Clinical trial NCT04311424
Conditions: Healthy
Sponsor: Eli Lilly and Company
Start date: 2020-07-28; Completion date: 2020-10-02
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to look at how much tirzepatide gets into the bloodstream and how long the body takes to get rid of it. This study will involve a single dose of 14C radiolabelled tirzepatide. This means that a radioactive tracer substance, C14, will be incorporated into the study drug to investigate the study drug and its breakdown products and to find out how much of these pass from blood into urine, feces and expired air.

Screening is required within 28 days prior to the start of the study. For each participant, the total duration of the clinical trial will be approximately 15 weeks, including screening.

Detailed description:

Arms: arm 1: A single dose of \[14C\]-tirzepatide administered subcutaneously (SC).
Interventions: intervention 1: 14C Tirzepatide
Intervention descriptions: intervention 1: Administered SC.

Protocol documents:
Prot_000.pdf: 
Protocol I8F-MC-GPHX (a)
Disposition of [14C]-Tirzepatide Following Subcutaneous Administration in Healthy Male Subjects
NCT04311424    
Approval Date: 19-May-2020


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Approval Date: 19-May-2020 GMT


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Table of Contents
Disposition of [14C]-Tirzepatide Following Subcutaneous 
Administration in Healthy Male Subjects
Section
Page
Protocol I8F-MC-GPHX (a) Disposition of [14C]-Tirzepatide Following 
Subcutaneous Administration in Healthy Male Subjects......................................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis................................................................................................................8
2.
Schedule of Activities .......................................................................................................10
3.
Introduction ......................................................................................................................17
3.1.
Study Rationale............................................................................................................17
3.2.
Background..................................................................................................................17
3.3.
Benefit/Risk Assessment..............................................................................................18
4.
Objectives and Endpoints..................................................................................................19
5.
Study Design.....................................................................................................................20
5.1.
Overall Design .............................................................................................................20
5.2.
Number of Participants.................................................................................................23
5.3.
End of Study Definition ...............................................................................................23
5.4.
Scientific Rationale for Study Design...........................................................................23
5.5.
Justification for Dose ...................................................................................................23
6.
Study Population...............................................................................................................25
6.1.
Inclusion Criteria..........................................................................................................25
6.2.
Exclusion Criteria ........................................................................................................26
6.3.
Lifestyle and/or Dietary Requirements .........................................................................28
6.3.1.
Meals and Dietary Restrictions.............................................................................28
6.3.2.
Caffeine, Alcohol, and Tobacco ...........................................................................29
6.3.3.
Activity................................................................................................................29
6.4.
Screen Failures.............................................................................................................29
7.
Treatment..........................................................................................................................30
7.1.
Treatment Administered...............................................................................................30
7.1.1.
Packaging and Labeling .......................................................................................30
7.2.
Method of Treatment Assignment ................................................................................30
7.2.1.
Selection and Timing of Dose ..............................................................................31
7.3.
Blinding .......................................................................................................................31
7.4.
Dose Modification........................................................................................................31


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7.4.1.
Study Release Criteria..........................................................................................31
7.5.
Preparation/Handling/Storage/Accountability...............................................................31
7.5.1.
Safety Procedure in the Event of a Retrospective Positive 
Sterility Finding from Extemporaneously Prepared Study 
Treatment.............................................................................................................32
7.6.
Treatment Compliance .................................................................................................32
7.7.
Concomitant Therapy...................................................................................................32
7.8.
Treatment after the End of the Study............................................................................32
8.
Discontinuation Criteria ....................................................................................................33
8.1.
Discontinuation from Study Treatment.........................................................................33
8.1.1.
Discontinuation of Inadvertently Enrolled Subjects..............................................33
8.2.
Discontinuation from the Study....................................................................................33
8.3.
Subjects Lost to Follow-up...........................................................................................33
9.
Study Assessments and Procedures ...................................................................................34
9.1.
Efficacy Assessments...................................................................................................34
9.2.
Adverse Events ............................................................................................................34
9.2.1.
Serious Adverse Events........................................................................................35
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................36
9.2.2.
Complaint Handling.............................................................................................36
9.3.
Treatment of Overdose.................................................................................................36
9.4.
Safety...........................................................................................................................36
9.4.1.
Laboratory Tests ..................................................................................................36
9.4.1.1.
Amylase and Lipase Measurements ................................................................36
9.4.2.
Glucose Monitoring .............................................................................................36
9.4.2.1.
Hypoglycemia ................................................................................................36
9.4.3.
Vital Signs ...........................................................................................................38
9.4.4.
Electrocardiograms ..............................................................................................38
9.4.5.
Injection-Site Reactions .......................................................................................39
9.4.6.
Hypersensitivity Reactions...................................................................................39
9.4.7.
Safety Monitoring ................................................................................................40
9.4.7.1.
Hepatic Safety................................................................................................40
9.4.7.1.1.
Close hepatic monitoring ..........................................................................40
9.4.7.1.2.
Comprehensive hepatic evaluation............................................................41
9.4.7.1.3.
Additional hepatic data collection (hepatic safety 
eCRF) in subjects who have abnormal liver tests 
during the study........................................................................................41
9.5.
Pharmacokinetics .........................................................................................................42
9.5.1.
Whole Blood and Plasma Samples .......................................................................42
9.5.2.
Urine and Feces Sampling....................................................................................42


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9.5.3.
Expired Air Samples ............................................................................................42
9.5.4.
Bioanalysis...........................................................................................................43
9.6.
Pharmacodynamics ......................................................................................................43
9.7.
Immunogenicity Assessments.......................................................................................43
9.8.
Genetics .......................................................................................................................43
9.9.
Biomarkers...................................................................................................................44
9.10. Health Economics ........................................................................................................44
10.
Statistical Considerations and Data Analysis.....................................................................45
10.1. Sample Size Determination ..........................................................................................45
10.2. Populations for Analyses..............................................................................................45
10.2.1.
Study Participant Disposition ...............................................................................45
10.2.2.
Study Participant Characteristics ..........................................................................45
10.3. Statistical Analyses ......................................................................................................45
10.3.1.
Safety Analyses....................................................................................................45
10.3.1.1.
Clinical Evaluation of Safety..........................................................................45
10.3.1.2.
Statistical Evaluation of Safety.......................................................................46
10.3.1.3.
Injection-Site Reactions..................................................................................46
10.3.2.
Pharmacokinetic Analyses....................................................................................46
10.3.2.1.
Pharmacokinetic Parameter Estimation...........................................................46
10.3.2.2.
Pharmacokinetic Statistical Inference .............................................................46
10.3.3.
Interim Analyses..................................................................................................46
11.
References ........................................................................................................................47
12.
Appendices .......................................................................................................................48


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List of Tables
Table
Page
Table GPHX.1.
Objectives and Endpoints .......................................................................19
Table GPHX.2.
Treatments Administered........................................................................30


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List of Figures
Figure
Page
Figure GPHX.1.
Illustration of study design for Protocol I8F-MC-GPHX.........................22


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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................49
Appendix 2.
Clinical Laboratory Tests........................................................................53
Appendix 3.
Study Governance, Regulatory and Ethical Considerations.....................54
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............57
Appendix 5.
Blood Sampling Summary......................................................................58
Appendix 6.
Pancreatic Monitoring ............................................................................59
Appendix 7.
Classification of Contraceptive Methods.................................................62
Appendix 8.
Protocol Amendment I8F-MC-GPHX (a) Summary 
Disposition of [14C]-Tirzepatide Following Subcutaneous 
Administration in Healthy Male Subjects................................................63


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1. Protocol Synopsis
Title of Study:
Disposition of [14C]-Tirzepatide Following Subcutaneous Administration in Healthy Male Subjects.
Rationale: 
Tirzepatide, a dual agonist of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 
(GLP-1) is being developed for the treatment of type 2 diabetes mellitus (T2DM).  This study is being conducted to 
determine the disposition of radioactivity and tirzepatide (LY3298176) in healthy male subjects following a single 
subcutaneous (SC) injection of approximately 4.1 mg tirzepatide containing approximately 100 µCi 
[14C]-tirzepatide. The 100 μCi dose of the radiotracer will be administered to each subject to facilitate 
characterization of physiological disposition and metabolism of tirzepatide.
Objectives/Endpoints:
Objectives
Endpoints
Primary
To determine the disposition of radioactivity in healthy
male subjects following SC administration of a single
dose of approximately 4.1 mg (approximately 100 μCi) 
[14C]-tirzepatide.
Urinary and fecal excretion of total radioactivity over
time expressed as a percentage of the total radioactive
dose.
Secondary

To determine the PK of tirzepatide in plasma and 
total radioactivity in plasma and whole blood.

To assess the mass balance of tirzepatide by 
quantifying radioactivity recovered in urine, feces,
and expired air (if applicable).

To assess the metabolism of tirzepatide in plasma,
urine, and feces (if applicable).

To assess the safety and tolerability of a single 
dose of tirzepatide in healthy male subjects.

AUC(0-tlast), AUC(0-∞), and Cmax for tirzepatide 
in plasma and radioactivity in plasma and whole 
blood.

Total radioactivity recovered in urine, feces, and 
expired air (if applicable).

Total number of metabolites.

Incidence of AEs.
Abbreviations: AE = adverse event; AUC(0-tlast) = area under the concentration-time curve from time 0 to time of 
the last measurable concentration; AUC(0-∞) = area under the concentration-time curve from time 0 extrapolated 
to infinity; Cmax = maximum observed drug concentration; PK = pharmacokinetics; SC = subcutaneous.
Summary of Study Design:
Study I8F-MC-GPHX is an open-label, single-center study to determine the disposition of radioactivity and
pharmacokinetics (PK) of tirzepatide in healthy male subjects following a single dose of approximately 4.1 mg 
tirzepatide containing approximately 100 μCi of [14C]-tirzepatide administered as an SC injection.
Treatment Arms and Planned Duration for an Individual Subject:  
Subjects will participate in a screening visit, a single study period, follow-up visit(s), and a follow-up assessment.  
Subjects will be admitted to the clinical research unit (CRU) on the day prior to dosing (Day -1) and will receive a 
single subcutaneous dose of [14C]-tirzepatide on Day 1.  Subjects will remain resident at the CRU for a minimum of 


I8F-MC-GPHX Clinical Pharmacology Protocol (a)
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7 days postdose (Day 8) up to a maximum of 14 days postdose (Day 15).  Subjects can be discharged from the CRU 
at any time after 7 days postdose (Day 8) if both of the following release criteria have been met: 

≥90% of the administered radioactivity (based on the actual dose) has been recovered.

<1.0% of the total administered radioactivity is recovered in each combined urine and feces collections 
from 2 consecutive 24-hour urine and fecal sample collections (where both collections have occurred).
If subjects have not met both release criteria by 14 days postdose (Day 15), they will be required to return to the 
CRU for up to seven 48-hour residential inpatient follow-up visits. Samples will be collected for PK and the 
measurement of remaining radioactivity in urine and feces during the inpatient follow-up visits. Subjects will be 
required to attend all inpatient follow -up visits as scheduled until such time that the second release criterion (<1.0% 
total radioactivity in excreta) is met or up to a maximum of 63 days postdose (Day 64), whichever occurs first.
A follow-up assessment, conducted by telephone, will be performed 7 ± 2 days after each subject has completed the 
final study visit or after early discontinuation from the study.
Number of Subjects:
Up to 8 subjects will be enrolled.  It is planned that up to 6 subjects will be dosed initially and 2 additional subjects
will be dosed if needed, in order that a minimum of 4 subjects complete the study.
Statistical Analysis:
Pharmacokinetic parameter estimates for plasma and whole blood radioactivity, and plasma tirzepatide will be 
calculated by standard noncompartmental methods of analysis and summarized using descriptive statistics. The 
whole blood:plasma ratio of total radioactivity will be calculated for each time point.  The percent of radiolabeled 
dose recovered in feces, urine, and expired air (if applicable) will be calculated.  Safety assessments will be 
conducted for all enrolled subjects, whether or not they complete all protocol requirements. These parameters will 
be listed and summarized using standard descriptive statistics. No formal statistical analyses are planned.


