Clinical trial NCT04235959
Conditions: Diabetes Mellitus, Type 2
Sponsor: Eli Lilly and Company
Start date: 2020-10-21; Completion date: 2021-08-17
Enrollment: 24 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main purpose of this study is to learn more about the safety and side effects of tirzepatide in Chinese participants with type 2 diabetes mellitus. The study will also measure how much tirzepatide gets into the bloodstream and how long it takes the body to remove it. The study will last about six or eight months for each participant.

Detailed description:

Arms: arm 1: Participants received placebo once weekly (QW) subcutaneously (SC). arm 2: Participants in Cohort 1 received weekly SC doses of tirzepatide with titration regimen starting from 2.5 mg for Weeks 0 through 3 followed by 5 mg for Weeks 4 through 7, 7.5 mg for Weeks 8 through 11, and 10 mg for Weeks 12 through 15.

Participants in Cohort 2 received weekly SC doses of tirzepatide with titration regimen starting from 2.5 mg for Weeks 0 through 3 followed by 5 mg for Weeks 4 through 7, 7.5 mg for Weeks 8 through 11, and 10 mg for Weeks 12 through 15, 12.5 mg for Weeks 16 through 19, and 15 mg for Weeks 20 through 23.
Interventions: intervention 1: Tirzepatide intervention 2: Placebo
Intervention descriptions: intervention 1: Administered SC intervention 2: Administered SC

Protocol documents:
Prot_000.pdf: 
 
 
 
Protocol I8F-MC-GPHT(b) 
 
 
A Multiple Dose Titration Study in Chinese Patients with Type 2 Diabetes Mellitus to 
Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of 
Tirzepatide 
  
NCT04235959 
 
Approval Date: 01-Jul-2020 
 
 


I8F-MC-GPHT(b) Clinical Pharmacology Protocol
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LY3298176
Protocol I8F-MC-GPHT(b)
A Multiple Dose Titration Study in Chinese Patients with 
Type 2 Diabetes Mellitus to Investigate the Safety, 
Tolerability, Pharmacokinetics, Pharmacodynamics, and 
Efficacy of Tirzepatide
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 (FOIA) 
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
13 March 2019
Amendment (a) Electronically Signed and Approved by Lilly on
14 February 2020
Amendment (b) Electronically Signed and Approved by Lilly on approval date provided 
below.
Approval Date: 01-Jul-2020 GMT


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Table of Contents
A Multiple Dose Titration Study in Chinese Patients with Type 
2 Diabetes Mellitus to Investigate the Safety, Tolerability, 
Pharmacokinetics, Pharmacodynamics, and Efficacy of 
Tirzepatide
Section
Page
Protocol I8F-MC-GPHT(b) A Multiple Dose Titration Study in Chinese 
Patients with Type 2 Diabetes Mellitus to Investigate the Safety, 
Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of 
Tirzepatide..........................................................................................................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis................................................................................................................8
2.
Schedule of Activities .......................................................................................................10
3.
Introduction ......................................................................................................................25
3.1.
Study Rationale............................................................................................................25
3.2.
Background..................................................................................................................25
3.3.
Benefit/Risk Assessment..............................................................................................27
4.
Objectives and Endpoints..................................................................................................29
5.
Study Design.....................................................................................................................30
5.1.
Overall Design .............................................................................................................30
5.2.
Number of Participants.................................................................................................32
5.3.
End of Study Definition ...............................................................................................32
5.4.
Scientific Rationale for Study Design...........................................................................32
5.5.
Justification for Dose ...................................................................................................32
6.
Study Population...............................................................................................................34
6.1.
Inclusion Criteria..........................................................................................................34
6.2.
Exclusion Criteria ........................................................................................................36
6.2.1.
Medical Conditions..............................................................................................36
6.2.2.
Prior/Concomitant Therapy..................................................................................38
6.2.3.
Prior/Concurrent Clinical Trial Experience...........................................................38
6.2.4.
Other Exclusions..................................................................................................38
6.3.
Lifestyle and/or Dietary Requirements .........................................................................39
6.3.1.
Meals and Dietary Restrictions.............................................................................39
6.3.2.
Caffeine, Alcohol, and Tobacco ...........................................................................40


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6.3.3.
Activity................................................................................................................40
6.4.
Screen Failures.............................................................................................................40
7.
Treatment..........................................................................................................................41
7.1.
Treatment Administered...............................................................................................41
7.1.1.
Packaging and Labeling .......................................................................................42
7.1.2.
Medical Devices...................................................................................................42
7.2.
Method of Treatment Assignment ................................................................................42
7.2.1.
Selection and Timing of Doses.............................................................................42
7.3.
Blinding .......................................................................................................................42
7.4.
Dose Modification........................................................................................................43
7.5.
Preparation/Handling/Storage/Accountability...............................................................43
7.6.
Treatment Compliance .................................................................................................43
7.7.
Concomitant Therapy...................................................................................................44
7.7.1.
Management of Patients with Gastrointestinal Symptoms.....................................45
7.8.
Treatment after the End of the Study............................................................................45
8.
Discontinuation Criteria ....................................................................................................46
8.1.
Discontinuation from Study Treatment.........................................................................46
8.1.1.
Discontinuation of Inadvertently Enrolled Patients...............................................46
8.2.
Discontinuation from the Study....................................................................................47
8.3.
Patients/Subjects Lost to Follow-up..............................................................................47
9.
Study Assessments and Procedures ...................................................................................48
9.1.
Efficacy Assessments...................................................................................................48
9.2.
Adverse Events ............................................................................................................49
9.2.1.
Serious Adverse Events........................................................................................50
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................51
9.2.2.
Complaint Handling.............................................................................................51
9.3.
Treatment of Overdose.................................................................................................51
9.4.
Safety...........................................................................................................................51
9.4.1.
Laboratory Tests ..................................................................................................51
9.4.2.
Vital Signs ...........................................................................................................51
9.4.3.
Electrocardiograms ..............................................................................................52
9.4.4.
Safety Monitoring ................................................................................................53
9.4.4.1.
Hepatic Safety................................................................................................53
9.4.4.2.
Pancreatic Safety............................................................................................54
9.4.4.3.
Hypersensitivity Reactions .............................................................................55
9.4.4.3.1.
Injection-site Reactions.............................................................................55
9.4.4.4.
Glucose Monitoring........................................................................................56
9.4.4.4.1.
Hyperglycemia and Hypoglycemia Reporting...........................................56


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LY3298176
9.4.4.5.
Nausea and Vomiting .....................................................................................59
9.4.4.6.
Thyroid Malignancies and C-Cell Hyperplasia................................................59
9.5.
Pharmacokinetics .........................................................................................................59
9.5.1.
Bioanalysis...........................................................................................................60
9.6.
Pharmacodynamics ......................................................................................................60
9.6.1.
Lipids...................................................................................................................60
9.6.2.
Meal Intake and Appetite .....................................................................................60
9.6.3.
Immunogenicity Assessments ..............................................................................61
9.7.
Genetics .......................................................................................................................62
9.8.
Biomarkers...................................................................................................................62
9.9.
Health Economics ........................................................................................................62
10.
Statistical Considerations and Data Analysis.....................................................................63
10.1. Sample Size Determination ..........................................................................................63
10.2. Populations for Analyses..............................................................................................63
10.2.1.
Study Participant Disposition ...............................................................................63
10.2.2.
Study Participant Characteristics ..........................................................................63
10.3. Statistical Analyses ......................................................................................................63
10.3.1.
Safety Analyses....................................................................................................64
10.3.1.1.
Clinical Evaluation of Safety..........................................................................64
10.3.1.2.
Statistical Evaluation of Safety.......................................................................64
10.3.2.
Efficacy Analyses ................................................................................................64
10.3.3.
Pharmacokinetic Analyses....................................................................................64
10.3.3.1.
Pharmacokinetic Parameter Estimation...........................................................64
10.3.3.2.
Pharmacokinetic Statistical Inference .............................................................65
10.3.4.
Evaluation of Pharmacodynamics.........................................................................65
10.3.5.
Evaluation of Immunogenicity .............................................................................65
10.3.6.
Interim Analyses..................................................................................................65
11.
References ........................................................................................................................66


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List of Tables
Table
Page
Table GPHT.1.
Objectives and Endpoints .......................................................................29


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List of Figures
Figure
Page
Figure GPHT 5.1.
Illustration of study design for Protocol I8F-MC-GPHT. ........................30


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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................68
Appendix 2.
Clinical Laboratory Tests........................................................................73
Appendix 3.
Study Governance, Regulatory, and Ethical Considerations....................74
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............77
Appendix 5.
Blood Sampling Summary......................................................................78
Appendix 6.
Protocol Amendment I8F-MC-GPHT(b) Summary - A Multiple 
Dose Titration Study in Chinese Patients with Type 2 Diabetes 
Mellitus to Investigate the Safety, Tolerability, Pharmacokinetics, 
Pharmacodynamics, and Efficacy of Tirzepatide.....................................79


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1. Protocol Synopsis
Title of Study: 
A Multiple Dose Titration Study in Chinese Patients with Type 2 Diabetes Mellitus to Investigate the Safety, 
Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of Tirzepatide.
Rationale: 
Tirzepatide is a dual agonist of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors 
being developed as a weekly treatment for type 2 diabetes mellitus (T2DM). This study of tirzepatide, I8F-MC-
GPHT (GPHT), will investigate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and 
efficacy of tirzepatide administered once weekly for 16 or 24 weeks as subcutaneous (SC) injections to Chinese 
patients with T2DM. 
Objective(s)/Endpoints:  
Objectives
Endpoints
Primary
To investigate the safety and tolerability of tirzepatide
after multiple SC doses administered to Chinese 
patients with T2DM
Incidence of TEAEs
Secondary
To characterize the PK of tirzepatide after multiple SC 
doses in Chinese patients with T2DM
AUC and Cmax of tirzepatide
Abbreviations: AUC = area under the concentration-time curve; Cmax = maximum observed drug concentration; 
PK = pharmacokinetics; SC = subcutaneous; 7p-SMPG = 7-point self-monitored plasma glucose; T2DM = type 2 
diabetes mellitus.
Summary of Study Design:
Study GPHT is a Phase 1, randomized, placebo-controlled, multiple dose titration study in Chinese patients with 
T2DM. 
Treatment Arms and Planned Duration for an Individual patient:  
This study consists of 2 cohorts. Approximately 12 Chinese patients with T2DM will be randomized within a cohort 
to receive tirzepatide or placebo. For Cohort 1, 16 weekly SC doses of tirzepatide or placebo will be administered in 
a ratio of 10 tirzepatide:2 placebo. For Cohort 2, 24 weekly SC doses of tirzepatide or placebo will be administered 
in a ratio of 10 tirzepatide:2 placebo. 
Patients in Cohort 1 will receive either tirzepatide with titration regimen starting from 2.5 mg for Days 1, 8, 15, and 
22 (Weeks 0 to 3), 5 mg for Days 29, 36, 43, and 50 (Weeks 4 to 7), 7.5 mg for Days 57, 64, 71, and 78 (Weeks 8 to 
11), and 10 mg for Days 85, 92, 99, and 106 (Weeks 12 to 15), or corresponding volume-matched placebo. 
Patients in Cohort 2 will receive either tirzepatide with titration regimen starting from 2.5 mg for Days 1, 8, 15, and 
22 (Weeks 0 to 3), 5 mg for Days 29, 36, 43, and 50 (Weeks 4 to 7), 7.5 mg for Days 57, 64, 71, and 78 (Weeks 8 to 


I8F-MC-GPHT(b) Clinical Pharmacology Protocol
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LY3298176
11), 10 mg for Days 85, 92, 99, and 106 (Weeks 12 to 15), 12.5 mg for Days 113, 120, 127, and 134 (Weeks 16 to 
19), and 15 mg for Days 141, 148, 155, and 162 (Weeks 20 to 23), or corresponding volume-matched placebo. 
Number of Patients:
Approximately 24 Chinese patients with T2DM may be enrolled to ensure approximately 16 patients complete the 
study, in compliance with the defined dosing regimen.
Statistical Analysis:
Pharmacokinetics, PD, and efficacy analyses will be conducted on data from all patients who receive at least 1 dose 
of the IP and have evaluable PK, PD, and efficacy data. Safety analyses will be conducted for all enrolled patients, 
whether or not they completed all protocol requirements. 
Safety: All IP and protocol procedure-related adverse events will be listed, and if the frequency of events allows, 
safety data will be summarized using descriptive methodology.  Safety parameters that will be assessed include 
safety laboratory parameters, vital signs, electrocardiogram parameters, injection-site reactions, and hypoglycemia.
Efficacy: The efficacy of tirzepatide to reduce glucose and weight will be assessed. All parameters will be listed and 
summarized using standard descriptive statistics. 
Pharmacodynamics: Lipids and subjective appetite sensation (VAS) will be listed and summarized using descriptive 
methodology.
Pharmacokinetics: The primary parameters for analysis will be maximum drug concentration (Cmax), area under the 
concentration-time curve (AUC), and time to Cmax (Tmax) of tirzepatide. Other noncompartmental parameters, such 
as half-life, apparent clearance, and apparent volume of distribution may be reported. Pharmacokinetic parameters 
will be summarized using descriptive statistics. The mean concentration-time profiles in linear and semilog scale for 
each tirzepatide-treated group will be presented.
Immunogenicity: The frequency and percentage of subjects/patients with preexisting antidrug antibodies (ADAs)
and with treatment-emergent (TE) ADA to tirzepatide will be tabulated. The frequency of neutralizing antibodies to 
tirzepatide and/or cross-reactive to endogenous counterparts may also be tabulated in TE ADA patients.
The relationship between the presence of antibodies, antibody titres, and clinical parameters (for example, AEs) may 
be assessed. Likewise, the relationship between antibody titers, PK parameters, and PD response to tirzepatide may 
be assessed.


I8F-MC-GPHT(b) Clinical Pharmacology Protocol
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LY3298176
2. Schedule of Activities


I8F-MC-GPHT(b) Clinical Pharmacology Protocol
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Study Schedule Protocol I8F-MC-GPHT Cohort 1 Except for Treatment Period
Procedure
Screening
Lead-in 
Treatment Period
Follow-Up
Days
Day -28 ~ -17
Day -14 ±1
Day 120 ±2
Day 141 ±2
ED2a
Outpatient Visit
1
2
13
14
Fasting Visit b
X
X
X
Informed Consent
X
Outpatient Visit
X
X
X
X
X
Dispense Study Diary & Training
X
BG Meters/Test Stripes Dispense & Training 
X
Study Drug Injection Training
X
Medical History
X
Pre-existing Disease and AEs
X
X
X
X
X
Hypoglycemic Events
X
X
X
X
X
Concomitant Treatment
X
X
X
X
X
Height, Race
X
Body Weight c
X
X
X
Body Temperature
X
X
X


I8F-MC-GPHT(b) Clinical Pharmacology Protocol
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Procedure
Screening
Lead-in 
Treatment Period
Follow-Up
Days
Day -28 ~ -17
Day -14 ±1
Day 120 ±2
Day 141 ±2
ED2a
Outpatient Visit
1
2
13
14
Fasting Visit b
X
X
X
Vital Signs (BP/PR)
X
X
X
Physical Examinations d
X
X
X
12-lead ECG
X
X
X
Chest X-Ray e
X
Clinical Safety Lab (Hematology, Chemistry, Urinalysis) f
X
X
X
Clinical Safety Lab (Pancreatic Enzyme) f
X
X
X
Serology (HBV/HCV/HIV) f
X
Urine Drug and Alcohol Screen f, g
X
Pregnancy Test, FSH f, h
X
Calcitonin
X
Hemoglobin A1c 
X
7-Point SMPG
X i


I8F-MC-GPHT(b) Clinical Pharmacology Protocol
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Procedure
Screening
Lead-in 
Treatment Period
Follow-Up
Days
Day -28 ~ -17
Day -14 ±1
Day 120 ±2
Day 141 ±2
ED2a
Outpatient Visit
1
2
13
14
Fasting Visit b
X
X
X
PK Sampling j
X
X
X
Immunogenicity
X
X


I8F-MC-GPHT(b) Clinical Pharmacology Protocol
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Study Schedule Protocol I8F-MC-GPHT Cohort 1 for Treatment Period
Treatment 
Period
2.5 mg
5 mg
7.5 mg
10 mg
Week
0
1
2
4
6
7
8
10
12
13
14
15
16
Day
-1
1
2
3
4
8
15
±1
29
±1
43
±1
4
9
50
51
52
53
57
±1
71
±1
85
±1
92
±1
99
±1
10
5
10
6
10
7
10
8
10
9
11
3
ED
1a
Visit
V
3
V3
a
V
3b
V
3c
V
3d
V4
TV
V5
TV
V
6
V6
a
V
6b
V
6c
V
6d
V7
TV
V8
V9
V1
0
V
11
V1
1a
V1
1b
V1
1c
V1
1d
V1
2
Fasting 
Visit b
X
X
X
X
X
X
X
X
X
Admission
to CRU
X
X
X
Inpatient 
stay at 
CRU k
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Discharge 
from CRU
X
X
X
Outpatient 
Visit
X
X
X
X
X
X
X
Randomiza
tion
X
Dose 
Administra
tion l
X
X
X
X
X
X
X
X
X
X
X
X
Pre-
existing 
Disease 
and AEs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hypoglyce
mic Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomita
nt 
Treatment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Body 
Temperatu
re
X
Pre
X


