Conditions: Healthy
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 27
Healthy volunteers: yes

Brief summary:
The purpose of this study is to evaluate a new formulation of dulaglutide (study drug) administered under the skin as one injection using a single dose pen compared to three injections using a pre filled syringe.

This study will evaluate how much of the study drug enters the body and how long it takes the body to get rid of it. Information about any side effects that may occur will also be collected.

The study will last about 84 days, including screening and will require overnight stays in the clinical research unit (CRU).

Detailed description:

Arms:
arm 1: Dulaglutide 4.5 mg administered subcutaneously (SC) in 3 prefilled syringes (PFS) in one of two study periods arm 2: Dulaglutide 4.5 mg administered SC in 1 single dose pen (SDP) in one of two study periods

Interventions: intervention 1: Dulaglutide (Reference) intervention 2: Dulaglutide (Test)
Intervention descriptions: intervention 1: Administered SC intervention 2: Administered SC

Protocol document:
Prot_001.pdf: 
H9X-MC-GBGM Protocol 
Relative Bioavailability of an Investigational Single Dose of Dulaglutide after Subcutaneous 
Administration by a Single Dose Pen Compared to a Prefilled Syringe in Healthy Subjects 
 
NCT03363906 
 
Approval Date: 24-Sep-2017 
 
 
 


H9X-MC-GBGM Clinical Pharmacology Protocol
Page 1
Dulaglutide (LY2189265)
Protocol H9X-MC-GBGM
Relative Bioavailability of an Investigational Single Dose of 
Dulaglutide after Subcutaneous Administration by a Single 
Dose Pen Compared to a Prefilled Syringe in Healthy 
Subjects
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 confidential information exempt from public disclosure.  Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release.  In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
Dulaglutide (LY2189265)
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Clinical Pharmacology Protocol Electronically Signed and Approved by Lilly on date 
provided below.
Approval Date: 24-Sep-2017 GMT


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Dulaglutide (LY2189265)
Table of Contents
Relative Bioavailability of an Investigational Single Dose of 
Dulaglutide after Subcutaneous Administration by a Single 
Dose Pen Compared to a Prefilled Syringe in Healthy 
Subjects
Section
Page
Protocol H9X-MC-GBGM Relative Bioavailability of an Investigational 
Single Dose of Dulaglutide after Subcutaneous Administration by a 
Single Dose Pen Compared to a Prefilled Syringe in Healthy Subjects ................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis................................................................................................................7
2.
Schedule of Activities .........................................................................................................9
3.
Introduction ......................................................................................................................12
3.1.
Study Rationale............................................................................................................12
3.2.
Background..................................................................................................................12
3.3.
Benefit/Risk Assessment..............................................................................................12
4.
Objectives and Endpoints..................................................................................................14
5.
Study Design.....................................................................................................................15
5.1.
Overall Design .............................................................................................................15
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.
Study Population...............................................................................................................17
6.1.
Inclusion Criteria..........................................................................................................17
6.2.
Exclusion Criteria ........................................................................................................19
6.2.1.
Rationale for Exclusion of Certain Study Candidates ...........................................21
6.3.
Lifestyle and/or Dietary Requirements .........................................................................21
6.3.1.
Meals and Dietary Restrictions.............................................................................21
6.3.2.
Caffeine, Alcohol, and Tobacco ...........................................................................21
6.3.3.
Activity................................................................................................................21
6.4.
Screen Failures.............................................................................................................21
7.
Treatment..........................................................................................................................22
7.1.
Treatment Administered...............................................................................................22
7.1.1.
Packaging and Labeling .......................................................................................22


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Dulaglutide (LY2189265)
7.1.2.
Drug Delivery Devices.........................................................................................23
7.2.
Method of Treatment Assignment ................................................................................23
7.2.1.
Selection and Timing of Doses.............................................................................23
7.3.
Blinding .......................................................................................................................23
7.4.
Dose Modification........................................................................................................23
7.4.1.
Special Treatment Considerations ........................................................................23
7.5.
Preparation/Handling/Storage/Accountability...............................................................24
7.6.
Treatment Compliance .................................................................................................24
7.7.
Concomitant Therapy...................................................................................................24
7.8.
Treatment after the End of the Study............................................................................24
8.
Discontinuation Criteria ....................................................................................................25
8.1.
Discontinuation from Study Treatment.........................................................................25
8.1.1.
Discontinuation of Inadvertently Enrolled Subjects..............................................25
8.2.
Discontinuation from the Study....................................................................................25
8.3.
Subjects Lost to Follow-up...........................................................................................26
9.
Study Assessments and Procedures ...................................................................................27
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.
Complaint Handling.............................................................................................29
9.3.
Treatment of Overdose.................................................................................................29
9.4.
Safety...........................................................................................................................29
9.4.1.
Laboratory Tests ..................................................................................................29
9.4.1.1.
Amylase and Lipase Tests ..............................................................................29
9.4.2.
Vital Signs ...........................................................................................................29
9.4.3.
Electrocardiograms ..............................................................................................30
9.4.4.
Physical Examination...........................................................................................30
9.4.5.
Body Weight........................................................................................................30
9.4.6.
Injection Site Reactions........................................................................................30
9.4.7.
Safety Monitoring ................................................................................................31
9.4.7.1.
Hepatic Safety................................................................................................31
9.5.
Pharmacokinetics .........................................................................................................31
9.5.1.
Bioanalysis...........................................................................................................31
9.6.
Pharmacodynamics ......................................................................................................32
9.6.1.
Immunogenicity Assessments ..............................................................................32
9.7.
Genetics .......................................................................................................................32
9.8.
Biomarkers...................................................................................................................33


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Dulaglutide (LY2189265)
9.9.
Health Economics ........................................................................................................33
10.
Statistical Considerations and Data Analysis.....................................................................34
10.1. Sample Size Determination ..........................................................................................34
10.2. Populations for Analyses..............................................................................................34
10.2.1.
Study Participant Disposition ...............................................................................34
10.2.2.
Study Participant Characteristics ..........................................................................34
10.3. Statistical Analyses ......................................................................................................34
10.3.1.
Safety Analyses....................................................................................................34
10.3.1.1.
Clinical Evaluation of Safety..........................................................................34
10.3.1.2.
Statistical Evaluation of Safety.......................................................................35
10.3.2.
Pharmacokinetic Analyses....................................................................................35
10.3.2.1.
Pharmacokinetic Parameter Estimation...........................................................35
10.3.2.2.
Pharmacokinetic Statistical Inference .............................................................35
10.3.3.
Evaluation of Immunogenicity .............................................................................36
10.3.4.
Interim Analyses..................................................................................................36
11.
References ........................................................................................................................37


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Dulaglutide (LY2189265)
List of Tables
Table
Page
Table GBGM.1.
Objectives and Endpoints .......................................................................14
Table GBGM.2.
Treatments Administered........................................................................22
Table GBGM.3.
Treatment Sequences..............................................................................23


H9X-MC-GBGM Clinical Pharmacology Protocol
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Dulaglutide (LY2189265)
List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................38
Appendix 2.
Clinical Laboratory Tests........................................................................41
Appendix 3.
Study Governance, Regulatory and Ethical Considerations.....................42
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............45
Appendix 5.
Blood Sampling Summary......................................................................46
Appendix 6.
Pancreatic Monitoring ............................................................................47


H9X-MC-GBGM Clinical Pharmacology Protocol
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Dulaglutide (LY2189265)
1. Protocol Synopsis
Title of Study:
Relative Bioavailability of an Investigational Single Dose of Dulaglutide after Subcutaneous Administration by a
Single Dose Pen Compared to a Prefilled Syringe in Healthy Subjects
Rationale:  The current commercially used single dose pen (SDP) at the same injection volume (0.5 mL) and a new
higher dulaglutide concentration formulation will be used for dose delivery in future Phase 3 studies evaluating 
investigational dulaglutide doses that are higher than the currently approved 0.75- and 1.5-mg doses.
Study GBGM will evaluate the relative bioavailability of a 4.5-mg dulaglutide dose administered subcutaneously 
(SC) as a single SDP injection of the higher dulaglutide concentration (test) compared to the same dose administered 
as three 1.5-mg prefilled syringe (PFS) injections of the current commercial formulation (reference).
Objectives/Endpoints:
Objectives
Endpoints
Primary
To evaluate the relative bioavailability of a single dose 
of dulaglutide administered SC to healthy subjects as a 
single injection by SDP (test) compared to 3 injections 
by PFS (reference).
Pharmacokinetic parameters including area under the 
concentration versus time curve (AUC) and maximum 
observed drug concentration (Cmax) for dulaglutide 
administered by a SDP compared to PFS.
Secondary
To assess the tolerability of a single dose of dulaglutide 
administered SC to healthy subjects as a single 
injection by SDP compared to 3 injections by PFS.
Incidence of treatment-emergent adverse events (AEs).
Summary of Study Design:
Study H9X-MC-GBGM is a Phase 1, single-center, open-label, randomized, 2-period, crossover study in healthy 
subjects to evaluate the relative bioavailability of 4.5 mg dulaglutide administered SC as a single injection by SDP
(test) compared to 3 injections by PFS (reference).
Treatment Arms and Planned Duration for an Individual Subject:
Subjects will undergo a screening examination within 27 days prior to enrollment.  For Periods 1 and 2, on the 
morning of Day 1 of each period, subjects will receive a single SC dose of dulaglutide administered according to 
their assigned treatment sequence following an overnight fast of approximately 8 hours.  At a minimum, subjects 
will remain at the clinical research unit (CRU) until collection of the 168-hour (Day 8) pharmacokinetic (PK)
sample.  There will be a washout period of at least 28 days between doses in Periods 1 and 2.  Each subject will be 
required to return to the CRU for a follow-up visit 28±3 days after the last dulaglutide dose.  The total duration for 
each subject (from screening through the follow-up visit) is approximately 84 days.
Number of Subjects:
Approximately 24 subjects will be enrolled in order that at least 18 subjects complete the study.


