Clinical trial NCT04004988
Conditions: Healthy
Sponsor: Eli Lilly and Company
Start date: 2019-08-19; Completion date: 2019-12-16
Enrollment: 47 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to compare the amount of tirzepatide that gets into the blood stream and how long it takes the body to get rid of it, when given as a solution formulation via an autoinjector versus a conventional prefilled syringe. The tolerability of tirzepatide will also be evaluated and information about any adverse effects experienced will be collected.

Screening is required within 28 days prior to the start of the study. For each participant, the total duration of the clinical trial will be about 14 weeks, including screening.

Detailed description:

Arms: arm 1: Participants received single dose of 5 milligram (mg) Tirzepatide by subcutaneous injection (SC) via an autoinjector (AI) in one of two study periods. arm 2: Participants received single dose of 5mg Tirzepatide by subcutaneous injection (SC) via a prefilled syringe (PFS) in one of two study periods.
Interventions: intervention 1: Tirzepatide intervention 2: Prefilled syringe (PFS) intervention 3: Auto-injector (AI)
Intervention descriptions: intervention 1: Administered SC intervention 2: PFS used to administer tirzepatide intervention 3: AI used to administer tirzepatide

Protocol documents:
Prot_000.pdf: 
I8F-MC-GPGS Clinical Pharmacology Protocol  
 
 
A Study to Compare the Pharmacokinetics of Tirzepatide Administered Subcutaneously by an 
Autoinjector versus Prefilled Syringe in Healthy Subjects  
 
 
NCT04004988  
 
 
Approval Date: 04-Jun-2019 
 
 


I8F-MC-GPGS Clinical Pharmacology Protocol
Page 1
Tirzepatide (LY3298176)
Protocol I8F-MC-GPGS
A Study to Compare the Pharmacokinetics of Tirzepatide 
Administered Subcutaneously by an Autoinjector versus
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 
tirzepatide (LY3298176), 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 Exemption 4 and 
may not be reproduced or otherwise disseminated without the written approval of Eli Lilly 
and Company or its subsidiaries.
Tirzepatide (LY3298176)
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Clinical Pharmacology Protocol Electronically Signed and Approved by Lilly on date 
provided below.
Approval Date: 04-Jun-2019 GMT


I8F-MC-GPGS Clinical Pharmacology Protocol
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Tirzepatide (LY3298176)
Table of Contents
A Study to Compare the Pharmacokinetics of Tirzepatide 
Administered Subcutaneously by an Autoinjector versus 
Prefilled Syringe in Healthy Subjects
Section
Page
Protocol I8F-MC-GPGS A Study to Compare the Pharmacokinetics of 
Tirzepatide Administered Subcutaneously by an Autoinjector versus 
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..............................................................................................13
4.
Objectives and Endpoints..................................................................................................14
5.
Study Design.....................................................................................................................15
5.1.
Overall Design .............................................................................................................15
5.2.
Number of Participants.................................................................................................16
5.3.
End of Study Definition ...............................................................................................16
5.4.
Scientific Rationale for Study Design...........................................................................16
5.5.
Justification for Dose ...................................................................................................16
6.
Study Population...............................................................................................................17
6.1.
Inclusion Criteria..........................................................................................................17
6.2.
Exclusion Criteria ........................................................................................................19
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
6.3.4.
Screen Failures.....................................................................................................21
7.
Treatment..........................................................................................................................22
7.1.
Treatment Administered...............................................................................................22
7.1.1.
Packaging and Labeling .......................................................................................23
7.1.2.
Medical Devices...................................................................................................23
7.2.
Method of Treatment Assignment ................................................................................23
7.2.1.
Selection and Timing of Doses.............................................................................23


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Tirzepatide (LY3298176)
7.3.
Blinding .......................................................................................................................23
7.4.
Dose Modification........................................................................................................23
7.5.
Preparation/Handling/Storage/Accountability...............................................................23
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 Measurements ................................................................29
9.4.2.
Glucose Monitoring .............................................................................................30
9.4.2.1.
Hyperglycemia and Hypoglycemia Reporting.................................................30
9.4.3.
Vital Signs ...........................................................................................................31
9.4.4.
Electrocardiograms ..............................................................................................32
9.4.5.
Injection-site Reactions ........................................................................................32
9.4.6.
Hypersensitivity Reactions...................................................................................33
9.4.7.
Safety Monitoring ................................................................................................33
9.4.7.1.
Hepatic Safety................................................................................................34
9.5.
Pharmacokinetics .........................................................................................................34
9.5.1.
Bioanalysis...........................................................................................................34
9.6.
Pharmacodynamics ......................................................................................................35
9.7.
Immunogenicity Assessments.......................................................................................35
9.8.
Genetics .......................................................................................................................36
9.9.
Biomarkers...................................................................................................................36
9.10. Health Economics ........................................................................................................36
10.
Statistical Considerations and Data Analysis.....................................................................37
10.1. Sample Size Determination ..........................................................................................37


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Tirzepatide (LY3298176)
10.2. Populations for Analyses..............................................................................................37
10.2.1.
Study Participant Disposition ...............................................................................37
10.2.2.
Study Participant Characteristics ..........................................................................37
10.3. Statistical Analyses ......................................................................................................37
10.3.1.
Safety Analyses....................................................................................................37
10.3.1.1.
Clinical Evaluation of Safety..........................................................................37
10.3.1.2.
Statistical Evaluation of Safety.......................................................................38
10.3.1.3.
Injection-site Reactions...................................................................................38
10.3.2.
Pharmacokinetic Analyses....................................................................................38
10.3.2.1.
Pharmacokinetic Parameter Estimation...........................................................38
10.3.2.2.
Pharmacokinetic Statistical Inference .............................................................38
10.3.3.
Evaluation of Immunogenicity .............................................................................38
10.3.4.
Data Review During the Study.............................................................................39
10.3.5.
Interim Analyses..................................................................................................39
11.
References ........................................................................................................................40
12.
Appendices .......................................................................................................................41


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Tirzepatide (LY3298176)
List of Tables
Table
Page
Table GPGS.1.
Objectives and Endpoints .......................................................................14
Table GPGS.2.
Treatments Administered........................................................................22


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Tirzepatide (LY3298176)
List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................42
Appendix 2.
Clinical Laboratory Tests........................................................................45
Appendix 3.
Study Governance, Regulatory and Ethical Considerations.....................46
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............49
Appendix 5.
Blood Sampling Summary......................................................................50
Appendix 6.
Classification of Contraceptive Methods.................................................51
Appendix 7.
Pancreatic Monitoring ............................................................................52


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Tirzepatide (LY3298176)
1. Protocol Synopsis
Title of Study:
A Study to Compare the Pharmacokinetics of Tirzepatide Administered Subcutaneously by an Autoinjector versus 
Prefilled Syringe in Healthy Subjects.
Rationale: 
Study I8F-MC-GPGS (GPGS) will assess the pharmacokinetics (PK), safety and tolerability of a 5 mg subcutaneous 
(SC) dose of tirzepatide solution formulation administered via autoinjector (AI) (test) versus a prefilled syringe 
(PFS) (reference). The PFS is being used in one of the 5 Phase 3 studies implemented in the T2DM clinical 
programme, while the AI will be used in the remaining 4 Phase 3 studies. The AI device is planned as the eventual
commercial product for use in the future. This study will provide tirzepatide PK comparability data when 
tirzepatide is administered via the AI (test) versus the PFS (reference) device.
Objective(s)/Endpoints:  
Objectives
Endpoints
Primary
To establish comparability between the autoinjector 
(AI; test) and the prefilled syringe (PFS; reference), as 
assessed by tirzepatide pharmacokinetics in healthy 
subjects.
Maximum drug concentration (Cmax) and area under 
the concentration versus time curve from zero to 
infinity [AUC(0-∞)] 
Secondary
To compare the safety and tolerability of a single 
subcutaneous dose of tirzepatide administered by AI 
(test) versus PFS (reference).
Incidence of adverse events (AEs)
Summary of Study Design:  
Study I8F-MC-GPGS is a single center, open-label, randomized, 2-period, 2-sequence, crossover study conducted in 
healthy subjects.
Treatment Arms and Planned Duration for an Individual Subject:  
The study involves a comparison of:

a single dose of 5 mg tirzepatide administered SC via AI

a single dose of 5 mg tirzepatide administered SC via PFS
The study duration for individual subjects, inclusive of screening is expected to be approximately 14 weeks, divided 
as follows:

Screening:  up to 27 days prior to Day -1

Treatment Periods 1 and 2:  Day 1 to Day 36, including single dosing with tirzepatide on Day 1 of each 
period

Washout:  there will be a washout of at least 35 days between tirzepatide doses


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Tirzepatide (LY3298176)

Follow-up:  Period 2, Day 36 (±1) will be considered as the final follow-up visit
Number of Subjects:
Up to 48 subjects may be enrolled to ensure that approximately 36 subjects with evaluable results complete the 
study.
Statistical Analysis:
The primary PK parameters for analysis will be Cmax and AUC(0-∞).
Two one-sided equivalence tests (TOST) will be applied to the ratios of each of Cmax and AUC using the AI as the 
test sample and the PFS as the reference.  Test limits of the ratios to establish comparability are 0.8 and 1.25.  
Pharmacokinetic parameters will be evaluated to estimate the relative bioavailability.  Log-transformed Cmax and 
AUC(0-∞) will be evaluated in a linear mixed-effects model with fixed effects for device, sequence, period, and a 
random effect for subject.  The treatment differences will be back-transformed to present the ratios of geometric 
means and the corresponding 90% CI.  
The tmax will be analyzed using a Wilcoxon signed rank test.  Estimates of the median difference based on the 
observed medians and 90% CIs from the Wilcoxon test will be calculated.
Planned PK parameters will also be summarized with descriptive statistics.
All investigational product and protocol procedure AEs, and device complaints will be listed, and if the frequency of 
events allows, data will be summarized using descriptive methodology.
Safety parameters that will be assessed include adverse events, safety lab parameters (including amylase, lipase, and 
blood glucose), and vital signs.  The parameters will be listed and summarized using standard descriptive statistics, 
where appropriate. 
Physical examinations and ECGs will be performed for safety monitoring purposes and will not be presented.  If 
warranted, additional analysis will be performed upon review of the data.
Incidence of erythema, induration, pain, itching, and edema will be listed and summarized.    
Additional analyses may be performed, if appropriate.