I8F-MC-GPHT(b) Clinical Pharmacology Protocol
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Treatment 
Period
2.5 mg
5 mg
7.5 mg
10 mg
Week
0
1
2
4
6
7
8
10
12
13
14
15
16
Day
-1
1
2
3
4
8
15
±1
29
±1
43
±1
4
9
50
51
52
53
57
±1
71
±1
85
±1
92
±1
99
±1
10
5
10
6
10
7
10
8
10
9
11
3
ED
1a
Visit
V
3
V3
a
V
3b
V
3c
V
3d
V4
TV
V5
TV
V
6
V6
a
V
6b
V
6c
V
6d
V7
TV
V8
V9
V1
0
V
11
V1
1a
V1
1b
V1
1c
V1
1d
V1
2
Fasting 
Visit b
X
X
X
X
X
X
X
X
X
Vital Signs 
(BP/PR)
X
Pre
, 
2h, 
4h, 
8h
24
h
48
h
72
h
Pre
Pre
Pre
Pre
Pre
Pre
X
X
Physical 
Examinati
ons d
X
12-lead 
ECG
X
Pre 
24
h
48
h
72
h
Pre
Pre
Pre 
Pre
Pre
Pre
24h
48
h
72h
X
X
Clinical 
Safety Lab 
(Hematolo
gy, 
Chemistry, 
Urinalysis) 
f
X
24
h
48
h
72
h
Pre
Pre
Pre
Pre
Pre
X
X
Clinical 
Safety Lab 
(Pancreatic
Enzyme) f
X
Pre
Pre
Pre
Pre
Pre
X
X
Calcitonin
Pre
X
X
Hemoglobi
n A1c
Pre
Pre
Pre
Pre
X
X
7-Point 
SMPG 
X
X
X
X
X
X
FBG
Pre
Pre
Pre
Pre
Pre
X
Lipid 
Panel
Pre
Pre
Pre
Pre
Pre
X


I8F-MC-GPHT(b) Clinical Pharmacology Protocol
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Treatment 
Period
2.5 mg
5 mg
7.5 mg
10 mg
Week
0
1
2
4
6
7
8
10
12
13
14
15
16
Day
-1
1
2
3
4
8
15
±1
29
±1
43
±1
4
9
50
51
52
53
57
±1
71
±1
85
±1
92
±1
99
±1
10
5
10
6
10
7
10
8
10
9
11
3
ED
1a
Visit
V
3
V3
a
V
3b
V
3c
V
3d
V4
TV
V5
TV
V
6
V6
a
V
6b
V
6c
V
6d
V7
TV
V8
V9
V1
0
V
11
V1
1a
V1
1b
V1
1c
V1
1d
V1
2
Fasting 
Visit b
X
X
X
X
X
X
X
X
X
Body 
Weight c
Pre
Pre
Pre
Pre
Pre
Pre
,
X
Meal 
Intake and 
Appetite m
L/
D
L/
D
L/
D
L/
D
PK 
Sampling j
Pre
D, 
8h
24
h
48
h
72
h
16
8h
Pre
D
Pre
D, 
8h
24
h
48
h
72
h
Pre
D
Pre
D
Pre
D
Pre
D
Pre
D, 
8h
24h
48
h
72h
16
8h
X
Immunoge
nicity
Pre
Pre
Pre
Pre
X
X
Pharmacog
enetic 
Samples
Pre


I8F-MC-GPHT(b) Clinical Pharmacology Protocol
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Study Schedule Protocol I8F-MC-GPHT Cohort 2 except for Treatment Period
Procedure
Screening
Lead-in 
Treatment Period
Follow-Up
Days
Day -28 ~ -17
Day -14 ±1
Day 176 ±2
Day 197 ±2
ED2a
Outpatient Visit
1
2
15
16
Fasting Visit b
X
X
X
Informed Consent
X
Lead-in
X
Outpatient Visit
X
X
X
X
X
Dispense Study Diary & Training
X
BG Meters/Test Stripes Dispense & Training 
X
Study Drug Injection Training
X
Medical History
X
Pre-existing Disease and AEs
X
X
X
X
X
Hypoglycemic Events
X
X
X
X
X
Concomitant Treatment
X
X
X
X
X
Height, Race
X


I8F-MC-GPHT(b) Clinical Pharmacology Protocol
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LY3298176
Procedure
Screening
Lead-in 
Treatment Period
Follow-Up
Days
Day -28 ~ -17
Day -14 ±1
Day 176 ±2
Day 197 ±2
ED2a
Outpatient Visit
1
2
15
16
Fasting Visit b
X
X
X
Body Weight c
X
X
X
Body Temperature
X
X
X
Vital Signs (BP/PR)
X
X
X
Physical Examinations d
X
X
X
12-lead ECG
X
X
X
Chest X-Ray e
X
Clinical Safety Lab (Hematology, Chemistry, Urinalysis) f
X
X
X
Clinical Safety Lab (Pancreatic Enzyme) f
X
X
X
Serology (HBV/HCV/HIV) f
X
Urine Drug and Alcohol Screen f, g
X
Pregnant Test, FSH f, h
X
Calcitonin
X


I8F-MC-GPHT(b) Clinical Pharmacology Protocol
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LY3298176
Procedure
Screening
Lead-in 
Treatment Period
Follow-Up
Days
Day -28 ~ -17
Day -14 ±1
Day 176 ±2
Day 197 ±2
ED2a
Outpatient Visit
1
2
15
16
Fasting Visit b
X
X
X
Hemoglobin A1c 
X
7-Point SMPG
X i
PK Sampling j
X
X
X
Immunogenicity
X
X


I8F-MC-GPHT(b) Clinical Pharmacology Protocol
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LY3298176
Study Schedule Protocol I8F-MC-GPHT Cohort 2 for Treatment Period
Treatm
ent 
Period
2.5 mg
5 mg
7.5 mg
10 mg
12.5 mg
15 mg
Week
0
1
2
4
6
7
8
1
0
1
2
1
4
16
18
20
21
22
23
2
4
Day
-
1
1
2
3
4
8
15
±
1
29
±
1
43
±
1
4
9
50
5
1
5
2
5
3
57
71
±
1
85
±
1
99
±
1
11
3±
1
12
7±
1
14
1±
1
14
8±
1
15
5±
1
16
1±
1
16
2
16
3
16
4
16
5
16
9
E
D
1a
Visit
V
3
V
3a
V
3
b
V
3
c
V
3
d
V
4
T
V
V
5
T
V
V
6
V
6a
V
6
b
V
6
c
V
6
d
V
7
T
V
V
8
T
V
V9
T
V
V1
0
V1
1
V1
2
V1
3
V
13
a
V
13
b
V
13
c
V
13
d
V
14
Fasting 
Visit b
X
X
X
X
X
X
X
X
X
Admissi
on to 
CRU
X
X
X
Inpatien
t stay at 
CRU k
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dischar
ge from 
CRU
X
X
X
Outpatie
nt Visit
X
X
X
X
X
X
X
X
X
X
Random
ization
X
Dose 
Adminis
tration l
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pre-
existing 
Disease 
and AEs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


I8F-MC-GPHT(b) Clinical Pharmacology Protocol
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LY3298176
Treatm
ent 
Period
2.5 mg
5 mg
7.5 mg
10 mg
12.5 mg
15 mg
Week
0
1
2
4
6
7
8
1
0
1
2
1
4
16
18
20
21
22
23
2
4
Day
-
1
1
2
3
4
8
15
±
1
29
±
1
43
±
1
4
9
50
5
1
5
2
5
3
57
71
±
1
85
±
1
99
±
1
11
3±
1
12
7±
1
14
1±
1
14
8±
1
15
5±
1
16
1±
1
16
2
16
3
16
4
16
5
16
9
E
D
1a
Visit
V
3
V
3a
V
3
b
V
3
c
V
3
d
V
4
T
V
V
5
T
V
V
6
V
6a
V
6
b
V
6
c
V
6
d
V
7
T
V
V
8
T
V
V9
T
V
V1
0
V1
1
V1
2
V1
3
V
13
a
V
13
b
V
13
c
V
13
d
V
14
Fasting 
Visit b
X
X
X
X
X
X
X
X
X
Hypogly
cemic
Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concom
itant 
Treatme
nt
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Body 
Temper
ature
X
Pr
e
X
Vital 
Signs 
(BP/PR)
X
Pr
e, 
2h
, 
4h
, 
8h
2
4
h
4
8
h
7
2
h
Pr
e
Pr
e
Pr
e
Pr
e
Pr
e
Pr
e
Pr
e
Pr
e
X
X
Physical 
Examin
ations d
X
12-lead 
ECG
X
Pr
e
2
4
h
4
8
h
7
2
h
Pr
e
Pr
e
Pr
e
Pr
e
Pr
e
Pr
e
Pr
e
Pr
e
24
h
48
h
72
h
X
X


I8F-MC-GPHT(b) Clinical Pharmacology Protocol
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LY3298176
Treatm
ent 
Period
2.5 mg
5 mg
7.5 mg
10 mg
12.5 mg
15 mg
Week
0
1
2
4
6
7
8
1
0
1
2
1
4
16
18
20
21
22
23
2
4
Day
-
1
1
2
3
4
8
15
±
1
29
±
1
43
±
1
4
9
50
5
1
5
2
5
3
57
71
±
1
85
±
1
99
±
1
11
3±
1
12
7±
1
14
1±
1
14
8±
1
15
5±
1
16
1±
1
16
2
16
3
16
4
16
5
16
9
E
D
1a
Visit
V
3
V
3a
V
3
b
V
3
c
V
3
d
V
4
T
V
V
5
T
V
V
6
V
6a
V
6
b
V
6
c
V
6
d
V
7
T
V
V
8
T
V
V9
T
V
V1
0
V1
1
V1
2
V1
3
V
13
a
V
13
b
V
13
c
V
13
d
V
14
Fasting 
Visit b
X
X
X
X
X
X
X
X
X
Clinical 
Safety 
Lab 
(Hemato
logy, 
Chemist
ry,  
Urinalys
is) f
X
2
4
h
4
8
h
7
2
h
Pr
e
Pr
e
Pr
e
Pr
e
Pr
e
Pr
e
X
X
Clinical 
Safety 
Lab 
(Pancrea
tic
Enzyme
) f
X
Pr
e
Pr
e
Pr
e
Pr
e
Pr
e
Pr
e
X
X
Calciton
in
Pr
e
X
X
Hemogl
obin 
A1c
Pr
e
Pr
e
Pr
e
Pr
e
Pr
e
Pr
e
X
X
7-Point 
SMPG 
X
X
X
X
X
X
X
X


I8F-MC-GPHT(b) Clinical Pharmacology Protocol
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LY3298176
Treatm
ent 
Period
2.5 mg
5 mg
7.5 mg
10 mg
12.5 mg
15 mg
Week
0
1
2
4
6
7
8
1
0
1
2
1
4
16
18
20
21
22
23
2
4
Day
-
1
1
2
3
4
8
15
±
1
29
±
1
43
±
1
4
9
50
5
1
5
2
5
3
57
71
±
1
85
±
1
99
±
1
11
3±
1
12
7±
1
14
1±
1
14
8±
1
15
5±
1
16
1±
1
16
2
16
3
16
4
16
5
16
9
E
D
1a
Visit
V
3
V
3a
V
3
b
V
3
c
V
3
d
V
4
T
V
V
5
T
V
V
6
V
6a
V
6
b
V
6
c
V
6
d
V
7
T
V
V
8
T
V
V9
T
V
V1
0
V1
1
V1
2
V1
3
V
13
a
V
13
b
V
13
c
V
13
d
V
14
Fasting 
Visit b
X
X
X
X
X
X
X
X
X
FBG
Pr
e
Pr
e
Pr
e
Pr
e
Pr
e
Pr
e
Pr
e
X
Lipid 
Panel
Pr
e
Pr
e
Pr
e
Pr
e
Pr
e
Pr
e
Pr
e
X
Body 
Weight c
Pr
e
Pr
e
Pr
e
Pr
e
Pr
e
Pr
e
Pr
e
X
Meal 
Intake 
and 
Appetite 
m
L
/
D
L/
D
L/
D
L/
D
PK 
Samplin
g j
Pr
eD
, 
8h
2
4
h
4
8
h
7
2
h
16
8h
Pr
e
D
Pr
eD
, 
8h
2
4
h
4
8
h
7
2
h
16
8h
Pr
e
D
Pr
eD
Pr
eD
Pr
eD
Pr
eD
Pr
eD
, 
8h
24
h
48
h
72
h
16
8h
X
Immuno
genicity
Pr
e
Pr
e
Pr
e
Pr
e
X
X
Pharmac
ogenetic 
Samples
Pr
e


I8F-MC-GPHT(b) Clinical Pharmacology Protocol
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LY3298176
Abbreviations:  AE= adverse event; BG=blood glucose; BP=blood pressure; CRU = clinical research unit; ECG=electrocardiogram; ED=early discontinuation; 
FBG=fasting blood glucose; FSH = follicle-stimulating hormone; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; 
IP=investigational product; lab = laboratory; L/D = lunch and dinner; PK = pharmacokinetics; PR=pulse rate; Pre = predose; PreD = predose for PK sampling; 
SC = subcutaneous; SMPG=self-monitored plasma glucose; TV=telephone visit; V = visit.
a A patient who discontinues from Cohort 1 between Day 1 and Day 113, inclusive, will complete ED1 procedures as soon as possible.  The patient will be asked 
to complete ED2 procedures after a washout period of at least 28 days from the last IP administration.  The patient who discontinues from Cohort 1 after the 
completion of Day 113 will complete ED2 procedures after a washout period of at least 28 days from the last IP administration.  A patient who discontinues from 
Cohort 2 between Day 1 and Day 169, inclusive, will complete ED1 procedures as soon as possible.  The patient will be asked to complete ED2 procedures after 
a washout period of at least 28 days from the last IP administration.  The patient who discontinues from Cohort 2 after the completion of Day 169 will complete 
ED2 procedures after a washout period of at least 28 days from the last IP administration.
b Patients will be required to fast overnight for at least 8 hours before taking the first SC dose of tirzepatide (or placebo) and before each blood sample draw on 
fasting visit. 
c Weight will be measured in a consistent way per Section 9.1, always predose.
d Full physical examination / medical assessment at screening.  Symptom-directed physical examination/medical assessment at all other time points, and as 
deemed necessary by the investigator.
e Patients who have completed chest x-ray within the past 12 months and whose x-ray and/or report are available for review are exempt from the chest x-ray 
examination.  The required chest x-ray is a single posterior anterior (PA) x-ray.  If evidence of an abnormality, a lateral chest x-ray will be performed.
f These tests will be performed at the local laboratory.
g Additional urine drug screen or breath ethanol tests may be performed at the investigator’s discretion.
h Females only.  Blood pregnancy test will be done on screening; urine test at other times as indicated, or when performed at the investigator’s discretion.
i Patients will conduct the 7-point SMPG every 3 days since Day -13 during lead-in period and will record readings in patient diary.
j A maximum of 3 samples may be collected at additional time points during the study if warranted and agreed upon by both the investigator and sponsor.
k Patients may be required to remain at the CRU longer than the planned discharge day at the investigator’s discretion to assure patients’ safety or to provide 
additional safety monitoring.
l If a dose of tirzepatide is missed, the patient should take it as soon as possible unless it is within 72 hours of the next dose in which case, that dose should be 
skipped and the next dose should be taken at the appropriate time. In Cohort 1, apart from time points indicated in SOA, tirzepatide should also be administered 
in Weeks 3, 5, 9, and 11. In Cohort 2, apart from time points indicated in SOA, tirzepatide should also be administered in Weeks 3, 5, 9, 11, 13, 15, 17, and 19.
m  Meal intake and subjective rating of appetite sensation will be evaluated before and 4 to 5 hours after standardized lunch and dinner meals on Days –1 and 2 
Day 51 (for both cohorts), and Day 107 for Cohort 1 and Day 163 for Cohort 2.  The standardized lunch and dinner meals will be provided at least 4 hours after 
the previous meal.  The subjective rating of appetite sensations is measured using a 100-mm visual analogue scale (VAS) for parameters of hunger, fullness, 
satiety, and prospective food consumption before and 4 to 5 hours after the standardized lunch and dinner meals. Refer to Section 9.6.2 for details.