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2. Schedule of Activities


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Study Schedule Protocol I8F-MC-GPHX
Screening
Check-
in
Study Days
Dischargea
Follow-up 
48-hour I/P 
Visitsb
Follow-
up O/P 
Visitc
Follow-up 
Phone 
Assessment
Comments
Procedure
Days -28 
to -2
Day -1
Day 1
Day 2 
up to 
14
Up to 
Day 15 or 
ED
Days 20 to 22, 27 
to 29, 34 to 36, 
41 to 43, 48 to 
50, 55 to 57 and 
62 to 64
Day 29
7 ± 2 days 
after last visit
or ED
Informed Consent
X
Subject Admission 
to CRU
X
Day 20, 27, 
34, 41, 48, 55 
and 62
Subjects will be resident in 
the CRU for 48 hours during 
Follow-up inpatient visits.
Subject Discharge 
from CRU
Xd
Day 22, 29, 
36, 43, 50, 57
and 64
In case of ED, efforts will be 
made to perform all 
discharge procedures.
Follow-up 
Assessment
X
Follow-up assessment may 
be conducted by telephone 
and include recording of AEs 
and concomitant medication.
[14C]-tirzepatide 
Subcutaneous
Administration
0 hours
Dosing occurs after all 
predose procedures and 
predose sample collections 
are completed.
Medical History
X
Height
X
Weight
X
Day 20, 27, 
34, 41, 48, 55 
and 62
X
Temperature
X
Predose
Urine Drug Screen 
and Alcohol Breath 
Test
X
X
Day 20, 27, 
34, 41, 48, 55 
and 62
X
Only the alcohol breath test 
will be conducted at the 
follow-up visit(s)
Cotinine Screen
X
X


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Screening
Check-
in
Study Days
Dischargea
Follow-up 
48-hour I/P 
Visitsb
Follow-
up O/P 
Visitc
Follow-up 
Phone 
Assessment
Comments
Procedure
Days -28 
to -2
Day -1
Day 1
Day 2 
up to 
14
Up to 
Day 15 or 
ED
Days 20 to 22, 27 
to 29, 34 to 36, 
41 to 43, 48 to 
50, 55 to 57 and 
62 to 64
Day 29
7 ± 2 days 
after last visit
or ED
Physical 
Exam/Medical 
Assessment
X
X
Xd
Day 20, 27, 
34, 41, 48, 55 
and 62
After screening, medical 
assessment only performed to 
include medical review and 
targeted examination, as 
appropriate.
At admission to the CRU for 
any follow-up visits a 
symptom-directed physical 
exam will be performed.  
Genetic Sample
Predose
Single sample taken prior to 
dosing on Day 1
Clinical Lab Tests
X
X
Xd
Day 29 and 57
X
See Appendix 2, Clinical 
Laboratory Tests, for details.
Vital Signs (supine)
X
X
Predose, 
12 hours
24, 48 
and 72 
hours
Xd
Day 20, 27, 
34, 41, 48, 55 
and 62
X
Additional time points may 
be added, if warranted at the 
investigator’s clinical 
discretion.
12-Lead ECG
X
Predose, 
24 
hours
Xd
X
Single safety ECG will be 
collected.  ECGs must be 
recorded before collecting 
any blood samples at each 
time point.  Subjects must be 
supine for 5 minutes before 
ECG collection, and remain 
supine but awake during 
ECG collection. Additional 
timepoints may be added, if 


I8F-MC-GPHX Clinical Pharmacology Protocol (a)
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Screening
Check-
in
Study Days
Dischargea
Follow-up 
48-hour I/P 
Visitsb
Follow-
up O/P 
Visitc
Follow-up 
Phone 
Assessment
Comments
Procedure
Days -28 
to -2
Day -1
Day 1
Day 2 
up to 
14
Up to 
Day 15 or 
ED
Days 20 to 22, 27 
to 29, 34 to 36, 
41 to 43, 48 to 
50, 55 to 57 and 
62 to 64
Day 29
7 ± 2 days 
after last visit
or ED
warranted, at the 
investigator’s clinical 
discretion. 
AEs/Concomitant 
Medications
X
X
X
X
X
X
X
X
Ongoing assessment
Immunogenicity 
Samples 
Predose
Day 29
X
Where applicable, collection 
times should match with PK 
sampling time points.  In the 
event of immediate or non-
immediate drug 
hypersensitivity reactions, 
unscheduled samples will be 
collected as detailed in 
Section 9.4.6.  Subjects with 
TE-ADA at follow-up will 
undergo additional follow-up 
as detailed in Section 9.7.
Blood Glucose 
Monitoringe
Predose 
and 12 
hours
24, 36, 
48 and 
72 
hours
Performed using a bedside 
glucose monitor.
Additional unscheduled 
measurements may be taken 
at the discretion of the 
investigator where clinically 
indicated.


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Screening
Check-
in
Study Days
Dischargea
Follow-up 
48-hour I/P 
Visitsb
Follow-
up O/P 
Visitc
Follow-up 
Phone 
Assessment
Comments
Procedure
Days -28 
to -2
Day -1
Day 1
Day 2 up
to 14
Up to 
Day 15 or 
ED
Days 20 to 22, 
27 to 29, 34 to 
36, 41 to 43, 48 
to 50, 55 to 57 
and 62 to 64
Day 29
7 ± 2 days 
after last visit
or ED
PK Samplese
(tirzepatide and 
total radioactivity)
Predose 
and 8 
hours 
24, 48, 
72, 96,
120, 144, 
168, 240, 
and 288
hours
336 hours
Day 22, 29, 
36, 43, 50, 57 
and 64
X
Sampling times are relative 
to the time of study treatment 
administration and are given 
as targets to be achieved 
within reasonable limits 
(±10 minutes for time points 
from 2 to 24 h; ±1 h for time 
points later than 24 h).
One sample will be collected 
at each follow-up visit.  
Metabolite 
Profiling Samples
8 hours
24, 48, 
72 96, 
120, 144, 
168, 240, 
and 288
hours
336 hours
Metabolite profiling samples 
will be collected separately to 
PK samples.
Urine Samplesf
Predose,
0-12 and
12-24 
hours
X
X
X (2 x 24-
hour 
collections at 
each visit)
Samples collected for 
24-hour intervals, except as 
specified on Day 1, until 
release criteria are met.
Urine samples to be collected 
for the determination of total 
radioactivity and metabolite 
profiling (total number and 
identity) only.


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Screening
Check-
in
Study Days
Dischargea
Follow-up 
48-hour I/P 
Visitsb
Follow-
up O/P 
Visitc
Follow-up 
Phone 
Assessment
Comments
Procedure
Days -28 
to -2
Day -1
Day 1
Day 2 
up to 
14
Up to 
Day 15 or 
ED
Days 20 to 22, 27 
to 29, 34 to 36, 
41 to 43, 48 to 
50, 55 to 57 and 
62 to 64
Day 29
7 ± 2 days 
after last visit 
or ED
Feces Samplesf
Predose 
and 
0-24 
hours
X
X
X (2 x 24-hour 
collections at 
each visit)
Samples collected for 
24-hour intervals until 
release criteria are met.
The inability to produce a 
fecal sample will not be 
considered a protocol 
deviation.
Feces samples to be collected 
for the determination of total 
radioactivity and metabolite 
profiling (total number and 
identity) only. 
Expired Air 
Samples
Predose, 
2, 4, and 
8 hours
X
X
Samples collected for 
24-hour intervals, except as 
specified on Day 1, until 
release criteria are met.
Abbreviations:  AE = adverse event; CRU = clinical research unit; ECG = electrocardiogram; ED = early discontinuation; I/P = inpatient; O/P = outpatient;
PK = pharmacokinetics; TE-ADA = treatment-emergent antidrug antibodies.
a Subjects may be discharged from the CRU at any time, once the study release criteria have been met, up to a maximum stay of 14 days postdose (Day 15).
b If subjects do not meet the release criteria by Day 15 (Section 5.1) they will return for up to seven 48-hour I/P visits until <1.0% of the total administered 
radioactivity is excreted in 2 consecutive 24-hour urine and fecal sample collections or until a maximum of Day 64.
c Immunogenicity and PK samples are required from all subjects on Day 29 (28 days postdose).  These samples will be collected during the course of the Day 27 
to 29 I/P follow-up visit;  any subjects not attending the Day 27 to 29 I/P follow-up visit will alternatively be required to return for an outpatient visit on Day 29 
for the collection of these samples.
d Only to be performed at the time of discharge or early discontinuation for each subject.


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e Specified times are approximate, and actual times will be recorded. Actual sampling time should not exceed 1 hour prior to dosing for the predose sample.
f Predose urine and feces will be collected as spot/single samples.  A urine spot sample will be collected within 3 hours prior to dosing and a single predose fecal 
sample collected from Day -1 to 0 hours on Day 1.
Note:  if multiple procedures take place at the same time point, the following order of the procedure should be use: ECGs, vital signs, PK sample (record of 
actual PK sampling time is the priority), urine and feces sample for radioactivity, metabolite profiling samples, blood glucose, clinical laboratory sample, 
immunogenicity and pharmacogenetic sample. Unless otherwise specified, predose procedures and samples may be performed within an hour prior to 
[14C]-tirzepatide dosing.


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3. Introduction
3.1.
Study Rationale
Tirzepatide is being developed for the treatment of type 2 diabetes mellitus (T2DM) as an 
adjunct to diet and exercise.  In addition, it is being developed as a therapy for the indications of 
chronic weight management and nonalcoholic steatohepatitis.  
Study I8F-MC-GPHX (GPHX) is being conducted to determine the disposition of radioactivity 
and pharmacokinetics (PK) of tirzepatide (LY3298176) in healthy male subjects following a 
single subcutaneous (SC) injection of approximately 4.1 mg tirzepatide containing 
approximately 100 µCi [14C]-tirzepatide.  The 100-μCi dose of the radiotracer will be 
administered to each subject to facilitate characterization of physiological disposition and 
metabolism of tirzepatide.  The tirzepatide dose is therefore dependent upon the specific activity 
of the drug substance.  At the target drug substance specific activity, the tirzepatide dose will be 
4.1 mg. However, based on variability in the drug substance specific activity, the final 
tirzepatide dose will be approximately 4.1 mg and will be no higher than 5 mg.
3.2.
Background
The available preclinical and clinical data indicate that dual-stimulation of glucose-dependent 
insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors may enhance
insulin secretion, improve insulin sensitivity, and reduce body weight beyond the effect of 
selective GLP-1 receptor stimulation (Frias et al. 2018; Coskun et al. 2018).
Tirzepatide, a dual agonist of GIP and GLP-1, is a 39-amino acid synthetic peptide.  Its structure 
is based on the GIP sequence and includes a C20 fatty di-acid moiety that prolongs the duration 
of action.  It has a chemical structure and pharmacologic profile that is distinct from the GLP-1 
receptor agonists due to the addition of GIP, which is unique among the marketed incretin 
mimetics.
In a Phase 1 study (Coskun et al. 2018) that included single- and multiple-ascending-dose (SAD, 
MAD) parts, tirzepatide has been administered as single SC doses up to 8 mg in healthy subjects.  
In the MAD part, higher doses up to 10 mg were attained in healthy subjects via dose escalation.  
Doses up to 15 mg were achieved in patients with T2DM via dose escalation.  In this study, 
gastrointestinal (GI) adverse events (AEs) (nausea, vomiting, diarrhea, abdominal distension) 
and decreased appetite were the most frequently reported events by both healthy subjects and 
patients with T2DM and were dose related.  Most AEs were mild in severity, a few were 
moderate, and none were reported as severe.  During the single-ascending-dose study, the high 
incidence of GI AEs, notably vomiting, were considered to be dose limiting at the 8-mg dose; 
therefore, the 5-mg dose was considered the maximum tolerated dose.  A dose-dependent 
increase in heart rate was detected for both healthy subjects and patients with T2DM who 
received tirzepatide, similar to what was observed with selective GLP-1 receptor agonists.  A 
few subjects experienced transient elevations in lipase and/or amylase levels, but these episodes 
were not associated with any relevant clinical outcomes.  Once-weekly doses of 1, 5, 10, and 
15 mg have been further investigated in a Phase 2 study (Frias et al, 2018).  An additional dose 


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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, 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, with maximum 
observed drug concentration (Cmax) occurring 24 to 72 hours postdose.  The pharmacokinetics of 
tirzepatide appears linear across the dose range evaluated (single doses from 0.25 to 8 mg or 
multiple weekly doses up to 15 mg) previously in clinical studies.
Overall, the safety and tolerability, and PK/pharmacodynamic profiles of tirzepatide support 
further development of tirzepatide in patients with T2DM.  Further details can be found in the 
Investigator’s Brochure (IB).
3.3.
Benefit/Risk Assessment
Risks of tirzepatide have been consistent with risks associated with other GLP-1 receptor 
agonists currently marketed.  Potential risks include, but are not limited to, GI effects, acute 
pancreatitis, increases in heart rate, and hypoglycemic events (GLP-1 receptor agonist class 
effect).
No clinically significant safety or tolerability concerns have been identified in subjects to date 
for a single dose of tirzepatide up to the maximum tolerated dose of 5 mg (dose escalation from 
0.25 to 8 mg) or multiple weekly doses when escalated up to 15 mg.  Based on this information, 
the single maximum 5-mg dose to be administered in Study GPHX is reasonably anticipated to 
be tolerable in this group of healthy subjects.
There is no anticipated therapeutic benefit for the subjects.
More information about the known and expected benefits, risks, serious adverse events (SAEs) 
and reasonably anticipated AEs of tirzepatide are to be found in the IB.


