The Effect of Tirzepatide on α and β Cell Function and Insulin Sensitivity in Patients With Type 2 Diabetes Mellitus
Phase: PHASE1
Conditions: Diabetes Mellitus, Type 2
Sponsor: Eli Lilly and Company

Clinical Study Protocol Version (d) I8F-MC-GPGT 
 
The Effect of Tirzepatide on α and β Cell Function and Insulin Sensitivity in Patients with Type 2 
Diabetes Mellitus 
NCT03951753 
Approval Date: 10-Jun-2020 

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 1
LY3298176
Protocol I8F-MC-GPGT(d)
The Effect of Tirzepatide on α and β Cell Function and
Insulin Sensitivity in Patients with Type 2 Diabetes Mellitus
EudraCT No. 2018-003343-37
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: 
15 March 2019
Amendment (a) Electronically Signed and Approved by Lilly: 10 May 2019
Amendment (b) Electronically Signed and Approved by Lilly:  10 July 2019
Amendment (c) Electronically Signed and Approved by Lilly:  05 May 2020
Amendment (d) Electronically Signed and Approved by Lilly
on approval date provided below.
Approval Date: 10-Jun-2020 GMT

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 2
LY3298176
Table of Contents
The Effect of Tirzepatide on α and β Cell Function and Insulin 
Sensitivity in Patients with Type 2 Diabetes Mellitus
Section
Page
Protocol I8F-MC-GPGT(d) The Effect of Tirzepatide on α and β Cell 
Function and Insulin Sensitivity in Patients with Type 2 Diabetes 
Mellitus................................................................................................................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis.................................................................................................................9
2.
Schedule of Activities ........................................................................................................12
3.
Introduction........................................................................................................................24
3.1.
Study Rationale............................................................................................................24
3.2.
Background..................................................................................................................24
3.3.
Benefit/Risk Assessment..............................................................................................26
4.
Objectives and Endpoints...................................................................................................27
5.
Study Design......................................................................................................................31
5.1.
Overall Design .............................................................................................................31
5.1.1.
Screening and Lead-In .........................................................................................32
5.1.1.1.
Screening........................................................................................................32
5.1.1.2.
Lead-in...........................................................................................................33
5.1.2.
Treatment.............................................................................................................33
5.1.3.
Safety Follow-Up.................................................................................................35
5.2.
Number of Participants.................................................................................................35
5.3.
End of Study Definition ...............................................................................................35
5.4.
Scientific Rationale for Study Design...........................................................................35
5.5.
Justification for Dose ...................................................................................................36
6.
Study Population................................................................................................................38
6.1.
Inclusion Criteria..........................................................................................................38
6.2.
Exclusion Criteria ........................................................................................................40
6.3.
Lifestyle and/or Dietary Requirements .........................................................................44
6.3.1.
Meals and Dietary Restrictions.............................................................................44
6.3.2.
Caffeine, Alcohol, and Tobacco ...........................................................................44
6.3.3.
Activity................................................................................................................44
6.4.
Screen Failures.............................................................................................................44
7.
Treatment...........................................................................................................................45
7.1.
Treatment Administered...............................................................................................45

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 3
LY3298176
7.1.1.
Packaging and Labeling .......................................................................................45
7.2.
Method of Treatment Assignment ................................................................................46
7.2.1.
Selection and Timing of Doses.............................................................................46
7.3.
Blinding .......................................................................................................................46
7.4.
Dose Modification........................................................................................................47
7.4.1.
Special Treatment Considerations ........................................................................47
7.4.1.1.
Management of Hypoglycemia .......................................................................47
7.4.1.2.
Management of Hyperglycemia......................................................................47
7.4.1.3.
Treatment of Hypoglycemia and Hypokalemia during 
Hyperinsulinemic Euglycemic Clamp.............................................................48
7.5.
Preparation/Handling/Storage/Accountability...............................................................48
7.6.
Treatment Compliance .................................................................................................48
7.7.
Concomitant Therapy...................................................................................................48
7.7.1.
Management of Patients with Gastrointestinal Symptoms.....................................50
7.8.
Treatment after the End of the Study............................................................................50
8.
Discontinuation Criteria .....................................................................................................51
8.1.
Discontinuation from Study Treatment.........................................................................51
8.1.1.
Permanent Discontinuation from Study Treatment ...............................................51
8.1.2.
Temporary Interruption of Study Drug.................................................................52
8.1.3.
Discontinuation of Inadvertently Enrolled Patients...............................................52
8.2.
Discontinuation from the Study....................................................................................52
8.3.
Patients Lost to Follow-Up...........................................................................................53
9.
Study Assessments and Procedures ....................................................................................54
9.1.
Efficacy Assessments...................................................................................................54
9.1.1.
Primary Efficacy Assessments and Procedures.....................................................54
9.1.2.
Secondary Efficacy Assessments and Procedures.................................................55
9.1.3.
Exploratory Efficacy Assessments and Procedures...............................................56
9.2.
Adverse Events ............................................................................................................58
9.2.1.
Serious Adverse Events........................................................................................59
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................60
9.2.2.
Adverse Events of Special Interest .......................................................................60
9.2.2.1.
Hypoglycemia ................................................................................................60
9.2.2.2.
Severe, Persistent Hyperglycemia...................................................................62
9.2.2.3.
Pancreatitis.....................................................................................................62
9.2.2.4.
Thyroid Malignancies and C-Cell Hyperplasia................................................63
9.2.2.5.
Major Adverse Cardiovascular Events............................................................64
9.2.2.6.
Supraventricular Arrhythmias and Cardiac Conduction 
Disorders........................................................................................................64

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 4
LY3298176
9.2.2.7.
Hypersensitivity Events..................................................................................64
9.2.2.7.1.
Injection Site Reactions ............................................................................64
9.2.2.8.
Diabetic Retinopathy Complications...............................................................64
9.2.2.9.
Hepatobiliary Disorders..................................................................................64
9.2.2.10.
Severe Gastrointestinal Adverse Events..........................................................65
9.2.2.11.
Acute Renal Events ........................................................................................65
9.2.2.12.
Metabolic Acidosis, Including Diabetic Ketoacidosis .....................................65
9.2.2.13.
Amputation/Peripheral Revascularization .......................................................65
9.2.2.14.
Major Depressive Disorder/Suicidal Ideation..................................................65
9.2.3.
Complaint Handling.............................................................................................65
9.3.
Treatment of Overdose.................................................................................................66
9.4.
Safety...........................................................................................................................66
9.4.1.
Laboratory Tests ..................................................................................................66
9.4.2.
Vital Signs ...........................................................................................................66
9.4.3.
Electrocardiograms ..............................................................................................66
9.4.4.
Physical Examinations .........................................................................................67
9.4.5.
Safety Monitoring ................................................................................................67
9.4.5.1.
Hepatic Safety................................................................................................67
9.5.
Pharmacokinetics .........................................................................................................67
9.5.1.
Bioanalysis...........................................................................................................68
9.6.
Pharmacodynamics ......................................................................................................68
9.6.1.
Immunogenicity Assessments ..............................................................................68
9.6.2.
Body Weight and Waist Circumference................................................................69
9.7.
Genetics .......................................................................................................................69
9.8.
Biomarkers...................................................................................................................70
9.9.
Health Economics ........................................................................................................70
10. Statistical Considerations and Data Analysis ......................................................................71
10.1. Sample Size Determination ..........................................................................................71
10.2. Populations for Analyses..............................................................................................71
10.2.1.
Study Participant Disposition ...............................................................................71
10.2.2.
Study Participant Characteristics ..........................................................................71
10.2.3.
Treatment Compliance .........................................................................................71
10.3. Statistical Analyses ......................................................................................................71
10.3.1.
Safety Analyses....................................................................................................71
10.3.1.1.
Clinical Evaluation of Safety..........................................................................71
10.3.1.2.
Statistical Evaluation of Safety.......................................................................72
10.3.2.
Pharmacokinetic Analyses....................................................................................72
10.3.2.1.
Pharmacokinetic Parameter Estimation...........................................................72

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 5
LY3298176
10.3.2.2.
Pharmacokinetic Statistical Inference .............................................................72
10.3.3.
Pharmacodynamic Analyses.................................................................................72
10.3.3.1.
Pharmacodynamic Parameter Estimation ........................................................72
10.3.3.2.
Pharmacodynamic Statistical Inference...........................................................74
10.3.4.
Evaluation of Immunogenicity .............................................................................74
10.3.5.
Interim Analyses..................................................................................................74
11. References .........................................................................................................................76
12. Appendices ........................................................................................................................80

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 6
LY3298176
List of Tables
Table
Page
Table GPGT.1.
Objectives and Endpoints .......................................................................27
Table GPGT.2.
Exposure Multiples for Subcutaneous Administration of 
Tirzepatide Based on Systemic Exposure................................................37
Table GPGT.3.
Study Treatments and Dose Escalation ...................................................45
Table GPGT.4.
Time Schedule for Hyperinsulinemic Euglycemic Clamp .......................99
Table GPGT.5.
Time Schedule for Hyperglycemic Clamp and Arginine 
Stimulation...........................................................................................101
Table GPGT.6.
Approximate Composition of an Individualized Standardized Meal 
with a Fixed Nutrient Ratio (900 kcal Meal Example) ..........................104
Table GPGT.7.
Standardized Mixed-Meal Tolerance Test.............................................105

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 7
LY3298176
List of Figures
Figure
Page
Figure GPGT.1.
Illustration of study design for Protocol I8F-MC-GPGT. ........................32

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 8
LY3298176
List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ........................................................................81
Appendix 2.
Clinical Laboratory Tests................................................................................88
Appendix 3.
Study Governance, Regulatory and Ethical 
Considerations ...................................................................................................................89
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent 
Abnormality.......................................................................................................................92
Appendix 5.
Blood Sampling Summary..............................................................................96
Appendix 6.
Assessments of Glucose and Lipid Metabolism and 
Appetite and Food Intake ...................................................................................................98
Appendix 7.
Pancreatic Monitoring ..................................................................................109
Appendix 8.
Highly Effective Contraceptive Methods ......................................................111
Appendix 9.
Protocol Amendment I8F-MC-GPGT(d) Summary The 
Effect of Tirzepatide on α and β Cell Function and Insulin Sensitivity 
in Patients with Type 2 Diabetes Mellitus.........................................................................113

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 9
LY3298176
1. Protocol Synopsis
Title of Study:
The Effect of Tirzepatide on α and β Cell Function and Insulin Sensitivity in Patients with Type 2 Diabetes Mellitus
Rationale: 
Study I8F-MC-GPGT is a 28-week Phase 1 study designed to examine and cell function, insulin sensitivity, 
glucose and lipid metabolism, food intake, and energy expenditure in patients with type 2 diabetes mellitus (T2DM) 
treated with tirzepatide.  Tirzepatide is a long-acting, dual incretin mimetic (dual agonist) that binds to the 
glucose-dependent insulinotropic peptide (GIP) receptor (GIPR) and the glucagon-like peptide-1 (GLP-1) receptor
(GLP-1R).  The available preclinical and clinical data indicate that co-stimulation of these receptors may enhance 
insulin secretion, improve insulin sensitivity, and reduce body weight beyond the effect of selective GLP-1R 
stimulation.  These actions of dual GIPR and GLP-1R agonism (GIPRA/GLP-1RA) may provide improved 
glycemic control and reduced risk of chronic macro- and microvascular complications in patients with T2DM.
Objectives/Endpoints:  
Objectives
Endpoints
Primary
To compare the effect of tirzepatide 15 mg dose and 
placebo on total cDI after 28 weeks of treatment, 
including the dose escalation phase, in T2DM patients 
on metformin.

The change from baseline in total cDI
Secondary
To compare the effects of tirzepatide 15 mg relative to 
placebo (except for the primary efficacy measure) and 
semaglutide 1 mg after 28 weeks of treatment on:

Insulin secretion and insulin sensitivity 
combined outcome

The change in total cDI (for tirzepatide versus 
semaglutide comparison only)

Glucose control

The change from baseline in fasting and postmeal 
glucose (total and incremental AUC0-240min) 
during sMMTT

The change from baseline in hemoglobin A1c

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 10
LY3298176
Objectives/Endpoints:
Objectives
Endpoints
Secondary (continued)

Insulin secretion

The change in the first phase incremental 
ISR0-8min from hyperglycemic clamp

The change in second phase total ISR20-120min
from hyperglycemic clamp

The change in total ISR0-120min from 
hyperglycemic clamp

The change from baseline in insulin response to 
arginine (incremental AUCarginine0-10min and 
incremental AUCarginine0-30min) from 
hyperglycemic clamp

The change from baseline in β cell GS from 
hyperglycemic clamp

The change in β cell GS from sMMTT

The change from baseline in ISRg from sMMTT

Insulin sensitivity

The change from baseline in hyperinsulinemic 
euglycemic clamp M-value

Glucagon secretion

The change from baseline in glucagon 
concentration at fasting and postmeal during 
sMMTT (total and incremental AUC0-240min)

Appetite and food intake

The change from baseline in food intake during 
ad libitum meal served buffet style
Abbreviations:  AUC = area under the concentration versus time curve; AUC0-240min = AUC from time zero to 
240 minutes after start of the meal; AUCarginine0-10min = AUC in response to arginine from time zero to 
10 minutes; AUCarginine0-30min = AUC in response to arginine from time zero to 30 minutes; cDI = clamp 
disposition index; GS =  glucose sensitivity; ISR = insulin secretion rate; ISR0-8min = first phase insulin 
secretion rate; ISR0-120min = total insulin secretion rate from hyperglycemic clamp; ISR20-120min = second 
phase insulin secretion rate; ISRg = insulin secretion rate at fixed glucose concentration; sMMTT = standardized
mixed-meal tolerance test; T2DM = type 2 diabetes mellitus.
Summary of Study Design:
This is a Phase 1, multicenter, randomized, sponsor, investigator- and patient-blind, parallel arm study in patients 
with T2DM to compare the effect of tirzepatide 15 mg dose and placebo on total clamp disposition index (cDI) after 
28 weeks of treatment, including the dose escalation phase.  The study will also compare the effects of tirzepatide 
15 mg relative to placebo and semaglutide (positive control) on additional parameters of pancreatic α and β cell 
function, insulin sensitivity, glucose and lipid metabolism, and energy balance (food intake and energy expenditure).
Treatment Arms and Planned Duration for an Individual Patient:
Patients will be screened up to 56 days prior to start of lead-in on Day -3. The study will consist of 3 periods:  
approximately 5- to 8-week screening/lead-in period, 28-week treatment period, and a 4-week safety follow-up 
period.  Patients will be randomized in a 3:3:2 ratio to once weekly (QW) tirzepatide 15 mg, semaglutide 1 mg, 
or placebo.
Number of Patients:
Approximately 117 patients may be enrolled.  Approximately 99 patients are expected to complete the study.

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 11
LY3298176
Statistical Analysis:
Pharmacodynamic analyses will be conducted on data from all patients who receive at least 1 dose of the 
investigational product and have evaluable data.  Data will be censored once patients discontinue their randomized 
treatment or initiated additional rescue treatment.
Safety analyses will be conducted for all enrolled patients whether or not they completed all protocol requirements.
Additional exploratory analyses of the data will be conducted as deemed appropriate.

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 12
LY3298176
2. Schedule of Activities

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 13
LY3298176
Study Schedule Protocol I8F-MC-GPGT:  Screening and Lead-In
Procedure
Screening
Lead-In
Comments
Visit
1
2
Week of Treatment
-8 to -1
-1
Study Day
-59 to -4
-3
-2
-1
Screening for patients on metformin: Days -35 to -4.
Screening for patients on metformin+other OAMs: Days -59 to -4. This period 
includes the required 4-week washout.
Screening Procedures
Informed consent
X
Informed consent will be performed at least 1 day before other screening procedures.
Medical history
X
Drug and alcohol screen
X
Procedures may be repeated throughout the study as deemed necessary by the 
investigator.
Physical examination
X
X
Height
X
Weight and waist circumference
X
X
Vital signs (BP/PR/body temperature)
X
X
Vital sign measurements whose nominal times are not listed in the schedule should 
be taken before PK samples scheduled on the same day.  Blood pressure and PR 
measurements will be taken after at least 5 minutes in the supine position.
ECGs
X
X
Single 12-lead ECGs will be collected. Electrocardiograms must be recorded before 
collecting any blood samples using equipment available at the study site.  Patients 
must be supine for at least 5 minutes before ECG collection, and remain supine but 
awake during ECG collection.
Concomitant medications
X
X
Inclusion/exclusion criteria
X
Clinical Procedures
CRU admission
X
Dispense glucose meters, test strips, 
diaries, SMPG and disease 
management training
X
These SMPG-related procedures will be performed after eligibility is confirmed and 
may commence between screening and start of lead-in.
AEs
X
X
X
X
Glucose Management
SMPG
X
X
SMPG will start latest at the beginning of the lead-in period and will be conducted 
daily throughout the study except while resident at the CRU. Patients subject to 
OAMs washout should start SMPG during the screening period.

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 14
LY3298176
Procedure
Screening
Lead-In
Comments
Visit
1
2
Week of Treatment
-8 to -1
-1
Study Day
-59 to -4
-3
-2
-1
Screening for patients on metformin: Days -35 to -4.
Screening for patients on metformin+other OAMs: Days -59 to -4. This period 
includes the required 4-week washout.
Review of study diary for SMPG
X
Applies to eligible patients after the completion of screening.
Laboratory Tests
Safety laboratory tests (including 
fasting glucose)
X
X
See Appendix 2 for details.  Patients will fast for at least 8 hours before each blood 
sample is collected.
Pregnancy test
X
X
Serum pregnancy test at screening and urine pregnancy test on Day -1.
Calcitonin
X
Hemoglobin A1c
X
X
Fasting insulin, C-peptide, glucagon
X
X
Full sampling schedule is provided in Appendix 6 for sMMTT on Day -2 and 
hyperinsulinemic euglycemic and hyperglycemic clamps on Day -1.
Proinsulin
X
Full sampling schedule is provided in Appendix 6 for sMMTT on Day -2.
PP
X
Full sampling schedule is provided in Appendix 6 for sMMTT on Day -2.
Leptin, adiponectin, IGFBP 1 and 2
X
Sampling schedule is provided in Appendix 6 for sMMTT on Day -2.
Lipid panel: 
triglycerides
total cholesterol
LDL-C
VLDL-C
HDL-C
ApoB-48
ApoB-100
ApoC-III
LPL
X
X
On Day -1, only triglycerides will be collected during the hyperglycemic clamp.  On 
Day -2, full lipid panel will be collected during sMMTT. See Appendix 6 for 
sampling schedule.
β-hydroxybutyrate, pyruvate, lactate, 
FFA, glycerol
X
X
Peripheral plasma samples will be taken during microdialysis at fasting, sMMTT,
and hyperglycemic clamp. See Appendix 6 for details on sampling schedule.
Glucose, pyruvate, lactate, glycerol, 
ethanol in dialysate during 
microdialysis
X
X
Adipose tissue samples during microdialysis at fasting, sMMTT, and hyperglycemic 
clamp. See Appendix 6 for details on sampling schedule.

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 15
LY3298176
Procedure
Screening
Lead-In
Comments
Visit
1
2
Week of Treatment
-8 to -1
-1
Study Day
-59 to -4
-3
-2
-1
Screening for patients on metformin: Days -35 to -4.
Screening for patients on metformin+other OAMs: Days -59 to -4. This period 
includes the required 4-week washout.
Investigative Tests
Body composition plethysmography
X
See Appendix 6 for details.
Hyperinsulinemic euglycemic clamp
X
Patients will fast for approximately 12 hours before the hyperinsulinemic 
euglycemic clamp. See Appendix 6 for details of the procedure and sampling plan.
Hyperglycemic clamp
X
Hyperglycemic clamp will follow hyperinsulinemic euglycemic clamp.  
Hyperglycemic clamp will end with the arginine test. See Appendix 6 for details of 
the procedure and sampling plan.
sMMTT
X
See Appendix 6 for details of the procedure and sampling plan.
Appetite (VAS) with sMMTT
X
See Appendix 6 for details.
Appetite (VAS) at fasting
X
Ad libitum food intake 
X
Ad libitum meal will be provided at noon. See Appendix 6 for details.
Indirect calorimetry
X
See Appendix 6 for details.
Microdialysis
X
X
See Appendix 6 for details.
Diagnostics
Nonpharmacogenetic stored samples 
X

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 16
LY3298176
Study Schedule Protocol I8F-MC-GPGT: Treatment Period
Procedure
Treatment
Comments
Visit
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Week of 
Treatment
1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Study Day
1
3
+1 
8
±1
15
±1
22
±1
29
±1
36
±1
43
±1
50
±1
57
±1
64
±1
71
±1
78
±1
85
±1
92
±1
99
±1
106
±1
113
±1
120
±1
127
±1
134
±1
Clinical 
Procedures
CRU discharge
X
Telephone visit
X
Randomization
P
Performed after 
baseline 
procedures.
Weight and waist 
circumference
P
P
P
P
Vital signs 
(BP/PR/body 
temperature)
P
P
P
P
Refer also to 
screening and 
lead-in table.
ECGs
X
X
Refer also to 
screening and 
lead-in table.
Concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AEs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Investigational 
Product
Dose 
administration
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 17
LY3298176
Procedure
Treatment
Comments
Visit
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Week of 
Treatment
1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Study Day
1
3
+1 
8
±1
15
±1
22
±1
29
±1
36
±1
43
±1
50
±1
57
±1
64
±1
71
±1
78
±1
85
±1
92
±1
99
±1
106
±1
113
±1
120
±1
127
±1
134
±1
Glucose 
Management
SMPG
X
Refer also to 
screening and 
lead-in table.
Review of study 
diary for SMPG
P
X
X
X
X
Laboratory Tests
Safety laboratory 
tests (including 
fasting glucose)
P
Refer also to 
screening and 
lead-in table.
Pregnancy test 
(urine)
X
X
Hemoglobin A1c
X
Fasting insulin, 
proinsulin, 
C-peptide, 
glucagon, PP
X
Leptin, 
adiponectin, 
IGFBP 1 and 2
X

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 18
LY3298176
Procedure
Treatment
Comments
Visit
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Week of 
Treatment
1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Study Day
1
3
+1 
8
±1
15
±1
22
±1
29
±1
36
±1
43
±1
50
±1
57
±1
64
±1
71
±1
78
±1
85
±1
92
±1
99
±1
106
±1
113
±1
120
±1
127
±1
134
±1
Lipid panel:
triglycerides
total cholesterol
LDL-C
VLDL-C
HDL-C
ApoB-48
ApoB-100
ApoC-III
LPL
X
Refer also to 
screening and 
lead-in table.
Investigative 
Tests
Appetite (VAS) at 
fasting
X
X
X
X
Ad libitum food 
intake
X
X
Ad libitum meal 
will be provided 
at noon.  See 
Appendix 6
for details.
Diagnostics
PGx sample
P
Single sample 
for PGx analysis 
taken predose on 
Day 1.