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Tirzepatide (LY3298176)
2. Schedule of Activities


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Tirzepatide (LY3298176)
Study Schedule Protocol I8F-MC-GPGS
Screening
Periods 1 and 2 Study Days – at least 35 days washout between Day 1 doses
EDc
Comments
Procedure
D-28 to D-
2
D-1b
D1b
D2
D3
D4
D5
D6
D7
D8
D15
D21
D36
(±1)b
Informed Consent
X
Subject Admission to 
CRU
X
Tirzepatide Dosing
0 hour
Study drug will be administered after an overnight 
fast of at least 8 hours.
Subject Discharge 
from CRU
X
Subjects’ CRU stay may be extended at the 
investigator’s discretion for safety monitoring.
Outpatient Visit
X
X
X
X
X
X
X
X
Medical History and 
Demographics
X
Physical Examination 
/Medical Assessment
X
Predose
X
X
X
Physical examination at screening. Thereafter, 
targeted reviews and medical assessments as 
appropriate.
Weight
X
Predose
X
X
Height
X
Temperature
X
Predose
Safety 12-lead ECGa
X
Predose
X
X
X
X
X
Single safety ECG will be collected.  ECGs must be 
recorded before collecting any blood samples at each 
timepoint.  Subjects must be supine for 
approximately 5 to 10 minutes before ECG 
collection, and remain supine but awake during ECG 
collection.
Supine Vital Signs 
(hours)
X
Predose,
12
24
48
72
X
X
X
X
X
Additional time points may be added, if warranted 
and agreed upon between Lilly and the investigator.
Clinical Laboratory 
Tests
X
Predose
X
X
X
X
X
X
See Appendix 2 for details. Day 1 predose sample is 
for baseline only.
Pregnancy Test
X
X
X
X
Female subjects only.  Serum pregnancy test will be 
performed at screening and urine pregnancy tests at 
subsequent visits.  
FSH test, if 
applicable
X
Female subjects considered to be postmenopausal 
only.  Women with confirmed nonchildbearing 
potential status can be exempted from further 
pregnancy tests during the study after screening.
AEs/Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pharmacogenetic 
Samplea
Predose
Single sample in Period 1 only.


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Tirzepatide (LY3298176)
Screening
Periods 1 and 2 Study Days – at least 35 days washout between Day 1 doses
EDc
Comments
Procedure
D-28 to D-
2
D-1b
D1b
D2
D3
D4
D5
D6
D7
D8
D15
D21
D36
(±1)b
Immunogenicitya
Predose
X
X
X
Where applicable, collection times should match with 
PK sampling time points. In the event of immediate 
or non-immediate drug hypersensitivity reactions, 
unscheduled samples will be collected as detailed in 
Section 9.4.6. Subjects with TE ADA at 
follow-up/ED will undergo additional follow-up as 
detailed in Section 9.7.
Blood glucose 
monitoring (hours)a
Predose,
12
24, 
36
48
72
Performed using a bedside glucose monitor.  
Additional unscheduled measurements may be taken 
at the discretion of the investigator where clinically 
indicated.
PK Sampling 
(hours)a
Predose,
8, 12
24, 
36
48
72
96
120
144
168
336
480
X
X
Up to a 10% deviation from the nominal collection
time is permissible as long as actual sampling time is 
recorded.
Abbreviations:  ADA = antidrug antibodies; AE = adverse event; CRU = clinical research unit; D or d = day; ECG = electrocardiogram; ED = early 
discontinuation; PK = pharmacokinetic(s); TE ADA = treatment-emergent antidrug antibodies.  
Note:  All sampling times are given relative to dosing (Time 0 hour) with tirzepatide (predose or hours postdose). Unless otherwise indicated, predose procedure 
may be performed any time prior to dosing.
If multiple procedures take place at the same time point, the following order of the procedures should be used:  ECGs, vital signs, PK sample (record of actual 
PK sampling time is the priority), clinical laboratory sample, immunogenicity, blood glucose and pharmacogenetic sample.
a
Specified times are approximate, and actual times will be recorded.  Actual sampling time should not exceed 1 hour prior to dosing for the predose sample.
b
Period 2, Day -1 procedures (pregnancy tests) and some Period 2, Predose procedures (physical examinations, medical assessments, and clinical laboratory
assessments) may be omitted if Period 1, D36 (±1) procedure dates occur within 4 days of Period 2 dosing.  Period 2, Day 36 (±1) will also be considered as 
the final follow-up visit.
c
Within 7 to 14 days upon confirmation of early discontinuation.


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Tirzepatide (LY3298176)
3. Introduction
3.1.
Study Rationale
Tirzepatide (LY3298176) is being developed for the treatment of type 2 diabetes mellitus 
(T2DM) as an adjunct to diet and exercise.  In addition, it is being developed as a therapy for the 
indications of chronic weight management and nonalcoholic steatohepatitis (NASH). It is 
administered once weekly by SC injection.
Study I8F-MC-GPGS (GPGS) will assess the pharmacokinetics (PK), safety and tolerability of a 
5 mg subcutaneous (SC) dose of tirzepatide solution formulation administered using autoinjector 
or AI (test) versus prefilled syringe or PFS (reference).
The PFS device is being used in first of the 5 planned Phase 3 studies in the T2DM clinical 
program of tirzepatide.  The following 4 Phase 3 T2DM studies will use the AI device.  
Additionally, the AI device is intended as the eventual commercial product for future use in 
patients.
3.2.
Background
The available preclinical and clinical data indicate that co-stimulation of glucose-dependent 
insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors may enhance 
insulin secretion, improve insulin sensitivity, and reduce body weight beyond the effect of 
selective GLP-1R stimulation (Frias et al. 2018; Coskun et al. 2018). 
Tirzepatide, a dual agonist of GIP and GLP-1, is a 39-amino acid synthetic peptide.  Its structure 
is based on the GIP sequence and includes a C20 fatty di-acid moiety that prolongs the duration 
of action.  It has a chemical structure and pharmacologic profile that is distinct from the GLP-1 
receptor agonists due to the addition of GIP, which is unique among the marketed incretin 
mimetics.
In a Phase 1 study (Coskun et al. 2018) that included single and multiple ascending dose (SAD, 
MAD) parts, tirzepatide has been administered as single SC doses up to 8 mg in healthy subjects. 
In the MAD part, higher doses up to 10 mg were attained in healthy subjects via dose escalation.  
Doses up to 15 mg were achieved in patients with T2DM via dose escalation. In this study, 
gastrointestinal (GI) adverse events (AEs) (nausea, vomiting, diarrhea, abdominal distension) 
and decreased appetite were the most frequently reported events by both healthy subjects and 
also by patients with T2DM and were dose related.  Most AEs were mild in severity, a few were 
moderate, and none were reported as severe.  During the single ascending dose study, the high 
incidence of GI AEs, notably vomiting, were considered to be dose limiting at the 8-mg dose; 
therefore, the 5-mg dose was considered the maximum tolerated dose.  A dose-dependent 
increase in heart rate was detected for both healthy subjects and patients with T2DM who 
received tirzepatide, similar to what was observed with selective GLP-1 receptor agonists.  A 
few subjects experienced transient elevations in lipase and/or amylase levels, but these episodes 
were not associated with any relevant clinical outcomes. Once-weekly doses of 1, 5, 10, and 15 
mg have been further investigated in a Phase 2 study (Frias et al, 2018).  An additional dose level 
of 12 mg and alternate dose escalation schemes were investigated in a 12-week Phase 2 study.  


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Tirzepatide (LY3298176)
Doses above 5 mg of tirzepatide were attained via step-wise dose escalation.  Results from the 
two Phase 2 studies demonstrated that tirzepatide at doses between 5 and 15 mg provided 
clinically meaningful efficacy in both glucose- and body weight-lowering.  
Gastrointestinal-related AEs (nausea, diarrhea, vomiting) were the most frequently reported AEs 
in Phase 2 studies.  The majority of the treatment emergent adverse events (TEAEs) were mild or 
moderate in severity. There were no other clinically relevant safety observations in the Phase 1 
and 2 studies.
Tirzepatide terminal half-life was estimated to be approximately 5 days, thus supporting a 
once-weekly (QW) dosing regimen, with maximum observed drug concentration (Cmax) 
occurring 24 to 72 hours postdose.   
Overall, the safety and tolerability, and PK/PD profiles of tirzepatide support further 
development of tirzepatide in patients with T2DM.  Further details can be found in the 
Investigator’s Brochure (IB).
3.3.
Benefit/Risk Assessment
Risks of tirzepatide have been consistent with risks associated with other GLP-1 receptor 
agonists currently marketed.  Potential risks include, but are not limited to, gastrointestinal (GI)
effects, acute pancreatitis, increases in heart rate, and hypoglycemic events (GLP-1 receptor 
agonist class effect).
No clinically significant safety or tolerability concerns have been identified during clinical 
investigation of tirzepatide up to the highest single dose level of 8 mg or multiple weekly doses, 
when escalated up to 15 mg.  Based on this information, the 2 × single 5-mg doses to be 
administered in Study GPGS are reasonably anticipated to be tolerable in this group of healthy 
subjects.
There is no anticipated therapeutic benefit in these healthy subjects.
More information about the known and expected benefits, risks, serious adverse events (SAEs) 
and reasonably anticipated AEs of tirzepatide are to be found in the IB.


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Tirzepatide (LY3298176)
4. Objectives and Endpoints
Table GPGS.1 shows the objectives and endpoints of the study.
Table GPGS.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To establish comparability between the autoinjector
(AI; test) and the prefilled syringe (PFS; reference), as 
assessed by tirzepatide pharmacokinetics in healthy 
subjects.
Maximum drug concentration (Cmax) and area under 
the concentration versus time curve from zero to 
infinity [AUC(0-∞)]
Secondary
To compare the safety and tolerability of a single 
subcutaneous dose of tirzepatide administered by AI
(test) versus PFS (reference).
Incidence of AEs


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Tirzepatide (LY3298176)
5. Study Design
5.1.
Overall Design
This study is a single center, open-label, randomized, 2-period, 2-sequence, crossover study 
conducted in healthy subjects.
The study design is as follows:
      
Abbreviation:  AI = autoinjector; CRU = clinical research unit; PFS = prefilled syringe; PK = pharmacokinetics.
Site staff will administer all injections.  All injections will be administered in the abdomen whilst 
the subject is in a sitting or reclining position.  Injections will be given in the lower abdominal 
quadrant.  Study injections should be given by a limited number of individuals for consistency.
There will be a washout of at least 35 days between tirzepatide doses.  Subjects will be 
randomized to 1 of the 2 treatment sequences shown above.  It is intended that the same number 
of subjects will be randomized into each treatment sequence.
Study governance considerations are described in detail in Appendix 3.