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4. Objectives and Endpoints
Table GPHX.1 shows the objectives and endpoints of the study.
Table GPHX.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To determine the disposition of radioactivity in healthy
male subjects following SC administration of a single 
dose of approximately 4.1mg (approximately 100 μCi) 
[14C]-tirzepatide.
Urinary and fecal excretion of total radioactivity over
time expressed as a percentage of the total radioactive
dose.
Secondary

To determine the PK of tirzepatide in plasma and 
total radioactivity in plasma and whole blood.

To assess the mass balance of tirzepatide by 
quantifying radioactivity recovered in urine, feces,
and expired air (if applicable).

To assess the metabolism of tirzepatide in plasma,
urine, and feces (if applicable).

To assess the safety and tolerability of a single 
dose of tirzepatide in healthy male subjects.

AUC(0-tlast), AUC(0-∞), and Cmax for tirzepatide 
in plasma and radioactivity in plasma and whole 
blood.

Total radioactivity recovered in urine, feces, and 
expired air (if applicable).

Total number of metabolites.

Incidence of AEs.
Abbreviations: AE = adverse event; AUC(0-tlast) = area under the concentration-time curve from time 0 to time of 
the last measurable concentration; AUC(0-∞) = area under the concentration-time curve from time 0 extrapolated 
to infinity; Cmax = maximum observed drug concentration; PK = pharmacokinetics; SC = subcutaneous.


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5. Study Design
5.1.
Overall Design
This is a Phase 1, open-label, single-center study in healthy male subjects following a single dose 
of approximately 4.1 mg tirzepatide containing approximately 100 µCi of [14C]-tirzepatide 
administered as an SC injection.
Subjects will participate in a screening visit, a single study period, up to 7 follow-up visits and a 
follow-up telephone assessment.  Subjects will be admitted to the clinical research unit (CRU) on 
the day prior to dosing (Day -1) and will receive a single SC injection of [14C]-tirzepatide, 
administered by clinical site staff, on Day 1.
Subjects will remain resident in the CRU for 14 days postdose (Day15), but, may be discharged 
earlier if both the following release criteria have been met: 

≥90% of the administered radioactivity (based on the actual dose) has been recovered,
AND

24-hour urine and fecal samples from 2 consecutive collections (where both collections 
have occurred) where each combined urine and feces collection has a radioactivity level 
<1.0% of the total administered radioactivity.
If subjects have not met both release criteria by 14 days postdose (Day 15), they will be required 
to return to the CRU for up to seven 48-hour residential inpatient follow-up visits.  Samples will 
be collected for PK and the measurement of remaining radioactivity in urine and feces during the 
inpatient follow-up visits.  Subjects will be required to attend all inpatient follow -up visits as 
scheduled until such time that the second release criterion (<1.0% total radioactivity in excreta) 
is met or up to a maximum of 63 days postdose (Day 64), whichever occurs first.  
An immunogenicity and corresponding PK sample are required from all subjects on Day 29.  If 
subjects have not previously met the release criteria and are returning for the Day 27 to 29 
inpatient follow-up visit, then the immunogenicity and PK samples will be collected in the 
course of this visit.  Subjects that have met the release criteria prior to the Day 27 to 29 inpatient 
visit will be required to attend a single outpatient visit on Day 29 for the collection of PK and 
immunogenicity samples.
A follow-up assessment will be conducted by telephone and will include recording of AEs and 
concomitant medication.  The follow-up assessment will be performed 7 ± 2 days after each 
subject has completed the final study visit or following early discontinuation from the study.
Sequential blood samples will be obtained predose and after dose administration to quantify the
PK of the total radioactivity in whole blood and plasma, and tirzepatide in plasma.  Separate 
blood samples will also be taken at selected time points for metabolite profiling.
Sequential urine and fecal samples will be obtained to determine the mass balance of tirzepatide
by quantification of radioactivity and to identify metabolites.  Samples of expired air will also be 
collected for the analysis of 14CO2 at selected time points.  If a significant amount of 


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administered radioactivity is present in expired air samples, these data will be extrapolated to 
estimate the radioactive dose recovery.  The percent of the dose eliminated in excreta will be 
estimated by measuring the amount of radioactivity in the urine and/or feces for each collection 
period.
Safety evaluations will include recording of AEs, clinical laboratory tests, glucose monitoring,
injection-site and hypersensitivity reactions, vital sign measurements, 12-lead electrocardiograms 
(ECGs), and physical examinations.
Study governance considerations are described in detail in Appendix 3.
Figure GPHX.1 illustrates the study design.


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Abbreviations: ED = early discontinuation; PK = pharmacokinetic
a Immunogenicity and PK samples are required from all subjects on Day 29 (28 days postdose).  Subjects attending the Day 27 to 29 inpatient visit will have 
these samples collected during the course of the visit.  Subjects not attending the Day 27 to 29 inpatient visit will return to the CRU for a single outpatient visit 
on Day 29 for the collection of these samples.
Figure GPHX.1.
Illustration of study design for Protocol I8F-MC-GPHX.


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5.2.
Number of Participants
Up to 8 subjects may be enrolled.  It is planned that up to 6 subjects will be dosed initially and 
2 additional subjects may be dosed if needed, in order that a minimum of 4 subjects complete the 
study.  For purposes of this study, a subject completes the study when all scheduled procedures 
shown in the Schedule of Activities (Section 2) have been finished.
5.3.
End of Study Definition
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last subject.
5.4.
Scientific Rationale for Study Design
This clinical study will be conducted to determine the disposition of radioactivity and PK of
tirzepatide in healthy male subjects following a single SC injection of tirzepatide labeled with
14C.  The radiolabeled tirzepatide enables identification of circulatory and excretory metabolites
and understanding of the clearance pathways.
Conducting the study in healthy subjects mitigates the potential confounding effects of the
disease state and of concomitant medications.  This study has an open-label design with no
control treatment.  This type of design is standard and widely used in radiolabeled studies.  
Subcutaneous administration has been chosen as this is the intended clinical route of tirzepatide
administration.
Based on available clinical PK data for tirzepatide and human excretion data from a related
GLP-1 analog (Jensen et al., 2017), the duration of clinical confinement will be up to 14 days
postdose (Day 15).  
5.5.
Justification for Dose
Based on data from a quantitative whole-body autoradiography disposition study for tirzepatide 
in male rats, a whole-body radiation dose in a 70-kg man following administration of a single SC
100-μCi (3.7-MBq) dose of [14C]-tirzepatide was calculated to be 97.7 mrem (0.977 mSv).  This 
effective radiation dose is defined as being within dose limits for members of the public 
(Category II study; World Health Organization, 1977) with a minor associated risk (risk 
Category IIa; International Commission on Radiological Protection [ICRP], 1992).  Therefore, 
administration of a single SC 100-μCi (3.7-MBq) dose of [14C]-tirzepatide would not be 
expected to represent a significant radiation exposure risk in man.  
The specific activity of [14C]-tirzepatide is approximately 20-24 µCi/mg. A dose of tirzepatide 
that can provide a radioactive dose of 100 µCi per subject, is considered sufficient to facilitate 
characterization of the physiological disposition and metabolism of tirzepatide whilst complying 
with the “as low as (is) reasonably achievable” (ALARA) principle prescribed by the ICRP. 
Hence a tirzepatide dose of approximately 4.1 mg has been selected for this study.
Data from Phase 1 study GPGA has shown that a 5-mg dose of tirzepatide was well tolerated by 
healthy subjects and patients with T2DM, and is also planned as one of the doses to be


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investigated in Phase 3 studies. Doses higher than 5 mg were achieved via escalation since a 
5 mg dose was considered the MTD when administered as a single dose.
The study will be submitted for approval by the Administration of Radioactive Substances 
Advisory Committee.


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6. Study Population
Eligibility of subjects for the study will be based on the results of screening medical history, 
physical examination, vital signs, clinical laboratory tests, and 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 27 days prior to check-in.  Subjects who are not enrolled within 
27 days of screening may be subjected to an additional medical assessment and/or clinical 
measurements to confirm their eligibility.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
6.1.
Inclusion Criteria
Subjects are eligible for inclusion in the study only if they meet all of the following criteria at 
screening and/or check-in:
[1]
are overtly healthy males, as determined by medical history and physical 
examination  
[1a] male subjects, regardless of their fertility status, with non-pregnant women of 
childbearing potential partners must agree to either remain abstinent (if this 
is their preferred and usual lifestyle) or use condoms plus 1 additional highly 
effective (less than 1% failure rate) method of contraception (such as 
combination oral contraceptives, implanted contraceptives, or intrauterine 
device) or effective method of contraception, (such as diaphragms with 
spermicide or cervical sponge) for the duration of the study and for at least 
90 days following administration of the investigational product (IP). A full 
list of permitted highly effective and effective methods of contraception is 
presented in Appendix 7.
[1b] male subjects 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.
[1c] periodic abstinence, declaration of abstinence just for the duration of a trial, 
and withdrawal are not acceptable methods of contraception.
[1d] male subjects with pregnant partners should use condoms during intercourse 
for the duration of the study and for at least 90 days after dosing.
[1e] male subjects should refrain from sperm and blood donation for the duration 
of the study and for at least 90 days after dosing.


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[1f] male subjects who are in exclusively same-sex relationships (as their 
preferred and usual lifestyle) are not required to use contraception.
[2]
are 30 to 55 years old, inclusive, at the time of screening.
[3]
have a body mass index (BMI) of 18.0 to 32.0 kg/m2, inclusive, at screening.
[4]
have clinical laboratory test results within normal reference range for the 
population or investigative site, or results with acceptable deviations that are 
judged to be not clinically significant by the investigator.
[5]
have venous access sufficient to allow for blood sampling as per the protocol.
[6]
are willing to receive study treatment by SC injections.
[7]
are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures.
[8]
are able and willing to give signed informed consent.
6.2.
Exclusion Criteria
Subjects will be excluded from study enrollment if they meet any of the following criteria at 
screening and/or check-in:
[9]
are investigative site personnel directly affiliated with this study and their 
immediate families.  Immediate family is defined as a spouse, biological or 
legal guardian, child, or sibling.
[10] are Lilly or Covance employees.
[11] 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.
[12] have participated, within the last 3 months, in a clinical study involving an IP.  
If the previous IP has a long half-life, 5 half-lives or 3 months (whichever is 
longer) should have passed, prior to dosing on Day 1.
[13] have previously completed or withdrawn from this study or any other study 
investigating tirzepatide, and have previously received the IP.
[14] have had any exposure to tirzepatide, other GLP-1 analogs, or other related 
compounds within the prior 3 months, or any history ever of allergies to these 
medications.
[15] have any abnormality in the 12-lead ECG at screening that, in the opinion of 
the investigator, increases the risks associated with participating in the study.
[16] have an abnormal blood pressure and/or pulse rate as determined by the 
investigator at screening or check-in.


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[17] have significant history of or current cardiovascular, respiratory, hepatic, 
renal, gastrointestinal, 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.
[18] have evidence of significant active neuropsychiatric disease, as determined by 
the investigator.
[19] have a positive alcohol breath test result or positive urine drug screen 
(confirmed by repeat) at screening or check-in.
[20] show evidence of human immunodeficiency virus (HIV) infection and/or 
positive human HIV antibodies.
[21] show evidence of hepatitis C and/or positive hepatitis C antibody.
[22] show evidence of hepatitis B and/or positive hepatitis B surface antigen.
[23] have used or plan to use over-the-counter or prescription medication, and/or 
herbal supplements (with the exception of vitamin/mineral supplements and/or 
thyroid replacement therapy) within 14 days prior to dosing and for the 
duration of the study, including any medications that reduce GI motility, 
including, but not limited to, anticholinergics, antispasmodics, 
5-hydroxytryptamine-3 receptor antagonists, dopamine antagonists, and 
opiates.
[24] have donated blood of more than 500 mL within the previous 3 months of 
study screening.
[25] have an average weekly alcohol intake that exceeds 21 units per week, or are 
unwilling to stop alcohol consumption from 36 hours prior to check-in and 
while resident in the CRU (1 unit = 1/2 pint or 284 mL of beer; 25 mL of 
distilled spirits; 3 units = 250 mL of wine).
[26] are unwilling to refrain from consuming caffeine- or xanthine-containing food 
and drink from 48 hours prior to admission and while resident in the CRU.
[27] are currently or have been smokers, users of tobacco, users of nicotine 
replacement products, or users of any vaping/e-cigarette devices within the 
3 months prior to admission and/or have positive cotinine at screening or 
check-in.
[28] have had exposure to significant diagnostic, therapeutic, or 
employment-related radiation within 12 months prior to dosing (e.g., serial 
x-ray or computed tomography scans, barium meal, current employment in a 
job requiring radiation exposure monitoring).
[29] have a history of constipation or have had acute constipation within 3 weeks 
prior to check-in.