H9X-MC-GBGM Clinical Pharmacology Protocol
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Dulaglutide (LY2189265)
Statistical Analysis:
Pharmacokinetic:  The primary PK parameters to be estimated for dulaglutide will be Cmax and AUC from time zero 
to infinity (AUC[0-∞]). Other noncompartmental parameters, such as AUC from time zero to 168 hours 
(AUC[0-168h]), AUC from time zero to 336 hours (AUC[0-336h]), time to Cmax (tmax), apparent terminal 
elimination half-life, apparent total body clearance of drug, apparent volume of distribution, and AUC from time 
zero to time t, where t is the last time point with a measurable concentration (AUC[0-tlast]), may be reported.
The PK parameter estimates will be evaluated to determine the relative bioavailability of dulaglutide administered 
SC by SDP (test) compared to dulaglutide administered by PFS (reference).  The PK parameters will be summarized 
using descriptive statistics by treatment. Log-transformed Cmax and AUC(0-∞) (primary parameters) and 
AUC(0-168h) and AUC(0-336h) (secondary parameters) will be evaluated in a linear mixed-effects analysis of 
variance model with fixed effects for treatment (SDP or PFS), period, and sequence and a random effect for subject 
within sequence.  The ratios of least squares geometric means of SDP compared to PFS, as well as the 
corresponding 90% confidence intervals (CIs), will be estimated and reported.  The tmax will be analyzed 
nonparametrically using the Wilcoxon ranked sum test.  Estimates of the median difference and the corresponding 
90% CIs will be calculated.  Additional analysis may be conducted if deemed appropriate.
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.  The 
number of investigational product-related serious AEs will be reported.  Safety parameters that will be assessed 
include safety clinical laboratory parameters and vital signs.  The parameters will be listed and summarized using 
standard descriptive statistics.  The change from baseline (Day 1 predose of each period) in vital signs will be 
analyzed and summarized.  The change from baseline (Day -1 of each period) in amylase and lipase will also be 
summarized.  Electrocardiograms and physical examinations will be performed for safety monitoring purposes and 
will not be presented.  Additional analysis will be performed if warranted upon review of the data.


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Dulaglutide (LY2189265)
2. Schedule of Activities


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Dulaglutide (LY2189265)
Study Schedule Protocol H9X-MC-GBGM
Screening
Periods 1 and 2
ET/Follow-up
Comments
Procedure
Days -28 
to -2
Day 
-1
Day
1
Day 
2
Day 
3
Day 
4
Day 
5
Day 
6
Day 
7
Day 
8
Day 
15
28 ±3 days
after last 
dulaglutide 
dose
Informed Consent
X
Subject 
Admission to 
CRU
X
Subject Discharge 
from CRU
X
Outpatient Visit
X
X
X
Investigational 
Product 
Administration
X
There is a minimum of 28 days washout 
period between doses for Period 1 and 
Period 2.  
Medical History
X
Height
X
Weight
X
X
X
X
Vital Signs 
(supine) (hours)
X
X
Predose
24
48
X
Time points may be added for each study 
period, if warranted and agreed upon between 
Lilly and the investigator.
Clinical 
Laboratory Tests
X
X
X
X
See Appendix 2, Clinical Laboratory Tests, 
for details.  
Adverse Event
X
X
X
X
X
X
X
X
X
X
X
X
Injection Site 
Reaction 
Assessment
(hours)
Predose, 
0, 6, 12
24
X
X
X
X
0-hour assessment should be performed 
within 5 minutes after subcutaneous injection.  
Additional assessments may be performed if 
deemed necessary by the investigator.
PK Samples
(hours)
Predose
24
48
72
96
120
144
168
336
X
Sampling times are relative to the time of 
study treatment administration (0 hour).  
Sampling times are given as targets to be 
achieved within reasonable limits.  If a subject 
withdraws from the study prior to completion 
of scheduled PK sampling for a given period, 
every effort will be taken to draw an 
unscheduled blood sample for PK assessment.  
This will not be required if a sample has 
already been taken within the previous 
24 hours.  For ET, a PK sample can be taken 
at any time during the visit timed close to the 
immunogenicity sample.


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Dulaglutide (LY2189265)
Screening
Periods 1 and 2
ET/Follow-up
Comments
Procedure
Days -28 
to -2
Day 
-1
Day
1
Day 
2
Day 
3
Day 
4
Day 
5
Day 
6
Day 
7
Day 
8
Day 
15
28 ±3 days
after last 
dulaglutide 
dose
Pregnancy Test 
X
X
X
Females only.  Serum pregnancy test will be 
performed at screening.  Urine pregnancy test 
will be performed for women of childbearing 
potential at Day -1 for each period and at 
ET/Follow-up.
Physical Exam
X
X
X
After screening, medical assessment only 
performed to include medical review and 
targeted examination, as appropriate.
12-lead ECG
X
X
Single 12-lead ECG will be collected.  ECGs 
must be recorded before collecting any blood 
samples.  Subjects must be supine for at least 
5 minutes before ECG collection and remain 
supine but awake during ECG collection.
Genetic Sample
X
Single sample for pharmacogenetic analysis 
taken prior to dosing on Day 1 in Period 1 
only.
Immunogenicity 
Samples
Predose
X
All samples for immunogenicity should be 
taken predose, when applicable and possible.
Abbreviations:  CRU = clinical research unit; ECG = electrocardiogram; ET = early termination; PK = pharmacokinetic(s).
Note:  If multiple procedures take place at the same time point, the following order of the procedures should be used: ECG, vital signs, and venipuncture.


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Dulaglutide (LY2189265)
3. Introduction
3.1.
Study Rationale
Presently there is an ongoing Phase 2 study (Protocol H9X-MC-GBGJ / Double-Blind, 
Placebo-Controlled, 18-Week Trial of Investigational Dulaglutide Doses versus Placebo in 
Patients with Type 2 Diabetes on Metformin Monotherapy) designed to provide initial safety and 
efficacy data for 2 investigational dulaglutide doses (3.0 mg and 4.5 mg) that are higher than the 
currently approved 0.75- and 1.5-mg doses; these higher doses could provide data that show 
improved clinical benefits, including greater reduction in hemoglobin A1c (HbA1c) and greater 
body weight reduction, with an acceptable safety profile.  Prefilled syringes (PFSs) are being
used to administer dulaglutide doses in this Phase 2 study.  
To confirm applicability of the GBGJ safety and efficacy data to future Phase 3 studies where a 
single dose pen (SDP) and new formulation (Table GBGM.2) will be used, Study GBGM will 
evaluate the relative bioavailability of a 4.5-mg dulaglutide dose administered subcutaneously 
(SC) as a single SDP injection of the new higher dulaglutide concentration (test) compared to the 
same dose administered as three 1.5-mg PFS injections of the current commercial formulation 
(reference).  Details regarding the new formulation are presented in Module 3 of the CTA.
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 type 2 
diabetes (T2D).
Dulaglutide received regulatory approval for the treatment of T2D in the United States on 
18 September 2014, and in the European Union on 21 November 2014 for use as 0.75- and 
1.5-mg doses administered by SDP or PFS (Trulicity® United States Prescribing Information
[USPI] 2017; Trulicity® Summary of Product Characteristics [SmPC] 2016).  
3.3.
Benefit/Risk Assessment
The proposed dose of dulaglutide to be used in this study is 4.5 mg.
Dulaglutide is currently approved for use as 0.75- and 1.5-mg doses.  A higher dulaglutide dose
of 4.5 mg in healthy subjects was chosen for this study (GBGM) based on simulations which 
included data collected in Studies GBCD and GBCF (Barrington et al. 2011, Skrivanek et al. 
2014).
Study GBCD was a multiple ascending dose study where dulaglutide doses up to 8 mg were
administered weekly for 5 weeks to patients with T2D. GLP-1-related gastrointestinal effects 
(nausea, vomiting, and diarrhea) were of mild to moderate in intensity over the dose range of 1 to 
8 mg; therefore, the 8-mg dose was considered to be a tolerable dose. Robust glucodynamic 
activity consistent with sustained GLP-1 pharmacology was observed over the dose range 0.3 to 
8 mg dulaglutide. Reductions in fasting and postprandial glucose, and glucose-dependent insulin 


H9X-MC-GBGM Clinical Pharmacology Protocol
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Dulaglutide (LY2189265)
secretion were demonstrated after 5 weeks of once-weekly SC dulaglutide administration.  Study 
GBCF was a Phase 2/3 study in patients with T2D in which dulaglutide doses up to 3 mg were 
administered weekly, with a limited number of patients at the highest dose of 3 mg. The 
benefit/risk profile favored the 1.5-mg dulaglutide dose for further development based on a 
predefined clinical utility index.
The results of simulations including data from Studies GBCD and GBCF suggest the 4.5-mg
dose may provide a clinically relevant improvement in Hb1Ac and body weight reduction in 
comparison to the 1.5-mg dose after 26 weeks.
Nonclinical studies and clinical studies in healthy subjects and in patients with T2D support that 
dulaglutide may be safely administered to humans with careful monitoring for potential adverse 
effects.  Dulaglutide-related changes in both rat and monkey chronic repeat-dose toxicity studies 
(6 months duration in rats; 9 months duration in monkeys) were generally consistent with, or 
secondary to, GLP-1 pharmacology.  The primary effects of dulaglutide administration to rats 
and monkeys were dose dependent decreases in food consumption with secondary decreases in 
body weight gain.  None of these effects were adverse to the health of the animals.  No 
dose-limiting target organ toxicity occurred in either species.  The no-observed-adverse-effect 
levels (NOAELs) for target organ toxicity in chronic repeat-dose toxicity studies of dulaglutide 
in rats (6 months) and monkeys (9 months) were 16.3 mg/kg and 8.15 mg/kg, respectively.
Relative to the maximum human dose in Study GBGJ (4.5 mg/week), the predicted area under 
the concentration versus time curve (AUC) exposure multiples at the NOAELs in rats and 
monkeys are 55- and 162-fold, respectively.  Similar to other GLP-1R agonists, fetal skeletal 
effects were observed in the embryo-fetal development studies of dulaglutide in pregnant rats 
and rabbits.  The fetal skeletal effects occurred at 15- and 4-fold the 4.5-mg/week dulaglutide 
dose in pregnant rats and rabbits, respectively, based on AUC.
There is no anticipated therapeutic benefit for the subjects in this study.
More information about the known and expected benefits, risks, serious adverse events (SAEs),
and reasonably anticipated adverse events (AEs) of dulaglutide are to be found in the 
Investigator’s Brochure (IB).
In addition, detailed information about the known and expected benefits and risks of dulaglutide 
may be found in the Trulicity USPI (2017) and SmPC (2016).