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Tirzepatide (LY3298176)
5.2.
Number of Participants
Up to 48 subjects may be enrolled so that approximately 36 evaluable subjects complete the 
study. A subject who discontinued before completing study activities may be replaced at the 
discretion of the investigator in consultation with the sponsor in order to meet the study 
objectives.
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
A population of healthy subjects was selected since this will permit an objective assessment of 
PK between the 2 devices.
A healthy subject population will allow assessments of the PK, safety, and tolerability of 
tirzepatide with a reduced likelihood of physiologic variability. Also, healthy subjects are 
usually devoid of other confounding factors, such as concomitant medications.
This study will be open-label as the study primary endpoint PK measures are objective rather 
than subjective.
In order to minimize any potential period-effect and to allow each subject to act as their own 
control, a randomized, 2-sequence, crossover design has been selected. A washout period of at 
least 35 days between doses is considered sufficient to minimize any carryover of tirzepatide 
concentrations from the first period into the second period.
5.5.
Justification for Dose
Data from Phase 1 study GPGA has shown that a 5 mg dose of tirzepatide was well tolerated by 
healthy subjects and patients with T2DM, and is also planned as one of the doses to be 
investigated in Phase 3 studies.  Doses higher than 5 mg were achieved via escalation since a 
5 mg dose was considered the MTD when administered as a single dose.


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Tirzepatide (LY3298176)
6. Study Population
Eligibility of subjects for the study will be largely based on the results of screening and/or 
Day -1 medical history, physical examination, vital signs, clinical laboratory tests and 
electrocardiogram (ECG). 
The nature of any conditions present at the time of the physical examination and any preexisting 
conditions will be documented.
Screening may occur up to 28 days prior to enrollment.  Subjects who are not enrolled within 
28 days of screening may be subjected to an additional medical assessment and/or clinical 
measurements to confirm their eligibility.
If the investigator decides not to administer the dose to a subject or not to enroll a subject on a 
particular day, the subject’s visit may be rescheduled and any assessments or procedures 
performed up to that point may be repeated 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 Day -1:
[1]
are overtly healthy males or females, as determined by medical history and 
physical examination.
[1a] male subjects: Men, regardless of their fertility status, with non-pregnant women 
of childbearing potential partners must agree to either remain abstinent (if this is 
their preferred and usual lifestyle) or use condoms plus one additional highly 
effective (less than 1% failure rate) method of contraception (such as combination 
oral contraceptives, implanted contraceptives, or intrauterine device) or effective 
method of contraception (such as diaphragms with spermicide or cervical sponge) 
for the duration of the study and for at least 90 days after dosing.  A full list of 
permitted highly effective and effective methods of contraception is presented in 
Appendix 6.
o
Men and their partners may choose to use a double-barrier method of 
contraception.  Barrier protection methods without concomitant use of a 
spermicide are not an effective or acceptable method of contraception.  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.


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Tirzepatide (LY3298176)
o
Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation
methods), declaration of abstinence just for the duration of a trial, and 
withdrawal are not acceptable methods of contraception.
Men with pregnant partners should use condoms during intercourse for the 
duration of the study and until the end of estimated relevant potential exposure in 
women of childbearing potential.
Men who are in exclusively same-sex relationships (as their preferred and usual 
lifestyle) are not required to use contraception.
Men should refrain from sperm donation for the duration of the study and for at 
least 90 days after dosing.
[1b] female subjects: Women of childbearing potential are excluded from the 
study.  Women not of childbearing potential may participate and include 
those who are:
A. infertile due to surgical sterilization (hysterectomy, bilateral oophorectomy, or 
tubal ligation), congenital anomaly such as mullerian agenesis; or
B. postmenopausal – defined as either:
i.
A woman at least 50 years of age with an intact uterus, not on hormone 
therapy, who has had either:
a) cessation of menses for at least 1 year, or
b) at least 6 months of spontaneous amenorrhea with a 
follicle-stimulating hormone >40 IU/mL; or
ii.
A woman 55 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 between 21 years and 70 years of age, inclusive, at the time of screening.
[3]
have a body mass index (BMI) of 18.0 to 32.0 kg/m2, inclusive, and a 
minimum body weight of 45 kg.
[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 willing to receive study treatment by SC injections.
[7]
have given written informed consent approved by Lilly and the ethical review 
board (ERB) governing the site.


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Tirzepatide (LY3298176)
[8]
have blood pressure, pulse rate, and an ECG reading that are considered to be 
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 limits as determined by the investigator.
6.2.
Exclusion Criteria
Subjects will be excluded from study enrollment if they meet any of the following criteria at 
screening and/or Day -1:
[9] 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.
[10] are Lilly employees or are employees of a third-party organization involved 
with the study.
[11] are currently enrolled in a clinical study involving an investigational product 
(IP) or any other type of medical research judged not to be scientifically or 
medically compatible with this study.  
[12] have received treatment with a drug that has not received regulatory approval 
for any indication within 30 days of screening.
[13] have previously completed or withdrawn from this study or any other study 
investigating tirzepatide, and have previously received the IP.
[14] have had any exposure to tirzepatide, other GLP-1 analogs, or other related 
compounds within the prior 3 months, or any history ever of allergies to these 
medications.
[15] have any abnormality in the 12-lead ECG at screening that, in the opinion of 
the investigator, increases the risks associated with participating in the study.
[16] have a significant history of or current cardiovascular (eg, myocardial 
infarction, congestive heart failure, cerebrovascular accident, venous 
thromboembolism, etc), respiratory, hepatic, renal, GI, endocrine, 
hematological (including history of thrombocytopenia) or neurological 
disorders capable of significantly altering the absorption, metabolism, or 
elimination of drugs, or of constituting a risk when taking the study 
medication, or of interfering with the interpretation of data.
[17] have evidence of significant active neuropsychiatric disease, as determined by 
the investigator.
[18] regularly use known drugs of abuse
[19] have evidence of human immunodeficiency virus (HIV) infection and/or are 
positive for human HIV antibodies.
[20] have evidence of hepatitis C and/or are positive for hepatitis C antibodies.


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[21] have evidence of hepatitis B and/or are positive for hepatitis B surface 
antigen.
[22] smoke > 10 cigarettes per day, or the equivalent, or are unable or unwilling to 
refrain from nicotine while resident in the CRU.
[23] have used or plan to use over-the-counter or prescription medication, and/or
herbal supplements (with the exception of vitamin/mineral supplements, any
hormone replacement therapy, and/or thyroid replacement therapy) within 
14 days prior to dosing and for the duration of the study, including any 
medications that reduce GI motility, including, but not limited to, 
anticholinergics, antispasmodics, 5-hydroxytryptamine-3 receptor antagonists, 
dopamine antagonists, and opiates.
[24] have donated blood of more than 450 mL or more in the last 3 months, have 
participated in a clinical study that required a similar blood volume be drawn 
in the last 3 months, or have had any blood donation within the last month 
prior to screening.
[25] have an average weekly alcohol intake that exceeds 21 units per week (males) 
or 14 units per week (females), OR are unwilling to stop alcohol consumption 
during study visits/time in the CRU
(1 unit of alcohol = 12 oz or 360 mL of beer; 5 oz or 150 mL of wine; 1.5 oz 
or 45 mL of distilled spirits)
[26] have a history or presence of pancreatitis (history of chronic pancreatitis or 
idiopathic acute pancreatitis), elevation in serum amylase or lipase (>1.5-fold 
the upper limit of normal [ULN]), GI disorder (eg, relevant esophageal reflux 
or gall bladder disease), or any GI disease which impacts gastric emptying 
(eg, gastric bypass surgery, pyloric stenosis [with the exception of 
appendectomy]) or could be aggravated by GLP-analogs or dipeptidyl 
peptidase IV (DPP-IV) inhibitors.  Subjects with dyslipidemia and subjects 
who had cholecystolithiasis (with removal of gallstones) and/or 
cholecystectomy (removal of the gall bladder) in the past, with no further 
sequelae, may be included in the study, at the discretion of the investigator.
[27] have a history of atopy or clinically significant multiple or severe drug 
allergies, intolerance to topical corticosteroids, or severe posttreatment 
hypersensitivity reactions (including, but not limited to, erythema multiforme 
major, linear immunoglobulin A dermatosis, toxic epidermal necrolysis, or 
exfoliative dermatitis).
[28] have a personal or family history of medullary thyroid carcinoma or have 
multiple endocrine neoplasia syndrome type 2.
[29] have serum aspartate aminotransferase (AST) or alanine aminotransferase 
(ALT) >2 × ULN or total bilirubin (TBL) >1.5 × ULN.
[30] have a history of malignancy within 5 years prior to screening.
[31] have a triglyceride (TG) ≥5 mmol/L (442.5 mg/dL) at screening.


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[32] are deemed unsuitable by the investigator for any other reason.
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
Subjects will be required to fast overnight for at least 8 hours before being given any SC dose of 
tirzepatide, and when clinical laboratory test samples are taken (see Schedule of Activities).  A 
meal will be offered to study subjects at around 2 hours postdose.  During inpatient stays, 
subjects may not consume any food other than that provided by the CRU.  Water may be 
consumed freely.
6.3.2. Caffeine, Alcohol, and Tobacco
No alcohol will be allowed from 24 hours prior to each dose and whilst resident at the CRU, or 
completion of all study procedures.  No nicotine use will be permitted while in the CRU.  While 
not resident in the CRU, subjects must consume no more than 10 cigarettes or the equivalent per 
day.
Subjects will be allowed to maintain the regular caffeine consumption throughout the study 
period (except during specific fasting time periods).
6.3.3. Activity
No strenuous physical activity will be allowed for 48 hours prior to dosing until discharge from 
the CRU, and 24 hours prior to each outpatient visit.
6.3.4. Screen Failures
Screening tests such as clinical laboratory tests and vital signs/ECGs may be repeated at the 
discretion of the investigator.  As this is a healthy volunteer only study, individuals who do not 
meet the criteria for participation in this study (screen failure) may not be rescreened.


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7. Treatment
7.1.
Treatment Administered
Each subject will receive 2 doses of tirzepatide administered via 2 different devices.  Each dose 
of IP will comprise 1 SC injection of 5 mg tirzepatide into the abdomen.  All doses will be 
administered by clinical site staff.
The study involves a comparison of:

a single dose of 5 mg tirzepatide administered SC via AI (Test)

a single dose of 5 mg tirzepatide administered SC via PFS (Reference)
Prior to injection, the investigator or designee will clean the subject’s skin. During each of the 
2 study periods, the injection will be administered to the lower abdominal quadrant, 
approximately 5 cm from the umbilicus (ie, left lower quadrant and right lower quadrant).  
Detailed instructions for use will be provided by the sponsor. 
A limited number of clinical site staff will perform SC administration for consistency reasons.
Table GPGS.2 shows the treatment regimens.
Table GPGS.2.
Treatments Administered
Treatment Name
Test Treatment
Reference Treatment
Dosage Formulation
solution for injection
solution for injection
Dose
5 mg tirzepatide / 0.5 mL
5 mg tirzepatide / 0.5 mL
Route of Administration
SC injection
SC injection
Delivery Method
autoinjector
prefilled syringe
Abbreviations:  SC = subcutaneous.
The investigator or designee is responsible for:

explaining the correct use of the IP(s) to the site personnel.

verifying that instructions are followed properly.

maintaining accurate records of IP dispensing and collection.

returning all unused medication to Lilly or its designee at the end of the study.