I8F-MC-GPHT(b) Clinical Pharmacology Protocol
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3. Introduction
3.1.
Study Rationale
Tirzepatide is a dual agonist of glucose-dependent insulinotropic polypeptide (GIP) and 
glucagon-like peptide-1 (GLP-1) receptors being developed for the treatment of type 2 diabetes 
mellitus (T2DM). This study of tirzepatide, I8F-MC-GPHT (GPHT), will investigate the safety, 
tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of tirzepatide
administered once weekly (QW) for either 16 weeks or 24 weeks as subcutaneous (SC) 
injections to Chinese patients with T2DM.
3.2.
Background
Tirzepatide, a peptide with a modified GIP sequence, is a dual receptor agonist that binds both 
GIP and GLP-1 receptors.  Following a meal, enteroendocrine cells in the gut secrete the 
incretins GIP and GLP-1. These incretins enhance the sensation of satiety, insulin secretion, and 
nutrient disposal (Baggio and Drucker 2007).  Patients with T2DM have impaired incretin 
responses (Baggio and Drucker 2007).  Currently available incretin-based treatments fall within 
2 classes:  GLP-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-IV) inhibitors 
(Neumiller 2015).  
Tirzepatide, a GIPR and GLP1R coagonist, is a chemically synthesized peptide consisting of a
linear peptide component of 39 amino acid residues conjugated to a C20 fatty acid moiety. As a 
dual agonist, tirzepatide binds both GIP and GLP-1 receptors and combines the signalling of 
each receptor for improved glycaemic control.  By virtue of being a dual incretin mimetic, 
tirzepatide has the potential of reaching higher efficacy in target tissues, such as the insulin-
producing pancreatic ß-cells that express both GIPR and GLP-1R before reaching its therapeutic 
limitation.  Furthermore, tirzepatide may attain additional efficacy by recruiting metabolically 
active tissues not targeted by selective GLP-1R analogues (for example, adipose tissue as 
indicated by the observation of increased energy utilization) (Baggio and Drucker 2007). 
The clinical data to date have characterized the PK, PD, as well as preliminary efficacy and 
safety results of tirzepatide.  Three tirzepatide clinical trials have completed dosing and analyses:  
(1) Phase 1 Study I8F-MC-GPGA, a single-ascending dose/multiple-ascending dose study in 
healthy subjects and multidose study in patients with T2DM, (2) Phase 2 Study I8F-MC-GPGB 
(GPGB), a placebo- and active-controlled dose-ranging study in T2DM, and (3) Phase 2 Study 
I8F-MC-GPGF (GPGF), a placebo-controlled efficacy and titration study in patients with T2DM.
The Phase 1 Study GPGA was a combination of single ascending dose (SAD) and multiple 
ascending dose (MAD) study in healthy subjects and a multiple dose study in patients with 
T2DM.  Study GPGA investigated the safety, tolerability, pharmacokinetics (PK), and 


I8F-MC-GPHT(b) Clinical Pharmacology Protocol
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pharmacodynamics (PD) of tirzepatide administered as SC injections.  A total of 142 subjects 
(89 healthy subjects and 53 patients with T2DM) received at least 1 dose of treatment.  Doses of 
tirzepatide ranged from 0.25 mg to 8 mg in the SAD (with maximum tolerated dose achieved at 5 
mg); multiple doses from 0.5 mg to 4.5 mg QW; and titrated doses up to 10 mg QW for 4 weeks 
in healthy subjects; and multiples doses at 0.5 mg and 5 mg QW and titrated to 15 mg QW for 
4 weeks in T2DM patients. 
Doses higher than 5 mg were better tolerated when attained via escalation.  Maximum tolerated 
dose of tirzepatide in healthy subjects following single-dose administration was 5 mg.  A dose of 
15 mg tirzepatide was administered in patients with T2DM by accelerated dose escalation over 4 
weeks (5/5/10/15 mg) and while considered to be safe, was associated with high incidence of 
gastrointestinal (GI) events. Gastrointestinal adverse events (AEs) (nausea, vomiting, diarrhea, 
decreased appetite, abdominal distension) were the most frequently reported events by both 
healthy subjects and patients with T2DM and were dose related.  Most AEs were mild in 
severity, few were moderate, and none were reported as severe.  There were no apparent trends 
in chemistry, hematology, or urinalyses.  A few subjects experienced elevations in lipase and/or 
amylase levels, but these episodes were not associated with drug-related risk of pancreatitis.
Phase 2 studies have evaluated the efficacy, tolerability, and safety of tirzepatide in patients with 
T2DM with inadequate glycemic control on diet and exercise alone or on a stable dose of 
metformin monotherapy.  Study GPGB, a 26-week Phase 2 study, compared the efficacy, 
tolerability, and safety of 4 doses (1, 5, and 10 mg [titrated]; and 15 mg [titrated]), of QW 
tirzepatide compared with QW dulaglutide 1.5 mg and QW placebo in 318 patients with T2DM,
with inadequate glycemic control on diet and exercise alone or on a stable dose of metformin 
monotherapy.  Tirzepatide 5mg, 10mg, and 15-mg significantly lowered glycated hemoglobin 
(HbA1c) and body weight in a dose-dependent manner, in comparison to placebo. In addition, 
reductions in HbA1c for the tirzepatide 5-, 10-, and 15-mg doses were greater than with 
dulaglutide 1.5 mg QW. Similar to adverse events (AEs) observed with the GLP-1 receptor 
agonist class and the Phase 1 Study GPGA, most of the tirzepatide AEs were gastrointestinal 
(GI)-related, consisting mainly of nausea, vomiting, and diarrhea, which were mild-to-moderate 
in intensity and dose-dependent.  Serious AEs (SAEs) were balanced across the treatment 
groups, and none of the groups in either study reported severe hypoglycemia (Frias et al. 2018).
Study GPGF, a 3-month Phase 2 study, was designed to examine the efficacy, safety, and 
tolerability of QW tirzepatide administered in 3 different titration schemes (longer time intervals 
between dose escalations and different dose escalations), to reach the highest tirzepatide planned 
doses of 12 mg and 15 mg, compared with placebo, in patients with T2DM who have inadequate 
glycemic control with diet and exercise alone or with a stable dose of metformin monotherapy 
and was designed to support evaluation of optimized dosing regimen(s) in Phase 3.
As it was recognised that the titration scheme employed in Study GPGB was unlikely to be 
optimal for reduction of GI-related AEs expected with tirzepatide, Study GPGF was designed to 


I8F-MC-GPHT(b) Clinical Pharmacology Protocol
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LY3298176
explore alternative titration schemes (longer time intervals between dose escalations and 
different dose escalations) to support evaluation of optimised dosing regimen(s) in Phase 3.  
Study GPGF demonstrated that a longer time between dose increases and/or smaller dose 
escalations are better tolerated than rapid or large step-size dose escalations, as indicated by 
lower frequency of GI tolerability AEs and fewer patients discontinuing treatment compared to 
the data observed in Study GPGB.  
In addition, the safety, tolerability, and PK/PD of tirzepatide are being evaluated in the ongoing 
Study GPGC; a Phase 1, 8-week multiple ascending dose (MAD) study in Japanese patients with 
T2DM. This study involves a comparison of 3 once-weekly SC dose levels of tirzepatide
(2.5 mg to 10 mg titration regimen for Cohort 1; 5 mg to 15 mg titration regimen for Cohort 2;
and 5 mg fixed dose for Cohort 3), or placebo. The safety and tolerability data of Study GPGC 
supports the use of doses up to 15 mg of tirzepatide in Japanese patients.  
Tirzepatide PK was studied across a range of doses administered as single doses or multiple 
doses via a once-weekly dosing regimen.  Based on the cumulative data to date, tirzepatide PK 
appeared linear and dose proportional during the dose range studied.  Peak concentrations were 
observed at 1 to 2 days postdose, and the half-life was approximately 5 days.
In summary, the data from Study GPGB and Study GPGF support continued development of 
tirzepatide as a treatment for T2DM.  Lilly proposes to conduct five Phase 3 randomised, 
controlled glycaemic-control trials.  The doses selected for this study are 2.5, 5, 7.5, 10, 12.5,
and 15 mg, which will be administered in a dose-escalation scheme that uses 2.5-mg dose 
increments and 4-week intervals.  
3.3.
Benefit/Risk Assessment
To minimize the risk of hyperglycemia due to the washout of prestudy oral antidiabetic 
medication, patients will monitor their fasting glucose levels using self-monitored plasma 
glucose (SMPG). Episodes of hyperglycemia will be reported and managed by the investigator 
or designated physician (Section 9.4.4.4.1).
Because tirzepatide is a long-acting, GIP and GLP-1 receptor dual agonist, the potential risks 
associated with tirzepatide may be similar to the risks associated with other long-acting GLP-1 
receptor agonists. The known risks associated with increased GLP-1 receptor activity include 
but are not limited to GI-related adverse reactions (particularly nausea, vomiting, and diarrhea), 
pancreatitis, cardiovascular risk (increased heart rate), hypoglycemia, systemic allergic reaction, 
injection-site reactions, antibody formation, and medullary thyroid carcinoma (MTC).  In 
previous tirzepatide Phase 1 and Phase 2 studies, the observed AEs were consistent with that of 
other GLP-1 agonists.    


I8F-MC-GPHT(b) Clinical Pharmacology Protocol
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LY3298176
More information about the known and expected benefits, risks, SAEs, and reasonably 
anticipated AEs of tirzepatide is to be found in the Investigator’s Brochure (IB).
More information about the known risks for the QW GLP-1 receptor agonists can be found in the 
Bydureon® ([exenatide extended-release] for injectable suspension) package insert (Astra Zeneca
2018, China).


I8F-MC-GPHT(b) Clinical Pharmacology Protocol
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LY3298176
4. Objectives and Endpoints
Table GPHT.1 shows the objectives and endpoints of the study.
Table GPHT.1.
Objectives and Endpoints
Primary Objectives
Endpoints
To investigate the safety and tolerability of tirzepatide
after multiple SC doses administered to Chinese patients 
with T2DM
Incidence of TEAEs
Secondary Objectives
Endpoints
To characterize the PK of tirzepatide after multiple SC 
doses in Chinese patients with T2DM
AUC and Cmax of tirzepatide
Exploratory Objectives
Endpoints
To investigate the efficacy of tirzepatide after multiple 
SC doses administered to Chinese patients with T2DM
Hemoglobin A1c, body weight, fasting plasma glucose 
levels, 7p-SMPG
To investigate the exploratory PD effects of tirzepatide
after multiple SC doses administered to Chinese patients 
with T2DM
Lipids, subjective appetite sensation (VAS)
To evaluate the formation of ADAs to tirzepatide after 
multiple SC doses administered to Chinese patients with 
T2DM
Presence of ADAs to tirzepatide
Abbreviations:  ADA = antidrug antibody; AUC = area under the concentration-time curve; Cmax = maximum 
observed drug concentration; PD = pharmacodynamic; PK = pharmacokinetics; SC = subcutaneous;
7p-SMPG = 7-point self-monitored plasma glucose; T2DM = type 2 diabetes mellitus; VAS = visual analogue 
scale.


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5. Study Design
5.1.
Overall Design
Study GPHT is a Phase 1, patient- and investigator-blind, placebo-controlled, randomized, 
multiple dose titration study in Chinese patients with T2DM.
Study governance considerations are described in detail in Appendix 3.  Figure GPHT 5.1
illustrates the study design.
Abbreviations: LY = tirzepatide; PL = placebo; QW = once weekly.
Figure GPHT 5.1.
Illustration of study design for Protocol I8F-MC-GPHT.
Patients will be administered either 16 or 24 weekly SC doses of tirzepatide or placebo. 
Section 2 outlines study procedures and timing for pre-study, treatment, and follow-up phases.
Screening (Visit 1)
The purpose of screening procedures at Visit 1 is to establish initial eligibility and to obtain 
blood samples for laboratory assessments needed to confirm eligibility at Visit 2. Before 
performing any study procedures, the patient will sign the informed consent form (ICF).  
Procedures at this visit will be performed as shown in the Schedule of Activities, Section 2. 
Patients who meet all applicable inclusion criteria and none of the applicable exclusion criteria 
(Section 6) at Visit 1 will continue on their prestudy therapy between Visits 1 and 2.
Lead-in (Visit 2 to Visit 3)
At Visit 2, patients and their caregiver(s), if applicable, will receive a glucometer, study diaries,
and training on how to perform self-monitoring of plasma glucose and record blood glucose 


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values, hypoglycemic events, medications, and AEs. Patients will also be trained on disease 
management and study procedures; this training can be repeated at subsequent visits as deemed 
appropriate. 
Patients will conduct the 7-point SMPG approximately every 3 days since Day -13 during the 
lead-in period and will record readings in patient diary. Prior oral antidiabetic medication 
(OAM) should be discontinued during the lead-in period.
Treatment Period
Patients will be admitted to the clinical research unit (CRU) on Day -1. If the investigator 
decides not to administer the first dose to a patient on a particular day based on the results of 
medical assessments, vital signs, or electrocardiograms (ECGs), the patient’s visit may be 
rescheduled, and any procedures performed up to that point may be repeated.
Cohort 1
Patients in Cohort 1 will receive either tirzepatide with titration regimen starting from 2.5 mg for
Weeks 0 through 3 followed by 5 mg for Weeks 4 through 7, 7.5 mg for Weeks 8 through 11, 
and 10 mg for Weeks 12 through 15, or corresponding volume-matched placebo.  During CRU 
visits 3a, 4, 5, 6a, 7, 8, 9, 10 and 11a, site staff will administer SC doses of tirzepatide or 
placebo.  Patients may either self-administer or visit the CRU to have staff administer SC doses 
of tirzepatide or placebo at the beginning of Weeks 2, 3, 5, 6, 9, 10, and 11.  
Cohort 2 
Patients in Cohort 2 will receive either tirzepatide with titration regimen starting from 2.5 mg for 
Weeks 0 through 3 followed by 5 mg for Weeks 4 through 7, 7.5 mg for Weeks 8 through 11, 10 
mg for Weeks 12 through 15, 12.5 mg for Weeks 16 through 19, and 15 mg for Weeks 20 
through 23, or corresponding volume-matched placebo.  During CRU visits 3a, 4, 5, 6a, 7, 8, 9, 
10, 11, 12 and 13a, site staff will administer SC doses of tirzepatide or placebo.  Patients may 
either self-administer or visit the CRU to have staff administer SC doses of tirzepatide or placebo 
at the beginning of Weeks 2, 3, 5, 6, 9, 10, 11, 13, 14, 15, 17, 18, and 19.  
Pharmacokinetic sampling and safety assessments, including AEs, concomitant medications, 
medical assessments, clinical laboratory tests, vital signs, and ECGs, will be performed 
according to the Schedule of Activities (Section 2).
The investigator or qualified designee will review all available inpatient safety data before 
discharging patients from the CRU on the morning of each planned discharge day, provided they 
are deemed medically fit by the investigator. Patients may be required to remain at the CRU 
longer than the planned discharge day at the investigator’s discretion to assure patients’ safety or 


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to provide additional safety monitoring. Patients will be discharged after the review of all final 
safety assessments from the last follow-up visit is completed by the investigator.
Follow-Up Period
Visits for safety follow-up and PK sampling will occur on 2 separate visits. These visits will be 
approximately 7 and 28 days after the last dose of investigational product (IP). 
5.2.
Number of Participants
Approximately 24 Chinese patients with T2DM may be enrolled so that approximately 16
complete the study, in compliance with the defined dosing regimen.  For purposes of this study, a 
patient completes the study when all scheduled procedures shown in the Schedule of Activities
(Section 2) have been finished.
5.3.
End of Study Definition
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) or the date of the last ADA follow-up visit for the last patient.
5.4.
Scientific Rationale for Study Design
The patient- and investigator-blinded, randomized, placebo-controlled design minimizes the bias 
on safety and tolerability assessments and allows for a strong comparison between tirzepatide
and placebo.
The selection of patients with T2DM is appropriate and in keeping with standard regional 
practices for clinical pharmacology studies.  The inclusion and exclusion criteria are chosen to 
select patients free from other significant illnesses or conditions that could affect their safety or 
interfere with the study objectives.  
The proposed PK sampling scheme enables understanding of the PK at the starting dose and at 
interim time points prior to achieving the final doses of 10 or 15 mg in the respective cohorts.  
Based upon the available clinical PK data for tirzepatide, the follow-up period of this study is 
considered adequate to achieve the study objectives.
5.5.
Justification for Dose
In this study, 10 mg and 15 mg doses were selected to evaluate safety, tolerability, PK, PD, and 
efficacy of tirzepatide in Chinese patients with T2DM. Also, these selected doses will support 
dose selection in future clinical trials in patients with T2DM in China.  These doses and 
associated titration schemes were selected based on low ethnic sensitivity of GLP-1 RA class for 
T2DM treatment and assessment of safety, efficacy (glycemic and weight loss benefit), and GI 


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tolerability data followed by exposure response modeling of data in patients with T2DM in Phase 
1 and 2 studies. Dosing algorithms starting at a low dose of 2.5 mg accompanied by dose 
escalation in 2.5-mg increments every 4 weeks would permit adequate time for development of 
tolerance to GI events and are predicted to minimize GI tolerability concerns.
The anticipated dose-limiting safety and tolerability of tirzepatide are GI-related AEs, such as
nausea and vomiting (Section 3.2), which have been consistently demonstrated with the GLP-1 
drug class.  The selected dose and titration scheme would enable further evaluation of 
benefit/risk considerations for 10 mg and 15 mg doses of tirzepatide.


