliance
Overall treatment compliance, overall investigational product compliance, treatment compliance 
(not missing more than 2 consecutive weekly injections of investigational product) and treatment 
compliance (not missing >14 consecutive daily injections of insulin) will be summarized by 
treatment group using FAS. Listing will also be made using FAS.


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The overall treatment compliance is defined as taking at least 75% of the required doses of 
investigational product and not missing more than 2 consecutive weekly injections of dulaglutide 
or >14 consecutive daily injections of insulin.  Similarly, a patient will be considered non-
compliant if he/she is judged by the investigator to have intentionally or repeatedly taken more 
than the prescribed amount of medication.  The overall treatment compliance in percentage will 
be calculated by the number of patients who meet overall treatment compliance divided by the 
total number of patient *100.
In addition, the overall investigational product compliance will be calculated for each patient.  
This will be calculated by taking the number of injections the patient took divided by the total 
number of scheduled injections for this patient.  
The treatment compliance (not missing more than 2 consecutive weekly injections of 
investigational product) in percentage will be calculated by the number of patients who meet 
treatment compliance (not missing more than 2 consecutive weekly injections of investigational 
product) divided by the total number of patient *100.
The treatment compliance (not missing >14 consecutive daily injections of insulin) in percentage 
will be calculated by the number of patients who meet treatment compliance (not missing >14 
consecutive daily injections of insulin) divided by the total number of patient *100.
5.9.
Treatment Exposure
Treatment exposure will be summarized and listed using safety analysis set.
Treatment exposure is defined as the time from when the patient is randomized at Visit 3 and 
receives study drug until the patient either permanently discontinues from investigational product
or completes the treatment period.
Duration of exposure will be categorized into the following groups: >0 weeks, ≥16 weeks, and
≥52 weeks. These categories will be summarized as frequency by treatment.
5.10. Efficacy Analysis
5.10.1. Primary Efficacy Analysis
Analysis of HbA1c based on MMRM will be summarized by treatment group using FAS. The 
primary analysis model is shown in 5.10.1.2.
5.10.1.1. Additional Analyses for Primary Endpoint
Analysis of HbA1c based on MMRM will be summarized by treatment group using PPS. Also, 
analysis of HbA1c based on ANCOVA will be summarized by treatment group using FAS.
5.10.1.2. Primary Analysis Model
The primary analysis model will be an MMRM for HbA1c change from baseline to 16 weeks 
(Visit 7) using REML with treatment, insulin regimen (basal insulin, premixed insulin, or 


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basal/mealtime insulin), visit, and treatment-by-visit as fixed effects, baseline HbA1c as a 
covariate, and patient as a random effect.
An unstructured covariance structure will be used to model the within-patient variability and 
implicitly adjust for missing data.  If this analysis 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 Kenward-Roger approximation 
will be used to estimate denominator degrees of freedom.  Significance tests will be based on least 
squares (LS) means using Type III sum of squares.
5.10.1.3. Secondary Analysis Model
The secondary analysis for the primary endpoint will be an ANCOVA for HbA1c change from 
baseline to the Week 16 endpoint with treatment, and insulin regimen (basal insulin, premixed 
insulin, or basal/mealtime insulin) as fixed effects and baseline HbA1c as a covariate, with 
missing endpoints imputed with last observation carried forward (LOCF) using postbaseline data 
only.  If there are no data after the date of randomization, the endpoint will be considered missing.
5.10.2. Secondary Efficacy Analysis
Secondary efficacy measures that are continuous variables (changes from baseline) other than 
HbA1c will be analyzed using MMRM on the FAS. The MMRM model will include treatment, 
baseline HbA1c (<8.5%, ≥8.5%), and insulin regimen (basal insulin, premixed insulin, or 
basal/mealtime insulin) as fixed effects and a covariate of baseline value. Also, the ANCOVA 
models will include treatment, baseline HbA1c (<8.5%, ≥8.5%), and insulin regimen (basal insulin, 
premixed insulin, or basal/mealtime insulin) as fixed effects and a covariate of baseline value.
5.10.2.1. Percentage of Patients Achieving HbA1c of <7.0% and ≤6.5%
Analysis of patients achieving  HbA1c levels <7.0% or ≤6.5% based on repeated measures 
logistic regression with generalized linear mixed model will be summarized by treatment group 
using FAS. The model will include independent variables of treatment, insulin regimen (basal 
insulin, premixed insulin, or basal/mealtime insulin), visit, and treatment-by-visit interaction as 
fixed effects, and baseline HbA1c as a covariate.


