Clinical trial NCT03315780
Conditions: Type 2 Diabetes
Sponsor: Eli Lilly and Company
Start date: 2017-10-28; Completion date: 2018-02-28
Enrollment: 12 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to evaluate the glucodynamic effects of dulaglutide in Japanese participants with type 2 diabetes mellitus.

Detailed description:

Arms: arm 1: Dulaglutide 0.75 mg administered subcutaneously (SC) once weekly for 4 weeks in period 1 followed by placebo administered SC once weekly for 4 weeks in Period 2. There is a 4 to 6 week washout period between Period 1 and Period 2. arm 2: Placebo administered SC once weekly for 4 weeks in Period 1 followed by Dulaglutide 0.75 mg administered SC for 4 weeks in Period 2. There is a 4 to 6 week washout period between Period 1 and Period 2.
Interventions: intervention 1: Dulaglutide intervention 2: Placebo
Intervention descriptions: intervention 1: Administered SC intervention 2: Administered SC

Protocol documents:
Prot_000.pdf: 
Protocol H9X-JE-GBGK(a) 
 
 
A Phase 4 Study to Evaluate Glucodynamic Effects of Dulaglutide in Japanese Patients with 
Type 2 Diabetes Mellitus 
 
 
NCT03315780 
 
 
Approval Date: 12-Jul-2017 


H9X-JE-GBGK(a)Clinical Pharmacology Protocol
Page 1
Dulaglutide (LY2189265)
Protocol H9X-JE-GBGK(a)
A Phase 4Study to Evaluate Glucodynamic Effectsof 
Dulaglutide in Japanese Patients with Type 2 Diabetes 
Mellitus
Confidential Information
The information contained in this protocol is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
dulaglutide (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 confidentialinformation 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.  
Approval Date: 26-Sep-2017 GMT
Dulaglutide(LY2189265)
Eli Lilly Japan K.K.
Kobe, Hyogo Japan
Clinical Pharmacology Protocol Electronically Signed 
and Approved by Lilly on 12 Jul 2017.
Amendment (a) Electronically Signed and Approved by Lilly
on approval date provided below


H9X-JE-GBGK(a) Clinical Pharmacology Protocol
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Dulaglutide (LY2189265)
Table of Contents
A Phase 4 Study to Evaluate Glucodynamic Effects of 
Dulaglutide in Japanese Patients with Type 2 Diabetes 
Mellitus
Section
Page
3.1.
Study Rationale............................................................................................................12
3.2.
Background..................................................................................................................12
3.3.
Benefit/Risk Assessment..............................................................................................12
5.1.
Overall Design .............................................................................................................14
5.2.
Number of Participants.................................................................................................15
5.3.
End of Study Definition ...............................................................................................15
5.4.
Scientific Rationale for Study Design...........................................................................15
5.5.
Justification for Dose ...................................................................................................16
6.1.
Inclusion Criteria..........................................................................................................17
6.2.
Exclusion Criteria ........................................................................................................19
6.3.
Lifestyle and/or Dietary Requirements .........................................................................20
6.3.1.
Meals and Dietary Restrictions.............................................................................20
6.3.2.
Activity................................................................................................................20
6.3.3.
Blood Donation....................................................................................................21
6.4.
Screen Failures.............................................................................................................21
7.1.
Treatment Administered...............................................................................................22
7.1.1.
Packaging and Labeling .......................................................................................22
7.2.
Method of Treatment Assignment ................................................................................22
7.2.1.
Selection and Timing of Doses.............................................................................22
7.3.
Blinding .......................................................................................................................23
7.4.
Dose Modification........................................................................................................23
7.5.
Special Treatment Considerations ................................................................................23
7.5.1.
Management of Increased Hypoglycemia Risk.....................................................23
7.5.2.
Management of Severe Hyperglycemia ................................................................24
7.6.
Preparation/Handling/Storage/Accountability...............................................................24
7.7.
Treatment Compliance .................................................................................................24
7.8.
Concomitant Therapy...................................................................................................24
7.9.
Treatment after the End of the Study............................................................................24
8.1.
Discontinuation from Study Treatment.........................................................................25
8.1.1.
Discontinuation of Inadvertently Enrolled Patients...............................................25
8.2.
Discontinuation from the Study....................................................................................26
8.3.
Patients Lost to Follow-up............................................................................................26


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Dulaglutide (LY2189265)
9.1.
Efficacy Assessments...................................................................................................27
9.2.
Adverse Events ............................................................................................................27
9.2.1.
Serious Adverse Events........................................................................................28
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................29
9.2.2.
Adverse Events of Interest....................................................................................29
9.2.2.1.
Pancreatitis.....................................................................................................29
9.2.2.2.
C-Cell Hyperplasia and C-Cell Neoplasms .....................................................30
9.2.3.
Complaint Handling.............................................................................................30
9.3.
Treatment of Overdose.................................................................................................30
9.4.
Safety...........................................................................................................................31
9.4.1.
Laboratory Tests ..................................................................................................31
9.4.2.
Vital Signs ...........................................................................................................31
9.4.3.
Electrocardiograms ..............................................................................................31
9.4.4.
Other Tests...........................................................................................................32
9.4.4.1.
Continuous Glucose Monitoring .....................................................................32
9.4.4.2.
Patient Reported Outcomes.............................................................................32
9.4.4.2.1.
Satiety after Standardized Test Meal.........................................................32
9.4.5.
Safety Monitoring ................................................................................................32
9.4.5.1.
Hepatic Safety................................................................................................32
9.5.
Pharmacokinetics .........................................................................................................33
9.6.
Pharmacodynamics ......................................................................................................33
9.6.1.
Primary Measure..................................................................................................33
9.6.2.
Secondary Measures.............................................................................................33
9.7.
Genetics .......................................................................................................................33
9.8.
Biomarkers...................................................................................................................34
9.9.
Health Economics ........................................................................................................34
10.1. Sample Size Determination ..........................................................................................35
10.2. Populations for Analyses..............................................................................................35
10.2.1.
Study Participant Disposition ...............................................................................35
10.2.2.
Study Participant Characteristics ..........................................................................35
10.3. Statistical Analyses ......................................................................................................35
10.3.1.
Safety Analyses....................................................................................................35
10.3.1.1.
Clinical Evaluation of Safety..........................................................................35
10.3.1.2.
Statistical Evaluation of Safety.......................................................................36
10.3.2.
Pharmacokinetic Analyses....................................................................................36
10.3.3.
Pharmacodynamic Analyses.................................................................................36
10.3.3.1.
Pharmacodynamic Parameter Estimation ........................................................36
10.3.3.2.
Pharmacodynamic Statistical Inference...........................................................36


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Dulaglutide (LY2189265)
10.3.4.
Other Analyses.....................................................................................................36
10.3.5.
Data Review During the Study.............................................................................36
10.3.6.
Interim Analyses..................................................................................................37


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Dulaglutide (LY2189265)
List of Tables
Table
Page
Table GBGK.1.
Objectives and Endpoints .......................................................................13
Table GBGK.2.
Treatments Administered........................................................................22


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Dulaglutide (LY2189265)
List of Figures
Figure
Page
Figure GBGK.5.1.
General study design for Protocol H9X-JE-GBGK. ................................15


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Dulaglutide (LY2189265)
List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................40
Appendix 2.
Clinical Laboratory Tests........................................................................44
Appendix 3.
Study Governance, Regulatory and Ethical Considerations.....................45
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............48
Appendix 5.
Blood Sampling Summary......................................................................49
Appendix 6.
Meal Tolerance Test...............................................................................50
Appendix 7.
Protocol Amendment H9X-JE-GBGK(a) Summary: A Phase 4 
Study to Evaluate Glucodynamic Effects of Dulaglutide in 
Japanese Patients with Type 2 Diabetes Mellitus ....................................51


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Dulaglutide (LY2189265)
1. Protocol Synopsis
Title of Study:
A Phase 4 Study to Evaluate Glucodynamic Effects of Dulaglutide in Japanese Patients with Type 2 Diabetes 
Mellitus.
Rationale: 
In the clinical development program of dulaglutide in Japan, meal tolerance test (MTT) after administration of 
0.75 mg of dulaglutide in patients with type 2 diabetes mellitus (T2D) was not performed.  Furthermore, 
postprandial glucose metabolic hormones after administration of 0.75 mg of dulaglutide were not assessed.  These 
data are frequently requested by healthcare providers.
Study GBGK will evaluate detailed 4-hour postprandial data at 1, 2, and 4 weeks after starting administration of 
0.75 mg of dulaglutide once weekly, and these data will provide information not collected in previous studies for 
dulaglutide in Japanese patients with T2D.
Objectives/Endpoints:
Objectives
Endpoints
Primary
The primary objective of this study is to evaluate 
glucodynamic effects of dulaglutide 0.75 mg compared 
with placebo in area under the glucose concentration 
versus time curve from 0 to 4 hours (glucose 
AUC[0-4h]) at 4 weeks in Japanese patients with T2D.

The change from baseline in glucose AUC(0-4h) at
4 weeks
Secondary
To evaluate pharmacodynamic (PD) effects of 
dulaglutide 0.75 mg compared with placebo at 4 weeks.

The change from baseline in fasting blood glucose
at 4 weeks

The change from baseline in postprandial blood 
glucose at 4 weeks

The change from baseline in insulin at 4 weeks

The change from baseline in c-peptide at 4 weeks

The change from baseline in glucagon at 4 weeks

The change from baseline in triglyceride at 
4 weeks
To evaluate safety and tolerability of dulaglutide 
0.75 mg for 4 weeks.

Treatment-emergent adverse events (TEAEs)

Incidence of hypoglycemic episodes
Summary of Study Design:
Study GBGK is a Phase 4, single-center, randomized, cross-over, single-blind, placebo-controlled study to evaluate 
glucodynamic effects of dulaglutide in Japanese patients with T2D after a standardized test meal.
Treatment Arms and Planned Duration for an Individual Patient:  
Two cohorts of dulaglutide 0.75 mgplacebo or placebodulaglutide 0.75 mg.
The patient will be randomized in a 1:1 ratio to dulaglutide 0.75 mgplacebo or placebodulaglutide 0.75 mg.  
Ten- to 28-day screening period.


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Dulaglutide (LY2189265)
Cross-over design with 4 weeks’ treatment and additional 4 weeks’ cross-over treatment after 4 to 6 weeks’ washout
period.
Number of Patients:
Up to 14 patients may be entered to randomize 12 patients and complete at least 11 patients.
Statistical Analysis:
The PD parameters on Weeks 0, 1, 2, and 4  will be analyzed using a mixed-effects linear model.  The PD
parameters for glucose, insulin, glucagon, c-peptide, and triglyceride that will be statistically evaluated include 
area under the curve, fasting and postprandial values at each time point.  The model will include treatment, 
sequence, day, and treatment-by-day interaction as fixed effects, baseline as covariate, and patient as random 
effect.  The baseline is the predose value on Day 1.  The least squares means and the 95% confidence intervals
(CIs) by treatment group will be tabulated and plotted.  Comparisons between dulaglutide and placebo will be 
performed.  Difference of least squares means of dulaglutide to placebo, and the 95% CIs, will be tabulated.  