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6. Study Population
Eligibility of patients for the study will be based on the results of screening medical history, 
physical examination, vital signs, clinical laboratory tests, and ECG. 
A chest x-ray will be completed at screening unless one has been obtained within the past 
12 months, and the x-ray and/or report are available for review.  For this study, the required chest 
x-ray is a single posterior anterior (PA) x-ray.  Only if the PA x-ray shows evidence of an 
abnormality, a lateral chest x-ray will be performed.   
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 Day -28 to Day -17 prior to enrollment. Patients who are not enrolled 
within 12 days of screening may be subjected to an additional medical assessment and/or clinical 
measurements to confirm their eligibility.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
Patients are eligible for inclusion in the study only if they meet all of the following criteria at 
screening:
[1]
Chinese males or females with T2DM between the ages of 20 and 70 years,
inclusive, at screening. Native Chinese is defined as a patient who has all 4 
biological grandparents and both biological parents to be of Chinese origin
[1a] male patients:
agree to use an effective method of contraception (barrier contraceptives 
such as latex condoms) for the duration of the study and or at least 3 months 
after the last dose of IP
[1b] female patients:
women not of childbearing potential because of surgical sterilization (hysterectomy 
or bilateral oophorectomy or tubal ligation) or menopause; women with an intact 
uterus are deemed postmenopausal if they are aged 45 years or older, and

who have not taken hormones or oral contraceptives within the past year and 
have had cessation of menses for at least 1 year


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OR

who had at least 6 months of amerorrhoea with follicle-stimulating hormone 
(FSH) and estradiol levels consistent with a postmenopausal state (FSH 
≥40 mIU/mL and estradiol <30 pg/mL)
OR
women patients of childbearing potential (not surgically sterilized and between 
menarche and 1-year postmenopausal) must 

test negative for pregnancy at Visit 1 based on a serum pregnancy test
AND

if sexually active, agree to use 2 forms of effective contraception, where at 
least 1 form is highly effective for the duration of the trial and for 30 days 
thereafter
[2]
have T2DM controlled with diet and exercise alone or are stable on a single 
OAM, metformin, acarbose, or sulphonylureas only (other types of OAM 
[DPP-IV inhibitors, sodium-glucose cotransporter-2 inhibitors, and
thiazolidinediones] are not allowed in this study), for at least 3 months
[3]
have a HbA1c ≥7.0% and ≤10.5% for patients treated with diet and exercise 
only, and for the patients treated with antidiabetic medications, HbA1c ≥6.5% 
and ≤10.0%, at screening visit
[4]
have a body mass of ≥23 kg/m2, inclusive
[5]
have clinical laboratory test results within normal reference range for the 
population or study site, or results with acceptable deviations that are judged 
to be not clinically significant by the investigator; abnormalities of blood 
glucose, serum lipids, urinary glucose, and urinary protein consistent with 
T2DM are acceptable
[6]
have venous access sufficient to allow for blood sampling as per the protocol
[7]
are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures
[8]
are able and willing to give signed informed consent


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6.2.
Exclusion Criteria
Patients will be excluded from study enrollment if they meet any of the following criteria at 
screening:
6.2.1. Medical Conditions
[9]
have type 1 diabetes mellitus
[10] have a history of proliferative diabetic retinopathy, diabetic maculopathy or 
nonproliferative diabetic retinopathy that requires acute treatment
[11] have a history of ketoacidosis or hyperosmolar state/coma requiring 
hospitalization within the 6 months prior to Visit 1
[12] Have a history of severe hypoglycemia and/or hypoglycemia unawareness 
within the 6 months prior to Visit 1
[13] have known hemoglobinopathy (alpha-thalassemia), hemolytic anemia, sickle 
cell anemia, a hemoglobin value <11.0 g/dL (males) or <10.0 g/dL (females), 
or any other condition known to interfere with HbA1c methodology
[14] have a history of heart block or PR interval >220 msec or 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
[15] have a history or presence of pancreatitis (history of chronic pancreatitis or 
idiopathic acute pancreatitis) or GI disorder (for example, relevant esophageal
reflux or gall bladder disease) or a GI disease that impacts gastric emptying 
(for example, gastric bypass surgery, pyloric stenosis, with the exception of 
appendectomy) or could be aggravated by GLP-1 analogues or DPP-IV 
inhibitors; patients with dyslipidemia and patients who have had 
cholecystolithiasis (removal of gall stones) and/or cholecystectomy (removal 
of gall bladder) in the past, with no further sequelae, may be included in the 
study at the discretion of the investigator 
[16] have a personal or family history of MTC or have multiple endocrine 
neoplasia syndrome type 2 (MEN-2)
[17] have a serum calcitonin level of ≥35 ng/L (pg/mL), as determined by central 
laboratory at Visit 1
[18] have any skin conditions (including, but not limited to, tattoos or scars) that 
may interfere with the interpretation of assessment or administration of IP


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[19] have known allergies to tirzepatide, GLP-1 analogues, or related compounds
or any components of the formulation
[20] have a history of atopy or clinically significant multiple or severe drug 
allergies, intolerance to topical corticosteroids, or severe postdose
hypersensitivity reactions (including, but not limited to, erythema multiforme 
major, linear immunoglobulin A dermatosis, toxic epidermal necrolysis, or 
exfoliative dermatitis)
[21] have serum aspartate aminotransferase (AST) or alanine aminotransferase
(ALT) >2× the upper limit of normal (ULN) or total bilirubin level (TBL) 
>1.5× ULN (with the exception of Gilbert’s syndrome)
[22] have an eGFR <45 mL/min/1.73 m2 at screening, calculated by Chronic 
Kidney Disease-Epidemiology (CKD-EPI), as determined at Visit 1
[23] have evidence of significant active neuropsychiatric disorders
[24] show evidence of human immunodeficiency virus (HIV) infection and/or 
positive human HIV antibodies and/or HIV antigen at screening
[25] show evidence of hepatitis B or positive hepatitis B surface antigen at 
screening
[26] show evidence of hepatitis C or positive hepatitis C antibody at screening
[27] have a history of malignancy within 5 years before screening
[28] have a significant history of or current cardiovascular (for example, 
myocardial infarction, congestive heart failure, cerebrovascular accident, 
venous thromboembolism), respiratory, hepatic, renal, GI, endocrine, 
hematological, or neurological disorders capable of significantly altering the 
absorption, metabolism, or elimination of drugs; of constituting a risk while 
taking the IP; or of interfering with the interpretation of data


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6.2.2. Prior/Concomitant Therapy
[29] have used or intend to use over-the-counter or prescription medication (herbal 
supplements, systemic glucocorticoids, immunomodulatory drugs, drugs with 
propensity for dermal reactions, drugs with known liver toxicity, etc.) within 7 
days prior to dosing and during the study without agreement by the sponsor;
for inclusion, stable doses of antihypertensive agents, aspirin, and lipid-
lowering agents are allowed; occasional paracetamol/acetaminophen up to a 
2-g dose in a 24-hour period may be allowed for inclusion at the discretion of 
the investigator (refer to Section 7.7)
[30] have a history of insulin therapy except for the use of insulin for treatment of 
gestational diabetes or acute, temporary use of insulin (≤14 days), for 
example, for acute illness, hospitalization, elective surgery
[31] have received chronic (lasting >14 consecutive days) systemic glucocorticoid 
therapy (excluding topical, intra-articular, and inhaled preparations) in the 
past year or have received any glucocorticoid therapy within 30 days before 
screening
[32] have used any traditional Chinese treatments within 30 days prior to study 
enrollment or intend to use any traditional Chinese treatment during the study
6.2.3. Prior/Concurrent Clinical Trial Experience
[33] are currently enrolled in a clinical study involving an IP or any other type of 
medical research judged not to be scientifically or medically compatible with 
this study
[34] have participated, within the past 30 days, in a clinical study involving an IP.  
If the previous IP has a long half-life, 5 half-lives or 30 days (whichever is 
longer) should have passed
[35] have previously completed or withdrawn from this study or any other study 
investigating tirzepatide, and have previously received the IP
6.2.4. Other Exclusions
[36] are study site or hospital personnel directly affiliated with this study and their 
immediate families.  Immediate family is defined as a spouse, biological or 
legal guardian, child, or sibling.
[37] are Lilly employees
[38] are women who are lactating


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[39] have donated blood of more than 400 mL within the previous 12 weeks
(males) or in the past 16 weeks (females), any blood donation (including 
apheresis) within the past 4 weeks, or total volume of blood donation in the 
past year is 1200 mL (males) or 800 mL (females) or more at screening
[40] have an average weekly alcohol intake that exceeds 21 units per week (males) 
and 14 units per week (females) (1 unit = 12 oz or 360 mL of beer, 5 oz or 150 
mL of wine, 1.5 oz or 45 mL of distilled spirits) or are unwilling to stop 
alcohol consumption during the 24 hours before and 72 hours post dose
administration, and 24 hours before each admission to CRU and each 
outpatient visit, and throughout the duration of each CRU visit
[41] currently smoke in excess of 10 cigarettes/day or use tobacco or nicotine 
substitutes (within the past 6 months of screening), or subjects unwilling to 
refrain from smoking or are unable to abide by CRU restrictions
[42] regularly use known drugs of abuse or show positive findings on drug 
screening
[43] in the opinion of the investigator or sponsor, are unsuitable for inclusion in the 
study
6.3.
Lifestyle and/or Dietary Requirements
Throughout the study, patients may undergo medical assessments and review of compliance with 
requirements before continuing in the study.
6.3.1. Meals and Dietary Restrictions
Patients will be required to fast overnight for at least 8 hours on fasting visit as described in the 
Schedule of Activities (Section 2).  During fasting, water may be consumed freely. Standard 
meals will be provided after approximately 15 minutes from IP administration in the CRU.  
Standardized lunch and dinner meals will be provided in the CRU to assess meal intake and 
subjective rating of appetite sensation (Section 9.6.2).
When not residing in the CRU, patients should maintain their routine prestudy dietary patterns as 
much as possible. 


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6.3.2. Caffeine, Alcohol, and Tobacco
Caffeine: During the stay at CRU, patients should refrain from caffeinated foods and beverages 
such as cola, chocolate drinks, tea, and coffee. Patients will be allowed to maintain their regular 
caffeine consumption outside the CRU throughout the study period.
Alcohol: No alcohol will be allowed 24 hours before each admission to CRU and each 
outpatient visit, throughout the duration of each CRU visit, and 72 hours following IP 
administration.  Between CRU visits, daily alcohol consumption should not exceed 3 units for 
males and 2 units for females (a unit is defined in Exclusion Criterion [40], Section 6.2)
Tobacco: No nicotine use will be permitted while at the CRU.  When not at the CRU, patients 
may smoke no more than 10 cigarettes or consume the equivalent amount of nicotine per day. 
6.3.3. Activity
Patients will be advised to maintain their regular levels of physical activity/exercise during the 
study.  When certain study procedures are in progress at the site, patients may be required to 
remain supine, recumbent, or sitting.
6.4.
Screen Failures
Individuals who do not meet this study’s participation criteria may be re-screened once.  The 
interval between re-screenings should be at least 2 weeks.  If re-screened, the individual must 
sign a new ICF and will be assigned a new identification number.  Repeating laboratory or 
clinical tests is not considered a re-screen. 


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7. Treatment
7.1.
Treatment Administered
This study involves a comparison of QW SC dose levels of tirzepatide (2.5 mg to 10 mg titration 
regimen for Cohort 1 and 2.5 mg to 15 mg titration regimen for Cohort 2) with corresponding 
volume-matched placebo. Table GPHT.2 shows the treatment regimens.
For Cohort 1, the starting dose of tirzepatide will be 2.5 mg QW for 4 weeks, then the dose will 
be increased by 2.5 mg every 4 weeks (2.5 mg to 5 mg to 7.5 mg to 10 mg) until the 10-mg dose 
is reached and maintained for the duration of the study.  For Cohort 2, the starting dose of 
tirzepatide will be 2.5 mg QW for 4 weeks, then the dose will be increased by 2.5 mg every 4 
weeks (2.5 mg to 5 mg to 7.5 mg to 10 mg to 12.5 mg to 15 mg) until the 15-mg dose is reached 
and maintained for the duration of the study.
Table GPHT.2.
Tirzepatide Treatment Regimens
Cohort
Treatment Period Interval
Weeks
Weeks
Weeks
Weeks
Weeks
Weeks
0 to 3
4 to 7
8 to 11
12 to 15
16 to 19
20 to 23
1
2.5 mg
5 mg
7.5 mg
10 mg
2
2.5 mg
5 mg
7.5 mg
10 mg
12.5 mg
15 mg
Note:  All doses will be administered once weekly using a single-dose pen.
All injections will be administered into the SC tissue of the abdominal wall. Injection sites will
be alternated weekly between 4 sites on the abdominal wall (that is, right and left upper
quadrants and right and left lower quadrants). During CRU visits as shown in the Schedule of 
Activities, Section 2, site staff will administer SC doses of tirzepatide or placebo.  For dosing at 
non-CRU visits, patients may either self-administer or visit the CRU to have staff administer SC 
doses of tirzepatide or placebo.  
The investigator or designee is responsible for

explaining the correct use of the IP to the site personnel and the patient

verifying that instructions are followed properly

maintaining accurate records of IP dispensing and collection

instructing patients to discard all used single-dose pens (SDPs) for tirzepatide in a 
closeable, puncture-resistant container and dispose according to local regulations


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7.1.1. Packaging and Labeling
The sponsor will provide tirzepatide in SDP.  These will be dispensed via an interactive web-
response system (IWRS).  SDP will be packaged in cartons to be dispensed. Each SDP contains 
a specific dose and is administered as a single injection.  The SDP will be packaged for each 
dose strength: 2.5mg, 5mg, 7.5mg, 10mg, 12.5mg, 15mg and placebo to match.  The IP will be 
labeled according to the country’s regulatory requirements.
7.1.2. Medical Devices
The products provided for use in the study are tirzepatide investigational SDP.  
7.2.
Method of Treatment Assignment
Patients who meet all criteria for enrollment will be randomized to receive either tirzepatide or 
placebo in a 5:1 ratio at Visit 3a.  Assignment to treatment groups will be determined by a 
computer-generated random sequence using an IWRS.
7.2.1. Selection and Timing of Doses
There are no restrictions on the time of day each weekly dose of tirzepatide is given, but it is 
advisable to administer the SC injections on the same day and same time each week. The actual 
date and time of dose administrations will be recorded by investigator at dosing visit on site or
by the patient on self-administration day. 
If a dose of tirzepatide is missed, the patient should take it as soon as possible unless it is within 
72 hours of the next dose, in which case, that dose should be skipped and the next dose should be 
taken at the appropriate time.  Missed doses may not result in patient discontinuation from the 
study. For more information on missed doses, please refer to Section 7.6.
7.3.
Blinding
The dosing regimen is patient- and investigator-blind.  Investigators, site staff, clinical monitors,
and patients will remain blinded to the treatment assignments until the study is complete.
Blinding will be maintained throughout the study as described in the separate Blinding Plan.
Emergency unblinding for AEs may be performed through the IWRS, which may supplement or 
take the place of emergency codes generated using a computer drug-labeling system.  This 
option may be used ONLY if the patient’s well-being requires knowledge of the patient’s 
treatment assignment.  All calls resulting in an unblinding event are recorded and reported by the 
IWRS.


