Conditions: Diabetes Mellitus, Type 2 Hypoglycemia
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 42
Healthy volunteers: no

Brief summary:
The main purpose of this study is to learn more about how tirzepatide affects the body's response to low blood sugar (hypoglycemia). The study is open to participants with type 2 diabetes. It will last about 42 weeks for each participant.

Detailed description:

Arms:
arm 1: Participants received a starting dose of 2.5 mg tirzepatide once weekly (QW) for 2 weeks, followed by an increase to 5 mg QW for 2 weeks, and 10 mg QW for 4 weeks until the 15-mg dose was reached and maintained for the remainder of the treatment period (4 weeks) administered subcutaneously (SC) in one of two study periods. arm 2: Participants received placebo QW administered SC in one of two study periods.

Interventions: intervention 1: Tirzepatide intervention 2: Placebo
Intervention descriptions: intervention 1: Administered SC intervention 2: Administered SC

Protocol document:
Prot_000.pdf: 
 
 
 
Protocol I8F-MC-GPHG(d) 
 
 
A Randomized, Placebo-Controlled, Crossover Study to Investigate the Effect of Once-Weekly 
Tirzepatide on the Counter-Regulatory Response to Hypoglycemia in Patients with Type 2 
Diabetes Mellitus 
  
 
NCT04050553 
 
Approval Date: 17-Sep-2020 
 
 
 
 
 
 


I8F-MC-GPHG(d) Clinical Pharmacology Protocol
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LY3298176
Protocol I8F-MC-GPHG(d)
A Randomized, Placebo-Controlled, Crossover Study to 
Investigate the Effect of Once-Weekly Tirzepatide on the 
Counter-Regulatory Response to Hypoglycemia in Patients 
with Type 2 Diabetes Mellitus
EudraCT No. 2019-001360-29
Confidential Information
The information contained in this protocol is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
tirzepatide (LY3298176), unless such persons are bound by a confidentiality agreement 
with Eli Lilly and Company or its subsidiaries.
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure.  Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release.  In 
the United States, this document is subject to Freedom of Information Act Exemption 4 and 
may not be reproduced or otherwise disseminated without the written approval of Eli Lilly 
and Company or its subsidiaries.  
Tirzepatide (LY3298176)
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Clinical Pharmacology Protocol Electronically Signed and Approved by Lilly:  
08 July 2019
Amendment (a) Electronically Signed and Approved by Lilly:  23 July 2019
Amendment (b) Electronically Signed and Approved by Lilly: 04 May 2020
Amendment (c) Electronically Signed and Approved by Lilly: 23 July 2020
Amendment (d) Electronically Signed and Approved by Lilly on approval date provided 
below
Approval Date: 17-Sep-2020 GMT


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Table of Contents
A Randomized, Placebo-Controlled, Crossover Study to 
Investigate the Effect of Once-Weekly Tirzepatide on the 
Counter-Regulatory Response to Hypoglycemia in Patients 
with Type 2 Diabetes Mellitus
Section
Page
Protocol I8F-MC-GPHG(d) A Randomized, Placebo-Controlled, 
Crossover Study to Investigate the Effect of Once-Weekly 
Tirzepatide on the Counter-Regulatory Response to Hypoglycemia in 
Patients with Type 2 Diabetes Mellitus ...............................................................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis................................................................................................................9
2.
Schedule of Activities .......................................................................................................12
3.
Introduction ......................................................................................................................22
3.1.
Study Rationale............................................................................................................22
3.2.
Background..................................................................................................................22
3.3.
Benefit/Risk Assessment..............................................................................................24
4.
Objectives and Endpoints..................................................................................................26
5.
Study Design.....................................................................................................................28
5.1.
Overall Design .............................................................................................................28
5.1.1.
Screening, Lead-in, and Randomization ...............................................................29
5.1.2.
Treatment.............................................................................................................30
5.1.3.
Washout Between Treatment Periods...................................................................31
5.2.
Number of Participants.................................................................................................31
5.3.
End of Study Definition ...............................................................................................31
5.4.
Scientific Rationale for Study Design...........................................................................31
5.5.
Justification for Dose ...................................................................................................31
6.
Study Population...............................................................................................................33
6.1.
Inclusion Criteria..........................................................................................................33
6.2.
Exclusion Criteria ........................................................................................................36
6.3.
Lifestyle and/or Dietary Requirements .........................................................................39
6.3.1.
Meals and Dietary Restrictions.............................................................................39
6.3.2.
Caffeine, Alcohol, and Tobacco ...........................................................................39
6.3.3.
Activity................................................................................................................39
6.4.
Screen Failures.............................................................................................................39
7.
Treatment..........................................................................................................................40


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7.1.
Treatment Administered...............................................................................................40
7.1.1.
Packaging and Labeling .......................................................................................40
7.1.2.
Medical Devices...................................................................................................41
7.2.
Method of Treatment Assignment ................................................................................41
7.2.1.
Selection and Timing of Doses.............................................................................41
7.3.
Blinding .......................................................................................................................41
7.4.
Dose Modification........................................................................................................41
7.4.1.
Special Treatment Considerations ........................................................................41
7.4.1.1.
Management of Hypoglycemia .......................................................................42
7.4.1.2.
Management of Hyperglycemia......................................................................42
7.4.1.3.
Treatment of Hypoglycemia during Hypoglycemic 
Clamp.............................................................................................................42
7.5.
Preparation/Handling/Storage/Accountability...............................................................43
7.6.
Treatment Compliance .................................................................................................43
7.7.
Concomitant Therapy...................................................................................................43
7.7.1.
Management of Patients with Gastrointestinal Symptoms.....................................45
7.8.
Treatment after the End of the Study............................................................................45
8.
Discontinuation Criteria ....................................................................................................46
8.1.
Discontinuation from Study Treatment.........................................................................46
8.1.1.
Permanent Discontinuation from Study Treatment ...............................................46
8.1.2.
Temporary Interruption of Study Drug.................................................................47
8.1.3.
Discontinuation of Inadvertently Enrolled Patients...............................................47
8.2.
Discontinuation from the Study....................................................................................48
8.3.
Patients Lost to Follow-up............................................................................................48
9.
Study Assessments and Procedures ...................................................................................49
9.1.
Efficacy Assessments...................................................................................................49
9.2.
Adverse Events ............................................................................................................49
9.2.1.
Serious Adverse Events........................................................................................50
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................51
9.2.2.
Adverse Events of Special Interest .......................................................................51
9.2.2.1.
Severe Gastrointestinal Adverse Events..........................................................51
9.2.2.2.
Hypoglycemia ................................................................................................51
9.2.2.3.
Severe, Persistent Hyperglycemia...................................................................53
9.2.2.4.
Pancreatitis.....................................................................................................53
9.2.2.5.
Thyroid Malignancies and C-Cell Hyperplasia................................................54
9.2.2.6.
Major Adverse Cardiovascular Events............................................................55
9.2.2.7.
Supraventricular Arrhythmias and Cardiac Conduction 
Disorders........................................................................................................55


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9.2.2.8.
Hypersensitivity Events..................................................................................55
9.2.2.9.
Injection-site Reactions...................................................................................55
9.2.2.10.
Diabetic Retinopathy Complications...............................................................55
9.2.2.11.
Hepatobiliary Disorders..................................................................................55
9.2.2.12.
Acute Renal Events ........................................................................................56
9.2.2.13.
Metabolic Acidosis, Including Diabetic Ketoacidosis .....................................56
9.2.2.14.
Amputation/Peripheral Revascularization .......................................................56
9.2.2.15.
Major Depressive Disorder/Suicidal Ideation..................................................56
9.2.3.
Complaint Handling.............................................................................................56
9.3.
Treatment of Overdose.................................................................................................56
9.4.
Safety...........................................................................................................................57
9.4.1.
Laboratory tests....................................................................................................57
9.4.2.
Vital Signs ...........................................................................................................57
9.4.3.
Electrocardiograms ..............................................................................................57
9.4.4.
Physical Examinations .........................................................................................58
9.4.5.
Safety Monitoring ................................................................................................58
9.4.5.1.
Hepatic Safety................................................................................................58
9.4.6.
Injection-site Reactions ........................................................................................58
9.5.
Pharmacokinetics .........................................................................................................59
9.5.1.
Bioanalysis...........................................................................................................59
9.6.
Pharmacodynamics ......................................................................................................59
9.6.1.
Primary Pharmacodynamic Assessments and Procedures .....................................60
9.6.2.
Secondary Pharmacodynamic Assessments and Procedures .................................60
9.6.3.
Exploratory Pharmacodynamic Assessments and Procedures ...............................61
9.6.4.
Immunogenicity Assessments ..............................................................................61
9.6.5.
Body Weight........................................................................................................62
9.7.
Genetics .......................................................................................................................63
9.8.
Biomarkers...................................................................................................................63
9.9.
Health Economics ........................................................................................................64
10.
Statistical Considerations and Data Analysis.....................................................................65
10.1. Sample Size Determination ..........................................................................................65
10.2. Populations for Analyses..............................................................................................65
10.2.1.
Study Participant Disposition ...............................................................................65
10.2.2.
Study Participant Characteristics ..........................................................................65
10.3. Statistical Analyses ......................................................................................................65
10.3.1.
Safety Analyses....................................................................................................65
10.3.1.1.
Clinical Evaluation of Safety..........................................................................65
10.3.1.2.
Statistical Evaluation of Safety.......................................................................65


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10.3.1.3.
Injection-site Reactions...................................................................................66
10.3.2.
Pharmacokinetic Analyses....................................................................................66
10.3.2.1.
Pharmacokinetic Parameter Estimation...........................................................66
10.3.2.2.
Pharmacokinetic Statistical Inference .............................................................66
10.3.3.
Pharmacodynamic Analyses.................................................................................66
10.3.3.1.
Pharmacodynamic Parameter Estimations.......................................................66
10.3.3.2.
Pharmacodynamic Statistical Inference...........................................................67
10.3.4.
Evaluation of Immunogenicity .............................................................................68
10.3.5.
Interim Analyses..................................................................................................68
11.
References ........................................................................................................................69
12.
Appendices .......................................................................................................................71


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List of Tables
Table
Page
Table GPHG.1.
Objectives and Endpoints .......................................................................26
Table GPHG.2.
Dose Titration.........................................................................................40


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List of Figures
Figure
Page
Figure GPHG.1
Illustration of study design for Protocol I8F-MC-GPHG.........................29
Figure GPHG.2
Hypoglycemic clamp..............................................................................87


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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................72
Appendix 2.
Clinical Laboratory Tests........................................................................77
Appendix 3.
Study Governance, Regulatory and Ethical Considerations.....................78
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............81
Appendix 5.
Blood Sampling Summary......................................................................83
Appendix 6.
Hypoglycemic Clamp Procedure ............................................................84
Appendix 7.
Pancreatic Monitoring ............................................................................91
Appendix 8.
Hypersensitivity Laboratory Testing.......................................................94
Appendix 9.
Protocol Amendment I8F-MC-GPHG(d) Summary:
A Randomized, Placebo-Controlled, Crossover Study to 
Investigate the Effect of Once-Weekly Tirzepatide on the Counter-
Regulatory Response to Hypoglycemia in Patients with Type 2 
Diabetes Mellitus....................................................................................96


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1. Protocol Synopsis
Title of Study:
A Randomized, Placebo-Controlled, Crossover Study to Investigate the Effect of Once-Weekly Tirzepatide on the 
Counter-Regulatory Response to Hypoglycemia in Patients with Type 2 Diabetes Mellitus.
Rationale: 
Study I8F-MC-GPHG (Study GPHG) is an approximately 38 to 42 week Phase 1 study designed to examine the 
effect of tirzepatide (LY3298176) on hypoglycemic counter-regulation in patients with type 2 diabetes mellitus 
(T2DM) when compared to placebo treatment.  Tirzepatide is a long-acting, dual incretin mimetic (dual agonist) that 
binds to the glucose-dependent insulinotropic polypeptide receptor (GIPR) and the glucagon-like peptide-1 (GLP-1) 
receptor (GLP-1R).  Dual GIPR and GLP-1R agonism may provide improved glycemic control in patients with 
T2DM, engaging multiple physiologic pathways, including glucagon secretion by the pancreatic α cell.  Since 
glucagon plays a key role in defense against hypoglycemia, it is important to assess the effects of tirzepatide on the 
physiologic response to hypoglycemia.  Understanding the effect of tirzepatide on the counter-regulatory response to 
a hypoglycemic stimulus will provide important safety information for potential future clinical use.
Objectives/Endpoints:  
Objectives
Endpoints
Primary
To compare the effect of tirzepatide 15 mg 
once-weekly (QW) and placebo on glucagon response 
during hypoglycemia in T2DM patients following 
12 weeks of treatment
Change in mean glucagon concentration during 
induced hypoglycemia from target plasma glucose 
(PG) concentration of 100 mg/dL to a nadir target of 
45 mg/dL
Secondary
To compare the effect of tirzepatide 15 mg QW and 
placebo in T2DM patients following 12 weeks of 
treatment on:

Other counter-regulatory hormone responses 
during hypoglycemia, insulin and C-peptide

Change in mean glucagon concentration from target 
PG concentration of 100 mg/dL to 63 mg/dL and to 
recovery (PG concentration 72 mg/dL) from 
induced hypoglycemia 

Change in mean glucagon concentration from 
ambient PG to target PG concentrations of 100, 63,
and 45 mg/dL, and to recovery (PG concentration 
72 mg/dL) from induced hypoglycemia 

Change in mean insulin, C-peptide, growth 
hormone, cortisol, adrenaline, and noradrenaline 
concentrations from target PG concentration of 
100 mg/dL to 63 and 45 mg/dL, and to recovery 
(PG concentration 72 mg/dL) from induced 
hypoglycemia

Time to hypoglycemia recovery

Time from termination of insulin infusion at PG 
concentration of 45 mg/dL to reach recovery PG 
concentration (72 mg/dL) (tPG_nadir-72 mg/dL)


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
Clinical hypoglycemia

Hypoglycemic symptoms score at PG 
concentrations of 100, 63, and 45 mg/dL and after 
recovery (PG concentration 72 mg/dL) from 
induced hypoglycemia

Hypoglycemic awareness at PG concentrations of 
100, 63, and 45 mg/dL and after recovery (PG 
concentration 72 mg/dL) from induced 
hypoglycemia

Vital signs during hypoglycemia

Change in mean systolic and diastolic blood 
pressure and pulse rate from target PG 
concentration of 100 mg/dL to 63, and 45 mg/dL, 
and to recovery (PG concentration 72 mg/dL) from 
induced hypoglycemia

Additional safety and tolerability

Adverse events (AEs)

Incidence of hypoglycemia outside of the 
hypoglycemic clamps
Plasma glucose concentrations:  100 mg/dL = 5.5 mmol/L; 72 mg/dL = 4.0 mmol/L; 63 mg/dL = 3.5 mmol/L; 
45 mg/dL = 2.5 mmol/L;  glucagon at ambient PG measured in the pre-prandial state prior to clamp initiation.  
Summary of Study Design:  
This is a Phase 1, single-center, 2-period, crossover, randomized, patient- and investigator-blind study in T2DM 
patients. This study is designed to compare tirzepatide 15 mg QW and placebo with respect to secretion of 
counter-regulatory hormones in response to a hypoglycemic stimulus and parameters of recovery from 
hypoglycemia.
Eligibility for this study for patients on metformin only will be assessed at the screening (Visit 1) up to 17 days prior 
to enrollment (Day -14 ±3) and confirmed at the beginning of the lead-in period (Visit 2).
Eligibility for patients on metformin and one other oral antidiabetic medication (OAM) will be assessed at the 
screening (Visit 1) up to 45 days prior to enrollment and confirmed at the beginning of the lead-in period (Visit 2), 
followed by discontinuation and a washout period for OAMs, other than metformin. The washout period for these 
patients will last at least 4 weeks between Visit 2 and Visit 3.
Eligible patients will undergo 2 treatment periods and will be randomized (Visit 3) to receive tirzepatide 15 mg QW
in 1 period followed by placebo in the other, or vice versa, in a crossover fashion. Tirzepatide 15 mg will be attained 
via step-wise dose escalation to reduce the risk of gastrointestinal AEs.  
There will also be a washout period of at least 8 weeks between the last dose of study drug in Period 1 and the first 
dose in Period 2.  
At the end of each treatment period, patients will undergo a hypoglycemic clamp procedure.  


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Treatment Arms and Planned Duration for an Individual patient:
Each patient will receive tirzepatide 15 mg followed by placebo or vice versa in a crossover fashion.  Tirzepatide 
dosing will start at a dose of 2.5 mg QW for 2 weeks, followed by step-wise escalation to 5 mg QW for the next 
2 weeks, 10 mg QW for the next 4 weeks, and 15 mg QW for the final 4 weeks.  
The planned study duration for an individual patient from screening through safety follow-up will be approximately 
38 to 42 weeks.  
Number of Patients:
Approximately 38 patients are planned to be enrolled so that 30 patients complete the study.  
Statistical Analysis:
The primary pharmacodynamic (PD) parameter for analysis will be the change in mean glucagon concentration 
between the 100 mg/dL (5.5 mmol/L) clamp step and the nadir target 45 mg/dL (2.5 mmol/L) step.  This will be 
evaluated using a linear mixed-effects model, with treatment, treatment period, and treatment sequence as fixed 
effects, and patient as a random effect.  From the model, the difference between tirzepatide and placebo in least 
squares means estimates and the corresponding 95% confidence intervals for the difference will be calculated.  
The secondary PD measures for statistical analysis are:  

Change in mean glucagon concentration from target PG concentration of 100 mg/dL (5.5 mmol/L) to 63 mg/dL 
(3.5 mmol/L) and to recovery (PG concentration 72 mg/dL [4.0 mmol/L]) from induced hypoglycemia

Change in mean glucagon concentration from ambient PG to target PG concentrations of 100, 63, and 45 mg/dL 
(5.5, 3.5, and 2.5 mmol/L), and to recovery (PG concentration 72 mg/dL [4.0 mmol/L]) from induced 
hypoglycemia

Change in mean insulin, C-peptide, growth hormone, cortisol, adrenaline, and noradrenaline concentrations 
from target PG concentration of 100 mg/dL (5.5 mmol/L), to 63 and 45 mg/dL (3.5 and 2.5 mmol/L), and to 
recovery (PG concentration 72 mg/dL [4.0 mmol/L]) from induced hypoglycemia

tPG_nadir-72 mg/dL
These parameters will be analyzed using a similar model to that described for the primary endpoint.  If the 
tPG_nadir-72 mg/dL is highly skewed, a log-transformation may be considered.  If the assumptions of the model 
appear to be violated, a non-parametric analysis may be performed.
Change in mean systolic and diastolic blood pressure and pulse rate from target PG concentration of 100 mg/dL 
(5.5 mmol/L) to 63, 45, and 72 mg/dL (3.5, 2.5, and 4.0 mmol/L), and hypoglycemic symptom and awareness scores 
at target PG concentrations of 100, 63, and 45 mg/dL (5.5, 3.5, 2.5 mmol/L) and after recovery (PG concentration 
72 mg/dL [4.0 mmol/L]) from induced hypoglycemia will be listed and summarized.


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2. Schedule of Activities


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Study Schedule Protocol I8F-MC-GPHG: Screening, Lead-in, Randomization/Dose 1 Period 1, and Dose 1 Period 2
Procedure
Screening
Lead-in (with 
or without 
washout)
Randomization
and
Dose 1, Treatment 
Period 1
Dose 1, 
Treatment 
Period 2
Comments
Visit
1
2
3
10
Study Period Week 
-6/-2
a
-5/-1
a
1
1
Study Period Day
-14 ±3a or
-42 ±3a
-7 ± 3
a or
-35 ±3a (prior to 
randomization)
1
1
Patients on metformin only should perform Visits 1 
and 2 approximately 2 and 1 week prior to Visit 3.
Patients on metformin and one additional OAM should 
perform Visit 1 about 6 weeks prior to Visit 3, in order 
to permit eligibility assessment at Visit 2. OAMs other 
than metformin will be discontinued immediately after 
Visit 2 followed by at least 4-weeks washout between 
Visit 2 and Visit 3.
Informed consent
X
Medical history
X
Drug and alcohol 
screen
X
May be repeated throughout the study as deemed 
necessary by the investigator.
Physical examination / 
medical assessments
X
Full physical examination at screening. After 
screening, medical assessments only performed to 
include medical review and targeted examination, as 
appropriate.
Height
X
Weight
X
P
P
Vital signs 
(BP/PR/body 
temperature)
X
P
P
Blood pressure and PR measurements will be taken 
after at least 5 minutes in the supine position.
ECGs
X
P
P
Single 12-lead ECGs will be collected.  
Electrocardiograms will be recorded using equipment 
available at the CRU.  Patients must be supine for at 
least 5 minutes before ECG collection, and remain 
supine but awake during ECG collection.
AEs
X


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Procedure
Screening
Lead-in (with 
or without 
washout)
Randomization
and
Dose 1, Treatment 
Period 1
Dose 1, 
Treatment 
Period 2
Comments
Visit
1
2
3
10
Study Period Week 
-6/-2
a
-5/-1
a
1
1
Study Period Day
-14 ±3a or
-42 ±3a
-7 ± 3
a or
-35 ±3a (prior to 
randomization)
1
1
Patients on metformin only should perform Visits 1 
and 2 approximately 2 and 1 week prior to Visit 3.
Patients on metformin and one additional OAM should 
perform Visit 1 about 6 weeks prior to Visit 3, in order 
to permit eligibility assessment at Visit 2. OAMs other 
than metformin will be discontinued immediately after 
Visit 2 followed by at least 4-weeks washout between 
Visit 2 and Visit 3.
Concomitant 
medications
X
X
Inclusion/exclusion 
criteria
X
X
For patients requiring OAM washout, eligibility must
be confirmed prior to discontinuing the OAM.
Randomization
P
To occur after all other predose assessments are 
conducted.
Investigational Product
Tirzepatide or placebo 
administration
X
X
Clinical Procedures
Outpatient visit
X
X
X
X
Laboratory Tests
Safety laboratory tests
X
P
P
See Appendix 2 for details.  Patients will fast for at 
least 8 hours before each blood sample is collected 
(fasting).  If not fasted prior to screening, patient may 
return for test within the screening window.
Serology
X
See Appendix 2 for details.  
Pregnancy test (women 
of childbearing 
potential)
X
Xb
P
P
Serum pregnancy test will be performed at screening.  
Urine pregnancy test will be performed at other times.  
Performed by local laboratory or on site.
Insulin, C-peptide
P
P
Fasting.  Performed by central laboratory.


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Procedure
Screening
Lead-in (with 
or without 
washout)
Randomization
and
Dose 1, Treatment 
Period 1
Dose 1, 
Treatment 
Period 2
Comments
Visit
1
2
3
10
Study Period Week 
-6/-2
a
-5/-1
a
1
1
Study Period Day
-14 ±3a or
-42 ±3a
-7 ± 3
a or
-35 ±3a (prior to 
randomization)
1
1
Patients on metformin only should perform Visits 1 
and 2 approximately 2 and 1 week prior to Visit 3.
Patients on metformin and one additional OAM should 
perform Visit 1 about 6 weeks prior to Visit 3, in order 
to permit eligibility assessment at Visit 2. OAMs other 
than metformin will be discontinued immediately after 
Visit 2 followed by at least 4-weeks washout between 
Visit 2 and Visit 3.
Glucagon
P
P
Fasting.  Performed by central laboratory.
Calcitonin
X
Fasting.  If not fasted prior to screening, patient may 
return for test within the screening window.  Central 
laboratory.
Glucose Management
Dispense blood glucose 
meters, test strips, 
study diaries, and 
disease management 
training
X
These SMPG-related procedures will be performed 
after eligibility is confirmed.
SMPG
X
X
For patients undergoing OAM washout, phone 
interviews will be conducted during lead-in to assess 
acceptability of glycemic control. Refer to Section 
5.1.1 for further details
Review of study diary 
for SMPG
P
P


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Procedure
Screening
Lead-in (with 
or without 
washout)
Randomization
and
Dose 1, Treatment 
Period 1
Dose 1, 
Treatment 
Period 2
Comments
Visit
1
2
3
10
Study Period Week 
-6/-2
a
-5/-1
a
1
1
Study Period Day
-14 ±3a or
-42 ±3a
-7 ± 3
a or
-35 ±3a (prior to 
randomization)
1
1
Patients on metformin only should perform Visits 1 
and 2 approximately 2 and 1 week prior to Visit 3.
Patients on metformin and one additional OAM should 
perform Visit 1 about 6 weeks prior to Visit 3, in order 
to permit eligibility assessment at Visit 2. OAMs other 
than metformin will be discontinued immediately after 
Visit 2 followed by at least 4-weeks washout between 
Visit 2 and Visit 3.
Diagnostics
PK sample
P
P
PK and immunogenicity to be time-matched as much 
as possible.
Immunogenicity 
P
P
Pharmacogenetic 
sample
P
Single sample taken predose on Day 1 Period 1.
Nonpharmacogenetic 
stored samples
P
P
Fasting sample.
Abbreviations: AE = adverse event; BP = blood pressure; ECG = electrocardiogram; FSH = follicle-stimulating hormone; P = predose; PK = pharmacokinetic; 
PR = pulse rate; SMPG = self-monitoring of blood glucose.  
a
Visit windows are relative to randomization (Period 1, Day 1).
b
A serum pregnancy test will be taken during Visit 2 if the FSH ≤40mIU/mL at Visit 1.
Note:  If multiple procedures take place at the same time point, the following order may be consulted for prioritization:  ECG, vital signs, counter-regulatory 
hormone samples, safety laboratory tests, PK samples, immunogenicity samples, storage samples.