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Dulaglutide (LY2189265)
4. Objectives and Endpoints
Table GBGM.1 shows the objectives and endpoints of the study.
Table GBGM.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To evaluate the relative bioavailability of a single dose 
of dulaglutide administered subcutaneously (SC) to 
healthy subjects as a single injection by single dose pen 
(SDP; test) compared to 3 injections by prefilled 
syringe (PFS; reference).
Pharmacokinetic parameters AUC and maximum 
observed drug concentration (Cmax) for dulaglutide 
administered by a SDP compared to PFS.
Secondary
To assess the tolerability of a single dose of dulaglutide 
administered SC to healthy subjects as a single 
injection by SDP compared to 3 injections by PFS.
Incidence of treatment-emergent adverse events.


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Dulaglutide (LY2189265)
5. Study Design
5.1.
Overall Design
Study GBGM is a Phase 1, single-center, open-label, randomized, 2-period, crossover study in 
healthy subjects to evaluate the relative bioavailability of 4.5 mg of a new formulation 
(Table GBGM.2) of dulaglutide administered SC as a single injection by SDP (test) compared to 
3 injections by PFS (reference).  Treatment sequences and randomization are described in 
Section 7.2.
Each subject will provide informed consent for study participation and will undergo a screening 
examination within 27 days prior to enrollment.
In each treatment period, subjects will be admitted to the clinical research unit (CRU) on Day -1.  
On the morning of Day 1, following an overnight fast of approximately 8 hours, subjects will 
receive a single SC dose of dulaglutide administered according to their assigned treatment
sequence.  Blood samples will be collected predose and up to 336 hours postdose to measure 
dulaglutide concentrations.  At a minimum, subjects will remain at the CRU until collection of 
the 168-hour (Day 8) pharmacokinetic (PK) sample in each period.
There will be a washout period of at least 28 days between doses in Periods 1 and 2. Each 
subject will be required to return to the CRU for a follow-up visit 28 ±3 days after the last 
dulaglutide dose.  The total duration for each subject (from screening through the follow-up 
visit) is approximately 84 days.
Safety and tolerability will be assessed throughout the study by means of vital sign measurement, 
physical examination, clinical laboratory tests, electrocardiograms (ECGs), and AE recording.
Study governance considerations are described in detail in Appendix 3.
5.2.
Number of Participants
Approximately 24 subjects may be enrolled so that at least 18 evaluable subjects complete the 
study.  For purposes of this study, a subject completes the study when all scheduled procedures 
shown in the Schedule of Activities (Section 2) 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 subject.
5.4.
Scientific Rationale for Study Design
Conducting this study in healthy subjects mitigates the potential confounding effects of the 
disease state and concomitant medications in patients.
An open-label design is required, as subjects and staff administering the injections will be able to 
distinguish between the SDP and PFS, including number of injections. In order to minimize any 
potential period-effect, a randomized, 2-sequence, crossover design has been selected. Based on 
the apparent terminal elimination half-life (t1/2) of dulaglutide of approximately 5 days 


H9X-MC-GBGM Clinical Pharmacology Protocol
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Dulaglutide (LY2189265)
(Trulicity® USPI 2017), a washout period of at least 28 days between doses is considered 
sufficient not to impact the PK outcome of the second period.
Pharmacokinetic sampling up to 336 hours is sufficient to generate an evaluable PK profile for 
dulaglutide.  A single dose of dulaglutide will be administered in each period, as this is 
considered sufficient to evaluate the relative bioavailability of dulaglutide administered via the
2 devices (SDP versus PFS).
5.5.
Justification for Dose
The dose selected for this study (4.5 mg) is the highest dose for the Phase 2 study (GBGJ).  
Based on PK/pharmacodynamic model projections, doses higher than the currently approved 
0.75- and 1.5-mg doses that are included in Study GBGJ were identified based on their potential 
to yield greater HbA1c reductions and weight loss, with an acceptable safety and tolerability 
profile.  Based on predicted plasma exposures in patients with T2D receiving the highest 
investigational dulaglutide dose of 4.5 mg, the margins of safety (i.e., plasma exposure multiples 
at the NOAEL) in chronic toxicology studies in monkeys and rats were 162-fold and 55-fold, 
respectively.  Additional details are provided in Section 3.3.
Dulaglutide is approved for SC administration by SDP or PFS (Trulicity® USPI 2017; previously 
demonstrated to be bioequivalent). Therefore, this study will compare the PK of 2 formulations 
of dulaglutide administered by these 2 devices.  Safety and efficacy data using the commercial 
formulation and device will also be obtained in the planned Phase 3 trial (Study GBGL).


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Dulaglutide (LY2189265)
6. Study Population
Eligibility of subjects for the study will be based on the results of screening medical history, 
physical examination, vital signs, clinical laboratory tests, and ECG.
The nature of any conditions present at the time of the physical examination and any preexisting 
conditions will be documented.
Screening may occur up to 27 days prior to enrollment.  Subjects who are not enrolled within 
27 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
Subjects are eligible for inclusion in the study only if they meet all of the following criteria at 
screening and/or enrollment:
[1]
are overtly healthy males or females, as determined by medical history and 
physical examination
[1a] male subjects:
i.
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 1 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 subject 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.)
ii.
Men should refrain from sperm donation for the duration of the 
study and for 120 days after the last dose of study drug
iii.
Men who are in exclusively same sex relationships (when it is 
their preferred and usual lifestyle) are not required to use 
contraception


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Dulaglutide (LY2189265)
[1b] female subjects:
i.
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
ii.
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 2 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 1 highly effective method of contraception (such as 
combination oral contraceptives, implanted contraceptives, or 
intrauterine device) or a combination of 2 effective methods 
of contraception (such as male or female condoms with 
spermicide, diaphragms with spermicide, or cervical sponges) 
will be used.  The subject 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
iii.
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. post-menopausal – defined as
i. A woman at least 50 years of age with an intact uterus, 
not on hormone therapy, who has had either
1. cessation of menses for at least 1 year, or
2. at least 6 months of spontaneous amenorrhea 
with a follicle-stimulating hormone >40 
mIU/mL; or


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Dulaglutide (LY2189265)
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]
are at least 18 years old
[3]
have a body mass index (BMI) ≥23 kg/m2
[4]
have clinical laboratory test results within normal reference range for the 
population or investigative site, or results with acceptable deviations that are 
judged to be not clinically significant by the investigator
[5]
have venous access sufficient to allow for blood sampling as per the protocol
[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
Subjects 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 or are employees of a third-party involved in the study who 
require exclusion of their 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 any other study 
investigating dulaglutide within 3 months prior to screening
[13]
have known allergies to GLP-1-related compounds including dulaglutide, any 
components of the formulation, or history of significant atopy
[14]
have an abnormality in the 12-lead ECG that, in the opinion of the investigator, 
increases the risks associated with participating in the study


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Dulaglutide (LY2189265)
[15]
have an abnormal blood pressure and/or pulse rate as determined by the 
investigator
[16]
have a history or presence of cardiovascular, respiratory, hepatic, renal, 
endocrine, hematological, or neurological disorders capable of significantly 
altering the absorption, metabolism, or elimination of drugs; of constituting a risk 
when taking the investigational product; or of interfering with the interpretation of 
data
[17]
have a history or presence of pancreatitis (history of chronic pancreatitis or 
idiopathic acute pancreatitis) or gastrointestinal disorder (e.g., relevant esophageal 
reflux or gall bladder disease) or any gastrointestinal disease which impacts 
gastric emptying (e.g., gastric bypass surgery, pyloric stenosis, with the exception 
of appendectomy) or could be aggravated by GLP-1 analogs.  Subjects with 
dyslipidemia and subjects who had cholecystolithiasis (removal of gall stones) 
and/or cholecystectomy (removal of gall bladder) in the past, with no further 
sequelae, may be included in the study at the discretion of the screening physician
[18]
have family history of medullary thyroid cancer (MTC) or a genetic condition that 
predisposes to MTC
[19]
have known or ongoing psychiatric disorders considered clinically significant in 
the opinion of the investigator
[20]
regularly use known drugs of abuse and/or show positive findings on drug 
screening
[21]
show evidence of human immunodeficiency virus (HIV) infection and/or positive 
HIV antibodies
[22]
show evidence of hepatitis C and/or positive hepatitis C antibody
[23]
show evidence of hepatitis B and/or positive hepatitis B surface antigen
[24]
are women who are pregnant or lactating
[25]
have donated blood of more than 500 mL within 4 weeks prior to screening
[26]
have used or intend to use over-the-counter medication other than acetaminophen 
within 7 days prior to dosing or prescription medication (with the exception of 
vitamin/mineral supplements and/or hormone replacement therapy [HRT]) within 
14 days prior to dosing
[27]
have an average weekly alcohol intake that exceeds 21 units per week (males up 
to age 65) or 14 units per week (males over 65 and females), are unwilling to stop 
alcohol consumption from at least 48 hours prior to Check-in (Day -1) until 
discharge from the CRU in each period, or are unwilling to limit intake to a 
maximum of 2 units per day on all other days from screening through follow-up


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Dulaglutide (LY2189265)
(1 unit = 12 oz or 360 mL of beer; 5 oz or 150 mL of wine; 1.5 oz or 45 mL of 
distilled spirits)
[28]
smoke more than 10 cigarettes (or equivalent in nicotine) per day, and are 
unwilling to refrain from smoking on the day of dulaglutide administration or are 
unable to abide by CRU restrictions
[29]
in the opinion of the investigator or sponsor, are unsuitable for inclusion in the 
study
6.2.1. Rationale for Exclusion of Certain Study Candidates
Criteria [8] and [9] prevent conflict of interest in study participants. Criteria [10] through [29] 
exclude medical conditions, medication intolerance, concomitant medication use, and other items
that may confound the assessment of study endpoints.
6.3.
Lifestyle and/or Dietary Requirements
Throughout the study, subjects may undergo medical assessments and review of compliance with 
requirements before continuing in the study.  
6.3.1. Meals and Dietary Restrictions
Prior to dulaglutide dosing (Day 1 of Periods 1 and 2), subjects will be fasted for approximately
8 hours and a standard breakfast will be provided approximately 15 minutes after dosing.
6.3.2. Caffeine, Alcohol, and Tobacco
No alcohol will be allowed from at least 48 hours prior to admission (Day -1) until discharge, 
and alcohol intake will be limited to a maximum of 2 units/day on all other days from screening 
through the follow-up visit (1 unit = 12 oz or 360 mL of beer; 5 oz or 150 mL of wine; 1.5 oz or 
45 mL of distilled spirits).
Subjects will be questioned about their smoking habits at screening. Smoking will not be 
permitted on dosing days and subjects will abide by CRU restrictions.
6.3.3. Activity
Subjects should not undertake unaccustomed vigorous or prolonged exercise from screening 
through the post study follow-up visit.
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
re-screened.