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If a patient’s study treatment assignment is unblinded, the patient must discontinue from the 
study, unless the investigator obtains specific approval from a Lilly clinical pharmacologist or 
clinical research physician (CRP) for the study participant to continue in the study.  During the 
study, emergency unblinding should occur only by accessing the study patient’s emergency code.
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a patient’s treatment assignment is warranted for medical management of the event. The 
patient’s safety must always be the first consideration in making such a determination. If the 
investigator decides that unblinding is warranted, the investigator must promptly document the 
decision and rationale and notify Lilly as soon as possible.
For the blinded items in the clinical laboratory tests, please refer to Appendix 2.
7.4.
Dose Modification
Dose adjustments are not permitted in this study.
7.5.
Preparation/Handling/Storage/Accountability
The investigator or designee must confirm the maintenance of appropriate temperature 
conditions (2oC to 8oC), as communicated by the sponsor, during transit for all IPs received. The 
investigator or designee should report and resolve any discrepancies before use of the IP.
Only participants enrolled in the study may receive the IPs or study materials, and only 
authorized site staff may supply or administer IP. All IPs should be stored in an environmentally 
controlled and monitored (manual or automated) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for IP accountability, reconciliation, and record maintenance (such as receipt, 
reconciliation, and final disposition records).
Patients will receive insulated bags with cooling gel packs for use in transporting the IP carton 
from the site to home.
Study site staff must regularly assess whether the patient is correctly administering the assigned 
IP and storing the study drug according to the provided instructions.
7.6.
Treatment Compliance
Study drug compliance will be determined by the following:

study drug administration data will be recorded by the investigator or patient (self-
administration), and reviewed by the investigator at each study visit and


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
the patients will be instructed to return any unused study drug and/or empty cartons at the 
next visit to the study site for the purpose of performing drug accountability.
Patients who are significantly noncompliant will be permanently discontinued from study 
medication. A patient will be considered significantly noncompliant if he /she misses 4 or more 
doses of study medication. Similarly, a patient will be considered significantly noncompliant if 
they are judged by the investigator to have intentionally or repeatedly taken more than the 
prescribed amount of medication.
In addition to the assessment of a patient’s compliance with IP administration, other aspects of 
compliance with the study treatments will be assessed at each visit based on the patient’s 
adherence to the visit schedule, compliance with the concomitant medication, completion of 
study diaries, the results of home blood glucose monitoring, and any other parameters the 
investigator considers necessary.
Initially, patients considered to be poorly compliant with their medication and/or the study 
procedures will receive additional training and instruction, as required, and will be reminded of 
the importance of complying with the protocol.
7.7.
Concomitant Therapy
Treatment with drugs that are excluded under the entry criteria (Section 6) is not permitted.
These medications include traditional Chinese medicines, herbal supplements, systemic 
glucocorticoids, immunomodulatory drugs, drugs with propensity for dermal reactions, drugs
with known liver toxicity, etc.
Patients on stable concomitant medication at the time of study entry should continue their 
regular, unchanged dose throughout the study. These medications (refer to Section 6) include
antihypertensive agents, aspirin, and lipid-lowering agents.
Apart from those listed earlier, patients should avoid concomitant medication; however, at their 
discretion, the investigator may administer acetaminophen (1 g, maximum 2 g/day) for treatment 
of headache, etc.  If the need for concomitant medication (other than acetaminophen) arises, 
inclusion or continuation of the patient may be at the discretion of the investigator after 
consultation with a Lilly clinical pharmacologist, CRP, or clinical research scientist (CRS).
Study site personnel will record any concomitant medications used during the course of the study 
in the electronic case report form (eCRF).


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7.7.1. Management of Patients with Gastrointestinal Symptoms
Patients will be guided on dietary behaviors that may help mitigate symptoms of nausea and
vomiting, for example, eating smaller meals, splitting 3 daily meals into 4 or smaller ones, and 
stopping eating when they feel full. For patients experiencing intolerable persistent GI
symptoms, the investigator may consider prescribing symptomatic medication (for example,
antiemetic medication).
7.8.
Treatment after the End of the Study
Not applicable for this study.


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8. Discontinuation Criteria
Patients discontinuing from the treatment prematurely for any reason should complete AE and 
other follow-up procedures per Section 2 of this protocol.
8.1.
Discontinuation from Study Treatment
Discontinuation of the IP for abnormal liver tests should be considered by the investigator when 
a patient meets 1 of the following conditions after consultation with the Lilly-designated medical 
monitor:

ALT or AST >8X ULN

ALT or AST >5X ULN sustained for more than 2 weeks or

ALT or AST >3X ULN and TBL >2X ULN or international normalized ratio >1.5 or

ALT or AST >3X ULN with the appearance of fatigue, nausea, vomiting, right 
upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)

alkaline phosphatase (ALP) >3X ULN

ALP >2.5X ULN and TBL >2X ULN

ALP >2.5X ULN with the appearance of fatigue, nausea, vomiting, right quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (>5%).
In addition, a patient will be discontinued from using the IP in case of abnormal pancreatic tests 
when he or she meets the following condition: 

lipase and/or amylase are confirmed to be ≥3× ULN.  Please refer to the algorithm for the 
monitoring of pancreatic events in Appendix 5. 
8.1.1. Discontinuation of Inadvertently Enrolled Patients
If the sponsor or investigator identifies a patient who did not meet enrollment criteria and was 
inadvertently enrolled, a discussion must occur between the Lilly clinical pharmacologist/CRP 
and the investigator to determine if the patient may continue in the study.  If both agree, it is 
medically appropriate to continue, the investigator must obtain documented approval from the 
Lilly clinical pharmacologist/CRP to allow the inadvertently enrolled patient to continue in the 
study with or without continued treatment with IP.


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8.2.
Discontinuation from the Study
Patients will be discontinued under the following circumstances:

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 patient should be discontinued from the study
o
if the patient, for any reason, requires treatment with another therapeutic agent 
that has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study occurs prior to introduction of the new agent

Patient decision
o
the patient, or legal representative, requests to be withdrawn from the study.
8.3.
Patients/Subjects Lost to Follow-up
The investigator will consider a patient lost to follow-up if they repeatedly miss scheduled visits 
and cannot be contacted by the study site.  Site personnel are expected to make diligent attempts 
to contact patient who miss scheduled visits 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.
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.  The investigator or sponsor 
may retain certain samples for a longer period, if necessary, to comply with applicable laws, 
regulations, or laboratory certification standards.
9.1.
Efficacy Assessments
The following efficacy measures will be collected at the times shown in the Schedule of 
Activities.

Change in HbA1c from baseline to prespecified time points.

Change in weight from baseline to prespecified time points. Site personnel will measure 
weight in a consistent manner using a calibrated scale according to the Schedule of 
Activities (Section 2).  Patients will be weighted in light clothing at approximately the 
same time in the morning before dosing and after an overnight fast and evacuation of the 
bowels and the bladder, if possible.  During the treatment period, weight will be 
measured twice on each scheduled occasion, with the patient stepping off the scale 
between measurements.  The personnel will record both weight measurements in the 
source document and the eCRF. Whenever possible, patients will use the same scale for 
all weight measurements throughout the study.

Fasting serum glucose level measured in the central laboratory (actual values and change 
from baseline to predefined time points).

7-point SMPG profile (actual values and change from baseline to pre-specified time
points). Patients will be asked to perform 7-point SMPG profiles over a 24-hour period, 
on nonconsecutive days, according to the Schedule of Activities. The 7-point profile 
consists of pre-meal and 2-hour postprandial SMPG measurements for the morning, 
midday, and evening meals in 1 day, and at bedtime. Pre-meal measurements should be 
taken before the patient begins eating the meal. Patients should record their glucose 
measurements in their patient diaries, which are considered source documents and are to 


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be returned to the investigator at each study visit. Values from the 7-point SMPG profile 
will be transferred from the diary and recorded on the eCRF.
9.2.
Adverse Events
Investigators are responsible for monitoring the safety of patients who have entered this study
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the patient.  The investigator will record all relevant 
AE/SAE information in the CRF.  
The investigator is responsible for the appropriate medical care of patients during the study.
Investigators must document their review of each laboratory safety report.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the IP or the study, 
or that caused the patient to discontinue the IP before completing the study. The patient should 
be followed up until the event resolves, stabilizes with appropriate diagnostic evaluation, or is 
reasonably explained.  The frequency of follow-up evaluations of the AE is left to the discretion 
of the investigator.
After the ICF is signed, study site personnel will record, via eCRF, the occurrence and nature of 
each patient’s preexisting conditions, including clinically significant signs and symptoms of the 
disease under treatment in the study.  Additionally, site personnel will record any change in the 
condition(s) and the occurrence and nature of any AEs.
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, or a study procedure, taking into account the disease, 
concomitant treatment, or pathologies.
A “reasonable possibility” means that there is a potential cause and effect relationship between 
the 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 patient’s IP is discontinued as a result of an AE, study site personnel must report this to Lilly 
or its designee via eCRF.


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9.2.1. Serious Adverse Events
An SAE is any AE from this study that results in 1 of the following:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

important medical events that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the patient or may require intervention to prevent 1
of the other outcomes listed in the definition above.
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 up with official notification 
on study-specific SAE forms.  This 24-hour notification requirement refers to the initial SAE 
information and all follow-up SAE information.
Although all AEs are recorded in the eCRF after signing informed consent, SAE reporting to the 
sponsor begins after the patient has signed informed consent and has received IP.  However, if an 
SAE occurs after signing informed consent, but prior to receiving IP, AND is considered 
Reasonably Possibly Related to a study procedure then it MUST be reported.
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued from and/or completed the study (the patient’s summary eCRF has been 
completed).  However, if the investigator learns of any SAE, including a death, at any time after 
a patient has been discharged from the study, and he/she considers the event reasonably possibly 
related to the study treatment or study participation, the investigator must promptly notify Lilly. 
Pregnancy (maternal or paternal exposure to IP) does not meet the definition of an AE.  
However, to fulfill regulatory requirements, any pregnancy should be reported following the 
SAE process to collect data on the outcome for both mother and fetus.


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9.2.1.1. Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the 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 to 
ensure the safety of study participants, monitor quality, and to facilitate process and product 
improvements.
Patients should be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the 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.
Refer to the IB for tirzepatide.
9.4.
Safety
9.4.1. Laboratory Tests
For each patient, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities (Section 2).
9.4.2. Vital Signs
For each patient, vital sign measurements should be conducted according to the Schedule of 
Activities (Section 2).
Blood pressure and pulse rate should be measured after approximately 5 minutes in the supine
position.
If orthostatic measurements are required, patients should be supine for approximately 5 minutes 
and stand for at least 2 minutes.  If the patient feels unable to stand, personnel will record only 
the supine vital signs. 


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Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or 
posture-induced symptoms. If warranted, site personnel may measure additional vital signs 
during each study period.
Body temperature will be measured as specified in the Schedule of Activities and as clinically 
indicated (Section 2). 
9.4.3. Electrocardiograms
For each patient, 12-lead digital ECGs should be collected according to the Schedule of 
Activities (Section 2).
Site personnel should report any clinically significant findings from ECGs that result in a 
diagnosis and occur after the patient receives the first dose of the IP to Lilly, or its designee, as 
an AE via eCRF.
For each patient, personnel will collect a single 12-lead digital ECG at screening and follow-up 
or early termination visit according to the Schedule of Activities (Section 2).  Electrocardiograms
may be obtained at additional times, when deemed clinically necessary.  The investigational site 
should store all ECGs recorded.
Electrocardiograms must be recorded before collecting any blood samples for safety or PK tests.  
Patients must be supine for approximately 5 to 10 minutes before ECG collection and remain 
supine but awake during ECG collection.  
At the site, a qualified physician (the investigator or qualified designee) will interpret ECGs as 
soon as possible. Ideally, ECG interpretation will occur while the patient is still present to 
determine whether the patient meets entry criteria at the relevant visit(s) and for immediate 
patient management, should any clinically relevant findings be identified.  
If a clinically significant quantitative or qualitative change from baseline is identified (including, 
but not limited to, changes in QT interval/QT interval corrected for heart rate using Fridericia’s 
formula from baseline) after enrollment, the investigator will assess the patient for symptoms 
(for example, palpitations, near syncope, syncope) to determine whether the patient can continue 
in the study.  The investigator or qualified designee is responsible for determining if any change 
in patient management is needed and must document their review of the ECG printed at the time 
of evaluation from at least 1 of the replicate ECGs from each time point.  Any new clinically 
relevant finding should be reported as an AE.


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9.4.4. Safety Monitoring
The Lilly clinical pharmacologist or CRP/scientist will monitor safety data throughout the course 
of the study.
Lilly will review SAEs within time frames mandated by company procedures.  The Lilly clinical 
pharmacologist, CRP, or CRS will periodically review the following data:

trends in safety data

laboratory analytes 

AEs including GI events, hypoglycemia, injection-site reactions, hypersensitivity 
reactions, and pancreatitis
When appropriate, the Lilly clinical pharmacologist, CRP, or CRS will consult with the 
functionally independent Global Patient Safety therapeutic area physician or CRS.
9.4.4.1. Hepatic Safety
If a study patient experiences elevated ALT ≥3X ULN, ALP ≥2X ULN, or elevated TBL ≥2X 
ULN, liver tests (Appendix 4) should be repeated within 3 to 5 days including ALT, AST, ALP, 
TBL, direct bilirubin, gamma-glutamyl transferase, and creatine kinase to confirm the 
abnormality and to determine if it is increasing or decreasing.  If the abnormality persists or 
worsens, the investigator should initiate clinical and laboratory monitoring based on consultation 
with the Lilly clinical pharmacologist, CRP, or CRS.  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 ≥5X ULN on 2 or more consecutive blood tests

Elevation of serum TBL to ≥2X ULN (except for cases of known Gilbert’s 
syndrome)

elevation of serum ALP to ≥2X ULN on 2 or more consecutive blood tests 

patient/subject discontinued from treatment due to a hepatic event or abnormality 
of liver tests

hepatic event considered to be an SAE.


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9.4.4.2. Pancreatic Safety
Acute pancreatitis is defined as an AE of interest in all trials with tirzepatide including this trial.  
Acute pancreatitis is an acute inflammatory process of the pancreas that may also involve 
peripancreatic tissues and/or remote organ systems (Banks and Freeman 2006).  The diagnosis of 
acute pancreatitis requires 2 of the following 3 features: 
-
abdominal pain, characteristic of acute pancreatitis (generally located in the epigastrium 
and radiates to the back in approximately half the cases [Banks and Freeman 2006; Koizumi et 
al. 2006]; the pain is often associated with nausea and vomiting)
-
serum amylase (total and/or pancreatic) and/or lipase ≥3X ULN
-
characteristic findings of acute pancreatitis on computed tomography (CT) scan or 
magnetic resonance imaging (MRI)
If acute pancreatitis is suspected, appropriate laboratory tests (including levels of pancreatic 
amylase [p-amylase] and lipase) should be obtained via the local laboratory.  Imaging studies, 
such as abdominal CT scan with or without contrast, MRI, or gallbladder ultrasound, should be 
performed.  If laboratory values and/or abdominal imaging support the diagnosis of acute 
pancreatitis, the patient must discontinue therapy with investigational product, but will continue 
in the study on another glucose-lowering regimen (details on rescue intervention will be 
provided).  The most appropriate diabetes therapeutic regimen will be decided by the 
investigator, based on the patient’s clinical status.  A review of the patient’s concomitant 
medications should be conducted to assess any potential causal relationship with pancreatitis. 
Each case of an AE of pancreatitis must be reported.  If typical signs and/or symptoms of 
pancreatitis are present and confirmed by laboratory values (lipase or amylase [total and/or 
pancreatic]) and imaging studies, the event must be reported as an SAE.  For a potential case that 
does not meet all of these criteria, it is up to the investigator to determine the seriousness of the 
case (AE or SAE) and the relatedness of the event to study drug. 
Each patient will have measurements of p-amylase and lipase (assessed at the local laboratory) as 
shown on the Schedule of Activities (Section 2) to assess the effects of the investigational doses 
of tirzepatide on pancreatic enzyme levels. Serial measures of pancreatic enzymes have limited 
clinical value for predicting episodes of acute pancreatitis in asymptomatic patients (Nauck et al. 
2017; Steinberg et al. 2017a, b). Thus, further diagnostic follow-up of cases of asymptomatic 
pancreatic hyperenzymemia (lipase and/or p-amylase ≥3X ULN) is not mandated but may be 
performed based on the investigator’s clinical judgment and assessment of the patient’s overall 
clinical condition. Only cases of pancreatic hyperenzymemia that undergo additional diagnostic 
follow-up and/or are accompanied by symptoms suggestive of pancreatitis will be submitted for 
adjudication. 