H9X-JE-GBGK(a) Clinical Pharmacology Protocol
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Dulaglutide (LY2189265)
2. Schedule of Activities
Study Schedule Protocol H9X-JE-GBGK(a)
Screening
CGM 
Initiation
Period 1
(4 weeks)
Washout
(4-6 weeks)
CGM 
Initiation
Period 2
(4 weeks)
E/Ti
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
ET
Study Day
-28~-10
-7 or -6
1
8
15
22
29
30~56
50 or 51
57
(1)
64
(8)
71
(15)
78
(22)
85
(29)
Allowance (days)
1
1
1
1
+14
1
1
1
1
Informed Consent
X
Medical History
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
Hypoglycemia
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
Weight a
X
X
X
X
X
X
Physical Exam
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs (sitting) b
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG
X
X
X
Pregnancy Test c
X
X
X
X
Fasting Blood Glucose d
X
Serology
X
Hematology, Clinical 
Chemistry, Endocrinology, 
HbA1c d
X
X
X
X
X
X
Urinalysis, UACR d
X
X
X
X
X
MTT e
X
X
X
X
X
X
X
X
X j
Satiety Evaluation (VAS) f
X
X
X
X
X
X
X
X
X j
Continuous Glucose 
Monitoring g
Investigational Product
Administration h
X
X
X
X
X
X
X
X


H9X-JE-GBGK(a) Clinical Pharmacology Protocol
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Dulaglutide (LY2189265)
Abbreviations: ECG = electrocardiogram; E/T = early termination visit; HbA1c = glycated hemoglobin; UACR = urine albumin/creatinine ratio; MTT = meal 
tolerance test; VAS = visual analog scale.  
a
Body weight will be measured once in light clothing with shoes removed.
b
For each parameter (systolic blood pressure, diastolic blood pressure, and pulse rate), 3 measurements will be taken 1 minute 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.  See Appendix 6, Meal Tolerance Test, for details.
c
Serum pregnancy test will be performed at Visit 1.  Urine pregnancy test will be performed at Visit 2, 3, and 9, if applicable.
d
Fasting condition.  See Appendix 2, Clinical Laboratory Tests, and Appendix 6, Meal Tolerance Test, for details.
e
Blood sampling for glucose, insulin, c-peptide, glucagon, and triglyceride will occur at 0, 30, 60, 90, 120, 180, and 240 minutes after the standardized test 
meal.  See Appendix 6, Meal Tolerance Test, for details.
f
Satiety will be assessed at 0, 60, 120, 180, and 240 minutes after the standardized test meal.  See Appendix 6, Meal Tolerance Test, for details.
g
Continuous glucose monitoring will be initiated on Day -7 (or -6) and Day 50 (or 51) and will end on Day 8 and Day 64.  
h
Investigational product will be administered at study site after all examinations, including MTT, are completed.  See Appendix 6, Meal Tolerance Test, for 
details.
i
Patients discontinuing from the study prematurely for any reason should complete adverse event and other follow-up procedures.
j
Optional.


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Dulaglutide (LY2189265)
3. Introduction
3.1.
Study Rationale
In the clinical development program of dulaglutide in Japan, meal tolerance test (MTT) after 
administration of 0.75 mg of dulaglutide in patients with type 2 diabetes mellitus (T2D) was not 
performed.  Furthermore, postprandial glucose metabolic hormones after administration of 
0.75 mg of dulaglutide were not assessed.  These data are frequently requested by healthcare 
providers.
Study GBGK will evaluate detailed 4-hour postprandial data at 1, 2, and 4 weeks after starting 
administration of 0.75 mg of dulaglutide once weekly, and these data will provide information 
not collected in previous studies for dulaglutide in Japanese patients with T2D.
In addition, continuous glucose monitoring (CGM) will be performed in each study period in 
order to evaluate the glucodynamic effects of dulaglutide 0.75 mg during the first week.
3.2.
Background
Dulaglutide exhibits glucagon-like peptide-1 (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
This study will assess detailed plasma glucose (PG) profiles, insulin, c-peptide, glucagon, and 
triglyceride, and satiety after standardized test meal.  These outcomes will be supportive data to 
understand the mechanism of action of dulaglutide, and to answer the frequently asked questions 
by healthcare providers.
For the patients participating in this study, there is no anticipated therapeutic benefit because of 
the short treatment period (4 weeks).
No clinically significant safety or tolerability concerns about dulaglutide 0.75 mg have been 
identified in patients to date.
More detailed information about the known and expected benefits and risks of dulaglutide 
0.75 mg may be found in the Package Insert.


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Dulaglutide (LY2189265)
4. Objectives and Endpoints
Table GBGK.1 shows the objectives and endpoints of the study.
Table GBGK.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
The primary objective of this study is to 
evaluate glucodynamic effects of dulaglutide 
0.75 mg compared with placebo in area under 
the glucose concentration versus time curve 
from 0 to 4 hours (glucose AUC[0-4h]) at 
4 weeks in Japanese patients with T2D.

The change from baseline in glucose AUC(0-4h) at 4 weeks
Secondary
To evaluate pharmacodynamic (PD) effects of 
dulaglutide 0.75 mg compared with placebo at 
4 weeks.

The change from baseline in fasting blood glucose at 4 weeks

The change from baseline in postprandial blood glucose at
4 weeks

The change from baseline in insulin at 4 weeks

The change from baseline in c-peptide at 4 weeks

The change from baseline in glucagon at 4 weeks

The change from baseline in triglyceride at 4 weeks
To evaluate safety and tolerability of 
dulaglutide 0.75 mg for 4 weeks

Treatment-emergent adverse events (TEAEs)

Incidence of hypoglycemic episodes
Tertiary/Exploratory Objectives
To evaluate daily glucose variability

Time course of daily average glucose by CGM during the 
first week
To evaluate satiety after standardized test 
meal

The change from baseline in satiety (full and hungry) in 
visual analog scale (VAS) at 1, 2, and 4 weeks


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Dulaglutide (LY2189265)
5. Study Design
5.1.
Overall Design
Study GBGK is a Phase 4, single-center, randomized, cross-over, single-blind, 
placebo-controlled study to evaluate glucodynamic effects of dulaglutide after standardized test
meal in Japanese patients with T2D.
The study includes a 10- to 28-day screening period, a 4-week treatment period (Period 1), a 4-
to 6-week washout period, and a 4-week treatment period (Period 2).  
Screening tests will be performed at Visit 1.  After confirming eligibility, the patient will be 
randomized in a 1:1 ratio to dulaglutide 0.75 mg or placebo treatment in Period 1.
Meal tolerance test will be performed at baseline, 1, 2, and 4 weeks for each period.  Time points 
for blood sampling will be 0, 30, 60, 90, 120, 180, and 240 minutes after the start of standardized 
test meal.  Satiety will be also assessed at 0, 60, 120, 180, and 240 minutes after the start of 
standardized test meal.  Detailed schedule of MTT is described in Appendix 6.  After completion 
of Period 1, all patients must have a 4- to 6-week washout period, and then will start Period 2 on 
the opposite treatment (patients taking dulaglutide will be switched to placebo and patients 
taking placebo will be switched to dulaglutide).
This is a single-blind study, and the treatment assignments will be blinded to patients until study 
completion.
Study governance considerations are described in detail in Appendix 3.
Figure GBGK.5.1 illustrates the study design.


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Dulaglutide (LY2189265)
Abbreviations:  CGM = continuous glucose monitoring; dula = dulaglutide; n = number of patients.
Figure GBGK.5.1.
General study design for Protocol H9X-JE-GBGK.
5.2.
Number of Participants
Up to 14 patients may be entered to randomize 12 patients and complete at least 11 patients. For 
the purposes of this study, a patient completes the study when all scheduled procedures shown in 
the Schedule of Activities have been finished.
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 is designed to evaluate glucodynamic effects after standardized test meal.  Cross-over 
design was selected to minimize the effect of confounding factors between patients.  Placebo will 
be used to minimize the effect of bias including placebo effects.  Duration of washout period (4
to 6 weeks) was set based on the results of Japan Phase 3 monotherapy study (GBDP).  In the 
GBDP study, fasting blood glucose was returned to baseline 4 weeks after discontinuation of 
study drug.  Patients with T2D who have diet and exercise therapy only will be enrolled to 
exclude background effect of other antidiabetic agents.  Japanese standardized test meal
(480 kcal, carbohydrate: protein: fat = 2.8:1:1) was selected because that was used in the 
previous MTTs conducted in Japan (Lee et al.  2010, Yabe et al.  2010, Yabe et al.  2015).
Japanese patients are leaner compared with the Western population and eat rice as their staple 
diet.  As a result, insulin secretion in the Japanese is lower than that in the Western population, 
and postprandial glucose tends to be increased (Obika and Trence 2010).  Therefore, reduction of 
postprandial glucose is relatively more important for Japanese patients compared with the 
Caucasian patients.  Also, postprandial insulin, c-peptide, glucagon, and triglyceride data will be 
supportive data to consider the mechanism of action of this drug.


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Dulaglutide (LY2189265)
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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Dulaglutide (LY2189265)
6. Study Population
Eligibility of patients for the study will be based on the results of screening medical history, 
physical examination, vital signs, clinical laboratory tests, and electrocardiogram (ECG).  
The nature of any conditions present at the time of the physical examination and any preexisting 
conditions will be documented.
Screening may occur 10 to 28 days prior to enrollment.  Patients who are not enrolled within 
28 days of screening may be subjected to an additional medical assessment and/or clinical 
measurements to confirm their eligibility.
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 for inclusion in the study only if they meet all of the following criteria at 
screening and/or enrollment:
[1] are males or females ages of 20 and 75 years at Visit 1;
[1a] male patients:

Men with partners of childbearing potential, for the duration of the study and 
for 120 days after the last dose of study drug, will either remain abstinent (if 
this is their preferred and usual lifestyle) or use at least one highly effective 
(less than 1% failure rate) method of contraception (such as combination oral 
contraceptives, implanted contraceptives, or intrauterine device) or an effective 
method of contraception (such as male or female condoms with spermicide, 
diaphragms with spermicide, or cervical sponges).  The patient may choose to 
use a barrier method of contraception.  Barrier protection methods without 
concomitant use of a spermicide are not an effective or acceptable method.  
Thus, each barrier method must include use of a spermicide.  It should be 
noted, however, that the use of male and female condoms as a double barrier 
method is not considered acceptable due to the high failure rate when these 
barrier methods are combined.

Men should refrain from sperm donation for the duration of the study and for 
120 days after the last dose of study drug.

Men who are in exclusively same sex relationships (when it is their preferred 
and usual lifestyle) are not required to use contraception.
[1b] female patients:
1)
Women of childbearing potential who are abstinent (if this is complete 
abstinence, as their preferred and usual lifestyle) or in a same sex relationship 
(as part of their preferred and usual lifestyle) must agree to either remain 
abstinent or stay in a same sex relationship without sexual relationships with 
males.