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[30] have evidence of active renal disease (e.g., diabetic renal disease, polycystic 
kidney disease) or an estimated creatinine clearance of <80 mL/minute, 
calculated using the Chronic Kidney Disease-Epidemiology.
[31] have participated in any clinical trial involving a radiolabeled IP within 
12 months prior to check-in.
[32] have a history or presence of pancreatitis (history of chronic pancreatitis or 
idiopathic acute pancreatitis), elevation in serum amylase or lipase (>1.5-fold 
the upper limit of normal [ULN]).
[33] have a GI disorder (e.g., relevant esophageal reflux or gall bladder disease), or 
any GI disease which impacts gastric emptying (e.g., gastric bypass surgery, 
pyloric stenosis [with the exception of appendectomy]) or could be aggravated 
by GLP-analogs.  Subjects with dyslipidemia and subjects who had 
cholecystolithiasis (with removal of gallstones) and/or cholecystectomy 
(removal of the gall bladder) in the past, with no further sequelae, may be 
included in the study, at the discretion of the investigator.
[34] have a history of atopy or clinically significant multiple or severe drug 
allergies, or severe post-treatment hypersensitivity reactions (including, but 
not limited to, erythema multiforme major, linear immunoglobulin A 
dermatosis, toxic epidermal necrolysis, or exfoliative dermatitis).
[35] have a personal or family history of medullary thyroid carcinoma or have 
multiple endocrine neoplasia syndrome type 2, or a screening calcitonin
≥20 pg/mL at screening.
[36] have Gilbert’s syndrome.
[37] have serum aspartate aminotransferase (AST) or alanine aminotransferase 
(ALT) >2 × ULN or total bilirubin (TBL) >1.5 × ULN at screening.
[38] have a history of malignancy within 5 years prior to screening.
[39] have a triglyceride ≥5 mmol/L (442.5 mg/dL) at screening.
[40] in the opinion of the investigator or sponsor, are unsuitable for inclusion in the 
study.
6.3.
Lifestyle and/or Dietary Requirements
Throughout the study, subjects may undergo medical assessments and review of compliance with 
requirements before continuing in the study.  
6.3.1. Meals and Dietary Restrictions
Subjects will be required to fast overnight for at least 8 hours before being administered the SC 
dose of tirzepatide, and when clinical laboratory test samples are taken (Schedule of Activities; 
Section 2).  A meal will be offered to study subjects at approximately 2 hours postdose.  During 
inpatient stays, subjects will receive a standardized, high-fiber diet at scheduled times that do not 
conflict with other study-related activities.  Prune juice may be administered on an as-needed 


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basis to aid in normal bowel function and will not be considered a concomitant medication.  
Water may be consumed freely.
6.3.2. Caffeine, Alcohol, and Tobacco

Caffeine - Subjects will refrain from consuming caffeine- or xanthine-containing food 
and drink from 36 hours prior to admission until discharge from the CRU.

Alcohol - Subjects will not consume alcohol for 36 hours prior to admission until 
discharge from the CRU and will abide by study restrictions (i.e. no more than 3 units 
of alcohol per day - see Exclusion Criteria [25] for unit definition) at other times 
throughout the study.

Tobacco - Subjects will not be permitted to smoke, use tobacco, or use products 
containing nicotine within 3 months prior to admission until final discharge from the 
study.
6.3.3. Activity
No strenuous physical activity will be allowed for 48 hours prior to dosing until discharge from 
the CRU, and 24 hours prior to each follow-up visit (inpatient and outpatient).
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
re-screened.  


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7. Treatment
7.1.
Treatment Administered
After an overnight fast of at least 8 hours, IP is to be administered subcutaneously to each subject 
by injection into the abdomen.  The IP will consist of [14C]-tirzepatide to provide approximately
4.1 mg tirzepatide with approximately 100 µCi of radioactivity in each unit dose.  The proposed 
[14C]-tirzepatide IP will be manufactured extemporaneously as sterile solutions for SC injection, 
as described in the Pharmacy Protocol approved by the sponsor.  All doses will be administered 
by clinical site staff.  The study regimen is indicated in Table GPHX.2.
Prior to injection, the investigator or designee will clean the subject’s skin and the injection will 
be administered to the lower abdominal quadrant, approximately 5 cm from the umbilicus (i.e., 
left or right lower quadrant).  Detailed instructions for use will be provided by the sponsor.  A 
limited number of clinical site staff will perform SC administration for consistency reasons.
Each dose syringe will be retained for analysis of residual radioactivity.  Any unused assembled 
unit doses will be retained until completion of the study.
Table GPHX.2.
Treatments Administered
Treatment Name
[14C]-tirzepatide
Dosage Formulation
Solution
Unit Dose Strength/Dosage Level
Approx. 4.1 mg tirzepatide (~100 µCi)/1 mL
Route of Administration
SC injection
Delivery Method
Fixed Needle Syringe 
Abbreviations:  Approx.  = approximately; SC = subcutaneous.
The investigator or designee is responsible for:

explaining the correct use of the IP to the site personnel 

verifying that instructions are followed properly

maintaining accurate records of IP dispensing and collection

returning all unused medication to Lilly or its designee at the end of the study
7.1.1. Packaging and Labeling
[14C]-tirzepatide will be supplied by the sponsor or its designee in accordance with current good
manufacturing practice, labeled according to the country’s regulatory requirements.
7.2.
Method of Treatment Assignment
All subjects will receive the same treatment; the study will not be subject to randomization.


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7.2.1. Selection and Timing of Dose
The IP will be administered on the morning of Day 1 after a minimum 8-hour fast.  The actual
time of dose administration will be recorded in the subject’s electronic case report form (eCRF).
7.3.
  Blinding
This study is open-label.
7.4.
Dose Modification
Dose modification is not permitted in this study.
7.4.1. Study Release Criteria
Subjects will remain at the CRU until they have met the specified release criteria (Section 5.1) or 
up to a maximum of 14 days postdose (Day 15).  In no case will subjects be retained in CRU 
longer than the maximum duration of 14 days postdose but may be required to return for up to 
7 inpatient follow-up visits each consisting of a 48-hour residential stay in the CRU, if release 
criteria have not been met by Day 15 (14 days postdose).  Subjects will attend inpatient 
follow-up visit(s) until the second release criterion (i.e., < 1% radioactivity in the excreta for two 
24-hour collections) it met or up to a maximum of 63 days postdose (Day 64).  A PK and an 
immunogenicity sample are required from all subjects on Day 29, subjects not attending an 
inpatient follow-up visit at this time will be required to return for a single outpatient visit on 
Day 29 for the collection of these samples.
7.5.
Preparation/Handling/Storage/Accountability
The [14C]-tirzepatide solution for administration will be prepared in the CRU by qualified 
pharmacy staff, details of dose preparation will be provided in the Pharmacy Protocol.
The investigator or designee must confirm appropriate temperature conditions have been 
maintained, as communicated by sponsor, during transit for all IP received and any discrepancies 
are reported and resolved before use of the study treatment.
Only subjects enrolled in the study may receive IP or study materials, and only authorized site 
staff may administer the IP.  All IP should be stored in an environmentally controlled and 
monitored (manual or automated) area in accordance with the labeled storage conditions with 
access limited to the investigator and authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (such as
receipt, reconciliation, and final disposition records).


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7.5.1. Safety Procedure in the Event of a Retrospective Positive 
Sterility Finding from Extemporaneously Prepared Study 
Treatment
If a positive sterility finding were to arise in the sterile filtered product, the subjects who were 
dosed from the impacted batch should be immediately contacted and asked to return to the CRU 
for a full medical examination.  This should include a physical examination, including blood 
pressure, pulse rate, and body temperature.  Blood samples should be collected for culture and 
assayed for inflammatory markers such as C-reactive protein and elevations in white blood cell 
counts.
If the signs and symptoms indicate a subject is suffering from possible infection(s), they will be 
clinically managed, treated, and followed up until resolution.  Any AEs will be recorded as 
appropriate.
7.6.
Treatment Compliance
The IP will be administered at the clinical site, and documentation of treatment administration 
will occur at the site.
7.7.
Concomitant Therapy
In general, concomitant medication should be avoided; however, acetaminophen (maximum 
3 g/24 hours) may be administered at the discretion of the investigator for treatment of headaches 
etc.  If the need for concomitant medication (other than acetaminophen) arises, inclusion or 
continuation of the subject may be at the discretion of the investigator after consultation with a 
Lilly CP, CRP or designee.  Any medication used during the course of the study must be 
documented.
7.8.
Treatment after the End of the Study
Not applicable.


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8. Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
Subjects discontinuing from the study prematurely for any reason must complete AE and 
follow-up procedures per Section 2 of this protocol.
8.1.1. Discontinuation of Inadvertently Enrolled Subjects
If the sponsor or investigator identifies a subject who did not meet enrollment criteria and was 
inadvertently enrolled, a discussion must occur between the Lilly CP/CRP and the investigator to 
determine if the patient may continue in the study.  If both agree it is medically appropriate to 
continue, the investigator must obtain documented approval from the Lilly CP/CRP to allow the 
inadvertently enrolled subject to continue in the study.
8.2.
Discontinuation from the Study
Subjects will be discontinued 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 (GCP).  
The study will be halted, and the risk to other potential subjects evaluated if any of the 
following criteria are met:
o
if serious adverse reaction (i.e. an SAE considered at least possibly related to 
[14C]-tirzepatide administration) occur in 1 (or more) subject; 
o
severe non-serious adverse reactions (ie severe non-serious AE considered as, at 
least possibly related to [14C]-tirzepatide administration) in 2 subjects, 
independent of within or not within the same system organ class.

Investigator Decision
o
the investigator decides that the subject should be discontinued from the study.

Subject Decision
o
the subject requests to be withdrawn from the study.
8.3.
Subjects Lost to Follow-up
A subject will be considered lost to follow-up if he repeatedly fails to return for scheduled visits 
and is unable to be contacted by the study site.  Site personnel are expected to make diligent 
attempts to contact subjects who fail to return for a scheduled visit or were otherwise unable to 
be followed up by the site.


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9. Study Assessments and Procedures
Section 2 lists the Schedule of Activities, detailing the study procedures and their timing 
(including tolerance limits for timing).
Appendix 2 lists the clinical 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 blood 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 subject 
defaulting or turning up late on an agreed scheduled procedure) will not be considered as 
protocol deviations but the CRU must notify the sponsor in writing via a file note to facilitate 
data reconciliation.
Unless otherwise stated in subsections below, all samples collected for specified laboratory tests 
will be destroyed within 60 days of receipt of confirmed test results.  Certain samples may be 
retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards.
9.1.
Efficacy Assessments
This section is not applicable for this study.
9.2.
Adverse Events
Investigators are responsible for monitoring the safety of subjects who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the subject.
The investigator is responsible for the appropriate medical care of subjects during the study.
Investigators must document their review of each laboratory safety report.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the IP or the study, 
or that caused the subject to discontinue the IP before completing the study.  The subject should 
be followed until the event resolves, stabilizes with appropriate diagnostic evaluation, or is 
reasonably explained.  The frequency of follow-up evaluations of the AE is left to the discretion 
of the investigator.
The investigator will record all relevant AE and SAE information in the eCRF.  After the 
informed consent form is signed, study site personnel will record, via eCRF, the occurrence and 
nature of each subject’s preexisting conditions, including clinically significant signs and 


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symptoms of the disease under treatment in the study.  Additionally, site personnel will record 
any change in the condition(s) and the occurrence and nature of any AEs.  
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, study device, or a study procedure, taking into account the 
disease, concomitant treatment or pathologies.  
A “reasonable possibility” means that there is a potential cause and effect relationship between 
the 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.
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 CP/CRP, or its designee, of any SAE as soon as 
practically possible.
Additionally, study site personnel must alert Lilly Global Patient Safety, or its designee, of any 
SAE within 24 hours of investigator awareness of the event via a sponsor-approved method.  If 
alerts are issued via telephone, they are to be immediately followed with official notification on 
study-specific SAE forms.  This 24-hour notification requirement refers to the initial SAE 
information and all follow-up SAE information.  
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued from and/or completed the study (the subject summary eCRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a subject has 
been discharged from the study, and he/she considers the event reasonably possibly related to the 
study treatment or study participation, the investigator must promptly notify Lilly.  
Pregnancy of a female partner (paternal exposure to IP) does not meet the definition of an AE.  
However, to fulfill regulatory requirements any pregnancy should be reported following the SAE 
process to collect data on the outcome for both mother and fetus.