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All suspected cases of acute or chronic pancreatitis will be adjudicated by an independent 
clinical endpoint committee.  In addition, AEs of severe or serious abdominal pain of unknown 
etiology will also be submitted to the adjudication committee to assess for possible pancreatitis 
or other pancreatic disease. Relevant data from patients with acute or chronic pancreatitis and 
those with severe or serious abdominal pain will be entered into a specifically designed eCRF 
page by study site or Lilly staff. The adjudication committee representative will enter the results 
of adjudication in a corresponding eCRF page.
9.4.4.3. Hypersensitivity Reactions
The investigator will report all hypersensitivity reactions either as AEs or, if any serious criterion 
is met, as SAEs.  In the event of suspected drug hypersensitivity reactions (immediate or 
nonimmediate) 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 immunoglobulin E, 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.
9.4.4.3.1. 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


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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 
and laboratory evaluations (ALT, AST, complete blood count with absolute count for 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.
9.4.4.4. Glucose Monitoring
Site personnel will instruct patients on how to use the glucose meter provided by the site and 
conduct SMPG tests.  In addition to the plasma glucose (PG) monitoring, patients will be 
educated on the symptoms of hypoglycemia and hyperglycemia.  Throughout their participation 
in the study, patients will monitor PG levels.  The site will provide patients with diaries and 
instructions on how to record PG results whenever the patient experiences symptoms of 
hypoglycemia, while not in the CRU.  The investigator or designee will review PG results 
clinically indicative of hypoglycemia or hyperglycemia. 
Additionally, site personnel will require patients who were taking OAM at screening to monitor 
their PG in the morning before breakfast during the lead-in period.
9.4.4.4.1. Hyperglycemia and Hypoglycemia Reporting
Episodes of hyperglycemia (fasting plasma/serum glucose >270 mg/dL [15 mmol/L]) or 
hypoglycemia (plasma/serum glucose ≤70 mg/dL [3.9 mmol/L]) will be reported by the 
investigator or designated physician who will be responsible for advising the patient on what 
further actions to take.  At their discretion, the investigator may request additional monitoring.
If the fasting plasma/serum glucose during the dosing period exceeds the acceptable level, 
defined as hyperglycemia on 3 or more separate days during any 2-week period between 
screening and the end of the dosing period, the patient will be evaluated further at the study site.  
If fasting plasma/serum glucose continues to exceed the acceptable level, the investigator will 
discontinue the IP and initiate treatment with an appropriate antidiabetic agent.  The patient will 
continue to be followed up in the study (for safety, PK, and immunogenicity assessment) for at 
least 28 days after their last dose.  If hyperglycemia occurs during the follow-up period, the 
patient will remain in the study until completion of the planned follow-up.


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Site personnel will record hypoglycemia episodes on specific eCRF pages.  The investigator will 
treat hypoglycemia appropriately and may perform additional monitoring of plasma/serum 
glucose levels.  The following categories of the 2017 American Diabetes Association position 
statement on glycemic targets (America Diabetes Association 2017) on the basis of 
recommendations of the International Hypoglycaemia Study Group (International 
Hypoglycaemia Study Group 2017) should be applied for reporting in the eCRF and evaluation 
of hypoglycemic events.
The main categories of hypoglycemia are outlined as follows:
Documented Glucose Alert Level (Level 1): plasma/serum glucose ≤70 mg/dL (3.9 mmol/L)

Documented symptomatic hypoglycemia: with typical symptoms of hypoglycemia.

Documented asymptomatic hypoglycemia: without typical symptoms of hypoglycemia.

Documented unspecified hypoglycemia: with no information about symptoms of 
hypoglycemia available.  (This has been called unclassifiable hypoglycemia.)
Documented Clinically Significant Hypoglycemia (Level 2): with similar criterion as above 
except for the threshold plasma/serum glucose <54 mg/dL (3.0 mmol/L)

Level 2 documented symptomatic hypoglycemia

Level 2 documented asymptomatic hypoglycemia

Level 2 documented unspecified hypoglycemia
Severe Hypoglycemia (Level 3)

Severe hypoglycemia (in adults): Patients had altered mental status, and could not 
assist in their own care, or were semiconscious or unconscious, or experienced coma with 
or without seizures, and the assistance of another person required to actively administer 
carbohydrate, glucagon, or other resuscitative actions.  Plasma/serum glucose 
measurements may not be available during such events, but neurological recovery 
attributable to the restoration of plasma/serum glucose concentration to normal is 
considered sufficient evidence that the event was induced by a low plasma/serum 
concentration (plasma/serum glucose ≤70 mg/dL [3.9 mmol/L]).

Severe hypoglycemia requiring medical attention: Severe hypoglycemic events when 
patients require therapy by health care providers (Emergency Medical Technicians, 
emergency room personnel, etc.) are of particular interest to payers.  Therefore, some 


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clinical trials may collect data on this subset of severe hypoglycemia episodes, especially 
if economic outcomes analyses may be based on trial results.
Other Hypoglycemia

Nocturnal hypoglycemia: Any documented hypoglycemic event (including severe 
hypoglycemia) that occurs at night and presumably during sleep.  At Lilly, this is 
captured as hypoglycemia that occurs between bedtime and waking.  This definition is 
more useful than the commonly used ~midnight to ~6 AM definition, which does not take 
patients’ individual sleep times into consideration and is consistent with the American 
Diabetes Association recommendations for reporting events that occur during sleep 
(American Diabetes Association 2005).  It is also important to collect the actual time a 
hypoglycemic event occurred to allow further characterization of hypoglycemia timing 
(for example, to allow analysis of frequency of events occurring during a 24-hr time 
period).  Nocturnal hypoglycemia may occur at severity Levels 1, 2, or 3. 

Relative hypoglycemia (also referred to as pseudohypoglycemia [Seaquist et al. 
2013]): An event during which typical symptoms of hypoglycemia occur, that does not 
require the assistance of another person, and is accompanied by plasma/serum glucose 
>70 mg/dL (3.9 mmol/L).  The plasma/serum glucose value for patients with chronically 
poor glycemic control can decrease so rapidly that patients may report symptoms of 
hypoglycemia before their plasma/serum glucose concentration falls below 70 mg/dL 
(3.9 mmol/L).  Events with plasma/serum glucose ≤7 mg/dL should not be categorized as 
relative hypoglycemia.  Evaluation and statistical analysis of this category is optional.  
However, if a patient reports a relative hypoglycemic event where assistance from 
another person was received or the patient experienced significant symptoms, the study 
team should clarify the circumstances to ensure the event is not a severe hypoglycemia
event and report it appropriately.

Probable symptomatic hypoglycemia: Symptoms of hypoglycemia were present, but a 
plasma/serum glucose measurement was not reported.

Overall (or total) hypoglycemia: This optional category combines most cases of 
hypoglycemia (documented hypoglycemia and probable symptomatic hypoglycemia, 
including severe hypoglycemia).  It does not include relative hypoglycemia.  Nocturnal 
and severe hypoglycemia are special cases of documented or probable hypoglycemia.  If 
an event of hypoglycemia falls into multiple subcategories, that event should only be 
counted once in the category of overall (or total) hypoglycemia.
If a hypoglycemic event meets the criteria of severe, it needs to be recorded as serious in the 
eCRF (that is, recorded as an SAE).  In the case of a hypoglycemic event (other than severe), the 
actual glucose value, if measured, should be recorded in the eCRF, with any treatments 


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administered, and not be recorded as an AE.  Cases of hypoglycemia may be treated with foods 
rich in carbohydrates such as fruit, juice, skimmed milk, or energy bars.  All episodes of 
hypoglycemia that are determined by the investigator to constitute severe hypoglycemia
according to the definition above should be reported as SAEs.
9.4.4.5. Nausea and Vomiting
Nausea and vomiting events are considered AEs of interest and will be recorded as AEs in the 
eCRF.  For event assessment of severity, duration, and investigator’s opinion of relatedness to IP
and protocol procedure will be captured. 
9.4.4.6. Thyroid Malignancies and C-Cell Hyperplasia
Individuals with personal or family history of MTC and/or MEN-2 will be excluded from the
study. The assessment of thyroid safety during the trial will include reporting of any case of
thyroid malignancy including MTC and papillary carcinoma and measurements of calcitonin.
This data will be captured in specific eCRFs. The purpose of calcitonin measurements is to
assess the potential of tirzepatide to affect thyroid C-cell function, which may indicate
development of C-cell hyperplasia and neoplasms. Tirzepatide should be discontinued (after first
confirming the value) if post randomization calcitonin value is ≥35 ng/L (pg/mL) and has
increased at least 50% over baseline. A consultation with a thyroid specialist (if not available, an
endocrinologist) should be obtained.
If the increased calcitonin value (≥35 pg/mL and increases by ≥50% compared to baseline) is
observed in a patient who has administered a medication that is known to increase serum
calcitonin, this medication should be stopped and calcitonin levels should be measured after an
appropriate wash out period. If the confirmed calcitonin value is <35 pg/mL, tirzepatide should
be restarted when it is safe to do so.
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 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 time period) of each sampling will be recorded.
Drug concentration information that may unblind the study will not be reported to study sites or 
blinded personnel until the study has been unblinded.


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9.5.1. Bioanalysis
A laboratory approved by the sponsor will analyze samples. A facility designated by the sponsor
will store samples.
Concentrations of tirzepatide will be assayed using a validated liquid chromatography mass 
spectrometry method.  Analyses of samples collected from patient who received placebo are not 
planned.
Bioanalytical samples collected to measure IP concentrations will be retained for a maximum of 
1 year following last patient visit for the study.  
9.6.
Pharmacodynamics
Assessment of tirzepatide pharmacology may include lipid profile (total cholesterol, high-density 
lipoprotein and low-density lipoprotein cholesterol, triglycerides), meal intake and appetite, and 
immunogenicity assessments.  Additional exploratory PD analysis may be analyzed as deemed 
appropriate. 
Blood samples will be obtained for the measurement of PD.  The scheduled times for the 
collection of these samples are as listed in the Schedule of Activities (Section 2).  The timing of 
PD samples is intended to assess pharmacologic effects of tirzepatide.  The sampling times may 
be modified at the discretion of the sponsor, but the total number of the samples or total blood 
volume will not increase.
The sample(s) will be stored for up to a maximum of 1 year after the last patient visit for the 
study at a facility selected by the sponsor. The chemistry panel will be destroyed in 60 days and 
7-point samples will not be stored.
9.6.1. Lipids
Lipid profile (total cholesterol, high-density lipoprotein, very low-density lipoprotein, and 
triglycerides), as indicated in the Schedule of Activities (Section 2), will be assayed using 
validated analytical methods.  Instructions for the collection and handling of blood samples for 
these analyses will be provided by the sponsor.
9.6.2. Meal Intake and Appetite
To explore the effects of tirzepatide on meal intake and appetite sensation, patients will be 
provided standardized lunch and dinner meals with an approximate total energy and 
macronutrient contents of 700 kCal and 20% protein, 25% fat, and 55% carbohydrate according 
to the Schedule of Activities (Section 2). The meal intake will be recorded in the source 


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document. The subjective rating of appetite sensations is measured using a 100-mm visual 
analogue scale (VAS) for parameters of hunger, fullness, satiety, and prospective food 
consumption before and 4 to 5 hours after the standardized lunch and dinner meals. The 
standardized lunch and dinner meals will be provided at least 4 hours after the previous meal. 
The VAS is a validated tool to assess appetite sensation parameters (Flint et al. 2000). The VAS 
is presented as a 10-cm (100-mm) line, anchored by verbal descriptors, usually “extremely” and 
“not at all.” Patients are required to rate their subjective sensations on four 100-mm scales 
combined with the questions: “How hungry do you feel right now?”, “How satisfied do you feel 
right now?”, “How full do you feel right now?”, and “How much food do you think you could 
eat right now?” A staff member will use a caliper to measure the distance from 0 to the mark 
that the patient placed on the VAS and record the measurement in the source document. Overall 
appetite score is calculated as the average of the 4 individual scores—satiety + fullness + (100-
prospective food consumption) + (100-hunger) / 4 (van Can et al. 2014). The higher overall 
appetite score indicates less appetite, and the lower score indicates more appetite.
9.6.3. Immunogenicity Assessments 
At the visits and times specified in the Schedule of Activities (Section 2), venous blood samples 
will be collected to determine antidrug antibody (ADA) production against the tirzepatide.   To 
interpret the results of immunogenicity, a venous blood sample will be collected at the same time 
point to determine the plasma concentrations of tirzepatide.  All samples for immunogenicity 
should be taken predose when applicable and possible. All patients will have an ADA sample 
measured at early discontinuation or at the follow-up visit (Day 141 for Cohort 1 and Day 197 
for Cohort 2) approximately 5 weeks after the last dose of tirzepatide. Follow-up visit will 
assess immunogenicity at washout of tirzepatide (5 half-lives at the end of treatment).
In the event of a drug hypersensitivity reaction, see Section 9.4.4.3 for instructions of collection 
and handling of blood samples.
Immunogenicity will be assessed using a validated assay designed to detect and titer ADA in the 
presence of tirzepatide at a laboratory approved by the sponsor.  Samples with detected ADA 
will be tested for cross-reactive binding to native GIP and GLP-1. Antibodies may be further 
evaluated for their ability to neutralize the activity of tirzepatide. In vivo laboratory indicators 
for glycemic control (fasting blood glucose and HbA1c), effect on weight loss, and PK will be 
utilized to detect potential neutralizing effect of ADA against tirzepatide. 
Treatment-emergent (TE) ADAs are defined in Section 10.3.5.
Antidrug antibody samples will be stored as per local regulation/EC requirements. Samples will 
be immediately destroyed once tirzepatide is launched or there is no further request on testing the
samples from China authority.


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9.7.
Genetics
A blood sample will be collected for pharmacogenetic analysis as specified in the Schedule of 
Activities (Section 2), where local regulations allow.  
Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future.  Samples will be used to investigate variable exposure or response to 
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 patient number.  These samples and any data generated can 
be linked back to the patient only by the investigative site personnel.
Samples will be retained for a maximum of 15 years after the last patient 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.  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 or after 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. 
9.8.
Biomarkers
This section is not applicable for this study.
9.9.
Health Economics
This section is not applicable for this study.


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10.
Statistical Considerations and Data Analysis
10.1. Sample Size Determination
The sample size for the study was chosen to provide sufficient data to evaluate the primary 
objective of this study and is not intended to achieve any priori statistical requirements.
Approximately 24 Chinese patients with T2DM may be enrolled so that approximately 16
patients complete the study with compliant defined dosing regimen. Patients will be 
administered either 16 (Cohort 1) or 24 (Cohort 2) weekly SC doses of tirzepatide or placebo in a 
ratio of 10 tirzepatide:2 placebo for both cohorts.  
Replacement of discontinued patients is not planned because the sample size is determined 
considering the expected drop-out rate.
10.2. Populations for Analyses
10.2.1. Study Participant Disposition
All patients 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 patient’s age, sex, weight, height, or other demographic characteristics will be recorded and 
may be used in the PK, PD, efficacy, and safety analyses as quantitative or classification 
variables.
10.3. Statistical Analyses
Statistical analysis of this study will be the responsibility of Eli Lilly and Company or its 
designee.
Pharmacokinetics, PD, and efficacy analyses will be conducted on data from all patients who 
receive at least 1 dose of the IP and have evaluable PK, PD, and efficacy data.
Patients who received placebo within each cohort of the study will be pooled for PD, efficacy,
and safety analyses.
Safety analyses will be conducted for all enrolled patients, whether or not they completed all 
protocol requirements.


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Additional exploratory analyses of the data will be conducted as deemed appropriate. Statistical 
analyses will be fully detailed in the statistical analysis plan.
10.3.1. Safety Analyses
10.3.1.1. Clinical Evaluation of Safety
All IP and protocol procedure-related AEs will be listed, and if the frequency of events allows, 
safety data will be summarized using descriptive methodology.
The incidence of symptoms for each treatment will be presented by severity and by association 
with IP as perceived by the investigator. Symptoms reported to occur before the first IP dosing
will be distinguished from those reported as new or increased in severity during the study.  Each 
symptom will be classified by the most suitable term from the Medical Dictionary for Regulatory 
Activities.
The number of IP-related SAEs will be reported.
10.3.1.2. Statistical Evaluation of Safety
Safety parameters that will be assessed include safety laboratory parameters, vital signs, ECG 
parameters, injection-site reactions, and hypoglycemia. The parameters will be listed and 
summarized using standard descriptive statistics. Additional analysis will be performed if 
warranted upon review of the data.
10.3.2. Efficacy Analyses
The efficacy of tirzepatide to reduce glucose and weight will be assessed. Efficacy measures that 
will be assessed include HbA1c, body weight, fasting PG, and 7p-SMPG. All parameters will be 
listed and summarized using standard descriptive statistics. Further analysis may be performed.
The individual observed and mean time profile of the postdose efficacy parameters will be 
plotted by treatment group.
10.3.3. Pharmacokinetic Analyses
10.3.3.1. Pharmacokinetic Parameter Estimation
Pharmacokinetic parameter estimates for tirzepatide will be calculated using standard 
noncompartmental methods of analysis.
The primary parameters for analysis will be maximum drug concentration (Cmax), area under the 
concentration-time curve (AUC), and time to Cmax (Tmax) of tirzepatide. Other 


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noncompartmental parameters, such as half-life, apparent clearance, and apparent volume of 
distribution may be reported.  Model-based analysis may be performed combined with data from 
other studies.
10.3.3.2. Pharmacokinetic Statistical Inference
Pharmacokinetic parameters will be summarized using descriptive statistics by dosing regimen.
The mean concentration-time profiles in linear and semilog scales for each tirzepatide-treated 
group will be presented.
10.3.4. Evaluation of Pharmacodynamics
Pharmacodynamic parameters that will be assessed include lipids and subjective appetite 
sensation (VAS). The parameters will be listed and summarized using standard descriptive 
statistics.
10.3.5. Evaluation of Immunogenicity
The frequency and percentage of subjects/patients with preexisting ADA and with TE ADA to 
tirzepatide will be tabulated.  Treatment-emergent ADA 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).  For the TE ADA patients,
the distribution of maximum titers will be described.  The frequency of neutralizing antibodies to 
tirzepatide and/or cross-reactive to endogenous counterparts may be tabulated in TE ADA 
patients.
The relationship between the presence of antibodies, antibody titers, and clinical parameters (for 
example, AEs) may be assessed.  Likewise, the relationship between antibody titers, PK 
parameters, and PD response to tirzepatide may be assessed.
10.3.6. Interim Analyses
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the Lilly clinical pharmacologist, CRP/investigator, or designee will consult with the 
appropriate medical director or designee to determine if it is necessary to amend the protocol.