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Dulaglutide (LY2189265)
7. Treatment
7.1.
Treatment Administered
On Day 1 of each period, subjects will receive a single dose of 4.5 mg dulaglutide administered 
SC as a single SDP injection or as 3 injections by PFS according to the randomization schedule.  
There will be a minimum 28-day washout period between doses. Table GBGM.2 shows the 
treatment regimens.
Doses will be administered into the SC tissue of the abdominal wall.  A separate Instructions for 
Use document will be provided by Lilly.  Where possible, the same member of staff should 
administer the injections to all subjects.  Prior to dulaglutide dosing, subjects will be fasted for 
approximately 8 hours and a standard breakfast will be provided approximately 15 minutes after 
dosing.
Table GBGM.2.
Treatments Administered
Treatment Name
LY2189265
LY2189265
Formulation and Presentation
Solution in a prefilled syringe
Solution in a single dose pena
Dose
3 x 1.5 mg (4.5 mg total dose)
1 x 4.5 mg (4.5 mg total dose)
Concentration
3.0 mg/mL
9.0 mg/mL
Volume per Injection
0.5 mL
0.5 mL
Number of Injections
3
1
Dosing Instructions
SC injection in abdomen
SC injection in abdomen
Abbreviations:  SC = subcutaneous.
a
Increased polysorbate 80 content to accommodate higher dulaglutide content.
The investigator or designee is responsible for:

explaining the correct use of the investigational product(s) to the site personnel 

verifying that instructions are followed properly

maintaining accurate records of investigational product dispensing and collection

returning all unused medication to Lilly or its designee at the end of the study
Note: In some cases, sites may destroy the material if, during the investigative site selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose of clinical materials. 
7.1.1. Packaging and Labeling
Dulaglutide will be supplied by Lilly as a 3.0-mg/mL solution in PFS (Trulicity® USPI 2017)
and as a 9.0-mg/mL solution in SDP. Both the PFS and the SDP should be stored refrigerated 
(2°C to 8°C) and allowed to warm to room temperature for at least 30 minutes (up to 24 hours) 
prior to use.
The investigational product will be labeled according to the country’s regulatory requirements.


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Dulaglutide (LY2189265)
7.1.2. Drug Delivery Devices
The manufactured medical devices provided for use in the study include a PFS containing 1.5 mg 
dulaglutide (0.5 mL at 3.0 mg/mL) and a SDP containing 4.5 mg dulaglutide (0.5 mL at 
9.0 mg/mL).
The medical devices will be labeled according to the country’s regulatory requirements.
7.2.
Method of Treatment Assignment
Eligible subjects will be randomized to 1 of the 2 treatment sequences (Table GBGM.3).  
Randomization tables will be prepared by the statistician or designee for the study and provided 
to the site pharmacists involved in dose preparation.  The allocation and dispensing of the 
investigational product will be fully documented and verified by a second person.  Detailed 
records of the amounts of the investigational product received, dispensed, and remaining at the 
end of the study will be maintained by the site pharmacist.
Approximately the same number of subjects will be randomized to each treatment sequence.
Table GBGM.3.
Treatment Sequences
Treatment Sequence
Period 1
Period 2
1
Prefilled Syringe
Single Dose Pen
2
Single Dose Pen
Prefilled Syringe
7.2.1. Selection and Timing of Doses
The doses will be administered according to the randomization schedule at approximately the 
same times on each day.  The actual time of all dose administrations will be recorded in the 
subject’s electronic case report form (eCRF).
Prior to dulaglutide dosing, subjects will be fasted for approximately 8 hours and a standard 
breakfast will be provided approximately 15 minutes after dosing.
7.3.
Blinding
This is an open-label study due to the objective nature of the PK data and the different 
appearance, shape, size, and functionality of the devices.
7.4.
Dose Modification
Dose adjustments are not allowed in this study.
7.4.1. Special Treatment Considerations
If a device malfunctions before the needle is inserted (i.e., unable to activate the device, unable 
to unlock and/or unable to pull the needle shield), a replacement will be given. If the device 
malfunctions during the injection process (e.g., needle did not retract), the device will not be 
replaced, and all planned assessments will continue. The investigator or designee will fill out a 


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Dulaglutide (LY2189265)
complaint form, collect the associated device, submit the complaint form, and return the suspect 
device to Lilly.
7.5.
Preparation/Handling/Storage/Accountability
Both the PFS and the SDP should be stored refrigerated (2°C to 8°C) and allowed to warm to 
room temperature for at least 30 minutes (up to 24 hours) prior to use.
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 products 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).
At the end of the study, and with agreement from Lilly, both used and unused PFSs and SDPs, 
with the exception of a product complaint, may be destroyed by a qualified vendor.  
7.6.
Treatment Compliance
The investigational product will be administered at the clinical site, and documentation of 
treatment administration will occur at the site.
7.7.
Concomitant Therapy
With the exception of vitamin/mineral supplements and/or HRT, prescription medications are not 
to be taken from 14 days prior to drug administration and throughout the study.  
Over-the-counter medications other than acetaminophen are not to be taken from 7 days prior to 
drug administration and throughout the study. The use of topical medication may be permitted if 
no evidence of chronic dosing with the risk of systemic absorption exists.
In general, concomitant medication should be avoided; however, acetaminophen (1 g, maximum 
4 g per 24 hours) may be administered at the discretion of the investigator for treatment of 
headaches, etc.  If the need for concomitant medication (other than acetaminophen) arises, 
inclusion or continuation of the subject may be at the discretion of the investigator after 
consultation with a Lilly Clinical Pharmacologist (CP) or Clinical Research Physician (CRP).  
Any medication used during the course of the study must be documented.
7.8.
Treatment after the End of the Study
Not applicable for this study.


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Dulaglutide (LY2189265)
8. Discontinuation Criteria
Subjects discontinuing from the treatment/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
If the subject has an elevated amylase and/or lipase value, or is suspected of having pancreatitis, 
please refer to the pancreatic safety monitoring algorithm (Appendix 6).
Discontinuation of the investigational product for abnormal liver tests should be considered by 
the investigator when a subject meets 1 of the following conditions after consultation with the 
Lilly designated medical monitor:

Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >5× upper limit of 
normal (ULN)

ALT or AST >3× ULN sustained for more than 2 weeks, or

ALT or AST >3× ULN and total bilirubin level (TBL) >2× ULN or international 
normalized ratio >1.5, or

ALT or AST >3× ULN with the appearance of fatigue, nausea, vomiting, right upper-
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)

Alkaline phosphatase (ALP) >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%)
8.1.1. Discontinuation of Inadvertently Enrolled Subjects
If the sponsor or investigator identifies a subject who did not meet enrollment criteria and was 
inadvertently enrolled, a discussion must occur between the Lilly CP/CRP and the investigator to 
determine if the subject may continue in the study.  If both agree it is medically appropriate to 
continue, the investigator must obtain documented approval from the Lilly CP/CRP to allow the 
inadvertently enrolled subject to continue in the study with or without continued treatment with 
investigational product.  
8.2.
Discontinuation from the Study
Subjects 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


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Dulaglutide (LY2189265)

Investigator Decision
o
the investigator decides that the subject should be discontinued from the study

Subject Decision
o
the subject, or legal representative, requests to be withdrawn from the study
8.3.
Subjects Lost to Follow-up
A subject 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 subjects who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the site.


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Dulaglutide (LY2189265)
9. Study Assessments and Procedures
Section 2 lists the Schedule of Activities, detailing the study procedures and their timing.
Appendix 2 lists the clinical laboratory tests that will be performed for this study.
Appendix 5 provides a summary of the maximum number and volume of invasive samples, for 
all sampling, during the study.
Unless otherwise stated in 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 subjects 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 subject.
The investigator is responsible for the appropriate medical care of subjects 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 subject to discontinue the investigational product before 
completing the study.  The subject 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 informed consent form is signed, study site personnel will record, via eCRF, the 
occurrence and nature of each subject’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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Dulaglutide (LY2189265)
If a subject’s investigational product is discontinued as a result of an AE, study site personnel 
must report this to Lilly or its designee via eCRF.
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 (i.e., 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 subject or may require intervention to prevent 
one of the other outcomes listed in the definition above

when a condition related to the SDP or PFS 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 CRP/CP, 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 eCRF after signing informed consent, SAE reporting to the 
sponsor begins after the subject 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 subjects once they have 
discontinued from and/or completed the study (the subject summary eCRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a subject has 
been discharged from the study, and the investigator 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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Dulaglutide (LY2189265)
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator 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. 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.
Subjects 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
Effects of overdose with dulaglutide in clinical studies have included gastrointestinal disorders 
and hypoglycemia. In the event of overdose, appropriate supportive treatment (including 
frequent plasma glucose monitoring) should be initiated according to the subject’s clinical signs 
and symptoms.
Refer to the IB and Trulicity® USPI (2017).
9.4.
Safety
9.4.1. Laboratory Tests
For each subject, clinical laboratory tests detailed in Appendix 2 should be conducted according 
to the Schedule of Activities (Section 2) and as clinically indicated. Clinical laboratory 
assessments will include amylase and lipase.
9.4.1.1.
Amylase and Lipase Tests
Serum amylase and lipase measurements will be collected as part of the clinical laboratory 
testing as well as at time points specified in the Schedule of Activities (Section 2).  Where 
indicated in the Schedule of Activities, amylase and lipase results must be reviewed by the study 
physician prior to dulaglutide dosing on subsequent days.  Additional measurements may be 
performed at the investigator’s discretion.  Further diagnostic assessments will be recommended 
whenever lipase and/or amylase is/are confirmed to be ≥3× ULN at any visit post randomization, 
even if the subject is asymptomatic (as per the algorithm for the monitoring of pancreatic events 
in Appendix 6, and if pancreatitis is confirmed, the case will be further defined during an 
adjudication process).
9.4.2. Vital Signs
For each subject, vital sign measurements should be conducted according to the Schedule of 
Activities (Section 2).  