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9.2.1.1.
Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator reports as related to IP or procedure.  Lilly has procedures that 
will be followed for the recording and expedited reporting of SUSARs that are consistent with 
global regulations and the associated detailed guidances.
9.2.2. Complaint Handling
Lilly collects product complaints on IPs and drug delivery systems used in clinical trials in order 
to ensure the safety of study subjects, monitor quality, and to facilitate process and product 
improvements.
9.3.
Treatment of Overdose
For the purposes of this study, an overdose of tirzepatide is considered any dose higher than the 
planned study dose.
There is no specific antidote for tirzepatide.  In the event of an overdose, the subject should 
receive appropriate supportive care and any AEs should be documented.  
Refer to the IB.
9.4.
Safety
9.4.1. Laboratory Tests
For each subject, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities (Section 2).  
9.4.1.1.
Amylase and Lipase Measurements
Serum amylase and lipase measurements will be collected as part of the clinical laboratory 
testing and as specified in the Schedule of Activities (Section 2).  Additional measurements may 
be performed at the investigator’s discretion.  Further diagnostic assessments will be 
recommended as per the algorithm (refer to Appendix 6) for the monitoring of pancreatic events 
whenever lipase and/or amylase is confirmed to be ≥3 × ULN at any visit postdose, even if the 
subject is asymptomatic.
9.4.2. Glucose Monitoring
For safety purposes, blood glucose measurements will be performed using a bedside glucose 
monitor as specified in the Schedule of Activities (Section 2).  Additional blood glucose monitor 
measurements may also be taken during the study as deemed necessary by the investigator where 
clinically indicated.
9.4.2.1.
Hypoglycemia
Site personnel will collect information on episodes of hypoglycemia at each study visit according 
to the Schedule of Activities.  Subjects will be trained by site personnel about signs and 
symptoms of hypoglycemia, how to treat hypoglycemia, and how to collect appropriate 


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information for each episode of hypoglycemia.  Site personnel will enter this information into the 
eCRF at each visit. 
Investigators should use the following definitions and criteria when diagnosing and categorizing 
an episode considered to be related to hypoglycemia (the plasma glucose [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) (ADA 2019).
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).
Clinically Significant Hypoglycemia (Level 2):

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 <54 mg/dL (<3.0 mmol/L).

Documented asymptomatic hypoglycemia is defined as any event not 
accompanied by typical symptoms of hypoglycemia, but with a measured PG 
<54 mg/dL (<3.0 mmol/L).

Documented unspecified hypoglycemia is defined as any event with no 
information about symptoms of hypoglycemia available, but with a measured PG 
<54 mg/dL (<3.0 mmol/L).
Severe hypoglycemia (Level 3):

Severe hypoglycemia is defined as an episode with severe cognitive impairment 
requiring the assistance of another person to actively administer carbohydrate, 
glucagon, or other resuscitative actions.  These episodes may be associated with 
sufficient neuroglycopenia to induce seizure or coma.  Blood glucose (BG)
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.


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If a hypoglycemic event meets the criteria of severe, the investigator must record the event as 
serious on the AE eCRF and report it to Lilly as an SAE (see Section 9.2.1 for details regarding 
SAE reporting).
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 by the investigator.  The subject should 
receive additional education, if deemed appropriate.
9.4.3. Vital Signs
For each subject, vital signs measurements should be conducted according to the Schedule of 
Activities (Section 2) and as clinically indicated.
Blood pressure and pulse rate should be measured after at least 5 minutes supine.  
Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or 
posture-induced symptoms.  Additional vital signs may be measured, if warranted, at the clinical 
discretion of the investigator.
9.4.4. Electrocardiograms
For each subject, ECGs should be collected according to the Schedule of Activities (Section 2).
Any clinically significant findings from ECGs that result in a diagnosis and that occur after the 
subject receives the dose of IP, should be reported to Lilly, or its designee, as an AE via eCRF.  
For each subject, a single 12-lead digital ECGs will be collected according to the Schedule of 
Activities.  Electrocardiograms must be recorded before collecting any blood samples.  Subjects 
must be supine for approximately 5 minutes before ECG collection and remain supine but awake 
during ECG collection.  Electrocardiograms may be obtained at additional times, when deemed 
clinically necessary.  All ECGs recorded should be stored at the investigational site.
Electrocardiograms will be interpreted by a qualified physician (the investigator or qualified 
designee) at the site as soon after the time of ECG collection as possible, and ideally while the 
subject is still present, to determine whether the subject meets entry criteria at the relevant 
visit(s) and for immediate subject management, should any clinically relevant findings be 
identified.  
If a clinically significant finding is identified (including, but not limited to, changes in QT/QTc 
interval from baseline) after enrollment, the investigator will determine if the subject can 
continue in the study.  The investigator, or qualified designee, is responsible for determining if 
any change in subject management is needed and must document his/her review of the ECG 


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printed at the time of collection.  Any new clinically relevant finding should be reported as an 
AE.
Additional ECGs may be measured, if warranted, at the clinical discretion of the investigator.
9.4.5. Injection-Site Reactions
Injection-site assessments for local tolerability will be conducted, when reported as:

an AE from a subject, or

a clinical observation from an investigator.
Reported injection-site reactions will be characterized within the following categories:

edema

erythema

induration

itching

pain.
All injection-site reactions reported as AEs will be closely monitored until resolution.  The report 
of a clinically significant AE of injection-site reaction may prompt notification of the sponsor, 
clinical photography, and referral for dermatologic evaluation and consideration of a skin biopsy 
and laboratory evaluations (ALT, AST, complete blood count with percent eosinophils, and 
additional immunogenicity testing).
Investigational site staff will be provided with separate instructions/training on how to evaluate 
injection-site reactions and their severity in a consistent manner.  Photographs of injection-site 
reactions may be taken in a standardized manner for record-keeping purposes; however, the 
photographs will not be used to evaluate the severity of the injection-site reaction.
9.4.6. Hypersensitivity Reactions
All hypersensitivity reactions will be reported by the investigator as either AEs or, if any serious 
criterion is met, as SAEs.
In the event of suspected drug hypersensitivity reactions (immediate or non-immediate) in 
subjects who experience moderate-to-severe injection reactions as assessed by the investigator, 
unscheduled blood samples will be collected for PK and antidrug antibody analyses at the 
following time points:  

as close as possible to the onset of the event

at the resolution of the event

30 (±3) days following the event.  


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Additionally, unscheduled serum samples for immune safety laboratory testing (including, but 
not limited to β tryptase, total immunoglobulin E, complement and cytokine panel testing) 
should also be collected at approximately 60 to 120 minutes and 4 to 6 weeks after the onset of 
the event in these subjects.  
Instructions for the collection and handling of blood samples will be provided by the sponsor.  
The actual date and time (24-hour clock time) of each sampling will be recorded.
9.4.7. Safety Monitoring
The Lilly CP/CRP will monitor safety data throughout the course of the study.
Lilly will review SAEs within time frames mandated by company procedures.  The Lilly CP or 
CRP will periodically review the following data:

trends in safety data

laboratory analytes including glucose, amylase, and lipase

adverse events.
When appropriate, the Lilly CP or CRP will consult with the functionally independent Global 
Patient Safety therapeutic area physician or clinical research scientist.
9.4.7.1.
Hepatic Safety
9.4.7.1.1. Close hepatic monitoring 
If a subject who had normal or near normal baseline ALT, AST, alkaline phosphatase (ALP), 
TBL (i.e., <1.5x ULN), experiences elevated ALT≥3x ULN, AST≥3x ULN, ALP≥2x ULN, or 
TBL≥2x, laboratory tests (Appendix 4) should be repeated within 48 to 72 hours, including ALT, 
AST, ALP, TBL, direct bilirubin, gamma-glutamyltransferase, and creatinine phosphokinase to 
confirm the abnormality and to determine if it is increasing or decreasing.  
In subjects enrolled with elevated baseline ALT, AST, ALP or TBL (≥1.5x ULN), the thresholds 
for close monitoring are ALT≥2x baseline, AST≥2x baseline, ALP≥2x baseline, or TBL≥2x 
baseline.  If the abnormality persists or worsens, clinical and laboratory monitoring, and 
evaluation for possible causes of abnormal liver tests should be initiated by the investigator in 
consultation with the Lilly-designated medical monitor. At a minimum, this evaluation should 
include physical examination and a thorough medical history, including symptoms, recent 
illnesses, (for example, heart failure, systemic infection, hypotension, or seizures), recent travel, 
history of concomitant medications (including over-the-counter), herbal and dietary supplements, 
history of alcohol drinking and other substance abuse.  
Initially, monitoring of symptoms and hepatic biochemical tests should be done at a frequency of 
1 to 3 times weekly, based on the subject’s clinical condition and hepatic biochemical tests. 
Subsequently, the frequency of monitoring may be lowered to once every 1 to 2 weeks, if the 
subject’s clinical condition and lab results stabilize. Monitoring of ALT, AST, ALP and TBL 
should continue until levels normalize or return to approximate baseline levels. 


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9.4.7.1.2. Comprehensive hepatic evaluation
If a study subject, who had baseline ALT, AST, ALP, TBL<1.5x ULN, experiences elevated 
ALT≥5x ULN, AST≥5x ULN, ALP ≥3x ULN, TBL ≥2x ULN, or elevated ALT, AST ≥3x ULN 
with hepatic signs/symptoms (severe fatigue, nausea, vomiting, right upper quadrant abdominal 
pain, fever, rash, and/or eosinophilia>5%), a comprehensive evaluation should be performed to 
search for possible causes of liver injury.
In subjects who had elevated baseline ALT, AST, ALP, or TBL (≥1.5x ULN), the thresholds for 
performing this evaluation are ALT≥3x baseline, AST≥3x baseline, ALP≥2x baseline, TBL≥1.5x 
baseline, or ALT, AST ≥2x baseline with hepatic signs/symptoms.  
At a minimum, this evaluation should include physical examination and a thorough medical 
history, as outlined above, as well as tests for prothrombin time-international normalized ratio, 
viral hepatitis A, B, C, E, tests for autoimmune hepatitis, and an abdominal imaging study (for 
example, ultrasound or computed tomography [CT] scan).
Based on the patient’s history and initial results, further testing should be considered, in 
consultation with the Lilly-designated medical monitor, including tests for hepatitis D virus, 
cytomegalovirus, Epstein-Barr virus, acetaminophen levels, acetaminophen protein adducts, 
urine toxicology screen, Wilson’s disease, blood alcohol levels, urinary ethylglucuronide, and 
serum phosphatidylethanol. Based on the circumstances and the investigator’s assessment of the 
subject’s clinical condition, the investigator should consider referring the subject for a 
hepatologist/ gastroenterologist consultation, magnetic resonance cholangio-pancreatography, 
endospopic retrograde cholangio-pancreatography, cardiac echocardiogram, or a liver biopsy.
9.4.7.1.3. Additional hepatic data collection (hepatic safety eCRF) in subjects 
who have abnormal liver tests during the study
Additional hepatic safety data collection (hepatic safety eCRF) should be performed in subjects 
who meet 1 or more of the following 5 conditions: 
1. Elevation of serum ALT to ≥5× ULN on 2 or more consecutive blood tests (if baseline 
ALT<1.5x ULN) 
In subjects with baseline ALT≥1.5x ULN, the threshold is ALT≥3x baseline on 2 
or more consecutive tests 
2. Elevated TBL to ≥2× ULN (if baseline TBL <1.5x ULN) 
In subjects with baseline TBL ≥1.5x ULN, the threshold should be TBL ≥2x 
baseline 
3. Elevation of serum ALP to ≥2× ULN on 2 or more consecutive blood tests (if baseline 
ALP <1.5x ULN) 
In subjects with baseline ALP≥1.5x ULN, the threshold is ALP ≥2x baseline on 2 
or more consecutive blood tests 
4. Hepatic event considered to be an SAE 