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 19
LY3298176
Procedure
Treatment
Comments
Visit
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Week of 
Treatment
1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Study Day
1
3
+1 
8
±1
15
±1
22
±1
29
±1
36
±1
43
±1
50
±1
57
±1
64
±1
71
±1
78
±1
85
±1
92
±1
99
±1
106
±1
113
±1
120
±1
127
±1
134
±1
PK sample
P
P
P
All samples for 
immunogenicity 
should be taken 
predose and time 
matched with 
predose PK 
sample, 
whenever 
possible.
Immunogenicity
P
P
P

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 20
LY3298176
Study Schedule Protocol I8F-MC-GPGT:  Treatment Period Continued and Follow-Up/Early Termination
Procedure
Treatment
Follow-Up/ET
Comments
Visit
23
24
25
26
27
28
29
30
31
32
Week of Treatment
21
22
23
24
25
26
27
28
28
28
28
32
Study Day
141
±1
148
±1
155
±1
162
±1
169
±1
176
±1
183
±1
190
±1
191
192
193
Within 
4 weeks after 
last dose
Clinical Procedures
CRU admission
X
CRU discharge
X
Physical examination
X
Weight and waist 
circumference
P
P
X
X
Vital signs (BP/PR/body 
temperature)
P
P
X
X
Refer also to screening and 
lead-in table.
ECGs
X
X
X
Refer also to screening and 
lead-in table.
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
AEs
X
X
X
X
X
X
X
X
X
X
X
X
Investigational Product
Dose administration
X
X
X
X
X
X
X
X
Glucose Management
SMPG
X
X
Refer also to screening and 
lead-in table.
Review of study diary for 
SMPG
X
X
X
X
X
Laboratory Tests
Safety laboratory tests
(including fasting glucose)
P
X
Refer also to screening and 
lead-in table.
Pregnancy test
X
X
X
Urine pregnancy test on 
Days 141 and 191 and serum 
pregnancy test at follow-up.
Calcitonin
X
X
Hemoglobin A1c
X
X

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 21
LY3298176
Procedure
Treatment
Follow-Up/ET
Comments
Visit
23
24
25
26
27
28
29
30
31
32
Week of Treatment
21
22
23
24
25
26
27
28
28
28
28
32
Study Day
141
±1
148
±1
155
±1
162
±1
169
±1
176
±1
183
±1
190
±1
191
192
193
Within 
4 weeks after 
last dose
Fasting insulin, C-peptide, 
glucagon
X
X
X
See sampling schedule for 
sMMTT on Day 192 and 
hyperinsulinemic euglycemic 
and hyperglycemic clamps on 
Day 193 in Appendix 6.
Proinsulin
X
X
See sampling schedule for 
sMMTT on Day 192 in 
Appendix 6.
PP
X
X
See sampling schedule for 
sMMTT on Day 192 in 
Appendix 6.
Leptin, adiponectin, IGFBP 1 
and 2
X
X
See sampling schedule for 
sMMTT on Day 192 in 
Appendix 6.
Lipid panel:
triglycerides
total cholesterol
LDL-C
VLDL-C
HDL-C
ApoB-48
ApoB-100
ApoC-III
LPL
X
X
X
On Day 141, fasting samples 
will be collected.  On Day 192, 
full lipid panel will be collected 
during sMMTT.  On Day 193, 
only triglycerides will be 
collected. See Appendix 6 for 
sampling schedule.
β-hydroxybutyrate, pyruvate, 
lactate, FFA, glycerol
X
X
Peripheral plasma samples will 
be taken during microdialysis at 
fasting, sMMTT, and 
hyperglycemic clamp.  See 
Appendix 6 for details.

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 22
LY3298176
Procedure
Treatment
Follow-Up/ET
Comments
Visit
23
24
25
26
27
28
29
30
31
32
Week of Treatment
21
22
23
24
25
26
27
28
28
28
28
32
Study Day
141
±1
148
±1
155
±1
162
±1
169
±1
176
±1
183
±1
190
±1
191
192
193
Within 
4 weeks after 
last dose
Glucose, pyruvate, lactate, 
glycerol, and ethanol in
dialysate during microdialysis 
X
X
Adipose tissue samples during 
microdialysis at fasting, 
sMMTT, and hyperglycemic 
clamp.  See Appendix 6 for 
details.
Investigative Tests
Body composition 
plethysmography
X
See Appendix 6 for details.
Hyperinsulinemic 
euglycemic clamp
X
See Appendix 6 for details.
Hyperglycemic clamp
X
See Appendix 6 for details.
sMMTT
X
See Appendix 6 for details.
Appetite (VAS) with sMMTT
X
See Appendix 6 for details.
Appetite (VAS) at fasting
X
X
X
X
Ad libitum food intake
X
Ad libitum meal will be 
provided at noon. See 
Appendix 6 for details.
Indirect calorimetry
X
See Appendix 6 for details.
Microdialysis
X
X
See Appendix 6 for details.
Diagnostics
PK samples
P
X
X
Sampling times are relative to 
the time of dose administration 
(0 minutes). On Day 193, PK 
sample will be collected prior to 
hyperinsulinemic euglycemic 
and hyperglycemic clamps.

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 23
LY3298176
Procedure
Treatment
Follow-Up/ET
Comments
Visit
23
24
25
26
27
28
29
30
31
32
Week of Treatment
21
22
23
24
25
26
27
28
28
28
28
32
Study Day
141
±1
148
±1
155
±1
162
±1
169
±1
176
±1
183
±1
190
±1
191
192
193
Within 
4 weeks after 
last dose
Immunogenicity 
P
X
All samples for 
immunogenicity should be 
taken predose and time matched 
with predose PK sample, 
whenever possible.
Nonpharmacogenetic stored 
samples 
X
X
Abbreviations:  AEs = adverse events; ApoB-48 = apolipoprotein B-48; ApoB-100 = apolipoprotein B-100; ApoC-III = apolipoprotein C-III; BP = blood 
pressure; CRU = clinical research unit; ECG = electrocardiogram; ET = early termination; FFA = free fatty acid; HDL-C = high-density lipoprotein
cholesterol; IGFBP = insulin-like growth factor-binding protein; LDL-C = low-density lipoprotein cholesterol; LPL = lipoprotein lipase; OAM = oral 
antihyperglycemia medication; P = predose; PGx = pharmacogenetic; PK = pharmacokinetics; PR = pulse rate; PP = pancreatic polypeptide; 
sMMTT = standardized mixed-meal tolerance test; SMPG = self-monitoring of plasma glucose; VAS = visual analog scale; VLDL-C = very low-density 
lipoprotein cholesterol.
Note:  If multiple procedures take place at the same time point, the following order should be used:  ECG, vital signs, and venipuncture. Screening for patients 
who need to undergo washout of OAM treatment may occur from Day -59 to Day -4.

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 24
LY3298176
3. Introduction
3.1.
Study Rationale
Study I8F-MC-GPGT is a 28-week Phase 1 study designed to examine α and β cell function,
insulin sensitivity, glucose and lipid metabolism, food intake, and energy expenditure in patients 
with type 2 diabetes mellitus (T2DM) treated with tirzepatide. Tirzepatide is a long-acting, dual 
incretin mimetic (dual agonist) that binds to the glucose-dependent insulinotropic polypeptide 
(GIP) receptor (GIPR) and the glucagon-like peptide-1 (GLP-1) receptor (GLP-1R).  The 
available preclinical and clinical data indicate that co-stimulation of these receptors may enhance 
insulin secretion, improve insulin sensitivity, and reduce body weight beyond the effect of 
selective GLP-1R stimulation (Frias et al. 2018; Coskun et al. 2018). These actions of dual 
GIPR and GLP-1R agonism (GIPRA/GLP-1RA) may provide improved glycemic control and 
reduced risk of chronic macro-and microvascular complications in patients with T2DM.
3.2.
Background
The incretins GIP and GLP-1 are secreted from enteroendocrine cells in the gut following a 
meal. Their role is to enhance the physiologic response to food ingestion, including sensation of 
satiety and insulin secretion (Baggio and Drucker 2007).  In addition, GIPRs are present on 
adipose cells and their stimulation may have an important role in regulation of glucose and 
triglycerides turnover in this tissue and postprandial nutrient disposal. It has been reported that 
patients with T2DM have impaired incretin responses (Baggio and Drucker 2007). Several 
selective GLP-1RAs have been developed for treatment of T2DM. These agents have a 
beneficial effect on glucose metabolism through the enhancement of glucose-dependent insulin 
secretion, reduction of inappropriately elevated glucagon levels, delay in gastric emptying, and 
body weight reduction. The dosing of GLP-1RAs is limited by gastrointestinal (GI) adverse 
effect.  The frequency of these adverse events (AEs) can be reduced by step-wise dose escalation
at initiation. Despite the physiological role of GIP in glucose and lipid metabolism regulation, 
there are no GIPRAs approved for treatment of this disease as of yet.
Tirzepatide is a 39-amino acid synthetic peptide with agonist activity at both the GIP and GLP-1
receptors.  The structure of tirzepatide is based on the GIP sequence and includes a C20 fatty 
di-acid moiety 
. Because both 
GIPR-mediated, as well as GLP-1R-mediated actions are involved in regulation of insulin and 
glucagon secretion and body energy turnover, tirzepatide may have the potential of reaching 
greater glucose-lowering effects in comparison to selective GLP-1RAs.  Tirzepatide may 
furthermore attain additional efficacy by recruiting and regulating metabolically active tissues 
not controlled by GLP-1, for example, adipose tissue. Tirzepatide is currently being investigated 
in clinical trials to assess its effect on hyperglycemia and other comorbidities associated with 
T2DM. It is administered once weekly (QW) by subcutaneous (SC) administration.
Results from 4 tirzepatide clinical trials that have completed dosing are available, including 
2 Phase 1 studies, Study I8F-MC-GPGA (Study GPGA) and Study I8F-JE-GPGC 
(Study GPGC), and 2 Phase 2 studies, Study I8F-MC-GPGB (Study GPGB) and
Study I8F-MC-GPGF (Study GPGF).
CCI

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 25
LY3298176
Study GPGA was a combination single-ascending dose (SAD) and a multiple-ascending dose 
study (MAD) study in healthy subjects and a multidose study in patients with T2DM.  The 
study investigated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) 
of tirzepatide administered as SC injections. Weekly doses of tirzepatide ranged from 0.25 mg 
to 8 mg in the SAD. Maximum tolerated dose in healthy subjects following single-dose 
administration was 5 mg. In the 4-week MAD part of the study, doses up to 10 mg in healthy 
subjects or 15 mg in patients with T2DM were attained via a dose escalation approach. A dose 
of 15 mg tirzepatide attained by fast dose escalation over 4 weeks (5/5/10/15 mg), while 
considered to be safe, was associated with high incidence of GI events. Terminal half-life was 
estimated to be approximately 5 days, thus supporting a QW dosing regimen; with steady-state 
tirzepatide exposures expected to be attained following at least 4 weeks of QW dosing. Study 
GPGC was a MAD study to investigate the safety, tolerability, PK, and PD in Japanese patients 
with T2DM. Patients were randomized to 1 of 4 treatment groups:  2.5/5/10 mg QW titrated, 
5/10/15 mg QW titrated, 5 mg QW as a fixed dose, or placebo for 8 weeks.  Overall, tirzepatide
PK parameters in Japanese patients with T2DM appeared comparable to corresponding 
parameters from non-Japanese patients with T2DM observed in Study GPGA.  
Gastrointestinal AEs (nausea, vomiting, diarrhea, and abdominal distension) and decreased 
appetite were the most frequently reported events by both healthy subjects and patients with 
T2DM and were dose related in the 2 Phase 1 studies.  A dose-dependent increase in heart rate 
was detected for both healthy subjects and patients with T2DM who received tirzepatide, similar 
to what was observed with selective GLP-1RAs. A few subjects experienced transient elevations 
in lipase and/or amylase levels, but these episodes were not associated with any relevant clinical 
outcomes. There were no other clinically relevant safety observations in the Phase 1 studies.
Phase 2 studies evaluated the efficacy, tolerability, and safety of QW tirzepatide (including 1 mg, 
2.5 mg, 4 mg, 5 mg, 7.5 mg, 10 mg, 12 mg, and 15 mg) in patients with T2DM with inadequate 
glycemic control on diet and exercise alone or on a stable dose of metformin monotherapy up to 
26 weeks.  Results demonstrated that tirzepatide in doses between 5 mg and 15 mg provides a 
clinically meaningful glucose-lowering and body weight-lowering efficacy.  Similar to data from 
Study GPGA, most of the AEs associated with tirzepatide were GI-related, consisting mainly of 
nausea, vomiting, and diarrhea and were dose-dependent. In addition, patients treated with 
tirzepatide reported AEs of decreased appetite more frequently than patients who received 
1.5 mg dose of dulaglutide, a selective GLP-1RA.
An integrated clinical and PK/PD assessment of the GI tolerability AEs, and the effect of dose 
escalation regimens in the Phase 2 trials, suggested that dosing algorithms starting at a low dose 
of 2.5 mg accompanied by dose escalation of 2.5 mg increments every 4 weeks would permit 
time for development of tolerance to GI events and are predicted to minimize GI tolerability 
concerns.
Overall, the safety tolerability, and PK/PD profiles of tirzepatide support further development of 
tirzepatide in patients with T2DM.

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 26
LY3298176
3.3.
Benefit/Risk Assessment
The most common safety issue with administration of tirzepatide was related to frequent 
reporting of decreased appetite and GI side effects, most commonly nausea, vomiting, and 
diarrhea. No other clinically relevant safety concerns were identified in the dose range up to 
15 mg, the highest dose investigated in Phase 1 and Phase 2 trials, administered QW up to 
26 weeks. The data indicate that the safety profile for a dual GIPRA/GLP-1RA is similar to the 
safety profile of the selective GLP-1RAs. Potential risks are similar to the risks associated with 
currently available long-acting GLP-1RAs, including semaglutide, the active comparator in this 
trial.  These risks are clinically detectable and manageable, and will be monitored during the 
trial. Section 7.7.1 (Management of Patients with Gastrointestinal Symptoms) provides detailed 
information concerning the management of GI AEs.
The patients in the active treatment groups are expected to experience benefits of the study 
treatments, including improved glycemic control and reduced body weight. The patients in the 
placebo group may benefit from improved adherence to the non-pharmacological measures of 
treatment, but will be at higher risk of poor glycemic control. To avoid unacceptably high, 
prolonged hyperglycemia, the protocol includes several protective measures. In addition to the 
comprehensive safety monitoring plan for all patients included in this study, blood glucose (BG) 
levels will be regularly monitored to reduce risks related to acute diabetic complications. 
Section 9.2.2.2 (Severe, Persistent Hyperglycemia) describes definitions and criteria when 
diagnosing and categorizing an episode considered to be related to hyperglycemia. If a patient 
fulfils any of the rescue medication criteria, the patient will be offered rescue medication at the 
discretion of the investigator (Section 7.4.1.2 Management of Hyperglycemia).  
Section 7.4.1.3 (Treatment of Hypoglycemia and Hypokalemia during Hyperinsulinemic 
Euglycemic Clamp) describes how episodes of hypoglycemia or hypokalemia will be treated
during the hyperinsulinemic euglycemic clamp, if necessary.  Section 9.2.2.1 (Hypoglycemia) 
provides criteria for diagnosis and categorization of episodes of hypoglycemia.  
More information about the known and expected benefits, risks, serious adverse events (SAEs),
and reasonably anticipated AEs of tirzepatide are to be found in the Investigator’s Brochure (IB).  
Information on AEs expected to be related to the investigational product (IP) can be found in
Section 6 (Development Core Safety Information) of the IB. Information on SAEs that are
expected in the study population independent of drug exposure will be assessed by the sponsor in
aggregate, periodically during the course of the study, and can be found in Section 5 (Effects in
Humans) of the IB.

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 27
LY3298176
4. Objectives and Endpoints
Table GPGT.1 shows the objectives and endpoints of the study.  
Table GPGT.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To compare the effect of tirzepatide 15 mg dose and 
placebo on the total cDI after 28 weeks of treatment, 
including the dose escalation phase, in T2DM patients 
on metformin.

The change from baseline in total cDI
Secondary
To compare the effects of tirzepatide 15 mg relative to 
placebo (except for the primary efficacy measure) and 
semaglutide 1 mg after 28 weeks of treatment on:

Insulin secretion and insulin sensitivity combined
outcome

The change in total cDI (for tirzepatide versus 
semaglutide comparison only)

Glucose control

The change from baseline in fasting and postmeal 
glucose (total and incremental AUC0-240min)
during sMMTT

The change from baseline in hemoglobin A1c

Insulin secretion

The change in the first phase incremental 
ISR0-8min from hyperglycemic clamp

The change in second phase total ISR20-120min
from hyperglycemic clamp

The change in total ISR0-120min from 
hyperglycemic clamp

The change from baseline in insulin response to 
arginine (incremental AUCarginine0-10min and 
incremental AUCarginine0-30min) from 
hyperglycemic clamp

The change from baseline in β cell GS from 
hyperglycemic clamp

The change in β cell GS from sMMTT

The change from baseline in ISRg from sMMTT

Insulin sensitivity

The change from baseline in hyperinsulinemic 
euglycemic clamp M-value 

Glucagon secretion

The change from baseline in glucagon 
concentration at fasting and postmeal during 
sMMTT (total and incremental AUC0-240min)

Appetite and food intake

The change from baseline in food intake during 
ad libitum meal served buffet style

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 28
LY3298176
Objectives and Endpoints
Objectives
Endpoints
Exploratory
To compare the effects of tirzepatide 15 mg relative to
placebo and semaglutide 1 mg after 28 weeks of 
treatment on:

Glucose metabolism and turnover in adipose tissue

The change from baseline in glucose concentration
and blood flow in adipose tissue during 
hyperglycemic clamp (microdialysis0-120min)

The change from baseline in glucose concentration 
and blood flow in adipose tissue during sMMTT 
(microdialysis0-240min) 

Insulin secretion

The change in basal ISR (ISR[-10-0min]) from 
hyperglycemic clamp

The change in basal insulin concentration (basal 
insulin[-10-0min]) from hyperglycemic clamp

The change in the first phase insulin response
(incremental AUC0-10min) from hyperglycemic 
clamp

The change in the second phase insulin response
(total AUC20-120min) from hyperglycemic clamp

The change in steady-state ISR (total 
ISR80-120min) from hyperglycemic clamp

The change in total insulin response (total 
AUC0-120min) from hyperglycemic clamp

The change in basal ISR (total ISR-10-0min) prior 
to sMMTT

The change in total ISR (total ISR0-240min) from 
sMMTT

The change in ISRg adjusted for ISRgb from 
sMMTT

The change in RS from sMMTT

The change in PFR from sMMTT

The change in ICLb prior to sMMTT

The change in ICLm

The change in ratio of GS from sMMTT and from 
hyperglycemic clamp

The change in fasting proinsulin to insulin ratio

The change in II30min during the sMMTT

The change in fasting and postmeal insulin (total 
and incremental AUC0-240min) during the 
sMMTT

The change in fasting and postmeal C-peptide 
(total and incremental AUC0-240min) during 
the sMMTT

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 29
LY3298176
Objectives and Endpoints
Objectives
Endpoints
Exploratory (continued)

Insulin sensitivity

The change from baseline in hyperinsulinemic 
euglycemic M/I value (M-value divided by total 
insulin concentration)

The change from baseline in HOMA2-IR 

The change from baseline in postprandial insulin 
sensitivity indices (Matsuda, OGIS, Stumvoll 
indices) from sMMTT 

Glucagon secretion and PP secretion

The change from baseline in total glucagon 
AUC0-120min during hyperglycemic clamp

The change from baseline in incremental glucagon 
concentration after arginine stimulation 
(incremental AUCarginine0-30min) from 
hyperglycemic clamp

The change in glucagon/insulin ratio at fasting and 
during sMMTT (ratio of total glucagon 
AUC0-240min and total insulin AUC0-240min)

The change in PP concentration at fasting and 
postmeal (total and incremental AUC0-240min)
during sMMTT

Appetite (VAS) and food intake

The change in fasting appetite (VAS)

The change in appetite (VAS) score during 
sMMTT

Lipid metabolism and turnover in adipose tissue

The change from baseline in plasma (triglycerides, 
β-hydroxybutyrate, pyruvate, lactate, FFA, and 
glycerol) and adipose tissue (glucose, pyruvate, 
lactate, and glycerol [microdialysis0-120min]) lipid 
parameters and blood flow during 
hyperglycemic clamp

The change from baseline in plasma (triglycerides, 
β-hydroxybutyrate, pyruvate, lactate, FFA, 
glycerol, ApoB-48, ApoB-100, ApoC-III, LPL) 
and adipose tissue (glucose, pyruvate, lactate, and 
glycerol [microdialysis0-240min]) lipid parameters
and blood flow at fasting and during sMMTT

The change from baseline in fasting concentration 
of leptin, adiponectin, IGFBP 1 and 2

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 30
LY3298176
Objectives and Endpoints
Objectives
Endpoints
Exploratory (continued)

Body composition

The change from baseline in lean body mass 
(actual value and %)

The change from baseline in body fat mass (actual 
value and %)

The change from baseline in body weight

The change from baseline in waist circumference

Energy expenditure and substrate utilization

The change in resting metabolic rate (indirect 
calorimetry)

The change in respiratory quotient, diet-induced 
thermogenesis, carbohydrate and fat oxidation rates
before (-120 and -30 minutes) and 60, 120, 180, 
and 240 minutes after the start of sMMTT
(indirect calorimetry)

Safety and tolerability

Adverse events

Safety laboratory parameters

Incidence and rate of hypoglycemia
Abbreviations:  ApoB-48 = apolipoprotein B-48; ApoB-100 = apolipoprotein B-100; ApoC-III = apolipoprotein 
C-III; AUC = area under the concentration versus time curve; AUC0-10min = first phase insulin response;
AUC0-120min = AUC from time zero to 120 minutes after start of the meal; AUC0-240min = AUC from time zero 
to 240 minutes after start of the meal; AUC20-120min = second phase insulin response; AUCarginine0-10min = AUC 
in response to arginine from time zero to 10 minutes; AUCarginine0-30min = AUC in response to arginine from 
time zero to 30 minutes; basal insulin-10-0min = average insulin concentration between -10 minutes and 
0 minutes; cDI = clamp disposition index; FFA = free fatty acid; GS = glucose sensitivity; 
HOMA2 = Homeostatic Model Assessment of Insulin Resistance; HOMA2-IR = insulin resistance as measured 
by the HOMA2 method; ICLb = basal insulin clearance; ICLm = insulin clearance during sMMTT; 
IGFBP = insulin-like growth factor binding protein; II30min= insulinogenic index at 30 minutes; ISR = insulin 
secretion rate; ISR-10-0min = basal insulin secretion rate; ISR0-8min = first phase insulin secretion rate;
ISR0-120min = total insulin secretion rate from hyperglycemic clamp; ISR20-120min = second phase insulin 
secretion rate; ISR0-240min = total insulin secretion rate during sMMTT; ISR80-120min = steady-state insulin 
secretion rate; ISRg = ISR at fixed glucose concentration; ISRgb = ISR at fixed glucose concentration adjusted 
for basal potentiation; LPL =  lipoprotein lipase; microdialysis0-120min = microdialysis from zero to 120 minutes;
microdialysis0-240min = microdialysis from zero to 240 minutes; OGIS = Oral Glucose Insulin Sensitivity
Index; PFR = potentiation ratio; PP = pancreatic polypeptide; RS = rate sensitivity; sMMTT = standardized
mixed-meal tolerance test; T2DM = type 2 diabetes mellitus; VAS = visual analog scale.

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 31
LY3298176
5. Study Design
5.1.
Overall Design
This is a Phase 1, multicenter, randomized, sponsor, investigator- and patient-blind, parallel arm 
study in patients with T2DM to compare the effect of tirzepatide 15 mg dose and placebo on
total clamp disposition index (cDI) after 28 weeks of treatment, including the dose escalation
phase. The study will also compare the effects of tirzepatide 15 mg relative to placebo and a 
selective GLP-1 RA semaglutide (positive control) on additional parameters of pancreatic α and 
β cell function, insulin sensitivity, glucose and lipid metabolism, and energy balance (food intake 
and energy expenditure).  Ozempic® (semaglutide) will be used as a positive control for PD of 
GLP-1 pharmacology to investigate potential differences in the mechanisms of action between a 
dual GIPRA/GLP-1RA and a selective GLP-1RA.
The study will consist of 3 periods:  an approximately 5- to 8-week screening/lead-in period, a 
28-week treatment period, and a 4-week safety follow-up period. Patients will be randomized in 
a 3:3:2 ratio to QW tirzepatide 15 mg, semaglutide 1 mg, or placebo. Active treatments will be 
initially escalated with lower doses to reduce the risk of GI AEs. Immediately prior to 
randomization and approximately 1 to 3 days after the last dose of study drug, the patients will 
be admitted to the clinical research unit (CRU) to perform planned baseline and end-of-treatment 
inpatient study procedures, respectively. Section 2 (Schedule of Activities) presents all planned 
study visits and study procedures for this study. After the completion of the treatment period, a
follow-up visit will be performed 4 weeks later to assess patient safety.
Study governance considerations are described in detail in Appendix 3.  
Figure GPGT.1 illustrates the study design.