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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
Tirzepatide will be supplied by the sponsor or its designee in accordance with current good 
manufacturing practice, labeled according to the country’s regulatory requirements.
Each syringe of tirzepatide is designed to deliver 5 mg of tirzepatide.  The following products 
will be supplied by Lilly, with study-specific labels, for use in the study:

tirzepatide in 5 mg single-dose, pre-assembled, investigational AIs (Test)

tirzepatide in 5 mg single-dose, disposable manual PFS (Reference)
7.1.2. Medical Devices
The investigator or designee will ensure that the instructions have been followed properly; 
maintaining accurate records of study devices, dispensing, and collection.  The used or unused 
AI and PFS may be destroyed by a qualified vendor.
7.2.
Method of Treatment Assignment
Subjects will be randomly assigned to 1 of 2 possible treatment sequences using a 
computer-generated allocation code.
7.2.1. Selection and Timing of Doses
The actual time of all dose administrations will be recorded in the subject’s electronic case report 
form (eCRF).
7.3.
Blinding
This study is open-label.
7.4.
Dose Modification
Dose modification is not permitted in this study.
7.5.
Preparation/Handling/Storage/Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained, as communicated by sponsor, during transit for all IP received and that any 
discrepancies are reported and resolved before use of the study treatment.
Only participants enrolled in the study may receive IP or study materials, and only authorized 
site staff may supply or administer IP. All IP 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.


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The investigator is responsible for study treatment accountability, reconciliation, and record 
maintenance (such as receipt, reconciliation and final disposition records).
7.6.
Treatment Compliance
The IP will be administered at the clinical site, and documentation of treatment administration 
will occur at the site.
7.7.
Concomitant Therapy
In general, concomitant medication should be avoided; however, paracetamol (1g, maximum 
3g/24 hours) may be administered at the discretion of the investigator for treatment of headaches 
etc.  If the need for concomitant medication (other than paracetamol) arises, inclusion or 
continuation of the subject may be at the discretion of the investigator, preferably after 
consultation with a Lilly Clinical Pharmacologist (CP) or CRP or designee.  Any medication 
used during the course of the study must be documented.
7.8.
Treatment After the End of the Study
Not applicable.


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8. Discontinuation Criteria
Subjects discontinuing from the study and treatment prematurely for any reason should complete 
AE and other follow-up procedures per Schedule of Activities (Section 2) of this protocol.
8.1.
Discontinuation from Study Treatment
Discontinuation of the IP 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:

ALT or AST (aspartate aminotransferase) >5 × ULN

ALT or AST >3 × ULN sustained for more than 2 weeks or

ALT or AST >3 × ULN and 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 
IP.  
8.2.
Discontinuation from the Study

Enrollment in any other clinical study involving an IP or enrollment in any other type of 
medical research judged not to be scientifically or medically compatible with this study

Participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and good clinical practice (GCP)

Investigator Decision
o
the investigator decides that the subject should be discontinued from the study
o
if the subject, for any reason, requires treatment with another therapeutic agent 
that has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study occurs prior to introduction of the new agent


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
Subject Decision
o
the subject 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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9. Study Assessments and Procedures
Section 2 lists the Schedule of Activities, detailing the study procedures and their timing 
(including tolerance limits for timing).
Appendix 2 lists the laboratory tests that will be performed for this study.
Appendix 5 provides a summary of the maximum number and volume of invasive samples, for
all sampling, during the study.
The specifications in this protocol for the timings of safety and sample collections are given as 
targets to be achieved within reasonable limits.  Modifications may be made to the time points 
based upon emerging clinical information.  The scheduled time points may be subject to minor 
alterations; however, the actual time must be recorded correctly in the eCRF.  Failure or delays 
(ie, outside stipulated time allowances) in performing procedures or obtaining samples due to 
legitimate clinical issues (eg, equipment technical problems, venous access difficulty, or subject 
defaulting or turning up late on an agreed scheduled procedure) will not be considered as 
protocol deviations but the CRU will still be required to notify the sponsor in writing via a file 
note.
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
Not applicable.
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 IP or the study, 
or that caused the subject to discontinue the IP 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 (ICF) is signed, study site personnel will record, via eCRF, the 
occurrence and nature of each subject’s preexisting conditions, including clinically significant 


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signs and symptoms.  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 the AI or PFS, the IP, and/or a study procedure, taking into account 
concomitant treatment or pathologies.  
A “reasonable possibility” means that there is a potential cause and effect relationship between 
the IP, 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.
If a subject’s IP 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 (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

important medical events that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the subject or may require intervention to prevent 
one of the other outcomes listed in the definition above

when a condition related to the AI or the PFS, the IP, and/or study procedure 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.
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued from and/or completed the study (and the subject summary eCRF has been 
completed).  However, if the investigator learns of any SAE, including a death, at any time after 


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a subject has been discharged from the study, and he/she considers the event reasonably possibly 
related to the AI or PFS, the IP and/or study procedure, the investigator must promptly notify 
Lilly. 
Pregnancy (paternal exposure to IP) does not meet the definition of an adverse event.  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.
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 IP 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 IPs 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 IP or drug delivery system so that the situation can be assessed.
9.3.
Treatment of Overdose
For the purposes of this study, an overdose of tirzepatide is considered any dose higher than the 
dose assigned through randomization.
There is no specific antidote for tirzepatide.  In the event of an overdose, the subject should 
receive appropriate supportive care and any AEs should be documented.
Refer to the IB.
9.4.
Safety
9.4.1. Laboratory Tests
For each subject, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities (Section 2).
9.4.1.1.
Amylase and Lipase Measurements
Serum amylase and lipase measurements will be collected as part of the clinical laboratory 
testing and as specified in the Schedule of Activities (Section 2).  Additional measurements may 
be performed at the investigator’s discretion. Further diagnostic assessments will be 
recommended as per the algorithm (refer to Appendix 7) for the monitoring of pancreatic events 
whenever lipase and/or amylase is confirmed to be ≥3 × ULN at any visit postdose, even if the 
subject is asymptomatic.


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9.4.2. Glucose Monitoring
For safety purposes, plasma glucose measurements will be performed using a bedside glucose 
monitor as specified in the Schedule of Activities (Section 2).  Additional blood glucose monitor 
measurements may also be taken during the study as deemed necessary by the investigator where 
clinically indicated.
9.4.2.1.
Hyperglycemia and Hypoglycemia Reporting
Episodes of hyperglycemia (fasting plasma glucose >270 mg/dL [15 mmol/L]) or hypoglycemia 
(plasma glucose ≤70 mg/dL [3.9 mmol/L]) will be reported by the investigator or designated 
physician who will be responsible for advising the subject on what further actions to take.
Additional monitoring may be requested at the investigator’s discretion.
If the fasting plasma glucose during Periods 1 and 2, exceeds the acceptable level defined as 
hyperglycemia on 3 or more separate days over any 2-week period between screening and the 
end of the dosing period, the subject will be evaluated further at the study site. If fasting plasma 
glucose continues to exceed the acceptable level, treatment with an appropriate antidiabetic agent 
may be initiated by the investigator.
Hypoglycemia episodes will be recorded on specific eCRF pages. Hypoglycemia will be treated 
appropriately by the investigator and additional monitoring of plasma glucose levels may be 
performed. The following categories of the 2017 American Diabetes Association position 
statement on glycemic targets (ADA 2017) based on recommendations of the International 
Hypoglycaemia Study Group (IHSG 2017) should be applied for reporting in the eCRF and 
evaluating hypoglycemic events.
Hypoglycemia will be described using the following definitions:  

Documented Glucose Alert Level (Level 1), Plasma Glucose (PG) ≤70 mg/dL 
(3.9 mmol/L):  
o
Symptomatic hypoglycemia:  an event during which typical symptoms of 
hypoglycemia are accompanied by PG ≤70 mg/dL (3.9 mmol/L)
o
Asymptomatic hypoglycemia: an event not accompanied by typical symptoms 
of hypoglycemia but with PG ≤70 mg/dL (3.9 mmol/L)
o
Unspecified hypoglycemia: an event during which PG ≤70 mg/dL (3.9 mmol/L) 
but no information relative to symptoms of hypoglycemia was recorded

Documented Clinically Significant Hypoglycemia (Level 2) PG <54 mg/dL 
(3.0 mmol/L):
o
Symptomatic hypoglycemia: an event during which typical symptoms of 
hypoglycemia are accompanied by PG <54 mg/dL (3.0 mmol/L)
o
Asymptomatic hypoglycemia: an event not accompanied by typical symptoms 
of hypoglycemia but with PG <54 mg/dL (3.0 mmol/L)
o
Unspecified hypoglycemia: an event during which PG <54 mg/dL (3.0 mmol/L) 
but no information relative to symptoms of hypoglycemia was recorded


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
Severe hypoglycemia (Level 3): an event requiring assistance of another person to 
actively administer carbohydrate, glucagon, or other resuscitative actions.  During these 
episodes, the subject has an altered mental status and cannot assist in their care, is 
semiconscious or unconscious, or experienced coma with or without seizures and may 
require parenteral therapy. Plasma glucose measurements may not be available during 
such an event, but neurological recovery attributable to the restoration of blood glucose 
concentration to normal is considered sufficient evidence that the event was induced by a 
low PG concentration (PG ≤70 mg/dL [3.9 mmol/L])
o
Severe hypoglycemia requiring medical attention: a severe hypoglycemic 
event when subjects require therapy by healthcare professionals (eg, emergency 
medical technicians, emergency room personnel, etc.)
Other Hypoglycemia:

Nocturnal hypoglycemia: any hypoglycemic event (documented symptomatic, 
asymptomatic, probable symptomatic, or severe hypoglycemia) that occurs between 
bedtime and waking

Relative hypoglycemia: an event during which typical symptoms of hypoglycemia, that 
do not require the assistance of another person, are accompanied by PG >70 mg/dL 
(3.9 mmol/L), but these levels may be quickly approaching the 70 mg/dL (3.9 mmol/L) 
threshold

Overall (or total) hypoglycemia: This optional category combines all cases of 
hypoglycemia. If an event of hypoglycemia falls into multiple subcategories, the event is 
only counted once in this category

Probable symptomatic hypoglycemia: An event during which symptoms of 
hypoglycemia are not accompanied by a PG measurement but that was presumably 
caused by a blood glucose concentration ≤70 mg/dL (3.9 mmol/L).
The determination of a hypoglycemic event as an episode of severe hypoglycemia as defined 
above will be made by the investigator based on the medical need of the subject to have required 
assistance and is not predicated on the report of a subject simply having received assistance.
Hypoglycemic events will be recorded in the hypoglycemia module of the eCRF to allow for the 
collection of comprehensive safety information relating to these events.  All episodes of severe 
hypoglycemia will additionally be reported as SAEs (see Section 9.2.1 for details regarding SAE 
reporting).
9.4.3. Vital Signs
For each subject, vital signs measurements should be conducted according to the Schedule of 
Activities (Section 2).  
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.  Additional vital signs may be measured during each study period if 
warranted and agreed upon between Lilly and the investigator.