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5. Discontinuation of the IP due to a hepatic event  
Note: the interval between the 2 consecutive blood tests should be at least 2 days  
9.5.
Pharmacokinetics
9.5.1. Whole Blood and Plasma Samples
At the visits and times specified in the Schedule of Activities (Section 2), venous blood samples 
(approximate volumes listed in Appendix 5) will be collected to determine the whole blood and 
plasma concentrations of total radioactivity, the plasma concentrations of tirzepatide, and 
metabolite profiling (total number and identity) 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, this excludes any additional samples required for safety monitoring.  
Instructions for the collection and handling of blood samples will be provided by the sponsor in a 
Laboratory Manual.  The actual date and time (24-hour clock time) of each sampling will be 
recorded.
Plasma samples for metabolite profiling will be stored frozen pending confirmation from the 
sponsor of which samples are to be analyzed.
9.5.2. Urine and Feces Sampling
Urine and feces samples will be collected for the determination of total radioactivity and 
metabolite profiling (total number and identity) only.  Urine and feces will be collected before IP 
administration (control samples); however, the inability to produce a fecal sample will not be 
considered a protocol deviation.  After dosing with IP, cumulative feces and urine samples will 
be collected in specified containers according to the Schedule of Activities (Section 2) until the 
specified release criteria have been met.
Urine will be collected at the specified intervals, into 1 or more containers (depending on volume 
excreted), according to the Schedule of Activities (Section 2) until the specified release criteria 
have been met.  An aliquot of each sample will be analyzed to yield the percentage radioactivity 
recovered within that interval as well as to determine its metabolic profile.
Feces from each bowel movement will be collected and the time of collection will be noted.  
Fecal samples will be pooled over each 24-hour collection period (if applicable), see the 
Schedule of Activities (Section 2), and analyzed to yield the percentage radioactivity recovered 
over that period as well as to determine its metabolic profile. 
9.5.3.
Expired Air Samples
A sample of expired breath will be collected for analysis of 14CO2 at the times indicated in the 
Schedule of Activities (Section 2).  If a significant amount of the radioactivity is present in 
breath samples, the raw data will be extrapolated to provide an estimate of the percentage dose 
eliminated via 14CO2.  Additional breath samples may be collected at some or all of the times 
that blood samples are drawn and only analyzed if needed.


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9.5.4. Bioanalysis
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor.
Concentrations of tirzepatide will be assayed using a validated liquid chromatography tandem 
mass spectrometry method.  Metabolite identification will be determined using appropriate 
techniques such as liquid chromatography (LC)/radiodetection and LC/mass spectroscopy.
Whole blood, plasma, expired air, urine, and fecal concentrations of radioactivity will be 
determined using liquid scintillation counting techniques.  Whole blood and feces will be 
combusted prior to the liquid scintillation counting.
Bioanalytical samples collected during radiolabeled studies will be retained for a maximum of 
2 years following last subject visit for the study.  During this time, samples remaining after the 
bioanalyses may be used for exploratory analyses such as additional metabolism and/or protein 
binding work.
9.6.
Pharmacodynamics
Not applicable.
9.7.
Immunogenicity Assessments
At the times specified in the Schedule of Activities (Section 2), venous blood samples will be 
collected and stored for potential future analysis to determine antibody production against 
tirzepatide.  Antibodies may be further characterized for cross-reactive binding to native GIP and 
GLP-1 and their ability to neutralize the activity of tirzepatide. To interpret the results of 
immunogenicity, a venous blood sample will be collected at the same time points to determine 
the plasma concentrations of tirzepatide.  All samples for immunogenicity should be taken 
predose when applicable and possible. In the event of drug hypersensitivity reactions, 
unscheduled blood samples will be collected as specified in Section 9.4.7.
Samples will be retained for a maximum of 15 years after the last subject visit, or for a shorter 
period if local regulations and ethical review boards (ERBs) allow, at a facility selected by the 
sponsor.  The duration allows the sponsor to respond to future regulatory requests related to 
tirzepatide.  Any samples remaining after 15 years will be destroyed.
9.8.
Genetics
A blood sample will be collected for pharmacogenetic analysis as specified in the Schedule of 
Activities, where local regulations allow.
Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future.  Samples will be used to investigate variable exposure or response to 
tirzepatide and to investigate genetic variants thought to play a role in T2DM.  Assessment of 
variable response may include evaluation of AEs or differences in efficacy.


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All samples will be coded with the subject number.  These samples and any data generated can 
be linked back to the subject only by the investigative site personnel.  
Samples will be retained for a maximum of 15 years after the last subject visit, or for a shorter 
period if local regulations and/or ERBs impose shorter time limits, for the study at a facility 
selected by Lilly or its designee.  This retention period enables use of new technologies, response 
to regulatory questions, and investigation of variable response that may not be observed until 
later in the development of tirzepatide or after it is commercially available.  
Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named.  However, existing approaches include whole genome or exome 
sequencing, genome wide association studies, multiplex assays, and candidate gene studies.  
Regardless of technology utilized, data generated will be used only for the specific research 
scope described in this section.  
9.9.
Biomarkers
Not applicable.
9.10. Health Economics
This section is not applicable for this study.


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10.
Statistical Considerations and Data Analysis
10.1. Sample Size Determination
Up to 8 subjects will be enrolled.  It is planned that up to 6 subjects will be dosed initially and 
2 additional subjects will be dosed if needed, in order that a minimum of 4 subjects complete the 
study.
The sample size is customary for [14C]-disposition studies (Penner et al. 2009) and is chosen to 
provide adequate PK data while limiting the number of subjects exposed to radiopharmaceuticals 
in non-therapeutic research.
10.2. Populations for Analyses
10.2.1. Study Participant Disposition
A detailed description of subject disposition will be provided at the end of the study.  
10.2.2. Study Participant Characteristics
The subject’s age, sex, weight, height, BMI, race, and other demographic characteristics will be 
recorded and summarized using descriptive statistics.  
10.3. Statistical Analyses
Statistical analysis of this study will be the responsibility of Eli Lilly and Company or its 
designee.
Pharmacokinetic analyses will be conducted on data from all subjects who receive the IP and 
have evaluable PK.  
Safety summaries will be conducted for all enrolled subjects, whether or not they completed all 
protocol requirements.
Additional exploratory analyses of the data will be conducted as deemed appropriate.  Study 
results may be pooled with the results of other studies for population PK analysis purposes to 
avoid issues with post-hoc analyses and incomplete disclosures of analyses.  
10.3.1. Safety Analyses
10.3.1.1. Clinical Evaluation of Safety
All IP and protocol procedure AEs will be listed and, if the frequency of events allows, safety 
data will be summarized using descriptive methodology.
The incidence of symptoms for each treatment will be presented by severity and by association 
with IP as perceived by the investigator.  Symptoms reported to occur prior to enrollment will be 
distinguished from those reported as new or increased in severity during the study.  Each 
symptom will be classified by the most suitable term from the medical regulatory dictionary.
The number of IP-related SAEs will be reported.


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10.3.1.2. Statistical Evaluation of Safety
Safety parameters that will be summarized include incidence of AEs, safety lab parameters
(including BG, amylase, and lipase) and vital signs.  The parameters will be listed, and 
summarized using standard descriptive statistics.  Additional analysis will be performed if 
warranted upon review of the data.
Physical examinations and ECGs will be performed for safety monitoring purposes and will not 
be presented.  If warranted, additional analysis will be performed upon review of the data.
10.3.1.3. Injection-Site Reactions
Incidence of erythema, induration, pain, itching, and edema will be listed and summarized.
Additional analyses may be performed, if appropriate.
10.3.2. Pharmacokinetic Analyses
10.3.2.1. Pharmacokinetic Parameter Estimation
Pharmacokinetic parameter estimates for plasma and whole blood total radioactivity, and plasma
tirzepatide will be calculated by standard noncompartmental methods of analysis and 
summarized using standard descriptive statistics.
The primary PK parameters for analysis will be Cmax, area under the concentration-time curve 
(AUC) from time 0 to time of the last measurable concentration (AUC[0-tlast]) and AUC from 
time 0 extrapolated to infinity (AUC[0-∞]).  Other noncompartmental parameters, such as time 
to Cmax (tmax), half-life associated with the terminal rate constant in noncompartmental analysis 
(t1/2), apparent clearance (CL/F), and apparent volume of distribution (V/F) may be reported.  
The whole blood:plasma ratio of total radioactivity will be calculated for each time point.
The percent of radiolabeled dose recovered in feces, urine, and expired air (if applicable) will be 
calculated.
10.3.2.2. Pharmacokinetic Statistical Inference
No formal statistical analyses are planned.
10.3.3. Interim Analyses
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed
necessary, the Lilly CP, CRP, 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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12.
Appendices


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Appendix 1.
Abbreviations and Definitions


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Term
Definition
ADA
antidrug antibodies
AE
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product.
ALP
alkaline phosphatase
ALT
alanine aminotransferase
assent
Agreement from a child or other individual who is not legally capable of providing consent, 
but who can understand the circumstances and potential risks involved in participating in a 
study (required by some institutional review boards [IRBs]/ethical review boards [ERBs]).
AST
aspartate aminotransferase 
AUC
area under the concentration-time curve
AUC0-∞
AUC from time 0 extrapolated to infinity
AUC0-tlast
AUC from time 0 to time of the last measurable concentration
BG
blood glucose
BMI
body mass index
CIOMS
Council for International Organizations of Medical Sciences
Cmax
maximum observed drug concentration
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all the study-related requirements, good clinical practice (GCP) requirements, 
and the applicable regulatory requirements.
confirmation
A process used to confirm that laboratory test results meet the quality requirements defined 
by the laboratory generating the data and that Lilly is confident that results are accurate.  
Confirmation will either occur immediately after initial testing or will require that samples 
be held to be retested at some defined time point, depending on the steps required to obtain 
confirmed results.
CP
Clinical Pharmacologist
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
computerised tomography
ECG
electrocardiogram
eCRF
electronic case report form 
enroll
The act of assigning a subject to a treatment.  Subjects who are enrolled in the study are 
those who have been assigned to a treatment.
enter
Subjects entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ERB
ethical review board
GCP
good clinical practice
GI
gastrointestinal
GIP
glucose-dependent insulinotropic polypeptide 
GLP-1
glucagon-like peptide-1
IB
Investigator’s Brochure
ICH
International Council for Harmonization
ICRP
International Commission on Radiological Protection
informed consent
A process by which a subject voluntarily confirms his or her willingness to participate in a 
particular study, after having been informed of all aspects of the study that are relevant to 
the subject’s decision to participate.  Informed consent is documented by means of a 
written, signed and dated informed consent form.  
Investigational 
product (IP)
A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical study, including products already on the market when used or assembled 
(formulated or packaged) in a way different from the authorized form, or marketed products 
used for an unauthorized indication, or marketed products used to gain further information 
about the authorized form.
investigator
A person responsible for the conduct of the clinical study at a study site.  If a study is 
conducted by a team of individuals at a study site, the investigator is the responsible leader 
of the team and may be called the principal investigator.
open-label
A study in which there are no restrictions on knowledge of treatment allocation, therefore 
the investigator and the study subjects are aware of the drug therapy received during the 
study.
PG
plasma glucose
PK
pharmacokinetic(s)
randomize
the process of assigning subjects/patients to an experimental group on a random basis


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SAE
serious adverse event
SC
subcutaneous
screen
The act of determining if an individual meets minimum requirements to become part of a 
pool of potential candidates for participation in a clinical study.  
SUSARs
suspected unexpected serious adverse reactions
T2DM
type 2 diabetes mellitus
TBL
total bilirubin
TE-ADA
treatment-emergent antidrug antibodies
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 
tmax
time of last measurable concentration
ULN
upper limit of normal


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Appendix 2.
Clinical Laboratory Tests
Safety Laboratory Tests
Hematology
Clinical Chemistry
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Bicarbonate
Mean cell volume 
Chloride
Mean cell hemoglobin 
Calcium
Mean cell hemoglobin concentration 
Glucose (fasting)
Leukocytes (WBC) 
Blood urea nitrogen (BUN)
Total protein
Absolute counts of:
Albumin
Neutrophils
Total bilirubin
Lymphocytes
Alkaline phosphatase (ALP)
Monocytes
Aspartate aminotransferase (AST)
Eosinophils
Alanine aminotransferase (ALT)
Basophils
Creatinine
Platelets
Amylase
Lipase
Triglycerides
Calcitonina
Urinalysis
Specific gravity
pH
Urine drug screenb
Protein
Cotinine (urine)
Glucose
Ethanol testing (breath test)b
Ketones
Hepatitis B surface antigena
Bilirubin
Hepatitis C antibodya
Urobilinogen
HIVa
Blood
Nitrite
Leukocytes (WBC)
Microscopic examination of sedimentc
Abbreviations:  HIV = human immunodeficiency virus; RBC = red blood cells; WBC = white blood cells.
a
Performed at screening only.
b
Urine drug screen and ethanol level may be repeated prior to admission to the clinical research unit and at other 
times indicated in the Schedule of Activities. 
c
Test only if dipstick result is abnormal (i.e., positive for blood, protein, or nitrites) if clinically indicated, per 
investigator discretion.