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Dulaglutide (LY2189265)
Blood pressure and pulse rate should be measured after at least 5 minutes supine.
Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or 
posture-induced symptoms. If orthostatic measurements are required, subjects should be supine 
for at least 5 minutes and stand for at least 2 minutes.  If the subject feels unable to stand, supine 
vital signs only will be recorded. Additional vital signs may be measured during each study 
period if warranted.
9.4.3. Electrocardiograms
For each subject, a single 12-lead digital ECG will be collected according to the Schedule of 
Activities (Section 2).  Electrocardiograms must be recorded before collecting any blood 
samples.  Subjects must be supine for at least 5 minutes before ECG collection and remain 
supine but awake during ECG collection.  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 
subject is still present, to determine whether the subject meets entry criteria at the relevant 
visit(s) and for immediate subject management, should any clinically relevant findings be 
identified.  
If a clinically significant finding is identified (including, but not limited to, changes in QT
interval or corrected QT interval from baseline) after enrollment, the investigator will determine 
if the subject can continue in the study.  The investigator, or qualified designee, is responsible for 
determining if any change in subject management is needed, and must document his/her review 
of the ECG printed at the time of collection.  Any new clinically relevant finding should be 
reported as an AE.
9.4.4. Physical Examination
Physical examinations and routine medical assessments will be conducted as specified in the 
Schedule of Activities (Section 2) and as clinically indicated.
9.4.5. Body Weight
Body weight will be recorded as specified in the Schedule of Activities (Section 2) and as 
clinically indicated.
9.4.6. Injection Site Reactions
Local tolerability at the injection site will be evaluated for erythema, induration, pain, pruritus, 
rash, and edema as indicated in Section 2 and reported in the eCRF.  If one or more symptom(s) 
of an injection site reaction (ISR) is reported during the assessment, a single AE for ISR will be 
recorded on the AE page of the eCRF.


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Dulaglutide (LY2189265)
9.4.7. Safety Monitoring
The Lilly CP 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 CP or 
CRP will periodically review the following data:

trends in safety data

laboratory analytes including lipase and amylase

AEs including monitoring of ISRs
When appropriate, the Lilly CP or CRP will consult with the functionally independent Global 
Patient Safety therapeutic area physician or clinical research scientist.
9.4.7.1.
Hepatic Safety
If a study subject experiences elevated ALT ≥3× ULN, ALP ≥2× ULN, or elevated TBL ≥2×
ULN, liver tests (Appendix 4) should be repeated within 3 to 5 days including ALT, AST, ALP, 
TBL, direct bilirubin, gamma-glutamyl transferase, and creatinine kinase to confirm the 
abnormality and to determine if it is increasing or decreasing.  If the abnormality persists or 
worsens, clinical and laboratory monitoring should be initiated by the investigator based on 
consultation with the Lilly CP or CRP.  Monitoring should continue until levels normalize and/or 
are returning to approximate baseline levels.
Additional safety data should be collected if 1 or more of the following conditions occur:

elevation of serum ALT to ≥5× ULN on 2 or more consecutive blood tests

elevated serum TBL to ≥2× ULN (except for cases of known Gilbert’s syndrome)

elevation of serum ALP to ≥2× ULN on 2 or more consecutive blood tests 

subject discontinued from treatment due to a hepatic event or abnormality of liver tests

hepatic event considered to be an SAE
9.5.
Pharmacokinetics
At the visits and times specified in the Schedule of Activities (Section 2), venous blood samples 
of approximately 4 mL each will be collected to determine the plasma concentrations of 
dulaglutide.  Instructions for the collection and handling of blood samples will be provided by 
the sponsor.  The actual date and 24-hour clock time of each dose and PK sampling will be 
recorded.
9.5.1. Bioanalysis
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor.
Concentrations of dulaglutide will be assayed using a validated radioimmunoassay method.  


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Dulaglutide (LY2189265)
Bioanalytical samples collected to measure investigational product concentrations will be 
retained for a maximum of 1 year following last subject visit for the study.
9.6.
Pharmacodynamics
9.6.1. Immunogenicity Assessments
At the visits and times specified in the Schedule of Activities (Section 2), venous blood samples 
of approximately 10 mL each will be collected to determine antibody production against 
dulaglutide.  Additional samples may be collected if there is a possibility that an AE is 
immunologically mediated.
Immunogenicity will be assessed by a validated assay designed to detect anti-drug antibodies 
(ADA) in the presence of dulaglutide at a laboratory approved by the sponsor.  Antibodies may 
be further characterized and/or evaluated for their ability to neutralize the activity of dulaglutide.
Samples will be retained for a maximum of 15 years after the last subject visit, or for a shorter 
period if local regulations and ethical review boards (ERBs) allow, at a facility selected by the 
sponsor.  The duration allows the sponsor to respond to future regulatory requests related to 
dulaglutide.  Any samples remaining after 15 years will be destroyed.
9.7.
Genetics
A blood sample will be collected for pharmacogenetic analysis as specified in the Schedule of 
Activities (Section 2), where local regulations allow.  
Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future.  Samples will be used to investigate variable exposure or response to 
dulaglutide and to investigate genetic variants thought to play a role in insulin glucose 
homeostasis.  Assessment of variable response may include evaluation of AEs or differences in 
efficacy.  
All samples will be coded with the subject number.  These samples and any data generated can 
be linked back to the subject only by the investigative site personnel.  
Samples will be retained for a maximum of 15 years after the last subject visit, or for a shorter 
period if local regulations and/or ERBs impose shorter time limits, for the study at a facility 
selected by Lilly or its designee.  This retention period enables use of new technologies, response 
to regulatory questions, and investigation of variable response that may not be observed until 
later in the development of dulaglutide or after dulaglutide is commercially available.  
Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named.  However, existing approaches include whole genome or exome 
sequencing, genome wide association studies, multiplex assays, and candidate gene studies.  
Regardless of technology utilized, data generated will be used only for the specific research 
scope described in this section. 


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Dulaglutide (LY2189265)
9.8.
Biomarkers
This section is not applicable for this study.
9.9.
Health Economics
This section is not applicable for this study.


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Dulaglutide (LY2189265)
10.
Statistical Considerations and Data Analysis
10.1. Sample Size Determination
Approximately 24 subjects may be enrolled in order that at least 18 subjects complete the study.  
The sample size was based on a within-subject variability (coefficient of variation) of 21% for 
AUC and Cmax of dulaglutide from previous studies.  Eighteen subjects will provide a 90% 
probability that the half-width of the 90% confidence interval (CI) of the ratio of the geometric 
means for AUC and Cmax is no larger than 14%.
Subjects who are randomized may be replaced to ensure that at least 18 subjects may complete 
the study.
10.2. Populations for Analyses
10.2.1. Study Participant Disposition
A detailed description of subject disposition will be provided at the end of the study. All 
subjects who discontinue from the study will be identified, and the extent of their participation in 
the study will be reported.  If known, a reason for their discontinuation will be given.
10.2.2. Study Participant Characteristics
The subject’s age, sex, weight, height, BMI, race/sub-race, tobacco/nicotine habits, or other 
demographic characteristics will be recorded and may be used in the PK 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.
Pharmacokinetic analyses will be conducted on data from all subjects who receive at least one 
dose of dulaglutide and have evaluable PK.  
Safety analyses will be conducted for all enrolled subjects, whether or not they completed all 
protocol requirements.
Additional exploratory analyses of the data will be conducted as deemed appropriate.  Study 
results may be pooled with the results of other studies for population PK analysis purposes to 
avoid issues with post-hoc analyses and incomplete disclosures of analyses.  
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 


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Dulaglutide (LY2189265)
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.
The number of investigational product-related SAEs will be reported.
10.3.1.2. Statistical Evaluation of Safety
Safety parameters that will be assessed include safety clinical laboratory parameters and vital 
signs.  The parameters will be listed and summarized using standard descriptive statistics.  The 
change from baseline (Day 1 predose of each period) in vital signs will be analyzed and 
summarized.  The change from baseline (Day -1 of each period) in amylase and lipase will also 
be summarized.  Electrocardiograms and physical examinations will be performed for safety 
monitoring purposes and will not be presented.  Additional analysis will be performed if 
warranted upon review of the data.
10.3.2. Pharmacokinetic Analyses
10.3.2.1. Pharmacokinetic Parameter Estimation
Pharmacokinetic parameter estimates for dulaglutide will be calculated by standard 
noncompartmental methods of analysis.
The primary parameters for analysis will be Cmax and AUC from time zero to infinity 
(AUC[0-∞]), of dulaglutide.  Other noncompartmental parameters, such as AUC from time zero 
to 168 hours (AUC[0-168h]), AUC from time zero to 336 hours (AUC[0-336h]), time to Cmax
(tmax), t1/2, apparent total body clearance of drug, apparent volume of distribution, and AUC 
from time zero to time t, where t is the last time point with a measurable concentration
(AUC[0-tlast]), may be reported.
10.3.2.2. Pharmacokinetic Statistical Inference
The PK parameter estimates will be evaluated to determine the relative bioavailability of 
dulaglutide administered SC by SDP (test) compared to dulaglutide administered by PFS 
(reference).
The PK parameters will be summarized using descriptive statistics by treatment.
Log-transformed Cmax and AUC(0-∞) (primary parameters) and AUC(0-168h) and 
AUC(0-336h) (secondary parameters) will be evaluated in a linear mixed-effects analysis of 
variance model with fixed effects for treatment (SDP or PFS), period, and sequence and a 
random effect for subject within sequence.  The ratios of least squares geometric means of SDP
compared to PFS, as well as the corresponding 90% CIs, will be estimated and reported.
The tmax will be analyzed nonparametrically using the Wilcoxon ranked sum test.  Estimates of 
the median difference and the corresponding 90% CIs will be calculated.
Additional analysis may be conducted if deemed appropriate.