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9.4.4. Electrocardiograms
For each subject, ECGs should be collected according to the Schedule of Activities (Section 2).  
Any clinically significant findings from ECGs that result in a diagnosis and that occur after the 
subject receives the first dose of the IP, should be reported to Lilly, or its designee.
For each subject, a single12-lead digital electrocardiogram (ECG) will be collected according to 
the Schedule of Activities.  Electrocardiograms must be recorded before collecting any blood 
samples at individual timepoints.  Subjects must be supine for approximately 5 to 10 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/QTc 
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 
adverse event.
9.4.5. Injection-site Reactions
Injection-site assessments for local tolerability will be conducted, when reported as:

an AE from a subject, or

a clinical observation from an investigator.
Reported injection-site reactions will be characterized within the following categories:

edema

erythema

induration

itching

pain.
All injection-site reactions reported as AEs will be closely monitored until resolution.  The report 
of a clinically significant AE of injection-site reaction may prompt notification of the sponsor, 
clinical photography, and referral for dermatologic evaluation and consideration of a skin biopsy 


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Tirzepatide (LY3298176)
and laboratory evaluations (ALT, AST, complete blood count with percent eosinophils, and 
additional immunogenicity testing).
Investigational site staff will be provided with separate instructions/training on how to evaluate 
injection-site reactions and their severity in a consistent manner.  Photographs of injection-site 
reactions may be taken in a standardized manner for record-keeping purposes; however, the 
photographs will not be used to evaluate the severity of injection-site reaction.
9.4.6. Hypersensitivity Reactions
All hypersensitivity reactions will be reported by the investigator as either AEs or, if any serious 
criterion is met, as SAEs.
In the event of suspected drug hypersensitivity reactions (immediate or non-immediate) in 
subjects who experience moderate-to-severe injection reactions as assessed by the investigator, 
unscheduled blood samples will be collected for PK and ADA analyses at the following time 
points:  

as close as possible to the onset of the event

at the resolution of the event

30 (±3) days following the event.  
Additionally, unscheduled serum samples for immune safety laboratory testing (including, but 
not limited to β tryptase, total IgE, complement and cytokine panel testing) should also be 
collected at approximately 60 to 120 minutes and 4 to 6 weeks after the onset of the event in 
these subjects.  
Instructions for the collection and handling of blood samples will be provided by the sponsor.  
The actual date and time (24-hour clock time) of each sampling will be recorded.
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 glucose, amylase, and lipase

serious and nonserious AEs, including AEs of interest.
Further diagnostic assessments will be recommended whenever lipase and/or amylase are 
confirmed to be ≥3 × ULN at any visit postdose even if the subject is asymptomatic (as per the 
algorithm for the monitoring of pancreatic events in Appendix 7) and, if pancreatitis is suspected, 
the case will be further defined during an adjudication process.
When appropriate, the Lilly CP or CRP will consult with the functionally independent Global 
Patient Safety therapeutic area physician or clinical research scientist.


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9.4.7.1.
Hepatic Safety
If a study subject experiences elevated ALT ≥3 × ULN, ALP ≥2 × ULN, or elevated total 
bilirubin ≥2 × ULN, liver tests (Appendix 4) should be repeated within 3 to 5 days including 
ALT, AST, ALP, TBL, conjugated bilirubin, gamma-glutamyl transferase (GGT), 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 3 mL each will be collected to determine the plasma concentrations of 
tirzepatide.  A maximum of 3 unscheduled samples may be collected at additional time points 
during the study if warranted and agreed upon between both the investigator and sponsor.  
Instructions for the collection and handling of blood samples will be provided by the sponsor.  
The actual date and time (24-hour clock time) of each sampling will be recorded.
Failure or being late (ie, outside stipulated time allowances) to perform obtain samples due to 
legitimate clinical issues (eg, equipment technical problems, venous access difficulty, or subject 
defaulting or turning up late on an agreed scheduled procedure) will not be considered as 
protocol deviations but the CRU will have to notify the sponsor in writing via a file note.
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 tirzepatide will be assayed using a validated liquid chromatography tandem 
mass spectrometry method.  
Bioanalytical samples collected to measure IP concentrations will be retained for a maximum of 
2 years following last subject visit for the study.  During this time, samples remaining after the 
bioanalyses may be used for exploratory analyses, such as metabolism work, protein binding, or 
bioanalytical method cross-validation.


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9.6.
Pharmacodynamics
Not applicable.
9.7. Immunogenicity Assessments
For immunogenicity testing, venous blood samples of approximately 10 mL will be collected 
from each subject according to the Schedule of Activities (Section 2), to determine antibody 
production against tirzepatide.  Additional samples may be collected if there is a possibility that 
an AE is immunologically mediated (see Section 9.4.6).  All samples for immunogenicity testing 
should have a time-matched sample for PK analysis where relevant.  Detailed instructions for the 
sample collections and handling will be provided by the sponsor.  The actual date and 24-hour 
clock time of each sampling will be recorded.
Immunogenicity will be assessed by a validated assay designed to detect antidrug antibodies 
(ADA) in the presence of tirzepatide at a laboratory approved by the sponsor.  Antibodies may 
be further evaluated for their ability to neutralize the activity of tirzepatide on GIP and GLP-1 
receptors.  Positive tirzepatide ADA samples may also be tested for cross-reactivity against
native GIP and GLP-1, and, if positive, may then be tested for neutralizing antibodies against 
native GIP and/or GLP-1.
All subjects will have an ADA sample measured at early discontinuation or at Period 2, Day 36.  
A risk-based approach will be used to monitor subjects who develop treatment-emergent ADA 
(TE ADA), defined in Section 10.3.3 (Evaluation of Immunogenicity).
Clinically significant TE ADA will be defined as any TE ADA at the last visit with:

a high titer (1280) or an increasing titer from last measured value

an association with a moderate-to-severe injection-site reaction
Subjects who have clinically significant TE ADA at early discontinuation or at the safety 
follow-up should be followed with ADA testing every 3 months until the ADA titers have 
returned to the baseline ADA titer (defined as ADA titer within 2-fold of baseline) or for up to 
1 year, whichever is less. A PK sample may be collected at the follow-up immunogenicity 
assessment(s), if warranted and agreed upon by the investigator and sponsor.
Every effort should be made to contact subjects for the follow-up immunogenicity assessment; 
however, if subjects are unwilling or unable to return for the visit, this is not considered a 
protocol deviation.
Subjects followed for at least 1 year after dosing who have not returned to baseline, as defined 
above, will be assessed for safety concerns and, if no clinical sequelae are recognized by the 
clinical team, no further follow-up will be required.  Subjects who have clinical sequelae that are 
considered potentially related to the presence of TE ADA may also be asked to return for 
additional follow-up testing.
Samples will be retained for a maximum of 15 years after the last subject visit, or for a shorter 
period if local regulations and ERBs, at a facility selected by the sponsor.  The duration allows 


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the sponsor to respond to future regulatory requests related to the tirzepatide.  Any samples 
remaining after 15 years will be destroyed.  
9.8.
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
tirzepatide and to investigate genetic variants thought to play a role in T2DM.  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 tirzepatide 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. 
9.9.
Biomarkers
Not applicable.
9.10. Health Economics
This section is not applicable for this study.


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10.
Statistical Considerations and Data Analysis
10.1. Sample Size Determination
It is planned that up to approximately 48 subjects may be enrolled so that at least 36 evaluable 
subjects complete the study.  With 36 subjects, we expect the two one-sided tests (TOST) for 
equivalence applied to the lognormal mean ratio to have a power of 98%.  This assumes a
nominal expected mean ratio of 1.05 (autoinjector over prefilled syringe), a coefficient of 
variation of 19.6%, and significance level of 0.05 of each one-sided test when testing against an 
upper limit of 1.25 and lower limit of 0.80.  The source of the choice of coefficient of variation is 
from the final results of study I8F-MC-GPGE.
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, or other demographic characteristics will be 
recorded and may be used in the PK and safety analyses as quantitative of 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 the IP and have evaluable data.  
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.
10.3.1. Safety Analyses
10.3.1.1. Clinical Evaluation of Safety
All IP, study device, and protocol procedure AEs, and study device deficiencies/complaints will 
be listed, and if the frequency of events allows, data will be summarized using descriptive 
methodology.
The incidence of symptoms for each treatment will be presented by severity and by association 
with IP as perceived by the investigator.  Symptoms reported to occur prior to enrollment will be 


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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 IP-related SAEs will be reported.
10.3.1.2. Statistical Evaluation of Safety
Safety parameters that will be assessed include adverse events, safety lab parameters (including 
amylase, lipase, and blood glucose), and vital signs.  The parameters will be listed and 
summarized using standard descriptive statistics, where appropriate. 
Physical examinations and ECGs will be performed for safety monitoring purposes and will not 
be presented. If warranted, additional analysis will be performed upon review of the data.
10.3.1.3. Injection-site Reactions
Incidence of erythema, induration, pain, itching, and edema will be listed and summarized.    
Additional analyses may be performed, if appropriate.
10.3.2. Pharmacokinetic Analyses
10.3.2.1. Pharmacokinetic Parameter Estimation
Pharmacokinetic parameter estimates for tirzepatide will be calculated by standard 
noncompartmental methods of analysis.
The primary PK parameters for analysis will be Cmax and AUC(0-∞).  Other noncompartmental 
parameters, such as time to Cmax (tmax), AUC(0-tlast), half-life associated with the terminal rate 
constant in noncompartmental analysis (t1/2), apparent clearance (CL/F), and apparent volume 
of distribution (V/F) may be reported.
10.3.2.2. Pharmacokinetic Statistical Inference
Two one-sided equivalence tests (TOST) will be applied to the ratios of each of Cmax and AUC
using the AI as the test sample and the PFS as the reference.  Test limits of the ratios to establish 
comparability are 0.8 and 1.25.  
Pharmacokinetic parameters will be evaluated to estimate the relative bioavailability.  
Log-transformed Cmax and AUC(0-∞) will be evaluated in a linear mixed-effects model with
fixed effects for device, sequence, period, and a random effect for subject within sequence.  The 
treatment differences will be back-transformed to present the ratios of geometric means and the 
corresponding 90% CI.  Other parameters may be analyzed in this way as needed.
The tmax will be analyzed using a Wilcoxon signed rank test.  Estimates of the median difference 
based on the observed medians and 90% CIs from the Wilcoxon test will be calculated.
Planned PK parameters will also be summarized with descriptive statistics.
10.3.3. Evaluation of Immunogenicity
The frequency and percentage of subjects with preexisting ADA and with TE ADA+ to 
tirzepatide will be tabulated. Treatment-emergent ADAs are defined as those with a titer 2-fold 


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(1 dilution) greater than the minimum required dilution if no ADAs were detected at baseline 
(treatment-induced ADA) or those with a 4-fold (2 dilutions) increase in titer compared to 
baseline if ADAs were detected at baseline (treatment-boosted ADA). The minimum required 
dilution of the ADA assay is 1:10. For the TE ADA+ subjects, the distribution of maximum 
titers will be described.  The frequency of neutralizing antibodies if performed, will be tabulated 
in TE ADA+ subjects.  If cross-reactivity with to native GLP-1 and GIP or neutralizing 
antibodies against native GLP-1 and GIP assays are performed, the frequency of each will be 
reported.
10.3.4. Data Review During the Study
This section is not applicable for this study.
10.3.5. Interim Analyses
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the Lilly CP, CRP/investigator, or designee will consult with the appropriate medical 
director or designee to determine if it is necessary to amend the protocol.