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Study Schedule Protocol I8F-MC-GPHG: Treatment Periods 1 and 2
Procedure
Treatment Periods 1 and 2
Comments
Visit Period 1
Visit Period 2
4
11
5
12
6
13
7
14
8
15
9
16
9
16
Study Period Week
2
3
4
5
6
7
8
9
10
11
12
12
12
Study Period Day
8
±1
15
±1
22
29
±1
36
43
50
57
±1
64
71
78
±2
79
±2
80
±2
Patients should attend on stated 
day. When the patient is unable 
to attend CRU on the stated day,
visit windows should be used for 
dosing only.
Days 78, 79, and 80 should 
occur consecutively, without 
interruption.
Weight 
P
P
P
Vital signs (BP/PR/body 
temperature)
P
P
P
P
P
X
See Appendix 6
Refer to screening table.
ECGs
P
P
X
See Appendix 6
Refer to screening table.
Concomitant 
medications
X
AEs
X
Physical examination / 
medical assessments
X
X
Refer to screening table.
Alcohol breath test
X
CRU admission
X
CRU discharge
X
Outpatient visit
X
X
X
X
X
Dispense study 
treatment
X
X
X
For outpatient use.
Telephone visit
X
X
X
May be more frequent if there is 
evidence of missed doses.
Investigational Product
Tirzepatide or placebo 
administration
X
X
X
X
X
X
X
X
X
X
X
Patients will self-administer 
study drug when not in CRU.


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Procedure
Treatment Periods 1 and 2
Comments
Visit Period 1
Visit Period 2
4
11
5
12
6
13
7
14
8
15
9
16
9
16
Study Period Week
2
3
4
5
6
7
8
9
10
11
12
12
12
Study Period Day
8
±1
15
±1
22
29
±1
36
43
50
57
±1
64
71
78
±2
79
±2
80
±2
Patients should attend on stated 
day. When the patient is unable 
to attend CRU on the stated day,
visit windows should be used for 
dosing only.
Days 78, 79, and 80 should 
occur consecutively, without 
interruption.
Glucose Management
SMPG
X
Fasting blood glucose
P
P
The central laboratory will test 
fasting blood glucose.
Review of study diary 
for SMPG
X
X
X
X
X
Laboratory Tests
Safety laboratory tests
X
X
Refer to screening table.
Pregnancy test (women 
of childbearing 
potential)
X
X
X
Refer to screening table.
Insulin, C-peptide
X
See Appendix 6
Fasting. Performed by central 
laboratory.
Growth hormone, 
cortisol
Fasting.  Performed by central 
laboratory.
Adrenaline, 
noradrenaline
Fasting.  Performed by central 
laboratory.
Glucagon
Fasting.  Performed by central 
laboratory.


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Procedure
Treatment Periods 1 and 2
Comments
Visit Period 1
Visit Period 2
4
11
5
12
6
13
7
14
8
15
9
16
9
16
Study Period Week
2
3
4
5
6
7
8
9
10
11
12
12
12
Study Period Day
8
±1
15
±1
22
29
±1
36
43
50
57
±1
64
71
78
±2
79
±2
80
±2
Patients should attend on stated 
day. When the patient is unable 
to attend CRU on the stated day,
visit windows should be used for 
dosing only.
Days 78, 79, and 80 should 
occur consecutively, without 
interruption.
Investigative Tests
Hypoglycemic clamp
X 
See Appendix 6
Diagnostics
PK sample
P
P
PK and immunogenicity to be 
time-matched as much as 
possible.
Immunogenicity 
P
P
Nonpharmacogenetic 
stored samples
P
Fasting sample.
Cognitive Assessments
Hypoglycemic symptom 
awareness
X
See Appendix 6
Hypoglycemic 
symptoms score
Abbreviations:  AEs = adverse events; BP = blood pressure; CRU = clinical research unit; ECG = electrocardiogram; P = predose; PK = pharmacokinetics; 
PR = pulse rate; SMPG = self-monitoring of plasma glucose.
Note:  If multiple procedures take place at the same time point, the following order may be consulted for prioritization:  ECG, vital signs, glucose sampling, 
counter-regulatory hormone samples, safety laboratory tests, PK samples, immunogenicity samples, cognitive assessments, storage samples.


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Study Schedule Protocol I8F-MC-GPHG: Washout Period
Procedure
Washout Period
Visit
Study Weeka
12-20 (12-22)
Study Daya
81-135 (81-149)
Clinical Procedures
Washout / crossover
X
Concomitant medications
Xb
AEs
Xb
Glucose Management
SMPG
Xb
Abbreviations:  AEs = adverse events; SMPG = self-monitoring of plasma glucose.
a
Washout period is at least 8 weeks and up to 10 weeks, if necessary.
b
Data will be reviewed and recorded in the electronic case report form at the dose 1 Period 2 visit.  


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Study Schedule Protocol I8F-MC-GPHG: Follow-up / Early Termination
Procedure
ET
Final FU
Comments
Visit
-
17
Study Week 
-
36
Study Day
As soon as 
possible after 
discontinuation
decision
Within 4 weeks 
from last dose/ET
Clinical Procedures
Weight 
X
X
Vital signs (BP/PR/body temperature)
X
X
Refer to screening table.
ECGs
X
X
Refer to screening table.
Concomitant medications
X
X
AEs
X
X
Physical examination / medical assessments
X
X
Refer to screening table.
Outpatient visit
X
X
Glucose Management
Review of study diary for SMPGa
X
X
Study diary collection
X
Laboratory Tests
Pregnancy test (women of childbearing potential)
X
X
Refer to screening table.
Diagnostics
PK sample
X
X
Samples for immunogenicity and PK to be time-
matched as far as possible.
Immunogenicity 
X
X
Abbreviations:  AEs = adverse events; BP = blood pressure; ECG = electrocardiogram; ET = early termination; FU = follow-up; PK = pharmacokinetics; 
PR = pulse rate; SMPG = self-monitoring of plasma glucose; 
a
SMPG will continue until Follow-up visit.  
Note:  If multiple procedures take place at the same time point, the following order may be consulted for prioritization:  ECG, vital signs, PK samples, 
immunogenicity samples.


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3. Introduction
3.1.
Study Rationale
Study I8F-MC-GPHG (Study GPHG) is an approximately 38-42 week Phase 1 study designed to 
evaluate the effect of tirzepatide (LY3298176) on hypoglycemic counter-regulation in patients 
with type 2 diabetes mellitus (T2DM) when compared to placebo treatment.  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).  Dual GIPR and GLP-1R agonism (GIPRA/GLP-1RA) may provide 
improved glycemic control in patients with T2DM, engaging multiple physiologic pathways, 
including glucagon secretion by the pancreatic cell.  Since glucagon plays a key role in defense 
against hypoglycemia, it is important to assess the effects of tirzepatide on the physiologic 
response to hypoglycemia.  Understanding the effect of tirzepatide on the counter-regulatory 
response to a hypoglycemic stimulus will provide important safety information for potential 
future clinical use.
3.2.
Background
GLP-1 is synthesized and secreted from enteroendocrine L cells in the small and large intestine 
and is a well-characterized incretin hormone that potentiates insulin and reduces glucagon 
secretion, in a glucose-dependent manner, after meal ingestion.  GLP-1 exerts its insulinotropic 
action through distinct G-protein-coupled receptors highly expressed on islet cells and also in 
some non-islet cells.  For example, GLP-1Rs are expressed throughout the brain, in regions that 
control glucose homeostasis, gut motility, food intake, aversive signaling, and cardiovascular 
function (Campbell and Drucker 2013).  Currently, there are several regulatory approved GLP-1 
receptor agonists (GLP-1 RAs) for the treatment of diabetes and obesity.  The dosing of 
GLP-1RAs in man is limited by gastrointestinal (GI) adverse effects, such as nausea and 
vomiting.
GIP, also known as gastric inhibitory polypeptide, is synthesized and secreted by 
enteroendocrine K cells in the proximal intestine.  GIPR is widely expressed in islets, gut, 
adipose tissue, and brain.  GIP secretion is primarily regulated by nutrients, especially fats. GIP 
is responsible for the majority of the insulinotropic incretin effect in man and has important 
additional functions that are distinct from GLP-1. GIP promotes glucagon secretion at low blood 
glucose (BG) levels to augment endogenous glucose production.  It stimulates lipolysis and 
inhibits insulin-induced lipogenesis in human adipocytes.  In preclinical models, the effect of
selective GIP signaling on body weight regulation was neutral. However, recent preclinical 
reports have demonstrated that GIPR agonism complements GLP-1R agonism to improve energy 
homeostasis, in addition to glucose-lowering effects. Co-administration of individual 
mono-agonists as well as unimolecular co-agonists have shown profound weight-lowering 
benefits that exceed that of either agent alone (Finan et al. 2016). Despite the observed effects of 
GIP, currently, no pharmaceutical agents that are based on its structure and function have been 
developed for treatment of metabolic conditions.  


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Tirzepatide, a dual GIPRA/GLP-1RA, is a 39-amino acid synthetic peptide.  Its structure is based 
on the GIP sequence and includes a C20 fatty di-acid moiety which facilitates albumin binding 
and thus prolongs the duration of action.  It has a chemical structure and pharmacologic profile 
that is distinct from the GLP-1RA due to the addition of GIP, which is unique among the 
marketed incretin mimetics.  It is administered once-weekly (QW) by subcutaneous (SC) 
injection.
Tirzepatide is being developed as a therapy to improve glycemic control in adults with T2DM, as 
an adjunct to diet and exercise. Phase 3 studies are also planned for chronic weight management 
in obese/overweight adults and a Phase 2 study is planned for non-alcoholic steatohepatitis.  
In a Phase 1 study (Coskun et al. 2018) that included single and multiple ascending dose (SAD, 
MAD) parts, tirzepatide has been administered as single SC doses up to 8 mg in healthy subjects.  
In the MAD part, higher doses up to 10 mg were attained in healthy subjects via dose escalation.  
Doses up to 15 mg were achieved in patients with T2DM via dose escalation.  In this study, GI
adverse events (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.  Most AEs were mild in severity, a few were moderate, and none 
were reported as severe.  During the SAD part of the study, the high incidence of GI AEs, 
notably vomiting, were considered to be dose limiting at the 8-mg dose; therefore, the 5-mg dose 
was considered the maximum tolerated dose.  A dose-dependent increase in heart rate was 
detected for both healthy subjects and patients with T2DM who received tirzepatide, similar to 
what was observed with selective GLP-1 RAs.  A few subjects experienced transient elevations 
in lipase and/or amylase levels, but these episodes were not associated with any relevant clinical 
outcomes.  
Once-weekly doses of 1, 5, 10, and 15 mg have been further investigated in a Phase 2 study 
(Frias et al, 2018).  An additional dose level of 12 mg and alternate dose escalation schemes 
were investigated in a 12-week Phase 2 study. Doses above 5 mg of tirzepatide were attained via 
step-wise dose escalation.  Results from the two Phase 2 studies demonstrated that tirzepatide at 
doses between 5 and 15 mg provided clinically meaningful efficacy in both glucose- and body 
weight-lowering. Gastrointestinal-related AEs (nausea, diarrhea, and vomiting) were the most 
frequently reported AEs in Phase 2 studies.  The majority of the treatment-emergent adverse 
events (TEAEs) were mild or moderate in severity. There were no other clinically relevant 
safety observations in the Phase 1 and 2 studies.
Tirzepatide terminal half-life was estimated to be approximately 5 days, thus supporting a QW 
dosing regimen, with maximum observed drug concentration (Cmax) occurring 24 to 72 hours 
postdose.  Tirzepatide QW dosing at 5, 10, and 15 mg is currently being investigated in Phase 3 
safety and efficacy studies in patients with T2DM.  
Hypoglycemia is a common side effect of diabetes therapy, resulting in a lack of adequate 
cerebral glucose supply, leading to a range of neurogenic and neuroglycopenic symptoms, which 
in turn can lead to death if not treated in time (Balijepalli et al. 2017).  It is defined as the 
decrease of BG level below 70 mg/dL (3.9 mmol/L) with or without symptoms of autonomic 


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nervous system activation and neuroglycopenia (EMA 2012, Seaquist et al 2013).  
Hypoglycemia is common in T2DM patients using a combination of oral glucose-lowering
medications, in subgroups of T2DM patients with renal insufficiency, and in elderly patients 
(Morales and Schneider 2014).  Additionally, the counter-regulatory systems against 
hypoglycemia are also affected in diabetic patients.  The responsiveness of counter-regulatory 
hormones, especially glucagon, recovery from hypoglycemia, and awareness of symptoms of 
hypoglycemia is essential for a patient with diabetes in particular if treated with medications with 
known risk of causing hypoglycemia.
The effect of dual agonist tirzepatide on secretion of counter-regulatory hormones like glucagon
and on hypoglycemia symptoms is currently unknown.  Study GPHG aims to characterize the 
counter-regulatory hormone response throughout hypoglycemia while ensuring that safety is not 
compromised during a controlled hypoglycemic stimulus in patients with T2DM during 
treatment with tirzepatide compared to placebo.
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.  These GI events were generally mild in severity, with few moderate, and no severe 
events reported in a Phase 1 study.  No other clinically relevant safety concerns were identified 
in the dose range up to 15 mg, the highest dose investigated in Phase 1 and in Phase 2 studies in 
T2DM patients, 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, such as GI effects, acute pancreatitis, increases in heart rate, and hypoglycemic events are 
consistent with the risks associated with currently available long-acting GLP-1RAs.  These risks 
are clinically detectable and manageable, and will be monitored during the study.
During the hypoglycemic clamp procedures, plasma glucose (PG) levels will be closely 
monitored and glucose infused, if necessary, to prevent PG dropping below the target values.  
Should the symptoms of hypoglycemia become unacceptable, glucose will be infused to increase 
PG.  Vital signs and continuous electrocardiogram (ECG) will be monitored during the clamp 
procedures and the clamp will be terminated should the patient experience symptoms of 
cardiovascular stress (tachycardia, bradycardia, or other relevant changes in ECG), or 
neurological symptoms related to neuroglycopenia.
In addition to the comprehensive safety monitoring plan for all patients included in this study, 
PG levels will also be regularly monitored outside of the hypoglycemic clamps to reduce risks 
related to acute diabetic complications.  Section 9.2.2.2 (Hypoglycemia) and Section 9.2.2.3
(Severe, Persistent Hyperglycemia) describe definitions and criteria when diagnosing and 
categorizing an episode considered to be related to hypoglycemia or hyperglycemia.  If a patient 
fulfills 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 7.7.1
(Management of Patients with Gastrointestinal Symptoms) provides detailed information 
concerning the management of GI AEs.


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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.


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4. Objectives and Endpoints
Table GPHG.1 shows the objectives and endpoints of the study.
Table GPHG.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To compare the effect of tirzepatide 15 mg QW and 
placebo on glucagon response during hypoglycemia in 
T2DM patients following 12 weeks of treatment
Change in mean glucagon concentration during 
induced hypoglycemia from target PG concentration of 
100 mg/dL to a nadir target of 45 mg/dL
Secondary
To compare the effect of tirzepatide 15 mg QW and 
placebo in T2DM patients following 12 weeks of 
treatment on:

Other counter-regulatory hormone responses 
during hypoglycemia, insulin and C-peptide

Change in mean glucagon concentration from target 
PG concentration of 100 mg/dL to 63 mg/dL and to 
recovery (PG concentration 72 mg/dL) from 
induced hypoglycemia 

Change in mean glucagon concentration from 
ambient PG to target PG concentrations of 100, 63, 
and 45 mg/dL, and to recovery (PG concentration 
72 mg/dL) from induced hypoglycemia 

Change in mean insulin, C-peptide, growth 
hormone, cortisol, adrenaline, and noradrenaline 
concentrations from target PG concentration of 
100 mg/dL to 63 and 45 mg/dL, and to recovery 
(PG concentration 72 mg/dL) from induced 
hypoglycemia 

Time to hypoglycemia recovery

Time from termination of insulin infusion at PG 
concentration of 45 mg/dL to reach recovery PG 
concentration (72 mg/dL) (tPG_nadir-72 mg/dL)

Clinical hypoglycemia

Hypoglycemic symptoms score at PG 
concentrations of 100, 63, and 45 mg/dL and after 
recovery (PG concentration 72 mg/dL) from 
induced hypoglycemia

Hypoglycemic awareness at PG concentrations of 
100, 63, and 45 mg/dL and after recovery (PG 
concentration 72 mg/dL) from induced 
hypoglycemia

Vital signs during hypoglycemia

Change in mean systolic and diastolic blood 
pressure and pulse rate from target PG 
concentration of 100 mg/dL, to 63, and 45 mg/dL, 
and to recovery (PG concentration 72 mg/dL) from 
induced hypoglycemia

Additional safety and tolerability

AEs

Incidence of hypoglycemia outside of the 
hypoglycemic clamps


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Exploratory
To compare the effect of tirzepatide 15 mg QW and 
placebo in T2DM patients following 12 weeks of 
treatment on:

Other hypoglycemic clamp and recovery 
parameters

Amount of insulin required to reach PG 
concentrations of 63 and 45 mg/dL from 
100 mg/dL. 

AUCGIR,PG_nadir-72 mg/dL

Proportions of patients who require glucose infusion 
to attain recovery (PG concentration 72 mg/dL) and 
associated Gtot
PG achieved at the end of spontaneous recovery

Other safety parameters

Frequency of treatment-emergent anti-tirzepatide 
antibodies
Abbreviations:  AE = adverse event; AUCGIR,PG_nadir-72 mg/dL = area under the glucose infusion rate curve from 
time of termination of insulin infusion until recovery (PG concentration of 72 mg/dL); Gtot = total amount of 
glucose infused; PG = plasma glucose; QW = once-weekly; T2DM = type 2 diabetes mellitus.
Plasma glucose concentrations:  100 mg/dL = 5.5 mmol/L; 72 mg/dL = 4.0 mmol/L; 63 mg/dL = 3.5 mmol/L; 
45 mg/dL = 2.5 mmol/L;  glucagon at ambient PG measured in the pre-prandial state prior to clamp initiation.  


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5. Study Design  
5.1.
Overall Design
This is a Phase 1, single-center, 2-period, crossover, randomized, patient- and investigator-blind 
study in T2DM patients.  This study is designed to compare tirzepatide 15 mg QW and placebo 
with respect to secretion of counter-regulatory hormones in response to a hypoglycemic stimulus 
and parameters of recovery from hypoglycemia.
Eligibility for this study will be assessed at screening (Visit 1) and confirmed at the beginning of
the lead-in period (Visit 2).  After eligibility is confirmed at Visit 2, patients will receive training 
and information on how to subsequently monitor their own diabetes condition.  Where 
applicable, patients will be required to undergo a washout of OAMs other than metformin
between Visit 2 and Visit 3 (refer to Section 5.1.1 for details)
Following baseline assessments, eligible patients will be randomized (Visit 3) to treatment 
sequence.  All patients will undergo 2 treatment periods, receiving tirzepatide in 1 period and 
placebo in the other, in a crossover fashion.  
Tirzepatide 15 mg will be attained via step-wise dose escalation to reduce the risk of GI AEs as 
described in Section 5.1.2 (Treatment).  
There will be a washout period of at least 8 weeks between the last dose of study drug in 
Period 1 and the first dose in Period 2. The washout period will ensure sufficient washout of the 
study drug based on tirzepatide’s elimination half-life of approximately 5 days.
At the end of each treatment period, patients will undergo a hypoglycemic clamp procedure (see 
Appendix 6 for details).
Study governance considerations are described in detail in Appendix 3.
Figure GPHG.1 illustrates the study design.


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Figure GPHG.1
Illustration of study design for Protocol I8F-MC-GPHG.
5.1.1. Screening, Lead-in, and Randomization
Eligibility for this study will be assessed during the screening period (Visit 1).  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).  Final 
determination of eligibility will occur at the beginning of the lead-in period at Visit 2, after all 
screening results are available. Eligible patients are those with T2DM treated with diet, exercise, 
and metformin with or without one other allowed oral antidiabetic medication (OAM) as 
specified in Inclusion Criterion [2].  
Eligibility for this study for patients on metformin only will be assessed at the screening (Visit 1) 
up to 17 days prior to enrollment (Day -14 ±3) and confirmed at the beginning of the lead-in 
period (Visit 2). Eligible patients treated with metformin only will proceed to Visit 3 after 
approximately 1-week lead-in.  
Eligible patients who are, in addition to metformin, on 1 more OAM, will discontinue this OAM 
immediately after Visit 2 and will undergo a 4-week washout between Visit 2 and Visit 3.
During this washout period, the investigator will perform appropriate surveillance of the patients 
(by telephone interview and additional CRU visits, if necessary, at the investigators discretion) to 
monitor the safety and glycemic control of the patients. Once the 4-week washout period is 
completed, patients will proceed to Visit 3.  Upon entering the study, patients should remain on 
the same metformin dose throughout the course of the study.  Between screening and 
randomization (Day 1) eligible patients should continue their prestudy therapy with metformin.  
Patients who do not comply with requirements regarding metformin dosing will be discontinued 


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from the study prior to randomization.  After randomization, the metformin dose can only be 
reduced in accordance with country-specific label to protect patient safety (see Section 7.7
[Concomitant Therapy] for further details).
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 at the lead-in visit (Visit 2).  Patients will start performing daily SMPG and record all 
results, including any hypoglycemia episode, in diaries as soon as their eligibility is confirmed at 
Visit 2.  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 a stable diet and exercise plan throughout the course of the study
Patients will be randomized on Day 1 of Period 1 after undergoing baseline assessments; eligible 
patients will be randomized 1:1 to 12 weeks QW tirzepatide followed by 12 weeks QW placebo, 
or vice versa.  Patients will then receive their first dose of study treatment.  
5.1.2. Treatment
The tirzepatide treatment period will consist of a step-wise dose escalation.  The starting dose 
will be 2.5 mg QW for 2 weeks, followed by an increase to 5 mg QW for 2 weeks, and 10 mg 
QW for 4 weeks until the 15-mg dose is reached and maintained for the remainder of the 
treatment period (4 weeks), see Section 5.5 (Justification for Dose) for further details.  Patients 
will visit the clinical research unit (CRU) as outpatients 1 week after administration of the first 
dose (Week 2) and for administration of the first of each escalated dose during both the 
tirzepatide and placebo treatment periods (Weeks 3, 5 and 9 of each treatment period). Study 
drug will be dispensed to the patient at these visits for self-administration on all other dosing 
days.  Telephone visits will be conducted to ensure that outpatient dosing occurs and to monitor 
safety.
The schedule of clinic visits and study procedures during the treatment periods, including 
sampling for immunogenicity and pharmacokinetic (PK) assessments, are provided in Section 2
(Schedule of Activities).  
Patients will attend the CRU as outpatients on Week 12 of each treatment period to receive the 
final dose of study drug.  The following day, patients will be admitted to the CRU and will 
undergo a hypoglycemic clamp procedure as detailed in Appendix 6.
Patients who initiate rescue medication for treatment of severe hyperglycemia (Section 7.4.1.2
Management of Hyperglycemia) during the study may continue in the study but rescue 
medication will be discontinued 1 week before the clamp procedure to avoid interference with 
measurements planned during the hypoglycemic clamp.  
Patients who permanently discontinue study treatment early, 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 the decision to discontinue study 
treatment, followed by a safety follow-up visit up to 4 weeks later.