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Dulaglutide (LY2189265)
10.3.3. Evaluation of Immunogenicity
The frequency and percentage of subjects with preexisting ADA and with treatment-emergent 
ADA (TE ADA) to dulaglutide will be tabulated. Treatment-emergent ADA are defined as a 
change from negative at baseline to positive at endpoint with antibody titer greater or equal to 
1:4 or a positive at baseline to a positive at endpoint with greater or equal to 4-fold increases.  
That is, if a positive antibody titer changes from 1:2 at baseline to 1:8 at endpoint, it is 
considered treatment emergent.  For subjects with TE ADA, the distribution of maximum titers 
will be described.  If a neutralization assay is performed, the frequency of neutralizing antibodies 
will be tabulated in subjects with TE ADA.
The relationship between the presence (or absence) of antibodies and safety and PK parameters 
may be assessed.
10.3.4. Interim Analyses
An interim PK analysis (including Cmax and AUC[0-168h]) will be conducted 1 week after the 
start of Period 1.  The purpose of this analysis is to provide preliminary data to further support 
Phase 3 development.  The PK samples collected predose through 168-hour time point will be 
analyzed.


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Dulaglutide (LY2189265)
11.
References
Barrington P, Chien JY, Showalter HD, Schneck K, Cui S, Tibaldi F, Ellis B, Hardy TA. A 
5-week study of the pharmacokinetics and pharmacodynamics of LY2189265, a novel, 
long-acting glucagon-like peptide-1 analogue, in patients with type 2 diabetes. Diabetes Obes 
Metab. 2011;13(5):426-433.
Skrivanek Z, Gaydos BL, Chien JY, Geiger MJ, Heathman MA, Berry S, Anderson JH, Forst T, 
Milicevic Z, Berry D. Dose-finding results in an adaptive, seamless, randomized trial of 
once-weekly dulaglutide combined with metformin in type 2 diabetes patients (AWARD-5). 
Diabetes Obes Metab. 2014;16(8):748-756.
Trulicity United States Prescribing Information [USPI 2017]. Indianapolis, IN: Eli Lilly and 
Company;2014. Revised 2017. Available at:  http://pi.lilly.com/us/trulicity-uspi.pdf. Accessed 
April 26, 2017.
Trulicity Summary of Product Characteristics [SmPC 2016]. Available at:  
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/002825/WC500179470.pdf. Accessed April 26, 2017.


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Dulaglutide (LY2189265)
Appendix 1.
Abbreviations and Definitions
Term
Definition
ADA
anti-drug antibodies
AE
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An 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.
ALT
alanine aminotransferase
ALP
alkaline phosphatase
AST
aspartate aminotransferase
AUC
area under the concentration versus time curve
AUC(0-168h)
area under the concentration versus time curve from time zero to 168 hours
AUC(0-336h)
area under the concentration versus time curve from time zero to 336 hours
AUC(0-∞)
area under the concentration versus time curve from time zero to infinity
AUC(0-tlast)
area under the concentration versus time curve from time zero to time t, where t is the last 
time point with a measurable concentration
BMI
body mass index
CI
confidence interval
Cmax
maximum observed drug concentration
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.
CP
Clinical Pharmacologist


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Dulaglutide (LY2189265)
CRP
Clinical Research Physician:  Individual responsible for the medical conduct of the study.  
Responsibilities of the CRP may be performed by a physician, clinical research scientist, 
global safety physician, or other medical officer.
CRU
clinical research unit
ECG
electrocardiogram
eCRF
electronic case report form
enroll
The act of assigning a subject to a treatment.  Subjects who are enrolled in the study are 
those who have been assigned to a treatment.
enter
Subjects 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
GLP-1
glucagon-like peptide-1
HbA1c
hemoglobin A1c
HIV
human immunodeficiency virus
HRT
hormone replacement therapy
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
informed consent
A process by which a subject 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 subject’s decision to participate.  Informed consent is documented by means of a 
written, signed and dated informed consent form.  
interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
investigational 
product
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.
ISR
injection site reaction


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Dulaglutide (LY2189265)
MTC
medullary thyroid cancer
NOAEL
no-observed-adverse-effect level
open-label
A study in which there are no restrictions on knowledge of treatment allocation, therefore 
the investigator and the study participant are aware of the drug therapy received during the 
study.
PFS
prefilled syringe
PK
pharmacokinetic(s)
randomize
The process of assigning subjects to an experimental group on a random basis.
SAE
serious adverse event
SC
subcutaneous(ly)
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
SmPC
Summary of Product Characteristics
SUSARs
suspected unexpected serious adverse reactions 
t1/2
apparent terminal elimination half-life
T2D
type 2 diabetes 
TBL
total bilirubin level
TE ADA
treatment-emergent anti-drug antibodies
tmax
time to maximum observed drug concentration
ULN
upper limit of normal
USPI
United States Package Insert


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Dulaglutide (LY2189265)
Appendix 2.
Clinical Laboratory Tests
Safety Clinical Laboratory Tests
Hematology
Clinical Chemistry
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Chloride
Mean cell volume 
Calcium
Mean cell hemoglobin 
Glucose, random
Mean cell hemoglobin concentration 
Blood urea nitrogen
Leukocytes (WBC)
Total protein
Platelets
Albumin
Absolute counts of:
Total bilirubin
Neutrophils
Alkaline phosphatase
Lymphocytes
Aspartate aminotransferase
Monocytes
Alanine aminotransferase
Eosinophils
Creatinine
Basophils
Serum lipase
Serum amylase
Urinalysis
Specific gravity
pH
Protein
Ethanol testinga
Glucose
Urine drug screen (including cotinine)a
Ketones
Hepatitis B surface antigenb
Bilirubin
Hepatitis C antibodyb
Urobilinogen
HIVb
Blood
Pregnancy testc (females only)
Nitrite
FSHb,d (females only)
Abbreviations:  FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; RBC = red blood cells; 
WBC = white blood cells.
a
Ethanol testing and standard urine drug screen must be performed at screening, and upon admission to the 
clinical research unit.  Drug/ethanol testing may be repeated at the discretion of the investigator.
b
Performed at screening only.
c
Serum pregnancy test will be performed at screening.  Urine pregnancy test will be performed for women of 
childbearing potential at Day -1 for each period and at early termination/Follow-up.
d
To confirm postmenopausal status.


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Dulaglutide (LY2189265)
Appendix 3.
Study Governance, Regulatory and Ethical 
Considerations
Informed Consent
The investigator is responsible for:

ensuring that the subject 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 subject or legal representative.  This 
includes obtaining the appropriate signatures and dates on the informed consent form 
(ICF) prior to the performance of any protocol procedures and prior to the administration 
of investigational product.

answering any questions the subject may have throughout the study and sharing in a 
timely manner any new information that may be relevant to the subject’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 subjects.  Individual 
investigators may have additional local requirements or processes.  Study-specific recruitment 
material should be approved by Lilly.
Ethical Review
The investigator or appropriate local representative must give assurance that the ethical review 
board (ERB) was properly constituted and convened as required by International Council on 
Harmonisation (ICH) guidelines and other applicable laws and regulations.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site(s).  Lilly or its representatives must approve the ICF 
before it is used at the investigative site(s).  All ICFs must be compliant with the ICH guideline 
on good clinical practice (GCP).
The study site’s ERB(s) should be provided with the following:

the current Investigator’s Brochure or United States Package Insert and updates during 
the course of the study

ICF

relevant curricula vitae


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Dulaglutide (LY2189265)
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 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, each 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 electronic case report forms 
(eCRFs), and study procedures.

make periodic visits to the study site.

be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax.

review and evaluate eCRF data and/or use standard computer edits to detect errors in data 
collection.


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Dulaglutide (LY2189265)

conduct a quality review of the database.
In addition, Lilly or its representatives will periodically check a sample of the subject 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 clinical 
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 subject personal information collected will be provided in a written 
document to the subject 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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Dulaglutide (LY2189265)
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 subjects in consultation with Lilly or its designee Clinical Research 
Physician.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin Time
WBC
Prothrombin Time, INR
Neutrophils
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B Core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear Antibodya
AST
Alkaline Phosphatase Isoenzymesa
GGT
CK/CPK 
Anti-smooth Muscle Antibody (or anti-actin 
antibody)a
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CK = creatine kinase; 
CPK = creatine phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international 
normalized ratio; RBC = red blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.


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Dulaglutide (LY2189265)
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-MC-GBGM Sampling Summary
Purpose
Blood Volume per 
Sample (mL)
Number of Blood 
Samples
Total Volume 
(mL)
Screening testsa
8
1
8
Clinical laboratory testsa
8
5
40
Pharmacogenetics
10
1
10
Pharmacokinetics
4
19
76
Immunogenicity
10
3
30
Total
164
Total for clinical purposes (rounded up to nearest 10 mL)
170
a
Additional samples may be drawn if needed for safety purposes.


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Appendix 6.
Pancreatic Monitoring
Glucagon-like peptide-1(GLP-1) agonists have been associated with a possible risk of acute 
pancreatitis.  In 2006, the US prescribing information for exenatide was revised to include the 
event of pancreatitis.  In 2007, the US prescribing information for this medication was amended 
to include pancreatitis under precautions.  Epidemiologic studies have indicated that there is an 
increased incidence and prevalence of pancreatitis in persons with type 2 diabetes (T2D).
To enhance understanding of the natural variability of pancreatic enzymes in the T2D population 
and to assess for any potential effects of dulaglutide on the exocrine pancreas, amylase and lipase 
values will be monitored in clinical trials with dulaglutide.
Additional monitoring will be requested for amylase or lipase values ≥3x upper limit of normal 
(ULN) at any visit after randomization, even in asymptomatic subjects (see figure below).  
Lipase and amylase may also be obtained at any time during the clinical trials for any subject 
suspected of having symptoms suggestive of pancreatitis (such as severe gastrointestinal signs 
and/or symptoms), at the investigator's discretion.
Acute pancreatitis is an adverse event defined as an acute inflammatory process of the pancreas 
that may also involve peripancreatic tissues and/or remote organ systems.  The diagnosis of acute 
pancreatitis requires 2 of the following 3 features:

abdominal pain characteristic of acute pancreatitis

serum amylase and/or lipase >3x ULN

characteristic findings of acute pancreatitis on computed tomography scan or magnetic 
resonance imaging
Most subjects with acute pancreatitis experience abdominal pain that is located generally in the 
epigastrium and radiates to the back in approximately half the cases.  The pain is often associated 
with nausea and vomiting. However, experience with GLP-1 agonists has demonstrated that 
some subjects asymptomatic for classic pancreatitis may demonstrate significant elevations of 
lipase and/or amylase. For subjects considered by investigators to be asymptomatic for 
pancreatitis, but whose value(s) for lipase and/or amylase are ≥3x ULN, an algorithm is in place 
to follow these subjects safely and to quickly reach/or not a diagnosis of pancreatitis. 