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11.
References
American Diabetes Association. 6. Glycemic targets: Standards of Medical Care in Diabetes—
2018. Diabetes Care 2018;41(Suppl. 1):S55–S64 © 2017 by the American Diabetes Association.
Banks PA, Freeman ML. Practice guidelines in acute pancreatitis. Am J Gastroenterol. 
2006;101(10):2379-2400.
Coskun T, Sloop K, Loghin C, Alsina-Fernandez J, Urva S, Bokvist KB, Cui X, Briere DA,
Cabrera O, Roell WC, Kuchibhotla U, Moyers JS, Benson CT, Gimeno RE, D’Alessio DA,
Haupt A. LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2
diabetes mellitus: From discovery to clinical proof of concept. Molecular metabolism.
2018;18:3-14.
Frias JP, Nauck MA, Van J, Kutner ME, Cui X, Benson C, Urva S, Gimeno RE, Milicevic Z,
Robins D, Haupt A. Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor
agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active
comparator-controlled phase 2 trial. The Lancet. 2018;392(10160): 2180-2193.
International Hypoglycemia Study Group. Glucose Concentrations of Less Than 3.0 mmol/L 
(54 mg/dL) Should Be Reported in Clinical Trials: A Joint Position Statement of the American 
Diabetes Association and the European Association for the Study of Diabetes.  Diabetes Care 
2017;40(1): 155-157.
Koizumi M, Takada T, Kawarada Y, Hirata K, Mayumi T, Yoshida M, Sekimoto M, Hirota M, 
Kimura Y, Takeda K, Isaji S, Otsuki M, Matsuno S; JPN. JPN Guidelines for the management 
of acute pancreatitis: diagnostic criteria for acute pancreatitis. J Hepatobiliary Pancreat Surg.
2006;13(1):25-32.
Steinberg WM, Buse JB, Ghorbani MLM, Ørsted DD, Nauck MA; LEADER Steering 
Committee; LEADER Trial Investigators. Amylase, lipase, and acute pancreatitis in people with 
type 2 diabetes treated with liraglutide: results from the LEADER Randomized Trial. Diabetes 
Care. 2017a;40(7):966-972.
Steinberg WM, Rosenstock J, Wadden TA, Donsmark M, Jensen CB, DeVries JH. Impact of 
liraglutide on amylase, lipase, and acute pancreatitis in participants with overweight/obesity and 
normoglycemia, prediabetes, or type 2 diabetes: secondary analyses of pooled data from the 
SCALE clinical development program. Diabetes Care. 2017b;40(7):839-848.


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12.
Appendices


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Appendix 1.
Abbreviations and Definitions


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Term
Definition
AE
adverse event:  Any untoward medical occurrence in a subject 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.
assent
Agreement from a child or other individual who is not legally capable of providing consent, 
but who can understand the circumstances and potential risks involved in participating in a 
study (required by some ethical review boards [ERBs]). 
CIOMS
Council for International Organizations of Medical Sciences
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all the study-related requirements, good clinical practice (GCP) requirements, 
and the applicable regulatory requirements.
confirmation
A process used to confirm that laboratory test results meet the quality requirements defined 
by the laboratory generating the data and that Lilly is confident that results are accurate.  
Confirmation will either occur immediately after initial testing or will require that samples 
be held to be retested at some defined time point, depending on the steps required to obtain 
confirmed results.
CP
Clinical Pharmacologist
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.
enroll
The act of assigning a subject to a treatment sequence.  Subjects who are enrolled in the 
study are those who have been assigned to a treatment sequence.
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
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonization
IND
Investigational New Drug:  An application to the FDA to allow testing of a new drug in 
humans.


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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.  
Investigational 
product (IP)
A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical study, including products already on the market when used or assembled 
(formulated or packaged) in a way different from the authorized form, or marketed products 
used for an unauthorized indication, or marketed products used to gain further information 
about the authorized form.
investigator
A person responsible for the conduct of the clinical study at a study site.  If a study is 
conducted by a team of individuals at a study site, the investigator is the responsible leader 
of the team and may be called the principal investigator.
IV
intravenous
MTD
maximum tolerated dose
Non-
investigational 
product (non-IP)
A product that is not being tested or used as a reference in the clinical study, but is provided 
to subjects and used in accordance with the protocol, such as:  concomitant or rescue/escape 
medication for preventative, diagnostic, or therapeutic reasons, medication to ensure 
adequate medical care, and/or products used to induce a physiological response.
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.
randomize
The process of assigning subjects to an experimental group on a random basis
PK/PD
pharmacokinetic/pharmacodynamic
SAE
serious adverse event
screen
The act of determining if an individual meets minimum requirements to become part of a 
pool of potential candidates for participation in a clinical study.  
SUSARs
suspected unexpected serious adverse reactions
TEAE
treatment-emergent adverse event:  Any untoward medical occurrence that emerges during 
a defined treatment period, having been absent pretreatment, or worsens relative to the 
pretreatment state, and does not necessarily have to have a causal relationship with this 
treatment 


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Appendix 2.
Clinical Laboratory Tests
Safety Laboratory Tests
Hematologya
Clinical Chemistrya
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Bicarbonate
Mean cell volume 
Chloride
Mean cell hemoglobin 
Calcium
Mean cell hemoglobin concentration 
Glucose (fasting)
Leukocytes (WBC)
Blood urea 
Total protein
Absolute counts of:
Albumin
Neutrophils
Total bilirubin
Lymphocytes
Alkaline phosphatase
Monocytes
Aspartate aminotransferase
Eosinophils
Alanine aminotransferase
Basophils
Creatinine
Platelets
Amylase
Lipase
Triglyceridec
Urinalysisa
Specific gravity
Hepatitis B surface antigenc
pH
Hepatitis C antibodyc
Protein
HIV or HIV antibodyc
Glucose
FSHd
Ketones
Pregnancy testd
Bilirubin
Urobilinogen
Blood
Nitrite
Leukocytes (WBC)
Microscopic examination of sedimentb
Abbreviations:  FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; RBC = red blood cells; 
WBC = white blood cells.
a
Performed by local laboratory.  Results will be validated by the laboratory at the time of initial testing.
b
Test only if dipstick result is abnormal (ie, positive for blood, protein, or nitrites) if clinically indicated, per 
investigator discretion.
c
Performed by local laboratory at screening only.  Tests may be waived if they have been performed within 6 months 
before screening with reports available for review.
d
For women only. Serum pregnancy test will be performed at screening and urine pregnancy tests at subsequent 
visits.  For women who are considered to be postmenopausal, a blood sample for follicle stimulating hormone 
should be drawn at screening to confirm postmenopausal status as defined in inclusion criterion [1b]; women 
with confirmed nonchildbearing potential status can be exempted from further pregnancy tests during the study 
after screening.


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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.  This includes obtaining the 
appropriate signatures and dates on the ICF prior to the performance of any protocol 
procedures and prior to the administration of IP.

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 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 must give assurance that the ERB was properly constituted and convened as 
required by 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.  Lilly or its representatives must approve the ICF 
before it is used at the investigative site.  All ICFs must be compliant with the ICH guideline on 
GCP.
The study site’s ERB(s) should be provided with the following:

the current IB and updates during the course of the study

ICF

relevant curricula vitae
Regulatory Considerations
This study will be conducted in accordance with the protocol and with:
1) consensus ethics principles derived from international ethics guidelines, 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines 


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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 site, as appropriate.

provide training to instruct the investigators and study coordinators.  This training will 
give instruction on the protocol, the completion of the eCRFs, and study procedures.

make periodic visits to the study site.

be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax.

review and evaluate eCRF data and/or use standard computer edits to detect errors in data 
collection.

conduct a quality review of the database.
In addition, Lilly or its representatives will periodically check a sample of the 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 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.


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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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Tirzepatide (LY3298176)
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 CRP.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
WBC
Prothrombin Time, INR
Neutrophils
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B Core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Conjugated bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear antibodya
AST
Alkaline Phosphatase Isoenzymesa
GGT
Creatinine kinase
Anti-smooth muscle antibody (or anti-actin 
antibody)a
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; 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.


I8F-MC-GPGS Clinical Pharmacology Protocol
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Tirzepatide (LY3298176)
Appendix 5.
Blood Sampling Summary
This table summarizes the approximate number of venipunctures and blood volumes for all 
blood sampling (screening, safety laboratories, immunogenicity, pharmacokinetics, blood 
glucose, and bioanalytical assays) during the study.  
Protocol I8F-MC-GPGS Sampling Summary
Purpose
Blood Volume 
per Sample (mL)
Estimated Number 
of Blood Samples
Total 
Volume (mL)
Screening tests (local laboratory)a
20
1
20
Clinical laboratory tests (local laboratory)a

Study visits (2 periods)
10
6 × 2 periods = 12
120
Pharmacokinetics (central or referral laboratory)b

Study visits (2 periods)
3
14 × 2 periods (+3 
unscheduled) = 31
93
Immunogenicity (central or referral laboratory)

Study visits (2 periods)
10 
3 × 2 periods (+3 
unscheduled) = 9
90
Blood glucosea
0.3
6 (+5 discard for 
cannula patency +3 
unscheduled) x 2 
periods = 28
8.4
Pharmacogenetics (stored sample)
10
1
10
Total
341.4
Total for clinical purposes rounded up to nearest 10 mL
350
a
Additional samples may be drawn if needed for safety purposes.
b
Up to 3 additional unscheduled samples may be drawn based on emerging data.