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5.1.3. Washout Between Treatment Periods
There will be a washout period of at least 8 weeks, but not longer than 10 weeks, between the 
final dose of study drug in the first treatment period (on Week 12) and the first dose of study 
drug in the second treatment period based on tirzepatide’s elimination half-life of approximately 
5 days.
5.2.
Number of Participants
Approximately 38 patients may be enrolled so that 30 complete the study.  For the purposes of 
this study, a patient completes the study when all scheduled procedures through completion of 
the second hypoglycemic clamp procedure as per the Schedule of Activities (Section 2) have 
been finished.
5.3.
End of Study Definition
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last patient.
5.4.
Scientific Rationale for Study Design
Study GPHG will employ a crossover design which allows each patient to serve as his or her 
own control, thereby reducing variability.  The study is patient- and investigator-blind to 
minimize potential bias.
The use of a clamp procedure with regular glucose monitoring will permit the effects of 
tirzepatide and placebo to be compared in patients with T2DM with standardized, stable 
measurement conditions, with the highest safety standards with regards to hypoglycemia 
detection and treatment.  
Patients with T2DM are a target population of tirzepatide and therefore the appropriate 
population for conducting the study.  
The dose justification for tirzepatide is provided in Section 5.5 (Justification for Dose).
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 QW and will be escalated to 15 mg QW as 
described in Section 5.1.2 (Treatment).  The step-wise increments are based on cumulative 
understanding of safety and GI tolerability from Phase 1 and 2 studies and are expected to 
minimize GI tolerability concerns by permitting adequate time for development of tolerance to 
GI events.


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While a steeper dose escalation scheme with a higher starting dose of 5 mg, escalating to 15 mg 
within 7 weeks was previously implemented in Phase 2 and was found to be safe; this scheme 
was associated with some GI tolerability concerns.
To minimize the incidence of GI tolerability events, this study will employ a lower starting dose 
of 2.5 mg to initiate the dose escalation, permitting 8 weeks of step-wise escalation prior to
attaining a maintenance dose of 15 mg at Week 9.  Treatment will be continued for 4 weeks after 
reaching the 15-mg maintenance dose, to allow steady-state exposures to be attained.


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6. Study Population
Eligibility of patients for the study will be based on the results of screening medical history, 
physical examination, vital signs, safety laboratory tests, and 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 45 days prior to start of randomization for patients treated with 
metformin and one other OAM, who are required to perform a washout during lead-in. For all 
other patients, screening may occur up to 17 days prior to randomization and perform a
minimum 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 45 days 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 and/or at other visits prior to randomization, when indicated:
Disease Characteristics
[1]
Have had T2DM for at least 1 year;
[2]
Treated with diet and exercise and a stable dose of metformin (3 months prior 
to study entry) with or without 1 additional OAM other than metformin; doses 
of metformin will be considered stable if all prescribed doses for the previous 
3 months were ±850 mg from the most commonly prescribed dose; allowed 
OAMs, in combination with metformin are DPP-IV inhibitors, SGLT-2 
inhibitors, acarbose, glinides and sulfonylureas; in patients with established
cardiovascular disease who are treated with SGLT-2 inhibitors, this therapy
should not be discontinued and therefore, these patients will NOT be eligible 
for participation in the trial.
[3a] Have a hemoglobin A1c value at screening of ≥6.5% and ≤9.0% (48 to 
75 mmol/mol), if on metformin only; 
[3b] Have a hemoglobin A1c value at screening of ≥6.0% and ≤8.5% (42 to 
69 mmol/mol), if on metformin and 1 more allowed OAM; 
Patient Characteristics
[4]
Male or female patients aged 18 to 70 years, inclusive
[4a] Male patients:


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
Men, regardless of their fertility status, with nonpregnant women 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 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 method of contraception.  
Thus, each barrier method must include use of a spermicide.  It should 
be noted, however, that the use of male and female condoms as a 
double-barrier method is not considered acceptable due to the high 
failure rate when these barrier methods are combined).
o
Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
postovulation methods), declaration of abstinence just for the duration 
of the 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 (e.g., 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.


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o
Women of childbearing potential participating must test negative for 
pregnancy prior to initiation of treatment as indicated by a negative 
serum pregnancy test at the screening visit followed by a negative urine 
pregnancy test within 48 hours prior to exposure and at other times as 
specified in Section 2 (Schedule of Activities).  
o
Two forms of effective contraception, where at least 1 form is highly 
effective (less than 1% failure rate, such as combination oral 
contraceptives, implanted contraceptives, or intrauterine devices) will be 
used.  Effective contraception (such as male or female condoms with 
spermicide, diaphragms with spermicide, or cervical sponges) may be 
used as the second therapy.  Barrier protection methods without 
concomitant use of a spermicide are not a reliable or acceptable method.  
Thus, each barrier method must include use of a spermicide (that is, 
condom with spermicide, diaphragm with spermicide, female condom 
with spermicide).  It should be noted that the use of male and female 
condoms as a double-barrier method is not considered acceptable due to 
the high failure rate when these methods are combined.

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 either
i.
A woman at least 50 years of age with an intact uterus, not on 
hormone therapy, who has had either
a) cessation of menses for at least 1 year, or
b) at least 6 months of spontaneous amenorrhea with a 
follicle-stimulating hormone >40 mIU/mL; or
ii.
A woman at least 55 years of age not on hormone therapy, who 
has had at least 6 months of spontaneous amenorrhea; or
iii.
A woman at least 55 years of age with a diagnosis of 
menopause prior to starting hormone replacement therapy.
[5]
Have a body mass index between 23.0 kg/m2 and 45.0 kg/m2, inclusive, at screening; 
are of stable weight (±5%) >3 months prior to screening; and agree not to 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.


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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 and/or at other visits prior to randomization, when indicated:
Primary Study Condition - Diabetes Related
[9]
Have type 1 diabetes mellitus;
[10] Have had more than 1 episode of severe hypoglycemia, as defined by the 
American Diabetes Association criteria, within 6 months before screening 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;
[12] Have a history of proliferative retinopathy or maculopathy as determined by 
the investigator based on a recent (<6 months) ophthalmologic examination;
[13] Impaired renal estimated glomerular filtration rate <60 mL/min/1.73 m2
calculated by Chronic Kidney Disease-Epidemiology.  One retest may be 
performed in case of an initial result <60 mL/min/1.73 m2. The highest value 
from the 2 tests will be accepted.  
Prior/Concomitant Therapy - Glucose-Lowering Medications
[14] Have taken any glucose-lowering medications other than those indicated in 
Inclusion Criterion [2] during the last 3 months before screening or during the 
screening/lead-in 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 (see Section 7.7 Concomitant Therapy)
Medical Conditions - General
[15] Have a history or current cardiovascular, respiratory, hepatic, renal, GI, 
endocrine, hematological, 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;


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[17] Have a known clinically significant gastric emptying abnormality (e.g., severe 
diabetic gastroparesis or gastric outlet obstruction) or have undergone gastric 
bypass (bariatric) surgery or restrictive bariatric surgery (e.g., Lap-Band®);
[18] Have a personal or family history of medullary thyroid carcinoma (MTC), 
multiple endocrine neoplasia syndrome type 2 (MEN 2), or calcitonin 
≥20 pg/mL (≥ 5,85 pmol/L) at screening;
[19] Have had acute myocardial infarction, congestive heart failure New York 
Heart Association Class III or IV, history of or suspected ischemic heart 
disease, and/or cerebrovascular accident (stroke [including transient ischemic
attack]);
[20] Have findings in the 12-lead ECG at screening 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;
[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.  
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) >2.5× the upper limit of normal (ULN) or total bilirubin level (TBL) 
>1.5× ULN;
[25] Have had a blood donation of 500 mL or more in the last 3 months or any 
blood donation within the last month prior to screening;
[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;


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[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 4 hours 
before each CRU admission and outpatient visit, and throughout the duration 
of each CRU visit;
[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 each CRU admission and outpatient 
visit, and throughout the duration of each CRU visit;
[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 (e.g., 
sibutramine, mazindol, phentermine, lorcaserin, naltrexone/bupropion, 
liraglutide) or similar other body weight loss medications, including 
over-the-counter medications (e.g., alli®) within 3 months prior to screening 
or between screening and randomization;
[31] Have received chronic (lasting >14 consecutive days) systemic glucocorticoid 
therapy (excluding topical, intra-articular, and inhaled preparations) within 
1 month before screening, or between screening and randomization;
[32] Have received treatment with a drug that has not received regulatory approval 
for any indication within 1 month prior to screening; 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 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, University of Graz, or Covance employees.;
[38] Are deemed unsuitable by the investigator for any other reason.


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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 attend the CRU in a fasting state, after an overnight fast lasting at 
least 8 hours, for safety laboratory tests and hormone assessments, or for longer during the 
hypoglycemic clamp.
6.3.2. Caffeine, Alcohol, and Tobacco
No alcohol will be allowed at least 24 hours before each CRU admission and outpatient visit and 
throughout the duration of each CRU visit.  Caffeine consumption will not be permitted during 
the hypoglycemic clamp visits.  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
outpatient visit and throughout the duration of each CRU visit.  While not resident in the CRU, 
nicotine use must be 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 CRU, 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) may be re-screened up to 1 additional time.  
Additionally, individuals who had been rescreened once and marked as screen failures during the 
halt in enrolment due to the 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 site screening number.  
If patients are rescreened, they will be assigned a new screening number.  Patient 
numbers/enrollment numbers are assigned at Visit 2 to ensure only eligible patients enter the 
study.


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7. Treatment
7.1.
Treatment Administered
This study involves a crossover comparison of tirzepatide 15 mg and placebo administered SC 
QW for 12 weeks per treatment period with a washout of at least 8 weeks between treatment 
periods.
Table GPHG.2 shows the treatment regimens and dose escalation plan.
Table GPHG.2.
Dose Titration
Dose Titration Schemes 
Treatment
Week 1-2
Week 3-4
Week 5-8
Week 9-12
Tirzepatide
1 × 2.5-mg PFS
1 × 5-mg PFS
1 × 10-mg PFS
1 × 15-mg PFS
Placebo
1 × PFS
1 × PFS
1 × PFS
1 × PFS
Abbreviations:  PFS = prefilled syringe.
All treatments will be administered QW, either at the CRU or self-administered by the patient.  
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.  
The investigator or designee is responsible for:

explaining the correct use of the IP to the patient and 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 site will be instructed to discard used medications according to local regulations.
7.1.1. Packaging and Labeling
All strengths of tirzepatide will be provided as prefilled syringes (PFS) containing 0.5-mL 
solution and provided in individual cartons to be dispensed.  Placebo will also be provided as 
matching 0.5-mL PFS.
The IP will be labeled according to the country’s regulatory requirements.


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7.1.2. Medical Devices
The medical devices provided for patient use in the study (SMPG) are commercially available 
glucose meters and lancets.
7.2.
Method of Treatment Assignment
Patients who meet all criteria for enrollment will be randomized to receive either tirzepatide 
15 mg followed by placebo or vice versa.  Assignment to treatment sequence will be determined 
by a randomization table with treatment codes.  
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 and at approximately the same time of the day.  Visit windows should be used for 
dosing only when the patient is unable to attend the CRU on the scheduled day.  The actual time 
of all dose administrations will be recorded in the patient’s electronic case report form (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 72 hours prior to the next scheduled dose.  If the 
remaining time to the next scheduled dose is less than 72 hours, the dose will not be administered 
and will be considered a missed dose.
7.3.
Blinding
This study is a patient- and investigator-blind study.  Blinding will be maintained throughout the 
conduct of the study as described in the separate Blinding Plan.
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 patient to continue in the study.  During the study, 
emergency unblinding should occur only by accessing the patient’s emergency code.
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a patient’s treatment assignment is warranted for medical management of the event.  The 
patient’s safety must always be the first consideration in making such a determination.  If the 
investigator decides that unblinding is warranted, it is the responsibility of the investigator to 
promptly document the decision and rationale and notify Lilly as soon as possible.
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 during the 
dose escalation phase of the study, dosing can be interrupted temporarily (Section 8.1.2
Temporary Interruption of Study Drug).
7.4.1. Special Treatment Considerations
Plasma glucose values will be measured daily at fasting by the patient using the BG meter 
provided during the lead-in period, after the eligibility is confirmed.  Additional SMPG 


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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
To reduce the risk of hypoglycemia during the study, patients who have experienced more than 
1 episode of severe hypoglycemia, as defined by the American Diabetes Association criteria in 
the 6 months prior to screening, who have a history of hypoglycemia unawareness or poor 
recognition of hypoglycemic symptoms, or who cannot communicate an understanding of 
hypoglycemic symptoms and the appropriate treatment of hypoglycemia prior to the first dose of 
study drug, will not be enrolled in the study.  
If spontaneous 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.
Should severe hypoglycemic episodes with coma, seizure, or neurologic impairment occur at any 
time, the patient may be treated with intramuscular/SC glucagon and/or concentrated intravenous 
(IV) glucose and will be discontinued from the study.  Sustained carbohydrate intake and 
observation may be necessary because hypoglycemia may recur after apparent clinical recovery.  
For management of hypoglycemia during the clamp procedures, see Section 7.4.1.3 (Treatment 
of Hypoglycemia during Hypoglycemic Clamp).
For hypoglycemia reporting, see Section 9.2.2.2 (Hypoglycemia).
7.4.1.2.
Management of Hyperglycemia
If SMPG records indicate that PG values are exceeding the limits for severe, persistent 
hyperglycemia described in Section 9.2.2.3 (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 that does not 
interfere with study measurements.  Acceptable rescue medications are listed in Section 7.7
(Concomitant Therapy). Patients who initiate rescue medications will be advised to follow 
appropriate national and international standards of care for management of diabetes, including 
applicable glycemic targets and SMPG schedule.  
7.4.1.3.
Treatment of Hypoglycemia during Hypoglycemic Clamp
The aim of the hypoglycemic clamp is to induce hypoglycemia in a controlled manner, with PG 
closely monitored and variable glucose infusion preventing PG falling below the target 
concentration.  Should the symptoms of hypoglycemia become unacceptable, glucose will be 
infused to increase PG and this may result in PG concentrations above the target 45 mg/dL 
(2.5 mmol/L) being considered as the nadir.  


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7.5. Preparation/Handling/Storage/Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained, as communicated by the sponsor, during transit for all IP received and any 
discrepancies are reported and resolved before use of the study treatment.
Only participants enrolled in the study may receive IP or study materials, and only authorized 
site staff may supply IP to patients for self-administration, or administer IP when patients are at 
the CRU. At the CRU, 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.  Patients should store supplies for self-administration 
in accordance with the carton label.  
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
When the IP is administered at the study site, documentation of treatment administration will 
occur at the site.  When IP is self-administered by the patient, they will document administration 
in their diary.  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 dosing regimen 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 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.  In addition, one additional OAM is allowed prior to 
randomization (Refer to Inclusion Criterion [2]), but must be discontinued after eligibility is 
confirmed at Visit 2, in which case a 4-week minimum washout is required.
Refer to Section 5.1.1 and 5.1.3 for additional information on washout period prior to starting 
study treatment.
Patients are required to continue metformin as their only concomitant antihyperglycemic 
medication during the entire study. 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 country-specific label (for example, because 
of reduced renal function), the patient will be considered ineligible and will be discontinued from 
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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 study.  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.  
Glucose-lowering medications, other than rescue medications after randomization, 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. In the case of acute conditions, a short-term (<14 days) use 
of insulin is allowed any time prior to entry and after randomization, but not during the 
screening/lead-in period.  
The allowed rescue medications in the case of severe, persistent hyperglycemia after 
randomization are insulin and sulphonylureas. The preference should be given to the use of 
insulin, with sulphonylurea to be considered only if the patient is not willing to initiate insulin 
therapy. The sodium-dependent glucose co-transporter-2 (SGLT2) inhibitors should not be used 
because of possible interference with regulation of glucagon secretion. The GLP-1 RAs and 
dipeptidyl peptidase IV inhibitors should not be used because these classes of agents share the 
same mode of action pathways with dual GIP/GLP-1 RAs. Patients will be required to 
discontinue rescue medications 1 week prior to the clamp procedures.
After the completion of the treatment periods, patients can receive other glucose-lowering 
agents, except GLP-1 RAs.  
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 
study.  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 safety follow-up within 
4 weeks).  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 
study.  If used ≤14 days, the patient will be required to discontinue this treatment and continue in 
the study.


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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 they should not 
be used prophylactically. Similarly, antidiarrheal agents are allowed to be prescribed if the 
patient reports AEs 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).
7.7.1. Management of Patients with Gastrointestinal Symptoms
The tirzepatide dose escalation scheme has been designed to reduce the development of 
intolerable GI symptoms.  The escalation period for tirzepatide is considered to be 8 weeks to 
reach the 15-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 drug 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 will not be made available to patients after completion of the study.


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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 after randomization

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 at any time, including during the hypoglycemic clamp procedure,
with any other 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 a female patient becomes pregnant

If a patient is diagnosed with type 1 diabetes mellitus

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)
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


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
ALT or AST >3X ULN with the appearance of fatigue, nausea, vomiting, right 
upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)

alkaline phosphatase (ALP) >3X ULN

ALP >2.5X ULN and TBL >2X ULN

ALP >2.5X ULN with the appearance of fatigue, nausea, vomiting, right quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (>5%)
Patients who discontinue study drug early will also be 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 (i.e., while the dose is lower than 15 mg) and not during the 
4-week maintenance phase of dosing with 15 mg.  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 2 or more episodes of 
study interruptions occur in the same patient, these cases will be reviewed by the investigator (or 
his/her designee) and Lilly 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 specified 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.  


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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

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, in which case 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.


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9. Study Assessments and Procedures
Section 2 lists the Schedule of Activities, detailing the study procedures and their timing.
Appendix 2 lists the laboratory tests that will be performed for this study.
Appendix 5 provides a summary of the approximate number and volume of invasive samples, for 
all sampling, during the study.
The specifications in this protocol for the timings of safety and sample collections are given as 
targets to be achieved within reasonable limits.  Modifications may be made to the time points 
based upon emerging clinical information.  The scheduled time points may be subject to minor 
alterations; however, the actual time must be recorded correctly in the eCRF.  Failure or delays 
(i.e., outside stipulated time allowances) in performing procedures or obtaining samples due to 
legitimate clinical issues (e.g., equipment technical problems, venous access difficulty, or patient
defaulting or turning up late on an agreed scheduled procedure) will not be considered as 
protocol deviations but the CRU will still be required to notify the sponsor in writing via a file 
note.
Unless otherwise stated in subsections below, all samples collected for specified laboratory tests 
will be destroyed within 60 days of receipt of confirmed test results.  Certain samples may be 
retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards.
9.1.
Efficacy Assessments
Not applicable.
9.2.
Adverse Events
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the patient.
The investigator is responsible for the appropriate medical care of patients during the study.
Investigators must document their review of each laboratory safety report.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the 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, or is 
reasonably explained.  The frequency of follow-up evaluations of the AE is left to the discretion 
of the investigator.
The investigator will record all relevant 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 


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treatment in the study.  Additionally, site personnel will record any change in the condition(s) 
and the occurrence and nature of any AEs.  
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, study device, or a study procedure, taking into account the 
disease, concomitant treatment or pathologies.  
A “reasonable possibility” means that there is a potential cause and effect relationship between 
the 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.
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 eCRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a patient has 


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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.
Severe Gastrointestinal Adverse Events
Tirzepatide 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).
9.2.2.2.
Hypoglycemia
Patients will collect information on episodes of hypoglycemia starting immediately after their 
eligibility is confirmed until the last study visit (follow-up visit).  For that purpose, patients will 
be trained during 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.
Outside of the hypoglycemic clamp procedure, 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).

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).


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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.  Plasma 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 
eCRF and reported to Lilly as an SAE.
To avoid duplicate reporting, all consecutive PG 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).
Additional assessments related to hypoglycemia will be performed during the hypoglycemic 
clamp procedures, including responses of counter-regulatory hormones (glucagon, growth 
hormone, adrenaline and noradrenaline, and cortisol), symptoms of hypoglycemia, and 
parameters related to recovery from hypoglycemia. The measures to evaluate these aspects of 
hypoglycemia are included in the primary, secondary, and exploratory objectives of the study 
and are described in further details in Section 9.6 (Pharmacodynamics).


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9.2.2.3.
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 fasting PG is greater than 270 mg/dL (15 mmol/L) over any 2-week period 
between Day 1 and end of Week 6.

The average fasting PG is greater than 240 mg/dL (13.3 mmol/L) over any 2-week period 
between Week 7 and end of Week 12.
Section 7.4.1.2 (Management of Hyperglycemia) and Section 7.7 (Concomitant Therapy) 
provide treatment guidance for patients with severe, persistent hyperglycemia.
9.2.2.4.
Pancreatitis
Acute pancreatitis is defined as an AE of interest in all studies with tirzepatide including this 
study.  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 study drug, and will be discontinued from the study 
after completing all ET and follow-up 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 AE of pancreatitis must be reported.  If typical signs and/or symptoms of pancreatitis are 
present and confirmed by laboratory values (lipase or amylase [total and/or pancreatic]) and 
imaging studies, the event must be reported as an SAE.  For a potential case that does not meet 
all of these criteria, it is up to the investigator to determine the seriousness of the case (AE or 
SAE) and the relatedness of the event to study drug.
Each patient will have measurements of amylase and lipase, part of safety laboratory tests as 
shown in Section 2 (Schedule of Activities) to assess the effects of study drug on pancreatic 
enzyme levels.  Serial measures of pancreatic enzymes have limited clinical value for predicting 


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episodes of acute pancreatitis in asymptomatic patients (Nauck et al. 2017; 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 judgement and assessment of the patient’s 
overall clinical condition.  If further diagnostic assessment due to asymptomatic 
hyperenzymemia is 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.
9.2.2.5.
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 calcitonin values ≥20 pg/mL (≥5.89 pmol/L) 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 treatment 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 pg/mL.  If the calcitonin value decreases below 
35 pg/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 additional assessment will be 
collected in the specific section of the eCRF.  


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9.2.2.6.
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
9.2.2.7.
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.
9.2.2.8.
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 
via an eCRF created for this purpose.  Additional serum samples should also be collected as 
outlined in Appendix 8.  Study drug should be temporarily interrupted in any individual 
suspected of having a severe or serious allergic reaction to study drug.  Study drug may be 
restarted when/if it is safe to do so, in the opinion of the investigator.  If study drug 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).  
9.2.2.9.
Injection-site Reactions
Injection-site reactions will be collected on the eCRF created for these events (see Section 9.4.6).  
At the time of AE occurrence, samples will be collected for measurement of tirzepatide anti-drug 
antibody (ADA) and tirzepatide concentration.
9.2.2.10. Diabetic Retinopathy Complications
Treatment-emergent AEs related to diabetic retinal complications will be assessed by an 
ophthalmologist and should include dilated fundoscopic examination.  
9.2.2.11. 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 


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cases of elevated liver markers, hepatic monitoring should be initiated as outlined in 
Section 9.4.5.1 (Hepatic Safety) and Appendix 4.
9.2.2.12. 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.
9.2.2.13. 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 (13.9 mmol/L).  
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 decreased renal function.  If lactic acidosis is 
suspected, metformin should be temporarily discontinued until the resolution of the event.
9.2.2.14. Amputation/Peripheral Revascularization
All cases of amputation and peripheral revascularization should be reported as an AE.
9.2.2.15. 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.
9.3.
Treatment of Overdose
For the purposes of this study, an overdose of tirzepatide is considered any dose higher than the 
dose assigned through randomization or as defined by the protocol.  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


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9.4.
Safety
Safety measures to address the primary and secondary objectives of the study include glucagon 
and other counter-regulatory hormone concentrations, assessment of symptoms of hypoglycemia
and AEs, time to reach recovery PG concentrations (72 mg/dL [4.0 mmol/L]), and vital signs 
measurements taken during the hypoglycemic clamp procedures.  See Section 9.6
(Pharmacodynamics) for further details.  
9.4.1. Laboratory tests
For each patient, laboratory tests to assess PD and safety of study drug will be performed 
throughout the study according to the schedule provided in Section 2 (Schedule of Activities).  A 
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.
Systolic and diastolic blood pressure, pulse rates, and body temperature will also be measured 
throughout the hypoglycemic clamp procedures (see Section 9.6.2).  
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 entry 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/QT
corrected for heart rate [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.


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Electrocardiogram will be measured throughout the hypoglycemic clamp procedures (see 
Appendix 6).  
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, including GI events, 
pancreatitis, and serious hypoglycemic 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 patient experiences elevated ALT ≥3X ULN, ALP ≥2X ULN, or elevated total bilirubin ≥2X 
ULN, liver tests (Appendix 4) should be repeated within 3 to 5 days including ALT, AST, ALP, 
TBL, direct bilirubin, gamma-glutamyl transferase (GGT), and creatine phosphokinase to 
confirm the abnormality and to determine if it is increasing or decreasing.  If the abnormality 
persists or worsens, clinical and laboratory monitoring should be initiated by the investigator 
based on consultation with the Lilly CP or CRP.  Monitoring should continue until levels 
normalize and/or are returning to approximate baseline levels.  
Additional safety data should be collected if 1 or more of the following conditions occur: 

elevation of serum ALT to ≥ 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 discontinued from treatment due to a hepatic event or abnormality of liver 
tests

hepatic event considered to be a SAE.
9.4.6. Injection-site Reactions
Injection-site assessments for local tolerability will be conducted, when reported as:

an AE from a patient, or


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
a clinical observation from an investigator.
Reported injection-site reactions will be characterized within the following categories:

edema

erythema

induration

itching

pain
All injection-site reactions reported as AEs will be closely monitored until resolution.  The report 
of a clinically significant AE of injection-site reaction may prompt notification of the sponsor, 
clinical photography, and referral for dermatologic evaluation and consideration of a skin biopsy 
and laboratory evaluations (ALT, AST, complete blood count with percent eosinophils, and 
additional immunogenicity testing).
Site staff will be provided with separate instructions/training on how to evaluate injection-site 
reactions and their severity in a consistent manner.  Photographs of injection-site reactions may 
be taken in a standardized manner for record-keeping purposes; however, the photographs will 
not be used to evaluate the severity of injection-site reaction.
9.5.
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 
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 during placebo treatment are not planned.
Bioanalytical samples collected to measure IP concentrations will be retained for a maximum of 
2 years following last patient visit for the study.  During this time, samples remaining after the 
bioanalyses may be used for exploratory analyses such as metabolism work, protein binding, or 
bioanalytical method cross-validation.
9.6.
Pharmacodynamics
The samples 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.  