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5.10.2.2. Analysis of Fasting Serum Glucose (FSG) 
Summary and analysis of FSG based on MMRM will be displayed by treatment group using
FAS.
5.10.2.3. Analysis of 7-point SMPG profile
The 7-point SMPG profiles before and 2 hours after breakfast, before and 2 hours after lunch, 
before and 2 hours after dinner, and bedtime will be obtained within 2 weeks prior to 
corresponding visit. In general, the mean of the two daily mean values will be used for reporting 
purpose. If the value from either day is missing, then the non-missing value will be used as the 
mean of the two daily mean values. Also, if both two daily mean values are missing then the 
mean of the two daily mean values will be missing. The daily mean is calculated as the mean of 
available values collected on a particular day.
The following variables for 7-point SMPG profile will be analyzed using ANCOVA model with 
missing endpoints imputed with LOCF:
1. Pre morning meal PG (mg/dL)
2. 2-hour postprandial measurement for morning meal PG (mg/dL)
3. Pre midday meal PG (mg/dL)
4. 2-hour postprandial measurement for midday meal PG (mg/dL)
5. Pre evening meal PG (mg/dL)
6. 2-hour postprandial measurement for evening meals PG (mg/dL)
7. Bedtime BG (mg/dL)
8. Morning meal 2-hr excursion (mg/dL)
9. Midday meal 2-hr excursion (mg/dL)
10. Evening meal 2-hr excursion (mg/dL)
11. Mean of all meals 2-hr excursion
12. Mean of all 7-point PG (mg/dL)
13. Mean of all pre-meals PG (mg/dL)
14. Mean of all postprandial meals PG (mg/dL)
15. Circadian variation in 7-point PG (mg/dL)
For before and 2 hours after meal, and bedtime PG (reports 1-7), the mean PG value at each visit
is calculated as the average of 2 daily PG values. The change from baseline is calculated as the
mean PG value at endpoint minus the mean PG value at the baseline.
For the morning, midday and evening meal 2-hr excursion (reports 8-10), the daily excursion for
each meal is calculated as the postprandial meals PG minus the fasting plasma glucose (FPG). 
The mean glucose excursion for each meal at each visit is calculated as the average of 2 daily 
glucose excursions. The change from baseline is calculated as the mean excursion at endpoint 
minus the mean excursion at baseline.
For mean of all meals 2-hr excursion at each visit (report 11), the daily mean for all meals is
calculated as the average of glucose excursion for morning, midday and evening meals on a
particular day. The mean of all meals 2-hr excursion at each visit is calculated as the average of 2 


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daily means. The change from baseline is calculated as the mean of all meals 2-hr excursion at
endpoint minus the mean of all meals 2-hr excursion at baseline.
For mean of all 7-point PG (report 12), the daily mean is calculated as the average of 7 PG
values collected on a particular day. The mean of all 7-point PG at each visit is calculated as the
average of 2 daily means. The change from baseline is calculated as the mean of all 7-point PG
at endpointminus the mean of all 7-point PG at baseline.
For mean of all pre-meals PG (report 13), the pre-meal daily mean is calculated as the average
PG values collected for pre-morning, pre-midday and pre-evening meals on a particular day.The 
mean of all pre-meals PG at each visit is calculated as the average of 2 pre-meal dailymeans.
The change from baseline is calculated as the mean of all pre-meals PG at endpointminus the 
mean of all pre-meals PG at baseline.
For mean of all postprandial meals PG (report 14), the post-meal daily mean is calculated as the
average of 2-hr postprandial meals PGvalues of morning, midday and evening meals on a 
particular day. Themean of all postprandial meals PG at each visit is calculated as the average of 
2 post-meal dailymeans. The change from baseline is calculated as the mean ofall postprandial 
meals PG atendpoint minus the mean of all postprandial meals PG at baseline.
For circadian variation in 7-point PG (report 15), the daily circadian variation is calculated as the
difference between maximum and minimum (maximum –minimum) PG values collected on a
particular day. The mean circadian variation at each visit is calculated as the average of 2 daily
circadian variation. The change from baseline is calculated as the circadian variation at endpoint
minus the circadian variation at baseline.
Fasting PG during follow-up period will be plotted by patient.
5.10.2.4.Analysis of Body Weight
Analysis of body weight based on MMRM will be summarized by treatmentgroup usingFAS.
5.11.InsulinDose
For the analysis of insulin dose, only descriptive statistics will be provided.
Daily insulin dose (unit and unit/kg body weight) for each insulin regimen(i.e. basal insulin, 
premixed insulin, or basal/mealtime insulin) at the baseline and specific time point (i.e. Visit 7 
and Visit 12), and change from baseline will be summarized and listed using FAS. 
For the patientsusing basal/mealtime insulin, daily insulin dose (unit and unit/kg body weight) 
for each insulin type(i.e. basalor mealtime insulin) at the baseline andspecific time point (i.e. 
Visit 7 and Visit 12),and change from baseline will be summarized using FAS