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 32
LY3298176
Abbreviations:  CRU = clinical research unit; OAM = oral antihyperglycemia 
medication; QW = once weekly.
a Patients who are being treated with other OAMs, in addition to metformin, should 
discontinue these other OAMs after their eligibility is established, and should complete 
a 4-week washout period.  Once the 4-week washout period is completed, patients can 
be enrolled in the study.  Screening for patients who need to undergo washout of an 
additional OAM may last from Day -59 to Day -4, inclusive. This period includes the 
required 4-week washout. Screening procedures may be performed before washout 
from Day -59 to Day -31.  
Figure GPGT.1.
Illustration of study design for Protocol I8F-MC-GPGT.
5.1.1. Screening and Lead-In
5.1.1.1.
Screening
Eligibility for this study will be determined during the screening period. The patient will sign 
the informed consent form (ICF) before any study procedures are performed.  Screening 
procedures will be performed according to Section 2 (Schedule of Activities).

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 33
LY3298176
Eligible patients are those with T2DM treated with metformin, with or without oral 
antihyperglycemia medications (OAMs) other than metformin. Upon entering the study, patients 
should remain on the same metformin dose throughout the course of the study. After 
randomization, the metformin dose can be reduced in accordance with country-specific label to 
protect patient safety (see Section 7.7 [Concomitant Therapy] for further details). Those patients 
who are being treated with metformin in combination with other OAMs should discontinue all 
OAMs other than metformin after their eligibility is established, and should complete a 4-week 
washout prior to Visit 2 and CRU admission. During the washout period, the investigator will 
perform appropriate surveillance of the patients (by telephone interview or CRU visits, at the
investigator’s discretion) to monitor the safety and glycemic control of the patients.  Once the 
4-week washout period is completed, patients can be enrolled in the study.  Screening for 
patients who need to undergo washout of OAMs other than metformin may last from Day -59 to 
Day -4, inclusive. Screening procedures may be performed before washout from Day -59 to 
Day -31. For all other eligible patients, screening may occur between Day -35 to Day -4, 
inclusive.
Eligible patients will be trained on glucose monitoring and disease management procedures, 
glucometer use for self-monitoring of plasma glucose (SMPG), study diaries, and study 
procedures.  Patients will start performing daily SMPG and record all results, including any 
hypoglycemia episode, in diaries as soon as their eligibility is confirmed; these results will be 
used for glycemia management only. Patients will also follow the investigator’s instructions 
related to any additional SMPG measurements, when judged to be needed for safety or eligibility 
assessments. All patients will be encouraged to maintain their diet and exercise plan throughout
the course of the study.
5.1.1.2.
Lead-in 
During the lead-in period (Day -3 to Day -1), eligible patients should continue their prestudy 
therapy with metformin.  Patients who do not comply with requirements regarding metformin 
dosing and discontinuation of OAMs other than metformin (if used at study entry) will be 
discontinued from the study prior to randomization. In order to perform baseline procedures, 
including standardized mixed-meal tolerance tests (sMMTTs) and hyperinsulinemic euglycemic 
and hyperglycemic clamps, the patients will be admitted to the CRU at the beginning of the 
lead-in period, approximately 3 days prior to randomization. The list and timing of all baseline 
procedures are provided in Section 2 (Schedule of Activities).
5.1.2. Treatment
After completion of all baseline procedures, and while still in the CRU, eligible patients will be 
randomized in a 3:3:2 ratio to QW tirzepatide 15 mg, semaglutide 1 mg, or placebo. Following 
randomization, patients will participate in a 28-week treatment period that consists of a step-wise
dose escalation to reach and maintain the highest scheduled dose level of tirzepatide and 
semaglutide that can be safely administered. The first dose of study drug will be administered 
shortly after randomization while the patients are still in the CRU. The investigator or qualified 
designee will review all available inpatient safety data before discharging patients from the CRU 
on Day 1.  Patients may be required to remain at the CRU longer at the investigator’s discretion.

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 34
LY3298176
A telephone visit will be conducted 2 to 3 days (Days 3 or 4) after the first dose of study drug
and as needed, thereafter. At the telephone visits, study sites should check for any AEs, new 
concomitant medications, and glycemic control status. The patient should enter clinically 
relevant data in the diary. All data collected in the diaries will be reviewed by the investigator or 
her/his designee according to Section 2 (Schedule of Activities), and entered into the electronic 
case report form (eCRF), when applicable.
During the treatment period, the dose of tirzepatide and semaglutide will be escalated within 
each group according to schedules outlined in Figure GPGT.1.  Briefly, the maintenance dose of
semaglutide 1.0 mg will be reached after 4 QW doses of 0.25 mg, followed by 4 QW doses of 
0.5 mg, as required per label.  The starting dose of tirzepatide will be 2.5 mg QW for 4 weeks, 
followed by an increase to 5 mg QW for 4 weeks, followed by an increase to 7.5 mg QW for 
4 weeks, followed by an increase to 10 mg QW for 4 weeks, followed by an increase to 12.5 mg 
QW for 4 weeks until the 15 mg dose is reached and maintained for the duration of the study 
(see Figure GPGT.1). In order to maintain the blinding, all patients (including those on placebo 
and semaglutide) will undergo assessment by the investigator at 4 weekly intervals (4, 8, 12, 16,
and 20) prior to the timed up dose escalation as described in Figure GPGT.1.
The schedule of clinic visits and study procedures during the treatment period, including 
sampling for immunogenicity and PK assessments, are provided in Section 2 (Schedule of 
Activities).  Patients will return to the CRU every week for QW dose administration for 
28 weeks. They will then be readmitted to the CRU within the last week of study (Week 28) to 
perform end-of-treatment sMMTT, hyperinsulinemic euglycemic, and hyperglycemic clamps.  
These procedures will be performed approximately 1 to 3 days after the last dose of study drug
and according to the same schedule as during the lead-in period. Appendix 6 describes the key 
procedural features and the blood sampling plan during hyperglycemic clamp, hyperinsulinemic 
euglycemic clamp, microdialysis, sMMTT, appetite visual analog scale (VAS), ad libitum food 
intake, plethysmography for body composition, and ventilated hood for respiratory quotient 
procedures.  These procedures will be performed in accordance to site practices and processes.
Patients who initiate rescue medication for treatment of severe hyperglycemia (Section 7.4.1.2
Management of Hyperglycemia) during the study or patients who discontinue study treatment, 
irrespective of the reason, will be discontinued from the study (Section 8.1 Discontinuation from 
Study Treatment). They will perform an early termination (ET) visit as soon as possible after 
initiation of rescue medications or discontinuation of study treatment, followed by a safety 
follow-up visit approximately 4 weeks later.
For the reinstitution of washed out OAMs, the timing of the medication restart will be discussed 
between the patient and the investigator. The timing of the medication restart (approximately 
Day 193) is at the discretion of the investigator dependent upon blood glucose control as 
documented in the SMPG, which will continue in the 4 weeks between Day 193 and follow-up. 
Additional telephone visits or outpatient visits may be scheduled to monitor the restart of the 
patient’s baseline medication.

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 35
LY3298176
5.1.3. Safety Follow-Up 
All randomized patients who complete the treatment period or patients who perform ET will 
complete the safety follow-up within 4 weeks after the last dose according to Section 2
(Schedule of Activities).
5.2.
Number of Participants
Approximately 117 patients may be enrolled. Approximately 99 patients are expected to 
complete the study. Section 10.1 (Sample Size Determination) provides details on sample size 
calculation.
5.3.
End of Study Definition
End of the study is the date of the last visit or last scheduled procedure shown in Section 2
(Schedule of Activities) for the last patient.
5.4.
Scientific Rationale for Study Design
The 28-week duration of the treatment period includes a 20-week dose escalation phase and an
8-week maintenance phase on the final 15 mg dose for patients randomized to tirzepatide, and
includes an 8-week dose escalation phase and a 20-week maintenance phase on the final 1 mg
dose for patients randomized to semaglutide. The semaglutide dosing regimen is based on the
regulatory approved label (Ozempic Patient Leaflet, 2018). The tirzepatide dosing regimen
reflects the escalation scheme at initiation that is assessed in the Phase 3 tirzepatide development
program. These dosing regimens are expected to enable all on-treatment testing procedures to be
performed under the steady-state conditions in both groups. The effect on most variables
included in the assessment plan is expected to be at its plateau during this period. Differences in
the escalation algorithm between active treatment groups are not considered of relevance for the
planned assessments and timing of those assessments.  The inclusion of a placebo arm in the
study will enable characterization of the effects on study measures attributable exclusively to
tirzepatide.  Semaglutide is a selective GLP-1 RA that is considered the most effective agent in
the GLP-1 RA class. The inclusion of semaglutide as a positive control will provide comparative
data for a dual GIPR/GLP-1R agonist versus a selective GLP-1 RA.
The T2DM patient population selected to participate in this study, patients treated with up to 
2 OAMs (metformin with or without another OAM), are considered to be in an earlier stage in 
the natural course of disease that is characterized by partial preservation of the cell function. A 
preserved cell function is a prerequisite for glucose-lowering efficacy of incretins and for the 
investigations of the mechanism of action (Bunck et al. 2009).  Patients taking sodium-glucose 
transport protein 2 (SGLT-2) inhibitors can only be entered and washed out if there is no prior 
history of cardiovascular disease.
The cDI is chosen as the primary objective measure for this study because it integrates the effects
of randomized treatments on the islet cell and on insulin action, the 2 key pathophysiologic
problems in T2DM. It is a generally accepted measure of the body’s capacity to respond to
glycemic challenge or the challenge associated with the sMMTT (Ferrannini et al. 2014;

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 36
LY3298176
Utzschneider et al. 2009). Other secondary objectives are chosen based on the current
understanding of the physiologic and pharmacologic effects of dual GIPRA/GLP-1RA and
selective GLP-1RAs (parameters of pancreatic and cell function, insulin tissue sensitivity,
glucose and lipid metabolism, body weight regulation, and energy balance).
The dose justification for tirzepatide and semaglutide is provided in Section 5.5 (Justification for
Dose). It is expected that the 2 treatments have differential effect on the key mechanistic 
pathways of interest (Pratley et al. 2018). Therefore, the planned assessments of the mechanism 
of action of these agents may provide an understanding of the key actions responsible for 
potential difference in glucose- and weight-lowering effects between the dual GIPR/GLP-1R 
agonist versus the selective GLP-1RA, including the contribution of GIP-specific actions.  
The rationale for the sample size is provided in Section 10.1 (Sample Size Determination).
5.5.
Justification for Dose
The tirzepatide dose of 15 mg administered SC QW is selected based on current preclinical 
pharmacology, toxicology, and clinical data, and is the highest maintenance dose planned for 
evaluation in the Phase 3 program.
Tirzepatide dosing will start at a low dose of 2.5 mg accompanied by dose escalation in 2.5-mg 
increments every 4 weeks to attain a final dose of 15 mg. The step-wise increments are expected 
to permit adequate time for development of tolerance to GI events and are expected to minimize 
GI tolerability concerns. The proposed escalation scheme matches the escalation steps employed 
to attain a 15 mg tirzepatide dose in the Phase 3 program.
Tirzepatide 15 mg is predicted to maintain an exposure multiple of 1.6 to 2.4 to the 
no-observed-adverse-effect level doses in 6-month monkey and rat toxicology studies, 
respectively.  
Table GPGT.2 shows the exposure multiples for SC administration of tirzepatide based on 
systemic exposure.
The semaglutide 1 mg dose is selected because it is the highest approved dose of this agent that 
has been shown to provide greater efficacy compared to other GLP-1RA approved for treatment 
of T2DM (Pratley et al. 2018; Ahmann et al. 2018).  

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 37
LY3298176
Table GPGT.2.
Exposure Multiples for Subcutaneous Administration of Tirzepatide 
Based on Systemic Exposure
Dose
(mg/kg)
AUC0-τ, Steady-State 
(µg*hr/mL)
Exposure Multiple
Human (15 mg)
‒
205a
‒
Monkey NOAELb
0.5
337
1.6
Rat NOAELc
3.0
280
2.4
Developmental Rat NOAELd
0.1
4.01
0.082
Developmental Rabbit NOAELe
0.03
14.7
0.072
Abbreviations:  AUC = area under the plasma concentration-time curve; AUC0-τ = area under the plasma 
concentration-time curve from time zero to tau (dosing interval); NOAEL = no-observed-adverse-effect level; 
PK = pharmacokinetics.
a
Plasma PK parameters shown were computed based on the PK model-predicted tirzepatide concentration-time 
profile (based on baseline body weight of approximately 90 kg).
b NOAEL (0.5 mg/kg) determined in a 6-month repeat-dose toxicity study (8336517).  Exposure multiple (EM) is 
calculated as (AUC0-τ/τ in animals)/(AUC0-τ/τ in humans).  τ is 168 hours in monkeys and humans.  Therefore, 
EM in monkey = (337/168)/(human AUC/168).
c
NOAEL (3 mg/kg) determined in a 6-month repeat-dose toxicity study (8337876).  Exposure multiple is 
calculated as (AUC0-τ/τ in animals)/(AUC0-τ/τ in humans).  τ is 96 hours in rats and 168 hours in humans.  
Therefore, EM in rat = (280/96)/(human AUC/168).
d NOAEL (0.1 mg/kg) for developmental toxicity in an embryo-fetal development study in rats (WIL-353354).  
τ is 40 hours in maternal rats.  Exposure multiple is calculated as (AUC0-τ/τ in animals)/(AUC0-τ/τ in humans).  
τ is 40 hours in maternal rats and 168 hours in monkeys and humans.  Therefore, EM in maternal 
rat = (4.01/40)/(human AUC/168).
e
NOAEL (0.03 mg/kg) for developmental toxicity in an embryo-fetal development study in rabbits 
(WIL-353355).  Exposure multiple is calculated as (AUC0-τ/τ in animals)/(AUC0-τ/τ in humans).  τ is 168 hours 
in rabbits and humans.  Therefore, EM in rabbits = (14.7/168)/(human AUC/168).

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 38
LY3298176
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 electrocardiograms (ECGs).
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 56 days prior to start of lead-in on Day -3 for patients treated with
OAMs other than metformin, who are required to perform a washout for at least 4 weeks prior to 
lead-in. For all other patients, screening may occur up to 32 days prior to lead-in. All patients 
will then perform a 3-day lead-in. Patients who are not enrolled within these time periods may 
be subjected to an additional medical assessment and/or clinical measurements to confirm their 
eligibility.  Patients will be dosed only if safety laboratory results not older than 1 week are 
available.  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
6.1.
Inclusion Criteria
Patients are eligible for inclusion in the study only if they meet all of the following criteria at 
screening (Visit 1):
Disease Characteristics
[1]
Have T2DM for at least 6 months;
[2]
Treated with diet and exercise and stable dose(s) of metformin, with or 
without 1 additional stable dose of OAM other than metformin, 3 months
prior to study entry; doses of metformin will be considered stable if all 
prescribed doses for this period were ±850 mg from the most commonly 
prescribed dose; allowed OAMs, in combination with metformin, are 
dipeptidyl peptidase-4 (DPP-IV) inhibitors, SGLT-2 inhibitors, acarbose, and 
sulfonylureas; the second OAM dose will be considered stable if the 
prescribed dose is unchanged for at least 3 months prior to study entry.
[3]
Have a hemoglobin A1c value at screening (Visit 1) of ≥7.0% and ≤9.5% if on 
metformin only; or ≥6.5% and ≤9.0% if on metformin in combination with
OAMs other than metformin;
Patient Characteristics
[4]
Male or female patients between the ages of 20 and 74 years, inclusive
[4a] Male patients:

Men, regardless of their fertility status, with nonpregnant woman of 
childbearing potential (WOCBP) partners must agree to either remain 
abstinent (if this is their preferred and usual lifestyle) or use condoms as 
well as 1 additional highly effective (less than 1% failure rate) method 

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 39
LY3298176
of contraception (such as combination oral contraceptives, implanted 
contraceptives, or intrauterine devices) or effective method of 
contraception (such as diaphragms with spermicide or cervical sponges) 
for the duration of the study and until their plasma concentrations are 
below the level that could result in a relevant potential exposure to a 
possible fetus, predicted to be 90 days.
o
Men and their partners may choose to use a double–barrier method 
of contraception.  (Barrier protection methods without concomitant 
use of a spermicide are not an effective or acceptable methods of 
contraception.  Thus, each barrier method must include use of a 
spermicide.  It should be noted, however, that the use of male and 
female condoms as a double-barrier method is not considered 
acceptable due to the high failure rate when these barrier methods 
are combined).
o
Periodic abstinence (eg, calendar, ovulation, symptothermal, 
postovulation methods), declaration of abstinence just for the 
duration of a study, and withdrawal are not acceptable methods of 
contraception.

Men with pregnant partners should use condoms during intercourse for 
the duration of the study and until the end of estimated relevant potential 
exposure in WOCBP (90 days).

Men must agree to refrain from sperm donation for the duration of the 
study and until their plasma concentrations are below the level that could 
result in a relevant potential exposure to a possible fetus, predicted to be 
90 days following last dose of study drug.

Men who are in exclusively same-sex relationships (as their preferred 
and usual lifestyle) are not required to use contraception.
[4b] Female patients:

Women of childbearing potential who are abstinent (if this is complete 
abstinence, as their preferred and usual lifestyle) or in a same-sex relationship 
(as part of their preferred and usual lifestyle) must agree to either remain 
abstinent or stay in a same-sex relationship without sexual relationships with 
males.  Periodic abstinence (eg, calendar, ovulation, symptothermal, 
postovulation methods), declaration of abstinence just for the duration of a 
study, and withdrawal are not acceptable methods of contraception.

Otherwise, WOCBP participating must agree to use effective contraception, (see 
contraception guidance below), for the entirety of the study. Contraception 
must continue following completion of study drug administration for 30 days.
o
Women of childbearing potential participating must test negative for 
pregnancy prior to initiation of treatment as indicated by a negative serum

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 40
LY3298176
pregnancy test at the screening visit followed by a negative urine
pregnancy test within 48 hours prior to exposure and at other times as 
specified in Section 2 (Schedule of Activities).  
o
The inclusion of WOCBP requires use of a highly effective contraceptive 
measure (Appendix 8). Contraception should be maintained during 
treatment and until the end of estimated relevant potential exposure 
(90 days).

Must not be breastfeeding

Women who are not of childbearing potential may participate and 
include those who are: 
o
Infertile due to surgical sterilization (hysterectomy, bilateral 
oophorectomy, or tubal ligation), congenital anomaly such as 
mullerian agenesis, or
o
Postmenopausal – defined as no menses for 12 months without an 
alternative medical cause.  A high follicle-stimulating hormone 
(FSH) level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception 
or hormonal replacement therapy.  However, in the absence of 
12 months of amenorrhea, a single FSH measurement is 
insufficient.
[5]
Have a body mass index between 25 kg/m2 and 45 kg/m2, inclusive, at 
screening (Visit 1); are of stable weight (±5%) >3 months prior to screening
(Visit 1); and agree to not initiate an intensive diet and/or exercise program 
during the study with the intent of reducing body weight other than lifestyle 
and dietary measures for diabetes treatment;
[6]
Have venous access sufficient to allow for blood sampling as per the protocol.
Informed Consent
[7]
Are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures;
[8]
Have given written informed consent approved by Lilly and the ethical review 
board (ERB) governing the site.
6.2.
Exclusion Criteria
Patients will be excluded from study enrollment if they meet any of the following criteria at 
screening (Visit 1) and/or at other visits prior to randomization, when indicated:
Primary Study Condition - Diabetes Related
[9]
Have type 1 diabetes mellitus;

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 41
LY3298176
[10] Have had more than 1 episode of severe hypoglycemia, as defined by the 
American Diabetes Association criteria, within 6 months before screening
(Visit 1) or has a history of hypoglycemia unawareness or poor recognition of 
hypoglycemic symptoms; any patient that cannot communicate an 
understanding of hypoglycemic symptoms and the appropriate treatment of 
hypoglycemia prior to the first dose of study drug should also be excluded;
[11] Have had 1 or more episodes of ketoacidosis or hyperosmolar state/coma 
requiring hospitalization within the 6 months prior to screening (Visit 1);
[12] Have a history of proliferative retinopathy or maculopathy as determined by 
the investigator based on a recent (<1.5 years) ophthalmologic examination;
[13] Impaired renal estimated glomerular filtration rate <45 mL/min/1.73 m2
calculated by Chronic Kidney Disease-Epidemiology.
Prior/Concomitant Therapy - Glucose-Lowering Medications
[14] Have taken any glucose-lowering medications other than allowed OAMs any 
time during the last 3 months before screening (Visit 1) or during the 
screening period; short-term use of insulin (<14 days) for treatment of acute 
conditions is allowed in the 3 month period prior to entry and after 
randomization; after their eligibility is confirmed, patients will be required to 
discontinue all OAMs other than metformin and will then perform a required 
4-week washout prior to lead-in (Visit 2); in patients with established 
cardiovascular disease who are treated with SGLT-2 inhibitors, this therapy 
should not be discontinued; therefore, these patients will NOT be eligible for 
participation in the trial;
Medical Conditions - General
[15] Have a history or current cardiovascular, respiratory, hepatic, renal, GI, 
endocrine, haematological or neurological disorders capable of significantly 
altering the absorption, metabolism or elimination of drugs; of constituting a 
risk when taking the IP; or of interfering with the interpretation of data
[16] Have acute or chronic pancreatitis or a history of acute idiopathic pancreatitis;
patients who had cholecystolithiasis and/or cholecystectomy in the past, with 
no long-term complications, are eligible for participation;
[17] Have a known clinically significant gastric emptying abnormality (eg, severe 
diabetic gastroparesis or gastric outlet obstruction) or have undergone gastric 
bypass (bariatric) surgery or restrictive bariatric surgery (eg, Lap-Band®);
[18] Have a personal or family history of medullary thyroid carcinoma (MTC), 
multiple endocrine neoplasia syndrome type 2 (MEN 2), or a screening 
calcitonin ≥20 pg/mL at screening (Visit 1);

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 42
LY3298176
[19] Have had acute myocardial infarction, congestive heart failure NYHA class 
III or IV, and/or cerebrovascular accident (stroke]) within 3 months prior to 
screening (Visit 1); for patients taking SGLT-2 inhibitors: any history of 
congestive heart failure, myocardial infarction, unstable angina, or stroke;
[20] Have findings in the 12-lead ECG at screening (Visit 1) that, in the opinion of 
the investigator, may increase the risks of potentially clinically relevant 
worsening associated with participation in the study;
[21] Have an active or untreated malignancy or have been in remission from a 
clinically significant malignancy (other than basal or squamous cell skin 
cancer, in situ carcinomas of the cervix, or in situ prostate cancer) for <5 years 
prior to screening (Visit 1);
[22] Have evidence of human immunodeficiency virus (HIV) and/or positive HIV 
antibodies;
[23] Have evidence of hepatitis B or positive hepatitis B surface antigen and/or 
evidence of hepatitis C virus (HCV) or hepatitis C antibody (at screening
[Visit 1]). Patients with a previous diagnosis of HCV who have been treated 
with antiviral therapy and achieved a sustained virological response may be 
eligible for inclusion in the study, provided they have no detectable HCV 
RNA on the screening HCV polymerase chain reaction test.  A sustained 
virological response is defined as an undetectable HCV RNA level 24 weeks 
after completion of a full, documented course of an approved antiviral therapy 
for HCV. 
Patients who have spontaneously cleared HCV infection, defined as (1): a 
positive HCV antibody test and (2): a negative HCV RNA test, with no 
history of anti-HCV treatment, may be eligible for inclusion in the study, 
provided they have no detectable HCV RNA on screening for this study.
[24] Have serum aspartate aminotransferase (AST) or alanine aminotransferase 
(ALT) >2.5X the upper limit of normal (ULN) or total bilirubin level (TBL)
>1.5X ULN;
[25] Have had a blood donation of 450 mL or more in the last 3 months or any 
blood donation within the last month prior to screening (Visit 1);
[26] Have had a blood transfusion or severe blood loss within the last 3 months or 
have known hemoglobinopathy, hemolytic anemia, sickle cell anemia, or have 
a hemoglobin value <11 g/dL (males) or <10 g/dL (females), or any other 
condition known to interfere with hemoglobin A1c measurement;
[27] Have a history of drug or alcohol abuse; and/or smoke >10 cigarettes per day 
or the equivalent; or are unable or unwilling to refrain from nicotine during 
CRU admission;

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 43
LY3298176
[28] 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 24 hours before dosing and until discharge from the 
CRU;
[29] Have evidence of significant active neuropsychiatric disease as determined by 
the investigator;
Prior/Concomitant Therapy - General
[30] Have been treated with prescription drugs that promote weight loss (eg, 
Meridia® [sibutramine], Sanorex® [mazindol], Adipex® [phentermine], 
BELVIQ® [lorcaserin], Mysimba [naltrexone/bupropion], Saxenda®
[liraglutide]) or similar other body weight loss medications, including 
over-the-counter medications (eg, alli®) within 3 months prior to screening 
(Visit 1) or between Visit 1 and randomization (Visit 2);
[31] Have received chronic (lasting >14 consecutive days) systemic glucocorticoid 
therapy (excluding topical, intra-articular, and inhaled preparations) within 
1 month before screening (Visit 1), or between Visit 1 and randomization 
(Visit 2);
[32] Have received treatment with a drug that has not received regulatory approval 
for any indication within 1 month prior to screening (Visit 1); if the previous 
study drug has a long half-life, 3 months or 5 half-lives (whichever is longer) 
should have passed.
Prior/Concurrent Clinical Trial Experience
[33] Are persons who have previously completed or withdrawn after 
randomization from this study;
[34] Have previous exposure or known allergies to tirzepatide or related 
compounds, or have an intolerance to GLP-1RAs;
[35] 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.
Other Exclusions
[36] Are investigative site personnel directly affiliated with this study and their 
immediate families.  Immediate family is defined as a spouse, parent, child, or 
sibling, whether biological or legally adopted;
[37] Are Eli Lilly and Company, Profil, and Covance employees.;
[38] Are deemed unsuitable by the investigator for any other reason.