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A description of procedures for obtaining the samples for pharmacodynamic (PD) parameters is 
detailed in Appendix 6.  Briefly, PD assessments will include measurement of glucagon, insulin, 
C-peptide, growth hormone, cortisol, adrenaline, and noradrenaline before and/or during the 
hypoglycemic clamp, as well as clinical symptoms of hypoglycemia, hypoglycemia awareness,
and time to recovery from hypoglycemia following the clamp procedure.  Vital signs will also be 
measured during the procedure and data will be collected in the clinical trial database for 
analyses.  
9.6.1. Primary Pharmacodynamic Assessments and Procedures
The primary PD measure in this study is the mean glucagon concentration change from target PG 
of 100 mg/dL (5.5 mmol/L) to a target nadir PG of 45 mg/dL (2.5 mmol/L) during induced 
hypoglycemia for comparison of tirzepatide with placebo.  
Glucagon concentration at the PG target concentration of 100mg/dL (5.5 mmol/L) will be 
calculated as the mean of measurements taken 20, 10, and 0 minutes prior to induction of 
hypoglycemia.  Glucagon concentration at the PG target concentration of 45 mg/dL 
(2.5 mmol/L) will be calculated as the mean of measurements taken 10, 20, and 30 minutes after 
reaching a nadir PG of 45 mg/dL (2.5 mmol/L), or a higher nadir PG if 45 mg/dL (2.5 mmol/L) 
cannot be achieved for practical or safety reasons.  
9.6.2. Secondary Pharmacodynamic Assessments and Procedures
The following will be secondary PD measures in the study.
Secondary PD measures to assess the effect of tirzepatide compared to placebo on 
counter-regulatory hormone, insulin, and C-peptide concentrations.

Change in mean glucagon concentration (calculated as the mean of 3 measurements 
during the clamp, measured singly at recovery) from target PG concentration of 
100 mg/dL (5.5 mmol/L) to 63 mg/dL (3.5 mmol/L) and after recovery from induced 
hypoglycemia (PG 72 mg/dL [4.0 mmol/L]).

Change in mean glucagon concentration (calculated as the mean of 3 measurements 
during the clamp, measured singly at recovery) from ambient PG to target concentrations 
of 100, 63, and 45 mg/dL, and after recovery from induced hypoglycemia (PG 72 mg/dL)
(5.5, 3.5, 2.5, and 4.0 mmol/L, respectively).

Change in mean insulin, C-peptide, growth hormone, cortisol, adrenaline, and 
noradrenaline concentrations (calculated as the mean of 3 measurements during the 
clamp, measured singly at recovery) from target PG concentration of 100 mg/dL 
(5.5 mmol/L) to 63 and 45 mg/dL and after recovery from induced hypoglycemia 
(72 mg/dL) (3.5, 2.5, and 4.0 mmol/L, respectively).
Secondary PD measures to assess the effect of tirzepatide compared to placebo on time to 
recovery from hypoglycemia.


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
Time from termination of insulin infusion at PG concentration of 45 mg/dL (2.5 mmol/L) 
to reach recovery PG concentration (72 mg/dL [4.0 mmol/L]) (tPG_nadir-72 mg/dL).
Secondary PD measures to assess the effect of tirzepatide compared to placebo on vital signs 
during hypoglycemia.

Change in mean systolic and diastolic blood pressure and pulse rates (calculated as the 
mean of 2 measurements during the clamp, measured singly at recovery) from target PG 
concentration of 100 mg/dL (5.5 mmol/L) to 63, 45, and 72 mg/dL (3.5, 2.5, and 
4.0 mmol/L, respectively).
Secondary PD measures to assess the effect of tirzepatide compared to placebo on clinical 
hypoglycemia.

Hypoglycemic symptoms score (calculated as the mean of 2 measurements during the 
clamp, measured singly at recovery) at target PG concentrations of 100, 63, and 
45 mg/dL, and after recovery from induced hypoglycemia (72 mg/dL) (5.5, 3.5, 2.5, and 
4.0 mmol/L, respectively).  

Hypoglycemic awareness at PG concentrations of 100, 63, and 45 mg/dL, and after 
recovery from induced hypoglycemia (72 mg/dL) (5.5, 3.5, 2.5, and 4.0 mmol/L, 
respectively).  
Symptoms of hypoglycemia will be measured using the Edinburgh Hypoglycemia Scale and 
hypoglycemic awareness will be evaluated based on the patients’ response (yes/no) to the 
question “Do you feel hypoglycemic?”.  
9.6.3. Exploratory Pharmacodynamic Assessments and Procedures
Exploratory PD measures to assess the effect of tirzepatide compared to placebo on other 
hypoglycemic clamp parameters and recovery from hypoglycemia including:

Amount of insulin required to reach PG concentrations of 63 and 45 mg/dL (3.5 and 
2.5 mg/dL) from 100 mmol/L (5.5 mmol/L)

Area under the glucose infusion rate curve from time of termination of insulin infusion 
until recovery (PG concentration of 72 mg/dL [4.0 mmol/L]) (AUCGIR,PG_nadir-72 
mg/dL)

Proportions of patients who require glucose infusion to attain recovery (PG concentration 
72 mg/dL [4.0 mmol/L]) and associated total amount of glucose infused (Gtot)

Plasma glucose achieved at the end of the spontaneous recovery period
9.6.4. Immunogenicity Assessments
For immunogenicity testing, venous blood samples of approximately 10 mL will be collected 
from each patient according to the Schedule of Activities (Section 2 to determine antibody 
production against tirzepatide.  Additional samples may be collected if there is a possibility that 
an AE is immunologically mediated (see Section 9.4.6).  All samples for immunogenicity testing 


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should have a time-matched sample for PK analysis.  Detailed instructions on the sample 
collections and handling will be provided by Lilly or its designee.  The actual date and 24-hour 
clock time of each sampling will be recorded.
Immunogenicity will be assessed by a validated assay designed to detect ADA in the presence of 
tirzepatide at a laboratory approved by the sponsor.  Antibodies may be further evaluated for 
their ability to neutralize the activity of tirzepatide on GIP and GLP-1 receptors.  Positive 
tirzepatide ADA samples may be tested for cross-reactivity against native GIP and GLP-1, and, 
if positive, may then be tested for neutralizing antibodies against native GIP and/or GLP-1.
All patients will have an ADA sample measured at ET and at the safety follow-up visit. A 
risk-based approach will be used to monitor patients who develop treatment-emergent anti-drug 
antibodies (TE-ADA), defined in Section 10.3.4 (Evaluation of Immunogenicity).
Clinically significant TE-ADA will be defined as any TE-ADA at the last visit with:

a high titer (≥1280) or an increasing titer from last measured value

an association with a moderate-to-severe injection-site reaction or infusion-related 
reaction
Patients who have clinically significant TE-ADA at early discontinuation or at the safety 
follow-up visit, should have additional follow-up ADA testing every 3 months until the ADA 
titers have return to the baseline ADA titer (defined as ADA titer within 2-fold of baseline) or for 
up to 1 year, whichever is less. A PK sample may be collected at the additional 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 additional follow-up immunogenicity 
assessment; however, if patients are unwilling or unable to return for the visit, this is not 
considered a protocol deviation.
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, and if no clinical sequelae are recognized by the 
clinical team, 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.
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.  
9.6.5. Body Weight 
Weight will be measured according to Section 2 (Schedule of Activities).  Patients will be 
weighed at approximately the same time in the morning, before dosing, where applicable, 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 


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not be moved or recalibrated.  Weight 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, obesity, or 
diabetic complications.  Assessment of variable response may include evaluation of AEs or 
differences in efficacy.  
All samples will be coded with the patient number.  These samples and any data generated can 
be linked back to the patient only by the investigative site personnel.  
Samples will be retained for a maximum of 15 years after the last patient visit, or for a shorter 
period if local regulations and/or ERBs impose shorter time limits, for the study at a facility 
selected by Lilly.  This retention period enables use of new technologies, response to regulatory 
questions, and investigation of variable response that may not be observed until later in the 
development of tirzepatide or after tirzepatide is commercially available.  
Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named.  However, existing approaches include whole genome or exome 
sequencing, genome wide association studies, multiplex assays, and candidate gene studies.  
Regardless of technology utilized, data generated will be used only for the specific research 
scope described in this section.  
9.8.
Biomarkers
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 non-pharmacogenetic 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, pathways associated with T2DM, obesity, or diabetic complications, mechanism of 
action of tirzepatide, and/or research method, or for validating diagnostic tools or assay(s) related 
to T2DM, obesity, or diabetic complications.
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.  


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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 is commercially available.  
9.9.
Health Economics
This section is not applicable for this study.


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10.
Statistical Considerations and Data Analysis
10.1. Sample Size Determination
Approximately 38 patients are planned to be enrolled so that 30 patients complete the study 
assuming a 20% discontinuation rate. The calculation is based on the criterion that the width of 
the 95% confidence interval (CI) for the treatment comparison of the primary endpoint is within 
±23.65 pg/mL with approximately 80% probability, provided that the within-subject variability 
is 40 pg/mL (Korsatko et al. 2018).  
10.2. Populations for Analyses
10.2.1. Study Participant Disposition
A summary 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.
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 complete both 
hypoglycemic clamp procedures.  
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 
IP, 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.
10.3.1.2. Statistical Evaluation of Safety
Safety parameters that will be assessed include safety laboratory parameters, vital signs
(throughout the treatment periods and during the hypoglycemic clamp procedures), TEAEs 
(including TEAEs of special interest), and SAEs.  The parameters will be listed, and summarized 
using standard descriptive statistics.  Additionally, analyses may 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.


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Hypoglycemia rate outside of the hypoglycemic clamp will be summarized for each treatment 
group and visit as well as overall by mean, standard deviation, median, minimum, and 
maximum.  Hypoglycemia incidence outside of the hypoglycemic clamp 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.  
See Section 10.3.3.1 (Pharmacodynamic Parameter Estimations) for details of analysis of vital 
signs assessed during the clamp procedures.  
10.3.1.3. Injection-site Reactions
Incidence of erythema, induration, pain, itching, and edema will be listed and summarized by 
treatment.  
Additional analyses may be performed, if appropriate.
10.3.2. Pharmacokinetic Analyses
10.3.2.1. Pharmacokinetic Parameter Estimation
Pharmacokinetic samples will be collected 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 PK parameters will be derived; thus no analyses of PK parameters are planned.
10.3.3. Pharmacodynamic Analyses 
10.3.3.1. Pharmacodynamic Parameter Estimations
During the hypoglycemic clamp, for safety considerations, if the target PG concentrations are not 
achieved within 30 minutes of completion of the previous step, a higher PG concentration will be 
accepted as the PG concentration at which assessments are conducted. In case 45 mg/dL 
(2.5 mmol/L) cannot be reached or symptoms of hypoglycemia are unacceptable, nadir at a 
higher PG concentration will be accepted and data will be included in the analysis.  
Mean glucagon, insulin, C-peptide, growth hormone, cortisol, adrenaline, and noradrenaline 
concentrations at target PG concentration clamp steps of 100, 63, and 45 mg/dL (5.5, 3.5, and 
2.5 mmol/L) will be calculated from the 3 measurements taken during each clamp step.  The
concentrations are measured singly at ambient PG (glucagon only) and upon recovery to 
72 mg/dL (4.0 mmol/L).  
Mean systolic and diastolic blood pressure and pulse rate at target PG of 100, 63, and 45 mg/dL 
(5.5, 3.5, and 2.5 mmol/L) will be calculated using the average of the 2 measurements taken at
each corresponding PG level.  Blood pressure and pulse rate will be measured singly when 
recovery PG of 72 mg/dL (4.0 mmol/L) is reached.


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10.3.3.2. Pharmacodynamic Statistical Inference
The primary PD parameter for analysis will be the change in mean glucagon concentration 
between the 100 mg/dL (5.5 mmol/L) clamp step and the nadir target 45 mg/dL (2.5 mmol/L) 
step.  This will be evaluated using a linear mixed-effects model, with treatment, treatment period, 
treatment sequence as fixed effects, and patient as a random effect.  
From the model, the difference between tirzepatide and placebo in least squares means estimates 
and the corresponding 95% CIs for the difference will be calculated.  
The secondary PD measures for statistical analysis are:  

Change in mean glucagon concentration from target PG concentration of 100 mg/dL
(5.5 mmol/L) to 63 mg/dL (3.5 mmol/L) and to recovery (PG concentration 72 mg/dL
[4.0 mmol/L]) from induced hypoglycemia 

Change in mean glucagon concentration from ambient PG to target PG concentrations of 
100, 63, and 45 mg/dL (5.5, 3.5, and 2.5 mmol/L), and recovery (PG concentration 
72 mg/dL [4.0 mmol/L]) from induced hypoglycemia

Change in mean insulin, C-peptide, growth hormone, cortisol, adrenaline, and 
noradrenaline concentrations from target PG concentration of 100 mg/dL (5.5 mmol/L), 
to 63 and 45 mg/dL (3.5 and 2.5 mmol/L), and recovery (PG concentration of 72 mg/dL
[4.0 mmol/L]) from induced hypoglycemia

tPG_nadir-72 mg/dL 
These parameters will be analyzed using a similar model to that described for the primary 
endpoint. If the tPG_nadir-72 mg/dL is highly skewed, a log-transformation may be considered. If 
the assumptions of the model appear to be violated, a non-parametric analysis may be performed.
In addition, the following parameters will be listed and summarized using standard descriptive 
statistics:

Change in mean systolic and diastolic blood pressure and pulse rate from target PG 
concentration 100 mg/dL (5.5 mmol/L) to PG 63, 45, and 72 mg/dL, (3.5, 2.5, and 
4.0 mmol/L).

Hypoglycemic symptom scores at PG concentrations of 100, 63, and 45 mg/dL (5.5, 3.5, 
2.5 mmol/L) and after recovery (PG concentration 72 mg/dL [4.0 mmol/L]) from induced 
hypoglycemia.

Hypoglycemic awareness scores at PG concentrations of 100, 63, and 45 mg/dL (5.5, 3.5, 
2.5 mmol/L) and after recovery (PG concentration 72 mg/dL [4.0 mmol/L]) from induced 
hypoglycemia.
Analysis of exploratory objectives will be detailed in the statistical analysis plan.  


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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 ADA are defined as those with a titer 2-fold 
(1 dilution) greater than the minimum required dilution if no ADAs were detected at baseline 
(treatment-induced ADA) or those with a 4-fold (2 dilutions) increase in titer compared to 
baseline if ADAs were detected at baseline (treatment-boosted ADA).  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 if performed, will be tabulated 
in TE-ADA+ patients.  If cross-reactivity to native GLP-1 and GIP or neutralizing antibodies 
against native GLP-1 and GIP assays are performed, the frequency of each will be reported.
The relationship between the presence of antibodies and the tirzepatide concentrations 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 data may be reviewed periodically on an 
ongoing basis.  If an unplanned interim analysis is deemed necessary, the Lilly CP, 
CRP/investigator, or designee will consult with the appropriate medical director or designee to 
determine if it is necessary to amend the protocol.


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11.
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in Diabetes—2017. Diabetes Care. 2017;40(suppl 1):S48-S56.
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Diabetes—2018. Diabetes Care. 2018;41(suppl 1):S55–S64.
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.
Balijepalli C, Druyts E, Siliman G, Joffres M, Thorlund K, Mills EJ. Hypoglycemia: a review of 
definitions used in clinical trials evaluating hyperglycemic drugs for diabetes.  Clin Epidemiol. 
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Banks PA, Freeman ML. Practice guidelines in acute pancreatitis. Am J Gastroenterol. 
2006;101(10):2379-2400.
Campbell JE, Drucker DJ. Pharmacology, physiology, and mechanisms of incretin hormone 
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Coskun T, Sloop KW, 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. Mol Metab. 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
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EMA 2012. European Medicines Agency Guideline on Clinical Investigation of Medicinal 
Products in the Treatment or Prevention of Diabetes Mellitus. 2012. [Accessed December 5, 
2016]. Available at: 
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129256.pdf
Finan B, Müller TD, Clemmensen C, Perez-Tilve D, DiMarchi RD, Tschöp MH. Reappraisal of 
GIP pharmacology for metabolic disease. Trends Mol Med. 2016;22(5):359-376.
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. Lancet. 2018;392(10160): 2180-2193.
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.
Morales J, Schneider D. Hypoglycemia. Am J Med. 2014. 127(10 suppl):S17-24.  


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Nauck MA, Frossard J-L, Barkin JS, Anglin G, Hensley I, Harper KD, Milicevic Z. Assessment 
of pancreas safety in the development program of once-weekly GLP-1 receptor agonist 
dulaglutide. Diabetes Care. 2017;40(5):647.
Korsatko S, Jensen L, Brunner M, Sach-Friedl S, Tarp MD, Holst AG, Heller SR, Pieber TR.  
Effect of once-weekly semaglutide on the counterregulatory response to hypoglycaemia in 
people with type 2 diabetes: A randomized, placebo-controlled, double-blind, crossover trial. 
Diabetes Obes Metab. 2018;20(11):2565-2573. 
Seaquist ER, Anderson J, Childs B, et al. Hypoglycemia and diabetes: a report of a workgroup of 
the American Diabetes Association and the Endocrine Society. Diabetes 
Care. 2013;36(5):1384–1395.
Steinberg WM, Buse JB, Ghorbani MLM, Ørsted DD, Nauck MA; LEADER Steering 
Committee; LEADER Trial Investigators. Amylase, lipase, and acute pancreatitis in people 
with type 2 diabetes treated with liraglutide: results from the LEADER Randomized Trial. 
Diabetes Care. 2017a;40(7):966-972.
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.
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.


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12.
Appendices


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Appendix 1.
Abbreviations and Definitions


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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
AST
aspartate aminotransferase
AUCGIR,PG_nadir-72 mg/dL
area under the glucose infusion rate curve from time of termination of insulin infusion 
until recovery (plasma glucose concentration of 72 mg/dL)
BAT
basophil activation test
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/his staff and the patient are not.  A double-blind study is 
one in which neither the patient nor any of the investigator or sponsor staff who are 
involved in the treatment or clinical evaluation of the patients are aware of the treatment 
received.
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 (GCP) 
requirements, and the applicable regulatory requirements.
confirmation
A process used to confirm that laboratory test results meet the quality requirements 
defined by the laboratory generating the data and that Lilly is confident that results are 
accurate.  Confirmation will either occur immediately after initial testing or will require 
that samples be held to be retested at some defined time point, depending on the steps 
required to obtain confirmed results.
CP
Clinical Pharmacologist
CRP
Clinical Research Physician:  Individual responsible for the medical conduct of the study.  
Responsibilities of the CRP may be performed by a physician, clinical research scientist, 
global safety physician or other medical officer.


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CRU
clinical research unit
CT
computed tomography
ECG
Electrocardiogram
eCRF
electronic case report form
enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the study are 
those who have been assigned to a treatment.
enter
Patients entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ERB
ethical review board
ET
early termination
GCP
Good Clinical Practice
GI
Gastrointestinal
GIP
glucose-dependent insulinotropic polypeptide
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 agonist
HCV
hepatitis C virus
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICF
informed consent form
IgE
Immunoglobulin E
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.  


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Investigational 
product (IP)
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical study, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to gain 
further information about the authorized form.
investigator
A person responsible for the conduct of the clinical study at a study site.  If a study is 
conducted by a team of individuals at a study site, the investigator is the responsible 
leader of the team and may be called the principal investigator.
IV
Intravenous
Legal 
Representative
An individual or judicial or other body authorized under applicable law to consent, on 
behalf of a prospective patient, to the patient’s participation in the clinical study.
MAD
multiple ascending dose
MEN 2
multiple endocrine neoplasia syndrome type 2
MRI
magnetic resonance imaging
MTC
medullary thyroid carcinoma
NMH
N-methylhistamine
Non-investigational 
product (non-IP)
A product that is not being tested or used as a reference in the clinical study, but is 
provided to patients and used in accordance with the protocol, such as:  concomitant or 
rescue/escape medication for preventative, diagnostic, or therapeutic reasons, medication 
to ensure adequate medical care, and/or products used to induce a physiological response.
randomize
The process of assigning patients to an experimental group on a random basis.
PG
plasma glucose
PFS
prefilled syringe
PK/PD
pharmacokinetic/pharmacodynamic
QW
once-weekly
SAD
single ascending dose
SAE
serious adverse event
SC
subcutaneous(ly)
screen
The act of determining if an individual meets minimum requirements to become part of a 
pool of potential candidates for participation in a clinical study.  
SMPG
self-monitoring of plasma glucose
SUSARs
suspected unexpected serious adverse reactions 


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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 
tPG_nadir-72 mg/dL
time from termination of insulin infusion at plasma glucose concentration of 45 mg/dL to 
reach recovery plasma glucose concentration 72 mg/dL
ULN
upper limit of normal
WOCBP
women of childbearing potential


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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)
Glucose 
Platelets
Blood urea nitrogen
Absolute counts of:
Uric acid
Neutrophils
Total protein
Lymphocytes
Albumin
Monocytes
Total bilirubin
Eosinophils
Alkaline phosphatase
Basophils
Alanine aminotransferase
Aspartate aminotransferase
Creatinine
Lipase
Amylase
Total cholesterol
Triglyceride
Hemoglobin A1c
Urinalysis
Specific gravity
Endocrine
pH
Follicle-stimulating hormonea
Protein
Calcitoninb
Glucose
Ketones
Serologyc
Bilirubin
Hepatitis B surface antigen
Urobilinogen
Hepatitis C antibody, hepatitis C RNAd
Blood
HIV antibody
Leukocytes
Nitrite
Pregnancy test (urine, serum)e
Microscopya
Drug and alcohol screenf
Abbreviations:  HIV = human immunodeficiency virus; RBC = red blood cells; WBC = white blood cells.
Note:  Results of these assays will be validated by the 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 deviation.
a
If clinically indicated, per investigator’s discretion.
b
Calcitonin assay performed at central laboratory.
c
At screening only (unless previously performed within the last 6 months with reports available for review).
d
See exclusion criteria (Section 6.2) for further details.
e
Pregnancy tests will be performed for women of childbearing potential.  Serum pregnancy test is done at 
screening and urine pregnancy is performed at all other visits.
f
Performed at screening.  Procedures may be repeated throughout the study as deemed necessary by the 
investigator.


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Appendix 3.
Study Governance, Regulatory and Ethical 
Considerations
Informed Consent
The investigator is responsible for:

ensuring that the patient understands the nature of the study, the potential risks and 
benefits of participating in the study, and that their participation is voluntary.

ensuring that informed consent is given by each patient or legal representative.  This 
includes obtaining the appropriate signatures and dates on the informed consent form 
(ICF) prior to the performance of any protocol procedures and prior to the administration 
of investigational product (IP).

answering any questions the patient may have throughout the study and sharing in a 
timely manner any new information that may be relevant to the patient’s willingness to 
continue his or her participation in the study.

providing a copy of the ICF to the participant or the participant’s legal representative and 
retaining a copy on file.
Recruitment
Lilly or its designee is responsible for the central recruitment strategy for patients, where 
applicable.  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 sites.  Lilly or its representatives must approve the ICF 
before it is used at the investigative sites.  All ICFs must be compliant with the ICH guideline on 
Good Clinical Practice (GCP).
The study site’s ERB(s) should be provided with the following:

the current IB and updates during the course of the study

ICF

relevant curricula vitae


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Regulatory Considerations
This study will be conducted in accordance with the protocol and with:

consensus ethics principles derived from international ethics guidelines, 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences International Ethical Guidelines 

applicable ICH GCP Guidelines 

applicable laws and regulations
Some of the obligations of the sponsor will be assigned to a third-party organization.
Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.  
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
Final Report Signature
The investigator or designee will sign the clinical study report for this study, indicating 
agreement with the analyses, results, and conclusions of the report.
The sponsor’s responsible medical officer and statistician will sign/approve the final clinical 
study report for this study, confirming that, to the best of his or her knowledge, the report 
accurately describes the conduct and results of the study.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study site, as appropriate.

provide training to instruct the investigators and study coordinators.  This training will 
give instruction on the protocol, the completion of the electronic case report forms 
(eCRFs), and study procedures.

make periodic visits to the study site.

be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax.

review and evaluate eCRF data and/or use standard computer edits to detect errors in data 
collection.

conduct a quality review of the database.