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5.12. Health Outcome Analyses
5.12.1. DTSQs (Diabetes Treatment Satisfaction Questionnaire status)
Summary statistics for each dimension and total score by visit and change from baseline values 
will be provided using FAS.  Hyperglycemia, hypoglycemia, total score except blood glucose 
control score and total score at Week 16 will be compared between treatment groups using an
ANCOVA models that includes treatment and insulin regimen (basal insulin, premixed insulin, 
or basal/mealtime insulin) as fixed effects and a covariate of baseline value. The LS means and 
95% confidence intervals for treatment difference and p-values for comparisons will be reported. 
5.12.2. DTR-QOL (Diabetes Therapy Related-Quality of Life)
Summary statistics for each dimension and total score by visit and change from baseline values 
will be provided using FAS.  Each dimension and total score at Week 16 will be compared 
between treatment groups using an ANCOVA models that includes treatment and insulin 
regimen (basal insulin, premixed insulin, or basal/mealtime insulin) as fixed effects and a 
covariate of baseline value. The LS means and 95% confidence intervals for treatment difference 
and p-values for comparisons will be reported.
5.12.3. Device Questionnaire
Summary and analysis of device questionnaire will be made by treatment group using FAS.
For each item of device questionnaire in the first section, frequency and percentage of sum of 
“Strongly Agree” and “Agree” for Ateos, sum of “Strongly Agree” and “Agree” for Insulin 
Device, and “Both Devices are the same” will be presented by device at each scheduled visit.
Also, the overall preference for Ateos versus Insulin Device, which was evaluated by a
percentage of sum of “Strongly Agree” and “Agree” for Ateos will be presented.They will be
tested by the use of a one-sample binomial test using an exact method at each scheduled visit. 
The null hypothesis was that the preference for Ateos was equal to 50%, against the hypothesis 
that it was different from 50%.
For the summary of device questionnaire in the second section, the frequency and percentage of 
each category (i.e. “Rarely”, “Sometimes”, and “Always”) will be presented by device at each 
scheduled visit.
5.13. Other Exploratory Variables
5.13.1. Dietary Evaluation
Summary statistics for total fats, total carbohydrates, total protein, and caloric intake amount 
(actual) by visit and change from baseline values will be provided using FAS.


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5.14. Safety Analyses
Unless otherwise specified, the safety analysis set will be used for analyses of safety 
measurements. Also, p-values provided from all safety analyses will be used for guidance 
purposes only.
5.14.1. Adverse Events
An adverse event is any untoward medical event associated with the use of a drug in humans,
whether or not it is considered related to a drug. Adverse events will be classified according to
the Medical Dictionary for Regulatory Activities (MedDRA) and summarized by treatment
group. Adverse events will be summarized as treatment-emergent adverse events (TEAEs)
defined as events that are newly reported or reported to worsen in severity after the initiation of 
study drug through the treatment period. The incidence of patients with at least one TEAE and 
the incidence of TEAEs by MedDRA preferred term and system organ class will be presented by 
treatment group. The incidence of patients with at least one TEAE that is considered to be 
possibly related to the study drug in the opinion of the investigator will also be summarized. 
Fisher’s exact test will be used for treatment comparison. 
SAEs and AEs leading to discontinuation of the study drug will also be summarized and listed.
5.14.2. Adverse Events of Special Interest (AESI)
The following adverse events of special interest (AESIs) will be summarized and listed. For   
AEs of interest associated with the thyroid gland (benign and malignant neoplasms), listing will 
only be provided.