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 44
LY3298176
6.3.
Lifestyle and/or Dietary Requirements
Throughout the study, patients may undergo medical assessments and review of compliance with 
requirements described in this section before continuing in the study.
6.3.1. Meals and Dietary Restrictions
During the study, patients should follow their usual dietary regimen that is a part of their diabetes 
management, as agreed with the investigator or his/her designee. For certain assessments, the 
patients will be required to come to the CRU in a fasting state, after an overnight fast lasting at 
least 8 hours for safety laboratory tests, 10 hours indirect calorimetry, or 12 hours for 
hyperinsulinemic euglycemic clamp as specified in Section 2 (Schedule of Activities).  
Additional dietary requirements for the planned assessments in the CRU at baseline and Week 28 
(for example, hyperinsulinemic euglycemic and hyperglycemic clamp procedures, sMMTT) are 
described in detail in Appendix 6.
6.3.2. Caffeine, Alcohol, and Tobacco
No alcohol, caffeine, and/or methylxanthine-containing products will be allowed at least 
24 hours before each CRU admission, and each outpatient visit and throughout the duration of 
each CRU visit. Between CRU visits, weekly alcohol should not exceed 21 units per week for 
males and 14 units per week for females (a unit is defined in Section 6.2 Exclusion Criteria). No 
nicotine use will be allowed at least 4 hours before each CRU admission and each outpatient visit 
and throughout the duration of each CRU visit. While not resident in the CRU, patients must 
consume no more than 10 cigarettes or equivalent per day.
6.3.3. Activity
Patients will be advised to maintain their regular levels of physical activity/exercise during the 
study. No intense physical activity will be allowed for at least 48 hours before each CRU 
admission.  When certain study procedures are in progress at the study site, patients may be 
required to remain recumbent or sitting.
6.4.
Screen Failures
Screening may include re-assessment of some parameters (for example, vital signs and ECGs) 
and laboratory tests at the discretion of the investigator. Individuals who do not meet the criteria 
for participation in this study (screen failure) or were unable to complete OAM washout may be 
re-screened up to 1 time. Individuals who had been rescreened once and marked as screen 
failures during the halt in enrollment due to the Coronavirus Disease 2019 (COVID-19)
pandemic may be allowed to be rescreened up to 1 more time. The interval between 
re-screenings should be at least 2 weeks.  When re-screening is performed, the individual must 
sign a new ICF and will be assigned a new screening number.  Screening number, starting with 
501 or 301 based on study site, will be assigned at the screening visit. If patients are re-screened, 
they will be assigned a new screening number.  Patient numbers/enrollment numbers are 
assigned in the morning of Day 1 to ensure only eligible patients enter the study.

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 45
LY3298176
7. Treatment
7.1.
Treatment Administered
Patients will receive up to 15 mg of tirzepatide, up to 1.0 mg of semaglutide, or placebo, all 
administered SC QW for 28 weeks.
Table GPGT.3 shows the study treatments and dose escalation for tirzepatide and semaglutide.
Table GPGT.3.
Study Treatments and Dose Escalation
Dose Escalation Schemes (dose in mg)
Treatment
Week
1-4
Week
5-8
Week
9-12 
Week
13-16
Week
17-20
Week
21-24
Week
25-28
Tirzepatide
2.5
5
7.5
10
12.5
15
15
Semaglutide
0.25
0.5
1.0
1.0
1.0
1.0
1.0
Placebo
X
X
X
X
X
X
X
All treatments will be administered QW at the CRU. All injections will be administered into the 
SC tissue of the abdominal wall. Injection sites will be alternated weekly between 4 sites (right 
and left upper quadrants and right and left lower quadrants) of the abdominal wall. Patients will 
be blinded to study drug administration by means of a blindfold.
Whenever possible, study drug administration should be carried out by the same personnel. The 
personnel who administer study drug will not be performing any study assessments with patients.
The investigator or designee is responsible for:

explaining the correct use of the IP to the site personnel

verifying that instructions are followed properly

maintaining accurate records of IP dispensing and collection

and returning all unused medication to Lilly or its designee at the end of the study
Note: In some cases, sites may destroy the material if, during the investigative site selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose of clinical materials.
The sites will be instructed to discard used medications according to local regulations.
7.1.1. Packaging and Labeling
Tirzepatide for SC administration after reconstitution will be provided as a lyophilized study 
drug in clear glass vials. Each vial of tirzepatide will contain 5 mg. Matching placebo vials will 
be provided as lyophilized excipient.  Tirzepatide and matching placebo will be supplied by 
Lilly. The diluent will be sterile water for injection (1.1 mL to give 5 mg/mL) and will be site 
sourced.

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 46
LY3298176
Semaglutide will be the positive control and the commercially available formulation 
(Ozempic pen) will be supplied by Lilly.
The IP will be labeled according to the country’s regulatory requirements.
7.2.
Method of Treatment Assignment
Patients who meet all criteria for enrollment will be randomized to one of the study treatment 
arms on Day 1 after completion of all baseline procedures and prior to dosing (Visit 2).  
Assignment to treatment arms will be determined by a randomization table with treatment codes.  
Patients will be randomized in a 3:3:2 ratio to receive QW tirzepatide 15 mg, semaglutide 1 mg, 
or placebo.
7.2.1. Selection and Timing of Doses
The doses will be administered QW according to the randomization schedule, on the same day of 
the week (±1 day) and at approximately the same time of the day.  The actual time of all dose 
administrations will be recorded in the patient’s eCRF. If a patient does not receive her/his 
planned treatment dose on the scheduled day, the dose should be administered as soon as 
possible and at least 48 hours prior to the next scheduled dose. If the remaining time to the next 
scheduled dose is less than 48 hours, the dose will not be administered and will be considered a
missed dose.
7.3.
Blinding
For tirzepatide, semaglutide, and placebo, the dosing will be sponsor, investigator, and patient
blinded. To preserve the blinding of the study for treatment allocation, all study site personnel, 
except staff who prepare, dispense, and administer study medication, will be blinded to treatment 
allocation.  Tirzepatide and placebo will be prepared by the site pharmacy in accordance to the 
pharmacy preparation instructions.  Semaglutide will be administered in accordance to its 
package insert instructions.  The site staff will take the necessary steps to ensure that patients 
will remain blinded to the treatment administration.
Blinding of tirzepatide, semaglutide, and placebo will be maintained throughout the conduct of 
the study until all data are cleaned to an acceptable level of quality and locked. The details are 
included in the separate Blinding/Unblinding Plan.
The staff who prepare and dispense study medication will receive a randomization table with 
treatment codes to enable preparation of blinded doses.
Emergency codes will be available to the investigator.  A code, which reveals the treatment for a 
specific study patient, may be opened during the study only if the patient’s well-being requires 
knowledge of the patient’s treatment assignment.
If a patient’s study treatment assignment is unblinded, the patient must be discontinued from the 
study unless the investigator obtains specific approval from a Lilly clinical pharmacologist (CP)
or clinical research physician (CRP) for the study participant to continue in the study.

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 47
LY3298176
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, it is the responsibility of the investigator to 
promptly document the decision and rationale and notify Lilly as soon as possible. The 
investigator should make every effort to contact the Lilly CP or CRP before unblinding a study 
patient’s treatment assignment unless this could delay emergency treatment of the patient.  If a 
study patient’s treatment assignment is unblinded, Lilly must be notified immediately.
Upon completion of the study, all codes must be returned to Lilly or its designee.
7.4.
Dose Modification
The patient should follow the planned dosing regimen. In the case of poor tolerability at any 
time during the study, dosing can be interrupted temporarily (Section 8.1.2 Temporary 
Interruption of Study Drug).
7.4.1. Special Treatment Considerations
Fasting plasma glucose (FPG) values will be measured daily by the patient using the BG meter 
provided during the screening period, after the eligibility is confirmed (between Visits 1 and 2).  
Additional SMPG measurements may be required, if needed, and will be agreed between the 
patient and the investigator or her/his designee.
7.4.1.1.
Management of Hypoglycemia
If hypoglycemia occurs, each episode will be treated according to the standards of care by the 
investigator and additional monitoring of glucose levels may be requested at the investigator’s 
discretion (American Diabetes Association 2018). If an adjustment in treatment regimen would 
be needed to address increased frequency of hypoglycemia after randomization, the dose of 
metformin must be first reduced or, if clinically appropriate, metformin can be discontinued.
For management of hypoglycemia during the clamp procedures see Section 7.4.1.3 (Treatment of 
Hypoglycemia and Hypokalemia during Hyperinsulinemic Euglycemic Clamp).
For hypoglycemia reporting see Section 9.2.2.1 (Hypoglycemia).
7.4.1.2.
Management of Hyperglycemia
If SMPG records indicate that plasma glucose (PG) values are exceeding the limits for severe, 
persistent hyperglycemia described in Section 9.2.2.2 (Severe, Persistent Hyperglycemia), and 
no intercurrent cause of the hyperglycemia is evident, rescue medications should be considered 
at the next scheduled clinic visit.  The patient will be prescribed a rescue medication at the
discretion of the investigator. Rescue medications will be prescribed by the health care 
professional responsible for the patient’s usual medical care. Only the GLP-RAs are not allowed 
as rescue medications to avoid interference with safety assessments during the safety follow-up.  
Patients who receive rescue therapy will be discontinued from the study after performing ET 
visit and safety follow-up visit 4 weeks later. If hyperglycemia occurs during the follow-up 
period, the patient will remain in the study until completion of the planned follow-up.

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 48
LY3298176
For criteria for hyperglycemia reporting see Section 9.2.2.2 (Severe, Persistent Hyperglycemia).
7.4.1.3.
Treatment of Hypoglycemia and Hypokalemia during Hyperinsulinemic 
Euglycemic Clamp
During hyperinsulinemic euglycemic clamp, excess insulin administration may cause 
hypoglycemia and hypokalemia. Mild episodes of hypoglycemia can be treated with glucose.  
More severe episodes with coma, seizure, or neurologic impairment may be treated with 
intramuscular/SC glucagon or concentrated intravenous (IV) glucose.  Sustained carbohydrate 
intake and observation may be necessary because hypoglycemia may recur after apparent clinical 
recovery. Hypokalemia must be corrected appropriately.
7.5.
Preparation/Handling/Storage/Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained, as communicated by sponsor, during transit for all IP received and any discrepancies 
are reported and resolved before use of the study treatment.
Only patients enrolled in the study may receive IP or study materials, and only authorized site 
staff may supply or administer IP. All IP should be stored in an environmentally controlled and 
monitored (manual or automated) area in accordance with the labeled storage conditions with 
access limited to the investigator and authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (such as
receipt, reconciliation and final disposition records).
7.6.
Treatment Compliance
The IP will be administered at the study site and documentation of treatment administration will 
occur at the site. Patients will be considered compliant if they received at least 75% of their 
scheduled doses for each 4-week interval during the treatment period.  When assessing treatment 
compliance, the missed doses (Section 7.2.1 Selection and Timing of Doses) and interrupted 
doses (Section 8.1.2 Temporary Interruption of Study Drug) will be taken into consideration. 
Patients who are repeatedly (2 or more episodes) noncompliant with the maintenance doses will
be reviewed by the investigator and sponsor to determine if the patient should continue treatment 
or be discontinued from the study.
7.7.
Concomitant Therapy
Glucose-Lowering Medications
Section 6.1 (Inclusion Criteria) and Section 6.2 (Exclusion Criteria) provide requirements 
regarding the use of glucose-lowering medications prior to entry and during the screening/lead-in 
period.  All patients in the study are required to be treated with stable doses of metformin for at 
least 3 months prior to study entry. Patients are required to continue metformin as their only 
concomitant antihyperglycemic medication during the entire trial. The dose of metformin should 
remain unchanged during the screening/lead-in and the treatment periods. If the dose of 
metformin would need to be decreased or discontinued before randomization per 

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 49
LY3298176
country-specific label (for example, because of reduced renal function), the patient will be 
considered as ineligible and will be discontinued from the study immediately. Dose adjustment 
or discontinuation after randomization is allowed only if required per country-specific label to 
protect patient safety, in which case the patient will be allowed to continue her/his participation 
in the trial.  If a patient changes the formulation from the immediate-release formulation of 
metformin to the sustained-release formulation, or vice versa, the change will be on a 
milligram-per-milligram basis.  
Patients treated with other OAMs at study entry, in addition to metformin, are allowed to 
participate in the study (refer to Inclusion Criteria [2] and [3] for details) but must discontinue 
OAMs other than metformin as soon as their eligibility is confirmed, and must complete a 4-
week washout period prior to the lead-in period and randomization. Once the 4-week washout 
period is completed, patients can be enrolled in the study. The allowed OAMs, in combination 
with metformin, are DPP-IV inhibitors, SGLT-2 inhibitors, acarbose, and sulfonylureas.
Short-term (<14 days) use of insulin for treatment of acute conditions is allowed 3 months prior 
to screening (Visit 1) and after randomization. If used >14 days after randomization, the patient 
will be discontinued from study treatment and from the study.
Other glucose-lowering medications are not allowed at any time during the 3-month period prior 
to study entry and any time after study entry until the end of the treatment period. After the 
completion of the treatment period, patients can receive other glucose-lowering agents, except 
GLP-RAs. The patients who receive glucose-lowering agents that are prohibited during the 
treatment period for >14 days, including patients who initiate rescue interventions for severe 
hyperglycemia, will be immediately discontinued from the study treatment and from the study 
after the completion of the end-of-study procedures (ET visit and 4-week safety follow-up). If 
used ≤14 days for any other reason, the patient will be required to discontinue this treatment and 
continue in the trial.
Weight-Lowering Medications
Section 6.2 (Exclusion Criteria) provides requirements regarding prescription drugs that promote 
weight loss prior to entry and during the screening/lead-in period.  Prescription or 
over-the-counter medications to promote weight loss are not allowed after randomization. If 
used ≤14 days, the patient will be required to discontinue this treatment and continue in the trial. 
If used >14 days after randomization, the patient will be immediately discontinued from the 
study drug and will perform end-of-study procedures (ET visit and 4-week safety follow-up).  If 
prescription or over-the-counter medications to promote weight loss are used, this will be 
considered a protocol deviation.
Corticosteroids
Section 6.2 (Exclusion Criteria) provides requirements regarding the use of chronic systemic 
glucocorticoids prior to entry and during the screening/lead-in period. Patients treated with 
systemic glucocorticoid therapy after randomization for >14 consecutive days (with the
exception of topical, intra-articular, and inhaled preparations) will be discontinued from the 

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 50
LY3298176
study. If used ≤14 days, the patient will be required to discontinue this treatment and continue in 
the study.
Other Medications
All other concomitant medications that the patient is already taking are allowed. If the need for 
dose adjustment for the currently used concomitant medications or addition of a new 
concomitant medication arises, the patient may be continued in the study on study medication if, 
in the investigator’s opinion, the addition of the new medication does not pose a safety risk. 
Nausea and/or vomiting during this study may be treated with anti-emetics but should not be 
used prophylactically. Similarly, anti-diarrheal agents are allowed to be prescribed if the patient 
reports AE of diarrhea. For details on the use of symptomatic agents for treatment of GI AEs,
see Section 7.7.1 (Management of Patients with Gastrointestinal Symptoms).
If an additional concomitant medication that is either prohibited per study protocol or may 
interfere with efficacy or safety assessment is started, the site monitor and sponsor should be 
informed as soon as possible.  Any new medications used during the course of the study 
(including those not requiring sponsor notifications) must be documented in the eCRF.
7.7.1. Management of Patients with Gastrointestinal Symptoms
The tirzepatide and semaglutide dose escalation schemes have been designed to minimize the 
development of intolerable GI symptoms.  The escalation period for tirzepatide is considered to
be 20 weeks to reach the 15 mg maintenance dose and additional 4 weeks to reach steady-state.  
The escalation period for semaglutide is considered to be 8 weeks to reach the 1 mg maintenance 
dose and additional 4 weeks to reach steady-state.  During the dose escalation period, every 
effort should be made by the investigator to be able to escalate and maintain patients on the 
corresponding study drug dosage.  
To mitigate GI symptoms and manage patients with poorly tolerated GI AEs, the investigator 
should:

Advise patients to eat smaller meals, for example, splitting 3 daily meals into 4 or more 
smaller meals, and to stop eating when they feel full.

Prescribe symptomatic medication (for example, anti-emetic or anti-diarrheal medication) 
per local country availability and individual patient needs.

Temporarily interrupt study per guidance provided in Section 8.1.2 (Temporary 
Interruption of Study Drug).
7.8.
Treatment after the End of the Study
Not applicable. Tirzepatide and semaglutide will not be made available to patients after 
completion of the study.

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 51
LY3298176
8. Discontinuation Criteria
Patients discontinuing from the study prematurely for any reason should complete ET visit and 
safety follow-up visit procedures according to Section 2 (Schedule of Activities).
8.1.
Discontinuation from Study Treatment
8.1.1. Permanent Discontinuation from Study Treatment
Possible reasons leading to permanent discontinuation of IP:

The patient requests to discontinue IP

If a patient is inadvertently enrolled and it is determined that continued treatment with
study drug would not be medically appropriate (Section 8.1.3 Discontinuation of 
Inadvertently Enrolled Patients)

If a patient is diagnosed with acute or chronic pancreatitis

If a patient is diagnosed with MTC after randomization

If a patient is diagnosed with an active or untreated malignancy (other than basal or
squamous cell skin cancer, in situ carcinomas of the cervix, or in situ prostate cancer)
after randomization

If a patient is diagnosed with a significant study drug-related hypersensitivity reaction

If a patient is diagnosed with any other treatment-emergent adverse event (TEAE), SAE, 
or clinically significant laboratory value for which the investigator believes that 
permanent study drug discontinuation is the appropriate measure to be taken

If female patient becomes pregnant

If a patient is diagnosed with type 1 diabetes mellitus

If a patient experiences severe, persistent hyperglycemia (Section 7.4.1.2 and 
Section 9.2.2.2)
Discontinuation of the IP for abnormal liver function tests should be considered by the 
investigator when a patient meets any 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

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 52
LY3298176

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%)

Drug-related vomiting requiring IV hydration treatment or causing severe distress 
(prevents daily activities and results in no appetite, or requires an emergency department 
visit or hospitalization), that cannot be resolved by temporary interruption of study drug 
(Section 8.1.2. Temporary Interruption of Study Drug).
Patients who discontinue study drug early will be also discontinued from the study after 
performing ET visit and safety follow-up visit procedures, as specified in Section 2
(Schedule of Activities).
8.1.2. Temporary Interruption of Study Drug
In certain situations after randomization, for example, if GI tolerability AEs occur, the 
investigator may need to temporarily interrupt study drug. Temporary interruptions are allowed 
during the dose escalation phase and not during the maintenance phase.  Investigators should 
immediately inform the sponsor, that study drug has been temporarily interrupted. During an 
event that requires temporary interruption of study treatment, only 1 dose may be skipped. 
Every effort should be made by the investigator to maintain patients on study drug and to restart 
study drug after temporary interruption, as soon as it is assessed as safe to do so. The patient 
should resume study treatment administration at the scheduled dose level, per protocol. If more 
than 2 episodes of study interruptions occur in the same patient, these cases will be reviewed by 
the investigator (or his/her designee) and Lilly sponsor to assess the feasibility of the patient’s 
further participation in the study. If study drug interruption is due to an AE, the event will be 
documented and followed according to the procedures in Section 9.2 (Adverse Events).  The data 
related to temporary interruption of study treatment will be documented in source documents and 
entered into the eCRF.
8.1.3. Discontinuation of Inadvertently Enrolled Patients
If the sponsor or investigator identifies a patient who did not meet enrollment criteria and was 
inadvertently enrolled, the patient must be discontinued from the study unless there are 
extenuating circumstances that make it medically necessary for the patient to continue on study 
treatment.  If the investigator and the sponsor CRP agree that it is medically appropriate to 
continue, the investigator must obtain documented approval from the sponsor CRP to allow the 
inadvertently enrolled patient to continue in the study with or without treatment with study drug. 
8.2.
Discontinuation from the Study
In addition to the situations that result in study drug discontinuation described in Section 8.1.1
(Permanent Discontinuation from Study Treatment), patients will be discontinued from the study
in 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

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 53
LY3298176

Participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and good clinical practice

Investigator Decision
o
the investigator decides that the patient should be discontinued from the study for 
any reason
o
if the patient, for any reason, requires treatment with another therapeutic agent 
that has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study occurs prior to introduction of the new agent

Patient Decision
o
the patient, or legal representative, requests to be withdrawn from the study.
8.3.
Patients Lost to Follow-Up
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Site personnel are expected to make 
diligent attempts to contact patients who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the study site.