I8F-MC-GPGS Clinical Pharmacology Protocol
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Tirzepatide (LY3298176)
Appendix 6.
Classification of Contraceptive Methods
Highly Effective (Less Than 1% Failure Rate) Methods of Contraception:

Combined oral contraceptive pill and mini pill

NuvaRing

Implantable contraceptives

Injectable contraceptives (such as Depo-Provera®)

Intrauterine device (such as Mirena® and ParaGard®)

Contraceptive patch – ONLY women <198 pounds or 90 kg

Total abstinence or in a same-sex relationship (if this is their preferred and usual 
lifestyle).  Note:  periodic abstinence (for example, calendar, ovulation, symptothermal, 
postovulation methods), declaration of abstinence just for the duration of a trial, and 
withdrawal are not acceptable methods of contraception

Vasectomy – for men in clinical trials
Effective Methods of Contraception (Must Use Combination of 2 Methods):

Male condom with spermicide*

Female condom with spermicide*

Diaphragm with spermicide

Cervical sponge

Cervical cap with spermicide
* The use of male and female condoms as a double-barrier method is not considered acceptable.


I8F-MC-GPGS Clinical Pharmacology Protocol
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Tirzepatide (LY3298176)
Appendix 7. Pancreatic Monitoring
Glucagon-like peptide-1 agonists have been associated with a possible risk of acute pancreatitis.  
In 2006, the United States prescribing information for exenatide was revised to include the event 
of pancreatitis.  In 2007, the United States 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 T2DM.
To enhance understanding of the natural variability of pancreatic enzymes in the T2DM 
population and, in order to assess for any potential effects of tirzepatide on the exocrine 
pancreas, amylase and lipase values will be monitored in all current and future clinical trials with 
tirzepatide.
Additional monitoring will be requested for amylase and/or lipase values ≥3 × ULN at any visit, 
even in asymptomatic subjects (see figure below).  Lipase and amylase values may also be 
obtained at any time during the clinical trials for any subject suspected of having symptoms 
suggestive of exenatide pancreatitis (such as severe GI signs and/or symptoms), at the 
investigator’s discretion.
Acute pancreatitis is an AE 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 ≥3 × ULN

characteristic findings of acute pancreatitis on CT 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 one-half of 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 ≥3 × ULN, an 
algorithm is in place to follow these subjects safely and to quickly reach (or not reach) a 
diagnosis of pancreatitis.


I8F-MC-GPGS Clinical Pharmacology Protocol
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Tirzepatide (LY3298176)
Abbreviations:  CBC = complete blood count; CT = computed tomography; 
LFTs = liver function tests; MRI = magnetic resonance imaging.


I8F-MC-GPGS Clinical Pharmacology Protocol
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Tirzepatide (LY3298176)
Subjects diagnosed with pancreatitis will be discontinued from the study.  Investigators will be 
responsible for following, through an appropriate healthcare option, these pancreatitis AEs until 
the events resolve or are explained.  Adverse events that meet the diagnostic criteria of acute 
pancreatitis will be captured as SAEs.  For all other pancreatic AEs (such as idiopathic or 
asymptomatic pancreatic enzyme abnormalities), the investigator will be responsible for 
determining the seriousness of the event (AE or SAE) and the relatedness of the event to study 
drug.


Leo Document ID = 27265f5a-b6df-450c-be6b-adf215abc354
Approver: 
Approval Date & Time: 04-Jun-2019 11:32:58 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 04-Jun-2019 15:51:32 GMT
Signature meaning: Approved
PPD
PPD

SAP_001.pdf: 
Statistical Analysis Plan  
 
 
A Study to Compare the Pharmacokinetics of Tirzepatide Administered Subcutaneously by an 
Autoinjector versus Prefilled Syringe in Healthy Subjects  
 
 
NCT04004988  
 
 
Approval Date: 09-Aug-2019 
 
 


Final: 08 August 2019
             Page 1 of 16
STATISTICAL ANALYSIS PLAN
A Study to Compare the Pharmacokinetics of Tirzepatide Administered Subcutaneously by 
an Autoinjector versus Prefilled Syringe in Healthy Subjects
Statistical Analysis Plan Status: Final
Statistical Analysis Plan Date: 08-August-2019
Study Drug: Tirzepatide (LY3298176)
Sponsor Reference: I8F-MC-GPGS
Covance CRU Study: 1001215-8399714
Clinical Phase I
Approval Date: 09-Aug-2019 GMT


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             Page 2 of 16
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.: 1001215-8399714
Sponsor Reference: I8F-MC-GPGS
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.
TREATMENT .....................................................................................................................6
7.
SAMPLE SIZE JUSTIFICATION .......................................................................................7
8.
DEFINITION OF ANALYSIS POPULATIONS..................................................................7
9.
STATISTICAL METHODOLOGY .....................................................................................7
9.1
General..........................................................................................................................7
9.2
Demographics and Subject Disposition..........................................................................8
9.3
Pharmacokinetic Assessment.........................................................................................8
9.3.1
Pharmacokinetic Analysis.....................................................................................8
9.3.2
Pharmacokinetic Statistical Methodology ...........................................................12
9.4
Safety and Tolerability Assessments............................................................................12
9.4.1
Adverse events ...................................................................................................12
9.4.2
Glucose Monitoring and Hypoglycemia..............................................................13
9.4.3
Concomitant medication.....................................................................................14
9.4.4
Clinical laboratory parameters............................................................................14
9.4.5
Vital signs ..........................................................................................................14
9.4.6
Electrocardiogram (ECG)...................................................................................14
9.4.7
Injection-Site Reactions......................................................................................14
9.4.8
Hepatic Monitoring ............................................................................................15
9.4.9
Hypersensitivity reactions...................................................................................15
9.4.10
Immunogenicity Assessments.............................................................................15
9.4.11
Other assessments...............................................................................................15
9.4.12
Safety and Tolerability Statistical Methodology..................................................15
10. INTERIM ANALYSES .....................................................................................................16
11. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ............16
12. REFERENCES ..................................................................................................................16
13. DATA PRESENTATION ..................................................................................................16
13.1 Derived Parameters .....................................................................................................16
13.2 Missing Data ...............................................................................................................16
13.3 Insufficient Data for Presentation ................................................................................16


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.: 1001215-8399714
Sponsor Reference: I8F-MC-GPGS
2. ABBREVIATIONS
Abbreviations pertain to the Statistical Analysis Plan (SAP) only (not the tables, figures and 
listings [TFLs]).
%AUC(tlast-∞)
Percentage of AUC(0-∞) extrapolated
ADA
Anti-drug antibody
AE
Adverse event
AI
Autoinjector
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AUC
Area under the concentration versus time curve
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 timepoint with a measurable concentration
BQL
Below the lower limit of quantification
CL/F
Apparent total body clearance of drug calculated after extra-vascular
administration
Clast
Last quantifiable drug concentration
Cmax
Maximum observed drug concentration
CRF
Case Report Form
CRU
Clinical Research Unit
CSR
Clinical Study Report
CV
Coefficient of variation
ECG
Electrocardiogram
ICH
International Conference on Harmonisation
LLOQ
Lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
MRE
Magnetic resonance elastography
PFS
Prefilled syringe
PG
Plasma Glucose
PK
Pharmacokinetic(s)
SAP
Statistical Analysis Plan
SC
Subcutaneous


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.: 1001215-8399714
Sponsor Reference: I8F-MC-GPGS
SD
Standard deviation 
t1/2
Half-life associated with the terminal rate constant (λz) in 
non-compartmental analysis
TBL
Total bilirubin
TE
Treatment emergent
TFLs
Tables, Figures, and Listings
tmax
Time of maximum observed drug concentration
ULN
Upper limit of normal
Vss/F
Apparent volume of distribution at steady state after extravascular 
administration
Vz/F
Apparent volume of distribution during the terminal phase after 
extra-vascular administration
WHO
World Health Organization


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.: 1001215-8399714
Sponsor Reference: I8F-MC-GPGS
3. INTRODUCTION
This SAP has been developed after review of the Clinical Study Protocol (final version dated 
4th June 2019).
This SAP describes the planned analysis of the pharmacokinetic (PK), safety and tolerability 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 with Eli Lilly and Company. 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 treatment 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 with
Eli Lilly and Company 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 
Conference 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 establish comparability between the autoinjector (AI; test) and the prefilled syringe (PFS; 
reference), as assessed by tirzepatide PK in healthy subjects.
4.2
Secondary Objective
To compare the safety and tolerability of a single subcutaneous (SC) dose of tirzepatide 
administered by AI (test) versus PFS (reference).
5. STUDY DESIGN
This study is a single center, open-label, randomized, 2-period, 2-sequence, crossover study 
conducted in healthy subjects.


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.: 1001215-8399714
Sponsor Reference: I8F-MC-GPGS
The study design is as follows:
Abbreviations: AI = autoinjector; CRU = clinical research unit; PFS = prefilled syringe; PK = pharmacokinetics.
Site staff will administer all injections. All injections will be administered in the abdomen whilst
the subject is in a sitting or reclining position. Injections will be given in the lower abdominal
quadrant. Study injections should be given by a limited number of individuals for consistency.
There will be a washout of at least 35 days between tirzepatide doses. Subjects will be
randomized to 1 of the 2 treatment sequences shown above. It is intended that the same number
of subjects will be randomized into each treatment sequence.
6. TREATMENT
The following is a list of the study treatment abbreviations that will be used in the TFLs.
Study Treatment Name
Treatment order in TFL
5 mg tirzepatide SC (AI)
1
5 mg tirzepatide SC (PFS)
2


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.: 1001215-8399714
Sponsor Reference: I8F-MC-GPGS
7. SAMPLE SIZE JUSTIFICATION
It is planned that up to approximately 48 subjects may be enrolled so that at least 36 evaluable 
subjects complete the study.
With 36 subjects, we expect the two one-sided tests for equivalence applied to the lognormal 
mean ratio to have a power of 98%. This assumes a nominal expected mean ratio of 1.05 
(autoinjector over prefilled syringe), a coefficient of variation of 19.6%, and significance level of 
0.05 of each one-sided test when testing against an upper limit of 1.25 and lower limit of 0.80. 
The source of the choice of coefficient of variation is from the final results of study 
I8F-MC-GPGE.
8. DEFINITION OF ANALYSIS POPULATIONS
The “Safety” population will consist of all enrolled subjects who receive at least one dose of 
tirzepatide, whether or not they completed all protocol requirements.
The “Pharmacokinetic” population will consist of all subjects who received at least one dose of 
tirzepatide 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 are 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: area under the concentration 
versus time curve [AUCs] and maximum observed drug concentration [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.


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.: 1001215-8399714
Sponsor Reference: I8F-MC-GPGS
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. All other demographic 
variables will be listed only.
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 8.1 or later).
Plasma concentrations of tirzepatide (LY3298176) will be used to determine the following PK 
parameters, when possible: 
Parameter
Units
Definition
AUC(0-tlast)
ng.h/mL
area under the concentration versus time curve from time 
zero to time t, where t is the last timepoint with a measurable 
concentration
AUC(0-∞)
ng.h/mL
area under the concentration versus time curve from time 
zero to infinity
%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.