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Dulaglutide (LY2189265)
2)
Otherwise, women of childbearing potential participating must agree to use one 
highly effective method (less than 1% failure rate) of contraception, or a 
combination of two effective methods of contraception for the entirety of the 
study.
A.  Women of childbearing potential must test negative for pregnancy prior to 
initiation of treatment as indicated by a negative serum pregnancy test at the 
screening visit followed by a negative urine pregnancy test within 24 hours 
prior to exposure.  
B.  Either one highly effective method of contraception (such as combination 
oral contraceptives, implanted contraceptives, or intrauterine device) or a 
combination of two effective methods of contraception (such as male or 
female condoms with spermicide, diaphragms with spermicide, or cervical 
sponges) will be used.  The patient may choose to use a double barrier 
method of contraception.  Barrier protection methods without concomitant 
use of a spermicide are not a reliable or acceptable method.  Thus, each 
barrier method must include use of a spermicide.  It should be noted that the 
use of male and female condoms as a double barrier method is not 
considered acceptable due to the high failure rate when these methods are 
combined.
3)
Women not of childbearing potential may participate and include those who are:
A.  infertile due to surgical sterilization (hysterectomy, bilateral oophorectomy, 
or tubal ligation) or congenital anomaly such as mullerian agenesis; or
B.  postmenopausal – defined as either
i.
A woman at least 50 years of age with an intact uterus, not on hormone 
therapy, who has had either
a) cessation of menses for at least 1 year, or
b) at least 6 months of spontaneous amenorrhea with a 
follicle-stimulating hormone >40 mIU/mL; or
ii.
A woman 55 years or older not on hormone therapy, who has had at 
least 6 months of spontaneous amenorrhea; or
iii.
A woman at least 55 years of age with a diagnosis of menopause prior 
to starting hormone replacement therapy.
[2]
have T2D (based on the World Health Organization’s [WHO] diagnostic 
criteria) for at least 1 year.
[3]
have diet and exercise therapy only (no oral antihyperglycemic medication for 
at least 3 months prior to Visit 1).  
[4]
have a fasting blood glucose value of ≥120 and ≤200 mg/dL at Visit 1.
[5]
have a screening body weight of 50 and ≤80 kg.


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Dulaglutide (LY2189265)
[6]
are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures.
[7]
are able and willing to give signed informed consent.
6.2.
Exclusion Criteria
Patients will be excluded from study enrollment if they meet any of the following criteria at 
screening and/or enrollment:
[8]
are investigative site personnel directly affiliated with this study and their 
immediate families.  Immediate family is defined as a spouse, biological or 
legal guardian, child, or sibling.
[9]
are Lilly employees.  
[10]
are currently enrolled in a clinical study involving an investigational product 
or any other type of medical research judged not to be scientifically or 
medically compatible with this study.  
[11]
have participated, within the last 30 days, in a clinical study involving an 
investigational product.  If the previous investigational product has a long 
half-life, 5 half-lives or 30 days (whichever is longer) should have passed.
[12]
have previously completed or withdrawn from this study or have previously 
received dulaglutide within the 3 months prior to Visit 1.
[13]
have known allergies to dulaglutide, or other GLP-1 receptor agonists.  
[14]
have had any of the following cardiovascular conditions within the 3 months 
prior to Visit 1:  acute myocardial infarction, New York Heart Association 
(NYHA) Class III or Class IV heart failure, or cerebrovascular accident 
(stroke).
[15]
have a known clinically significant gastric emptying abnormality or have 
undergone gastric bypass surgery or restrictive bariatric surgery.
[16]
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 local laboratory at Visit 1.
[17]
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.
[18]
have an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2, 
calculated by the Japanese Society of Nephrology equation, at Visit 1 (eGFR 
[mL/min/1.73 m2] = 194 × Cr-1.094 × Age-0.287 × 0.739 [if female]).
[19]
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.


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[20]
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).
[21]
have serum calcitonin ≥20 pg/mL, as determined by the local laboratory at 
Visit 1.
[22]
Positive human immunodeficiency virus (HIV) antigen and antibody, hepatitis 
C antibody, hepatitis B surface antigen, or syphilis at Visit 1.  
[23]
have evidence of a significant, active uncontrolled endocrine or autoimmune 
abnormality, as judged by the investigator at Visit 1.
[24]
have a history of transplanted organ.
[25]
are receiving systemic glucocorticoid therapy.
[26]
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.
[27]
have donated 400 mL or more blood in the last 12 weeks (males) or in the last 
16 weeks (females), or any blood donation (including apheresis) within the 
last 4 weeks, or total volume of blood donation within 12 months is 1200 mL 
(males) / 800 mL (females) or more at Visit 1.
[28]
have an average weekly alcohol intake that exceeds 21 units per week (males 
up to age 65) and 14 units per week (females and males over 65) at Visit 1.  
(1 unit = 360 mL of beer; 150 mL of wine; 45 mL of distilled spirits.)
[29]
in the opinion of the investigator or sponsor, are unsuitable for inclusion in the 
study.
6.3.
Lifestyle and/or Dietary Requirements
Throughout the study, patients may undergo medical assessments and review of compliance with 
requirements before continuing in the study.  
6.3.1. Meals and Dietary Restrictions
Study participants should be instructed to continue diet therapy during study period.
Solid Japanese standardized test meal (480 kcal, carbohydrate: protein: fat = 2.8:1:1) will be 
supplied for MTT.  The menu will be prepared by managerial dietitian at study site.  Identical 
meal will be supplied for each test.  Patients should ingest standardized test meal within 
15 minutes.
6.3.2. Activity
Study participants should be instructed to continue exercise therapy during study period.


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6.3.3. Blood Donation
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 be 
re-screened once.  The interval between re-screenings should be at least 2 weeks.  Each time 
re-screening is performed, the individual must sign a new informed consent form (ICF) and will 
be assigned a new identification number.


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7. Treatment
7.1.
Treatment 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).  
Investigational product will be injected subcutaneously in the abdomen.  Trained site staff will
administer the injection.  
Table GBGK.2 shows the treatment regimens.
Table GBGK.2.
Treatments Administered
Treatment Name
Dulaglutide
Placebo
Dosage Formulation
single-dose pen
single-dose pen
Unit Dose Strength(s)/
Dosage Level(s)
0.75 mg (0.5 mL)
0 mg (0.5 mL)
Route of Administration
subcutaneous injection
subcutaneous injection
Dosing Instructions
once weekly
once weekly
The investigator or his/her designee is responsible for maintaining accurate records of 
investigational product dispensing and collection.  
7.1.1. Packaging and Labeling
The sponsor will provide dulaglutide and placebo in SDPs.  Each SDP (0.75 mg dulaglutide in 
0.5 mL OR placebo in 0.5 mL) is packaged in cartons of 4 pens.
The investigational product 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 at Visit 3 in a 1:1 ratio to 
dulaglutide 0.75 mg or placebo.  Assignment to treatment groups will be determined by a 
randomization table.
7.2.1. Selection and Timing of Doses
Investigational product will be administered once weekly.  It is recommended that patients 
receive the investigational product on the same day each week.  The doses will be administered 
at approximately the same times on each day.
The actual time of all dose administrations will be recorded in the patient’s case report form 
(CRF).


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7.3.
Blinding
Single-blind (patient-blind) is adopted for this study.  Glucose data (including CGM data) will
not be disclosed to patients during study period.  
Blinding will be maintained throughout the conduct of the study as described in the separate 
Blinding Plan.
7.4.
Dose Modification
Dose adjustments are not allowed in this study.
7.5.
Special Treatment Considerations
7.5.1.
Management of Increased Hypoglycemia Risk
If a hypoglycemic event occurs, the patient should record in the study diary the episode and 
associated symptoms and/or signs, and rescue treatment (if taken).  
Study site personnel will record information related to hypoglycemia such as start and end date 
and time of the episode, hypoglycemia signs and symptoms present. Following definitions and 
criteria will be used for categorizing an episode considered to be related to hypoglycemia (the 
PG values in this section refer to values determined by a laboratory or International Federation of 
Clinical Chemistry and Laboratory Medicine plasma-equivalent glucose meters and strips) 
(American Diabetes Association 2005):

Documented symptomatic hypoglycemia is defined as any time a patient feels that 
he/she is experiencing symptoms and/or signs associated with hypoglycemia, and has a 
PG level of ≤70 mg/dL (≤3.9 mmol/L).

Asymptomatic hypoglycemia is defined as 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.
If a hypoglycemic event meets the criteria of severe, it needs to be recorded as serious on the 
adverse event (AE) CRF and reported to Lilly as a serious adverse event (SAE).  


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7.5.2. Management of Severe Hyperglycemia
If a patient experiences severe hyperglycemia, the patient must discontinue from the study.  
Severe hyperglycemia is defined as follows: the patient’s fasting blood glucose concentrations 
are >270 mg/dL (>15.0 mmol/L) on two or more occasions.
7.6.
Preparation/Handling/Storage/Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained, as communicated by sponsor, during transit for all investigational product received 
and any discrepancies are reported and resolved before use of the study treatment.
Only participants enrolled in the study may receive investigational product or study materials, 
and only authorized site staff may supply or administer investigational product.  All 
investigational product should be stored in an environmentally controlled and monitored (manual 
or automated) area in accordance with the labeled storage conditions with access limited to the 
investigator and authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (such as
receipt, reconciliation, and final disposition records).
7.7.
Treatment Compliance
The investigational product will be administered at the clinical site, and documentation of 
treatment administration will occur at the site.
7.8.
Concomitant Therapy
Concomitant non-study antidiabetic medication is not allowed in this study.  Concomitant 
systemic glucocorticoid therapy is also not allowed in this study.
Patients on stable concomitant medication other than antidiabetic medication or systemic 
glucocorticoid therapy at the time of study entry should continue their regular, unchanged dose 
throughout the study.  
In general, additional concomitant medication should be avoided; however, rescue medicine such 
as acetaminophen (up to 2 g) may be administered at the discretion of the investigator for 
treatment of headaches etc.  Any medication used during the course of the study must be 
documented.
7.9.
Treatment after the End of the Study
Not applicable.


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8. Discontinuation Criteria
Patients discontinuing from the study prematurely for any reason should complete AE and other 
follow-up procedures per Section 2 of this protocol.
8.1.
Discontinuation from Study Treatment
Discontinuation of the investigational product for abnormal liver tests should be considered by 
the investigator when a patient meets 1 of the following conditions after consultation with the 
Lilly designated medical monitor:

ALT (alanine aminotransferase) or AST (aspartate aminotransferase) >8× ULN (upper 
limit of normal)

ALT or AST >5× ULN sustained for more than 2 weeks or

ALT or AST >3× ULN and total bilirubin level (TBL) >2× ULN or International 
Normalized Ratio (INR) >1.5 or

ALT or AST >3× ULN the appearance of fatigue, nausea, vomiting, right upper-quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (>5%)

ALP (alkaline phosphatase) >3× ULN

ALP >2.5× ULN and TBL >2× ULN

ALP >2.5× ULN with the appearance of fatigue, nausea, vomiting, right quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (>5%).
In addition, patients will be discontinued from the investigational product 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 8.1.1);

The patient’s fasting blood glucose concentrations are >270 mg/dL (>15.0 mmol/L) on 
two or more occasions (see Section 7.5.2);

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 (see Section 9.2.2.1);

The patient develops Exclusion Criterion [18] (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 (systemic glucocorticoids).
8.1.1. Discontinuation of Inadvertently Enrolled Patients
If the sponsor or investigator identifies a patient who did not meet enrollment criteria and was 
inadvertently enrolled, a discussion must occur between the Lilly clinical pharmacologist and the 


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Dulaglutide (LY2189265)
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 Lilly clinical 
pharmacologist to allow the inadvertently enrolled patient to continue in the study with or 
without continued treatment with investigational product.  
8.2.
Discontinuation from the Study
Patients will be discontinued in the following circumstances:

Enrollment in any other clinical study involving an investigational product or enrollment 
in any other type of medical research judged not to be scientifically or medically 
compatible with this study

Participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and good clinical practice (GCP)

Investigator Decision
o
the investigator decides that the patient should be discontinued from the study
o
if the patient, for any reason, requires treatment with another therapeutic agent 
that has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study occurs prior to introduction of the new agent

Patient Decision
o
the patient, or legal representative, requests to be withdrawn from the study.
8.3.
Patients Lost to Follow-up
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Site personnel are expected to make 
diligent attempts to contact patients who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the site.