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Dulaglutide (LY2189265)
PPD


Leo Document ID = 948ee6c3-b43f-4f4d-9b4e-cd88319bcaf9
Approver: 
)
Approval Date & Time: 22-Sep-2017 16:26:51 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 24-Sep-2017 00:19:36 GMT
Signature meaning: Approved
PPD
PPD

SAP_000.pdf: 
H9X-MC-GBGM Statistical Analysis Plan  
Relative Bioavailability of an Investigational Single Dose of Dulaglutide after Subcutaneous 
Administration by a Single Dose Pen Compared to a Prefilled Syringe in Healthy Subjects 
 
NCT03363906 
 
Approval Date: 06-Dec-2017 
 
 
 


Final, 24 Nov 2017
             Page 1 of 14
STATISTICAL ANALYSIS PLAN
Relative Bioavailability of an Investigational Single Dose of Dulaglutide after Subcutaneous 
Administration by a Single Dose Pen Compared to a Prefilled Syringe in Healthy Subjects
Statistical Analysis Plan Status:  Final
Statistical Analysis Plan Date:  24-November-2017
Study Drug: Dulaglutide (LY2189265)
Sponsor Reference:  H9X-MC-GBGM
Covance CRU Study: 1000071-8368080
Clinical Phase I
Approval Date: 06-Dec-2017 GMT


Final, 24 Nov 2017
             Page 2 of 14
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8368080
Sponsor Reference H9X-MC-GBGM
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 Objective................................................................................................ 5
5.
STUDY DESIGN........................................................................................................... 5
6.
TREATMENTS............................................................................................................. 6
7.
SAMPLE SIZE JUSTIFICATION ................................................................................. 6
8.
DEFINITION OF ANALYSIS POPULATIONS............................................................ 7
9.
STATISTICAL METHODOLOGY ............................................................................... 7
9.1
General.................................................................................................................... 7
9.2
Demographics and Subject Disposition.................................................................... 7
9.3
Pharmacokinetic Assessment................................................................................... 8
9.3.1
Pharmacokinetic Analysis............................................................................... 8
9.3.2
Pharmacokinetic Statistical Methodology ..................................................... 11
9.4
Safety and Tolerability Assessments...................................................................... 12
9.4.1
Adverse events ............................................................................................. 12
9.4.2
Concomitant medication............................................................................... 12
9.4.3
Clinical laboratory parameters...................................................................... 12
9.4.4
Vital signs .................................................................................................... 12
9.4.5
Hepatic Monitoring ...................................................................................... 12
9.4.6
Injection Site Reaction Assessment .............................................................. 13
9.4.7
Immunogenicity ........................................................................................... 13
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 ...... 14
12. REFERENCES ............................................................................................................ 14
13. DATA PRESENTATION ............................................................................................ 14
13.1 Derived Parameters ............................................................................................... 14
13.2 Missing Data ......................................................................................................... 14
13.3 Insufficient Data for Presentation .......................................................................... 14


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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
AUC(0-tlast)
Area under the concentration versus time curve from time zero to 
time t, where t is the last time point with a measurable concentration
AUC(0-∞)
Area under the concentration versus time curve from time zero to 
infinity
AUC(0-168h)
Area under the concentration versus time curve from time zero to 168 hours 
post dose
AUC(0-336h)
Area under the concentration versus time curve from time zero to 336 hours 
post dose
AUC(0-tlast)
Area under the concentration versus time curve from time zero to time t, 
where t is the last time point with a measurable concentration
%AUC(tlast-∞)
Percentage of AUC(0-∞) extrapolated
BQL
Below the quantifiable lower limit of the assay
Cmax
Maximum observed drug concentration
CI
Confidence interval
CL/F
Apparent total body clearance of drug calculated after extra-vascular
administration
CRF
Case Report Form
CRU
Clinical research unit
CSR
Clinical Study Report
CV
Coefficient of variation
EC
Early Clinical 
ECG
Electrocardiogram
e.g.
For example (Latin: exempli gratia)
ICH
International Council on Harmonisation
LLOQ
Lower limit of quantitation
LS
Least square


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MedDRA
Medical Dictionary for Regulatory Activities
MRE
Magnetic resonance elastography
NA
Not applicable
PK
Pharmacokinetic
PFS
Prefilled syringe 
SAP
Statistical Analysis Plan
SC
Subcutaneous 
SD
Standard deviation 
SDP
Single dose pen
SOP
Standard Operating Procedure
TBL
Total bilirubin
TFLs
Tables, Figures, and Listings
t1/2
Half-life associated with the terminal rate constant (λz) in non-
compartmental analysis
tmax
Time of maximum observed drug concentration
ULN
Upper limit of normal
Vss/F
Apparent volume of distribution at steady state after extra-vascular 
administration
Vz/F
Apparent volume of distribution during the terminal phase after 
extra-vascular administration
WHO
World Health Organization


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3. INTRODUCTION
This SAP has been developed after review of the Clinical Study Protocol (final version dated 24 
September 2017).
This SAP describes the planned analysis of the safety, tolerability and pharmacokinetic (PK) 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 PK 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 subject 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

To evaluate the relative bioavailability of a single dose of dulaglutide administered 
subcutaneously (SC) to healthy subjects as a single injection by single dose pen (SDP; 
test) compared to 3 injections by prefilled syringe (PFS; reference).
4.2
Secondary Objective

To assess the tolerability of a single dose of dulaglutide administered SC to healthy 
subjects as a single injection by SDP compared to 3 injections by PFS.
5. STUDY DESIGN
This study is a Phase 1, single-center, open-label, randomized, 2-period, crossover study in
healthy subjects to evaluate the relative bioavailability of 4.5 mg of a new formulation of 


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dulaglutide administered SC as a single injection by SDP (test) compared to 3 injections by PFS 
(reference).
Each subject will provide informed consent for study participation and will undergo a screening
examination within 27 days prior to enrollment.
In each treatment period, subjects will be admitted to the clinical research unit (CRU) on Day -1.
On Day 1 of each period, subjects will receive a single dose of 4.5 mg dulaglutide administered
SC as a single SDP injection or as 3 injections by PFS according to the randomization schedule. 
Blood samples will be collected predose and up to 336 hours postdose to measure dulaglutide 
concentrations. At a minimum, subjects will remain at the CRU until collection of the 168-hour 
(Day 8) PK sample in each period.
There will be a washout period of at least 28 days between doses in Periods 1 and 2. Each subject 
will be required to return to the CRU for a follow-up visit 28 ±3 days after the last dulaglutide 
dose. The total duration for each subject (from screening through the follow-up visit) is 
approximately 84 days. The treatment sequences are detailed below:
Treatment Sequence
Period 1
Period 2
1
Prefilled Syringe
Single Dose Pen
2
Single Dose Pen
Prefilled Syringe
Safety and tolerability will be assessed throughout the study by means of vital sign measurement,
physical examination, clinical laboratory tests, electrocardiograms (ECGs), and AE recording.
6. TREATMENTS
The following is a list of the study treatment abbreviations that will be used in the TFLs.
Study Treatment Name
Abbreviation
Treatment order in TFL
4.5 mg Dulaglutide (Prefilled Syringe)
Dulaglutide (PFS)
1
4.5 mg Dulaglutide (Single Dose Pen)
Dulaglutide (SDP)
2
7. SAMPLE SIZE JUSTIFICATION
Approximately 24 subjects may be enrolled in order that at least 18 subjects complete the study.
The sample size was based on a within-subject variability (coefficient of variation) of 21% for
the area under the concentration versus time curve (AUC) and maximum observed drug 
concentration (Cmax) of dulaglutide from previous studies. Eighteen subjects will provide a 90%


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probability that the half-width of the 90% confidence interval (CI) of the ratio of the geometric
means for AUC and Cmax is no larger than 14%.
Subjects who are randomized may be replaced to ensure that at least 18 subjects may complete
the study.
8. DEFINITION OF ANALYSIS POPULATIONS
The “Safety” population will consist of all enrolled subjects, whether or not they completed all 
protocol requirements.
The “Pharmacokinetic” population will consist of all subjects who received at least one dose of 
dulaglutide and have evaluable PK data.  
All protocol deviations that occur during the study will be considered for their severity/impact 
and will be taken into consideration when subjects 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 (e.g. the PK parameters: AUCs and Cmax) 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 subjects 
up to the point of withdrawal, with any subjects excluded from the relevant population 
highlighted. Summary statistics and statistical analyses will generally only be performed for 
subjects 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 subjects’ change from baseline values. 
Each individual change from baseline will be calculated by subtracting the individual subject’s 
baseline value from the value at the timepoint. The individual subject’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 9.4 or greater.
9.2
Demographics and Subject Disposition
Subject disposition will be listed. The demographic variables age, sex, race, ethnicity, body 
weight, height and body mass index will be summarized and listed. Tobacco/nicotine habits will 
be listed.


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9.3
Pharmacokinetic Assessment
9.3.1
Pharmacokinetic Analysis
Pharmacokinetic parameter estimates will be determined using non-compartmental procedures in 
validated software program (Phoenix WinNonlin Version 6.4 or later).
Plasma concentrations of dulaglutide will be used to determine the following PK parameters, 
when possible:  
Parameter
Units
Definition
AUC(0-)
ng.h/mL
area under the concentration versus time curve from time zero to 
infinity
AUC(0-168h)
ng.h/mL
area under the concentration versus time curve from time zero to 
168 hours post dose
AUC(0-336h)
ng.h/mL
area under the concentration versus time curve from time zero to 
336 hours post dose
AUC(0-tlast)
ng.h/mL
area under the concentration versus time curve from time zero to 
time t, where t is the last time point with a measurable 
concentration
%AUC(tlast-)
%
percentage of AUC(0-∞) extrapolated
Cmax
ng/mL
maximum observed drug concentration
tmax
h
time of maximum observed drug concentration
t½
h
half-life associated with the terminal rate constant (λz) in 
non-compartmental analysis
CL/F
L/h
apparent total body clearance of drug calculated after 
extra-vascular administration
Vz/F
L
apparent volume of distribution during the terminal phase after 
extra-vascular administration
Vss/F
L
apparent volume of distribution at steady state after extra-vascular 
administration
Additional PK parameters may be calculated, as appropriate.  The software and version used for 
the final analyses will be specified in the clinical study report. Any exceptions or special 
handling of data will be clearly documented within the final study report.
Formatting of tables, figures and abbreviations will follow the Eli Lilly Global PK/PD/TS Tool: 
NON-COMPARTMENTAL PHARMACOKINETIC STYLE GUIDE. The version of the tool
effective at the time of PK analysis will be followed.
General PK Parameter Rules

Actual sampling times will be used in the final analyses of individual PK parameters, 
except for non-bolus pre-dose sampling times which will be set to zero. 