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 54
LY3298176
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.
Appendix 6 describes methods for assessment of glucose and lipid metabolism, and appetite and 
food intake during the study (hyperglycemic clamp, hyperinsulinemic euglycemic clamp, 
microdialysis, sMMTT, appetite (VAS), ad libitum food intake, plethysmography for body 
composition, and ventilated hood for respiratory quotient procedures, including the sampling 
plan).  A complete description of each of these procedures is included in operation manuals 
available at the study site.
The specifications in this protocol for the timings of safety and sample collections are given as 
targets to be achieved within reasonable limits.  Modifications may be made to the time points 
based upon emerging clinical information.  The scheduled time points may be subject to minor 
alterations; however, the actual time must be recorded correctly in the eCRF.  Failure or delays 
(i.e., outside stipulated time allowances) in performing procedures or obtaining samples due to 
legitimate clinical issues (eg, equipment technical problems, venous access difficulty, or patient 
defaulting or turning up late for an agreed scheduled procedure) will not be considered as 
protocol deviations but the CRU will still be required to notify the sponsor in writing via a 
file note.
Unless otherwise stated in subsections below, all samples collected for specified laboratory tests 
will be destroyed within 60 days of receipt of confirmed test results.  Certain samples may be 
retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards.
9.1.
Efficacy Assessments
In this study, the measures used to assess mechanisms of action of study treatments on glucose 
and lipid metabolism, appetite and food intake are considered efficacy measures. The planned 
assessments will be performed at baseline and at the end of the treatment period at 28 weeks.
All parameter calculations, when applicable, and analyses are described in Section 10.3
(Statistical Analyses) and in the statistical analysis plan (SAP).
9.1.1. Primary Efficacy Assessments and Procedures
The primary efficacy measure in the study is the change from baseline to Week 28 in total cDI
for comparison of tirzepatide with placebo.  Total cDI, which is a product of insulin secretion 
and insulin sensitivity, will be calculated from total insulin secretion rate during the 120-minute
hyperglycemic clamp determined from C-peptide concentrations using the deconvolution 
technique (ISR0-120min) divided by glucose area under the concentration versus time curve from 

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 55
LY3298176
0 to +120 minutes (total AUC from time zero to 120 minutes after start of the hyperglycemic 
clamp [AUC0-120min]) and insulin sensitivity expressed as M-value from hyperinsulinemic 
euglycemic clamp, respectively (Van Cauter et al. 1992; Sjaarda et al. 2012).
9.1.2. Secondary Efficacy Assessments and Procedures
The change in total cDI measure will also be used for secondary objective to compare tirzepatide 
with semaglutide.
Secondary efficacy measure to assess the effect of study treatments on glucose control:

fasting and postmeal glucose (total and incremental AUC from time zero to 240 minutes
after start of the meal [AUC0-240min]) during sMMTT;

hemoglobin A1c
Secondary efficacy measures to assess the effect of study treatments on cell function:

ISR0-8min from hyperglycemic clamp, defined as average incremental insulin secretion 
(incremental ISR AUC/time interval), during the 0 to +8 minute clamp period (first phase 
insulin secretion index);

ISR20-120min from hyperglycemic clamp, defined as average total insulin secretion (ISR 
AUC/time interval) during the +20 to +120-minute clamp period (second phase insulin 
secretion index);

ISR0-120min from hyperglycemic clamp, defined as average total insulin secretion (ISR 
AUC/time interval) during the entire clamp 120-minute period;

Insulin AUCarginine0-10min and AUCarginine0-30min from hyperglycemic clamp, defined as 
incremental insulin AUC/time interval, between +120 to +130 minute and +120 to 
+150 minute of clamp period, respectively;

β cell glucose sensitivity (GS) from hyperglycemic clamp, defined as 
[ISR80-120min-ISR10-0min]/[glucose increment from basal to final period]; mean glucose 
in the basal and final periods are calculated during the same time interval in which 
ISR10-0min and ISR80-120min are determined;

β cell GS from sMMTT, defined as the slope of the dose-response for insulin secretion 
versus glucose during the sMMTT, determined by modeling analysis;

ISR at fixed glucose concentration (ISRg) from sMMTT, defined as insulin secretion 
corresponding to a fixed glucose level representative of the basal value in the study 
population, and calculated from the dose-response;
Secondary efficacy measures to assess the effect of study treatments on insulin sensitivity:

hyperinsulinemic euglycemic clamp M-value, calculated from glucose infusion rate
(GIR) over the last 30 minutes, corresponding to steady-state (+150 to +180 minutes), 
corrected for space (DeFronzo et al. 1979);

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 56
LY3298176
Secondary efficacy measures to assess the effect of study treatments on glucagon secretion:

glucagon concentration at fasting and postmeal during sMMTT (total and incremental
AUC0-240min);
Secondary efficacy measures to assess the effect of study treatments on appetite and food intake:

ad libitum caloric intake with standardized meal served buffet style;
9.1.3. Exploratory Efficacy Assessments and Procedures
Exploratory efficacy measures to assess the effect of study treatments on glucose metabolism 
and turnover in adipose tissue:

glucose concentration in adipose tissue microdialysis from zero to 120 minutes
(microdialysis0-120min) during hyperglycemic clamp, estimated from the average of 
measurements from dialysate performed every 30 minutes starting at time point 0, and 
from changes in tissue blood flow; 

glucose concentration in adipose tissue microdialysis from zero to 240 minutes
(microdialysis0-240min) during sMMTT, estimated from the average of measurements 
from dialysate performed every 60 minutes starting at time point 0, and from changes in 
tissue blood flow;
Exploratory efficacy measures to assess the effect of study treatments on cell function:

basal insulin secretion rate (ISR-10-0min) from hyperglycemic clamp, defined as average 
insulin secretion (ISR AUC/time period) between -10 minutes and 0 minutes;

basal insulin concentration (basal insulin-10-0min) from hyperglycemic clamp, defined as 
average insulin concentration between -10 minutes and 0 minutes;

first phase insulin response (incremental AUC0-10min) from hyperglycemic clamp, 
defined as incremental insulin AUC between 0 minutes and +10 minutes;

second phase insulin response (total AUC20-120min) from hyperglycemic clamp, defined 
as total insulin AUC between +20 minutes and +120 minutes;

steady-state insulin secretion rate (total ISR80-120min) from hyperglycemic clamp,
defined as average total insulin secretion (ISR AUC/time interval) during the +80 minute 
to +120 minute clamp period;

total insulin response (total AUC0-120min) from hyperglycemic clamp, defined as total 
insulin AUC from time 0 minutes to +120 minutes;

basal ISR prior to sMMTT; defined as average insulin secretion at time point from -10 to 
0 minutes;

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 57
LY3298176

total insulin secretion rate (total ISR0-240min) from sMMTT; defined as average total 
insulin secretion (ISR AUC0-240min/time interval) during the entire sMMTT 240-minute
period; 

ISRg adjusted for basal potentiation (ISRgb) from sMMTT, defined as ISRg multiplied 
by the basal potentiation factor value;

rate sensitivity from sMMTT, determined by modeling analysis;

potentiation ratio (PFR) from sMMTT, defined as relative enhancement of ISR, as 
predicted by the dose-response from basal to +120 minute (PFR120), +180 minute,
(PFR180) and +240 minute (PFR240) time points, determined by modeling analysis;

basal insulin clearance (ICLb) prior to sMMTT, defined as the ratio of insulin secretion 
to insulin concentration at fasting prior to sMMTT;

insulin clearance during sMMTT (ICLm), defined as the ratio of insulin secretion to 
insulin concentration AUCs during the sMMTT;

ratio of GS from sMMTT and from hyperglycemic clamp (estimate of the incretin effect);

fasting proinsulin to insulin ratio;

insulinogenic index at 30 minutes (II30min), defined as the ratio of increments in insulin 
and glucose concentrations from time point 0 to +30 minutes during the sMMTT;

fasting and postmeal insulin (total and incremental AUC0-240min) during the sMMTT;

fasting and postmeal C-peptide (total and incremental AUC0-240min) during the sMMTT;
Exploratory efficacy measures to assess the effect of study treatments on insulin sensitivity:

hyperinsulinemic euglycemic M/I value, defined as the M-value divided by total insulin 
over the same time period (+150 to +180 minutes).

insulin resistance as measured by the HOMA2 method (HOMA2-IR) (Hill et al. 2013);

postprandial insulin sensitivity indices from sMMTT, as previously published (Matsuda
Index [Schlichtkrull et al. 1965; Matsuda and DeFronzo 1999; Service and O’Brien
2001], Oral Glucose Insulin Sensitivity [OGIS] Index [Mari et al. 2001], and Stumvoll 
Index [Stumvoll et al. 2000]);
Exploratory efficacy measures to assess the effect of study treatments on glucagon and 
pancreatic polypeptide (PP) secretion:

total glucagon AUC0-120min during hyperglycemic clamp;

incremental glucagon AUC/time interval after arginine stimulation from hyperglycemic 
clamp between +120 and +150 min;

glucagon/insulin ratio at fasting and during sMMTT, defined as ratio of total glucagon 
AUC0-240min and total insulin AUC0-240min;

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 58
LY3298176

PP concentration at fasting and postmeal (total and incremental AUC0-240min) during 
sMMTT;
Exploratory efficacy measures to assess the effect of study treatments on appetite (VAS) and 
food intake:

appetite sensations VAS scores for hunger, fullness, satiety, prospective food 
consumption, desire for specific foods, and the overall appetite score, assessed at fasting 
and during sMMTT (van Can et al. 2014; Flint et al. 2000; Flint et al. 2013);
Exploratory biomarkers to assess the effect of study treatments of lipid metabolism and turnover 
in adipose tissue:

plasma (triglycerides, β-hydroxybutyrate, pyruvate, lactate, free fatty acid (FFA), and 
glycerol) and adipose tissue (glucose, pyruvate, lactate, and glycerol
[microdialysis0-120min]) lipid parameters and blood flow during hyperglycemic clamp;

plasma (triglycerides, β-hydroxybutyrate, pyruvate, lactate, FFA, glycerol, 
apolipoprotein B-48 [ApoB-48], apolipoprotein B-100 [ApoB-100], apolipoprotein C-III
[ApoC-III], lipoprotein lipase [LPL]) and adipose tissue (glucose, pyruvate, lactate, FFA, 
and glycerol [microdialysis0-240min]) lipid parameters and blood flow at fasting and 
during sMMTT;

fasting concentration of leptin, adiponectin, insulin-like growth factor binding protein 
(IGFBP) 1 and 2;
Exploratory efficacy measures to assess the effect of study treatments on body composition, 
assessed with air displacement plethysmography, and body weight and waist circumference:

lean body mass (actual value and %);

body fat mass (actual value and %);

body weight;

waist circumference;
Exploratory efficacy measures to assess the effect of study treatments on energy expenditure and 
substrate utilization assessed with indirect calorimetry using ventilated hood system:

resting metabolic rate obtained by indirect calorimetry;

respiratory quotient, diet-induced thermogenesis, carbohydrate and fat oxidation rates 
before (-120 and -30 minutes) and 60, 120, 180, and 240 minutes after the start of 
sMMTT, obtained by indirect calorimetry;
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.

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 59
LY3298176
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 until the event resolves, stabilizes with appropriate diagnostic evaluation.  The 
frequency of follow-up evaluations of the AE is left to the discretion of the investigator.
The investigator will record all AE and SAE information in the eCRF. 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.  For each AE, the onset and duration, the seriousness 
and severity, and the actions taken will be recorded.
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, study device, or a study procedure, taking into account the 
disease, concomitant treatment or pathologies.
A “reasonable possibility” means that there is a potential cause and effect relationship between 
the 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.
9.2.1. Serious Adverse Events
An SAE is any AE from this study that results in one of the following:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

important medical events that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the patient or may require intervention to prevent 
one of the other outcomes listed in the definition above.
Study site personnel must alert the Lilly CRP/CP, or its designee, of any SAE as soon as 
practically possible.

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 60
LY3298176
Additionally, study site personnel must alert Lilly Global Patient Safety, or its designee, of any 
SAE within 24 hours of investigator awareness of the event via a sponsor-approved method.  If 
alerts are issued via telephone, they are to be immediately followed with official notification on 
study-specific SAE forms.  This 24-hour notification requirement refers to the initial SAE 
information and all follow-up SAE information.
Although all AEs are recorded in the eCRF after signing informed consent, SAE reporting to the 
sponsor begins after the 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 patients once they have 
discontinued from and/or completed the study (the patient summary CRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a patient has 
been discharged from the study, and he/she considers the event reasonably possibly related to the 
study treatment or study participation, the investigator must promptly notify Lilly.
Pregnancy (maternal or paternal exposure to 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.
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. Adverse Events of Special Interest
9.2.2.1.
Hypoglycemia
Patients will collect information on episodes of hypoglycemia starting immediately after their 
eligibility is confirmed until the last study visit (follow-up visit or ET visit).  For that purpose, 
patients will be trained between Visit 1 and Visit 2 about signs and symptoms of hypoglycemia, 
how to treat hypoglycemia, and how to collect appropriate information for each episode of 
hypoglycemia in the study according to Section 2 (Schedule of Activities).  Site personnel will 
enter this information into the eCRF at each visit.
Investigators should use the following definitions and criteria when diagnosing and categorizing 
an episode considered to be related to hypoglycemia (the PG values in this section refer to values 
determined by a laboratory or International Federation of Clinical Chemistry and Laboratory 
Medicine plasma-equivalent glucose meters and strips) (American Diabetes Association 2017):
Glucose Alert Value (Level 1):

Documented symptomatic hypoglycemia is defined as any time a patient feels 
that he or she is experiencing symptoms and/or signs associated with 
hypoglycemia, and has a PG level of ≤70 mg/dL (≤3.9 mmol/L).

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 61
LY3298176

Documented asymptomatic hypoglycemia is defined as any event not 
accompanied by typical symptoms of hypoglycemia, but with a measured PG 
≤70 mg/dL (≤3.9 mmol/L).

Documented unspecified hypoglycemia is defined as any event with no 
information about symptoms of hypoglycemia available, but with a measured PG 
≤70 mg/dL (≤3.9 mmol/L).
Clinically Significant Hypoglycemia (Level 2):

Documented symptomatic hypoglycemia is defined as any time a patient feels 
that he/she is experiencing symptoms and/or signs associated with hypoglycemia, 
and has a PG level of <54 mg/dL (<3.0 mmol/L).

Documented asymptomatic hypoglycemia is defined as any event not 
accompanied by typical symptoms of hypoglycemia, but with a measured PG 
<54 mg/dL (<3.0 mmol/L).

Documented unspecified hypoglycemia is defined as any event with no 
information about symptoms of hypoglycemia available, but with a measured PG 
<54 mg/dL (<3.0 mmol/L).
Severe Hypoglycemia (Level 3):

Severe hypoglycemia is defined as an episode with severe cognitive impairment 
requiring the assistance of another person to actively administer carbohydrate,
glucagon, or other resuscitative actions.  These episodes may be associated with 
sufficient neuroglycopenia to induce seizure or coma. Blood glucose 
measurements may not be available during such an event, but neurological 
recovery attributable to the restoration of BG to normal is considered sufficient 
evidence that the event was induced by a low BG concentration.  
Other Hypoglycemia Categories:

Nocturnal hypoglycemia is defined as any hypoglycemic event that occurs 
between bedtime and waking.
If a hypoglycemic event meets the criteria of severe, it needs to be recorded as serious on the AE 
CRF and reported to Lilly as an SAE.
To avoid duplicate reporting, all consecutive BG values ≤70 mg/dL (3.9 mmol/L) occurring 
within a 1-hour period may be considered to be a single hypoglycemic event (Weinberg et al. 
2010; Danne et al. 2013).
In each case of suspected or confirmed hypoglycemia, it is important that the event be properly 
categorized, the effect of the intervention be assessed, and the frequency of hypoglycemia be 
evaluated.  The role of dietary changes and physical exercise (or any other contributing factor) in 
the development of an event should be established.  The patient should receive additional 
education, if deemed appropriate.  The concomitant medications may need to be adjusted as 
outlined in in Section 7.4.1.1 (Management of Hypoglycemia) and Section 7.7
(Concomitant Therapy).

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 62
LY3298176
9.2.2.2.
Severe, Persistent Hyperglycemia
Data on episodes of severe, persistent hyperglycemia will be reported by the investigator during 
the study.  Events of interest related to hyperglycemia are those that require rescue therapy, per 
the following criteria:

The average FPG is greater than 240 mg/dL (13.3 mmol/L) over any 2-week period
between baseline and end of Week 12, as well as during the 4-week washout period for 
those discontinuing OAMs other than metformin use before randomization

The average FPG greater than 200 mg/dL (11.1 mmol/L) over any 2-week period
between Week 13 and end of the treatment period
Section 7.4.1.2 (Management of Hyperglycemia) provides treatment guidance for patients with 
severe, persistent hyperglycemia.
9.2.2.3.
Pancreatitis
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 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 IP(s), and will be discontinued from the 
study after completing all end-of-the trial procedures.  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 medical data, including concomitant medications, should be conducted to assess 
potential causes of pancreatitis.
Each case of AE of pancreatitis must be reported.  If typical signs and/or symptoms of 
pancreatitis are present and confirmed by laboratory values (lipase or amylase [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(s).
Each patient will have measurements of amylase and lipase, part of safety laboratory tests as 
shown in Section 2 (Schedule of Activities) to assess the effects of study treatments on 

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 63
LY3298176
pancreatic enzyme levels. Serial measures of pancreatic enzymes have limited clinical value for 
predicting episodes of acute pancreatitis in asymptomatic patients (Steinberg et al. 2017a; 
Steinberg et al. 2017b). Thus, further diagnostic follow-up of cases of asymptomatic pancreatic 
hyperenzymemia (lipase and/or pancreatic 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. If further diagnostic assessment due to asymptomatic hyperenzymemia will 
be warranted, it should follow Lilly standard algorithm for the monitoring of pancreatic enzymes 
(refer to Appendix 7).
All suspected cases of acute or chronic pancreatitis will be adjudicated by an independent 
clinical endpoint committee. In addition, all cases of pancreatic hyperenzymemia that undergo 
additional diagnostic follow-up, as well as the 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 possible, probable, or 
definite 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.
9.2.2.4.
Thyroid Malignancies and C-Cell Hyperplasia
Individuals with personal or family history of MTC and/or MEN 2 will be excluded from the 
study, as well as those with values above 20 pg/mL at screening.  The assessment of thyroid 
safety during the study will include reporting of any case of thyroid malignancy including MTC
and papillary carcinoma and measurements of calcitonin. This data will be captured in the 
specific section of the eCRFs.  The purpose of calcitonin measurements is to assess the potential 
of study treatments to affect thyroid C-cell function, which includes development of C-cell 
hyperplasia and neoplasms.  
Patients who develop calcitonin increases ≥50% of the mean of the screening value AND an 
absolute value ≥20 pg/mL and <35 pg/mL after randomization, will be asked to repeat the 
measurement within 1 month. If this repeat value is increasing (≥10% increase), the patient will 
be encouraged to undergo additional endocrine assessment and longer term follow-up by an 
endocrinologist to exclude a serious adverse effect on the gland.  Patients who develop calcitonin 
increases ≥50% of the mean of the screening value AND an absolute value ≥35 pg/mL after 
randomization will immediately undergo additional endocrine assessment and longer term 
follow-up by an endocrinologist. Study drug should be discontinued in situations when 
postrandomization calcitonin value is ≥35 ng/mL. If the calcitonin value decrease below 
35 ng/mL on repeat tests, study drug should be restarted if, in the opinion of the investigator, it is 
safe to do so.  If the increased calcitonin value 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 washout period.
For patients who require additional endocrine assessment because of increased calcitonin
concentration per criteria provided in this section, data from the follow-up assessment will be
collected in the specific section of the eCRF.

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 64
LY3298176
9.2.2.5.
Major Adverse Cardiovascular Events
Deaths and nonfatal cardiovascular AEs will be adjudicated by a committee of physicians 
external to Lilly with cardiology expertise.  The nonfatal cardiovascular AEs to be adjudicated 
include the following:  

myocardial infarction

hospitalization for unstable angina

hospitalization for heart failure

coronary interventions (such as coronary artery bypass graft or percutaneous coronary 
intervention)

cerebrovascular events, including cerebrovascular accident (stroke) and transient 
ischemic attack
9.2.2.6.
Supraventricular Arrhythmias and Cardiac Conduction Disorders
Treatment-emergent cardiac conduction disorders should be further evaluated.  Patients who 
develop any event from this group of disorders should undergo an ECG. Additional diagnostic 
tests to determine exact diagnosis should be performed, as needed. The specific diagnosis will 
be recorded as an AE. Events that meet criteria for serious conditions as described in 
Section 9.2.1 (Serious Adverse Events) must be reported as SAEs.
9.2.2.7.
Hypersensitivity Events
All allergic or hypersensitivity reactions will be reported by the investigator as either AEs or, if 
any serious criterion is met, as SAEs.  Additional data, such as type of reaction and treatment 
received, will be collected for any AEs or SAEs that the investigator deems related to study 
drug(s) via a CRF created for this purpose. Additional serum samples should also be collected as 
outlined in Section 9.6.1 (Immunogenicity Assessments). Study drug(s) should be temporarily 
interrupted in any individual suspected of having a severe or serious allergic reaction to study 
drug(s).  Study drug(s) may be restarted when/if it is safe to do so, in the opinion of the 
investigator.  If study drug(s) is permanently discontinued, the patient will receive another 
glucose-lowering treatment, judged by the investigator to be appropriate based on the patient’s 
clinical status, and will be discontinued from the study (Section 8.1.1 Permanent Discontinuation 
from Study Treatment).  
9.2.2.7.1. Injection Site Reactions
Injection site reactions will be collected on the eCRF created for these events. At the time of AE 
occurrence, samples will be collected for measurement of tirzepatide anti-drug antibody (ADA)
and tirzepatide concentration.
9.2.2.8.
Diabetic Retinopathy Complications
Treatment-emergent adverse events related to diabetic retinal complications will be assessed by 
an ophthalmologist and will include dilated fundoscopic examination.  
9.2.2.9.
Hepatobiliary Disorders
All events of treatment-emergent biliary colic, cholecystitis, or other suspected events related to 
gallbladder disease should be evaluated and additional diagnostic tests performed, as needed. In 

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 65
LY3298176
cases of elevated liver markers, hepatic monitoring should be initiated as outlined in 
Section 9.4.5.1 (Hepatic Safety) and Appendix 4.
9.2.2.10. Severe Gastrointestinal Adverse Events
Tirzepatide and semaglutide may cause severe GI AEs, such as nausea, vomiting, and diarrhea.  
Information about severe GI AEs as well as antiemetic/antidiarrheal use will be collected in the 
eCRF/AE form.  For detailed information concerning the management of GI AEs, refer to 
Section 7.7.1 (Management of Patients with Gastrointestinal Symptoms).
9.2.2.11. Acute Renal Events
Renal safety will be assessed based on laboratory renal functional assessment as well as 
assessment of AEs suggestive of acute renal failure or worsening of chronic renal failure.
Patients with GI AEs, including nausea, diarrhea, and vomiting are at increased risk of 
developing dehydration. Dehydration may cause a deterioration in renal function, including 
acute renal failure. Patients should be advised to notify investigators in case of severe nausea, 
frequent vomiting, or symptoms of dehydration.
9.2.2.12. Metabolic Acidosis, Including Diabetic Ketoacidosis
Ketoacidosis, a serious life-threatening condition requiring urgent hospitalization, has been 
reported rarely in patients with T2DM.  Patients who present with signs and symptoms consistent 
with severe metabolic acidosis should be assessed for ketoacidosis regardless of presenting BG 
levels, as ketoacidosis may be present even if BG levels are less than 250 mg/dL.  If ketoacidosis 
is suspected, prompt treatment should be instituted.  Treatment of ketoacidosis may require 
insulin, fluid, and carbohydrate replacement.
Lactic acidosis has been reported rarely in patients with T2DM associated with use of 
metformin, excessive alcohol intake and decrease renal function.  If lactic acidosis is suspected, 
metformin should be temporarily discontinued until the resolution of the event.
9.2.2.13. Amputation/Peripheral Revascularization
All cases of amputation and peripheral revascularization should be reported as an AE.
9.2.2.14. Major Depressive Disorder/Suicidal Ideation
The prevalence of depressive symptoms and disorders is increased in patients with T2DM
(Anderson et al. 2001).  Any AE of major depressive disorder or suicidal ideation should be 
reported.
9.2.3. Complaint Handling
Lilly collects product complaints on IPs and drug delivery systems used in clinical trials in order 
to ensure the safety of study participants, monitor quality, and to facilitate process and product 
improvements.
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.