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9. Study Assessments and Procedures
Section 2 lists the Schedule of Activities, detailing the study procedures and their timing.
Appendix 2 lists the laboratory tests that will be performed for this study.
Appendix 5 provides a summary of the maximum number and volume of invasive samples, for 
all sampling, during the study.
Appendix 6 provides a summary of MTT procedures.
Unless otherwise stated in 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
This section is not applicable for this study.
9.2.
Adverse Events
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the patient.
The investigator is responsible for the appropriate medical care of patients during the study.
Investigators must document their review of each laboratory safety report.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the investigational 
product or the study, or that caused the patient to discontinue the investigational product before 
completing the study.  The patient should be followed until the event resolves, stabilizes with 
appropriate diagnostic evaluation, or is reasonably explained.  The frequency of follow-up 
evaluations of the AE is left to the discretion of the investigator.
After the ICF is signed, study site personnel will record, via CRF, the occurrence and nature of 
each patient’s preexisting conditions, including clinically significant signs and symptoms of the 
disease under treatment in the study.  Additionally, site personnel will record any change in the 
condition(s) and the occurrence and nature of any AEs.  
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 potential cause and effect relationship between 
the investigational product, study device, and/or study procedure and the AE.
Planned surgeries should not be reported as AEs unless the underlying medical condition has 
worsened during the course of the study.


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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 CRF.
9.2.1. Serious Adverse Events
An SAE is any AE from this study that results in one of the following:

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

important medical events that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the patient or may require intervention to prevent 
one of the other outcomes listed in the definition above

when a condition related to the investigational device (SDP) necessitates medical or 
surgical intervention to preclude either permanent impairment of a body function or 
permanent damage to a body structure, the serious outcome of “required intervention” 
will be assigned.
Study site personnel must alert the Lilly clinical research physician (CRP)/clinical 
pharmacologist, or its designee, of any SAE as soon as practically possible.
Additionally, study site personnel must alert Lilly Global Patient Safety, 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.
Although all AEs are recorded in the CRF after signing informed consent, SAE reporting to the 
sponsor begins after the patient has signed informed consent and has received investigational 
product.  However, if an SAE occurs after signing informed consent, but prior to receiving 
investigational product, AND is considered reasonably possibly related to a study procedure then 
it MUST be reported.
Investigators are not obligated to actively seek AEs or SAEs in patients once they have 
discontinued from 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.  
Pregnancy (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.


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9.2.1.1.
Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the investigator’s brochure and that the investigator reports as related to investigational 
product or procedure.  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.
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 local laboratory.  Imaging studies, such as 
abdominal CT scan with or without contrast, MRI, or gallbladder ultrasound, should be 
performed.  If laboratory values and/or abdominal imaging support the diagnosis of acute 
pancreatitis, the patient must discontinue therapy with investigational product 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 and lipase at Visit 3, 7, 9, 13, and early 
termination 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 
total amylase are ≥3× ULN at any time during the study.  If this situation occurs at Visit 13, the 


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patient will undergo this additional work, and the data will be collected in the clinical trial 
database.
9.2.2.2.
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 TEAEs and measurements of calcitonin according to the Study Schedule 
(Section 2) at Visit 3, 7, 9, 13, and ET visit.  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 13 will be asked to repeat the 
measurement within 1 month.  If this repeat value is increasing (≥10% increase), the patient will 
be recommended that he or she undergo additional endocrine assessment and longer-term 
follow-up by an endocrinologist to exclude a serious adverse effect on the gland.  
Patients with an increase in serum calcitonin ≥50% of the mean of the baseline and screening 
values AND an absolute value ≥35 pg/mL at Visit 13 will be recommended to immediately 
undergo additional endocrine assessments and longer-term follow-up by an endocrinologist.
9.2.3. Complaint Handling
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical trials in order to ensure the safety of study participants, monitor quality, and to facilitate 
process and product improvements.
Patients should be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product or drug delivery system so that the 
situation can be assessed.
9.3.
Treatment of Overdose
For the purposes of this study, an overdose of dulaglutide is considered any dose higher than the 
dose assigned through randomization.
Effects of overdose with dulaglutide in clinical studies have included gastrointestinal disorders 
and hypoglycemia.  In the event of overdose, appropriate supportive treatment (including 
frequent PG monitoring) should be initiated according to the patient’s clinical signs and 
symptoms.
Refer to the dulaglutide Japan Package Insert.


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9.4.
Safety
9.4.1. Laboratory Tests
For each patient, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities (Section 2).  
9.4.2. Vital Signs
Systolic blood pressure, diastolic blood pressure, and pulse rate should be measured in triplicate 
in a sitting position.  
For each patient, vital signs measurements should be conducted according to the Schedule of 
Activities (Section 2).  
Vital signs should be taken before collection of blood samples for laboratory testing.  For each 
parameter, 3 measurements will be taken 1 minute apart using the same arm.  An appropriately 
sized cuff (cuff bladder encircling at least 80% of the upper arm) should be used to ensure the 
accuracy of blood pressure measurements.  The arm used for the blood pressure measurement 
should be supported at heart level.  Each measurement of sitting heart rate and blood pressure is 
to be recorded in the CRF.
9.4.3. Electrocardiograms
For each patient, a single 12-lead ECG will be obtained according to the Study Schedule 
(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/corrected 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.


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9.4.4. Other Tests
9.4.4.1. Continuous Glucose Monitoring
The 
 system ( 
) will be used for CGM in this study.  Continuous 
Glucose Monitoring will be performed in each study period.  Continuous Glucose Monitoring
will be initiatedon Day -7 (or -6) and Day 50 (or 51) and will last until Day8and Day 64.  
This CGM data will complement theevaluation ofthe glucodynamic effectsof dulaglutide 
0.75mg during the first week.
9.4.4.2. Patient Reported Outcomes
9.4.4.2.1. Satiety afterStandardized TestMeal
A perception of satiety (full and hungry) VAS should be performed by patients every hour for 
4hours following thestandardizedtest meal on each MTT day.  
9.4.5. Safety Monitoring
The Lilly clinical pharmacologist or CRP/scientist will monitor safety data throughout the course 
of the study.
Lilly will review SAEs within time frames mandated by company procedures.  The Lilly clinical 
pharmacologist will periodically review the following data:
trends in safety data
laboratory analytes
AEs,including hypoglycemia
When appropriate, the Lilly clinical pharmacologist will consult with the functionally 
independent Global Patient Safety therapeutic area physician or clinical research scientist.
9.4.5.1. Hepatic Safety
If a study patientexperiences elevated ALT ≥3×ULN, ALP ≥2×ULN, or elevated 
TBL≥2×ULN, liver tests (Appendix 4) should be repeated within 3 to5 days including ALT, 
AST, ALP, TBL, direct bilirubin, gamma-glutamyl transferase (GGT),and creatine kinaseto 
confirm the abnormality and to determine if it is increasing or decreasing.  If the abnormality 
persists or worsens, clinical and laboratory monitoring should be initiated by the investigator 
based on consultation with the Lilly clinical pharmacologist.  Monitoring should continue until 
levels normalize and/or are returningto approximate baseline levels.  
Additional safety data should be collected if 1or more of the following conditions occur: 
elevation of serum ALT to ≥ 5×ULN on two or more consecutive blood tests
elevated serum TBL to ≥ 2×ULN (except for cases of known Gilbert’s syndrome)
elevation of serum ALP to ≥ 2×ULN on 2or more consecutive blood tests 

CCI
patientdiscontinued from treatment due to a hepatic event or abnormality of liver 
tests
CCI


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Dulaglutide (LY2189265)

hepatic event considered to be an SAE.
9.5.
Pharmacokinetics
This section is not applicable for this study.
9.6.
Pharmacodynamics
At times specified in the Schedule of Activities (Section 2), venous blood samples will be 
collected and used to determine the PD effects of dulaglutide.  Blood will be collected by 
venipuncture in order to evaluate fasting blood glucose, postprandial blood glucose, insulin, 
c-peptide, glucagon, and triglyceride.
The sample(s) will be stored until testing is complete at a facility selected by the sponsor.  
9.6.1. Primary Measure
The primary measure of PD is change from baseline in glucose AUC(0-4h) at 4 weeks.
9.6.2. Secondary Measures
The following secondary measures of PD will be evaluated:

The change from baseline in fasting blood glucose at 1, 2, and 4 weeks

The change from baseline in postprandial blood glucose (30, 60, 90, 120, 180, and 
240 minutes) at 1, 2, and 4 weeks

The change from baseline in glucose AUC(0-4h) at 1 and 2 weeks

The change from baseline in insulin (30, 60, 90, 120, 180, and 240 minutes) at 1, 2, 
and 4 weeks

The change from baseline in insulin AUC(0-4h) at 1, 2, and 4 weeks

The change from baseline in c-peptide (30, 60, 90, 120, 180, and 240 minutes) at 1, 2, 
and 4 weeks

The change from baseline in c-peptide AUC(0-4h) at 1, 2, and 4 weeks

The change from baseline in glucagon (30, 60, 90, 120, 180, and 240 minutes) at 1, 2, 
and 4 weeks

The change from baseline in glucagon AUC(0-4h) at 1, 2, and 4 weeks

The change from baseline in triglyceride (30, 60, 90, 120, 180, and 240 minutes) at 1, 
2, and 4 weeks

The change from baseline in triglyceride AUC(0-4h) at 1, 2, and 4 weeks
9.7.
Genetics
No samples for pharmacogenetic test will be collected for this study.


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Dulaglutide (LY2189265)
9.8.
Biomarkers
No samples for non-pharmacogenetic biomarker will be collected for this study.  
9.9.
Health Economics
This section is not applicable for this study.