Allergic/hypersensitivity reactions

Cardiovascular events

Pancreatitis

AEs of interest associated with the thyroid gland (benign and malignant neoplasms) 
Because gastrointestinal AEs, such as nausea and vomiting, are among the most common events 
reported in patients treated with dulaglutide, summaries and analyses for time to onset, duration, 
and severity of nausea and vomiting will be provided.
5.14.3. Hypoglycemic Episodes
A listing of the individual hypoglycemic episodes by patient will be presented. 
Summary reports will include both incidence and rates of hypoglycemia using safety analysis set.
Hypoglycemia will be analyzed as “documented symptomatic,” “asymptomatic,” “probable,” 
“severe,” or “nocturnal” and for all events combined, “total hypoglycemia.” See protocol section 
7.4.1.2. Other categories, including the categories above defined with differing PG thresholds, 
may also be included in these analyses when deemed appropriate. The incidence of 
hypoglycemic episodes will be compared using Fisher’s exact test.


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Hypoglycemia rates will be summarized for periods of 1 year, 30 days, and 100 years (severe
hypoglycemia only). The rate of severe hypoglycemia per 100 years will be compared between
treatment groups using the empirical method (see Appendix 1). For each of the other categories 
of hypoglycemia, the number of hypoglycemia events during a specific period (rate) after 
randomization (for example, 0-16 weeks of treatment period) will be analyzed by using a 
negative binomial regression model. The model will include treatment and the baseline 
hypoglycemia rate (measured during lead-in) as a covariate. An offset defined as the log 
transformation of treatment exposure in the specific period (days)/365.25 days (or 30 days) will 
be included in the model to estimate the rate of hypoglycemia per year (or per 30 days). The
proportion of patients with at least 1 hypoglycemic event in each category (incidence) during a
specific period after randomization will be analyzed using a logistic regression model including
treatment and baseline hypoglycemia rate value in the model.
Time to the first onset of total hypoglycemia and time to glucose-lowering intervention due to 
severe, persistent hyperglycemia will be analyzed between the groups using the semi-parametric 
proportional hazard regression model with treatment, baseline HbA1c (<8.5%, ≥8.5%), insulin 
regimen (basal insulin, premixed insulin, or basal/mealtime insulin) as fixed effects and baseline 
hypoglycemia rate (measured during lead-in) as a covariate.  A Kaplan-Meier curve will be 
plotted for all treatments on the same graph, for presentation purposes.  The proportion of 
patients that required intervention will be analyzed using Fisher’s exact test.
5.14.4. Laboratory Analyses
All laboratory measurements including scheduled and unscheduled will be listed by patient by 
visit using all randomized patients.  An additional listing will be presented for selected 
laboratory measurements that are outside the normal range. The normal ranges are defined by a 
lower limit of normal (LLN) and an upper limit of normal (ULN). A result that is greater than or 
equal to the LLN and less than or equal to the ULN is considered to be within the normal ranges.
Laboratory measurements will be summarized with respect to observed values and change from 
baseline by treatment group at each scheduled visit.  For each analyte, the change from baseline 
to endpoint will be tested using Wilcoxon rank-sum test. Also, laboratory analytes with 
categorical responses will be summarized using frequency and percentage by visit and treatment 
group.  Treatment comparisons will be performed using a Fisher’s exact test.
The proportion of patients with treatment-emergent abnormal values defined by the outside of 
the normal ranges will also be summarized by treatment group and compared between treatment 
groups. The proportion will be calculated by dividing number of patients with abnormal value 
after baseline by number of patients with baseline and post-baseline values (patients who had 
abnormal baseline value in a same direction of interest will be excluded).
5.14.4.1. Amylase and Lipase
For amylase and lipase, the following variables will be analysed:


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1) Number and percent of patients having measurements above ULN/2xULN/3xULN at 
screening (Visit 1), baseline (Visit 3), and each post-randomization visit (Non-cumulative 
and cumulative incidence)
2) Number and percentage of patients having measurements above ULN at baseline (Visit 3) 
with post-randomization values decreased from baseline at each visit.
3) Number and percentage of patients having measurements above ULN at baseline (Visit 3) 
with post-randomization values increased from baseline at each visit.
4) Number and percentage of patients having normal measures at baseline (Visit 3) with 
post-randomization values increased from baseline above ULN/2xULN/3xULN at each 
visit.
The cumulative number of patients having amylase above ULN at post-randomization visit is the 
number of patients having amylase above ULN at least once at any post-randomization visit (e.g. 
patients with repeatedly increased value are counted only once). The same holds for lipase.
5.14.4.2. Calcitonin
Threshold analyses will be performed for calcitonin. Some of these analyses involve a composite 
criterion involving change from baseline of at least 50%. For alignment with the calcitonin 
monitoring algorithm used in study, the baseline value for this analysis will be the mean of all 
nonmissing baseline observations. In cases where baseline is missing but postbaseline is 
available, the percent-change criterion will be assumed to be satisfied.  Following threshold 
analyses will be provided:

postbaseline calcitonin ≥20 pg/mL

postbaseline calcitonin ≥35 pg/mL
Additionally, for each of these, a threshold analysis will be presented of patients also satisfying a
change from baseline of ≥50%.
A shift table will be provided of postbaseline calcitonin to and from the following categories: (i) 
<20 pg/mL, (ii) ≥20 pg/mL and <35 pg/mL, (iii) ≥35 pg/mL.
5.14.4.3. Lipid
Actual value and percent change from baseline at each visit for lipid measurement will be 
summarized by treatment group using safety analysis set. For the percent change from baseline 
to Visit 7, wilcoxon rank-sum test will be conducted.
The lipid measurements to summarize in this study are “Cholesterol (milligram/deciliter)”, 
“Direct LDL Cholesterol (milligram/deciliter)”, “HDL Cholesterol (milligram/deciliter)”, 
“Triglycerides (milligram/deciliter)”. LDL cholesterol is also calculated using the Friedwald 
equation. In addition, LDL cholesterol is calculated using the Friedwald equation only for the 
patients with TG (Triglyceride) < 400mg/dL. For the patients does not have a direct LDL 


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cholesterol, but LDL cholesterol can be calculated with Friedwald equation, then the LDL 
cholesterol value based on the Friedwald equation will be included for this summary.
5.14.5. Physical Characteristics and Vital Signs
The vital signs include measurements of blood pressures, body weight and BMI.  
Each patient will have their pulse rate and blood pressure measured 3 times. The measurements 
will be averaged separately for each patient at each visit; the average values will be used in the 
descriptive summaries and analyses.  
Descriptive statistics for the actual measurements and change from baseline by visit and 
treatment group will be presented. For the change from baseline to Visit 7, wilcoxon rank-sum 
test will be conducted.
The incidence of patients with at least 1 measurement above the following levels after baseline 
will be summarized by frequency and percentage for each treatment group (Table GBGF 5.3).
At the Visit 7, treatment comparisons between treatment groups will be performed using Fisher’s 
exact test.
Table GBGF 5.3.
Vitals Threshold for Study H9X-JE-GBGF
Systolic Blood Pressure (mm Hg)
≥140
Diastolic Blood Pressure (mm Hg)
≥90
Pulse Rate (beats per minute) 
>100
5.14.6. Adjudication of safety events
Deaths, cardiac biomarkers, possible cases of pancreatitis, and non-fatal cardiovascular AEs will 
be adjudicated by an outside judgment committee external to Lilly.  A listing of events that were 
sent for adjudication will be presented including the event as it was reported and how it was
adjudicated.
5.14.7. Renal safety
The following biomarker will be assessed:

Serum creatinine

Estimated glomerular filtration rate (eGFR) estimated by Modification of Diet in 
Renal Disease (MDRD) formula using the coefficient for Japanese (Matsuo et al., 
2009)