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 66
LY3298176
9.3.
Treatment of Overdose
For patients with suspected or confirmed overdose with tirzepatide or semaglutide, there is no 
specific antidote. The patient should be watched for GI symptoms and hypoglycemia.
Treatment is supportive, depending on the patient’s symptoms.  For detailed information, refer to 
the IB for tirzepatide and package insert for semaglutide.
9.4.
Safety
9.4.1. Laboratory Tests
For each patient, laboratory tests to assess efficacy and safety of study treatments will be 
performed throughout the study and at the end of the safety follow-up period according to the 
schedule provided in Section 2 (Schedule of Activities).  Detailed list of laboratory analytes is 
provided in Appendix 2.
9.4.2. Vital Signs
For each patient, vital signs should be assessed according to Section 2 (Schedule of Activities).  
Blood pressure and pulse rate should be measured after at least 5 minutes in the supine position.  
Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or 
posture-induced symptoms.  Additional vital signs may be measured during each study period 
if warranted.
9.4.3. Electrocardiograms
For each patient, a single 12-lead digital ECG for safety will be collected according to Section 2
(Schedule of Activities).
Electrocardiograms must be recorded before collecting any blood samples.  Patients must be 
supine for at least 5 minutes before ECG collection and remain supine but awake during ECG 
collection.  Electrocardiograms may be obtained at additional times, when deemed clinically 
necessary.  All ECGs recorded should be stored at the investigational site.
Electrocardiograms will be interpreted by a qualified physician (the investigator or qualified 
designee) at the site as soon after the time of ECG collection as possible, and ideally while the 
patient is still present, to determine whether the patient meets study inclusion criteria at the 
relevant visit(s) and for immediate patient management, should any clinically relevant findings 
be identified.
If a clinically significant finding is identified (including, but not limited to, changes in QT/QTc 
interval from baseline) after enrollment, the investigator will determine if the patient can 
continue in the study.  The investigator, or qualified designee, is responsible for determining if 
any change in patient management is needed, and must document his/her review of the ECG 
printed at the time of collection.  Any clinically significant findings from ECGs that result in a 
diagnosis and that occur after the patient receives the first dose of study drug, should be reported 
to Lilly, or its designee, as an AE via eCRF.

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 67
LY3298176
9.4.4. Physical Examinations
Physical examinations and routine medical assessments will be conducted as specified in 
Section 2 (Schedule of Activities) and as clinically indicated.
9.4.5. Safety Monitoring
The Lilly CP or CRP/scientist will monitor safety data throughout the course of the study.
Lilly will review SAEs within time frames mandated by company procedures. The Lilly CP or
CRP will periodically review the following data:

regular trial-level safety reviews to assess the overall trends in safety data;

safety laboratory analytes;

serious and nonserious AEs, including AEs of special interest, and reported and 
adjudicated pancreatitis and cardiovascular events;
When appropriate, the Lilly CP or CRP will consult with the functionally independent Global
Patient Safety therapeutic area physician or clinical research scientist.
9.4.5.1.
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 creatinine kinase to confirm the 
abnormality and to determine if it is increasing or decreasing.  If the abnormality persists or 
worsens, clinical and laboratory monitoring should be initiated by the investigator based on 
consultation with the Lilly CP or CRP according to Lilly standard hepatic monitoring algorithm.  
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

elevated 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.
9.5.
Pharmacokinetics
At the visits and times specified in Section 2 (Schedule of Activities), 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 

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 68
LY3298176
collection and handling of blood samples will be provided by the sponsor. The actual date and 
24-hour clock time of each sampling will be recorded.
9.5.1. Bioanalysis
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor.
Concentrations of tirzepatide will be assayed using a validated liquid chromatography mass 
spectrometry method.  Analyses of samples collected from placebo-treated patients 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
The sample(s) will be stored for up to a maximum of 1 year after last patient visit for the study at 
a facility selected by the sponsor.  
The description of the procedures for obtaining the samples for PD parameters is detailed in 
Appendix 6.  Briefly, PD assessments will include hyperinsulinemic euglycemic clamps for 
measure of insulin sensitivity; hyperglycemic clamp to assess β cell function/insulin secretion 
and α cell function; arginine stimulation test; microdialysis; a sMMTT to assess α and β cell 
function, insulin sensitivity, nutrient utilization, and metabolic flexibility under physiological 
conditions; VAS to determine effects of study treatments on appetite sensations and desire for 
specific food; ad libitum food intake test to determine effect of study treatments on meal intake; 
plethysmography for body composition, and indirect calorimetry to determine metabolic rate.
9.6.1. Immunogenicity Assessments
For immunogenicity testing, venous blood samples of approximately 10 mL will be collected
from each patient according to Section 2 (Schedule of Activities) to determine antibody
production against tirzepatide. Additional samples may be collected if there is a possibility that
an AE is immunologically mediated. All samples for immunogenicity testing should have a 
time-matched sample for PK analysis.  Detailed instructions on the sample collections will be 
provided by Lilly or its designee.
Immunogenicity will be assessed by a validated assay designed to detect ADA in the presence of
tirzepatide. Antibodies may be further evaluated for their ability to neutralize the activity of
tirzepatide on GIP and GLP-1 receptor. Positive tirzepatide ADA samples will be tested for 
cross-reactivity against native GIP and GLP-1, and, if positive, will be tested for neutralizing 
antibodies against native GIP and/or GLP-1 on GIP and GLP-1 receptor respectively.
All patients will have an ADA sample measured at early discontinuation or at the follow-up visit. 
A risk-based approach will be used to monitor patients who develop treatment-emergent
anti-drug antibodies (TE-ADAs) as defined in Section 10.3.4 (Evaluation of Immunogenicity).
A clinically significant TE-ADA will be defined as any TE-ADA at the last visit with:

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 69
LY3298176

a high titer (1280) or an increasing titer from last measured value

an association with a moderate-to-severe injection site reaction or infusion-related
reaction
Patients who are TE-ADA positive at the last scheduled assessment or discontinuation visit will 
have additional samples taken at 3, 6, 9 (optional), and 12 months after the last assessment until 
the titer returns to within 2-fold of baseline titer or for up to 1 year, whichever is less.  Patients 
followed for at least 1 year since last dose who have not returned to baseline as defined above 
will be assessed for safety concerns.  If no clinical sequelae are recognized by the clinical team, 
then no further follow-up will be required.  Patients who have clinical sequelae that are
considered potentially related to the presence of TE-ADA may also be asked to return for
additional follow-up testing.  A PK sample may be collected at the follow-up immunogenicity 
assessment(s), if warranted and agreed upon by the investigator and sponsor.
Every attempt should be made to contact patients for the follow-up immunogenicity assessment;
however, if patients are unwilling or unable to return for the visit, this is not considered a
protocol violation.
Samples will be retained for a maximum of 15 years after the last patient visit or for a shorter
period, if local regulations and ERBs allow, at a facility selected by the sponsor. The duration
allows the sponsor to respond to future regulatory requests related to tirzepatide. Any samples
remaining after 15 years will be destroyed.
9.6.2. Body Weight and Waist Circumference
Weight and waist circumference will be measured according to Section 2 (Schedule of 
Activities). Patients will be weighed at approximately the same time in the morning, before 
dosing, and after an overnight fast and evacuation of the bowel and bladder, if possible. 
Wherever possible, the same scale will be used for all weight measurements throughout the study 
and the scale will not be moved or recalibrated. Waist circumference will also be measured on 
each scheduled occasion.  Both weight and waist circumference measurements will be recorded 
in the source document and the eCRF.
9.7.
Genetics
A blood sample will be collected for pharmacogenetic analysis as specified in the Schedule of 
Activities, 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.

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 70
LY3298176
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
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, PD, mechanism of action, variability of patient response (including safety), and 
clinical outcome.  Sample collection is incorporated into clinical studies to enable examination of 
these questions through measurement of biomolecules including DNA, RNA, proteins, lipids, 
and other cellular elements.
Serum and plasma samples for nonpharmacogenetic biomarker research will be collected at the 
times specified in the Schedule of Activities (Section 2) where local regulations allow.
Samples will be used for research on the drug target, disease process, variable response to 
tirzepatide or semaglutide, pathways associated with T2DM, mechanism of action of tirzepatide, 
and/or research method, or for validating diagnostic tools or assay(s) related to T2DM.
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, 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 or is commercially available.
9.9.
Health Economics
This section is not applicable for this study.

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 71
LY3298176
10.
Statistical Considerations and Data Analysis
10.1. Sample Size Determination
Approximately 117 patients are planned to be randomized so that 99 patients complete the clamp
procedures assuming 15% discontinuation rate. The 117 patients will be randomized in a 
3:3:2 ratio to QW tirzepatide 15 mg, semaglutide 1 mg, or placebo.  To power the study, 
simulated data from PK/PD models were used. The log-scale variability of cDI is estimated to 
be 0.586 from the model and previous trials and the log-scale treatment difference is estimated to 
be 0.913 (tirzepatide minus placebo) and 0.417 (tirzepatide minus semaglutide). This provides 
over 90% power to show greater cDI for tirzepatide relative to placebo and 85% power for the 
comparison of tirzepatide versus semaglutide.
10.2. Populations for Analyses
10.2.1. Study Participant Disposition
A detailed description of patient disposition will be provided at the end of the study.
10.2.2. Study Participant Characteristics
Demographic and baseline characteristics will be summarized by treatment group.
10.2.3. Treatment Compliance
No analyses of treatment compliance are planned.
10.3. Statistical Analyses
Statistical analysis of this study will be the responsibility of Eli Lilly and Company or 
its designee.
Pharmacodynamic analyses will be conducted on data from all patients who receive at least 
1 dose of the IP and have evaluable data.  Data will be censored once patients discontinue their
randomized treatment or initiate additional rescue treatment.
Safety analyses will be conducted for all enrolled patients, whether or not they completed all 
protocol requirements.
Additional exploratory analyses of the data will be conducted as deemed appropriate.
10.3.1. Safety Analyses
10.3.1.1. Clinical Evaluation of Safety
The incidence of AEs for each treatment will be presented by severity and by association with 
study drug as perceived by the investigator.  Adverse events reported to occur prior to study 
entry will be distinguished from those reported as new or increased in severity during the study.  
Each AE will be classified by the most suitable term from the medical regulatory dictionary.
All AEs and SAEs will be reported.

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 72
LY3298176
10.3.1.2. Statistical Evaluation of Safety
Safety parameters that will be assessed include safety laboratory parameters, vital signs, ECGs, 
TEAEs (including TEAEs of special interest), and SAEs.  The parameters will be listed, and 
summarized using standard descriptive statistics.  Additional analysis will be performed if 
warranted upon review of the data. All AEs related to study or protocol procedure will be listed, 
and if the frequency of events allows, will be also summarized using descriptive methodology.
Hypoglycemia rate will be summarized for each treatment group and visit as well as overall by 
mean, SD, median, minimum, and maximum.  Hypoglycemia incidence will be summarized for 
each treatment group and visit as well as overall by percent (%) and n.
Vital signs will be summarized with respect to observed values and change from baseline (Day 1, 
predose) by treatment at each time point using descriptive statistics. For change from baseline 
values, a mixed-model repeated-measure (MMRM) method with treatment, visit, 
and treatment-by-visit interaction as fixed effects, patient as random effect, and baseline 
as covariate will be used.  An unstructured variance-covariance matrix will be used to model 
within-patient effects.
10.3.2. Pharmacokinetic Analyses
10.3.2.1. Pharmacokinetic Parameter Estimation
Sparse PK samples will be collected across the 28-week treatment duration according to 
Section 2 (Schedule of Activities). Tirzepatide concentrations will be determined to support an 
understanding of tirzepatide exposure over the treatment duration to compare with expected 
tirzepatide PK.
10.3.2.2. Pharmacokinetic Statistical Inference
No summaries and analyses of PK parameters are planned.
10.3.3. Pharmacodynamic Analyses
10.3.3.1. Pharmacodynamic Parameter Estimation
All AUC measures will be calculated using the trapezoidal rule.
Incremental AUC measures use the time zero value relative to the AUC measured unless 
otherwise specified.
The following variables will be calculated using the collected insulin and C-peptide 
measurements to be then included in the SAP:
Clamp disposition index:

cDI is defined as the product of the M-value derived from the hyperinsulinemic 
euglycemic clamp over the last 30 minutes and total insulin secretion (ISR0-120min) 
derived from the insulin secretion rate based on C-peptide using the using the 
deconvolution technique divided by the total glucose AUC0-120min from the 
hyperglycemic clamp portion of the study

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 73
LY3298176
o
cDI = [(ISR0-120min)/(glucose AUC0-120min)] × M-value
Insulin sensitivity:

M-value from hyperinsulinemic euglycemic clamp is the measure of insulin sensitivity; 
M-value is defined as the GIR over the last 30 minutes of the clamp (+150 to +180 
minutes) minus a correction factor for non-constant glucose level divided by body weight 
(DeFronzo et al. 1979).
ISR based on C-peptide using the deconvolution technique (Van Cauter et al. 1992):

ISR during the first phase calculated by the deconvolution method between time zero and 
the 8th minute of the hyperglycemic clamp (ISR0-8min)

ISR during the second phase calculated by the deconvolution method between the 20th
and 120th minute of the hyperglycemic clamp (ISR20-120min)

Insulin secretion rate calculated by the deconvolution method between time zero and 
the 120th minute of the hyperglycemic clamp, (ISR0-120min)

β cell GS from hyperglycemic clamp, defined as [ISR80-120min-ISR-10-0min]/[glucose 
increment from basal to final period]; mean glucose in the basal and final periods are 
calculated during the same time interval in which ISR-10-0min and ISR80-120min are 
determined.
Insulin secretion based on insulin AUC:

Insulin secretion during the first phase defined as the incremental AUC under the insulin 
concentration curve between time zero and 10th minute of the hyperglycemic clamp 
(AUC0-10min)

Insulin secretion during the second phase defined as the AUC under the insulin 
concentration curve between 20th and 120th minute of the hyperglycemic clamp 
(AUC20-120min)

Insulin secretion defined as the AUC under the insulin concentration between time zero 
and 120th minute of the hyperglycemic clamp (AUC0-120min)
Ad libitum food intake: 

The VAS scales will be analyzed as continuous variables on the 0-100 scale for 
individual components.  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; Flint et al. 2000; Flint et al. 2013). The higher 
overall appetite score indicates less appetite, and the lower score indicates more appetite.
Other PD measures and exploratory measures will be described in the SAP.

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 74
LY3298176
10.3.3.2. Pharmacodynamic Statistical Inference
The primary endpoint (change from baseline in cDI) will be calculated by first log transforming 
the data then computing the change from baseline. The primary analysis will be analyzed using 
an analysis of covariance model which has effects for treatment and baseline of the parameter 
measured to compare tirzepatide versus placebo.
Other PD parameters that are scheduled to be measured only once postbaseline will be analyzed 
using a similar model with baseline of the covariate measured as the covariate and a fixed effect 
for treatment. Insulin secretion rate AUC measures, insulin AUC measures, and C-peptide AUC 
measures will be log-transformed prior to being analyzed.  If the incremental insulin AUC and 
incremental ISR AUC values are positive for all patients and highly skewed, a 
log-transformation may be considered.  Other parameters that are positive and skewed may be 
log-transformed.
Other PD parameters that are scheduled to be measured at least twice post baseline will be 
analyzed using an MMRM method, which will have effects for treatment, visit, 
treatment-by-visit interaction, and baseline of parameter measured.  An unstructured 
variance-covariance matrix will be used to model the within-patient effects.  
All analyses will show least squares means of each treatment and the treatment difference 
transformed back to the original scale as well as standard error and 95% confidence interval (CI).  
All tests will be done at the 2-sided 0.05 α level unless otherwise specified.
Tirzepatide will be claimed to have a statistically significantly greater change in cDI than 
placebo if lower limit of the 2-sided CI of tirzepatide – placebo on the log scale is greater than 0, 
and a significantly greater change in cDI than semaglutide if the lower limit of the 2-sided CI of 
tirzepatide – semaglutide on the log scale is greater than 0.
10.3.4. Evaluation of Immunogenicity
The frequency and percentage of patients with preexisting ADA and with TE-ADA+ to 
tirzepatide will be tabulated. Treatment-emergent ADAs are defined as those with a titer 2-fold 
(1 dilution) greater than the minimum required dilution if no ADAs were detected at baseline 
(treatment-induced ADA) or those with a 4-fold (2 dilutions) increase in titer compared to 
baseline if ADAs were detected at baseline (treatment-boosted ADA). The minimum required 
dilution of the ADA assay is 1:10.  For the TE-ADA+ patients the distribution of maximum titers 
will be described.  The frequency of neutralizing antibodies will also be tabulated in TE-ADA+ 
patients.
The relationship between the presence of antibodies and the PK parameters and PD response
including safety and efficacy to tirzepatide may be assessed.
10.3.5. Interim Analyses
No interim analyses are planned for this study although blinded data may be reviewed 
periodically on an ongoing basis. If an unplanned interim analysis is deemed necessary, the 

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 75
LY3298176
appropriate Lilly CP, CRP/investigator, or designee, will consult with the appropriate medical 
director or designee to determine whether it is necessary to amend the protocol.

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 76
LY3298176
11.
References
[ADA] American Diabetes Association. Glycemic targets. Sec. 6. In Standards of Medical Care 
in Diabetes—2017. Diabetes Care. 2017;40(suppl 1):S48-S56.
[ADA] American Diabetes Association. 6. Glycemic targets: Standards of Medical Care in 
Diabetes—2018. Diabetes Care. 2018;41(suppl 1):S55–S64.
Ahmann AJ, Capehorn M, Charpentier G, Dotta F, Henkel E, Lingvay I, Holst AG, Annett MP, 
Aroda VR. Efficacy and safety of once-weekly semaglutide versus exenatide ER in subjects 
with type 2 diabetes (SUSTAIN 3): a 56-week, open-label, randomized clinical trial. Diabetes 
Care. 2018;41(2), 258-266.
Anderson RJ, Freedland KE, Clouse RE, Lustman PJ. The prevalence of co-morbid depression in 
adults with diabetes: a meta-analysis. Diabetes Care. 2001;24(6):1069–1078.
Arner P, Bolinder J, Eliasson A, Lundin A. Ungerstedt U. Microdialysis of adipose tissue and 
blood for in vivo lipolysis studies. Am J Physiol. 1988;255(5 Pt 1):E737-42.
Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology.
2007;132(6):2131-2157.
Banks PA, Freeman ML. Practice guidelines in acute pancreatitis. Am J Gastroenterol.
2006;101(10):2379-2400.
Benesch C, Heise T, Klein O, Heinemann L, Arnolds S. How to assess the quality of glucose 
clamps? Evaluation of clamps performed with ClampArt, a novel automated clamp device. 
J Diabetes Sci Technol. 2015;9(4):792-800.
Bunck MC, Diamant M, Cornér A, Eliasson B, Malloy JL, Shaginian RM, Deng W, Kendall 
DM, Taskinen MR, Smith U, Yki-Järvinen H, Heine RJ. One-year treatment with exenatide 
improves beta-cell function, compared with insulin glargine, in metformin-treated type 2 
diabetic patients: a randomized, controlled trial. Diabetes care 2009;32(5):762-768.
Coppack SW, Fisher RM, Humphreys SM, Clark ML, Pointon JJ, Frayn KN. Carbohydrate 
metabolism in insulin resistance: glucose uptake and lactate production by adipose and 
forearm tissues in vivo before and after a mixed meal. Clin Sci (Lond). 1996;90(5):409-415.
Coskun T, Sloop K, Loghin C, Alsina-Fernandez J, Urva S, Bokvist KB, Cui X, Briere DA, 
Cabrera O, Roell WC, Kuchibhotla U, Moyers JS, Benson CT, Gimeno RE, D’Alessio DA, 
Haupt A. LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 
diabetes mellitus: From discovery to clinical proof of concept. Molecular metabolism.
2018;18:3-14.
Danne T, Philotheou A, Goldman D, Guo X, Ping L, Cali A, Johnston P. A randomized trial 
comparing the rate of hypoglycemia – assessed using continuous glucose monitoring – in 
125 preschool children with type 1 diabetes treated with insulin glargine or NPH insulin (the 
PRESCHOOL study). Pediatr Diabetes. 2013;14(8):593-601.
DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin
secretion and resistance. Am J Physiol. 1979;237(3):E214-E223.
Dempster P and Aitkens S. A new air displacement method for the determination of human body 
composition. Med Sci Sports Exerc. 1995;27(12):1692–1697.

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 77
LY3298176
[FAO] Food and Nutrition Technical Report Series No. 1, Human energy requirements, Report 
of a joint FAO/WHO/UNU Expert Consultation, Rome 2001.
Felländer G, Linde B, Bolinder J. Evaluation of the microdialysis ethanol technique for 
monitoring of subcutaneous adipose tissue blood flow in humans. Int J Obes.
1996;20:220-226.
Ferrannini E. The theoretical bases of indirect calorimetry: a review. Metabolism. 1988; 
37(3):287-301.
Ferrannini E and Mari A. β-Cell function in type 2 diabetes. Metabolism.
2014;63(10):1217-1227.
Fields DA, Hunter GR, Goran MI. Validation of the BOD POD with hydrostatic weighing: 
influence of body clothing. Int J Obes. 2000; 24:200-205.
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.
2000;24:38-48.
Flint A, Kapitza C, Zdravkovic M. The once-daily human GLP-1 analogue liraglutide impacts 
appetite and energy intake in patients with type 2 diabetes after short-term treatment. Diabetes 
Obes Metab. 2013;15:958-962.
Frayn KN. Calculation of substrate oxidation rates in vivo from gaseous exchange. J Appl. 
Physiol. 1983;55(2):628-634.
Frias JP, Nauck MA, Van J, Kutner ME, Cui X, Benson C, Urva S, Gimeno RE, Milicevic Z, 
Robins D, Haupt A. Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor 
agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active 
comparator-controlled phase 2 trial. The Lancet. 2018;392(10160): 2180-2193.
Hannon TS, Kahn SE, Utzschneider KM, Buchanan TA, Nadeau KJ, Zeitler PS, Ehrmann DA, 
Arslanian SA, Caprio S, Edelstein SL, Savage PJ, Mather KJ for the RISE Consortium. 
Review of methods for measuring β-cell function: Design considerations from the Restoring 
Insulin Secretion (RISE) Consortium. Diabetes Obes Metab. 2018 ;20:14-24.
Hill NR, Levy JC, Matthews DR. Expansion of the homeostasis model assessment of β-cell 
function and insulin resistance to enable clinical trial outcome modeling through the 
interactive adjustment of physiology and treatment effects: iHOMA2. Diabetes Care.
2013;36(8):2324-30.
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.
Kuhlenkötter M, Heise T, Benesch C. Improved algorithm for automated glucose clamps. 
Diabetes Technol Ther. 2017;19(2):124-130.
Mari A, Pacini G, Murphy E, Ludvik B, Nolan J. A model-based method for assessing insulin 
sensitivity from the oral glucose tolerance test. Diabetes Care. 2001;24:539-548.

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 78
LY3298176
Matsuda M, DeFronzo RA. Insulin sensitivity indices obtained from oral glucose tolerance 
testing: comparison with the euglycemic insulin clamp. Diabetes Care. 1999;22(9):1462-70.
Müller MJ, Bosy-Westphal A, Klaus S, Kreymann G, Lührmann PM, Heuhäuser-Berthold M, 
Noack R, Pirke KM, Platte P, Selberg O, Steiniger J. World Health Organization equations 
have shortcomings for predicting resting energy expenditure in persons from a modern, 
affluent population: generation of a new reference standard from a retrospective analysis of a 
German database of resting energy expenditure. Am J Clin Nutr. 2004;80(5):1379-90.
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.
Ozempic [patient leaflet]. Denmark; Novo Nordisk Inc.; 2018.
Pratley RE, Aroda VR, Lingvay I, Ludemann J, Andreassen C, Navarria A, Viljoen A. 
Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): a 
randomised, open-label, phase 3b trial. The Lancet Diabetes & Endocrinology.
2018;6(4):275-286.
Schlichtkrull J, Munck O, Jersild M. The M-value, an index of blood-sugar control in diabetics. 
Acta Med Scand. 1965;177:95-102.
Service FJ, O’Brien PC. The relation of glycaemia to the risk of development and progression of 
retinopathy in the diabetic control and complications trial. Diabetologia.
2001;44(10):1215-1220.
Shah SS, Ramirez CE, Powers AC, Yu C, Shibao CA, Luther JM. Hyperglycemic clamp-derived 
disposition index is negatively associated with metabolic syndrome severity in obese subjects. 
Metabolism. 2016;65(6):835-42.
Sjaarda, LG, Bacha F, Lee S, Tfayli H, Andreatta E, Arslanian S. Oral disposition index in obese 
youth from normal to prediabetes to diabetes: relationship to clamp disposition index. J 
Pediatr. 2012;161(1):51-7.
Steinberg WM, Buse JB, Ghorbani MLM, Ørsted DD, Nauck MA; LEADER Steering 
Committee; LEADER Trial Investigators. Amylase, lipase, and acute pancreatitis in people 
with type 2 diabetes treated with liraglutide: results from the LEADER Randomized Trial. 
Diabetes Care. 2017a;40(7):966-972.
Steinberg WM, Rosenstock J, Wadden TA, Donsmark M, Jensen CB, DeVries JH. Impact of 
liraglutide on amylase, lipase, and acute pancreatitis in participants with overweight/obesity 
and normoglycemia, prediabetes, or type 2 diabetes: secondary analyses of pooled data from 
the SCALE clinical development program. Diabetes Care. 2017b;40(7):839-848.
Stumvoll M, Mitrakou A, Pimenta W, Jenssen T, Yki-Jarvinen H, Van Haeften T, Renn W, 
Gerich J. Use of the oral glucose tolerance test to assess insulin release and insulin sensitivity. 
Diabetes Care. 2000;23:295-301.
Utzschneider KM, Prigeon RL, Faulenbach MV, Tong J, Carr DB, Boyko, EJ, Leonetti DL, 
McNeely MJ, Fujimoto WY, Kahn SE. Oral disposition index predicts the development of 
future diabetes above and beyond fasting and 2-h glucose levels. Diabetes care.
2009;32(2):335-341.