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10.
Statistical Considerations and Data Analysis
10.1. Sample Size Determination
Up to 14 patients may be entered to randomize 12 patients and complete at least 11 patients.  
Patients will be randomized in a 1:1 ratio to one of two sequences.  Assuming one dropout, the
sample size of 11 patients would provide 93% power to demonstrate superiority of dulaglutide to 
placebo.  This computation assumes the true treatment difference in glucose AUC(0-4h) is 
190 mg*hr/dL, a common standard deviation of 140 mg*hr/dL, intra-patient correlation of 0.3,
and a one-sided significance level of 0.025.  
Patients who are randomized but do not complete study treatment may be replaced at the 
discretion of the investigator and Lilly clinical pharmacologist.  
10.2. Populations for Analyses
10.2.1. Study Participant Disposition
A detailed description of patients’ disposition will be provided at the end of the study.  
10.2.2. Study Participant Characteristics
The patients’ age, sex, weight, height, or other demographic characteristics will be summarized
and may be used in the PD and safety analyses as quantitative or classification variables.
10.3. Statistical Analyses
Statistical analysis of this study will be the responsibility of Eli Lilly and Company or its 
designee.  
Pharmacodynamic analyses will be conducted on data from all patients who receive at least one 
dose of the investigational product and have evaluable PD.  
Safety analyses will be conducted for all enrolled patients, whether or not they completed all 
protocol requirements.
Additional exploratory analyses of the data will be conducted as deemed appropriate.  
10.3.1. Safety Analyses
10.3.1.1. Clinical Evaluation of Safety
All investigational product and protocol procedure AEs will be listed, and if the frequency of 
events allows, safety data will be summarized using descriptive methodology.
The incidence of symptoms for each treatment will be presented by severity and by association 
with investigational product as perceived by the investigator.  Symptoms reported to occur prior 
to enrollment will be distinguished from those reported as new or increased in severity during the 
study.  Each symptom will be classified by the most suitable term from the medical regulatory 
dictionary.


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Dulaglutide (LY2189265)
The number of investigational product-related SAEs will be reported.
10.3.1.2. Statistical Evaluation of Safety
Safety laboratory parameters and vital signs will be listed, and summarized using standard 
descriptive statistics.  Additional analysis may be performed if warranted upon review of the 
data.
10.3.2. Pharmacokinetic Analyses
This section is not applicable for this study.
10.3.3. Pharmacodynamic Analyses
10.3.3.1. Pharmacodynamic Parameter Estimation
Pharmacodynamic parameters will be calculated for glucose, insulin, glucagon, c-peptide, and 
triglyceride data following the standardized test meal at Weeks 0, 1, 2, and 4.  The AUC(0-4h) 
will be calculated using the linear-trapezoidal method.  This analysis will be performed for both 
original data and adjusted data with the predose value at each period.  The parameters 
AUC(0-1h), AUC(0-2h), and AUC(0-3h) may also be calculated.
All PD parameters will be summarized and tabulated by treatment group and day.  Summary 
statistics will be provided.  The individual observed and mean time profile will be plotted by 
treatment group.
10.3.3.2. Pharmacodynamic Statistical Inference
The PD parameters on Weeks 0, 1, 2, and 4 will be analyzed using a mixed-effects linear model.  
The PD parameters for glucose, insulin, glucagon, c-peptide, and triglyceride that will be 
statistically evaluated include AUC, fasting and postprandial values at each time point.  The 
model will include treatment, sequence, day, and treatment-by-day interaction as fixed effects, 
baseline as covariate, and patient as random effect.  The baseline is the predose value on Day 1.  
The least squares means and the 95% CIs by treatment group will be tabulated and plotted.  
Comparisons between dulaglutide and placebo will be performed.  Difference of least squares 
means of dulaglutide to placebo, and the 95% CIs, will be tabulated.  
10.3.4. Other Analyses
Daily average, daily standard deviation, and daily mean amplitude of glycemic excursion 
(MAGE) from glucose data collected by a CGM device by treatment and day will be 
summarized.  Individual (by patient) or mean by treatment of glucose data will be plotted, if 
deemed appropriate.
Satiety after standardized test meal (full and hungry) in VAS will be summarized by treatment
and time after standardized test meal.
10.3.5. Data Review During the Study
Particular data review during the study is not planned for this study.  


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10.3.6. Interim Analyses
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the Lilly clinical pharmacologist, CRP/investigator, or designee will consult with the 
appropriate medical director or designee to determine if it is necessary to amend the protocol.


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11. References
.  Continuous glucose monitoring and AGP –
 web site.  
Available at: http://www.freestylelibrepro.us/index.html.  Accessed June 22, 2017.
American Diabetes Association.  Defining and reporting hypoglycemia in diabetes: a report from 
the American Diabetes Association Workgroup on Hypoglycemia.  Diabetes Care.  
2005;28(5):1245-1249.
Araki E, Inagaki N, Tanizawa Y, Oura T, Takeuchi M, Imaoka T.  Efficacy and safety of once 
weekly dulaglutide in combination with sulphonylurea and/or biguanide compared with once 
daily insulin glargine in Japanese patients with type 2 diabetes: a randomized, open-label, 
phase 3, non-inferiority study.  Diabetes Obes Metab.  2015;17(10):994-1002.
Banks PA, Freeman ML; Practice Parameters Committee of the American College of 
Gastroenterology.  Practice guidelines in acute pancreatitis.  Am J Gastroenterol.  
2006;101(10):2379-2400.
Emoto M, Terauchi Y, Ozeki A, Oura T, Takeuchi M, Imaoka T.  A 1-year safety study of 
dulaglutide in Japanese patients with type 2 diabetes on a single oral hypoglycemic agent: an 
open-label, nonrandomized, phase 3 trial.  Endocr J.  2015;62(12):1101-1114.
Koizumi M, Takada T, Kawarada Y, Hirata K, Mayumi T, Yoshida M, Sekimoto M, Hirota M, 
Kimura Y, Takeda K, Isaji S, Otsuki M, Matsuno S; JPN.  JPN Guidelines for the management 
of acute pancreatitis: diagnostic criteria for acute pancreatitis.  J Hepatobiliary Pancreat Surg.  
2006;13(1):25-32.
Lee S, Yabe D, Nohtomi K, Takada M, Morita R, Seino Y, Hirano T.  Intact glucagon-like 
peptide-1 levels are not decreased in Japanese patients with type 2 diabetes.  Endocr J.  
2010;57:119-126.  
Miyagawa J, Odawara M, Takamura T, Iwamoto N, Takita Y, Imaoka T.  Once weekly 
glucagon-like peptide-1 receptor agonist dulaglutide is non-inferior to once daily liraglutide 
and superior to placebo in Japanese patients with type 2 diabetes: a 26-week randomised phase 
3 study.  Diabetes Obes Metab.  2015;17(10):974-983.
Obika M, Trence DL.  Comparison of type 2 diabetes care in the United States and Japan.  
Endocr Pract.  2010;16(4):707-711.
Odawara M, Miyagawa J, Iwamoto N, Takita Y, Imaoka T, Takamura T.  Once weekly 
glucagon-like peptide-1 receptor agonist dulaglutide significantly decreases HbA1c compared 
with once daily liraglutide in Japanese patients with type 2 diabetes: 52 weeks of treatment in 
a randomized phase 3 study.  Diabetes Obes Metab.  2016;18(3):249-257.
Tamaki C, Takeuchi M, Iwamoto N, Glaesner W.  Pharmacologicalprofile and clinical trial 
results of a long-acting, once weekly human GLP-1 receptor agonist dulaglutide (genetical 
recombination).  Nihon Yakurigaku Zasshi.  2015;146(4):215-224.  (in Japanese)
Terauchi Y, Satoi Y, Takeuchi M, Imaoka T.  Monotherapy with the once weekly GLP-1 
receptor agonist dulaglutide for 12 weeks in Japanese patients with type 2 diabetes: dose-
dependent effects on glycaemic control in a randomised, double-blind, placebo-controlled 
study.  Endocr J
CCI
.  2014;61(10):949-959.
CCI


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Yabe D, Kuroe A, Lee S, Watanabe K, Hyo T, Hishizawa M, Kurose T, Deacon CF, Holst JJ, 
Hirano T, Inagaki N, Seino Y.  Little enhancement of meal-induced glucagon-like peptide 1 
secretion in Japanese: Comparison of type 2 diabetes patients and healthy controls.  J Diabetes 
Investig.  2010;1:56-59.
Yabe D, Kuroe A, Watanabe K, Iwasaki M, Hamasaki A, Hamamoto Y, Harada N, Yamane S, 
Lee S, Murotani K, Deacon CF, Holst JJ, Hirano T, Inagaki N, Kurose T, Seino Y.  Early 
phase glucagon and insulin secretory abnormalities, but not incretin secretion, are similarly 
responsible for hyperglycemia after ingestion of nutrients.  J Diabetes Complications.  
2015;29:413-421.


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Appendix 1.
Abbreviations and Definitions


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Dulaglutide (LY2189265)
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.
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC(0-4h)
area under the concentration versus time curve from time zero to 4 hours
blinding
A procedure in which one or more parties to the study are kept unaware of the treatment 
assignment(s).  Unless otherwise specified, blinding will remain in effect until final database 
lock.
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the patient is not, or vice versa, or when the sponsor is aware of the treatment 
but the investigator and/his staff and the patient are not.  A double-blind study is one in 
which neither the patient nor any of the investigator or sponsor staff who are involved in the 
treatment or clinical evaluation of the patients are aware of the treatment received
CGM
continuous glucose monitoring
CI
confidence interval
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.
compliance
Adherence to all the study-related requirements, good clinical practice (GCP) requirements, 
and the applicable regulatory requirements.
confirmation
A process used to confirm that laboratory test results meet the quality requirements defined 
by the laboratory generating the data and that Lilly is confident that results are accurate.  
Confirmation will either occur immediately after initial testing or will require that samples 
be held to be retested at some defined time point, depending on the steps required to obtain 
confirmed results.
CRF
case report form
CRP
clinical research physician
CT
computed tomography
ECG
electrocardiogram
eGFR
estimated glomerular filtration rate


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enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the study are those 
who have been assigned to a treatment.
enter
Patients entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ERB
ethical review board
GCP
good clinical practice
GGT
gamma-glutamyl transferase
GLP-1
glucagon-like peptide-1
HIV
human immunodeficiency virus
ICF
informed consent form
ICH
International Council for Harmonisation
informed consent
A process by which a patient voluntarily confirms his or her willingness to participate in a 
particular study, after having been informed of all aspects of the study that are relevant to 
the patient’s decision to participate.  Informed consent is documented by means of a written, 
signed and dated informed consent form.  
INR
International Normalized Ratio
Investigational 
product (IP)
A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical study, 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.
investigator
A person responsible for the conduct of the clinical study at a study site.  If a study is 
conducted by a team of individuals at a study site, the investigator is the responsible leader 
of the team and may be called the principal investigator.
Legal 
Representative
An individual or judicial or other body authorized under applicable law to consent, on behalf 
of a prospective patient, to the patient’s participation in the clinical study.
MAGE
mean amplitude of glycemic excursion
MEN
multiple endocrine neoplasia
MRI
magnetic resonance imaging
NYHA
New York Heart Association
Non-
investigational 
product (non-IP)
A product that is not being tested or used as a reference in the clinical study, but is provided 
to patients and used in accordance with the protocol, such as:  concomitant or rescue/escape 
medication for preventative, diagnostic, or therapeutic reasons, medication to ensure 
adequate medical care, and/or products used to induce a physiological response.
randomize
the process of assigning patients to an experimental group on a random basis