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


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


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Appendix 5.
Blood Sampling Summary
This table summarizes the approximate number of venipunctures and blood volumes for all 
blood sampling (screening, safety laboratories, and bioanalytical assays) during the study.  
Protocol I8F-MC-GPHG Sampling Summary
Purpose
Blood Volume per 
Sample (mL)
Number of Blood 
Samples
Total Volume 
(mL)
Screening testsa
23
1
23
Safety laboratory testsa
15
6
90
Pharmacokinetics 
3
8
24
Fasting blood glucose
2
4
8
Plasma glucose sampling (clamp)
20 (per clamp)
2
40
Fasting insulin, C-peptide
2.5
22
55
Glucagon
2
24
48
Growth hormone, cortisol
4
20
80
Adrenaline, noradrenaline
5
20
100
Immunogenicity
10
8
80
Pharmacogenetics
10
1
10
Nonpharmacogenetics
9
4
36
Total
594
Total for clinical purposes 
600
a
Additional samples may be drawn if needed for safety purposes.


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Appendix 6.
Hypoglycemic Clamp Procedure
The patient will be asked to attend the clinical unit at approximately 18:00 hours in the evening 
of Day 79 of each treatment period.  The patient will be served a standardized dinner at 
approximately 19:00 hours and thereafter will be fasted until the end of the clamp procedure on 
Day 80.  The clamp procedure will be initiated on Day 79 (clamp run-in period) and the 
hypoglycemic induction will be performed on Day 80 of each period.
Invasive procedures
For sampling of arterialized venous blood, a hand or antecubital vein of one arm will be 
cannulated.  This hand will remain in a heating environment throughout the procedure.  The 
heating of the hand results in an arterialization of the venous blood due to a reflective opening of
arteriovenous shunts.  The patency of the cannulation will be maintained with a 154 mmol/L 
NaCl infusion throughout the procedure.
An antecubital vein in the contralateral arm will be cannulated for the infusion of human soluble 
insulin and/or glucose 20%.
Clamp Run-in period
At approximately 22:00 hours in the evening of Day 79, a variable intravenous (IV) infusion of 
human soluble insulin (40 IU insulin lispro [100 IU/mL] in 99.6 mL saline) or a variable IV 
infusion of glucose will be initiated in order to obtain a plasma glucose (PG) target level of 
100 mg/dL (5.5 mmol/L).  The insulin infusion should be stopped completely if glucose has to be 
infused and vice versa.  The rates of the variable glucose infusion will be recorded whenever the 
infusion rate is changed (at least every 30 minutes).  The insulin infusion rate needed until 
initiation of the high constant insulin infusion will also be recorded whenever the infusion rate is 
changed (at least every 30 minutes).
Between 07:00 hours and 08:00 hours on Day 80, PG should be stable at 100 mg/dL 
(5.5 mmol/L) ±30% and no glucose should be infused.  In case this PG target range of 
100 mg/dL (5.5 mmol/L) ±30% cannot be achieved, this period can be extended until 
10:00 hours.
At 08:00 hours (10:00 hours latest), the insulin infusion rate will be increased to a constant rate 
of 2.5 mU/kg/min, based on patient body weight at Day 78 of each period.
Hypoglycemic induction
A PG target level of 100 mg/dL (5.5 mmol/L) ±30% should be kept constant from 60 minutes to 
30 minutes prior to hypoglycemia induction by a controlled variable glucose infusion.  
Moreover, the PG target level of 100 mg/dL (5.5 mmol/L) ±10% should be kept constant for the 
last 30 minutes prior to hypoglycemia induction while performing all assessments of plateau 
100 mg/dL (5.5 mmol/L).


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Hypoglycemic induction is defined as stop of glucose infusion after assessment plateau 
100 mg/dL (5.5 mmol/L) is completed.
After 30 minutes (09:00 hour) on the 100 mg/dL (5.5 mmol/L) assessment plateau, the glucose 
infusion will be interrupted, the PG will be allowed to decline to 63 mg/dL (3.5 mmol/L) and by 
restarting a variable glucose infusion, if needed, kept stable at 63 mg/dL (3.5 mmol/L).  
Assessments on the assessment plateau 63 mg/dL (3.5 mmol/L) will be performed.
After 30 min on the 63 mg/dL (3.5 mmol/L) assessment plateau, the glucose infusion will be 
interrupted and the PG will be allowed to decline to 45 mg/dL (2.5 mmol/L) or nadir at a higher 
PG concentration in case 45 mg/dL (2.5 mmol/L) cannot be reached or symptoms of 
hypoglycemia are unacceptable.  By restarting a variable glucose infusion, if needed, the PG will 
be kept stable at 45 mg/dL (2.5 mmol/L) or nadir, and assessments on the 45 mg/dL 
(2.5 mmol/L) or nadir assessment plateau, will be performed.
As soon as the 45 mg/dL (2.5 mmol/L) or nadir assessment plateau has been reached, the 
constant high insulin infusion will be terminated.  The 45 mg/dL (2.5 mmol/L) or nadir plateau 
will be further kept, if possible, for the total duration of 30 min.
Recovery phase
After, at the latest, 30 minutes’ duration of the 45 mg/dL (2.5 mmol/L) or nadir assessment 
plateau, the glucose infusion will be switched off to allow a spontaneous recovery from 
hypoglycemia.
The PG will not be allowed to fall below 40 mg/dL (2.2 mmol/L), if so, the variable glucose 
infusion will be initiated to raise the PG to 45 mg/dL (2.5 mmol/L).
If the PG has not reached ≥72 mg/dL (4.0 mmol/L) 45 minutes after termination of the constant 
insulin infusion, a constant glucose infusion (5.5 mg/kg/min, based on patient body weight at 
Day 78 of each period) will be initiated in order to increase the PG to 72 mg/dL (4.0 mmol/L).  
For medical reasons (e.g., if symptoms of hypoglycemia are unacceptable) the constant glucose 
infusion can be initiated earlier as judged by investigator.  
As soon as PG 72 mg/dL (4.0 mmol/L) is reached, assessments on the recovery time point will 
be performed.  When the assessments are finished, PG will actively be raised to 100 mg/dL 
(5.5mmol/L) by a variable glucose infusion and the whole clamp procedure terminated when 
deemed safe by the investigator.  Thereafter, patients will receive a meal (containing 
carbohydrates) and will be discharged after having achieved stable medical conditions, as judged 
by the investigator.
Safety considerations for assessment plateaus 
In case a patient’s PG does not decrease from 100 mg/dL (5.5 mmol/L) to 63 mg/dl 
(3.5 mmol/L) within 30 minutes, the 63 mg/dL (3.5 mmol/L) assessment plateau will be initiated 
in any case 30 minutes after the end of the assessment plateau at 100 mg/dL (5.5 mmol/L).


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In case a patient’s PG does not decrease from 63 mg/dL (3.5 mmol/L) to 45 mg/dL (2.5 mmol/L) 
within 30 minutes, the 45 mg/dL (2.5 mmol/L) assessment plateau will be initiated in any case 
30 minutes after the end of the assessment plateau at 63 mg/dL (3.5 mmol/L).  
In the above cases, the glucose infusion should not be initiated at the start of the assessment 
plateaus to allow a further decrease in PG levels to the scheduled target PG levels.
Based on the clinical judgement of the investigator, the PG can be increased to euglycemia by a 
variable glucose infusion at any time during the whole clamp procedure.
From the start of the constant high insulin infusion rate until end of the recovery phase, PG 
measurements (using SuperGL device) have to be performed every 5 to 30 minutes or more often 
as judged by investigator.
After initiation of the constant high insulin infusion rate, potassium concentration will be 
measured at the discretion of the investigator and potassium substituted if necessary.
Electrocardiogram will be continuously monitored from start of the constant high insulin 
infusion rate until completion of the recovery phase. Twelve-lead ECG will be recorded within 
15 minutes prior to start of the high insulin infusion rate, at timepoint 15 minutes (±5 minutes) of 
assessment plateau 45 mg/dL (2.5 mmol/L) or nadir assessment plateau and before discharge.
The clamp will be terminated for safety reasons should the patient experience symptoms of 
cardiovascular stress (tachycardia, bradycardia, or other relevant changes in ECG), or 
neurological symptoms related to neuroglycopenia, as judged by the investigator.


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Figure GPHG.2
Hypoglycemic clamp
Abbreviations: PG = plasma glucose.
Glucagon, fasting insulin, C-peptide, cortisol, growth hormone, adrenaline, and noradrenaline measured at 10, 20 and 30 minutes of each clamp 
plateau and once PG 72 mg/dL (4.0 mmol/L) is reached.
Blood pressure and pulse rate measured at 0 and 30 minutes of each plateau and once PG 72 mg/dL (4.0 mmol/L) is reached.
Hypoglycemic symptom score and hypoglycemic symptom awareness assessed at 0 and 30 minutes of each plateau and once PG 72 mg/dL 
(4.0 mmol/L) is reached.


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Approximate 
hour
Nominal 
timing
Procedure
Clamp 
glucose level
Blood sampling:
- Glucagon
- Fasting insulin
- C-peptide
- Growth 
hormone
- Cortisol
- Adrenaline
- Noradrenaline
Hypoglycemia 
symptoms 
awareness
Hypoglycemic 
symptoms 
score
Vital signs
and ECG
Glucose and GIR 
recorded
glucagon at 
ambient PG sample 
taken in 
pre-prandial state 
prior to clamp 
initiation
22:00 
-11 hours
Start run-in period:  
variable infusion of glucose 
or insulin lispro (40 IU 
[100 IU/mL] in 99.6 mL 
saline) targeting PG 
100 mg/dL (5.5 mmol/mL) 
(±30%)
100 mg/dL
(5.5 mmol/L)
Glucose
every 30 minutes
GIR 
at least every 
30 minutes and every 
time GIR is changed 
until time M
7:00
-2 to -1 
hours
Variable insulin infusion, 
no glucose infusion, 
targeting PG 100 mg/dL 
(5.5 mmol/L) (±30%)
100 mg/dL 
(5.5 mmol/L)
Glucose
every 5 to 30 minutes 
or more often as 
judged by 
investigator
8:00
-1 hours to 
-30
minutes
Increase insulin flow 
(2.5 mU/kg/min) 
Variable infusion of 
glucose targeting PG 
100 mg/dL (5.5 mmol/L) 
(±30%)
100 mg/dL
(5.5 mmol/L)
Start of 
continuous 
ECG 
measurement
Glucose
every 5 to 30 minutes 
or more often as 
judged by 
investigator


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Approximate 
hour
Nominal 
timing
Procedure
Clamp 
glucose level
Blood sampling:
- Glucagon
- Fasting insulin
- C-peptide
- Growth 
hormone
- Cortisol
- Adrenaline
- Noradrenaline
Hypoglycemia 
symptoms 
awareness
Hypoglycemic 
symptoms 
score
Vital signs
and ECG
Glucose and GIR 
recorded
8:30
-30 
minutes
Insulin flow (2.5 
mU/kg/min) .
Variable infusion of 
glucose to maintain PG 
100 mg/dL (5.5 mmol/L) 
(±10%)
100 mg/dL
(5.5 mmol/L)
-20 minutes,
-10 minutes,
0 minutes 
-30 minutes
0 minutes 
Vital signs
-30 minutes
0 minutes 
12-lead ECG
-15 minutes
Glucose
every 5 to 10 minutes 
or more often as 
judged by 
investigator
9:00
0 minutes
Start of hypoglycemic 
induction.  Terminate 
glucose infusion 
Glucose
every 5 minutes or 
more often as judged 
by investigator until 
Timepoint K
I minutes
PG 63 mg/dL (3.5 mmol/L)
reached
Variable glucose infusion if 
needed to maintain PG 
63 mg/dL (3.5 mmol/L)
63 mg/dL
(3.5 mmol/L)
I + 10 minutes
I + 20 minutes
I + 30 minutes 
I min
I + 30 minutes 
Vital signs
I min
I + 30 
minutes 
I + 30 
minutes
Terminate glucose infusion
J minutes
PG 45 mg/dL (2.5 mmol/L) 
or nadir reached 
Variable glucose infusion 
started, if needed, to 
maintain PG 45 mg/dL 
(2.5 mmol/L) or nadir
Terminate insulin infusion
45 mg/dL
(2.5 mmol/L)
J+ 10 minutes
J + 20 minutes
J + 30 minutes
J minutes
J + 30 minutes
Vital signs
J minutes
J + 30 
minutes
12-lead ECG
J + 15 
minutes
J + 30 
minutes
Switch off glucose infusion 
(infusion will restart if PG 
falls below 40 mg/dL until 
45 mg/dL is reached) 


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Approximate 
hour
Nominal 
timing
Procedure
Clamp 
glucose level
Blood sampling:
- Glucagon
- Fasting insulin
- C-peptide
- Growth 
hormone
- Cortisol
- Adrenaline
- Noradrenaline
Hypoglycemia 
symptoms 
awareness
Hypoglycemic 
symptoms 
score
Vital signs
and ECG
Glucose and GIR 
recorded
J + 45
minutes
Start of constant glucose 
infusion (5.5 mg/kg/min) 
until PG ≥72 mg/dL 
(4.0 mmol/L) is reached
K minutes
Time of recovery:  PG 
reaches 72 mg/dL 
(4.0 mmol/L)
Start variable glucose 
infusion
≥72 mg/dL
(4.0 mmol/L)
K minutes
K minutes
Vital signs
K minutes
Glucose
every 5 to 30 minutes 
or more often as 
judged by 
investigator
M minutes
PG reaches 100 mg/dL 
(5.5 mmol/L).  End of 
clamp.  Blood glucose 
controlled with insulin 
infusion.  Patient served a 
meal
End of 
continuous 
ECG
12-lead ECG 
prior to 
discharge
Abbreviations:  ECG = electrocardiogram; GIR = glucose infusion rate; I = time at which PG 63 mg/dL (3.5 mmol/L), or 30 minutes after the end of the 
100 mg/dL (5.5 mmol/L) assessment plateau, whichever is sooner;  J = time at which PG 45 mg/dL (2.5 mmol/L), or 30 minutes after the end of the 63 mg/dL 
(3.5 mmol/L) assessment plateau, whichever is sooner; K = time at which PG reaches 72 mg/dL (4.0 mmol/L); M = time at which PG reaches 100 mg/dL 
(5.5 mmol/L) at the end of the clamp;  PG = plasma glucose.
Based on the clinical judgement of the investigator, PG can be increased to euglycemia by a variable glucose infusion at any time during the clamp procedure.  
The insulin infusion rate will be recorded whenever the infusion rate is changed (at least every 30 minutes).  The end time of each clamp step, time to reach each 
plateau, and PG achieved at each plateau will be recorded.  Glucose infusion rates will also be captured.
Symptoms of hypoglycemia will be measured using the Edinburgh Hypoglycemia Scale and hypoglycemic awareness will be evaluated based on the patients’ 
response (yes/no) to the question “Do you feel hypoglycemic?”.  
The assessments scheduled for the same time point on each plateau will be performed in following order (priority): blood glucose, vital signs, blood sampling, 
hypoglycemia symptoms awareness, hypoglycemic symptoms score. The exact timing of each procedure will be recorded.    


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Appendix 7.
Pancreatic Monitoring
Glucagon-like peptide-1 agonists have been associated with a possible risk of acute pancreatitis.  
In 2006, the United States prescribing information for exenatide was revised to include the event 
of pancreatitis.  In 2007, the United States prescribing information for this medication was 
amended to include pancreatitis under “Precautions.”  Epidemiologic studies have indicated that 
there is an increased incidence and prevalence of pancreatitis in persons with type 2 diabetes 
mellitus (T2DM).
To enhance understanding of the natural variability of pancreatic enzymes in the T2DM 
population and, in order to assess for any potential effects of tirzepatide on the exocrine 
pancreas, amylase and lipase values will be monitored in all current and future clinical trials with 
tirzepatide.
Additional monitoring will be requested for amylase and/or lipase values ≥3 × the upper limit of 
normal (ULN) at any visit, even in asymptomatic patients (see figure below).  Lipase and 
amylase values may also be obtained at any time during the clinical trials for any subject 
suspected of having symptoms suggestive of exenatide pancreatitis (such as severe 
gastrointestinal (GI) signs and/or symptoms), at the investigator’s discretion.
Acute pancreatitis is an adverse event (AE) defined as an acute inflammatory process of the 
pancreas that may also involve peripancreatic tissues and/or remote organ systems.  
The diagnosis of acute pancreatitis requires 2 of the following 3 features:

abdominal pain characteristic of acute pancreatitis

serum amylase and/or lipase ≥3× ULN

characteristic findings of acute pancreatitis on computed topography scan or 
magnetic resonance imaging
Most patients with acute pancreatitis experience abdominal pain that is located generally in the 
epigastrium, and radiates to the back in approximately one-half of the cases.  The pain is often 
associated with nausea and vomiting.  However, experience with GLP-1 agonists has 
demonstrated that some patients asymptomatic for classic pancreatitis may demonstrate 
significant elevations of lipase and/or amylase.  For patients considered by investigators to be 
asymptomatic for pancreatitis, but whose value(s) for lipase and/or amylase are ≥3× ULN, an 
algorithm is in place to follow these patients safely and to quickly reach (or not reach) a 
diagnosis of pancreatitis.


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Abbreviations:  CT = computed tomography; L/A = lipase and/or amylase; MRI = magnetic resonance imaging; 
ULN = upper limit of normal.


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Patients diagnosed with pancreatitis will be discontinued from the study.  Investigators will be 
responsible for following, through an appropriate healthcare option, these pancreatitis AEs until 
the events resolve or are explained.  Adverse events that meet the diagnostic criteria of acute 
pancreatitis will be captured as 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.


I 8 F-M C -G P H G ( d) Cli ni c al P h ar m a c ol o g y Pr ot o c ol
P a g e 9 4
L Y 3 2 9 8 1 7 6
A p p e n di x 8.
H y p er s e n siti vit y  L a b or at or y Te sti n g
La b orat or y  testi n g s h o uld be perf or m e d at t he ti me of a S yste mic H yperse nsi tivi t y E ve nt.  
I mp orta nt i nf or m at i on a b o ut w h y , w he n, a n d w hat t o test f or are pr o vi de d bel o w.  T he 
ma na ge me nt of t he a d verse e ve nt ma y warra nt l a b testi n g be yo n d t hat descri be d bel o w a n d 
s h o uld be perf or m e d as cli nicall y i n dicate d.
La b orat or y  testi n g d uri n g a S yste mic H y perse nsiti vity E v e nt is n ot perf or me d f or dia g n ostic 
p ur p oses.  T he i nte nt is se veral f ol d:

T o hel p c haracteri ze a n d classif y s yste mic h y perse nsiti vity reactio ns

T o m eet re g ulat or y e x pectatio ns

T o i m pr o ve s u bse q ue nt cli nical ma na ge me nt b y  hel pi n g t o disti n g uis h bet wee n t he 
vari o us mec ha nist ic bases of a na p h yla xis
W he n s h o ul d la bs be o btai ne d?

I n t he prese nce of ge neraliz e d urticaria or if a na p h yla xis is s us pecte d.

After t he patie nt has bee n sta bilize d, o btai n a sa m ple wit hi n 1 -2 h o urs of t he e ve nt, 
h o we ver, sa m ples ma y  be o btai ne d as late as 1 2 h o urs after t he e ve nt as a nal ytes ca n 
r e mai n altere d f or a n e xte n de d peri o d o f ti me.  Rec or d t he ti me at w hic h t he sa m ple was 
c ollecte d.

O btai n a f o ll ow- u p sa mple at t he ne xt re g ularl y sc he d ule d visit or after 4 wee ks, 
w hic he ver i s later.
W hat l a bs s h o uld be o btai ne d?

Tr y ptase *

A D A a n d tirze pati de c o nce ntratio n ( P K)
o
A D A testi n g s h o ul d i ncl u de dr u g s pecific i m m u n o glo b uli n E ( I g E)
o
If a dr u g s pecific I g E assa y is n’t a vaila ble, a c o m merciall y a vaila ble alter nati ve 
test t hat ca n i n dicate t he prese nce of dr u g s pecific I g E i n ser u m is t he bas o p hil 
acti vat i on test ( B A T) #

C o m p le me nt
o
C 3a a n d C 5a

C y t o ki nes
o
I L-6, I L -1 β, I L -1 0 ( or a n y c yt o ki ne pa nel t hat i ncl u des t hese 3 c yt o ki nes)
*If a tr y ptase sa m ple is o btai ne d m ore t ha n 2 h o urs after t he e ve nt ( i.e. , wit hi n 2 -1 2 h o urs), or i s 
n ot o btai ne d beca use m ore t ha n 1 2 h o urs ha ve la pse d si nce t he e ve nt, o btai n uri ne f or 
N- met h yl hista mi ne ( N M H) testi n g .  N ote t hat f or tr y ptase ser u m  sa m ples o btai ne d withi n 
2- 1 2 h o urs of t he e ve nt, uri ne N M H testi n g is perf or me d i n a d dit i on t o tr y ptase testi n g .  C ollect 
t he first v oi d uri ne f o ll owi n g t he e ve nt .  O btai n a f oll o w - u p uri ne f or N M H testi n g at t he ne xt 
re g ularl y sc he d ule d visit or after 4 wee ks, w hic he ver is later.


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# The BAT is an in vitro cell based assay that only requires a serum sample.  It is a surrogate 
assay for drug specific IgE but is not specific for IgE.  If an in vivo assay is called for, the 
passive cutaneous anaphylaxis assay may be performed in rodents or non-human primates, is 
commercially available, and also only requires a serum sample.  Skin prick testing in humans is a 
sensitive and specific assay for drug specific IgE but requires qualification of the method in 
negative controls and patients with documented Type I hypersensitivity to the drug. 


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Appendix 9.
Protocol Amendment I8F-MC-GPHG(d) 
Summary:
A Randomized, Placebo-Controlled, Crossover Study to 
Investigate the Effect of Once-Weekly Tirzepatide on the 
Counter-Regulatory Response to Hypoglycemia in 
Patients with Type 2 Diabetes Mellitus
Overview
Protocol I8F-MC-GPHG, A Randomized, Placebo-Controlled, Crossover Study to Investigate 
the Effect of Once-Weekly Tirzepatide on the Counter-Regulatory Response to Hypoglycemia in 
Patients with Type 2 Diabetes Mellitus, has been amended. 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 protocol amendment is considered substantial as the updated criteria expands access to 
more patients.  As the changes were driven specifically by modifications to the Inclusion / 
Exclusion criteria, a full sponsor scientific peer review was not deemed necessary.
This protocol was amended to update the inclusion / exclusion criteria for consistency within the 
tirzepatide mechanism of action program. The overall changes made to this protocol are as 
follows:

The schedule of activities (Section 2), protocol synopsis were updated to reflect the 
additional requirements for enrolling patients who require OAM washout

Study duration was updated to include 4-week washout period 

Modified Inclusion Criteria [2] and [3] to include enrolling subjects on one additional 
OAM other than metformin, and Criterion [5] BMI cutoffs to align with other protocols
within the tirzepatide program

Exclusion Criterion [14] was edited in response to the changes to Inclusion Criterion [2]

Sections 5.1, 5.1.1, 5.1.3, 6, 7.7 and Figure GPHG.1. were edited to reflect the 
operational changes required as a result of the modification to Inclusion Criterion [2]

Modified Appendix 6 to make changes to the insulin infusion rate at -1 hour to -30 
minutes and -30 minutes

Minor editorial changes and formatting corrections were made but are not necessarily 
documented in the revision below.