Urinary albumin to creatinine ratio (UACR)
eGFR (mL/min/1.73 m2) = 175*[serum creatinine−1.154]*[age−0.203]*[0.742 if female]*[ 0.808 
if Japanese]


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Mean and mean change from baseline to endpoint of serum creatinine, eGFR, and UACR by 
treatment will be presented.  Proportions of patients shifting between CKD stages by eGFR from 
baseline by treatment will be presented.
Shift tables based on eGFR and UACR (Table GBGF 5.4 and Table GBGF 5.5) will be provided 
(CKD risk stratification in JSN 2012).  


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Table GBGF 5.4.
CKD Stage based on eGFR for Study H9X-JE-GBGF
GFR Stage
eGFR (mL/min/1.73 m2)
G1
≥90
G2
60≥and <90
G3a
45≥and <60
G3b
30≥and <45
G4
15≥and <30
G5
<15
Table GBGF 5.5.
CKD Stage based on UACR for Study H9X-JE-GBGF
Albuminuria
Stage
UACR (mg/g)
A1
<30
A2
30≥and <300
A3
≥300
The following threshold analyses (with eGFR by MDRD formula and UACR) will be presented:

Postbaseline eGFR <60 mL/min/1.73 m2

Postbaseline eGFR <60 mL/min/1.73 m2, or UACR >300 mg/g
5.15. Subgroup Analyses
Subgroup analyses will be conducted for the variables of HbA1c, body weight, and
hypoglycemia rate. 
The following are candidate subgroups that might be analyzed. This list is not necessarily
all
inclusive:

Baseline HbA1c (<8.5%, ≥8.5%)

Insulin regimen (basal insulin, premixed insulin, or basal/mealtime insulin).
For the subgroup analysis by insulin regimen, an analysis will be performed using an MMRM
model or negative binomial regression model that includes the same effects given for primary or 


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secondary efficacy measures plus subgroup, subgroup-by-treatment interaction, subgroup-by-
visit interaction, and subgroup-bytreatment-by-visit interaction. For the subgroup analysis by
baseline HbA1c strata (<8.5%, ≥8.5%), baseline HbA1c will not be included as a covariate. The 
treatment-by-subgroup interaction at Week 16 will be evaluated using a significance level of 
0.10, unadjusted.


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6.
Unblinding Plan
6.1.
Interim Analyses
No interim analyses are planned for this study. If an unplanned interim analysis is deemed 
necessary, the appropriate Lilly CRP or CRS, or designee, will be consulted to determine 
whether it is necessary to amend the protocol.
6.2.
Site Level Unblinding
This study includes a 16-week double-blind (dulaglutide versus placebo) primary treatment 
period, and a 36-week open-label extension treatment period.
To preserve the blinding of the study, the treatment assignments in the double-blind period will 
be blinded to patients and investigators until study completion.
Emergency unblinding for AEs may be performed through the IWRS, which may supplement or 
take the place of emergency codes generated by a computer drug-labeling system. This option 
may be used ONLY if the patient’s well-being requires knowledge of the patient’s treatment 
assignment. All actions resulting in an unblinding event are recorded and reported by the IWRS.
If an investigator, site personnel performing assessments, or patient is unblinded, the patient 
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 CRP or CRS for 
the patient to continue in the study.
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 or CRS prior to 
unblinding a patient’s treatment assignment unless this could delay emergency treatment of the 
patient. If a patient’s treatment assignment is unblinded, Lilly must be notified immediately.
6.3.
Sponsor/Trial Level Unblinding
The study team will remain blinded to treatment assignments until all patients have completed 
the study and the database has been finalized and locked for analysis. During this study, some 
members are unblinded (Table GBGF. 6.1). They do not have direct interaction with sites. They 
will not be allowed to join meetings which may affect the other members’ blind condition, such 
as trail level safety review (TLSR) and data review meetings.
Table GBGF. 6.1
Unblinded Members through GBGF Study
Role
Reason
Data source for unblinding
Product Delivery 
personnel
To provide and manage clinical 
trial materials
e-CTS


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Unblind Case Manager
To report SAE with unblinded 
information to Japan authority
e-CTS
Clinical Laboratory 
Operations
To manage and track sample 
shipping
CLRM
Abbreviations: CLRM = Clinical Laboratory Results Modernization; e-CTS = Enhanced Clinical 
Trials System; SAE = Serious Adverse Event.