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


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Regulatory Considerations
This study will be conducted in accordance with the protocol and with:
1) consensus ethics principles derived from international ethics guidelines, 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines 
2) applicable ICH GCP Guidelines 
3) applicable laws and regulations
Some of the obligations of the sponsor will be assigned to a third-party organization.
Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.  
After reading the protocol, the principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
Final Report Signature
The investigator or designee will sign the clinical study report for this study, indicating 
agreement with the analyses, results, and conclusions of the report.
The sponsor’s responsible medical officer and statistician will sign/approve the final clinical 
study report for this study, confirming that, to the best of his or her knowledge, the report 
accurately describes the conduct and results of the study.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate.

provide training to instruct the investigators and study coordinators.  This training will 
give instruction on the protocol, the completion of the 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 subject data 
recorded against source documents at the study site.  The study may be audited by Lilly and/or 
regulatory agencies at any time.  Investigators will be given notice before an audit occurs.
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to the original source 
documents.
Data Collection Tools/Source Data
An electronic data capture system will be used in this study.  The site must define and retain all 
source records and must maintain a record of any data where source data are directly entered into 
the data capture system.
Data Protection
Data systems used for the study will have controls and requirements in accordance with local 
data protection law.  
The purpose and use of subject personal information collected will be provided in a written 
document to the subject by the sponsor.
Study and Site Closure
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly or its designee, the investigator, or the ERB 
of the study site judges it necessary for medical, safety, regulatory, or other reasons consistent 
with applicable laws, regulations, and GCP.
Discontinuation of the Study
The study will be discontinued if Lilly or its designee judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP.


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


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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-GPHX Sampling Summary
Purpose
Blood Volume per 
Sample (mL)
Number of Blood 
Samples
Total Volume 
(mL)
Screening tests (clinical laboratory 
test and serology)a
11
1
11
Clinical laboratory testsa
7.5
4
30
Pharmacokinetics (tirzepatide and 
total radioactivity)
8
19 (+3)
176
Metabolite profiling
20
11
220
Immunogenicity (storage only)
10
2
20
Pharmacogenetics (stored sample)
10
1
10
Total
467
Total for clinical purposes rounded up to nearest 10 mL 
470
a
Additional samples may be drawn if needed for safety purposes.
If extra blood samples are required, the maximum blood volume withdrawn per subject during 
the study will not exceed that donated during a standard blood donation (approximately 500 mL).


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Appendix 6.
Pancreatic Monitoring
Glucagon-like peptide-1 agonists have been associated with a possible risk of acute pancreatitis.  
In 2006, the United States prescribing information for exenatide was revised to include the event 
of pancreatitis.  In 2007, the United States prescribing information for this medication was 
amended to include pancreatitis under “Precautions.” Epidemiologic studies have indicated that 
there is an increased incidence and prevalence of pancreatitis in persons with T2DM.
To enhance understanding of the natural variability of pancreatic enzymes in the T2DM 
population and, in order to assess for any potential effects of tirzepatide on the exocrine 
pancreas, amylase and lipase values will be monitored in all current and future clinical trials with 
tirzepatide.
Additional monitoring will be requested for amylase and/or lipase values ≥3× ULN at any visit, 
even in asymptomatic subjects (see figure below).  Lipase and amylase values may also be 
obtained at any time during the clinical trials for any subject suspected of having symptoms 
suggestive of pancreatitis (such as severe GI signs and/or symptoms), at the investigator’s 
discretion.
Acute pancreatitis is an AE defined as an acute inflammatory process of the pancreas that may 
also involve peripancreatic tissues and/or remote organ systems.  The diagnosis of acute 
pancreatitis requires 2 of the following 3 features:

abdominal pain characteristic of acute pancreatitis

serum amylase and/or lipase ≥3× ULN

characteristic findings of acute pancreatitis on CT scan or magnetic resonance 
imaging
Most subjects with acute pancreatitis experience abdominal pain that is located generally in the 
epigastrium, and radiates to the back in approximately one-half of the cases.  The pain is often 
associated with nausea and vomiting.  However, experience with GLP-1 agonists has 
demonstrated that some subjects asymptomatic for classic pancreatitis may demonstrate 
significant elevations of lipase and/or amylase.  For subjects considered by investigators to be 
asymptomatic for pancreatitis, but whose value(s) for lipase and/or amylase are ≥3× ULN, an 
algorithm is in place to follow these subjects safely and to quickly reach (or not reach) a 
diagnosis of pancreatitis.


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Abbreviations:  CT = computed tomography; MRI = magnetic resonance imaging; 
ULN = upper limit of normal.


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


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Appendix 7.
Classification of Contraceptive Methods
Highly Effective (Less Than 1% Failure Rate) Methods of Contraception:

Combined oral contraceptive pill and mini pill

NuvaRing

Implantable contraceptives

Injectable contraceptives (such as Depo-Provera®)

Intrauterine device (such as Mirena® and ParaGard®)

Contraceptive patch – females ONLY <198 pounds or 90 kg

Total abstinence or in a same-sex relationship (if this is their preferred and usual 
lifestyle).  Note:  periodic abstinence (for example, calendar, ovulation, symptothermal, 
postovulation methods), declaration of abstinence just for the duration of a trial, and 
withdrawal are not acceptable methods of contraception

Vasectomy – for males in clinical trials
Effective Methods of Contraception (Must Use Combination of 2 Methods):

Male condom with spermicide*

Female condom with spermicide*

Diaphragm with spermicide

Cervical sponge

Cervical cap with spermicide
* the use of male and female condoms as a double-barrier method is not considered acceptable.


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Appendix 8.
Protocol Amendment I8F-MC-GPHX (a) 
Summary 
Disposition of [14C]-Tirzepatide Following 
Subcutaneous Administration in Healthy Male Subjects
Overview
Protocol I8F-MC-GPHX ‘Disposition of [14C]-Tirzepatide Following Subcutaneous 
Administration in Healthy Male Subjects’ has been amended.  The new protocol is indicated by 
Amendment (a) and will be used to conduct the study in place of any preceding version of the 
protocol.  This amendment is not considered to be substantial.
The overall changes and rationale for the changes made to this protocol are as follows:

Clarified and expanded on further details in Section 8 on discontinuation criteria in 
response to the recommendations provide by the Medicines and Healthcare Products 
Regulatory Agency of the United Kingdom.  

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.
8.2 Discontinuation from the Study
Subjects will be discontinued 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 (GCP).  
The study will be halted, and the risk to other potential subjects evaluated if any of the 
following criteria are met:
o
if serious adverse reaction (i.e. an SAE considered at least possibly related to 
[14C]-tirzepatide administration) occur in 1 (or more) subject; 
o
severe non-serious adverse reactions (ie severe non-serious AE considered as, at 
least possibly related to [14C]-tirzepatide administration) in 2 subjects, 
independent of within or not within the same system organ class.

Investigator Decision
o
the investigator decides that the subject should be discontinued from the study.

Subject Decision
o
the subject requests to be withdrawn from the study.


L e o  D o c u m e n t  I D  =  3 7 e 9 e 1 4 a - 0 d 4 4 - 4 e 7 4 - a b f b - 0 3 c b 7 9 a f 2 b b 2
A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  1 9 - M a y - 2 0 2 0  1 1 : 1 6 : 3 0  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
A p p r o v e r :  
A p p r o v a l  D a t e  &  T i m e :  1 9 - M a y - 2 0 2 0  1 2 : 4 9 : 3 2  G M T
S i g n a t u r e  m e a n i n g :  A p p r o v e d
P P D
P P D

SAP_001.pdf: 
Statistical Analysis Plan: I8F-MC-GPHX
Disposition of [14C]-Tirzepatide Following Subcutaneous Administration in Healthy Male Subjects
NCT04311424   
Approval Date: 14-May-2020


Final, 12 May 2020
             Page 1 of 20
STATISTICAL ANALYSIS PLAN
Disposition of [14C]-Tirzepatide Following Subcutaneous Administration in Healthy Male 
Subjects
Statistical Analysis Plan Status: Final
Statistical Analysis Plan Date: 12-May-2020
Study Drug: Tirzepatide (LY3298176)
Sponsor Reference: I8F-MC-GPHX
Covance CRU Study: 1001215-8409944
Clinical Phase I
Approval Date: 14-May-2020 GMT


Final, 12 May 2020
             Page 2 of 20
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.1001215-8409944
Sponsor Reference I8F-MC-GPHX
1. TABLE OF CONTENTS
1.
TABLE OF CONTENTS .....................................................................................................2
2.
ABBREVIATIONS..............................................................................................................4
3.
INTRODUCTION ...............................................................................................................6
4.
STUDY OBJECTIVES........................................................................................................6
4.1
Primary Objective..........................................................................................................6
4.2
Secondary Objectives ....................................................................................................6
5.
STUDY DESIGN.................................................................................................................7
6.
TREATMENT .....................................................................................................................8
7.
SAMPLE SIZE JUSTIFICATION .......................................................................................8
8.
DEFINITION OF ANALYSIS POPULATIONS..................................................................8
9.
STATISTICAL METHODOLOGY .....................................................................................9
9.1
General..........................................................................................................................9
9.2
Demographics and Subject Disposition..........................................................................9
9.3
Pharmacokinetic Assessment.........................................................................................9
9.3.1
Pharmacokinetic Analysis.....................................................................................9
9.3.2
Pharmacokinetic Statistical Methodology ...........................................................14
9.4
Safety and Tolerability Assessments............................................................................14
9.4.1
Adverse events ...................................................................................................14
9.4.2
Glucose Monitoring and Hypoglycemia..............................................................15
9.4.3
Concomitant medication.....................................................................................16
9.4.4
Clinical laboratory parameters............................................................................16
9.4.5
Vital signs ..........................................................................................................16
9.4.6
Electrocardiogram (ECG)...................................................................................16
9.4.7
Body Weight ......................................................................................................16
9.4.8
Hepatic Monitoring ............................................................................................16
9.4.9
Hypersensitivity reactions...................................................................................18
9.4.10
Injection-Site Reactions......................................................................................18
9.4.11
Immunogenicity Assessments.............................................................................18
9.4.12
Other assessments...............................................................................................19
9.4.13
Safety and Tolerability Statistical Methodology..................................................19


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10. INTERIM ANALYSES .....................................................................................................19
11. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ............19
12. REFERENCES ..................................................................................................................19
13. DATA PRESENTATION ..................................................................................................19
13.1 Derived Parameters .....................................................................................................19
13.2 Missing Data ...............................................................................................................20
13.3 Insufficient Data for Presentation ................................................................................20


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2. ABBREVIATIONS
Abbreviations pertain to the Statistical Analysis Plan (SAP) only (not the tables, figures and 
listings [TFLs]).
%AUC(tlast-∞)
Percentage of AUC that is due to extrapolation from the last 
measurable concentration to infinity
ADA
Anti-drug antibody
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC
Area under the concentration versus time curve
AUC(0-∞)
Area under the concentration versus time curve from time zero to 
infinity
AUC(0-tlast)
Area under the concentration versus time curve from time zero to 
time t, where t is the last time point with a measurable concentration
BG
Blood glucose
BQL
Below the quantifiable lower limit of the assay
CL/F
Apparent total body clearance of drug calculated after extra vascular 
administration
Cmax
Maximum observed drug concentration
CRF
Case Report Form
CRU
Clinical Research Unit
CSR
Clinical Study Report
CT
Computed tomography
CV
Coefficient of variation
EC
Early Clinical 
ECG
Electrocardiogram
GIP
Glucose-dependent insulinotropic polypeptide
GLP-1
Glucagon-like peptide-1
ICH
International Conference on Harmonisation
MedDRA
Medical Dictionary for Regulatory Activities
PK
Pharmacokinetic
SAP
Statistical Analysis Plan


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SC
Subcutaneous
SD
Standard deviation 
SOP
Standard Operating Procedure
t1/2
Half-life associated with the terminal rate constant (λz) in 
non-compartmental analysis
TBL
Total bilirubin
TFLs
Tables, Figures, and Listings
tmax
Time of maximum observed drug concentration
ULN
Upper limit of normal
Vss/F
Apparent volume of distribution at steady state after extra-vascular 
administration
Vz/F
Apparent volume of distribution during the terminal phase after 
extra-vascular administration
WHO
World Health Organization


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3. INTRODUCTION
This SAP has been developed after review of the Clinical Study Protocol (final version dated 
18 February 2020).
This SAP describes the planned analysis of the safety, tolerability and pharmacokinetic (PK) data 
from this study. A detailed description of the planned TFLs to be presented in the clinical study 
report (CSR) is provided in the accompanying TFL shell document.
The intent of this document is to provide guidance for the statistical and PK analyses of data. In
general, the analyses are based on information from the protocol, unless they have been modified 
by agreement with Eli Lilly and Company. A limited amount of information concerning this 
study (e.g., objectives, study design) is given to help the reader’s interpretation. For open-label 
studies, this SAP must be signed off prior to first subject visit for this study. When the SAP and 
TFL shells are agreed upon and finalized, they will serve as the template for this study’s CSR.
This SAP supersedes the statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed and 
will be identified in the CSR. Any substantial deviations from this SAP will be agreed upon with
Eli Lilly and Company and identified in the CSR. Any minor deviations from the TFLs may not 
be documented in the CSR.
This SAP is written with consideration of the recommendations outlined in the International 
Conference on Harmonisation (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials1 and the ICH E3 Guideline entitled Guidance for Industry: Structure 
and Content of Clinical Study Reports2
4. STUDY OBJECTIVES
4.1
Primary Objective
To determine the disposition of radioactivity in healthy male subjects following subcutaneous
(SC) administration of a single dose of approximately 4.1 mg (approximately 100 μCi) 
[14C]-tirzepatide.
4.2
Secondary Objectives

To determine the PK of tirzepatide in plasma and total radioactivity in plasma and whole 
blood.