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11.
References
American Diabetes Association; Workgroup on Hypoglycemia. Defining and reporting
hypoglycemia in diabetes: a report from the American Diabetes Association Workgroup on
Hypoglycemia. Diabetes Care. 2005;28(5):1245-1249.
American Diabetes Association. Glycemic targets. Sec 6. In: Standards of Medical Care in 
Diabetes—2017. Diabetes Care. 2017;40(suppl 1):S48-S56.
Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology. 
2007;132(6):2131-2157.
Banks PA, Freeman ML; Practice Parameters Committee of the American College of 
Gastroenterology. Practice guidelines in acute pancreatitis. Am J Gastroenterol. 
2006;101(10):2379-2400.
Bydureon [package insert]. Wilmington, DE: AstraZeneca; 2015.
Frias JP, Nauck MA, Van J, et al. 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. [published online October 4, 2018]. Lancet.
Flint A, Raben A, Blundell JE, Astrup A. Reproducibility, power and validity of visual analogue
scales in assessment of appetite sensations in single test meal studies. Int J Obes Relat Metab
Disord. 2000;24(1):38-48.
International Hypoglycaemia 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.
Nauck MA, Meier JJ, Schmidt WE. Incretin-based glucose-lowering medications and the risk of 
acute pancreatitis and/or pancreatic cancer: reassuring data from cardio-vascular outcome 
trials. Diabetes Obes Metab. 2017;19(9):1327-1328.
Neumiller JJ. Incretin-based therapies. Med Clin North Am. 2015;99(1):107-129.
Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, Heller SR, Rodriguez H,
Rosenzweig J, Vigersky R. Hypoglycemia and diabetes: a report of a workgroup of the
American Diabetes Association and the Endocrine Society. Diabetes Care. 2013;36(5):1384-
1395.
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. 


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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.
van Can J, Sloth B, Jensen CB, Flint A, Blaak EE, Saris WH. Effects of the once-daily GLP-1
analog liraglutide on gastric emptying, glycemic parameters, appetite and energy metabolism
in obese, non-diabetic adults. Int J Obes (Lond). 2014;38(6):784-793.


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Appendix 1.
Abbreviations and Definitions


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Term
Definition
ADA
antidrug antibody
AE
adverse event: Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product.
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
blinding
A procedure in which 1 or more parties to the study are kept unaware of the treatment 
assignment(s). Unless otherwise specified, blinding will remain in effect until final 
database lock.
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the patient is not, or vice versa, or when the sponsor is aware of the treatment 
but the investigator and/his staff and the patient are not.  A double-blind study is one in 
which neither the patient nor any of the investigator or sponsor staff who are involved in the 
treatment or clinical evaluation of the subjects are aware of the treatment received.
Cmax
Maximum observed drug concentration
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all the study-related requirements, good clinical practice (GCP) requirements, 
and the applicable regulatory requirements.
confirmation
A process used to confirm that laboratory test results meet the quality requirements defined 
by the laboratory generating the data and that Lilly is confident that results are accurate.  
Confirmation will either occur immediately after initial testing or will require that samples 
be held to be re-tested at some defined time point, depending on the steps required to obtain 
confirmed results.


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CRP
clinical research physician:  Individual responsible for the medical conduct of the study.  
Responsibilities of the CRP may be performed by a physician, clinical research scientist, 
global safety physician, or other medical officer.
CRS
clinical research scientist
CRU
clinical research unit
CT
computed tomography
DPP
dipeptidyl peptidase
ECG
electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the study are 
those who have been assigned to a treatment.
enter
Patients entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ERB
ethical review board
FSH
follicle-stimulating hormone 
GCP
good clinical practice
GI
gastrointestinal
GIP
glucose-dependent insulinotropic polypeptide
GLP-1
glucagon-like peptide-1
HbA1c
hemoglobin A1c
HIV
human immunodeficiency virus


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IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
informed consent
A process by which a patient voluntarily confirms his or her willingness to participate in a 
particular study, after having been informed of all aspects of the study that are relevant to 
the patient’s decision to participate.  Informed consent is documented by means of a 
written, signed, and dated informed consent form.  
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.
IWRS
interactive web-response system
legal 
representative
An individual or judicial or other body authorized under applicable law to consent, on 
behalf of a prospective patient, to the patient’s participation in the clinical study.
MAD
multiple-ascending dose
MEN-2
multiple endocrine neoplasia syndrome type 2
MRI 
magnetic resonance imaging
MTC
medullary thyroid carcinoma
OAM
oral antidiabetic medication
PA
posterior anterior  
PG
plasma glucose
PK/PD
pharmacokinetic(s)/pharmacodynamic(s)


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QW
once weekly
RA
receptor agonist
randomize
the process of assigning subjects/patients to an experimental group on a random basis
SAE
serious adverse event
SC
subcutaneous
screen
The act of determining if an individual meets minimum requirements to become part of a 
pool of potential candidates for participation in a clinical study.  
SDP
single-dose pen
SMPG
self-monitored plasma glucose
SUSAR
suspected unexpected serious adverse reaction
T2DM
type 2 diabetes mellitus
TBL
total bilirubin level
TE
treatment emergent
Tmax
time to maximum drug concentration
ULN
upper limit of normal
VAS
visual analogue scale


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Appendix 2.
Clinical Laboratory Tests
Safety Laboratory Tests
Hematologya
Clinical Chemistry (Fasting)a
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Chloride
Mean cell volume 
Creatinine
Mean cell hemoglobin
Calcium
Mean cell hemoglobin concentration 
Phosphorus
Leucocytes (WBC)
Glucose 
Platelets
Blood urea nitrogen
Differential WBC absolute counts of:
Uric acid
Neutrophils
Total protein
Lymphocytes
Albumin
Monocytes
Total bilirubin
Eosinophils
Alkaline phosphatase (ALP)
Basophils
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Urinalysisa
Lipase
   Specific gravity
Amylase
pH
eGFRb
Protein
Glucose
Ketones
Bilirubin
Urobilinogen
Blood
Leucocytes
Microscopyc
Other Tests
Lipid Paneld,e
Pregnancy test (urine, serum)a,c
HDL-C
Follicle-stimulating hormonea,b,c
Fasting blood glucosed
LDL-C (calculated)
Urine drug and alcohol screena
Total cholesterol
Hemoglobin A1cd
Triglycerides
Pharmacogenetic sample (storage)b,d,e,
Calcitoninf
Serologya,b
Tirzepatide plasma levelsd,e,f
Hepatitis B surface antigen
Immunogenicitye,f
Hepatitis C antibody
HIV antibody and/or HIV antigen
Abbreviations:  eGFR = estimated glomerular filtration ratio; HDL-C = high-density lipoprotein cholesterol; HIV = 
human immunodeficiency virus; LDL-C = low-density lipoprotein cholesterol; RBC = red blood cell; WBC = 
white blood cell.
a
Performed at local laboratories.
b   Performed at screening only.
c
If clinically indicated, per investigator’s discretion.
d
Performed at a central laboratory.
e
These results will not be reported to study sites.
f
Assayed at Lilly-designated laboratory.


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


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Regulatory Considerations
This study will be conducted in accordance with the protocol and with
1) consensus ethics principles derived from international ethics guidelines, 
including the Declaration of Helsinki and Council for International 
Organisations of Medical Sciences International Ethical Guidelines 
2) applicable ICH GCP Guidelines
3) applicable laws and regulation
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 with the most enrolled patients will serve as the final report coordinating 
investigator.  If this investigator is unable to fulfill this function, another investigator will be 
chosen by Lilly to serve as the final report coordinating investigator.
The sponsor’s responsible medical officer and statistician will sign/approve the final clinical 
study report for this study, confirming that, to the best of his or her knowledge, the report 
accurately describes the conduct and results of the study.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate.

provide training to instruct the investigators and study coordinators.  This training will 
give instruction on the protocol, the completion of the case report forms, 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.


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


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


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Appendix 5.
Blood Sampling Summary
This table summarizes the approximate number of venipunctures and blood volumes for all 
blood sampling (screening, safety laboratories, and bioanalytical assays) during the study.  
Protocol I8F-MC-GPHT Sampling Summary
Purpose
Blood Volume 
per Sample 
(mL)
Number of Blood Samples
Total Volume (mL)
Cohort 1
Cohort 2
Cohort 1
Cohort 2
Screening serology and 
serum pregnancy testsa
9b
1
1
9
9
Clinical safety laboratory 
testsa
10b
12
13
120
130
Lipid panel
2.5
6
8
15
20
Pancreatic enzyme
3
9
10
27
30
Calcitonin
2.5
3
3
7.5
7.5
Tirzepatide
pharmacokinetics
3
24
26
72 
78
Potential additional 
tirzepatide
pharmacokinetic samples
3
3
3
9
9
Fasting blood glucose 
4.5
6
8
27
36
HbA1c
2
6
8
12
16
Immunogenicity
10
6
6
60
60
Pharmacogenetics
10
1
1
10
10
Total
369c
406c
Abbreviation: HbA1c = hemoglobin A1c.
a
Additional samples may be drawn if needed for safety purposes.
b
Because screening and safety (chemistry and hematology) tests are performed at local laboratories at each site, 
this volume is an estimate and will vary depending on the local laboratory’s testing requirements.
c
The maximum blood volume will increase if follow-up visits for antidrug antibody testing are needed.


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Appendix 6.
Protocol Amendment I8F-MC-GPHT(b) 
Summary - A Multiple Dose Titration Study in Chinese 
Patients with Type 2 Diabetes Mellitus to Investigate the 
Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, 
and Efficacy of Tirzepatide
Overview
Protocol I8F-MC-GPHT, A Multiple Dose Titration Study in Chinese Patients with Type 2 
Diabetes Mellitus to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, 
and Efficacy of Tirzepatide, has been amended.  The new protocol is indicated by 
Amendment (b) and will be used to conduct the study in place of any preceding version of the 
protocol.
This amendment is not considered a substantial protocol amendment.
The overall changes and rationale for the changes made to this protocol are as follows:

Single-site has been removed from the study design because more than one site may be 
used for screening and enrollment in this study.

The appendix referenced in Section 9.4.4.1 Hepatic Safety has been corrected to 
Appendix 4.


I8F-MC-GPHT(b) Clinical Pharmacology Protocol
Page 80
LY3298176
Revised Protocol Sections
Note:
All deletions have been identified by strikethroughs.
All additions have been identified by the use of underscore.
1.
Protocol Synopsis
Summary of Study Design:
Study GPHT is a Phase 1, single-site, randomized, placebo-controlled, multiple dose titration 
study in Chinese patients with T2DM.
5.1
Overall Design
Study GPHT is a Phase 1, single-site, patient- and investigator-blind, placebo-controlled, 
randomized, multiple dose titration study in Chinese patients with T2DM.
9.4.4.1.
Hepatic Safety
If a study patient experiences elevated ALT ≥3X ULN, ALP ≥2X ULN, or elevated TBL ≥2X 
ULN, liver tests (Appendix 54) should be repeated within 3 to 5 days including ALT, AST, ALP, 
TBL, direct bilirubin, gamma-glutamyl transferase, and creatine kinase to confirm the 
abnormality and to determine if it is increasing or decreasing.


Leo Document ID = c2c65942-890c-4aac-bd6e-19963ed91089
Approver:
Approval Date & Time: 29-Jun-2020 02:38:54 GMT
Signature meaning: Approved
Approver:
Approval Date & Time: 01-Jul-2020 01:12:34 GMT
Signature meaning: Approved
PPD
PPD

SAP_001.pdf: 
 
 
 
Statistical Analysis Plan I8F-MC-GPHT(b) 
 
 
A Multiple Dose Titration Study in Chinese Patients with Type 2 Diabetes Mellitus to 
Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of 
Tirzepatide 
 
  
NCT04235959 
 
Approval Date: 30-Apr-2020 
 
 


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STATISTICAL ANALYSIS PLAN
A Multiple Dose Titration Study in Chinese Patients with Type 2 Diabetes Mellitus to 
Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of 
Tirzepatide
Statistical Analysis Plan Status: Final
Statistical Analysis Plan Date: 24-April-2020
Study Drug: Tirzepatide (LY3298176)
Sponsor Reference: I8F-MC-GPHT
Covance CRU Study: 1000071-8420484
Clinical Phase I
Approval Date: 30-Apr-2020 GMT


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Statistical Analysis Plan 
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1. TABLE OF CONTENTS
1.
TABLE OF CONTENTS ............................................................................................... 2
2.
ABBREVIATIONS........................................................................................................ 4
3.
INTRODUCTION ......................................................................................................... 6
4.
STUDY OBJECTIVES.................................................................................................. 6
4.1
Primary Objective.................................................................................................... 6
4.2
Secondary Objective................................................................................................ 6
4.3
Exploratory Objectives ............................................................................................ 6
5.
STUDY DESIGN........................................................................................................... 7
6.
TREATMENTS............................................................................................................. 8
7.
SAMPLE SIZE JUSTIFICATION ................................................................................. 9
8.
DEFINITION OF ANALYSIS POPULATIONS............................................................ 9
9.
STATISTICAL METHODOLOGY ............................................................................. 10
9.1
General.................................................................................................................. 10
9.2
Demographics and Subject Disposition.................................................................. 10
9.3
Pharmacokinetic Assessment................................................................................. 10
9.3.1
Pharmacokinetic Analysis............................................................................. 10
9.3.2
Pharmacokinetic Statistical Methodology ..................................................... 14
9.4
Pharmacodynamic Assessments............................................................................. 14
9.4.1
Lipids Assessment........................................................................................ 14
9.4.2
Meal Intake and Appetite.............................................................................. 14
9.5
Efficacy Assessments ............................................................................................ 14
9.6
Safety and Tolerability Assessments...................................................................... 15
9.6.1
Adverse events ............................................................................................. 15
9.6.2
Glucose Monitoring and Hypoglycemia........................................................ 15
9.6.3
Concomitant medication............................................................................... 16
9.6.4
Clinical laboratory parameters...................................................................... 16
9.6.5
Pancreatic Enzymes...................................................................................... 17
9.6.6
Thyroid Malignancies and C-Cell Hyperplasia.............................................. 17
9.6.7
Vital signs .................................................................................................... 17
9.6.8
Electrocardiogram (ECG)............................................................................. 17
9.6.9
Hepatic Monitoring ...................................................................................... 17
9.6.10
Immunogenicity Assessments....................................................................... 18
9.6.11
Hypersensitivity reactions............................................................................. 18
9.6.12
Injection-Site Reactions................................................................................ 18
9.6.13
Other assessments......................................................................................... 18
9.6.14
Safety and Tolerability Statistical Methodology............................................ 18


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10. INTERIM ANALYSES ............................................................................................... 18
11. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ...... 18
12. REFERENCES ............................................................................................................ 19
13. DATA PRESENTATION ............................................................................................ 19
13.1 Derived Parameters ............................................................................................... 19
13.2 Missing Data ......................................................................................................... 19
13.3 Insufficient Data for Presentation .......................................................................... 19


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2. ABBREVIATIONS
Abbreviations pertain to the Statistical Analysis Plan (SAP) only (not the tables, figures and 
listings [TFLs]).
7p-SMPG
7-point self-monitored plasma glucose
ADA
Anti-drug antibody
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AUC
Area under the concentration versus time curve
AUC(0-168)
Area under the concentration versus time curve from time zero to 168 
hour postdose
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
GIP
Glucose-dependent insulinotropic polypeptide
GLP-1
Glucagon-like peptide-1
HbA1c
Hemoglobin A1c
ICH
International Conference on Harmonisation
IP
Investigational Product
LLOQ
Lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
MRE
Magnetic resonance elastography
OAM
Oral antidiabetic medication
PD
Pharmacodynamic
PG
Plasma glucose


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PK
Pharmacokinetic
QW
Once weekly
SAP
Statistical Analysis Plan
SC
Subcutaneous
SD
Standard deviation 
t1/2
Half-life associated with the terminal rate constant (λz) in 
non-compartmental analysis
T2DM
Type 2 Diabetes Mellitus
TBL
Total bilirubin
TE
Treatment emergent
TFLs
Tables, Figures, and Listings
tmax
Time of maximum observed drug concentration
ULN
Upper limit of normal
VAS
Visual analog scale
Vss/F
Apparent volume of distribution as 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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3. INTRODUCTION
This SAP has been developed after review of the Clinical Study Protocol (final version dated 
13 March 2019) and Protocol Amendment (a) (final version dated 14 February 2020).
This SAP describes the planned analysis of the safety, tolerability, pharmacokinetic (PK), 
pharmacodynamic (PD), and efficacy 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. 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 investigate the safety and tolerability of tirzepatide after multiple subcutaneous (SC) doses 
administered to Chinese patients with Type 2 Diabetes Mellitus (T2DM).
4.2
Secondary Objective
To characterize the PK of tirzepatide after multiple SC doses in Chinese patients with T2DM.
4.3
Exploratory Objectives

To investigate the efficacy of tirzepatide after multiple SC doses administered to Chinese 
patients with T2DM

To investigate the exploratory PD effects of tirzepatide after multiple SC doses 
administered to Chinese patients with T2DM

To evaluate the formation of anti-drug antibodies (ADAs) to tirzepatide after multiple SC 
doses administered to Chinese patients with T2DM


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5. STUDY DESIGN
Study GPHT is a Phase 1, single-site, patient- and investigator-blind, placebo-controlled, 
randomized, multiple dose titration study in Chinese patients with T2DM.
Figure 1 illustrates the study design.
Figure 1. Illustration of study design
Patients will be administered either 16 or 24 weekly SC doses of tirzepatide or placebo.
Screening (Visit 1)
The purpose of screening procedures at Visit 1 is to establish initial eligibility and to obtain
blood samples for laboratory assessments needed to confirm eligibility at Visit 2. Before
performing any study procedures, the patient will sign the informed consent form.
Lead-in (Visit 2 to Visit 3)
At Visit 2, patients and their caregiver(s), if applicable, will receive a glucometer, study diaries,
and training on how to perform self-monitoring of plasma glucose (PG) and record blood glucose
values, hypoglycemic events, medications, and adverse events (AEs). Patients will also be 
trained on disease management and study procedures; this training can be repeated at subsequent 
visits as deemed appropriate.
Patients will conduct the 7-point self-monitored plasma glucose (7p-SMPG) approximately every 
3 days since Day -13 during the lead-in period and will record readings in patient diary. Prior 
oral antidiabetic medication (OAM) should be discontinued during the lead-in period.
Additionally, site personnel will require patients who were taking OAM at screening to monitor
their PG in the morning before breakfast during the lead-in period.