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7.
References
Matsuo S, Imai E, Horio M et al. Revised equations for estimating GFR from serum creatinine in 
Japan. Am. J. Kidney Dis. 2009; 53:982-93.
[JSN] Japanese Society of Nephrology; Special issue: Clinical practice guidebook for diagnosis 
and treatment of chronic kidney disease 2012. Nihon Jinzo Gakkai Shi. 2012; 54(8):1034-191.


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8.
Appendices


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Appendix 1. Empirical method for the rate of severe 
hypoglycemia
Traditionally, Poisson distribution has been assumedto draw inference for the rate of rare events. 
When the event is rare and the sample size is large, it is known that the overall number of events 
is approximately from Poisson distribution.However, for some not very rare events such as 
severe hypoglycemic events in T1DM patients, the total number of events may not be distributed 
from Poisson and may be over-dispersed. Assuming Poisson distribution may significantly 
underestimate the variance, and therefore may reduce the overage probability and inflate the 
Type-I error. Below we describe an empirical method in estimating the variance of event rate 
without assuming any distribution on the number of events. 
Event rate without strata
Let  denote the count response variable for patientsjin treatment group i. Let   =∑ be 
the total number of events for treatment group i, and   denote the exposure for treatment group 
i. Let i= 0 for the control group and i= 1 for the experimental treatment group. The event rate 
for treatment group ican be calculated as
̂  =  The empirical variance of ̂  is 
 (̂)= ( )=    ,
where   is the variance of  for treatment group i. Using the delta-method, the variance of 
log(̂)can be estimated as
 (log(̂))=   The relative rate of the experimental treatment versus the control treatment is estimated as
 =̂ ̂ The variances of  and log()are 
 ()=  (log())
 log= (log(̂  ))+ (log(̂  ))=     +    Assuming log()is asymptotically from a normal distribution, the 100(1− )%confidence 
interval for log()can be constructed as
log −    log ,log +    log

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Then, the 100(1− )%confidence interval for  is
 exp −      log  ,
 exp       log  (1)
The p-value for testing the null hypothesis of   :=1 is calculated as
 =2Φ log/  log (2)
where Φis cumulative distribution function of the standard normal distribution.   
Event rate with strata or based on multiple studies
We use additional subscript “k” denote the corresponding variable for stratum (or study) k. The 
Mantel-Haenszel weighted estimate of  across strata is
 =
∑  ̂ ∑  ̂ where   =  ,+ ,. The variance of log is estimated as
 log =
∑   (̂ )
(∑  ̂ )
+
∑   (̂ )
(∑  ̂ )
The 95% confidence interval for  and the p-value can be constructed similarly using (1) and (2) 
as for the ratio rate without strata. 
The event rate for each treatment group is
̂  =
∑  ̂ ∑ , 
=0,1
and the variance estimation for the event rate is
 (̂)=
∑   (̂ )
(∑ )
, 
=0,1
Event rate in the cross-over study (no period effect)
For 2×2cross-over study, each patient may receive both treatments, e.g. control treatment in 
period 1 and experimental treatment in period 2. The above equation of event rate without strata 
for ̂  can still be applied to the calculation of event rate for each treatment group but the variance 
of relative rate is different from  ()due to the variance within patient. To distinguished from 
,   is used to indicate the relative rate of the experimental treatment versus the control 
treatment for the cross-over study
 =̂ ̂ 

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The variances of log() is
 (log())= (log(̂  ))+ (log(̂  ))−2Cov
log(̂  ),
log((̂ )=     +     −  Cov
  , Let   be the covariance of  and  for patientjand identical for all patient, and  ∗be the 
number of patientswho completed both the two cross-over periods, the variance of log() is 
 (log())=       +       −       ∗ (3)
With the variance of in (3) log(), the 95% confidence interval for  and the p-value can be 
constructed similarly using (1) and (2).