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
Cmax and tmax will be reported from observed values.  If Cmax occurs at more than one time 
point, tmax will be assigned to the first occurrence of Cmax. 

AUC parameters will be calculated using a combination of the linear and logarithmic 
trapezoidal methods (linear-log trapezoidal rule).  The linear trapezoidal method will be 
applied up to tmax and then the logarithmic trapezoidal method will be used after tmax. The 
minimum requirement for the calculation of AUC will be the inclusion of at least three 
consecutive plasma concentrations above the lower limit of quantification (LLOQ), with 
at least one of these concentrations following Cmax. AUC(0-) values where the 
percentage of the total area extrapolated is more than 20% will be flagged. Any AUC(0-
) value excluded from summary statistics will be noted in the footnote of the summary 
table.

Half-life (t½) will be calculated, when appropriate, based on the apparent terminal log-
linear portion of the concentration-time curve. The start of the terminal elimination phase 
for each subject will be defined by visual inspection and generally will be the first point 
at which there is no systematic deviation from the log-linear decline in plasma 
concentrations.  Half-life will only be calculated when a reliable estimate for this 
parameter can be obtained comprising of at least 3 data points.  If t½ is estimated over a 
time window of less than 2 half-lives, the values will be flagged in the data listings. Any 
t½ value excluded from summary statistics will be documented in the footnote of the 
summary table. 

A uniform weighting scheme will be used in the regression analysis of the terminal log-
linear portion of the concentration-time curve.

The parameters based on observed Clast will be reported.
Individual PK Parameter Rules

Only quantifiable concentrations will be used to calculate PK parameters with the 
exception of special handling of certain concentrations reported below the lower limit of 
quantitation (BQL).  Plasma concentrations reported as BQL will be set to a value of zero 
when all of the following conditions are met: 

The compound is non-endogenous.

The samples are from the initial dose period for a subject or from a 
subsequent dose period following a suitable wash-out period.

The time points occur before the first quantifiable concentration.

All other BQL concentrations that do not meet the above criteria will be set to missing. 

Also, where two or more consecutive concentrations are BQL towards the end of a 
profile, the profile will be deemed to have terminated and therefore any further 
quantifiable concentrations will be set to missing for the calculation of the PK parameters 
unless it is considered to be a true characteristic of the profile of the drug.
Individual Concentration vs. Time Profiles
o
Individual concentrations will be plotted utilizing actual sampling times.
o
The terminal point selections will be indicated on a semi-logarithmic plot.


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Average Concentration vs. Time Profiles
o
The average concentration profiles will be graphed using scheduled (nominal) 
sampling times. 
o
The average concentration profiles will be graphed using arithmetic average 
concentrations.
o
The pre-dose average concentration for single-dose data from non-endogenous 
compounds will be set to zero.  Otherwise, only quantifiable concentrations will 
be used to calculate average concentrations.
o
Concentrations at a sampling time exceeding the sampling time window specified 
in the protocol, or ± 10%, will be excluded from the average concentration 
profiles.
o
Concentrations excluded from the mean calculation will be documented in the 
final study report.
o
A concentration average will be plotted for a given sampling time only if 2/3 of 
the individual data at the time point have quantifiable measurements that are 
within the sampling time window specified in the protocol or ± 10%. An average 
concentration estimated with less than 2/3 but more than 3 data points may be 
displayed on the mean concentration plot if determined to be appropriate and will 
be documented within the final study report.
Treatment of Outliers during Pharmacokinetic Analysis
Application of this procedure to all pharmacokinetic analyses is not a requirement. Rather, this 
procedure provides justification for exclusion of data when scientifically appropriate. This 
procedure describes the methodology for identifying an individual value as an outlier for 
potential exclusion, but does not require that the value be excluded from analysis.  The following 
methodology will not be used to exclude complete profiles from analysis.
Data within an Individual Profile
A value within an individual profile may be excluded from analysis if any of the following 
criteria are met:

For pharmacokinetic profiles during single dosing of non-endogenous compounds, the 
concentration in a pre-dose sample is quantifiable.

For any questionable datum that does not satisfy the above criteria, the profile will be 
evaluated and results reported with and without the suspected datum. 
Data between Individual Profiles
1.
If n<6, then the dataset is too small to conduct a reliable range test.  Data will be 
analyzed with and without the atypical value, and both sets of results will be reported.  
2.
If n6, then an objective outlier test will be used to compare the atypical value to other 
values included in that calculation:
a.
Transform all values in the calculation to the logarithmic domain.
b. Find the most extreme value from the arithmetic mean of the log transformed 
values and exclude that value from the dataset.


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c.
Calculate the lower and upper bounds of the range defined by the arithmetic 
mean ±3*SD of the remaining log-transformed values.
d. If the extreme value is within the range of arithmetic mean ±3*SD, then it is 
not an outlier and will be retained in the dataset.
e.
If the extreme value is outside the range of arithmetic mean ±3*SD, then it is 
an outlier and will be excluded from analysis.
If the remaining dataset contains another atypical datum suspected to be an outlier and n ≥ 6 
following the exclusion, then repeat step 2 above. This evaluation may be repeated as many 
times as necessary, excluding only one suspected outlier in each iteration, until all data 
remaining in the dataset fall within the range of arithmetic mean ±3*SD of the log-transformed 
values.
Reporting of Excluded Values
Individual values excluded as outliers will be documented in the final report.  Approval of the 
final report will connote approval of the exclusion.
9.3.2
Pharmacokinetic Statistical Methodology
The PK parameters will be summarized using descriptive statistics by treatment and also 
presented graphically. Mean (with and without SD bars) and individual profiles over time will be 
presented for PK concentrations.
The PK parameter estimates will be evaluated to determine the relative bioavailability of
dulaglutide administered SC by SDP (test) compared to dulaglutide administered by PFS
(reference).
Log-transformed Cmax and AUC(0-∞) (primary parameters) and AUC(0-168h) and
AUC(0-336h) (secondary parameters) will be evaluated in a linear mixed-effects analysis of
variance model with fixed effects for treatment (SDP or PFS), period, and sequence and a
random effect for subject within sequence. The ratios of least squares geometric means of SDP
compared to PFS, as well as the corresponding 90% CIs, will be estimated and reported.
Example SAS code is given below:
proc mixed data=pk;
class subject treatment period sequence;
model log(pk) = treatment period sequence / ddfm=kr;
lsmeans treatment / pdiff alpha=0.1;
random intercept / subject=subject(sequence);
run;
The tmax will be analyzed nonparametrically using the Wilcoxon signed rank test. Estimates of
the median difference and the corresponding 90% CIs will be calculated.


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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 subject 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 dosing 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 AEs, the number of subjects 
experiencing an AE and the percentage of subjects experiencing an AE) of treatment-emergent 
AEs will be summarized by treatment, Medical Dictionary for Regulatory Activities (MedDRA)
version 20.0 system organ class and preferred term. The summary and frequency AE tables will 
be presented for all causalities and those considered related to the study drug. Any serious AEs
will be tabulated.
9.4.2
Concomitant medication
Concomitant medication will be coded using the WHO drug dictionary (Version March 2017).
Concomitant medication will be listed.
9.4.3
Clinical laboratory parameters
All clinical chemistry (including amylase and lipase), hematology and urinalysis data will be 
listed. Additionally clinical chemistry, hematology and urinalysis data outside the reference 
ranges will be listed.
Values for any clinical chemistry, hematology and urinalysis values outside the reference ranges 
will be flagged on the individual subject data listings.
9.4.4
Vital signs
Vital signs data will be summarized by treatment together with changes from baseline, where 
baseline is defined as Day 1 predose from each relevant period. Furthermore, values for 
individual subjects will be listed.
9.4.5
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.
If a patient has a liver abnormality then they will be included in the listings and summaries 
detailed below.


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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.
9.4.6
Injection Site Reaction Assessment
Local tolerability at the injection site will be evaluated for erythema, induration, pain, pruritus, 
rash, and edema. If one or more symptom(s) of an injection site reaction (ISR) is reported during 
the assessment, a single AE for ISR will be recorded as an AE. Data will be summarized in a 
frequency table and listed for individual subjects.
9.4.7
Immunogenicity
The frequency and percentage of subjects with pre-existing ADA and with treatment-emergent
ADA to dulaglutide will be tabulated. Treatment-emergent ADA are defined as a change from 
negative at baseline to positive at endpoint with antibody titer greater or equal to 1:4 or a positive 
at baseline to a positive at endpoint with greater or equal to 4-fold increases. That is, if a positive 
antibody titer changes from 1:2 at baseline to 1:8 at endpoint, it is considered treatment 
emergent. For subjects with treatment-emergent ADA, a listing of maximum titers will be 
produced. If a neutralization assay is performed, the frequency of neutralizing antibodies will be 
tabulated in subjects with treatment-emergent ADA.
The relationship between the presence (or absence) of antibodies and safety and PK parameters
may be assessed.
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
An interim PK analysis (including Cmax and AUC[0-168h]) will be conducted 1 week after the 
start of Period 1. The purpose of this analysis is to provide preliminary data to further support
Phase 3 development. The PK samples collected predose through 168-hour time point will be
analyzed.


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11.
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES
The protocol specified that tmax will be analyzed nonparametrically using the Wilcoxon ranked 
sum test however this has been amended to the Wilcoxon signed rank test as it is a crossover 
study.
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 (e.g. PK parameters) and appropriate summary statistics will be 
reported to three significant figures. Observed concentration data, e.g. Cmax, should be reported as 
received. Observed time data, e.g. tmax, should be reported as received. N and percentage values
should be reported as whole 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 subjects 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.”


Leo Document ID = d1bac6af-f4cb-44a5-9603-b49a671dbd2a
Approver: 
Approval Date & Time: 27-Nov-2017 15:12:38 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 28-Nov-2017 10:28:33 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 29-Nov-2017 09:15:32 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 06-Dec-2017 04:30:53 GMT
Signature meaning: Approved
PPD
PPD
PPD
PPD