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PD
pharmacodynamic
PG
plasma glucose
QTc
corrected QT interval
SAE
serious adverse event
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.  
SDP
single-dose pen
SUSARs
suspected unexpected serious adverse reactions
T2D
type 2 diabetes mellitus
TBL
total bilirubin level
TEAE
treatment-emergent adverse event:  Any untoward medical occurrence that emerges during a 
defined treatment period, having been absent pretreatment, or worsens relative to the 
pretreatment state, and does not necessarily have to have a causal relationship with this 
treatment 
ULN
upper limit of normal
VAS
visual analog scale
WHO
World Health Organization


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Appendix 2.
Clinical Laboratory Tests
Safety Laboratory Tests a
Hematology
Clinical Chemistry
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Calcium
Mean cell volume 
Chloride
Mean cell hemoglobin 
Uric acid
Mean cell hemoglobin concentration 
Total protein
Leukocytes (WBC) 
Albumin
Platelets
Total bilirubin
Alkaline phosphatase (ALP)
Differential WBC [%] of:
Aspartate aminotransferase (AST)
Neutrophils
Alanine aminotransferase (ALT)
Lymphocytes
Gamma-glutamyl transferase (GGT)
Monocytes
Blood urea nitrogen (BUN)
Eosinophils
Creatinine
Basophils
Creatine kinase (creatine phosphokinase)
Total cholesterol
Urinalysis
Low-density lipoprotein (LDL) cholesterol
Protein
High-density lipoprotein (HDL) cholesterol
Glucose
Triglyceride
Ketones
Blood
HbA1c
Urine albumin/creatinine ratio (UACR)
Meal tolerance test
Glucose
Serum pregnancy test [if applicable] b
Insulin
c-peptide
Urine pregnancy test [if applicable]
Glucagon
Triglyceride
Serology b
Hepatitis B surface antigen
Endocrinology
Hepatitis C antibody
Total amylase
HIV antigen and antibody
Lipase
Syphilis
Calcitonin
Abbreviations:  HIV = human immunodeficiency virus; HbA1c = glycated hemoglobin; RBC = red blood cells; 
WBC = white blood cells.
a
Assayed by local laboratory.
b
Performed at screening only.  


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Appendix 3.
Study Governance, Regulatory and Ethical 
Considerations
Informed Consent
The investigator is responsible for:

ensuring that the patient understands the nature of the study, the potential risks and 
benefits of participating in the study, and that their participation is voluntary.

ensuring that informed consent is given by each patient or legal representative.  This 
includes obtaining the appropriate signatures and dates on the ICF prior to the 
performance of any protocol procedures and prior to the administration of investigational 
product.

answering any questions the patient may have throughout the study and sharing in a 
timely manner any new information that may be relevant to the patient’s willingness to 
continue his or her participation in the study.

providing a copy of the ICF to the participant or the participant’s legal representative and 
retaining a copy on file.
Recruitment
Lilly or its designee is responsible for the central recruitment strategy for patients.  Individual 
investigators may have additional local requirements or processes.  Study-specific recruitment 
material should be approved by Lilly.
Ethical Review
The investigator must give assurance that the ethical review board (ERB) was properly 
constituted and convened as required by International Council for 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 
before it is used at the investigative site(s).  All ICFs must be compliant with the ICH guideline 
on GCP.
The study site’s ERB(s) should be provided with the following:

the package labeling and updates during the course of the study

ICF

relevant curricula vitae


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Regulatory Considerations
This study will be conducted in accordance with the protocol and with:
1) 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 
2) applicable ICH GCP Guidelines 
3) applicable laws and regulations
Some of the obligations of the sponsor will be assigned to a third party organization.
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, the principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
Final Report Signature
The investigator or designee will sign the clinical study report for this study, indicating 
agreement with the analyses, results, and conclusions of the report.
The sponsor’s responsible medical officer and statistician will sign/approve the final clinical 
study report for this study, confirming that, to the best of his or her knowledge, the report 
accurately describes the conduct and results of the study.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate.

provide training to instruct the investigators and study coordinators.  This training will 
give instruction on the protocol, the completion of the CRFs, and study procedures.

make periodic visits to the study site.

be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax.

review and evaluate CRF data and/or use standard computer edits to detect errors in data 
collection.

conduct a quality review of the database.


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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 and/or 
regulatory agencies at any time.  Investigators will be given notice before an audit occurs.
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to the original source 
documents.
Data Collection Tools/Source Data
An electronic data capture system will be used in this study.  The site must define and retain all 
source records and must maintain a record of any data where source data are directly entered into 
the data capture system.
Data Protection
Data systems used for the study will have controls and requirements in accordance with local 
data protection law.  
The purpose and use of patient personal information collected will be provided in a written 
document to the patient by the sponsor.
Study and Site Closure
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly or its designee, the investigator, or the ERB 
of the study site judges it necessary for medical, safety, regulatory, or other reasons consistent 
with applicable laws, regulations, and GCP.
Discontinuation of the Study
The study will be discontinued if Lilly or its designee judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP.


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


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Appendix 5.
Blood Sampling Summary
This table summarizes the approximate number of venipunctures and blood volumes for all 
blood sampling (screening, safety laboratories, and bioanalytical assays) during the study.  
Protocol H9X-JE-GBGK Sampling Summary
Purpose
Blood Volume per 
Sample (mL)
Number of Blood 
Samples
Total Volume 
(mL)
Hematology, clinical chemistry, 
endocrinology a
8
5
40
HbA1c
2
4
8
Serology tests
6
1
6
Serum pregnancy test
2
1
2
Fasting blood glucose
2
1
2
MTT (glucose, insulin, c-peptide, 
glucagon, and triglyceride)
6
56
336
Total
394
Abbreviations:  HbA1c = glycated hemoglobin; MTT = meal tolerance test.
a  Additional samples may be drawn if needed for safety purposes.


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Appendix 6.
Meal Tolerance Test
Time
Procedure
-120 min
Physical exam, vital signs (sitting)
Weight (only Day 1, Day 29, Day 57, and Day 85)
ECG (only Day 1 and Day 57)
Urine sampling for pregnancy test (only Day 1 and Day 57, if needed)
Urinalysis and UACR (only Day 1, Day 29, Day 57, and Day 85)
Blood sampling for hematology, clinical chemistry, endocrinology, HbA1c (only Day 
1, Day 29, Day 57, and Day 85)
Blood sampling for glucose, insulin, c-peptide, glucagon, and triglyceride (for 0 min)
Satiety evaluation (VAS) (for 0 min)
0 min
Start standardized test meal a
30 min
Blood sampling for glucose, insulin, c-peptide, glucagon, and triglyceride
60 min
Blood sampling for glucose, insulin, c-peptide, glucagon, and triglyceride
Satiety evaluation (VAS)
90 min
Blood sampling for glucose, insulin, c-peptide, glucagon, and triglyceride
120 min
Blood sampling for glucose, insulin, c-peptide, glucagon, and triglyceride
Satiety evaluation (VAS)
180 min
Blood sampling for glucose, insulin, c-peptide, glucagon, and triglyceride
Satiety evaluation (VAS)
240 min
Blood sampling for glucose, insulin, c-peptide, glucagon, and triglyceride
Satiety evaluation (VAS)
After MTT
Dose of dulaglutide 0.75 mg or placebo (except Days 29 and 85)
Abbreviations:  HbA1c = glycated hemoglobin; min = minutes; MTT = meal tolerance test; UACR = urine 
albumin/creatinine ratio; VAS = visual analog scale.
a Japanese standard test meal (480 kcal, carbohydrate: protein: fat = 2.8:1:1) should be ingested within 15 min.


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Dulaglutide (LY2189265)
Appendix 7.
Protocol Amendment H9X-JE-GBGK(a)
Summary: A Phase 4 Study to Evaluate Glucodynamic 
Effects of Dulaglutide in Japanese Patients with Type 2 
Diabetes Mellitus
Overview
Protocol H9X-JE-GBGK(a) A Phase 4 Study to Evaluate Glucodynamic Effects of Dulaglutide 
in Japanese Patients with Type 2 Diabetes Mellitus has been amended.  The new protocol is 
indicated by Amendment (a) and will be used to conduct the study in place of any preceding 
version of the protocol.
The overall changes and rationale for the changes made to this protocol are as follows:
Section 7.5.1:
The detailed method of a hypoglycemic event is added.
Section 9.2.2.1:
Pancreatitis adjudication by an independent committee of expert physicians is removed.  
Appendix 2:
The detailed item of the seerum pregnancy test is removed.
Appendix 6:
Time window before the meal tolerance test (MTT) is changed .
Minor editorial changes were made for accuracy, consistency and clarity.


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Dulaglutide (LY2189265)
Revised Protocol Sections
Note:
All deletions have been identified by strikethroughs.
All additions have been identified by the use of underscore.
The numbering system used for inclusion and exclusion criteria provides a unique number for 
each criterion and allows for efficiency in data collection.
In case an amendment to the protocol adds a criterion, that criterion will receive the next 
available number, regardless of whether it is an inclusion or exclusion criterion.
6.2.   Exclusion Criteria
[22]
Positive human immunodeficiency virus (HIV) antigen and antibody, hepatitis C 
antibody, hepatitis B surface antigen, or syphilis at Visit 1.     
7.5.  Special Treatment Considerations
7.5.1   Management of Increased Hypoglycemia Risk
If a hypoglycemic event occurs, the patient should record in the study diary the episode and 
associated symptoms and/or signs, and rescue treatment (if taken).  
Investigator should use Study site personnel will record information related to hypoglycemia 
such as start and end date and time of the following episode, hypoglycemia signs and symptoms 
present. Following definitions and criteria when diagnosing and will be used for categorizing an 
episode considered to be related to hypoglycemia (the PG values in this section refer to values 
determined by a laboratory or International Federation of Clinical Chemistry and Laboratory 
Medicine plasma-equivalent glucose meters and strips) (American Diabetes Association 2005):
9.2.2. Adverse Events of Interest
9.2.2.1. Pancreatitis
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 
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 CRF page by study site or Lilly staff.  The adjudication committee 
representative will enter the results of adjudication in a corresponding CRF page.