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 79
LY3298176
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. 2014;38(6):784-93.
Van Cauter E, Mestrez F, Sturis J, Polonsky KS. Estimation of insulin secretion rates from 
C-peptide levels: comparison of individual and standard kinetic parameters for C-peptide 
clearance. Diabetes. 1992;41(3): 368-377.
Weinberg ME, Bacchetti P, Rushakoff RJ. Frequently repeated glucose measurements 
overestimate the incidence of inpatient hypoglycemia and severe hyperglycemia. J Diabetes 
Sci Technol. 2010;4(3):577-582.

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 80
LY3298176
12.
Appendices

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 81
LY3298176
Appendix 1.
Abbreviations and Definitions

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 82
LY3298176
Term
Definition
ADA
anti-drug 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
ApoB-48
apolipoprotein B-48
ApoB-100
apolipoprotein B-100
ApoC-III
apolipoprotein C-III
AST
aspartate aminotransferase
AUC
area under the concentration versus time curve
AUC0-10min
first phase insulin response
AUC0-120min
AUC from time zero to 120 minutes after start of the meal
AUC0-240 min
AUC from time zero to 240 minutes after start of the meal
AUC20-120min
second phase insulin response
AUCarginine0-10min
AUC in response to arginine from time zero to 10 minutes
AUCarginine0-30min
AUC in response to arginine from time zero to 30 minutes
AUCglucose0-120min
AUC of glucose from time zero to 120 minutes
basal 
insulin-10-0min
average insulin concentration between -10 minutes and 0 minutes
BG
blood glucose
blinding
A procedure in which one or more parties to the study are kept unaware of the treatment 
assignment(s).  Unless otherwise specified, blinding will remain in effect until final 
database lock.
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the patient is not, or vice versa, or when the sponsor is aware of the treatment 
but the investigator and/or his staff and the patient are not.  A double-blind study is one in 
which neither the patient nor any of the investigator or sponsor staff who are involved in the 
treatment or clinical evaluation of the patients is aware of the treatment received.

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 83
LY3298176
cDI
clamp disposition index
CI
confidence interval
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 requirements, and 
the applicable regulatory requirements.
confirmation
A process used to confirm that laboratory test results meet the quality requirements defined 
by the laboratory generating the data and that Lilly is confident that results are accurate.  
Confirmation will either occur immediately after initial testing or will require that samples 
be held to be retested at some defined time point, depending on the steps required to obtain 
confirmed results.
COVID-19
Coronavirus Disease 2019
CP
Clinical Pharmacologist
CRF/eCRF
case report form/electronic case report form
CRP
Clinical Research Physician:  Individual responsible for the medical conduct of the study.  
Responsibilities of the CRP may be performed by a physician, clinical research scientist, 
global safety physician or other medical officer.
CRU
clinical research unit
CT
computed tomography
DPP-IV
dipeptidyl peptidase-4
ECG
electrocardiogram
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 representative(s).
ERB
ethical review board
ET
early termination
FFA
free fatty acid
FPG
fasting plasma glucose
FSH
follicle-stimulating hormone
GI
gastrointestinal
GIP
glucose-dependent insulinotropic polypeptide

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 84
LY3298176
GIPR
glucose-dependent insulinotropic polypeptide receptor
GIPRA
glucose-dependent insulinotropic polypeptide receptor agonism
GIR
glucose infusion rate
GLP-1
glucagon-like peptide 1
GLP-1R
glucagon-like peptide 1 receptor
GLP-1RA
glucagon-like peptide 1 receptor agonism
GS
glucose sensitivity
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HOMA2
Homeostatic Model Assessment of Insulin Resistance
HOMA2-IR
insulin resistance as measured by the HOMA2 method
IB
Investigator’s Brochure
ICF
informed consent form
ICLb
basal insulin clearance
ICLm
insulin clearance during sMMTT
IGFBP
insulin-like growth factor binding protein
II30min
insulinogenic index at 30 minutes
Imean
average steady-state plasma insulin response
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.
interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
Investigational 
product (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.

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 85
LY3298176
ISI
insulin sensitivity index
ISR
insulin secretion rate
ISR-10-0min
basal insulin secretion rate
ISR0-8min
first phase insulin secretion rate
ISR0-120min
total insulin secretion rate from hyperglycemic clamp
ISR20-120min
second phase insulin secretion rate
ISR0-240min
total insulin secretion rate during sMMTT
ISR80-120min
steady-state insulin secretion rate
ISRg
ISR at fixed glucose concentration
ISRgb
ISR at fixed glucose concentration adjusted for basal potentiation
IV
intravenous
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.
LPL
lipoprotein lipase
MAD
multiple-ascending dose
MCR
metabolic clearance rate of glucose
MEN 2
multiple endocrine neoplasia syndrome type 2
microdialysis0-120
min
microdialysis from zero to 120 minutes
microdialysis0-240
min
microdialysis from zero to 240 minutes
MMRM
mixed-model repeated-measure
MRI
magnetic resonance imaging
MTC
medullary thyroid carcinoma
OAM(s)
oral antihyperglycemia medication(s)
OGIS
Oral Glucose Insulin Sensitivity
PFR
potentiation ratio
PFR120
potentiation ratio from sMMTT, defined as relative enhancement of ISR, as predicted by 
the dose-response from basal to +120 minute

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 86
LY3298176
PFR180
potentiation ratio from sMMTT, defined as relative enhancement of ISR, as predicted by 
the dose-response from basal to +180 minute
PFR240
potentiation ratio from sMMTT, defined as relative enhancement of ISR, as predicted by 
the dose-response from basal to +240 minute
PG
plasma glucose
PK/PD
pharmacokinetic/pharmacodynamic
PP
pancreatic polypeptide
QT
QT interval
QTc
QT interval corrected for heart rate
QW
once weekly
randomize
the process of assigning patients to an experimental group on a random basis
SAD
single-ascending dose
SAE
serious adverse event
SAP
statistical analysis plan
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.
SGLT-2
sodium-glucose transport protein 2
sMMTT
standardized mixed-meal tolerance test
SMPG
self-monitoring of plasma glucose
SAP
statistical analysis plan
SUSAR
suspected unexpected serious adverse reaction
T2DM
type 2 diabetes mellitus
TBL
total bilirubin level
TE-ADA
treatment-emergent anti-drug antibody
TEAE
treatment-emergent adverse event:  Any untoward medical occurrence that emerges during 
a defined treatment period, having been absent pretreatment, or worsens relative to the 
pretreatment state, and does not necessarily have to have a causal relationship with 
this treatment

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 87
LY3298176
ULN
upper limit of normal
VAS
visual analog scale
WOCBP
woman of childbearing potential

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 88
LY3298176
Appendix 2.
Clinical Laboratory Tests
Safety Laboratory Tests
Hematology
Clinical Chemistry (fasting)
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Bicarbonate
Mean cell volume 
Chloride
Mean cell hemoglobin 
Calcium
Mean cell hemoglobin concentration 
Phosphorus
Leukocytes (WBC)
Absolute counts of:
Neutrophils
Glucose (fasting)
Blood urea nitrogen
Uric acid
Lymphocytes
Total protein
Monocytes
Albumin
Eosinophils
Total bilirubin
Basophils
Alkaline phosphatase
Platelets
Hemoglobin A1c
Alanine aminotransferase
Aspartate aminotransferase
Lipase (fasting)
Amylase
Urinalysis
Endocrine
Specific gravity
Follicle-stimulating hormonea
pH
Calcitonin
Protein
Glucose
Serologyb
Ketones
Hepatitis B surface antigen
Bilirubin
Hepatitis C antibody, hepatitis C RNAc
Urobilinogen
HIV antibody
Blood
Leukocytes
Pregnancy test (urine, serum)d
Microscopya
Drug and alcohol screene
Abbreviations:  HIV = human immunodeficiency virus; RBC = red blood cells; WBC = white blood cells.
Note:  Results of these assays will be validated by the central or local laboratory at the time of testing. Additional
tests may be performed or auto-calculated by the laboratory as part of its standard panel that cannot be removed.  
Some of the above parameters are calculated from measured values. Omission of calculated values will not be
considered a protocol violation.
a
If clinically indicated, per investigator’s discretion.
b
At screening only (unless previously performed within the last 6 months with reports available for review).
c
See exclusion criteria (Section 6.2) for further details.
d
Pregnancy tests (females, as appropriate) will be performed for women of childbearing potential.  Serum 
pregnancy test is done at screening and follow-up and urine pregnancy is performed at all other visits.
e
Performed at screening.  Drugs for drug screen include amphetamine, barbiturates, benzodiazepines, cannabis, 
cocaine, methadone, methamphetamine, opiates, phencyclidine, and tricyclic antidepressants. Procedures may be 
repeated throughout the study as deemed necessary by the investigator.

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 89
LY3298176
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 informed consent (ICF)
prior to the performance of any protocol procedures and prior to the administration of 
investigational product.

answering any questions the patient may have throughout the study and sharing in a 
timely manner any new information that may be relevant to the patient’s willingness to 
continue his or her participation in the study.

providing a copy of the ICF to the participant or the participant’s legal representative and 
retaining a copy on file.
Recruitment
Lilly or its designee is responsible for the central recruitment strategy for patients.  Individual 
investigators may have additional local requirements or processes.  Study-specific recruitment 
material should be approved by Lilly.
Ethical Review
The investigator must give assurance that the ethical review board (ERB) was properly 
constituted and convened as required by International Council for Harmonization (ICH)
guidelines and other applicable laws and regulations.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site(s).  Lilly or its representatives must approve the ICF 
before it is used at the investigative site(s).  All ICFs must be compliant with the ICH guideline 
on good clinical practice (GCP).
The study site’s ERB(s) should be provided with the following:

the current IB and updates during the course of the study

ICF

relevant curricula vitae

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 90
LY3298176
Regulatory Considerations
This study will be conducted in accordance with the protocol and with:
1) consensus ethics principles derived from international ethics guidelines, 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences International Ethical Guidelines 
2) applicable ICH GCP Guidelines
3) applicable laws and regulations
Some of the obligations of the sponsor will be assigned to a third party organization.
Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
Final Report Signature
The final report coordinating investigator or designee will sign the clinical study report for this 
study, indicating agreement that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study.
The investigator with the most enrolled patients will serve as the 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 eCRFs, and study procedures.

make periodic visits to the study site.

be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax.

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 91
LY3298176

review and evaluate eCRF data and/or use standard computer edits to detect errors in data 
collection.

conduct a quality review of the database.
In addition, Lilly or its representatives will periodically check a sample of the patient data 
recorded against source documents at the study site.  The study may be audited by Lilly and/or 
regulatory agencies at any time.  Investigators will be given notice before an audit occurs.
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to the original source 
documents.
Data Collection Tools/Source Data
An electronic data capture system will be used in this study.  The site must define and retain all 
source records and must maintain a record of any data where source data are directly entered into 
the data capture system.
Data Protection
Data systems used for the study will have controls and requirements in accordance with local 
data protection law.
The purpose and use of patient personal information collected will be provided in a written 
document to the patient by the sponsor.
Study and Site Closure
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly or its designee, the investigator, or the ERB 
of the study site judges it necessary for medical, safety, regulatory, or other reasons consistent 
with applicable laws, regulations, and GCP.
Discontinuation of the Study
The study will be discontinued if Lilly or its designee judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP.

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 92
LY3298176
Appendix 4.
Hepatic Monitoring Tests for 
Treatment-Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with patients in consultation with Lilly or its designee CRP.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin Time
WBC
Prothrombin Time, INR
Neutrophils
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B Core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Conjugated bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear antibodya
AST
Alkaline Phosphatase Isoenzymesa
GGT
CPK 
Anti-smooth muscle antibody (or anti-actin 
antibody)a
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatinine 
phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalized
ratio; RBC = red blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 93
LY3298176

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 94
LY3298176

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 95
LY3298176

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 96
LY3298176
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-GPGT Sampling Summary
Purpose
Blood Volume 
per Sample (mL)
Number of Blood 
Samples
Total Volume (mL)
Screening testsa
10
1
10
Safety laboratory tests (including fasting 
glucose and hemoglobin A1c)a
6
4
24
Tirzepatide pharmacokinetics 
3
6
18
Immunogenicity
10
5
50
Pharmacodynamics
β-hydroxybutyrate/FFA during sMMTT
2
6 x 2
24
β-hydroxybutyrate/FFA during 
hyperglycemic clamp
2
6 x 2
24
Calcitonin
2
3
6
Fasting insulin/C-peptide
2.5
2
5
Insulin/C-peptide during sMMTT
2.5
9 x 2
45
Insulin/C-peptide during clamps
2.5
33 x 2
165
Glucagon
2
2
4
Glucagon during sMMTT
2
6 x 2
24
Glucagon during clamps
2
33 x 2
132
Glucose during sMMTT
0.2
11 x 2
4.4
Glucose during clamps
0.2
34  x 2
13.6
Glucose for clamp calibration
0.2
12 x 2
4.8
Glycerol during sMMTT
2
6 x 2
24
Glycerol during clamp
2
6 x 2
24
IGFBP 1 and 2 
5
2
10
IGFBP 1 and 2 during sMMTT
5
1 x 2
10
Lactate during sMMTT 
2
6 x 2
24
Lactate during clamp
2
6 x 2
24
Leptin, Adiponectin
4
2
8
Leptin, Adiponectin during sMMTT
4
1 x 2
8
Lipid panel 
-
-
-
TG on Days -1 and 193
2.5
6 x 2
30
TG, total cholesterol, LDL-C, VLDL-C, 
HDL-C 
7.5
2
15
TG, total cholesterol, LDL-C, VLDL-C, 
HDL-C during sMMTT 
7.5
6 x 2
90
Apo B-48, Apo B-100, Apo C-III
3.5
2
7
Apo B-48, Apo B-100, Apo C-III during 
sMMTT 
3.5
6 x 2
42
LPL
2.5
2
5

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 97
LY3298176
Purpose
Blood Volume 
per Sample (mL)
Number of Blood 
Samples
Total Volume (mL)
LPL during sMMTT 
2.5
6 x 2
30
PP
5
2
10
PP during sMMTT
5
6 x 2
60
Proinsulin
2.5
2
5
Proinsulin during sMMTT
2.5
1 x 2
5
Pyruvate during sMMTT
2
6 x 2
24
Pyruvate during clamp
2
6 x 2
24
Pharmacogenetics
10
1
10
Pregnancy test (follow-up/ET)
2
1
2
Nonpharmacogenetic stored sample
10
3
30
Total
1074.8
Total for clinical purposes [rounded up to nearest 10 mL]
1080
Abbreviations:  ApoB-48 = apolipoprotein B-48; ApoB-100 = apolipoprotein B-100; ApoC-III = apolipoprotein 
C-III; EDTA = ethylenediaminetetraacetic acid; ET = early termination; FFA = free fatty acid;
HDL-C = high-density lipoprotein cholesterol; IGFBP = insulin-like growth factor-binding protein; 
LDL-C = low-density lipoprotein cholesterol; LPL = lipoprotein lipase; PP = pancreatic polypeptide; 
sMMTT = standardized mixed-meal tolerance test; TG = triglycerides; VLDL-C = very low-density lipoprotein
cholesterol.
a
Additional samples may be drawn if needed for safety purposes.

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 98
LY3298176
Appendix 6.
Assessments of Glucose and Lipid 
Metabolism and Appetite and Food Intake
6.1.
Hyperinsulinemic Euglycemic Clamp for Assessment of Insulin 
Sensitivity
Hyperinsulinemic euglycemic clamp (HEC) technique for assessment of insulin sensitivity has 
been previously described (De Fronzo et al. 1979). The aim of the HEC is to maintain glucose 
concentrations close to a predefined target during a constant insulin infusion rate (IIR), by means 
of variable glucose infusion rate (GIR), to reach the steady-state conditions. The varying GIR 
reflects the pharmacodynamic (or glucodynamic) effects of the insulin. After the steady-state 
conditions are achieved, the parameters of interest (insulin, C-peptide, and glucagon) are 
measured over a period of the next 30 minutes. The steady-state is defined as stable GIR under 
stable IIR over a period of time. The M-value is calculated from the parameters obtained during 
the steady-state period of the HEC. The parameters that will be obtained are listed in Section 9.1
(Efficacy Assessments).
Patients will be trained and informed to strictly follow their dietary plan during the last 3 days 
prior to admission to the CRU. The night before the clamp procedure, the patients will be served 
a standardized evening meal.  Investigator will ensure that the patient is fasting from 23:00 the 
night before and until the end of the clamp procedure (12 hour fast).
The HEC will be performed by means of an automated clamp system (ClampArt™) that
performs continuous blood glucose (BG) measurements, and controls a variable glucose infusion 
adjusted to keep the BG concentration at a constant level (Benesch et al. 2015; Kuhlenkötter et al. 
2017).  ClampArt automatically calculates the appropriate adjustments of the GIR using an
algorithm based on the actual measured BG concentration and the grade of variability in the 
preceding 1 minute.
The patients will be connected to ClampArt at approximately 8:00 AM. The patient will remain 
fasting and will stay in a supine or semi-supine position during HEC and will be allowed to 
consume water ad libitum during the procedure, but will otherwise have no oral intake.
For sampling of arterialised venous blood for ClampArt BG concentration measurements, a 
catheter will be inserted into a vein of a hand or forearm. This hand will remain under a heating 
pad (about 55oC) throughout the clamp procedure. The heating of the hand results in an 
arterialisation of the venous blood, that is, increasing oxygen and glucose content to values 
comparable to arterial blood mediated by the vasodilator effect from heating. A low dose 
heparin solution (100 U heparin/mL [10,000 U heparin/100 mL saline]) will be used to prevent 
blood clotting in the ClampArt double lumen catheter. The heparin solution will be taken up
with blood used for ClampArt BG measurement in the other lumen of the catheter. A second 
catheter will be inserted into a vein of the same arm for obtaining blood samples. This cannula
will be kept patent by use of a mandrin/stylet. A third catheter will be inserted into a vein of the 

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 99
LY3298176
contralateral arm for the infusion of insulin (50 IU of regular insulin in 49 mL isotonic saline and 
1 mL of the patient's own blood) or 20% glucose solution to maintain the defined HEC BG target 
level of 5.5 mmol/L (100 mg/dL). The GIR necessary to keep the BG concentration at the clamp 
target level will be adjusted and recorded every minute. Frequently or at least every 30 minutes 
throughout the glucose clamp, BG measurements for safety glucose monitoring and for 
verification of ClampArt measurements will be performed using the Super GL Glucose Analyzer.
At nominal time t = 0 min, immediately after blood sampling, a primed infusion of regular 
insulin will be established starting with an infusion rate of 255.2 mU/min/m2 which will be 
adapted from t = 0 min to t = 10 min (Table GPGT.4). The prime is followed by a constant 
regular insulin infusion at a rate of 80 mU/min/m2 lasting until t = 180 min.
Blood samples for analysis of glucose, insulin, C-peptide, and glucagon will be drawn according 
to sampling scheme in Table GPGT.4.
Table GPGT.4.
Time Schedule for Hyperinsulinemic Euglycemic Clamp
Approximate 
Hour
Nominal 
Timea
(Minutes)
Target 
Clamp 
Level
Sampling for Analysis
Comment
Insulin 
Infusion
[mU·min-
1·m-2]
Glucoseb
Insulin,
C-Peptide, 
Glucagon
07:40
-20
-
-
X
X
07:50
-10
-
-
X
X
08:00
0
100 
mg/dL
255.2
X
X
Insulin 
priming 
period
08:01
1
227.2
Approximately 
every 30 minutes
-
08:02
2
202.2
-
08:03
3
180.4
-
08:04
4
160.4
-
08:05
5
142.8
-
08:06
6
127.2
-
08:07
7
113.6
-
08:08
8
100.2
-
08:09
9
90.0
-
08:10
10
80.0
-
09:00
60
80.0
X
09:30
90
80.0
X
10:00
120
80.0
X
10:30
150
80.0
X
X
Steady-state 
periodc
10:40
160
80.0
X
X
10:50
170
80.0
X
X
11:00
180
80.0
X
X
Abbreviation:  eCRF = electronic case report form.
a
Nominal time is approximate.  Blood samples should be taken ± 1 minute from nominal time and actual time 
should be recorded in the eCRF.
b
Glucose concentrations will be checked with a laboratory glucose analyzer (Super GL).
c
Steady-state assessments can be delayed, if necessary, until the target glucose clamp level has been reached.
Glucose concentrations ≤70 mg/dL will not routinely be recorded as hypoglycemic events during 
the HEC procedure.  However, at the discretion of the investigator, decrease in glucose 

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 100
LY3298176
concentrations may be recorded as a hypoglycemic event based on clinical concern or related to 
technical issues resulting in hypoglycemia.
At the end of the steady-state period, the insulin infusion will be stopped. The ClampArt device 
will still infuse at a variable rate to keep the patients’ BG concentrations close to the target level 
of 100 mg/dL, if necessary. The infusion will cease once the BG values increase above the 
target level.
6.2.
Hyperglycemic Clamp for Assessment of First and Second 
Phase Insulin Secretion and Arginine Stimulation Test
The aim of the hyperglycemic clamp is to assess β cell function and insulin secretion, as well as 
cell function. Hyperglycemic clamp is a validated method in which the GIR needed to ensure 
constant BG at a predetermined level is used to determine islet β cell glucose sensitivity and 
insulin secretion capacity at various stages of the glucose exposure and after arginine stimulation 
under hyperglycemic conditions (Hannon et al. 2018; Shah et al. 2016).  The parameters that will 
be obtained are listed in Section 9.1 (Efficacy Assessments).
The target glucose concentration will be 16 mmol/L (216 mg/dL). The primed glucose infusion 
of 200 mg/kg body weight should start at approximately 13:00 (1PM; at least 120 minutes after 
the completion of the hyperinsulinemic euglycemic clamp and -120 minutes before the 
intravenous [IV] arginine bolus), followed by variable infusion of 20% glucose to maintain the 
target glucose level.  At approximately 15:00 (3PM), a 5 g arginine bolus will be administered by 
IV injection over 30 seconds (baseline time point 0).  The procedure will be completed at 15:30, 
or after 150 minutes of duration.
Blood samples for analysis of glucose, insulin, C-peptide, and glucagon will be drawn according 
to sampling scheme in Table GPGT.5.