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Revised Protocol Sections
Note:
All deletions have been identified by strikethroughs.
All additions have been identified by the use of underscore.
1. Protocol Synopsis
Rationale: 
Study I8F-MC-GPHG (Study GPHG) is an approximately 38 to 42 week Phase 1 study designed to examine the 
effect of tirzepatide (LY3298176) on hypoglycemic counter-regulation in patients with type 2 diabetes mellitus 
(T2DM) when compared to placebo treatment.  Tirzepatide is a long-acting, dual incretin mimetic (dual agonist) that 
binds to the glucose-dependent insulinotropic polypeptide receptor (GIPR) and the glucagon-like peptide-1 (GLP-1) 
receptor (GLP-1R).  Dual GIPR and GLP-1R agonism may provide improved glycemic control in patients with 
T2DM, engaging multiple physiologic pathways, including glucagon secretion by the pancreatic α cell.  Since 
glucagon plays a key role in defense against hypoglycemia, it is important to assess the effects of tirzepatide on the 
physiologic response to hypoglycemia.  Understanding the effect of tirzepatide on the counter-regulatory response to 
a hypoglycemic stimulus will provide important safety information for potential future clinical use.
Objectives
Endpoints
Secondary
To compare the effect of tirzepatide 15 mg QW and 
placebo in T2DM patients following 12 weeks of 
treatment on:
Other counter-regulatory hormone responses during 
hypoglycemia, insulin and C-peptide

Change in mean glucagon concentration from target 
PG concentration of 100 mg/dL to 63 mg/dL and to 
recovery (PG concentration 72 mg/dL) from 
induced hypoglycemia 

Change in mean glucagon concentration from 
ambient PG to target PG concentrations of 100, 63, 
and 45 mg/dL, and to recovery (PG concentration 
72 mg/dL) from induced hypoglycemia

Change in mean insulin, C-peptide, growth 
hormone, cortisol, adrenaline, and noradrenaline 
concentrations from target PG concentration of 
100 mg/dL to 63 and 45 mg/dL, and to recovery 
(PG concentration 72 mg/dL) from induced 
hypoglycemia
Summary of Study Design:
Eligibility for this study for patients on metformin only will be assessed at the screening (Visit 1) up to 17 days prior 
to enrollment (Day -14 ±3) and confirmed at the beginning of the lead-in period (Visit 2), approximately 10 to 4 
days prior to randomization (Day -7 ±3).  
Eligibility for patients on metformin and one other oral antidiabetic medication (OAM) will be assessed at the 
screening (Visit 1) up to 45 days prior to enrollment and confirmed at the beginning of the lead-in period (Visit 2), 
followed by discontinuation and a washout period for OAMs, other than metformin. The washout period for these 
patients will last at least 4 weeks between Visit 2 and Visit 3.


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Eligible patients will undergo 2 treatment periods and will be randomized (Visit 3) to receive tirzepatide 15 mg QW
in 1 period followed by placebo in the other, or vice versa, in a crossover fashion. Tirzepatide 15 mg will be attained 
via step-wise dose escalation to reduce the risk of gastrointestinal AEs.  
There will also be a washout period of at least 8 weeks between the last dose of study drug in Period 1 and the first 
dose in Period 2.
Treatment Arms and Planned Duration for an Individual patient:  
The planned study duration for an individual patient from screening through safety follow-up will be approximately 
38 to 42 weeks.  


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2. Schedule of Activities:
Procedure
Screening
Lead-in (with 
or without 
washout)
Randomization
and
Dose 1, 
Treatment 
Period 1
Dose 1, 
Treatment 
Period 2
Comments
Study Period 
Week
-3 -6/-2
a
-2 -5/-1
a
1
1
Study Period 
Day
-14 ±3aor -42
±3a
-7 ±3a or -35 ±3a
(prior to 
randomization)
1
1
Patients on 
metformin only 
should perform
Visits 1 and 2 
approximately 2 
and 1 week 
prior to Visit 3. 
Patients on 
metformin and 
one OAM 
should perform 
Visit 1 about 6 
weeks prior to 
Visit 3, in order
to permit 
eligibility 
assessment at 
Visit 2. OAMs 
other than 
metformin will 
be discontinued 
immediately 
after Visit 2 
followed by at 
least 4 weeks 
washout 
between Visit 2 
and Visit 3
SMPG
X
X
For patients 
undergoing 
OAM washout, 
phone 
interviews will 
be conducted 
during lead-in to 
assess 
acceptability of 
glycemic 
control. Refer to 
Section 5.1.1 for 
further details.


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3.1 Study Rationale:
Study I8F-MC-GPHG (Study GPHG) is an approximately 38-42 week Phase 1 study designed to 
evaluate the effect of tirzepatide (LY3298176) on hypoglycemic counter-regulation in patients 
with type 2 diabetes mellitus (T2DM) when compared to placebo treatment.  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).  Dual GIPR and GLP-1R agonism (GIPRA/GLP-1RA) may provide 
improved glycemic control in patients with T2DM, engaging multiple physiologic pathways, 
including glucagon secretion by the pancreatic cell.  Since glucagon plays a key role in defense 
against hypoglycemia, it is important to assess the effects of tirzepatide on the physiologic 
response to hypoglycemia.  Understanding the effect of tirzepatide on the counter-regulatory 
response to a hypoglycemic stimulus will provide important safety information for potential 
future clinical use.
3.3 Benefit Risk Assessment
During the hypoglycemic clamp procedures, plasma glucose (PG) levels will be closely 
monitored and glucose infused, if necessary, to prevent PG dropping below the target values.  
Should the symptoms of hypoglycemia become unacceptable, glucose will be infused to increase 
PG.  Vital signs and continuous electrocardiogram (ECG) will be monitored during the clamp 
procedures and the clamp will be terminated should the patient experience symptoms of 
cardiovascular stress (tachycardia, bradycardia, or other relevant changes in ECG), or 
neurological symptoms related to neuroglucopenia neuroglycopenia.
4. Objectives and Endpoints
Table GPHG. 1. Objectives and Endpoints
Objectives
Endpoints
Secondary
To compare the effect of tirzepatide 15 mg QW and 
placebo in T2DM patients following 12 weeks of 
treatment on:
Other counter-regulatory hormone responses during 
hypoglycemia, insulin and C-peptide

Change in mean glucagon concentration from target 
PG concentration of 100 mg/dL to 63 mg/dL and to 
recovery (PG concentration 72 mg/dL) from 
induced hypoglycemia 

Change in mean glucagon concentration from 
ambient PG to target PG concentrations of 100, 63,
and 45 mg/dL, and to recovery (PG concentration 
72 mg/dL) from induced hypoglycemia 

Change in mean insulin, C-peptide, growth 
hormone, cortisol, adrenaline, and noradrenaline 
concentrations from target PG concentration of 
100 mg/dL to 63 and 45 mg/dL, and to recovery 
(PG concentration 72 mg/dL) from induced 
hypoglycemia


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5. Study Design
5.1 Overall Design
Eligibility for this study will be assessed at the screening (Visit 1) up to 17 days (Day -14 ± 3) 
prior to enrollment and confirmed at the beginning of the lead-in period (Visit 2), 10 to 4 days 
prior to randomization (Day -7 ± 3) when laboratory test results are available.  After eligibility is 
confirmed at Visit 2, patients will receive training and information on how to subsequently 
monitor their own diabetes condition. Where applicable, patients will be required to undergo a 
washout of OAMs other than metformin between Visit 2 and Visit 3 (refer to Section 5.1.1 for 
details).
Figure GPHG.1
Illustration of study design for Protocol I8F0MC-GPHG.
5.1.1.   Screening, Lead-in and Randomization
Eligibility for this study will be assessed during the screening period (Visit 1).  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).  Final 
determination of eligibility will occur at the beginning of the lead-in period at Visit 2, after all 
screening results are available. Eligible patients are those with T2DM treated with diet, exercise, 
and metformin with or without one other allowed oral antidiabetic medication (OAM) as 
specified in Inclusion Criterion [2].


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Eligibility for this study for patients on metformin only will be assessed at the screening (Visit 1) 
up to 17 days prior to enrollment (Day -14 ±3) and confirmed at the beginning of the lead-in 
period (Visit 2). Eligible patients treated with metformin only will proceed to Visit 3 after 
approximately 1-week lead-in. 
Eligible patients who are, in addition to metformin, on 1 more OAM, will discontinue this OAM 
immediately after Visit 2 and will undergo a 4-week washout between Visit 2 and Visit 3. 
During this washout period, the investigator will perform appropriate surveillance of the patients 
(by telephone interview and additional CRU visits, if necessary, at the investigators discretion) to 
monitor the safety and glycemic control of the patients. Once the 4-week washout period is 
completed, patients will proceed to Visit 3. Upon entering the study, patients should remain on 
the same metformin dose throughout the course of the study.  Between screening and 
randomization (Day 1) eligible patients should continue their prestudy therapy with metformin.  
Patients who do not comply with requirements regarding metformin dosing will be discontinued 
from the study prior to randomization.  After randomization, the metformin dose can only be 
reduced in accordance with country-specific label to protect patient safety (see Section 7.7
[Concomitant Therapy] for further details).  
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 at the lead-in visit (Visit 2) 10 to 4 days prior to randomization (Day -7 ±3).  Patients 
will start performing daily SMPG and record all results, including any hypoglycemia episode, in 
diaries as soon as their eligibility is confirmed at Visit 2.  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 a stable 
diet and exercise plan throughout the course of the study.
5.1.3 Washout Between Treatment Periods
6. Study Population
Screening may occur up to 17 45 days prior to enrollment (Day -14 ±3).  All patients will then 
perform a lead-in start of randomization for patients treated with metformin and one other OAM, 
who are required to perform a washout during lead-in. For all other patients, screening may 
occur up to 17 days prior to randomization and perform a minimum 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 17 45 days are available.  


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6.1 Inclusion Criteria
[2]
Treated with diet and exercise and a stable dose of metformin (3 months prior 
to study entry) with or without 1 additional OAM other than metformin; doses 
of metformin will be considered stable if all prescribed doses for the previous 
3 months were ±850 mg from the most commonly prescribed dose.; allowed 
OAMs, in combination with metformin are DPP-IV inhibitors, SGLT-2 
inhibitors, acarbose, glinides and sulfonylureas; in patients with established 
cardiovascular disease who are treated with SGLT-2 inhibitors, this therapy 
should not be discontinued and therefore, these patients will NOT be eligible 
for participation in the trial.
[3a] Have a hemoglobin A1c value at screening of ≥6.5% and ≤9.0% (48 to 
75 mmol/mol), if on metformin only;
[3b] Have a hemoglobin A1c value at screening of ≥6.0% and ≤8.5% (42 to 
69 mmol/mol), if on metformin and 1 more allowed OAM;  
[5]
Have a body mass index between 25.0 23.0 kg/m2 and 40.0 45.0 kg/m2, inclusive, at 
screening; are of stable weight (±5%) >3 months prior to screening; and agree not to 
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;
6.2 Exclusion Criteria
[14] Have taken any glucose-lowering medications other than metformin anytime
those indicated in Inclusion Criterion [2] during the last 3 months before 
screening or during the screening/lead-in 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 (see Section 7.7 Concomitant Therapy)


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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 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. 
In addition, one additional OAM is allowed prior to randomization (Refer to Inclusion Criterion 
[2]), but must be discontinued after eligibility is confirmed at Visit 2, in which case a 4-week 
minimum washout is required. 
Refer to Section 5.1.1 and 5.1.3 for additional information on washout period prior to starting 
study treatment.
Appendix 6   Hypoglycemic Clamp Procedure
Clamp Run-In Period
At 08:00 hours (10:00 hours latest), the insulin infusion rate will be increased to a constant rate 
of 2.5 mU/kg/min, based on patient body weight at Day 78 of each period.
Recovery Phase
If the PG has not reached ≥72 mg/dL (4.0 mmol/L) 45 minutes after termination of the constant 
insulin infusion, a constant glucose infusion (5.5 mg/kg/min, based on patient body weight at 
Day 78 of each period) will be initiated in order to increase the PG to 72 mg/dL (4.0 mmol/L).  
For medical reasons (e.g., if symptoms of hypoglycemia are unacceptable) the constant glucose 
infusion can be initiated earlier as judged by investigator. 
Safety considerations for assessment plateaus 
The clamp will be terminated for safety reasons should the patient experience symptoms of 
cardiovascular stress (tachycardia, bradycardia, or other relevant changes in ECG), or 
neurological symptoms related to neuroglucopenia neuroglycopenia, as judged by the 
investigator.
Approxima
te hour
Nomin
al 
timing
Procedure
Clamp 
glucose 
level
Blood 
sampling:
- Glucagon
- Fasting 
insulin
- C-peptide
- Growth 
hormone
- Cortisol
- Adrenaline
Hypoglyce
mia 
symptoms 
awareness
Hypoglyce
mic 
symptoms 
score
Vital signs
and ECG
Glucose 
and GIR 
recorded


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Noradrenali
ne
8:00
-1 
hours 
to -30 
minutes
Increase 
insulin flow 
(2.5 mU/kg/m
in) (±30%).  
Variable 
infusion of 
glucose 
targeting PG 
100 mg/dL 
(5.5 mmol/L) 
(±30%)
100 mg/dL
(5.5 mmol/
L)
Start of 
continuous 
ECG 
measureme
nt
Glucose
every 5 to 
30 minute
s or more 
often as 
judged by 
investigat
or
8:30
-30 
minutes
Insulin flow 
(2.5 
mU/kg/min) 
(±30%).  
Variable 
infusion of 
glucose to 
maintain PG 
100 mg/dL 
(5.5 mmol/L) 
(±10%)
100 mg/dL
(5.5 mmol/
L)
-20 minutes,
-10 minutes,
0 minutes 
-30 minutes
0 minutes 
Vital signs
-30 
minutes
0 minutes 
12-lead 
ECG
-15 
minutes
Glucose
every 5 to 
10 minute
s or more 
often as 
judged by 
investigat
or
The assessments scheduled for the same time point on each plateau will be performed in following order (priority): 
blood glucose, vital signs, blood sampling, hypoglycemia symptoms awareness, hypoglycemic symptoms score. 
The exact timing of each procedure will be recorded.    


Leo Document ID = d5e67c84-0b39-49df-9af3-5300fc59bbee
Approver: 
Approval Date & Time: 16-Sep-2020 15:04:31 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 17-Sep-2020 01:26:42 GMT
Signature meaning: Approved
PPD
PPD

SAP_001.pdf: 
 
 
 
Statistical Analysis Plan Version 2 I8F-MC-GPHG 
 
 
A Randomized, Placebo-Controlled, Crossover Study to Investigate the Effect of Once-Weekly 
Tirzepatide on the Counter-Regulatory Response to Hypoglycemia in Patients with Type 2 
Diabetes Mellitus 
  
  
NCT04050553 
 
Approval Date: 26-Oct-2021 
 
 


I8F-MC-GPHG Statistical Analysis Plan Version 2
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1.
Statistical Analysis Plan  
I8F-MC-GPHG: A Randomized, Placebo-Controlled, 
Crossover Study to Investigate the Effect of Once-Weekly 
Tirzepatide on the Counter-Regulatory Response to 
Hypoglycemia in Patients with Type 2 Diabetes Mellitus
Confidential Information
The information contained in this document is confidential and the information contained 
within it may not be reproduced or otherwise disseminated without the approval of 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..
LY3298176 for Type 2 Diabetes Mellitus 
Phase 1, single-center, 2-period, crossover, randomized, patient- and investigator-blind 
study in patients with Type 2 Diabetes to compare tirzepatide 15 mg to placebo
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol I8F-MC-GPHG
Phase 1
Statistical Analysis Plan Version 1 electronically signed and approved by Lilly on 
10 September 2020.
Statistical Analysis Plan Version 2 electronically signed and approved by Lilly on date 
provided below.
Approval Date: 26-Oct-2021 GMT


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2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan   I8F-MC-GPHG:  A Randomized, Placebo-
Controlled, Crossover Study to Investigate the Effect of Once-
Weekly Tirzepatide on the Counter-Regulatory Response to 
Hypoglycemia in Patients with Type 2 Diabetes Mellitus....................................................1
2.
Table of Contents................................................................................................................2
3.
Revision History .................................................................................................................7
4.
Study Objectives.................................................................................................................8
5.
Study Design.....................................................................................................................10
5.1.
Study Design and Treatment ........................................................................................10
5.2.
Determination of Sample Size ......................................................................................10
6.
A Priori Statistical Methods ..............................................................................................13
6.1.
Populations for Analyses..............................................................................................13
6.2.
General Considerations ................................................................................................13
6.3.
Patient Characteristics ..................................................................................................13
6.4.
Patient Disposition .......................................................................................................15
6.5.
Concomitant Therapy...................................................................................................15
6.6.
Treatment Exposure and Compliance ...........................................................................15
6.6.1.
Treatment Exposure .............................................................................................15
6.6.2.
Treatment Compliance .........................................................................................15
6.7.
Important Protocol Deviations......................................................................................16
6.8.
Pharmacokinetic Analyses............................................................................................16
6.8.1.
Pharmacokinetic Parameter Estimation ................................................................16
6.8.2.
Pharmacokinetic Statistical Inference...................................................................16
6.9.
Pharmacodynamic Analyses.........................................................................................16
6.9.1.
Pharmacodynamic Parameter Estimation..............................................................16
6.9.2.
Pharmacodynamic Statistical Inference ................................................................20
6.9.2.1.
Primary Pharmacodynamic Analysis...............................................................20
6.9.2.2.
Secondary Pharmacodynamic Analysis...........................................................21
6.9.2.3.
Exploratory Pharmacodynamic Analysis.........................................................23
6.9.3.
Body Weight........................................................................................................26
6.10. Safety Analyses............................................................................................................26
6.10.1.
Adverse Events ....................................................................................................27
6.10.2.
Treatment-Emergent Adverse Events ...................................................................27
6.10.3.
Serious Adverse Events (SAEs) ...........................................................................27
6.10.4.
Adverse Events Leading to Discontinuation .........................................................27


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6.10.5.
Special Safety Topics...........................................................................................27
6.10.5.1.
Severe/Serious Gastrointestinal Adverse Events .............................................27
6.10.5.2.
Hypoglycemia ................................................................................................27
6.10.5.3.
Severe, Persistent Hyperglycemia...................................................................28
6.10.5.4.
Pancreatitis.....................................................................................................28
6.10.5.5.
Thyroid Malignancies and C-Cell Hyperplasia................................................28
6.10.5.6.
Major Adverse Cardiovascular Events (MACE) .............................................28
6.10.5.7.
Arrhythmias and Cardiac Conduction Disorders .............................................29
6.10.5.8.
Hypersensitivity Events..................................................................................29
6.10.5.9.
Injection Site Reactions ..................................................................................29
6.10.5.10. Diabetic Retinopathy Complications...............................................................29
6.10.5.11. Hepatobiliary Disorders..................................................................................29
6.10.5.11.1. Hepatic Monitoring...................................................................................29
6.10.5.12. Acute Renal Events ........................................................................................30
6.10.5.13. Metabolic Acidosis, Including Diabetic Ketoacidosis .....................................30
6.10.5.14. Amputation/Peripheral Revascularization .......................................................30
6.10.5.15. Major Depressive Disorder/Suicidal Ideation..................................................30
6.10.6.
Vital Signs ...........................................................................................................30
6.10.7.
Electrocardiogram................................................................................................31
6.10.8.
Safety Laboratory Parameters...............................................................................31
6.11. Evaluation of Immunogenicity .....................................................................................31
6.12. Interim Analyses ..........................................................................................................32
7.
Unblinding Plan................................................................................................................33
8.
Changes from the Protocol Specified Statistical Analyses .................................................34
9.
References ........................................................................................................................35
10.
Appendices .......................................................................................................................36


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Table of Contents
Table
Page
Table GPHG.1.
Objectives and Endpoints............................................................................8
Table GPHG.2.
Analysis Populations/Data Sets.................................................................13
Table GPHG.3.
Key Timepoints of Hypoglycemic Clamp Procedure On Day 80...............17
Table GPHG.4.
Measurements of Glucagon, Insulin, C-peptide, Growth Hormone, Cortisol, 
Adrenaline, and Noradrenaline from Blood Sampling During Hypoglycemic Clamp 
Procedure on Day 79 and Day 80.......................................................................................18
Table GPHG.5.
Hypoglycemic Symptom Score and Hypoglycemia Awareness During 
Hypoglycemic Clamp Procedure on Day 80 ......................................................................19
Table GPHG.6.
Vital Signs During Hypoglycemic Clamp Procedure on Day 80................20
Table GPHG.7.
Definitions of Hypoglycemic Event Categories.........................................28
Table GPHG.8.
Categorical Criteria for Treatment-Emergent Abnormal Blood Pressure and 
Pulse Measurements ..........................................................................................................31


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Table of Contents
Figure
Page
Figure GPHG.1.
Illustration of study design for Protocol I8F-MC-GPHG. ..........................11
Figure GPHG.2.
Hypoglycemic clamp. ...............................................................................12


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Table of Contents
Appendix
Page
Appendix 1.
Search Criteria For Adverse Events of Special Safety Topics..........................37


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3.
Revision History
Statistical analysis plan (SAP) Version 1 was approved September 10, 2020.
This is SAP Version 2.  The second version was approved before the final database lock.  The 
overall changes made in this SAP are as follows: 

updated to address the changes made in Protocol Amendment (d)

updated and clarified population for analyses

added additional details for summaries of baseline patient characteristics, disposition, and 
concomitant therapy

updated exposure and treatment compliance calculation, taking into account early 
termination

added additional details for summaries of body weight, safety labs, and immunogenicity 
data

updated and clarified details in treatment-emergent adverse event definition and special 
safety topics

added additional details for summaries of vital signs and added criteria for treatment-
emergent abnormal vital signs

added algorithm details on lab measurement for values below or above the quantification 
limit, and

made editorial changes and formatting corrections.


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4.
Study Objectives
Table GPHG.1 shows the objectives and endpoints of the study.  
Table GPHG.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To compare the effect of tirzepatide 15 mg QW and 
placebo on glucagon response during hypoglycemia in 
T2DM patients following 12 weeks of treatment
Change in mean glucagon concentration during 
induced hypoglycemia from target PG concentration of 
100 mg/dL to a nadir target of 45 mg/dL
Secondary
To compare the effect of tirzepatide 15 mg QW and 
placebo in T2DM patients following 12 weeks of 
treatment on:

Other counter-regulatory hormone responses, and 
responses of insulin and C-peptide during 
hypoglycemia

Change in mean glucagon concentration from target 
PG concentration of 100 mg/dL to 63 mg/dL and to 
recovery (PG concentration 72 mg/dL) from 
induced hypoglycemia 

Change in mean glucagon concentration from 
ambient PG to target PG concentrations of 100, 63,
and 45 mg/dL, and to recovery (PG concentration 
72 mg/dL) from induced hypoglycemia 

Change in mean insulin, C-peptide, growth 
hormone, cortisol, adrenaline, and noradrenaline 
concentrations from target PG concentration of 
100 mg/dL to 63 and 45 mg/dL, and to recovery 
(PG concentration 72 mg/dL) from induced 
hypoglycemia 

Time to hypoglycemia recovery

Time from termination of insulin infusion at PG 
concentration of 45 mg/dL to reach recovery PG 
concentration (72 mg/dL) (tPG_nadir-72 mg/dL)

Clinical hypoglycemia

Hypoglycemic symptoms score at PG 
concentrations of 100, 63, and 45 mg/dL and after 
recovery (PG concentration 72 mg/dL) from 
induced hypoglycemia

Hypoglycemia awareness at PG concentrations of 
100, 63, and 45 mg/dL and after recovery (PG 
concentration 72 mg/dL) from induced 
hypoglycemia

Vital signs during hypoglycemia

Change in mean systolic and diastolic blood 
pressure and pulse rate from target PG 
concentration of 100 mg/dL, to 63, and 45 mg/dL, 
and to recovery (PG concentration 72 mg/dL) from 
induced hypoglycemia

Additional safety and tolerability

AEs

Incidence of hypoglycemia outside of the 
hypoglycemic clamps


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Objectives
Endpoints
Exploratory
To compare the effect of tirzepatide 15 mg QW and 
placebo in T2DM patients following 12 weeks of 
treatment on:

Other hypoglycemic clamp and recovery 
parameters

Amount of insulin required to reach PG 
concentrations of 63 and 45 mg/dL from 
100 mg/dL.  

AUCGIR,PG_nadir-72 mg/dL

Proportions of patients who require glucose infusion 
to attain recovery (PG concentration 72 mg/dL) and 
associated Gtot

PG achieved at the end of spontaneous recovery

Other safety parameters

Frequency of treatment-emergent anti-tirzepatide 
antibodies
Abbreviations:  AE = adverse event; AUCGIR,PG_nadir-72 mg/dL = area under the glucose infusion rate curve from 
time of termination of insulin infusion until recovery (PG concentration of 72 mg/dL); Gtot = total amount of 
glucose infused; PG = plasma glucose; QW = once-weekly; T2DM = type 2 diabetes mellitus.
Plasma glucose concentrations:  100 mg/dL = 5.5 mmol/L; 72 mg/dL = 4.0 mmol/L; 63 mg/dL = 3.5 mmol/L; 
45 mg/dL = 2.5 mmol/L; ambient glucagon measured in the pre-prandial state prior to clamp initiation.  