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Treatment Period
Cohort 1
Patients in Cohort 1 will receive either tirzepatide with titration regimen starting from 2.5 mg for
Weeks 0 through 3 followed by 5 mg for Weeks 4 through 7, 7.5 mg for Weeks 8 through 11,
and 10 mg for Weeks 12 through 15, or corresponding volume-matched placebo. During clinical 
research unit (CRU) visits 3a, 4, 5, 6a, 7, 8, 9, 10 and 11a, site staff will administer SC doses of 
tirzepatide or placebo. Patients may either self-administer or visit the CRU to have staff 
administer SC doses of tirzepatide or placebo at the beginning of Weeks 2, 3, 5, 6, 9, 10, and 11.
Cohort 2
Patients in Cohort 2 will receive either tirzepatide with titration regimen starting from 2.5 mg for
Weeks 0 through 3 followed by 5 mg for Weeks 4 through 7, 7.5 mg for Weeks 8 through 11, 10
mg for Weeks 12 through 15, 12.5 mg for Weeks 16 through 19, and 15 mg for Weeks 20
through 23, or corresponding volume-matched placebo. During CRU visits 3a, 4, 5, 6a, 7, 8, 9,
10, 11, 12 and 13a, site staff will administer SC doses of tirzepatide or placebo. Patients may
either self-administer or visit the CRU to have staff administer SC doses of tirzepatide or placebo
at the beginning of Weeks 2, 3, 5, 6, 9, 10, 11, 13, 14, 15, 17, 18, and 19.
Follow-Up Period
Visits for safety follow-up and PK sampling will occur on 2 separate visits. These visits will be
approximately 7 and 28 days after the last dose of investigational product (IP).
6. TREATMENTS
The following is a list of the study treatment labels that will be used in the safety, PD, and 
efficacy TFLs.
Cohort
Study Treatment Name
Treatment order in TFL
All
Placebo QW SC
1
1
2.5-10 mg tirzepatide QW SC*
2
2
2.5-15 mg tirzepatide QW SC**
3
Abbreviations: QW = once weekly; SC = subcutaneous
* Patients receive 2.5 mg for Weeks 0 through 3, 5 mg for Weeks 4 through 7, 7.5 mg for Weeks 8 through 11, and 
10 mg for Weeks 12 through 15
** Patients receive 2.5 mg for Weeks 0 through 3, 5 mg for Weeks 4 through 7, 7.5 mg for Weeks 8 through 11, 10 
mg for Weeks 12 through 15, 12.5 mg for Weeks 16 through 19, and 15 mg for Weeks 20 through 23


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The following is a list of the study treatment labels that will be used in the PK TFLs, where a full 
profile is collected.
Cohort
Study Treatment Name
Treatment order in TFL
1
2.5 mg tirzepatide QW SC
1
5 mg tirzepatide QW SC
2
10 mg tirzepatide QW SC
3
2
2.5 mg tirzepatide QW SC
4
5 mg tirzepatide QW SC
5
15 mg tirzepatide QW SC
6
Abbreviations: QW = once weekly; SC = subcutaneous
For predose (trough) PK samples, the treatment labels will be consistent with the safety, PD and 
efficacy TFLs.
7. SAMPLE SIZE JUSTIFICATION
The sample size for the study was chosen to provide sufficient data to evaluate the primary 
objective of this study and is not intended to achieve any priori statistical requirements.
Approximately 24 Chinese patients with T2DM may be enrolled so that approximately 16 
patients complete the study with compliant defined dosing regimen. Patients will be administered 
either 16 (Cohort 1) or 24 (Cohort 2) weekly SC doses of tirzepatide or placebo in a ratio of 10 
tirzepatide:2 placebo for both cohorts.
Replacement of discontinued patients is not planned because the sample size is determined 
considering the expected drop-out rate.
8. DEFINITION OF ANALYSIS POPULATIONS
Safety analyses will be conducted for all enrolled patients, whether or not they completed all
protocol requirements.
The Pharmacokinetic population will consist of all patients who received at least 1 dose of the IP
and have evaluable PK data. 
The Pharmacodynamic population will consist of all patients who received at least 1 dose of the 
IP and have evaluable PD data. 
The Efficacy population will consist of all patients who received at least 1 dose of the IP and 
have evaluable efficacy 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.


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9. STATISTICAL METHODOLOGY
9.1
General
Data listings will be provided for all data that is databased. Summary statistics and statistical 
analysis will only be presented for data where detailed in this SAP. For continuous data, 
summary statistics will include the arithmetic mean, arithmetic standard deviation (SD), median, 
min, max and n; for log-normal data (e.g. the PK parameters: area under the concentration-time 
curve [AUC] 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.
9.2
Demographics and Subject Disposition
Subject disposition will be listed. 
The demographic variables age, sex, race, ethnicity, body weight, height, body mass index, 
hemoglobin A1c (HbA1c), duration of diabetes and OAM use will be summarized and listed. All 
other demographic variables will be listed only.
9.3
Pharmacokinetic Assessment
9.3.1
Pharmacokinetic Analysis
Noncompartmental methods applied with a validated software program (Phoenix WinNonlin 
Version 8.1 or later) to the plasma concentrations of tirzepatide will be used to determine the 
following pharmacokinetic parameters, when possible, on Days 1 (Week 0), 50 (Week 7), 106 
(Week 15 [Cohort 1 only]) and 162 (Week 23 [Cohort 2 only]): 


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Parameter
Units
Definition
AUC(0-168)
ng.h/mL
area under the concentration versus time curve from time zero to 
168 hour postdose
Cmax
ng/mL
maximum observed drug concentration
tmax
h
time of maximum observed drug concentration
t1/2
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
Vss/F
L
apparent volume of distribution as steady state after extravascular 
administration
Vz/F
L
apparent volume of distribution during the terminal phase after 
extra-vascular administration
Additional pharmacokinetic parameters may be calculated, as appropriate. The software and 
version used for the final analyses will be specified in the clinical study report. Any exceptions 
or special handling of data will be clearly documented within the final study report.
Formatting of tables, figures and abbreviations will follow the Eli Lilly Global PK/PD/TS Tool: 
NON-COMPARTMENTAL PHARMACOKINETIC STYLE GUIDE. The version of the tool
effective at the time of PK analysis will be followed.
General PK Parameter Rules

Actual sampling times will be used in the final analyses of individual PK parameters, 
except for non-bolus pre-dose sampling times which will be set to zero.

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 plasma concentrations above the lower limit of quantification (LLOQ), with 
at least one of these concentrations following Cmax.

Half-life (t½) will be calculated, when appropriate, based on the apparent terminal 
log-linear portion of the concentration-time curve. The start of the terminal elimination 
phase for each subject will be defined by visual inspection and generally will be the first 
point at which there is no systematic deviation from the log-linear decline in plasma
concentrations. Half-life will only be calculated when a reliable estimate for this 
parameter can be obtained comprising of at least 3 data points. If t½ is estimated over a 
time window of less than 2 half-lives, the values will be flagged in the data listings. Any 
t½ value excluded from summary statistics will be documented in the footnote of the 
summary table.


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
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 predicted last quantifiable drug concentration (Clast) will be 
reported.
Individual PK Parameter Rules

Only quantifiable concentrations will be used to calculate pharmacokinetic 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.
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.


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
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 pharmacokinetic analyses is not a requirement. Rather, this 
procedure provides justification for exclusion of data when scientifically appropriate. This 
procedure describes the methodology for identifying an individual value as an outlier for 
potential exclusion, but does not require that the value be excluded from analysis. The following 
methodology will not be used to exclude complete profiles from analysis.
Data within an Individual Profile
A value within an individual profile may be excluded from analysis if any of the following 
criteria are met:

For pharmacokinetic profiles during single dosing of non-endogenous compounds, the 
concentration in a pre-dose sample is quantifiable.

For any questionable datum that does not satisfy the above criteria, the profile will be 
evaluated and results reported with and without the suspected datum.
Data between Individual Profiles
1.
If n<6, then the dataset is too small to conduct a reliable range test. Data will be analyzed 
with and without the atypical value, and both sets of results will be reported. 
2.
If n6, then an objective outlier test will be used to compare the atypical value to other 
values included in that calculation:
a.
Transform all values in the calculation to the logarithmic domain.
b. Find the most extreme value from the arithmetic mean of the log transformed
values and exclude that value from the dataset.
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.


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e.
If the extreme value is outside the range of arithmetic mean ±3*SD, then it is 
an outlier and will be excluded from analysis.
If the remaining dataset contains another atypical datum suspected to be an outlier and n ≥ 6 
following the exclusion, then repeat step 2 above. This evaluation may be repeated as many 
times as necessary, excluding only one suspected outlier in each iteration, until all data 
remaining in the dataset fall within the range of arithmetic mean ±3*SD of the log-transformed 
values.
Reporting of Excluded Values
Individual values excluded as outliers will be documented in the final report. Approval of the 
final report will connote approval of the exclusion.
9.3.2
Pharmacokinetic Statistical Methodology
All PK parameters will be summarized by treatment and PK profile day, and listed.
Trough concentrations will be summarized by cohort and timepoint, and listed.
9.4
Pharmacodynamic Assessments
9.4.1
Lipids Assessment
Total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and
triglycerides data will be listed and summarized by treatment and timepoint. Changes from 
baseline will be presented, where baseline is defined as the Day 1 predose assessment.
9.4.2
Meal Intake and Appetite
The subjective rating of appetite sensations is measured using a 100-mm visual analogue scale 
(VAS) for parameters of hunger, fullness, satiety, and prospective food consumption before and 
4 to 5 hours after the standardized lunch and dinner meals.
Overall appetite score is calculated as the average of the 4 individual scores – satiety + fullness + 
(100-prospective food consumption) + (100-hunger) / 4. The higher overall appetite score 
indicates less appetite, and the lower score indicates more appetite.
The data will be listed and summarized by treatment and timepoint. Changes from the 
assessment before food consumption will also be presented.
9.5
Efficacy Assessments
The efficacy of tirzepatide to reduce glucose and weight will be assessed. Efficacy measures that
will be assessed include HbA1c, body weight, fasting PG, and 7p-SMPG.
All parameters will be listed and summarized by treatment and timepoint. Changes from baseline 
will be presented, where baseline is defined as the Day 1 predose assessment (HbA1c, body 
weight, fasting PG) or the Day -1 assessment (7p-SMPG).


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The individual observed and mean time profile of the postdose efficacy parameters will be
plotted by treatment group.
9.6
Safety and Tolerability Assessments
9.6.1
Adverse events
Where changes in severity are recorded in the Case Report Form (CRF), each separate severity 
of the 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, 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 22.1 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. AEs by week of onset will be presented.
Discontinuations due to AEs will be listed.
9.6.2
Glucose Monitoring and Hypoglycemia
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), 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 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)


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Statistical Analysis Plan 
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Covance Clinical Study No. 1000071-8420484
Sponsor Reference I8F-MC-GPHT
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

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.
9.6.3
Concomitant medication
Concomitant medication will be coded using the WHO drug dictionary (Version 
September 2019). Concomitant medication will be listed.
9.6.4
Clinical laboratory parameters
All clinical chemistry and hematology data will be summarized by parameter, treatment, and 
timepoint together with changes from baseline, where baseline is defined as the Day -1 
assessment. All clinical chemistry, hematology and 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.


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Statistical Analysis Plan 
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Covance Clinical Study No. 1000071-8420484
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9.6.5
Pancreatic Enzymes
Pancreatic amylase and lipase will be measured to monitor pancreatic safety. All parameters will
be listed and summarized by parameter and treatment together with changes from baseline, 
where baseline is defined as the Day -1 assessment. Data outside the reference range will also be 
listed and flagged on individual subject data listings.
9.6.6
Thyroid Malignancies and C-Cell Hyperplasia
The assessment of thyroid safety during the trial will include reporting of any case of thyroid 
malignancy including medullary thyroid carcinoma and papillary carcinoma and measurements 
of calcitonin.
Calcitonin data will be summarized by treatment and timepoint together with changes from 
baseline, where baseline is defined as the Day 1 predose assessment.
9.6.7
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.
9.6.8
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. 
9.6.9
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 medications 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.


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 1000071-8420484
Sponsor Reference I8F-MC-GPHT
9.6.10
Immunogenicity Assessments
Immunogenicity data will be listed and frequency tables will be presented. The frequency and 
percentage of subjects with pre-existing ADA and with treatment-emergent ADAs (TE ADAs) 
will be presented. TE ADAs are those that are boosted or induced by exposure to study drug, 
with a 4-fold increase in titer compared to baseline if ADAs were detected at baseline or a titer 
2-fold greater than the minimum required dilution (1:10) if no ADAs were detected at baseline, 
where baseline is defined as Day 1 predose.
If cross-reactivity with native glucagon-like peptide-1 (GLP-1) and glucose-dependent 
insulinotropic polypeptide (GIP) or a neutralization assay is performed, the frequency of each 
will be determined. 
The relationship between the presence of antibodies and PK parameters of tirzepatide may be 
assessed if deemed appropriate.
9.6.11 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.
9.6.12
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 summarized by treatment and listed.
9.6.13
Other assessments
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analyzed.
9.6.14
Safety and Tolerability Statistical Methodology
No inferential statistical analyses are planned.
10.
INTERIM ANALYSES
No interim statistical analyses are planned.
11.
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES
There were no changes from the protocol specified statistical analyses.


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Statistical Analysis Plan 
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Covance Clinical Study No. 1000071-8420484
Sponsor Reference I8F-MC-GPHT
12.
REFERENCES
1. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9), 5 February 1998.
2. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), 30 November 1995.
13.
DATA PRESENTATION
13.1
Derived Parameters
Individual derived parameters (e.g. PK parameters) and appropriate summary statistics will be 
reported to three significant figures. Observed concentration data, e.g. Cmax, should be reported 
as received. Observed time data, e.g. tmax, should be reported as received. N and percentage 
values should be reported as whole numbers. Median values should be treated as an observed 
parameter and reported to the same number of decimal places as minimum and maximum values.
13.2
Missing Data
Missing data will not be displayed in listings.
13.3
Insufficient Data for Presentation
Some of the TFLs may not have sufficient numbers of subjects or data for presentation. If this 
occurs, the blank TFL shell will be presented with a message printed in the center of the table, 
such as, “No serious adverse events occurred for this study.”


Leo Document ID = dcfb91b9-5ecf-4890-bfec-8f38ea433951
Approver: 
Approval Date & Time: 29-Apr-2020 08:29:03 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 29-Apr-2020 12:35:36 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 29-Apr-2020 14:50:08 GMT
Signature meaning: Approved
Approver:
Approval Date & Time: 30-Apr-2020 08:43:25 GMT
Signature meaning: Approved
PPD
PPD
PPD
PPD