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 101
LY3298176
Table GPGT.5.
Time Schedule for Hyperglycemic Clamp and Arginine Stimulation
Nominal 
Time
(Minutes)
Scheduled 
Timea
Target 
Clamp 
Level
Intervention
β-hydroxybutyrate, 
Pyruvate, Lactate, FFA, 
Glycerol, Triglycerides
Microdialysis Sampling 
Glucoseb
Glucagon, 
Insulin, 
C-peptideb
Glucose, Pyruvate, 
Lactate, Glycerol
Ethanol
-20
12:40
216 
mg/dL
X
X
-10
12:50
X
X
0
13:00
Start 
hyperglycemic 
clampc
X
X
X
Xd
Xd
2
13:02
X
X
4
13:04
X
X
6
13:06
X
X
8
13:08
X
X
10
13:10
X
X
20
13:20
X
X
30
13:30
X
X
X
X
X
60
14:00
X
X
X
X
X
90
14:30
X
X
X
X
X
100
14:40
X
X
110
14:50
X
X

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 102
LY3298176
Time Schedule for Hyperglycemic Clamp and Arginine Stimulation
Nominal 
Time
(Minutes)
Scheduled 
Timea
Target 
Clamp 
Level
Intervention
β-hydroxybutyrate, 
Pyruvate, Lactate, FFA, 
Glycerol, Triglycerides
Microdialysis Sampling 
Glucoseb
Glucagon, 
Insulin, 
C-peptideb
Glucose, Pyruvate, 
Lactate, Glycerol
Ethanol
120
15:00
IV injection 5 g 
arginine
X
X
X
Xe
Xe
122
15:02
X
X
123
15:03
X
X
124
15:04
X
X
125
15:05
X
X
130
15:10
X
X
135
15:15
X
X
140
15:20
X
X
150
15:30
End of 
hyperglycemic 
clamp
X
X
X
X
X
Abbreviations:  eCRF = electronic case report form; FFA = free fatty acid; IV = intravenous.
a
Scheduled starting time is approximate.  Blood samples should be taken ± 1 minute from nominal time and actual time should be recorded in the eCRF.
b
Blood sampling for assessment of concentration versus time profiles of glucose (Super GL glucose analyzer), insulin, glucagon, and C-peptide.  Basal 
concentrations of glucose, insulin, or C-peptide = mean concentrations at t = -20, -10, and 0 minutes.
c
The IV primed (200 mg/kg body weight) variable infusion of 20% glucose for adjustment of clamp level (16 mmol/L/216 mg/dL) starting at time = 0 minutes
d
The t = 0 samples will be collected prior to the glucose bolus initiation.
e
Blood samples to be drawn immediately prior to IV injection of arginine

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 103
LY3298176
6.3.
Microdialysis
Microdialysis is a minimally-invasive procedure to measure concentration of substances in the 
extracellular fluid of a tissue (Felländer et al. 1996). It is considered the standard technique to 
investigate adipose tissue physiology and the effects of interventions on subcutaneous abdominal 
lipolysis (Arner et al. 1988; Coppack et al. 1996).  The parameters that will be obtained are listed 
in Section 9.1 (Efficacy Assessments).
The microdialysis technique includes insertion of a semipermeable probe in the tissue of interest. 
The inlet of the probe is connected to a microdialysis pump and reservoir containing a 
physiological solution called the perfusate. The perfusate is pumped at a low flow rate (typically 
between 0.3 and 2 µL/min) through the probe. Once inserted, small solutes from the tissue fluid 
cross the membrane of the probe into the perfusate by passive diffusion. The solution leaving 
the probe (dialysate) is collected in a sample vial for the determination of substance 
concentrations (Felländer et al. 1996).
On assessments days, a microdialysis probe will be placed in the abdominal subcutaneous 
adipose tissue at areas different from the areas used for study drug administration. Sterile Ringer 
solution and ethanol will be used as perfusate and the dialysate will be analyzed for 
concentrations of glucose, pyruvate, lactate, glycerol, and ethanol. Ringer solution will be 
perfused at approximately 0.3 µL/minute for 2 hours, before the infusion rate will be increased to 
1.0 µL/minute 30 minutes before the start of the sMMTT and with the start of the hyperglycemic 
clamp procedure.  One dialysate sample will be collected per 30 minutes after start of the 
sMMTT and hyperglycemic clamp. Table GPGT.5 and Table GPGT.7 provide the time points at 
which dialysate samples will be analysed for pre-specified metabolic parameters.
6.4.
Standardized Mixed-Meal Tolerance Test
The key objectives of the sMMTT are to assess and cell function, insulin sensitivity, nutrient 
utilization and metabolic flexibility under physiological conditions.  The parameters that will be 
obtained are listed in Section 9.1 (Efficacy Assessments). The measurements that will be 
collected during the test and then used for parameter calculations are provided in Table GPGT.7.
During the morning before the start of the sMMTT, 2 IV cannulas (catheters) will be inserted, 
one cannula for serial measurements of BG, and one more in the contralateral arm for controlled 
variable infusion of glucose or rapidly-acting insulin glulisine (Apidra®), if needed to prevent 
hypoglycemia or hyperglycemia, respectively.  Blood glucose will be analysed using the Super
GL Glucose Analyzer.
The start of the meal will be defined as time point 0 (zero). A fixed nutrient ratio solid mixed 
meal (example is shown in Table GPGT.6) will be served and consumed by the patient, 
preferably within 15 minutes.  The standardized meal will be individualized for each individual 
randomized in the study with a fixed nutrients ratio.
The individual patients’ characteristics (weight, height, age, and gender) are used for the 
calculation of the resting metabolic rate (RMR) based on Müller equation (Müller et al. 2004).  A 
standard physical activity level (PAL) of 1.2 (20%) and a diet-induced thermogenesis of 10% are 

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 104
LY3298176
assumed and added to the RMR to achieve a weight-preserving energy intake per day during the 
inpatient period (FAO 2001).  The sMMTT will account for 35% of the total energy intake at the 
respective day.  Individually tailored menus are created by a Research Dietician or Head 
Metabolic Ward using a special software (PRODI).
The individual MMTTs will be identical at baseline and end of treatment.
The patient should refrain from eating until 4 hours after the meal (end of meal test). Water 
consumption will not be allowed during the first 2 hours after the start of the test.
Table GPGT.6.
Approximate Composition of an Individualized Standardized Meal 
with a Fixed Nutrient Ratio (900 kcal Meal Example)
Energy Supply
901
cal
3766
kJ
Amount
Protein
33.8
g
15
%
Fat
40.1
g
40
%
Carbohydrates
101.4
g
45
%
During the test meal procedure, patients will be asked to lie in a semi-supine position. Blood 
samples will be collected immediately before the start of the test meal (time point 0), followed 
by sampling after the start of the meal for measurement of the parameters of interest per schedule 
provided in Table GPGT.7.  Sampling times may be adjusted as necessary.
In case a patient’s BG concentration falls below 2.8 mmol/L (50 mg/dL), the patient must be 
treated to alleviate the hypoglycemia; the meal test procedure will be terminated and the date and 
time of termination will be documented in the eCRF. In case a patient’s BG concentration rises 
above 25 mmol/L (450 mg/dL), prandial insulin will be administered IV.  Likewise, patients with 
BG concentrations above 20 mmol/L (360 mg/dL) at the end of the meal test procedure will 
receive prandial insulin IV to quickly normalise concentrations.
After the end of the meal test procedure, the patient will be served a meal. All calculations and 
analyses are described in Section 9.1 (Efficacy Assessments) and Section 10.3 (Statistical 
Analysis) and in the statistical analysis plan.
During sMMTT, blood samples will be drawn according to sampling scheme in Table GPGT.7.

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 105
LY3298176
Table GPGT.7.
Standardized Mixed-Meal Tolerance Test
Timea
Nominal 
Time 
(Minutes)
Indirect 
Calorimetry Meal
Sampling for Analysis
Microdialysis
Microdialysis 
Sampling for 
Analysis
VAS
Comment
Blood 
Glucose
Insulin, 
C-peptide
Glucagon, 
PP
β-
hydroxy-
butyrate, 
Pyruvate, 
Lactate, 
FFA, 
Glycerol
Leptin, 
Adiponectin, 
IGFBP 1 and 2, 
Proinsulin 
Sample
Lipid 
Panelb
Perfusion 
Rate 
(µL/min)
Glucose, 
Pyruvate, 
Lactate, 
Glycerol
Ethanol
07:00
-180
Place 
microdialysis 
catheters
08:00
-120
Start
0.3
08:20
-100
Stop
0.3
09:00
-60
0.3
X
09:30
-30
Start
1.0
X
09:50
-10
Stop
X
X
1.0
09:59
-1
X
X
X
X
X
1.0
X
X
10:00
0
Start
X
1.0
10:15
15
Stop
X
X
1.0
10:30
30
X
X
1.0
11:00
60
Start
Xc
Xc
Xc
Xc
Xc
1.0
Xc
Xc
Xc
11:20
80
Stop
1.0
11:30
90
X
X
X
X
X
1.0

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 106
LY3298176
Standardized Mixed-Meal Tolerance Test
Timea
Nominal 
Time 
(Minutes)
Indirect 
Calorimetry Meal
Sampling for Analysis
Microdialysis
Microdialysis 
Sampling for 
Analysis
VAS Comment
Blood 
Glucose
Insulin, 
C-peptide
Glucagon, 
PP
β-
hydroxy-
butyrate, 
Pyruvate, 
Lactate, 
FFA, 
Glycerol
Leptin, 
Adiponectin, 
IGFBP 1 and 2, 
Proinsulin 
Sample
Lipid 
Panelb
Perfusion 
Rate 
(µL/min)
Glucose, 
Pyruvate, 
Lactate, 
Glycerol
Ethanol
12:00
120
Start
X
X
X
X
X
1.0
X
X
X
12:20
140
Stop
1.0
12:30
150
X
1.0
13:00
180
Start
X
X
X
X
X
1.0
X
X
X
13:20
200
Stop
1.0
13:30
210
X
1.0
14:00
240
Start
X
X
X
X
X
1.0
X
X
X
14:20
260
Stop
1.0
Abbreviations:  FFA = free fatty acid; IGFBP = insulin-like growth factor binding protein; VAS = visual analogue scale.
a
Approximate times only.
b
Lipid panel:  triglycerides, total cholesterol, low-density lipoprotein, very low-density lipoprotein, high-density lipoprotein, apolipoprotein B-48, 
apolipoprotein B-100, apolipoprotein C-III, and lipoprotein lipase. On Day -2 and Day 192, a full lipid panel will be collected during sMMTT. On Day -1 
and Day 193, only triglycerides will be collected.
c
Immediately before start of indirect calorimetry.
.

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 107
LY3298176
6.5.
Visual Analog Scales For Assessment of Appetite Sensations
The aim of the appetite visual analogue scale (VAS) is to determine the effects of study 
treatments on appetite sensations and desire for specific foods.  The parameters that will be 
obtained are listed in Section 9.1 (Efficacy Assessments).
Patients will be asked to rate their feelings on hunger, satiety, fullness, prospective food 
consumption, and desire for specific foods on a 10-cm (100-mm) line; anchored by verbal 
descriptors, usually “extremely” and “not at all.”  The ratings will include the following 
8 questions (Flint et al. 2000):

How hungry do you feel right now?

How satisfied do you feel right now?

How full do you feel right now?

How much food do you think you could eat right now?

Would you like to eat something sweet?

Would you like to eat something salty?

Would you like to eat something savoury?

Would you like to eat something fatty?
Patients will see the 10-cm line on a validated electronic device that will measure and record the 
exact position of the patient’s rating on the respective lines. For assessment of postprandial 
appetite sensations and desire for specific foods during sMMTT, the scores will be obtained 
immediately prior to the start of the meal (time point -1), and 60, 120, 180, and 240 minutes after 
the start of the meal . Overall appetite score is calculated as described in Section 10.3.3.1
(Pharmacodynamic Parameter Estimation).
6.6.
Ad Libitum Food Intake Test
The aim of the ad libitum food intake is to determine the effects of study treatments on meal 
intake. Brunch items will be served in a buffet-style setting. Ad libitum intake of food during a 
period of 45 minutes will be recorded by the site staff. Incompletely consumed items will be 
weighed and the weight will be recorded in the source data.  The total amount of calories as well 
as the amount of calories consumed from carbohydrates, protein, and fats will be calculated from 
the respective nutritional information of the food items.  The parameters that will be obtained are 
described in Section 9.1 (Efficacy Assessments).
6.7.
Plethysmography for Body Composition
The aim of plethysmography is to measure body composition (Fields et al. 2000; Dempster and 
Aitkens 1995).  Patients will undergo body composition assessment by way of noninvasive air 
displacement plethysmography (BOD POD® measurement system, COSMED, Rome, Italy).
The device utilizes whole body densitometry to estimate the amount of fat and lean tissue in the 

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 108
LY3298176
body. Whole body densitometry is based on the calculation of body density by measuring body 
mass and volume. Body mass is measured using an electronic scale, and body density is 
measured in a fiberglass test chamber (Dempster and Aitkens1995). Body composition will be 
performed according to Section 2 (Schedule of Activities) and more details will be provided in a 
separate operation manual. The parameters that will be obtained are listed in Section 9.1
(Efficacy Assessments).  Note:  Due to chamber size, measurements in patients with body weight 
above 150 kg are cumbersome. It will be decided on an individual basis whether the 
measurement can be performed.  In case patients do not fit inside the chamber, investigations can 
be skipped.
6.8.
Indirect Calorimetry
The aim of indirect calorimetry is to determine metabolic rate (Frayn 1983; Ferrannini 1988).  
The indirect calorimetry system (Quark RMR, COSMED, Rome, Italy) measures gas exchange 
by means of a ventilated canopy hood and experiments are performed under resting conditions.
The system measures the patient’s oxygen consumption (VO2) and carbon dioxide production 
(VCO2) (Frayn 1983; Ferrannini 1988). These measurements are used to calculate energy 
expenditure and substrate oxidation rates. The ratio of VO2 and VCO2 depends on the substrate 
used as energy source (fat, carbohydrate, or protein) and is the so-called respiratory exchange 
ratio and provides information on the substrate oxidation preference (Frayn 1983; Ferrannini 
1988). The parameters that will be obtained are listed in Section 9.1 (Efficacy Assessments).
For days with indirect calorimetry, the following requirements will be applied:

Fasting for at least 10 hours prior to baseline measurement (up to 200 mL of water are 
allowed);

No strenuous exercise within the last 48 hours before the measurement;

No protein-rich meal in the evening before;

No consumption of alcohol, caffeine- and/or methylxanthine-containing products in the 
last 24 hours before the measurement (i.e., coffee, coke, black/green tea, chocolate, 
cacao, energy drinks);

No smoking in the last 4 hours prior to measurement.

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 109
LY3298176
Appendix 7. Pancreatic Monitoring
Pancreatic Enzymes:  Safety Monitoring Algorithm
In Patients without Symptoms of Pancreatitis1,2
Follow this algorithm when the value(s) for serum amylase and/or lipase are = 3x upper limit of normal (ULN)
Test A/L every 4 Weeks 
(More Frequently if Protocol Visit  
Schedule is < 4 weeks)
Negative Imaging Results
Stop Injectable Study Drug5
Consult for Assessment and Management 
Assess for Causes of Pancreatitis 
Notify Lilly
Retest within 24 - 72 hours
Send sample to Laboratory
Amylase and/or Lipase (A/L3) = 3X ULN
A/L Not Decreasing
4.  Abdominal imaging is most valuable when performed 
at the time of elevated enzyme values.  If in the opinion 
of the radiologist or investigator, it is safe for the 
patient/subject to receive contrast, an enhanced 
abdominal CT is preferred. MRI is also an acceptable 
imaging modality.
3. A/L = amylase and/or lipase. Either or both 
enzymes can be used to meet the algorithm criteria.   
5. At a minimum, order a CBC and a pancreatic 
panel (which includes LFTs, calcium and 
triglycerides). Record all concomitant 
medications.
A/L Decreasing
Repeat Abdominal Imaging4
as Soon as Possible After 
Confirmation of Laboratory Values  
1. Symptomatic – related primarily to abdominal pain 
consistent with pancreatitis; however, in the opinion of 
the investigator severe nausea and vomiting plus
other symptoms consistent with pancreatitis may be
considered symptomatic as well.  
2. If in the opinion of the investigator, the patient 
has symptoms of acute pancreatitis:
(a) Stop injectable study drug 
(b) Consult for assessment and management 
(c) Assess for causes of pancreatitis 
(d) Notify Lilly
If A/L = 3X ULN, perform 
Abdominal Imaging4
Stop Injectable Study Drug5
Consult for Assessment and Management 
Assess for Causes of Pancreatitis
Notify Lilly
Test A/L Every 4 Weeks Until 
A/L = 3X ULN, 
Then Follow Protocol Schedule
Positive Imaging Results
Negative Imaging Results
Positive Imaging Results
Test A/L Every 4 Weeks Until 
A/L = 3X ULN, 
Then Follow Protocol Schedule
5
5

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 110
LY3298176
Abbreviations:  CBC = complete blood count; CT = computed tomography; 
LFTs = liver function tests; MRI = magnetic resonance imaging.
Patients diagnosed with pancreatitis will be discontinued from the study.  Investigators will be 
responsible for following, through an appropriate health care option, these pancreatitis AEs until 
the events resolve or are explained.  Adverse events that meet the diagnostic criteria of acute 
pancreatitis will be captured as serious adverse events (SAEs).  For all other pancreatic AEs 
(such as idiopathic or asymptomatic pancreatic enzyme abnormalities), the investigator will be 
responsible for determining the seriousness of the event (AE or SAE) and the relatedness of the 
event to study drug.

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 111
LY3298176
Appendix 8.
Highly Effective Contraceptive Methods

Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation1:
o
oral
o
intravaginal
o
transdermal

Progestogen-only hormonal contraception associated with inhibition of ovulation1:
o
oral
o
injectable
o
implantable2

Intrauterine device2

Intrauterine hormone-releasing system2

Bilateral tubal occlusion2

Vasectomised partner2,3

Sexual abstinence4
1 Hormonal contraception may be susceptible to interaction with the investigational product, which may reduce the 
efficacy of the contraception method.
2 Contraception methods that in the context of this guidance are considered to have low user dependency.
3 Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual partner of 
the woman of childbearing potential trial participant and that the vasectomised partner has received medical 
assessment of the surgical success.
4 In the context of this guidance, sexual abstinence is considered a highly effective method only if defined as
refraining from heterosexual intercourse during the entire period of risk associated with the study treatments.  
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the
preferred and usual lifestyle of the subject.
For hormonal contraception methods, caution should be taken to possible interaction with a
(nonbiologic) investigational medicinal product (IMP). Interaction with the IMP leading to 
reduced efficacy of the hormonal contraception method can occur due to e.g. increased 
metabolism (enzyme induction).
A potential human teratogen needs to be studied in vivo for effects on contraceptive steroids if
the drug is intended for use in fertile women, regardless on the in vitro induction study results. 
For the purpose of this guidance, an IMP with demonstrated or suspected human 
teratogenicity/fetotoxicity in early pregnancy is a potential human teratogen. For these IMPs, 

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 112
LY3298176
data from a clinical pharmacokinetic interaction study between the IMP and contraceptive 
steroids, if available, allow to conclude whether the efficacy of hormonal contraception is 
reduced. In the absence of such a clinical pharmacokinetic interaction study, any 
recommendation for use of hormonal contraceptives should be thoroughly justified by the 
sponsor.
For all other IMPs, recommendations should take into account both the evidence of the 
nonclinical reproductive toxicity data and available information related to the potential risk for
interaction, e.g. in vitro enzyme induction results, signs of autoinduction and results from clinical 
interaction studies.
As a general rule, use of hormonal contraception is not recommended if a clinically relevant
interaction with contraceptive steroids has been observed or is suspected. If an interaction with 
contraceptive steroids has been observed or is suspected, but the effect is considered to be of 
limited clinical significance, the hormonal contraception method must be supplemented with a 
barrier method (preferably male condom).
An assessment of the potential for interaction between the IMP and hormonal contraceptives
should be provided in the Investigator’s Brochure (IB), including a scientific rationale for the use 
of hormonal contraception methods with or without a supplementary barrier method (preferably 
male condom).

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 113
LY3298176
Appendix 9.
Protocol Amendment I8F-MC-GPGT(d) 
Summary The Effect of Tirzepatide on α and β Cell 
Function and Insulin Sensitivity in Patients with Type 2 
Diabetes Mellitus
Overview
Protocol I8F-MC-GPGT(c) The Effect of Tirzepatide on α and β Cell Function and Insulin 
Sensitivity in Patients with Type 2 Diabetes Mellitus has been amended in response to queries 
and feedback raised by the Ethics Committee (EC).  The new protocol is indicated by 
Amendment (d) and will be used to conduct the study in place of any preceding version of the 
protocol.
This amendment is considered a non-substantial protocol amendment, since enrolment criteria 
has been tightened.
The overall changes and rationale for the changes made to this protocol are as follows:

Provided additional clarity for Inclusion Criterion [2] that patients on a second OAM 
must be on stable, unchanged doses for at least 3 months.

Changed Inclusion Criterion [3] to set the HbA1c upper limit as ≤9.5% for patients on 
metformin only as requested by the EC.

Deleted ISI as an exploratory endpoint as it was considered redundant.

Clarified Section 10.3.3.2 that primary endpoint is change from baseline in cDI instead of 
cDI as a standalone measure.  Additional details describing the statistical analysis had 
been included.

Minor formatting and editorial changes have been performed but these may not be 
reflected in the section below.

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 114
LY3298176
Revised Protocol Sections
Note:
All deletions have been identified by strikethroughs.
All additions have been identified by the use of underscore.
6.1.
Inclusion Criteria
[2]
Treated with diet and exercise and stable dose(s) of metformin, with or 
without 1 additional stable dose of OAM other than metformin, 3 months 
prior to study entry; doses of metformin will be considered stable if all 
prescribed doses for this period were ±850 mg from the most commonly 
prescribed dose; allowed OAMs, in combination with metformin, are 
dipeptidyl peptidase-4 (DPP-IV) inhibitors, SGLT-2 inhibitors, acarbose, and 
sulfonylureas; the second OAM dose will be considered stable if the 
prescribed dose is unchanged for at least 3 months prior to study entry.
[3]
Have a hemoglobin A1c value at screening (Visit 1) of ≥7.0% and ≤9.510.0%
if on metformin only; or ≥6.5% and ≤9.0% if on metformin in combination 
with OAMs other than metformin;
7.7.
Concomitant Therapy
Paragraph 2
Patients treated with other OAMs at study entry, in addition to metformin, are allowed to 
participate in the study (refer to Inclusion Criteria [2] and [3] for details) but must discontinue 
OAMs other than metformin as soon as their eligibility is confirmed, and must complete a 4-
week washout period prior to the lead-in period and randomization.  Once the 4-week washout 
period is completed, patients can be enrolled in the study. The allowed OAMs, in combination 
with metformin, are DPP-IV inhibitors, SGLT-2 inhibitors, acarbose, and sulfonylureas.
9.1.3 Exploratory Efficacy Assessments and Procedures
Exploratory efficacy measures to assess the effect of study treatments on insulin 
sensitivity:  
•
insulin sensitivity index (ISI) from hyperinsulinemic euglycemic clamp, defined 
as MCR/Imean (Imean is average steady state plasma insulin response; MCR is 
metabolic clearance rate of glucose) (De Fronzo et al. 1979);
•
hyperinsulinemic euglycemic M/I value, defined as the M-value divided by total 
insulin over the same time period (+150 to +180 minutes).
10.3.3.1
Pharmacodynamic Parameter Estimation
Insulin sensitivity:
•
ISI for the clamp portion is calculated from the M value during the hyperinsulinemic 
euglycemic clamp test.  M-value from hyperinsulinemic euglycemic clamp is the measure 

I8F-MC-GPGT(d) Clinical Pharmacology Protocol
Page 115
LY3298176
of insulin sensitivity; M-value is defined as the GIR over the last 30 minutes of the clamp 
(+150 to +180 minutes) minus a correction factor for non constant glucose level divided 
by body weight (DeFronzo et al. 1979).
10.3.3.2.
Pharmacodynamic Statistical Inference
The primary endpoint (change from baseline in cDI for tirzepatide versus placebo) will 
be calculated by first log-transforming the data then computing the change from baseline. 
The primary analysis will be ed and then analyzed using an analysis of covariance model 
which has effects for treatment and baseline of the parameter measured to compare 
tirzepatide versus placebo.

Approver: 
Approval Date & Time: 10-Jun-2020 15:18:29 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 10-Jun-2020 15:28:03 GMT
Signature meaning: Approved
PPD
PPD
CCI