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5.
Study Design
5.1.
Study Design and Treatment 
This is a Phase 1, single-center, 2-period, crossover, randomized, patient- and investigator-blind 
study in patients with type 2 diabetes mellitus (T2DM).  This study is designed to compare 
tirzepatide 15 mg once-weekly (QW) and placebo with respect to secretion of counter-regulatory 
hormones in response to a hypoglycemic stimulus and parameters of recovery from 
hypoglycemia.
Eligibility for this study will be assessed at screening (Visit 1) and confirmed at the beginning of 
the lead-in period (Visit 2).  After eligibility is confirmed at Visit 2, patients will receive training 
and information on how to subsequently monitor their own diabetes condition.  Where 
applicable, patients will be required to undergo a washout of oral antidiabetic medications
(OAMs) other than metformin for at least 4 weeks between Visit 2 and Visit 3.  
Following baseline assessments, eligible patients will be 1:1 randomized (Visit 3; Day 1) to 
treatment sequence. All patients will undergo 2 treatment periods (12 weeks of treatment), 
receiving tirzepatide in 1 period and placebo in the other, in a crossover fashion.  
Tirzepatide 15 mg will be attained via step-wise dose escalation to reduce the risk of 
gastrointestinal adverse events (AE). Tirzepatide dosing will start at a dose of 2.5 mg QW for 2 
weeks, followed by step-wise escalation to 5 mg QW for the next 2 weeks, 10 mg QW for the 
next 4 weeks, and 15 mg QW for the final 4 weeks.  
There will be a washout period of at least 8 weeks (up to 10 weeks) between the last dose of 
study drug in Period 1 and the first dose in Period 2.  The washout period will ensure sufficient 
washout of the study drug based on tirzepatide’s elimination half-life of approximately 5 days.
At the end of each treatment period, patients will undergo a hypoglycemic clamp procedure (Day 
79 ±2 [clamp run-in period] and Day 80 ±2 [hypoglycemic induction]).  The hypoglycemic 
clamp procedure is detailed in protocol. 
The planned study duration for an individual patient from screening through safety follow-up 
will be approximately 38 to 42 weeks.
Figure GPHG.1 illustrates the study design.
Figure GPHG.2 illustrates the hypoglycemic clamp procedure.  
5.2.
Determination of Sample Size
Approximately 38 patients are planned to be enrolled so that 30 patients complete the study 
assuming a 20% discontinuation rate.  The calculation is based on the criterion that the width of 
the 95% confidence interval (CI) for the treatment comparison of the primary endpoint (change 
in glucagon from target plasma glucose concentration of 100 mg/dL to nadir target of 45 mg/dL) 
is within ±23.65 pg/mL with approximately 80% probability, provided that the within-subject 
variability is 40 pg/mL (Korsatko et al. 2018).


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Figure GPHG.1.
Illustration of study design for Protocol I8F-MC-GPHG.


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Abbreviations:  PG = plasma glucose.
Glucagon, insulin, C-peptide, cortisol, growth hormone, adrenaline, and noradrenaline 
measured at 10, 20 and 30 minutes of each clamp plateau and once PG 72 mg/dL (4.0 
mmol/L) is reached.
Blood pressure and pulse rate measured at 0 and 30 minutes of each plateau and once 
PG 72 mg/dL (4.0 mmol/L) is reached.
Hypoglycemic symptom score and hypoglycemia awareness assessed at 0 and 30 
minutes of each plateau and once PG 72 mg/dL (4.0 mmol/L) is reached.
Figure GPHG.2.
Hypoglycemic clamp.
-30 min
0 min
I min
I +30 min
J min
J +30 min
K min


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6.
A Priori Statistical Methods
6.1.
Populations for Analyses 
For the purpose of analysis, Table GPHG.2 defines 3 analysis sets.  
Table GPHG.2.
Analysis Populations/Data Sets
Population/Data Set
Definition
All randomized population
All patients who are randomly assigned to a treatment sequence.
Safety population
All randomized patients who are exposed to at least 1 dose of study drug 
(tirzepatide or placebo), regardless of whether they completed all protocol 
requirements.
PD analysis set *
Evaluable PD data from all randomized patients who are exposed to at least 1 
dose of study drug and complete both hypoglycemic clamp procedures.
Abbreviations:  PD = pharmacodynamic.
*  Protocol deviations will be considered for their severity/impact and taken into consideration whether subjects    
should be excluded from PD analysis set for hypoglycemic clamp data related analyses. 
6.2.
General Considerations
Statistical analysis of this study will be the responsibility of Eli Lilly and Company (Lilly) or its
designee. Any change to the statistical methods described in the protocol will require a protocol
amendment only if it changes a principal feature of the protocol. Any other change to the 
statistical analyses and the justification for the change will be documented in this SAP.  
Unless otherwise specified, safety analyses will be conducted on safety population (Table GPHG.2) 
and pharmacodynamic (PD) analyses will be conducted on PD analysis set (Table GPHG.2).  
Unless otherwise noted, all tests of treatment effects will be conducted at a 2-sided alpha level of 
0.05, and the CI will be calculated at 95%, 2-sided. 
If deemed necessary, additional analyses (e.g. linear mixed-effect models) of the endpoints on 
log transformed data will be conducted. 
6.3.
Patient Characteristics
The following patient demographic and clinical characteristics at study baseline (measurement 
collected at screening Visit 1 or during Period 1 Visit 3 Day 1 before first dose; details see 
below) will be summarized for the safety population and for PD analysis set by treatment 
sequence (i.e. tirzepatide/placebo and placebo/tirzepatide) and overall. 

age (years)

age (<65, ≥65 years)

sex (male, female)


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
race 

ethnicity (Hispanic or Latino, Not Hispanic or Latino)

height (cm)

duration of diabetes (years)
Note: for above parameters, the measurement collected at screening Visit 1 will be used.

body weight (kg)

body mass index (BMI) (kg/m2)

BMI groups (<30, ≥30 to <35, and ≥35 kg/m2) and (<27, ≥27 kg/m2)

hemoglobin A1c (% and mmol/mol)

fasting glucagon

fasting insulin

fasting C-peptide

fasting glucose

systolic blood pressure

diastolic blood pressure

pulse rate
Note: for above parameters, the measurement collected during Period 1 Visit 3 Day 1 before first 
dose will be used. 
In addition, the following patient clinical characteristics at baseline for each period will be 
summarized for the safety population and for the PD analysis set by treatment for each period, 
and by treatment (i.e. placebo: overall, period 1, period 2; tirzepatide: overall, period 1, period 
2).

body weight (kg)

body mass index (BMI) (kg/m2)

hemoglobin A1c (% and mmol/mol)

fasting glucagon 

fasting insulin 

fasting C-peptide 

fasting glucose 

systolic blood pressure

diastolic blood pressure


I 8 F-M C -G P H G St ati sti c al A n al y si s Pl a n V er si o n 2
P a g e 1 5
L Y 3 2 9 8 1 7 6

p ul se r at e
N ote: f or a b o ve para meters, t he meas ure me nts c ollecte d d uri n g Peri o d 1 Visit 3 Da y 1 bef ore 
first d ose a n d Perio d 2 Visi t 1 0 Da y  1 bef ore first d ose will be use d.  
6. 4.
P ati e nt Di s p o siti o n
A listi n g of  pati e nt di s p ositio n f or t he ra n d omize d p o p ul at i on will be pr o vi de d . Patie nt
di s p ositio n will  be s u m marize d b y tr e at me nt se q ue nce a n d p eri o d .
A listi n g of pati e nt s w h o disc o nti n ue fr om t he st u d y f or a n y reas o n f or t he ra n d o mize d 
p o p ul at i on will be pr o vi de d , a n d t he e xte nt of t heir partici pati on i n t he st u d y will be re p orte d.  
T he reas o n f or t heir disc o nti n uati o n fr om st u d y will be re p orte d.  T he listi n g will als o i ncl u de 
a ge, se x, race, treat me nt, a n d st u d y peri o d .
6. 5.
C o n c o mit a nt T h er a p y
C o nc o mita nt me d icati on will be liste d a n d su m marize d b y W o rld Heal t h Or ga nizati on Dr u g 
Di ct i onar y  Me dicat i on Class a n d Pr ef erre d Ter m f or t he safety p o p ulati o n . 
A listi n g of resc ue me dicati on f or h yper gl yce mia will be pr o vi de d.
6. 6.
Tr e at m e nt E x p o s ur e a n d C o m pli a n c e
6. 6. 1.
Tr e at m e nt E x p o s ur e
T he d urati o n of  e x p os ure t o st u d y me dicat i on ( tirze patide or place b o) i n eac h treat me nt peri o d is
defi ne d as:
D ate of l ast d ose of st u dy me dic ati o n - d ate of first d ose of st u dy me dic ati o n + 7 d ays
T he d urati o n of  e x p os ure t o st u d y me dicat i on f or eac h tr e at me nt peri o d will be liste d a n d
s u m marize d b y treat me nt f or eac h treat me nt peri o d a n d b y treat me nt o nl y usi n g t he safety
p o p ul at i on
6. 6. 2.
Tr e at m e nt C o m pli a n c e
Treat me nt c o m plia nce will be assesse d us i n g t he safety p o p ul at i on .  Treat me nt c o m plia nce f or 
eac h patie nt will be liste d, i ncl u di n g t he perce nt c o m plia nce f or 1 2 -wee k treat me nt peri o d ta ki n g 
i nto acc o u nt earl y ter mi nat i on .  Perce nt c o m plia nce a n d t reat me nt c o m plia nce will be 
s u m marize d b y tr e at me nt f or eac h peri o d a n d b y t reat me nt o nl y.
T he p erce nt c o mplia nce will be calc ulate d as:
(                        [                                ]
÷                                       ) × 1 0 0
P ati e nts will be c o nsi dere d tr e at me nt c o m p lia nt if ta ki n g ≥7 5 % of  t heir sc he d ule d d oses f or 1 2-
wee k treat me nt perio d ta ki n g i nt o acc o u nt earl y ter minat i on (s pecificall y e xcl u di n g t he peri o d 
after earl y ter mi nati on) .  


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When assessing treatment compliance, the missed doses and interrupted doses will be taken into 
consideration as described in protocol (Section 7.2.1 Selection and Timing of Doses and Section 
8.1.2 Temporary Interruption of Study Drug).
6.7.
Important Protocol Deviations
Important protocol deviations (IPDs) are defined as deviations from the study protocol that may 
significantly compromise the data integrity and/or patients’ safety.  The details of identification 
of IPDs is provided in a separate document (i.e., the trial issue management plan).  A listing/table
of IPDs will be provided by the study manager after database lock.  
6.8.
Pharmacokinetic Analyses
6.8.1. Pharmacokinetic Parameter Estimation
Pharmacokinetic (PK) samples will be collected across the study duration.  Tirzepatide
concentrations will be determined to support an understanding of tirzepatide exposure over the 
treatment duration to compare with expected tirzepatide PK.  
6.8.2. Pharmacokinetic Statistical Inference
No non-compartmental analysis dependent PK parameters will be derived, thus no statistical
analyses of PK parameters are planned.  
6.9.
Pharmacodynamic Analyses
6.9.1. Pharmacodynamic Parameter Estimation
Hypoglycemic Clamp Procedure Measurements
The clamp procedure will be initiated on Day 79 (clamp run-in period) and the hypoglycemic 
induction will be performed on Day 80 at the end of both treatment periods. The patient will be 
asked to attend the clinical research unit at approximately 18:00 hours in the evening of Day 79 
and will be served a standardized dinner at approximately 19:00 hours and thereafter will be 
fasted until the end of the clamp procedure on Day 80.  
Pharmacodynamic assessments will include counter-regulatory hormone responses (glucagon, 
growth hormone, cortisol, adrenaline, and noradrenaline), and responses of insulin and C-peptide
before and/or during the clamp, as well as clinical hypoglycemia (hypoglycemic symptom score
and hypoglycemia awareness), time to hypoglycemia recovery, vital signs during induced 
hypoglycemia, and other hypoglycemic clamp and recovery parameters.  
During the hypoglycemic clamp, for safety considerations, if the target PG concentrations are not 
achieved within 30 minutes of completion of the previous step, a higher PG concentration will be 
accepted as the PG concentration at which assessments are conducted. In case PG nadir 45 
mg/dL (2.5 mmol/L) target cannot be reached or symptoms of hypoglycemia are unacceptable, 
nadir at a higher PG concentration will be accepted (decision will be made by site personnel 
conducting the test) and data will be included in the analyses.  


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Hypoglycemic clamp
Clamp interventions are based on the mean PG reading (recorded in eCRF) as one blood sample 
will be measured twice.  The actual times (24 hour clock) of each stage of clamp procedure for 
each patient are provided through eCRF.  These actual times, corresponding to key clamp 
timepoints (see Table GPHG.3 for details) will be identified by programming.
Table GPHG.3.
Key Timepoints of Hypoglycemic Clamp Procedure On Day 80
Clamp PG Level
Planned Key Timepoints
eCRF Clamp Procedure Stage Comment
100 mg/dL
(5.5 mmol/L)
-30 minutes
Start plateau 5.5 mmol/L
End of 100 mg/dL
(5.5 mmol/L)
0 minutes
Stop plateau 5.5 mmol/L
Reaching 63 mg/dL
(3.5 mmol/L)
I minutes
Start plateau 3.5 mmol/L
End of 63 mg/dL
(3.5 mmol/L)
I+30 minutes
Stop plateau 3.5 mmol/L
Reaching 45 mg/dL 
(nadir; 2.5 mmol/L)
J minutes
Start plateau nadir
Stop constant insulin infusion
End of 45 mg/dL 
(nadir; 2.5 mmol/L)
J+30 minutes
Stop plateau nadir
Start recovery
Reaching 72 mg/dL
(4.0 mmol/L)
K minutes
Timepoint 4.0 mmol/L reached
* The PG level and duration of each plateau may vary due to patient’s conditions as described in Safety 
Considerations for Assessment Plateaus in Appendix 6 of Protocol.
Counter-regulatory hormone responses, and responses of insulin and C-peptide to 
hypoglycemic clamp
Glucagon, growth hormone, cortisol, adrenaline, noradrenaline, insulin, and C-peptide 
concentrations at target PG levels of 100 mg/dL (5.5 mmol/L), 63 mg/dL (3.5 mmol/L), and 45 
mg/dL (2.5 mmol/L) will be measured 3 times during each of these 3 plateaus (see Table GPHG.4
for details).

Mean concentrations at target PG levels of 100 mg/dL (5.5 mmol/L), 63 mg/dL (3.5 
mmol/L), and 45 mg/dL (2.5 mmol/L) will be calculated from the 3 measurements taken 
during each of these 3 plateaus for PD analyses.  If there is one missing measurement, the 
average value between 2 measurements will be used as the mean measurement.  If there 
is only one value, it will be used as the measurement.
The concentrations are measured once at ambient PG (glucagon only) and upon recovery to 
72 mg/dL (4.0 mmol/L) (see Table GPHG.4 for details).  


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Table GPHG.4.
Measurements of Glucagon, Insulin, C-peptide, Growth Hormone, 
Cortisol, Adrenaline, and Noradrenaline from Blood Sampling 
During Hypoglycemic Clamp Procedure on Day 79 and Day 80
Study Period Day
Clamp PG Level
Planned Timepoints* of Blood Sampling 
Day 79
Only glucagon at ambient PG sample was measured in 
pre-prandial state prior to clamp initiation
Day 80
100 mg/dL
(5.5 mmol/L)
-20 minutes
-10 minutes
0 minutes
Day 80
63 mg/dL
(3.5 mmol/L)
I + 10 minutes
I + 20 minutes
I + 30 minutes
Day 80
45 mg/dL
(nadir; 2.5 mmol/L)
J + 10 minutes
J + 20 minutes
J + 30 minutes
Day 80
72 mg/dL
(4.0 mmol/L)
K minutes
* The Planned Timepoints of blood sampling during clamp will be collected in eCRF. 
Clinical hypoglycemia
Hypoglycemic symptom score
Symptoms of hypoglycemia will be measured with a subjective, validated questionnaire, the 
Edinburgh Hypoglycemia Symptom Scale (EHSS), which measures the intensity of commonly 
experienced hypoglycemic symptoms on a 7-point Likert scale (1 = No symptom, 2 = very mild, 
3 = mild, 4 = mild to moderate, 5 = moderate, 6 = moderate to severe, and 7 = Severe). These 
symptoms have been grouped previously into neuroglycopenic symptoms (cognitive dysfunction 
and neuroglycopenia), and autonomic symptoms (McCrimmon et al. 2003). 
In this study, 13 questions are used to measure hypoglycemic symptoms. These data will be 
recorded in eCRF.

Neuroglycopenic symptoms (10)
o
Cognitive dysfunction (6): inability to concentrate, blurred vision, anxiety, 
confusion, difficulty speaking, and double vision
o
Neuroglycopenia (4): drowsiness, tiredness, hunger, and weakness

Autonomic symptoms (3): sweating, trembling, and warmness
The subscores of neuroglycopenic symptoms (cognitive dysfunction and neuroglycopenia), and 
autonomic symptoms, and the overall score (means of non-missing values) will be calculated and 
used for PD analyses based on responses to 13 questions, where lower score indicates fewer 
symptoms. 


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The EHSS questionnaire will be administered twice (0 and 30 minutes) at each of the 3 plateaus
(target levels of PG of 100 mg/dL [5.5 mmol/L], 63 mg/dL [3.5 mmol/L,] and PG of 45 mg/dL 
[2.5 mmol/L]) (see Table GPHG.5 for details).

The subscores and overall score (means of non-missing values) will be calculated for 
both collection timepoints in each plateau.  Mean hypoglycemic symptoms subscores and 
overall score at each plateau (mean of the 2 measurements taken) will be calculated and 
used for analyses.  
The EHSS questionnaire will be administered once when recovery PG of 72 mg/dL (4.0 
mmol/L) is reached (see Table GPHG.5 for details).  The subscores and overall score for this 
single recovery collection timepoint will be used for analyses.
Table GPHG.5.
Hypoglycemic Symptom Score and Hypoglycemia Awareness 
During Hypoglycemic Clamp Procedure on Day 80
Clamp PG Level
Planned Timepoints of Collecting 
Hypoglycemic Symptom Score and Hypoglycemia Awareness
100 mg/dL
(5.5 mmol/L)
-30 minutes
0 minutes
63 mg/dL
(3.5 mmol/L)
I minutes
I + 30 minutes
45 mg/dL
(nadir; 2.5 mmol/L)
J minutes
J + 30 minutes
72 mg/dL
(4.0 mmol/L)
K minutes
Hypoglycemia awareness
Hypoglycemia awareness will be evaluated based on the patients’ response (yes/no) to the 
question “Do you feel hypoglycemic?” during induced hypoglycemia. These data will be 
recorded in eCRF.  
Hypoglycemia awareness will be assessed twice (0 and 30 minutes) at each of the 3 plateaus
(target levels of PG of 100 mg/dL [5.5 mmol/L], 63 mg/dL [3.5 mmol/L], and PG of 45 mg/dL 
[2.5 mmol/L]) (see Table GPHG.5 for details).  

If the patient answered “yes” at least once when the question was asked twice in the same 
plateau, the patient is aware of hypoglycemia during induced hypoglycemia at that target 
PG level.  If the patient answered “no” to the question when asked twice in that plateau, 
the patient is unaware of hypoglycemia.  If there is only one non-missing value, it will be 
used as the measurement.  
Hypoglycemia awareness will be assessed once when recovery PG of 72 mg/dL (4.0 mmol/L) is 
reached (see Table GPHG.5 for details).


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Vital signs
Vital signs (that is, systolic blood pressure, diastolic blood pressure, pulse rate, and body 
temperature) at target PG of 100 mg/dL (5.5 mmol/L), 63 mg/dL (3.5 mmol/L), and 45 mg/dL
(2.5 mmol/L) will be measured twice at each of the 3 plateaus (see Table GPHG.6 for details).

Mean vital signs (systolic blood pressure, diastolic blood pressure, and pulse rate) at 
target PG of 100 mg/dL (5.5 mmol/L), 63 mg/dL (3.5 mmol/L), and 45 mg/dL (2.5 
mmol/L) will be calculated as the mean of the 2 measurements taken at each of these 3 
plateaus for PD analyses. If there is only one non-missing value, it will be used as the 
measurement.  
Vital signs will be measured once when recovery PG of 72 mg/dL (4.0 mmol/L) is reached (see 
Table GPHG.6 for details).
Table GPHG.6.
Vital Signs During Hypoglycemic Clamp Procedure on Day 80
Clamp PG Level
Planned Timepoints of Collecting Vital Signs
100 mg/dL
(5.5 mmol/L)
-30 minutes
0 minutes
63 mg/dL
(3.5 mmol/L)
I minutes
I + 30 minutes
45 mg/dL
(nadir; 2.5 mmol/L)
J minutes
J + 30 minutes
72 mg/dL
(4.0 mmol/L)
K minutes
6.9.2. Pharmacodynamic Statistical Inference
The counter-regulatory hormone responses (glucagon, growth hormone, cortisol, adrenaline, and 
noradrenaline), and responses of insulin and C-peptide will be reported in the International 
System of Units and conventional units.  
6.9.2.1.
Primary Pharmacodynamic Analysis
Glucagon counter-regulatory response during induced hypoglycemia
The primary PD parameter to assess the effect of tirzepatide 15 mg versus placebo will be the 
change in mean glucagon concentration from the target PG concentration of 100 mg/dL (5.5 
mmol/L) to the nadir target 45 mg/dL (2.5 mmol/L) (i.e., glucagon at nadir PG – glucagon at PG 
of 100mg/dL) during induced hypoglycemia. This will be evaluated using a linear mixed-effect 
model, with treatment, treatment period, and treatment sequence as fixed effects, and patient as a 
random effect using restricted maximum likelihood (REML) method in PD analysis set.  
Note: See Section 6.9.1 for calculation details.  Mean concentrations of glucagon at target PG 
levels of 100 mg/dL (5.5 mmol/L) and 45 mg/dL (2.5 mmol/L) will be calculated from the 3 


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measurements taken during these plateaus, respectively.  If there is one missing measurement, 
the average value between 2 measurements will be used as the mean measurement.  If there is 
only value, it will be used as the measurement.
Inferential statistics will include least squares (LS) means and standard error of glucagon
concentration change for tirzepatide versus placebo, the treatment difference (tirzepatide -
placebo), 95% CI, and associated p-values.  
Sensitivity analyses on primary endpoint among patients who reached nadir target PG of 45 
mg/dL (2.5 mmol/L) will be conducted in a similar manner if deemed appropriate, otherwise 
summary statistics will be sufficient. Patients who reached nadir are defined as the ones whose 
mean PG is ≤45 mg/dL at J minutes (Start plateau nadir).  

The actual PG level at nadir (J minutes) will be summarized by treatment. The frequency 
and proportion of patients who did not reach target nadir will be summarized.  
6.9.2.2.
Secondary Pharmacodynamic Analysis
The following measurements will be secondary PD measures in the study.  See Section 6.9.1 for 
data collection and calculation details.
Counter-regulatory hormone responses, and responses of insulin and C-peptide during 
induced hypoglycemia
Secondary PD measures to assess the effect of tirzepatide 15 mg versus placebo on 
counter-regulatory hormones, insulin, and C-peptide concentrations during induced 
hypoglycemia:
Glucagon 

Change in mean glucagon concentration from target PG concentration of 100 mg/dL
(5.5 mmol/L)
o
to target PG concentration of 63 mg/dL (3.5 mmol/L)
o
to target recovery PG concentration 72 mg/dL (4.0 mmol/L)

Change in mean glucagon concentration from ambient PG (see Table GPHG.4 for 
details)
o
to target PG concentration of 100 mg/dL (5.5 mmol/L)
o
to target PG concentration of 63 mg/dL (3.5 mmol/L)
o
to target PG nadir 45 mg/dL (2.5 mmol/L)
o
to target recovery PG concentration of 72 mg/dL (4.0 mmol/L)
Insulin, C-peptide, growth hormone, cortisol, adrenaline, and noradrenaline 

Change in mean insulin, C-peptide, growth hormone, cortisol, adrenaline, and 
noradrenaline concentrations from target PG concentration of 100 mg/dL (5.5 mmol/L) 


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o
to target PG concentration of 63 mg/dL (3.5 mmol/L)
o
to target PG nadir 45 mg/dL (2.5 mmol/L)
o
to target recovery PG concentration of 72 mg/dL (4.0 mmol/L)
The secondary PD parameters collected during hypoglycemic clamp procedure listed above 
(counter-regulatory responses) will be analyzed in a manner similar to the primary PD analysis 
using a linear mixed-effect model, respectively. 
Additional assessments on counter-regulatory response are described in Section 6.9.2.3 as 
exploratory endpoints.
Time to hypoglycemia recovery
Secondary PD measures to assess the effect of tirzepatide 15 mg versus placebo on time to 
recovery from induced hypoglycemia:

Time from termination of insulin infusion at PG concentration of nadir 45 mg/dL (2.5 
mmol/L) to reach recovery PG concentration (72 mg/dL [4.0 mmol/L]) 
o
That is, tPG_nadir-72 mg/dL [from Stop constant insulin infusion (J minutes) to the 
Timepoint 4.0 mmol/L reached (K minutes)]
o
The actual times (24 hour clock), corresponding to J and K minutes (see 
Table GPHG.3 for details) will be identified by statistical programming, and the 
time interval will calculated for PD analyses.
The tPG_nadir-72 mg/dL will be analyzed in a manner similar to the primary PD analysis using a linear
mixed-effect model.  
Clinical hypoglycemia
Secondary PD measures to assess the effect of tirzepatide 15 mg versus placebo on clinical 
hypoglycemia during induced hypoglycemia:

Hypoglycemic symptoms score (subscores and overall score) at the following times:
o
at target PG concentration of 100 mg/dL (5.5 mmol/L)
o
at target PG concentration of 63 mg/dL (3.5 mmol/L)
o
at target PG concentration of nadir 45 mg/dL (2.5 mmol/L)
o
at target recovery PG concentration of 72 mg/dL (4.0 mmol/L) 
The hypoglycemic symptom subscores and overall score at each of 4 target PG levels 
(i.e., 5.5 mmol/L, 3.5 mmol/L, nadir [2.5 mmol/L], and recovery [4.0 mmol/L]) during 
hypoglycemic clamp will be analyzed respectively in a manner similar to the primary PD 
analysis using a linear mixed-effect model.