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Dulaglutide (LY2189265)
9.4.2.  Vital Signs
Vital signs should be taken before collection of blood samples for laboratory testing.  For each 
parameter, 3 measurements will be taken 1 minute apart using the same arm.  An appropriately 
sized cuff (cuff bladder encircling at least 80% of the upperarm) should be used to ensure the 
accuracy of blood pressure measurements.  The arm used for the blood pressure measurement 
should be supported at heart level.  Each measurement of sitting heart rate and blood pressure is 
to be recorded in the CRF.
9.4.4.  Other Tests
9.4.4.1. Continuous Glucose Monitoring
The 
 system (
[WWW])) will be used for CGM in this study.  
Continuous Glucose Monitoring will be performed in each study period.  Continuous 
Glucose Monitoring will be initiated on Day -7 (or -6) and Day 50 (or 51) and will last 
until Day 8 and Day 64.  
Appendix 2.  Clinical Laboratory Tests
Safety Laboratory Tests a
Urine albumin/creatinine ratio(UACR)
Meal tolerance test
Glucose
Serum pregnancy test [if applicable]b
Insulin
Follicle-stimulating hormone
c-peptide
Urine pregnancy test[if applicable]
Glucagon
Triglyceride
Serology b
Hepatitis B surface antigen
Endocrinology
Hepatitis C antibody
Total amylase
HIVantigen andantibody
Lipase
Syphilis
Calcitonin
Abbreviations:  HIV = human immunodeficiency virus; HbA1c = glycated hemoglobin; RBC = red blood cells; 
WBC = white blood cells.
a Assayed by local laboratory.
b    
CCI
Performed at screening only.  
CCI


H9X-JE-GBGK(a) Clinical Pharmacology Protocol
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Dulaglutide (LY2189265)
Appendix 5.
Blood Sampling Summary
Protocol H9X-JE-GBGK Sampling Summary
Purpose
Blood Volume per 
Sample (mL)
Number of Blood 
Samples
Total Volume 
(mL)
Hematology, clinical chemistry, 
endocrinology a
8
5
40
HbA1c
2
4
8
Serology tests
56
1
56
Serum pregnancy test
2
1
2
Fasting blood glucose
2
1
2
MTT (glucose, insulin, c-peptide, 
glucagon, and triglyceride)
6
56
336
Total
393394
Abbreviations:  HbA1c = glycated hemoglobin; MTT = meal tolerance test.
a  Additional samples may be drawn if needed for safety purposes.
Appendix 6.  Meal Tolerance Test
Time
Procedure
-120 min
-60 min
Physical exam, vital signs (sitting)
Weight (only Day 1, Day 29, Day 57, and Day 85)
ECG (only Day 1 and Day 57)
Urine sampling for pregnancy test (only Day 1 and Day 57, if needed)
Urinalysis and UACR (only Day 1, Day 29, Day 57, and Day 85)
Blood sampling for hematology, clinical chemistry, endocrinology, HbA1c (only Day 
1, Day 29, Day 57, and Day 85)
Blood sampling for glucose, insulin, c-peptide, glucagon, and triglyceride (for 0 min) 
Satiety evaluation (VAS) (for 0 min)
Abbreviations:  HbA1c = glycated hemoglobin; min = minutes; MTT = meal tolerance test; UACR = urine 
albumin/creatinine ratio; VAS = visual analog scale.

SAP_001.pdf: 
Statistical Analysis Plan H9X-JE-GBGK 
 
 
A Phase 4 Study to Evaluate Glucodynamic Effects of Dulaglutide in Japanese Patients with 
Type 2 Diabetes Mellitus 
 
 
NCT03315780 
 
 
Approval Date: 25-Oct-2017 


Final, 25 October 2017
             Page 1 of 14
STATISTICAL ANALYSIS PLAN
A Phase 4 Study to Evaluate Glucodynamic Effects of Dulaglutide in Japanese Patients 
with Type 2 Diabetes Mellitus
Statistical Analysis Plan Status:  Final
Statistical Analysis Plan Date:  25-October-2017
Study Drug: Dulaglutide (LY2189265)
Sponsor Reference:  H9X-JE-GBGK
Covance CRU Study: 1000071-8370035
Clinical Phase IV
Approval Date: 25-Oct-2017 GMT


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8370035
Sponsor Reference H9X-JE-GBGK
1. TABLE OF CONTENTS
1.
TABLE OF CONTENTS ............................................................................................... 2
2.
ABBREVIATIONS........................................................................................................ 3
3.
INTRODUCTION ......................................................................................................... 5
4.
STUDY OBJECTIVES.................................................................................................. 5
4.1
Primary Objective.................................................................................................... 5
4.2
Secondary Objectives .............................................................................................. 5
4.3
Tertiary/Exploratory Objectives............................................................................... 6
5.
STUDY DESIGN........................................................................................................... 6
6.
TREATMENTS............................................................................................................. 7
7.
SAMPLE SIZE JUSTIFICATION ................................................................................. 7
8.
DEFINITION OF ANALYSIS POPULATIONS............................................................ 8
9.
STATISTICAL METHODOLOGY ............................................................................... 8
9.1
General.................................................................................................................... 8
9.2
Demographics and Patient Disposition..................................................................... 8
9.3
Pharmacodynamic Assessment ................................................................................ 9
9.3.1
Pharmacodynamic Analysis............................................................................ 9
9.3.2
Pharmacodynamic Statistical Methodology .................................................... 9
9.4
Safety and Tolerability Assessments...................................................................... 11
9.4.1
Adverse events ............................................................................................. 11
9.4.2
Concomitant medication............................................................................... 11
9.4.3
Clinical laboratory parameters...................................................................... 12
9.4.4
Vital signs .................................................................................................... 12
9.4.5
Satiety after Standardized Test Meal............................................................. 12
9.4.6
Hypoglycemic Episodes ............................................................................... 12
9.4.7
Hepatic Monitoring ...................................................................................... 12
9.4.8
Other assessments......................................................................................... 13
9.4.9
Safety and Tolerability Statistical Methodology............................................ 13
10. INTERIM ANALYSES ............................................................................................... 13
11. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ...... 13
12. REFERENCES ............................................................................................................ 13
13. DATA PRESENTATION ............................................................................................ 13
13.1 Derived Parameters ............................................................................................... 13
13.2 Missing Data ......................................................................................................... 14
13.3 Insufficient Data for Presentation .......................................................................... 14


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Statistical Analysis Plan 
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Covance Clinical Study No. 8370035
Sponsor Reference H9X-JE-GBGK
2. ABBREVIATIONS
Abbreviations pertain to the Statistical Analysis Plan (SAP) only (not the tables, figures and 
listings [TFLs]).
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AUC
Area under the concentration versus time curve
CGM
Continuous glucose monitoring
CI
Confidence interval
CL/F
Apparent total body clearance of drug calculated after extra-vascular
administration
CRF
Case Report Form
CSR
Clinical Study Report
CRU
Clinical Research Unit
CV
Coefficient of variation
EC
Early Clinical 
ECG
Electrocardiogram
e.g.
For example (Latin: exempli gratia)
iAUC
Invremental AUC
ICH
International Council on Harmonisation
LS
Least square
MedDRA
Medical Dictionary for Regulatory Activities
MRE
Magnetic resonance elastography
MTT
Meal tolerance test 
NA
Not applicable
PD
Pharmacodynamic
QW
Once weekly
SAP
Statistical Analysis Plan
SD
Standard deviation 
SOP
Standard Operating Procedure
TBL
Total bilirubin


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Statistical Analysis Plan 
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Covance Clinical Study No. 8370035
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T2D
Type 2 diabetes mellitus
TFLs
Tables, Figures, and Listings
ULN
Upper limit of normal
VAS
Visual analogue scale
WHO
World Health Organization


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Statistical Analysis Plan 
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3. INTRODUCTION
This SAP has been developed after review of the Clinical Study Protocol (final version dated 12 
July 2017).
This SAP describes the planned analysis of the safety, tolerability and pharmacodynamic (PD) 
data from this study. A detailed description of the planned TFLs to be presented in the clinical 
study report (CSR) is provided in the accompanying TFL shell document.
The intent of this document is to provide guidance for the statistical and PD analyses of data. In 
general, the analyses are based on information from the protocol, unless they have been modified 
by agreement between Eli Lilly and Company and Covance Early Clinical (EC) Biometrics. A 
limited amount of information concerning this study (e.g., objectives, study design) is given to 
help the reader’s interpretation. This SAP must be signed off prior to first patient administration
for this study. When the SAP and TFL shells are agreed upon and finalized, they will serve as 
the template for this study’s CSR.
This SAP supersedes the statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed and 
will be identified in the CSR. Any substantial deviations from this SAP will be agreed upon 
between Eli Lilly and Company and Covance EC Biometrics and identified in the CSR. Any 
minor deviations from the TFLs may not be documented in the CSR.
This SAP is written with consideration of the recommendations outlined in the International 
Council on Harmonisation (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials1 and the ICH E3 Guideline entitled Guidance for Industry: Structure 
and Content of Clinical Study Reports2.
4. STUDY OBJECTIVES
4.1
Primary Objective
The primary objective of this study is 

To evaluate glucodynamic effects of dulaglutide 0.75 mg compared with placebo in area 
under the glucose concentration versus time curve from 0 to 4 hours (glucose 
AUC[0-4h]) at 4 weeks in Japanese patients with type 2 diabetes mellitus (T2D).
4.2
Secondary Objectives
The secondary objectives of this study are:

To evaluate PD effects of dulaglutide 0.75 mg compared with placebo at 4 weeks.

To evaluate safety and tolerability of dulaglutide 0.75 mg for 4 weeks.


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Statistical Analysis Plan 
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4.3
Tertiary/Exploratory Objectives
The exploratory objectives are:

To evaluate daily glucose variability.

To evaluate satiety after standardized test meal.
5. STUDY DESIGN
This study is a Phase 4, single-center, randomized, cross-over, single-blind, placebo-controlled 
study to evaluate glucodynamic effects of dulaglutide after a standardized test meal in Japanese 
patients with T2D.
The study includes a 10- to 28-day screening period, a 4-week treatment period (Period 1), a 4-
to 6-week washout period, and a 4-week treatment period (Period 2).
Screening tests will be performed at Visit 1. After confirming eligibility, the patient will be
randomized in a 1:1 ratio to dulaglutide 0.75 mg or placebo treatment in Period 1.
Meal tolerance test (MTT) will be performed at baseline, 1, 2, and 4 weeks for each period. Time 
points for blood sampling will be 0, 30, 60, 90, 120, 180, and 240 minutes after the start of 
standardized test meal. Satiety will be also assessed at 0, 60, 120, 180, and 240 minutes after the 
start of standardized test meal. After completion of Period 1, all patients must have a 4- to 6-
week washout period, and then will start Period 2 on the opposite treatment (patients taking 
dulaglutide will be switched to placebo and patients taking placebo will be switched to 
dulaglutide).
This is a single-blind study, and the treatment assignments will be blinded to patients until study
completion.
Figure 1 illustrates the study design.


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Abbreviations: CGM = continuous glucose monitoring; dula = dulaglutide; n = number of patients.
Figure 1. General Study Design
6. TREATMENTS
The following is a list of the study treatment abbreviations that will be used in the TFLs.
Study Treatment Name
Treatment order in TFL
Placebo QW
1
0.75 mg dulaglutide QW
2
QW = once weekly
7. SAMPLE SIZE JUSTIFICATION
Up to 14 patients may be entered to randomize 12 patients and complete at least 11 patients. 
Patients will be randomized in a 1:1 ratio to one of two sequences. Assuming one dropout, the 
sample size of 11 patients would provide 93% power to demonstrate superiority of dulaglutide to 
placebo. This computation assumes the true treatment difference in glucose AUC(0-4h) is 190 
mg*hr/dL, a common standard deviation of 140 mg*hr/dL, intra-patient correlation of 0.3, and a 
one-sided significance level of 0.025.
Patients who are randomized but do not complete study treatment may be replaced at the 
discretion of the investigator and Lilly clinical pharmacologist.