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.: 1001215-8399714
Sponsor Reference: I8F-MC-GPGS
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.

Cmax and tmax will be reported from observed values. If Cmax occurs at more than 
one timepoint, 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 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 serum 
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 the last observed quantifiable drug concentration (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 
quantification (BQL). Plasma concentrations reported as BQL will be set to a value of 
zero when all of the following conditions are met:
o
The compound is non-endogenous.
o
The samples are from the initial dose period for a subject or from a subsequent 
dose period following a suitable wash-out period.


Final: 08 August 2019
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.: 1001215-8399714
Sponsor Reference: I8F-MC-GPGS
o
The timepoints 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

Individual concentrations will be plotted utilizing actual sampling times.

The terminal point selections will be indicated on a semi-logarithmic plot.
Average Concentration vs. Time Profiles

The average concentration profiles will be graphed using scheduled (nominal) sampling 
times.

The average concentration profiles will be graphed using arithmetic average 
concentrations.

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.

Concentrations at a sampling time exceeding the sampling time window specified in the 
protocol, or ± 10%, will be excluded from the average concentration profiles.

Concentrations excluded from the mean calculation will be documented in the final study 
report.

A concentration average will be plotted for a given sampling time only if 2/3 of the 
individual data at the timepoint 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 PK 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.


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.: 1001215-8399714
Sponsor Reference: I8F-MC-GPGS
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 PK 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.
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.


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.: 1001215-8399714
Sponsor Reference: I8F-MC-GPGS
9.3.2
Pharmacokinetic Statistical Methodology
Two one-sided equivalence tests will be applied to the ratios of each of Cmax and AUC(0-∞) 
using the AI as the test sample and the PFS as the reference. Test limits of the ratios to establish 
comparability are 0.8 and 1.25.
PK parameters will be evaluated to estimate the relative bioavailability. Log-transformed Cmax 
and AUC(0-∞) will be evaluated in a linear mixed-effects model3 with fixed effects for device, 
sequence, period, and a random effect for subject within sequence. The treatment differences will 
be back-transformed to present the ratios of geometric means between AI and PFS treatments
and the corresponding 90% CI. Other parameters may be analyzed in this way as needed.
Example SAS code for analysis:
proc mixed data=xxx;
    class sequence subject period device;
    model log_pk = sequence period device / ddfm=kr;
    random subject(sequence);
    lsmeans device / pdiff cl alpha=0.1; 
    ods output lsmeans=lsmeans diffs=diffs;
run;
The tmax will be analyzed through non-parametric methods. The median for each treatment and 
median of differences between the AI and PFS treatments will be presented, along with the 
approximate 90% CI for the difference. The p-value from a Wilcoxon signed-rank test will also 
be presented.
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 dosing. 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 (AI, PFS, and 
Overall), 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 22.0 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 by the investigator. Any serious AEs will be listed. 
Discontinuations due to AEs will be listed.


Final: 08 August 2019
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.: 1001215-8399714
Sponsor Reference: I8F-MC-GPGS
9.4.2
Glucose Monitoring and Hypoglycemia
During the study, blood glucose concentrations will be monitored for safety assessments.
Glucose data will be listed and summarized by treatment together with changes from baseline, 
where baseline is defined as Day 1 predose.
Hypoglycemic events will be appropriately recorded in the CRF. In the case of a hypoglycemic 
event, the actual blood glucose value, if measured, will be recorded in the CRF, together with 
any treatments administered. Each category of hypoglycemic events (defined below) will be 
listed and summarized by treatment. Hypoglycemia is defined as follows:

Documented Glucose Alert Level (Level 1), Plasma Glucose (PG) ≤70 mg/dL 
(3.9 mmol/L):
o
Symptomatic hypoglycemia: an event during which typical symptoms of 
hypoglycemia are accompanied by PG ≤70 mg/dL (3.9 mmol/L)
o
Asymptomatic hypoglycemia: an event not accompanied by typical symptoms of 
hypoglycemia but with PG ≤70 mg/dL (3.9 mmol/L)
o
Unspecified hypoglycemia: an event during which PG ≤70 mg/dL (3.9 mmol/L) 
but no information relative to symptoms of hypoglycaemia

Documented Clinically Significant Hypoglycemia (Level 2) PG ≤54 mg/dL 
(3.0 mmol/L):
o
Symptomatic hypoglycemia: an event during which typical symptoms of 
hypoglycemia are accompanied by PG ≤54 mg/dL (3.0 mmol/L)
o
Asymptomatic hypoglycemia: an event not accompanied by typical symptoms 
of hypoglycemia but with PG ≤54 mg/dL (3.0 mmol/L)
o
Unspecified hypoglycemia: an event during which PG ≤54 mg/dL (3.0 mmol/L) 
but no information relative to symptoms of hypoglycemia was recorded

Severe hypoglycemia (Level 3): an event requiring the assistance of another person to 
actively administer carbohydrate, glucagon, or other resuscitative actions. During these 
episodes, the subject has an altered mental status and cannot assist in their care, is 
semiconscious or unconscious, or experienced coma with or without seizures and may 
require parenteral therapy. Plasma glucose measurements may not be available during 
such an event, but neurological recovery attributable to the restoration of blood glucose 
concentration to normal is considered sufficient evidence that the event was induced by a 
low PG concentration (≤70 mg/dL [3.9 mmol/L]).
o
Severe hypoglycemia requiring medical attention: a severe hypoglycemic 
event when subjects require therapy by health care providers (emergency medical 
technicians, emergency room personnel, etc.).
Other Hypoglycemia:

Nocturnal hypoglycemia: any hypoglycemic event (documented symptomatic, 
asymptomatic, probable symptomatic, or severe hypoglycemia) that occurs between 
bedtime and waking


Final: 08 August 2019
             Page 14 of 16
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.: 1001215-8399714
Sponsor Reference: I8F-MC-GPGS

Relative hypoglycemia: an event during which typical symptoms of hypoglycemia, 
which do not require the assistance of another person, are accompanied by PG>70 mg/dL 
(3.9 mmol/L), but these levels may be quickly approaching the 70 mg/dL (3.9 mmol/L) 
threshold

Overall (or total) hypoglycemia: this optional category combines all cases of 
hypoglycemia. If an event of hypoglycemia falls into multiple subcategories, the event is 
counted only once in this category

Probable symptomatic hypoglycemia: an event during which symptoms of 
hypoglycemia are not accompanied by a PG measurement but that was presumably 
caused by PG ≤70 mg/dL (3.9 mmol/L).
Investigator review of glucose results clinically indicative of hypoglycemia will be required.
9.4.3
Concomitant medication
Concomitant medication will be coded using the WHO drug dictionary (Version March 2019). 
Concomitant medication will be listed.
9.4.4
Clinical laboratory parameters
All clinical chemistry and hematology data will be summarized by parameter and treatment, and 
listed. Urinalysis data will be listed. Additionally, clinical chemistry, hematology and urinalysis 
data outside the reference ranges will be listed and flagged on individual subject data listings.
9.4.5
Vital signs
Vital signs data will be summarized by treatment together with changes from baseline, where 
baseline is defined as the Day 1 predose assessment. Figures of mean vital signs and mean 
changes from baseline profiles will be presented by treatment. 
Values for individual subjects will be listed.
9.4.6
Electrocardiogram (ECG)
ECGs will be performed for safety monitoring purposes only and will not be presented. Any 
clinically significant findings from ECGs will be reported as an AE.
9.4.7
Injection-Site Reactions
Injection-site assessments for local tolerability will be conducted, when reported as:

an AE from a subject, or

a clinical observation from an investigator.
Injection site assessment data (erythema, induration, categorical pain, pruritus, and edema) will 
be listed and summarized by treatment in frequency tables.


Final: 08 August 2019
             Page 15 of 16
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.: 1001215-8399714
Sponsor Reference: I8F-MC-GPGS
9.4.8
Hepatic Monitoring
If a subject 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. Additional safety data may be collected if 
required, as defined in the protocol. Where applicable, the following will be presented.
The subjects’ liver disease history and associated person liver disease history data will be listed. 
Any concomitant that have potential for hepatotoxicity, including acetaminophen will be listed.
Results from any hepatic monitoring procedures, such as a magnetic resonance elastography 
(MRE) scan, and biopsy assessments will be listed, if performed.
Hepatic risk factor assessment data will be listed. Liver related signs and symptoms data will be 
summarized by treatment and 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 subject data listings.
9.4.9
Hypersensitivity reactions
For all drug hypersensitivity reactions that occur, additional follow-up data will be collected to
assess the patient’s medical history, alternative causes, and symptoms.
These data will be listed.
9.4.10
Immunogenicity Assessments
Immunogenicity data will be listed and frequency tables will be presented. The frequency and
percentage of patients with pre-existing antidrug antibody (ADA) and with treatment-emergent 
ADAs (TE ADAs) will be presented.
Treatment-emergent ADAs are defined as those with a titer 2-fold (1 dilution) greater than the 
minimum required dilution if no ADAs were detected at baseline (treatment-induced ADA) or 
those with a 4-fold (2 dilutions) increase in titer compared to baseline if ADAs were detected at 
baseline (treatment-boosted ADA). The minimum required dilution of the ADA assay is 1:10. 
For the TE ADA subjects, the distribution of maximum titers will be described. The frequency of 
neutralizing antibodies if performed, will be tabulated in TE ADA subjects. If cross-reactivity 
with to native GLP-1 and GIP or neutralizing antibodies against native GLP-1 and GIP assays 
are performed, the frequency of each will be reported.
9.4.11
Other assessments
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analyzed.
9.4.12
Safety and Tolerability Statistical Methodology
No inferential statistical analyses are planned.


Final: 08 August 2019
             Page 16 of 16
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.: 1001215-8399714
Sponsor Reference: I8F-MC-GPGS
10.
INTERIM ANALYSES
No interim statistical analyses are planned.
11.
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES
There were no changes from the protocol specified statistical analyses.
12.
REFERENCES
1. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9), 5 February 1998.
2. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), 30 November 1995.
3. Brown H, Prescott R. Applied Mixed Models in Medicine. Chichester: John Wiley & Sons, 
1999.
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 center of the table, 
such as, “No serious adverse events occurred for this study.”


Leo Document ID = 1d73bc7b-aa29-4442-b91e-6c539bf62e3e
Approver: 
)
Approval Date & Time: 09-Aug-2019 08:48:06 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 09-Aug-2019 09:35:07 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 09-Aug-2019 12:49:10 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 09-Aug-2019 14:32:41 GMT
Signature meaning: Approved
PPD
PPD
PPD
PPD