Hypoglycemia awareness (binary) at the following times:
o
at target PG concentration of 100 mg/dL (5.5 mmol/L)


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o
at target PG concentration of 63 mg/dL (3.5 mmol/L)
o
at target PG concentration of nadir 45 mg/dL (2.5 mmol/L)
o
at target recovery PG concentration of 72 mg/dL (4.0 mmol/L)  
The hypoglycemia awareness at each of 4 target PG levels (i.e., 5.5 mmol/L, 3.5 mmol/L, 
nadir [2.5 mmol/L], and recovery [4.0 mmol/L]) during hypoglycemic clamp will be 
analyzed with nonparametric McNemar test at each target PG level to examine if there is 
difference in hypoglycemia awareness in comparison of tirzepatide 15 mg versus 
placebo.  
The above PD parameters (hypoglycemic symptom scores and hypoglycemia awareness) 
collected at 4 target PG levels will be summarized by treatment using descriptive statistics.
Corresponding plots on the hypoglycemic symptom scores with mean and standard deviations of 
PD parameters of these target PG levels will be provided by treatment.
Vital signs during induced hypoglycemia
Secondary PD measures to assess the effect of tirzepatide 15 mg versus placebo on vital signs 
during induced hypoglycemia:

change in mean systolic blood pressure, diastolic blood pressure, and pulse rates from 
target PG concentration of 100 mg/dL (5.5 mmol/L)
o
to target PG concentration of 63 mg/dL (3.5 mmol/L)
o
to target PG nadir 45 mg/dL (2.5 mmol/L)
o
to target recovery PG concentration of 72 mg/dL (4.0 mmol/L)
The above changes in vital signs during induced hypoglycemia will be summarized by treatment, 
and will be analyzed respectively in a manner similar to the primary PD analysis using a linear
mixed-effect model.
6.9.2.3.
Exploratory Pharmacodynamic Analysis
AUC will be calculated using trapezoidal rule.  See Section 6.9.1 for data collection and 
calculation details.
Additional hypoglycemic clamp and recovery parameters
Insulin infusion related parameters
The human soluble insulin lispro (40 IU insulin lispro [100 IU/mL] in 99.6 mL saline) is used for 
intravenous infusion (insulin 40 IU/100 mL). Between 0 minutes [Stop plateau 5.5 mmol/L], I
minutes [Start plateau 3.5 mmol/L], and J minutes [Start plateau nadir, Stop constant insulin 
infusion], insulin is infused at a constant flow 2.5 mU/kg/min, based on the patient body weight 
at Day 78 predose of each period. Insulin infusion is terminated once PG reaches nadir 45 
mg/dL.
Unit conversion of insulin infusion rate (IIR) [mL/hour] to IIR [mU/min/kg]: 


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IIR [mL/hour] * concentration 0.4 IU/mL * 1000 mU/IU ÷ (60 min/hour) ÷ body weight [kg]
Exploratory PD measures to assess the effect of tirzepatide 15 mg versus placebo on the amount 
insulin needed include:

Amount of insulin [i.e. AUC of IIR; mU/kg] required to reach PG concentration of 63 
mg/dL (3.5 mmol/L) from 100 mg/dL (5.5 mmol/L)
o
The time interval from Stop plateau 5.5mmol/L (0 minutes) to Start plateau 
3.5mmol/L (I minutes) is of interest, where insulin is infused at a constant rate.

Amount of insulin [i.e. AUC of IIR; mU/kg] required to reach PG concentration of nadir 
45 mg/dL (2.5 mmol/L) from 100 mg/dL (5.5 mmol/L)
o
The time interval from Stop plateau 5.5mmol/L (0 minutes) to Start plateau Nadir
(J minutes) is of interest, where insulin is infused at a constant rate.  
Glucose infusion related parameters
The glucose 20% (200 mg/mL) is used for intravenous infusion. At J minutes [Start plateau 
nadir, Stop constant insulin infusion], variable glucose infusion started, if needed to maintain 
nadir PG 45 mg/dL.  At J+30 minutes [Stop plateau nadir, Stary recovery], glucose infusion if 
switched off, and will be restarted if PG falls below 40 mg/dL until 45 mg/dL is reached. At 
J+45 minutes, if PG doesn’t recover to 72 mg/dL, constant glucose infusion flow (5.5 
mg/kg/min) is started [Start constant glucose infusion] until PG ≥ 72 mg/dL (at K minutes: 
Timepoint 4.0 mmol/L reached), based on the patient body weight at Day 78 predose of each 
period.  
Unit conversion of glucose infusion rate (GIR) [mL/hour] to GIR [mg/min/kg]: 
GIR [mL/hour] * concentration 20 g/100 mL * 1000 mg/g ÷ (60 min/hour) ÷ body weight [kg]
Exploratory PD measures to assess the effect of tirzepatide 15 mg versus placebo on glucose 
infusion related parameters include:

Area under the glucose infusion rate curve from time of termination of insulin infusion 
until recovery (PG of 72 mg/dL [4.0 mmol/L]), AUCGIR,PG_nadir-72 mg/dL [mg/kg] 
o
The time interval from Stop constant insulin infusion (J minutes) to Timepoint 4.0
mmol/L reached (K minutes) is of interest.  

The total amount of glucose infused to attain recovery (PG of 72 mg/dL [4.0 mmol/L]), 
Gtot [mg/kg] (i.e. AUC of GIR)
o
The time interval from Start recovery (J +30 minutes) to Timepoint 4.0 mmol/L 
reached (K minutes) is of interest.

The proportion of patients who require glucose infusion to attain recovery (PG
concentration 72 mg/dL [4.0 mmol/L])
o
If the above calculated Gtot >0, the patient required glucose infusion to attain 
recovery. If Gtot = 0, the patient attained recovery without glucose infusion.


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
Average glucose infusion rate [mg/min/kg] from Start plateau 5.5 mmol/L (-30 minutes)
to Stop constant insulin infusion (J minutes)

Average glucose infusion rate [mg/min/kg] from Stop constant insulin infusion (J
minutes) to Timepoint 4.0 mmol/L reached (K minutes)
Hypoglycemia recovery parameters
Exploratory PD measure to assess the effect of tirzepatide 15 mg versus placebo on the recovery 
from hypoglycemia include:

PG achieved at the end of the spontaneous recovery period 
o
This is the PG level at 45 minutes after termination of the insulin infusion (J
minutes [Stop constant insulin infusion] + 45 minutes).  At J+45 minutes, if PG 
doesn’t recover to 72 mg/dL, Start constant glucose infusion.

The proportion of patients who recovered spontaneously 45 minutes after termination of 
the insulin infusion (J+45 minutes)

If the PG level at J+45 minutes ≥72 mg/dL, the patient recovered spontaneously at J+45
minutes.
The above other hypoglycemic clamp and recovery exploratory PD parameters (except the 
proportion of patients who require glucose infusion to attain recovery and the proportion of 
patients who recovered spontaneously at J+45 minutes) will be analyzed in a manner similar to 
the primary PD analysis using a linear mixed-effect model. 
The status of whether patients require glucose infusion to attain recovery and whether patients
recovered spontaneously at J+45 minutes will be analyzed in a similar manner to the secondary 
analyses on hypoglycemia awareness with nonparametric McNemar test.  
Counter-regulatory hormone responses, and responses of insulin and C-peptide, and vital
signs during induced hypoglycemia

Change in mean glucagon, insulin, C-peptide, growth hormone, cortisol, adrenaline, and 
noradrenaline concentrations from target PG nadir of 45 mg/dL (2.5 mmol/L) to 
72 mg/dL (4.0 mmol/L)
The above changes in counter-regulatory responses will be analyzed in a manner similar to the 
primary PD analysis using a linear mixed-effect model. 

Change in vital signs (systolic blood pressure, diastolic blood pressure, and pulse rate) 
from target PG nadir of 45 mg/dL (2.5 mmol/L) to 72 mg/dL (4.0 mmol/L)
The above changes in vital signs during induced hypoglycemia will be analyzed in a manner 
similar to the primary PD analysis using a linear mixed-effect model.
Additional exploratory PD parameters (counter-regulatory responses, vital signs, and 
AUCGIR) for analyses


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The following PD parameters collected at ambient PG sample (only glucagon), three 30-min 
target PG plateaus (5.5 mmol/L, 3.5 mmol/L, and nadir [2.5 mmol/L]) and recovery [4.0 
mmol/L] on Day 80 will be summarized by treatment using descriptive statistics. Corresponding 
plots of mean and standard deviations of these PD parameters over the target PG levels will be 
provided by treatment.
These PD parameters will be analyzed in a manner similar to the primary PD analysis using a 
linear mixed-effect model.  

Counter-regulatory hormone responses (glucagon, growth hormone, cortisol, adrenaline, 
and noradrenaline), and responses of insulin and C-peptide to induced hypoglycemia
o
Only glucagon will also collected at ambient PG sample under pre-prandial 
state, prior to clamp initiation on Day 79 

Vital signs (systolic blood pressure, diastolic blood pressure, and pulse rate) during 
induced hypoglycemia

AUCGIR [mg/kg] 
o
It will be calculated at each of the 3 plateaus (30 minutes each), and at 
recovery period (J+30 minutes to K minutes).
6.9.3. Body Weight
Weight will be measured at multiple visits in both treatment periods before dosing.  Descriptive 
summaries of body weight will be provided for actual values of Day 1, Day 29, Day 57, Day 78 
by treatment for each period, and by treatment only, and change from Day 1 values by treatment 
for each period, and by treatment only. Plots of mean body weight and mean changes from Day 
1 over time will be provided by treatment for each period, and by treatment only.
6.10. Safety Analyses
Safety measures include, but not limited to, AEs, treatment-emergent adverse events (TEAEs), 
serious adverse events (SAEs), adverse events of special interest (AESIs), vital signs, and safety 
laboratory measures.
Unless specified otherwise, safety analyses will be performed on the safety population.  
Unless specified otherwise, safety listings will display values/events during all study periods 
(i.e., treatment periods, washout, and follow-up period). Listings of AEs, death, SAE may
include (but not limited to): patient identification (ID) number, age, sex, race, treatment, dose,
Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC), Preferred 
Term (PT), and time of onset from the first dose of study drug, duration of the AE, seriousness, 
severity, relatedness to study drug, action taken, and outcome, as appropriate. Additional safety 
listings will be provided for safety parameters other than AEs in related sections below.  
Treatment, and treatment period will be displayed in listings.
For safety measurements, summary statistics will be provided by treatment. A summary will be 
provided for AEs with frequency ≥10 patients with such event. 


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6.10.1. Adverse Events
A listing of adverse events for the safety population will be provided, which includes MedDRA
SOC, and PT.
6.10.2. Treatment-Emergent Adverse Events
A TEAE is defined as an AE which first occurs post first dose of study drug (of Period 1) or 
which is present prior to first dose of study drug (of Period 1) and becomes more severe post first 
dose.  The maximum severity for each AE during the baseline period (prior to first dose of 
Period 1) including ongoing medical history will be used as baseline severity.
Treatment-emergent adverse events will be summarized by treatment, severity and relationship 
with study drug.
For TEAEs in wash-out period, the treatment arm from Period 1 will be used for summary.  For 
TEAEs in follow-up period, the treatment arm from Period 2 will be used.
6.10.3. Serious Adverse Events (SAEs)
A listing of patients with SAEs (including death) will be produced.  
6.10.4. Adverse Events Leading to Discontinuation
A listing of patients with AEs leading to discontinuation from study will be provided.
6.10.5. Special Safety Topics 
A listing of patients with all AESIs defined in Section 6.10.5 will be provided.
6.10.5.1. Severe/Serious Gastrointestinal Adverse Events
A listing of patients with severe/serious gastrointestinal AEs, such as nausea, vomiting, and 
diarrhea will be provided.  
Only the PTs in the gastrointestinal SOC MedDRA with serious/severe cases will be considered 
as AESIs.
6.10.5.2. Hypoglycemia
Only hypoglycemic events outside of hypoglycemic clamp procedure are applicable here.  A 
listing of clinically significant hypoglycemia (plasma glucose <54 mg/dL) and severe 
hypoglycemia events will be provided.  A listing of patients with hypoglycemic events will be 
provided. The category of hypoglycemic events (see Table GPHG.7 for details) will be 
presented. A summary will be provided by treatment.  The incidence of hypoglycemia will be 
reported.
Severe/Serious hypoglycemia will be considered as AESIs.


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Table GPHG.7.
Definitions of Hypoglycemic Event Categories
Symptoms and/or Signs of 
Hypoglycemia
Plasma Glucose Level
Glucose alert value
Yes/No/Unknown
≤70 mg/dL (3.9 mmol/L)
    Documented symptomatic hypoglycemia
Yes
    Documented asymptomatic hypoglycemia
No
    Documented unspecified hypoglycemia
Unknown
Clinically significant hypoglycemia
Yes/No/Unknown
<54 mg/dL (3.0 mmol/L)
    Documented symptomatic hypoglycemia
Yes
    Documented asymptomatic hypoglycemia
No
    Documented unspecified hypoglycemia
Unknown
Severe hypoglycemia: defined as an episode with severe cognitive impairment requiring the 
assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative 
actions.  Severe hypoglycemia will be reported as an SAE.
Nocturnal hypoglycemia: defined as any hypoglycemic event that occurs between bedtime and 
waking.
To avoid duplicate reporting, all consecutive plasma glucose values ≤70 mg/dL (3.9 mmol/L) 
occurring within a 1-hour period may be considered to be a single hypoglycemic event.
6.10.5.3. 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 criteria in Protocol Section 9.2.2.3.  
A listing of rescue medication for hyperglycemia will be provided (also noted in Section 6.5).  
6.10.5.4. Pancreatitis
A listing of patients with pancreatitis (including investigator-reported and adjudicated) will be 
provided.  Adjudication assessment results will be reported in the listing.
Treatment-emergent adjudication-confirmed pancreatitis will be considered as AESI.
6.10.5.5. Thyroid Malignancies and C-Cell Hyperplasia
A listing of patients with thyroid malignancies and C-cell hyperplasia (search criteria provided in 
Appendix 1) will be provided.
Thyroid malignancies and C-cell hyperplasia will be considered as AESI.
6.10.5.6. Major Adverse Cardiovascular Events (MACE)
A listing of patients with MACE (including investigator-reported and adjudicated) will be 
provided.  Adjudication assessment results will be reported in the listing.
Only positively adjudicated MACE will be considered as AESI.


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6.10.5.7. Arrhythmias and Cardiac Conduction Disorders
A listing of patients with arrhythmias and cardiac conduction disorders (search criteria provided
in Appendix 1) will be provided.  
Severe/serious treatment-emergent arrhythmias and cardiac conduction disorders will be 
considered as AESI.  The cardiovascular events will include clinically relevant rhythm and 
conduction disorders.
6.10.5.8. Hypersensitivity Events
A listing of patients with hypersensitivity reactions (search criteria provided in Appendix 1) will 
be provided.  
Only the serious/severe cases of hypersensitivity will be considered as AESIs.
6.10.5.9. Injection Site Reactions
Injection-site assessments for local tolerability will be conducted, when reported as an AE from a 
patient, or a clinical observation from an investigator.
A listing of patients with reported injection-site reactions (e.g., edema, erythema, induration, 
itching, and pain) will be provided. Detailed search criteria can be found in Appendix 1.
Only the severe/serious injection site reactions (e.g., abscess, cellulitis, erythema, 
hematomas/hemorrhage, exfoliation/necrosis, pain, subcutaneous nodules, swelling, indurating, 
inflammation) will be considered as AESIs.
6.10.5.10.
Diabetic Retinopathy Complications
A listing of patients with diabetic retinopathy complications (search criteria provided in 
Appendix 1) will be provided.
The cases with repeat fundoscopy during the course of the trial, based on clinical suspicion of 
worsening retinopathy that have either findings of de novo retinopathy or progression of 
retinopathy, and severe/serious adverse events from the PTs for diabetic retinopathy 
complications (search criteria provided in Appendix 1), will be classified as an AESI.
6.10.5.11.
Hepatobiliary Disorders
A listing of patients with events of biliary colic, cholecystitis, or other suspected events related to 
gallbladder disease will be provided. Detailed search criteria are provided in Appendix 1.
Severe/serious hepatobiliary disorders will be considered as AESIs.
6.10.5.11.1. Hepatic Monitoring
The patients’ liver disease history and associated person liver disease history data will be listed. 
Concomitant medications acetaminophen/paracetamol, that have potential to cause
hepatotoxicity, will be listed.  Results from any hepatic monitoring procedures, such as a 
magnetic resonance elastography (MRE) scan, and biopsy assessments will be listed, if 
performed.


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Hepatic risk factor assessment data will be listed. Liver related signs and symptoms data will be
listed, and it will be summarized by treatment if ≥10 patients with such data. Alcohol and 
recreational drug use data will also be listed.
All hepatic chemistry, hematology, coagulation, and serology data will be listed. Values outside 
the reference ranges will be flagged on the individual patient data listings.
6.10.5.12.
Acute Renal Events
A listing of patients with acute renal events (search criteria provided in Appendix 1) will be 
provided.
Severe/serious acute renal events will be considered as AESI.
6.10.5.13.
Metabolic Acidosis, Including Diabetic Ketoacidosis
A listing of patients with metabolic acidosis (search criteria provided in Appendix 1) will be 
provided.
Severe/serious Metabolic Acidosis, including Diabetic Ketoacidosis will be captured as AESIs.
6.10.5.14.
Amputation/Peripheral Revascularization
A listing of patients with amputation and peripheral revascularization (search criteria provided in 
Appendix 1) will be provided.
Amputation/Peripheral revascularization will be considered as AESIs.
6.10.5.15.
Major Depressive Disorder/Suicidal Ideation
A listing of patients with major depressive disorder/suicidal ideation (search criteria provided in 
Appendix 1) will be provided.  
The severe/serious major depressive disorder/suicidal ideation or behavior will be captured as 
AESI.
6.10.6. Vital Signs
Descriptive summaries of vital signs will be provided for actual values of Day 1, Day 8, Day 15, 
Day 29, Day 57, Day 78 by treatment for each period, and by treatment only, and change from 
Day 1 values by treatment for each period, and by treatment only. Plots of mean vital signs and 
mean changes from Day 1 over time will be provided by treatment for each period.  
The treatment-emergent abnormal vital signs will be listed.  The criteria for identifying patients 
with treatment-emergent vital sign abnormalities are stated in Table GPHG.8.


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Table GPHG.8. 
Categorical Criteria for Treatment-Emergent Abnormal Blood 
Pressure and Pulse Measurements 
Parameter 
Low 
High 
Systolic BP (mmHg) 
(Supine or sitting – 
forearm at heart level)
≤90 and decrease from baseline ≥20 
≥140 and increase from baseline ≥20 
Diastolic BP (mmHg) 
(Supine or sitting – 
forearm at heart level)
≤50 and decrease from baseline ≥10 
≥90 and increase from baseline ≥10 
Pulse (bpm) 
(Supine or sitting)
<50 and decrease from baseline ≥15 
>100 and increase from baseline ≥15 
Abbreviations: BP = blood pressure; bpm = beats per minute. 
 
For PD parameters of systolic, diastolic blood pressure, and pulse rate during hypoglycemic 
clamp procedures, see Section 6.9 for analyses details. 
6.10.7. Electrocardiogram 
Electrocardiograms will be performed for safety monitoring purposes only.  Any clinically 
significant ECG findings entered as AEs will be included in AE summaries. 
6.10.8. Safety Laboratory Parameters 
All laboratory data will be reported in the International System of Units and conventional units. 
Descriptive summaries of clinical chemistry, hematology, and endocrine (calcitonin) data will be 
provided for actual values of Day 1 predose, Day 29, Day 78, and their changes from Day 1 will 
by treatment for each period, and by treatment only.   
Additionally, clinical chemistry, hematology, urinalysis, and endocrine (calcitonin) data outside 
the reference ranges will be listed.   
If any safety lab measurements are (1) below the quantification limit (e.g. < QL), ½ × QL may 
be used for the calculation of summary statistics; (2) above the quantification limit (e.g. > QL), 
1.1 × QL may be used for the calculation of summary statistics, if deemed appropriate. 
6.11. Evaluation of Immunogenicity 
Baseline immunogenicity sample is collected on Day 1 pre-dose of period 1.  The 
immunogenicity tables will be presented with only one overall column.  The listings will report 
treatment and period.   
For the treatment-emergent (TE) antidrug antibody (ADA)-positive patients, the distribution of 
maximum titers may be described.   
The frequency and percentage of patients with preexisting ADA and with TE ADA-positive 
(TE-ADA+) to tirzepatide may be tabulated.   


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If cross-reactive antibodies to native GIP and GLP-1, neutralizing antibodies against tirzepatide 
activity on GIP and GLP-1 receptors, or neutralizing antibodies against native GLP-1 and GIP 
are performed, the frequency and percentage of each may be tabulated.
A listing will be provided of immunogenicity assessments.  This includes the tirzepatide
concentration from a simultaneous pharmacokinetic sample and the clinical interpretation result
(ADA Present, ADA Not Present, ADA Inconclusive, or Missing). A listing of TEAE for 
patients with TE ADA+ or Injection Site Reaction or Potential Hypersensitivity may be 
provided.
Cases of TE-ADA+ that are associated with AEs of either severe/serious hypersensitivity or 
severe/serious injection site reaction will be classified as AESI.  
6.12. Interim Analyses
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the Lilly clinical pharmacologist, clinical research physician, investigator, or designee 
will consult with the appropriate medical director or designee to determine if it is necessary to 
amend the protocol.


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7.
Unblinding Plan
The blinding/unblinding plan is not part of this SAP.  The approved blinding/unblinding plan is 
stored in Leo.


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8.
Changes from the Protocol Specified Statistical Analyses 
Changes from the protocol specified statistical analyses are as follows: 

Protocol Section 10 states “Safety analyses will be conducted for all enrolled patients 
whether or not they completed all protocol requirements” and “Pharmacodynamic 
analyses will be conducted on data from all patients who complete both hypoglycemic 
clamp procedures.” In this SAP, it is clarified that safety population includes all 
randomized patients, who are exposed to at least 1 dose of the study drug (tirzepatide or 
placebo), regardless of whether they completed all protocol requirements, and PD 
analysis set includes evaluable PD data from all randomized patients who are exposed to 
at least 1 dose of study drug and complete both hypoglycemic clamp procedures.  


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9.
References
Korsatko S, Jensen L, Brunner M, Sach-Friedl S, Tarp MD, Holst AG, Heller SR, Pieber TR. 
Effect of once-weekly semaglutide on the counterregulatory response to hypoglycaemia in 
people with type 2 diabetes: A randomized, placebo-controlled, double-blind, crossover trial. 
Diabetes Obes Metab. 2018;20(11):2565-2573. 
McCrimmon RJ, Deary IJ, Gold AE, Hepburn DA, MacLeod KM, Ewing FM, Frier BM. 
Symptoms reported during experimental hypoglycaemia: effect of method of induction of 
hypoglycaemia and of diabetes per se. Diabetic Medicine. 2003 Jun;20(6):507-509.


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10. Appendices


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Appendix 1.
Search Criteria For Adverse Events of Special 
Safety Topics
The search criteria for AEs of special safety topics and AESIs are stored in 
CLUWE:\statsclstr\qa\ly3298176\common\AESI_Lab\Search criteria AESIs_TZP.xlsx 


Leo Document ID = f86a6ca7-e5ba-482d-94a2-d23a79b52c05
Approver: 
Approval Date & Time: 26-Oct-2021 20:53:57 GMT
Signature meaning: Approved
PPD