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Statistical Analysis Plan 
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8. DEFINITION OF ANALYSIS POPULATIONS
The “Safety” population will consist of all patients who received at least one dose of study drug 
(dulaglutide or placebo), and have at least one postdose safety assessment.
The “Pharmacodynamic” population will consist of all patients who received at least one dose of 
study drug (dulaglutide or placebo), and have evaluable pharmacodynamic data.
All protocol deviations that occur during the study will be considered for their severity/impact 
and will be taken into consideration when patients are assigned to analysis populations.
9. STATISTICAL METHODOLOGY
9.1
General
Data listings will be provided for all data that is databased. Summary statistics and statistical 
analysis will only be presented for data where detailed in this SAP. For continuous data, 
summary statistics will include the arithmetic mean, arithmetic standard deviation (SD), median, 
min, max and N; for log-normal data the geometric mean and geometric coefficient of variation 
(CV%) will also be presented. For categorical data, frequency count and percentages will be 
presented. Data listings will be provided for all patients up to the point of withdrawal, with any 
patients excluded from the relevant population highlighted. Summary statistics and statistical 
analyses will generally only be performed for patients included in the relevant analysis 
population. For the calculation of summary statistics and statistical analysis, unrounded data will 
be used. 
Mean change from baseline is the mean of all individual patients’ change from baseline values. 
Each individual change from baseline will be calculated by subtracting the individual patient’s 
baseline value from the value at the timepoint. The individual patient’s change from baseline 
values will be used to calculate the mean change from baseline using a SAS procedure such as 
Proc Univariate.
Data analysis will be performed using SAS® Version 9.3 or greater.
9.2
Demographics and Patient Disposition
Patient disposition will be listed. The demographic variables age, sex, race, ethnicity, body 
weight, height, body mass index, duration of diabetes, screening HbA1c and fasting blood 
glucose will be summarized and listed.


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Statistical Analysis Plan 
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9.3
Pharmacodynamic Assessment
9.3.1
Pharmacodynamic Analysis
The baseline for all PD parameters is defined as the premeal value on Day 1 for the relevant 
period.        
Primary Measure
The primary measure of PD is the change from baseline in glucose AUC(0-4h) at 4 weeks.
Secondary Measures
The following secondary measures of PD will be evaluated:

The change from baseline in fasting blood glucose at 1, 2, and 4 weeks

The change from baseline in postprandial blood glucose (30, 60, 90, 120, 180, and
240 minutes) at 1, 2, and 4 weeks

The change from baseline in glucose AUC(0-4h) at 1 and 2 weeks

The change from baseline in insulin (30, 60, 90, 120, 180, and 240 minutes) at 1, 2,
and 4 weeks

The change from baseline in insulin AUC(0-4h) at 1, 2, and 4 weeks

The change from baseline in C-peptide (30, 60, 90, 120, 180, and 240 minutes) at 1, 2,
and 4 weeks

The change from baseline in C-peptide AUC(0-4h) at 1, 2, and 4 weeks

The change from baseline in glucagon (30, 60, 90, 120, 180, and 240 minutes) at 1, 2,
and 4 weeks

The change from baseline in glucagon AUC(0-4h) at 1, 2, and 4 weeks

The change from baseline in triglyceride (30, 60, 90, 120, 180, and 240 minutes) at 1,
2, and 4 weeks

The change from baseline in triglyceride AUC(0-4h) at 1, 2, and 4 weeks
PD AUCs will be calculated for glucose, insulin, glucagon, c-peptide, and triglyceride data 
following the standardized test meal at Weeks 0, 1, 2, and 4. The AUC(0-4h) will be calculated 
using the linear-trapezoidal method and actual times. This analysis will be performed for both 
original data and adjusted data with the predose value at each period, i.e. incremental AUC 
(iAUC). The parameters AUC(0-1h), AUC(0-2h), and AUC(0-3h) will also be calculated for 
glucose, insulin, C-peptide, glucagon and triglyceride together with the corresponding iAUCs.
9.3.2
Pharmacodynamic Statistical Methodology
All PD parameters will be listed and summarized by treatment group and week.  Individual 
observed and changes from baseline in glucose, insulin, glucagon, C-peptide, and triglyceride 
concentrations will be listed and summarized and their mean time profiles will be plotted by 
treatment group together with changes from baseline.
PD AUCs and iAUCs on Weeks 0, 1, 2, and 4 will be analyzed using a mixed-effects linear 
model for glucose, insulin, glucagon, C-peptide, and triglyceride . The model will include 


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Statistical Analysis Plan 
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Covance Clinical Study No. 8370035
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treatment, sequence, period, week and treatment-by-week interaction as fixed effects, baseline as 
a covariate and patient as random effect. 
The least squares means and the 95% CIs by treatment group will be tabulated and plotted.
Comparisons between dulaglutide and placebo will be performed. Difference of least squares
means of dulaglutide to placebo, and the 95% CIs, will be tabulated. Example SAS code is given 
below:
proc mixed data=pd;
class patient treatment sequence period week;
model pd = baseline treatment sequence period week treatment*week / ddfm=kr;
repeated week(treatment) / subject=patient type=un;
lsmeans treatment*week / pdiff alpha=0.05;
run;
The repeated patient effect models the within-patient errors using an unstructured variance-
covariance matrix. If the analysis fails to converge, the following variance-covariance matrix 
will be used (in order) until one converges:
1. compound symmetry,
2. banded, and then
3. first-order autoregressive.
Continuous plasma glucose monitoring (CGM)
For the CGM data, parameters will be derived from the raw data collected through Day -1 to Day 
6 (7 days),  of CGM device use by patient and treatment.
The following notation will be used in the definition:
n represents the number of time points within a day
i represents a time point within a day
m represents a day
Within-day glucose SD: 
1
n
)
n
BG
(BG
SD
2
n
1
i
i
n
1
i
i
m





















Final, 25 October 2017
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Statistical Analysis Plan 
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Mean amplitude of glycemic excursions (MAGE):  
this parameter is calculated based on the arithmetic mean of differences between consecutive 
peaks and nadirs of differences greater than one SD of mean glycemia.  Mean of the differences 
between consecutive peaks and nadirs in BG that meet qualifying criteria
where,
xl = the low point in consecutive BG time points for the Mth day (nadir)
xl-h = the high point in consecutive BG time points for the Mth day (peak)
p = the number of qualifying differences:  (BGl - BGl-h) ≥ 1 SD(daily BG values) 
and that follow the direction of the first qualifying difference within the BG time 
points for the Mth day
Daily average, daily standard deviation, and daily MAGE from glucose data will be summarized. 
Individual (by patient) and mean by treatment of glucose data will be plotted over the days.
9.4
Safety and Tolerability Assessments
9.4.1
Adverse events
Where changes in severity are recorded in the Case Report Form (CRF), each separate severity 
of the adverse event (AE) will be reported in the listings, only the most severe will be used in the 
summary tables. A pre-existing condition is defined as an AE that starts before the patient has 
provided written informed consent and is ongoing at consent. A non-treatment emergent AE is 
defined as an AE which starts after informed consent but prior to the first dose. A treatment-
emergent AE is defined as an AE which occurs postdose or which is present prior to the first 
dose and becomes more severe postdose.
All AEs will be listed.  Treatment-emergent AEs will be summarized by treatment, severity and 
relationship to the study drug. The frequency (the number of adverse events, the number of 
patients experiencing an adverse event and the percentage of patients experiencing an adverse 
event) of treatment-emergent adverse events will be summarized by treatment, Medical 
Dictionary for Regulatory Activities (MedDRA) version 20.0 system organ class and preferred 
term. The summary and frequency adverse event tables will be presented for all causalities and 
those considered related to the study drug. Any serious adverse events will be tabulated.
9.4.2
Concomitant medication
Concomitant medication will be coded using the WHO drug dictionary (Version March 2017 
Enhanced Dictionary Version B2 Format). Concomitant medication will be listed.
p
BG
BG
MAGE
p
1
l
h
l
l
m







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Statistical Analysis Plan 
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9.4.3
Clinical laboratory parameters
eGFR will be calculated as:
GFR(male)=194*Scr-1.094*age-0.287
GFR(female)=GFR(male)*0.739
All clinical chemistry, hematology, urinalysis, urine albumin/creatinine ratio (UACR), eGFR, 
HbA1c and endocrinology data will be listed. Additionally clinical chemistry, hematology, 
urinalysis, urine albumin/creatinine ratio (UACR), eGFR, HbA1c and endocrinology data
outside the reference ranges will be listed.
Values for any clinical chemistry, hematology, urinalysis, urine albumin/creatinine ratio 
(UACR), eGFR, HbA1c and endocrinology values outside the reference ranges will be flagged 
on the individual patient data listings.
9.4.4
Vital signs
Where two or more repeat measurements are performed for vital signs, the median of the original 
and the repeat values will be used in all subsequent calculations. Where only one repeat 
measurement is performed for vital signs, the repeat value will be used in all subsequent 
calculations.
Vital signs data will be summarized by treatment together with changes from baseline, where 
baseline is defined as Day 1 predose within each period. Figures of mean vital signs and mean 
changes from baseline profiles by treatment will be presented by treatment. Furthermore, values 
for individual patients will be listed.
Changes from baseline (predose) will be calculated for vitals signs. 
9.4.5
Satiety after Standardized Test Meal
A visual analogue scale (VAS) test will be performed to measure perception of satiety (full and 
hungry). Data will be summarized by treatment and listed along with mean plots showing the 
profiles for fullness and hunger by treatment and time.
9.4.6
Hypoglycemic Episodes
Hypoglycemic episodes will be listed.
9.4.7
Hepatic Monitoring
If a patient experiences elevated alanine aminotransferase (ALT) ≥3× upper limit of normal 
(ULN), alkaline phosphatase (ALP) ≥2× ULN, or elevated total bilirubin (TBL) ≥2× ULN, liver 
tests will be performed to confirm the abnormality.


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Statistical Analysis Plan 
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If a patient has a liver abnormality then they will be included in the listings and summaries 
detailed below.
The patients’ liver disease history and associated person liver disease history data will be 
listed. Any concomitant medication of acetaminophen/paracetamol will be listed. Results from 
any hepatic monitoring procedures, such as a magnetic resonance elastography (MRE) scan, and 
a biopsy assessment will be listed, if performed.
Hepatic risk factor assessment data will be listed. Liver related signs and symptoms data will be 
summarized in a frequency table by treatment and will also be listed.  Alcohol and recreational 
drug use data will also be listed.
All hepatic chemistry, hematology, coagulation, and serology data will be listed. Values outside 
the reference ranges will be flagged on the individual patient data listings.
9.4.8
Other assessments
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analyzed.
9.4.9
Safety and Tolerability Statistical Methodology
No inferential statistical analyses are planned.
10.
INTERIM ANALYSES
No interim statistical analyses are planned.
11.
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES
There were no changes from the protocol specified statistical analyses.
12.
REFERENCES
1. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9), 5 February 1998.
2. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), 30 November 1995.
13.
DATA PRESENTATION
13.1
Derived Parameters
Individual derived parameters and appropriate summary statistics will be reported to three 
significant figures. Observed concentration data should be reported as received. Observed time 
data should be reported as received. N and percentage values should be reported as whole 


Final, 25 October 2017
             Page 14 of 14
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8370035
Sponsor Reference H9X-JE-GBGK
numbers. Median values should be treated as an observed parameter and reported to the same 
number of decimal places as minimum and maximum values.
13.2
Missing Data
Missing data will not be displayed in listings.
13.3
Insufficient Data for Presentation
Some of the TFLs may not have sufficient numbers of patients or data for presentation. If this 
occurs, the blank TFL shell will be presented with a message printed in the centre of the table, 
such as, “No serious adverse events occurred for this study.”