To assess the mass balance of tirzepatide by quantifying radioactivity recovered in urine, 
feces, and expired air (if applicable).

To assess the metabolism of tirzepatide in plasma, urine, and feces (if applicable).

To assess the safety and tolerability of a single dose of tirzepatide in healthy male 
subjects.


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5. STUDY DESIGN
This is a Phase 1, open-label, single-center study in healthy male subjects following a single dose 
of approximately 4.1 mg tirzepatide containing approximately 100 μCi of [14C]-tirzepatide 
administered as an SC injection.
Subjects will participate in a screening visit, a single study period, up to 7 follow-up visits and a 
follow-up telephone assessment. Subjects will be admitted to the clinical research unit (CRU) on 
the day prior to dosing (Day -1) and will receive a single SC injection of [14C]-tirzepatide, 
administered by clinical site staff, on Day 1.
Subjects will remain resident in the CRU for 14 days postdose (Day 15), but, may be discharged 
earlier if both the following release criteria have been met: 

≥90% of the administered radioactivity (based on the actual dose) has been recovered,
AND

24-hour urine and fecal samples from 2 consecutive collections (where both collections 
have occurred) where each combined urine and feces collection has a radioactivity level 
<1.0% of the total administered radioactivity.
If subjects have not met both release criteria by 14 days postdose (Day 15), they will be required 
to return to the CRU for up to seven 48-hour residential inpatient follow-up visits. Samples will 
be collected for PK and the measurement of remaining radioactivity in urine and feces during the 
inpatient follow-up visits. Subjects will be required to attend all inpatient follow -up visits as 
scheduled until such time that the second release criterion (<1.0% total radioactivity in excreta) 
is met or up to a maximum of 63 days postdose (Day 64), whichever occurs first.
An immunogenicity and corresponding PK sample are required from all subjects on Day 29. If 
subjects have not previously met the release criteria and are returning for the Day 27 to 29 
inpatient follow-up visit, then the immunogenicity and PK samples will be collected in the 
course of this visit. Subjects that have met the release criteria prior to the Day 27 to 29 inpatient 
visit will be required to attend a single outpatient visit on Day 29 for the collection of PK and 
immunogenicity samples.
A follow-up assessment will be conducted by telephone and will include recording of adverse 
events (AEs) and concomitant medication. The follow-up assessment will be performed 7 ± 2 
days after each subject has completed the final study visit or following early discontinuation 
from the study. 
Sequential urine and fecal samples will be obtained to determine the mass balance of tirzepatide 
by quantification of radioactivity and to identify metabolites. Samples of expired air will also be 
collected for the analysis of 14CO2 at selected time points. If a significant amount of administered 
radioactivity is present in expired air samples, these data will be extrapolated to estimate the 
radioactive dose recovery. The percent of the dose eliminated in excreta will be estimated by 
measuring the amount of radioactivity in the urine and/or feces for each collection period.
Figure 1 illustrates the study design.


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Abbreviations: ED = early discontinuation; PK = pharmacokinetic
Figure 1 Illustration of study design
6. TREATMENT
The study treatment will be a single dose of approximately 4.1-mg (approximately 100 μCi) 
[14C]-tirzepatide. The treatment label presented in the TFLs will be ‘X.X mg [14C]-tirzepatide’, 
where the TFLs will show the actual dosage level administered.
7. SAMPLE SIZE JUSTIFICATION
Up to 8 subjects will be enrolled. It is planned that up to 6 subjects will be dosed initially and 2 
additional subjects will be dosed if needed, in order that a minimum of 4 subjects complete the 
study.
The sample size is customary for [14C]-disposition studies3 and is chosen to provide adequate PK 
data while limiting the number of subjects exposed to radiopharmaceuticals in non-therapeutic 
research.
8. DEFINITION OF ANALYSIS POPULATIONS
The “Safety” population will consist of all subjects who received at least one dose of study drug.
The “Pharmacokinetic” population will consist of all subjects who received at least one dose of 
study drug and have evaluable PK data. 
All protocol deviations that occur during the study will be considered for their severity/impact 
and will be taken into consideration when subjects are assigned to analysis populations.


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9. STATISTICAL METHODOLOGY
9.1
General
Data listings will be provided for all data that is databased. Summary statistics and statistical 
analysis will only be presented for data where detailed in this SAP. For continuous data, 
summary statistics will include the arithmetic mean, arithmetic standard deviation (SD), median, 
min, max and n; for log-normal data (e.g. the PK parameters: area under the concentration versus 
time curve [AUCs] and maximum drug concentration [Cmax]) the geometric mean and geometric 
coefficient of variation (CV%) will also be presented. For categorical data, frequency count and 
percentages will be presented. Data listings will be provided for all subjects up to the point of 
withdrawal, with any subjects excluded from the relevant population highlighted. Summary 
statistics and statistical analyses will generally only be performed for subjects included in the 
relevant analysis population. For the calculation of summary statistics and statistical analysis, 
unrounded data will be used. 
Mean change from baseline is the mean of all individual subjects’ change from baseline values. 
Each individual change from baseline will be calculated by subtracting the individual subject’s 
baseline value from the value at the timepoint. The individual subject’s change from baseline 
values will be used to calculate the mean change from baseline using a SAS procedure such as 
Proc Univariate.
Data analysis will be performed using SAS® Version 9.4 or greater.
9.2
Demographics and Subject Disposition
Subject disposition will be listed.
The demographic variables age, race, ethnicity, body weight, height and body mass index will be 
summarized and listed. All other demographic variables will be listed only.
9.3
Pharmacokinetic Assessment
9.3.1
Pharmacokinetic Analysis
The PK parameter estimates will be determined using non-compartmental methods in validated 
software program, Phoenix WinNonlin (Certara, Version 8.1 or later):
Plasma concentrations of tirzepatide (LY3298176) will be used to determine the following PK 
parameters, when possible: 


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Parameter
Units
Definition
AUC(0-∞)
ng.h/mL 
area under the concentration versus time curve from time zero to infinity
AUC(0-tlast)
ng.h/mL
area under the concentration versus time curve from time zero to time t, where t is 
the last time point with a measurable concentration
%AUC(tlast-∞)
%
percentage of AUC that is due to extrapolation from the last measurable 
concentration to infinity
Cmax
ng/mL
maximum observed drug concentration
tmax
h
time of maximum observed drug concentration
t1/2
h
half-life associated with the terminal rate constant (λz) in non-compartmental 
analysis
CL/F
L/h
apparent total body clearance of drug calculated after extra-vascular 
administration 
Vss/F
L
apparent volume of distribution at steady state after extra-vascular administration 
Vz/F
L
apparent volume of distribution during the terminal phase after extra-vascular 
administration 
The following pharmacokinetic parameters will be calculated for total radioactivity in plasma and 
whole blood:
Parameter
Units
Definition
AUC(0-∞)
ng equiv.h/mL 
area under the concentration versus time curve from time zero to infinity
AUC(0-tlast)
ng equiv.h/mL
area under the concentration versus time curve from time zero to time t, where t is 
the last time point with a measurable concentration
%AUC(tlast-∞)
%
percentage of AUC that is due to extrapolation from the last measurable 
concentration to infinity
Cmax
ng equiv/mL
maximum observed drug concentration
tmax
h
time of maximum observed drug concentration
t1/2
h
half-life associated with the terminal rate constant (λz) in non-compartmental 
analysis
Additional pharmacokinetic parameters may be calculated where appropriate.
The software and version used for the final analysis will be specified in the clinical study report. 
Any exceptions or special handling of data will be clearly documented within the final study report.
Pharmacokinetic analysis will, where possible, be carried out using actual postdose times 
recorded in the raw data. 
The ratio of total radioactivity in whole blood : plasma will be calculated for each time point. 
The ratio of plasma tirzepatide : plasma total radioactivity will be calculated for each time point.
The ratio of total radioactivity in whole blood : plasma will be calculated based upon Cmax, 
AUC(0-tlast) and AUC(0-).


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The ratio of plasma tirzepatide : plasma total radioactivity will be calculated based upon Cmax, 
AUC(0-tlast) and AUC(0-).
The percentage and cumulative percentage of radiolabeled dose excreted in expired air may also 
be presented, if applicable.
Analysis of the total radioactivity in faeces, urine, expired air, plasma and whole blood will be 
presented in a separate radioanalysis report. Cumulative recovery of total radioactivity in 
excreta will also be determined.
Formatting of tables, figures and abbreviations will follow the Eli Lilly Global PK/PD/TS Tool: 
NON-COMPARTMENTAL PHARMACOKINETIC STYLE GUIDE. The version of the tool
effective at the time of PK analysis will be followed. 
General PK Parameter Rules

Actual sampling times will be used in the final analyses of individual PK parameters, 
except for non-bolus pre-dose sampling times which will be set to zero.

Cmax and tmax will be reported from observed values. If Cmax occurs at more than one time 
point, tmax will be assigned to the first occurrence of Cmax.

Where concentration data are supplied in ng equiv/g a matrix density of 1g/mL will be 
used for pharmacokinetic calculation.

AUC parameters will be calculated using a combination of the linear and logarithmic 
trapezoidal methods (linear-log trapezoidal rule). The linear trapezoidal method will be 
applied up to tmax and then the logarithmic trapezoidal method will be used after tmax. The 
minimum requirement for the calculation of AUC will be the inclusion of at least three 
consecutive plasma concentrations above the lower limit of quantification (LLOQ), with 
at least one of these concentrations following Cmax. 

AUC(0-) values where the percentage of the total area extrapolated is more than 20% 
will be flagged. Any AUC(0-) value excluded from summary statistics will be noted in 
the footnote of the summary table. An alternative AUC measure, such as AUC to a 
common time point, may be calculated if AUC(0-∞) cannot be reliably calculated.

Half-life (t½) will be calculated, when appropriate, based on the apparent terminal 
log-linear portion of the concentration-time curve. The start of the terminal elimination 
phase for each subject will be defined by visual inspection and generally will be the first 
point at which there is no systematic deviation from the log-linear decline in plasma 
concentrations. Half-life will only be calculated when a reliable estimate for this 
parameter can be obtained comprising of at least 3 data points. If t½ is estimated over a 
time window of less than 2 half-lives, the values will be flagged in the data listings. Any 
t½ value excluded from summary statistics will be documented in the footnote of the 
summary table. 


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
A uniform weighting scheme will be used in the regression analysis of the terminal 
log-linear portion of the concentration-time curve.

The parameters based on the last predicted quantifiable drug concentration (Clast) will be 
reported.
Individual PK Parameter Rules

Only quantifiable concentrations will be used to calculate PK parameters with the 
exception of special handling of certain concentrations reported below the lower limit of 
quantitation (BQL). Plasma concentrations reported as BQL will be set to a value of zero
when all of the following conditions are met:
o
The compound is non-endogenous.
o
The samples are from the initial dose period for a subject or from a subsequent 
dose period following a suitable wash-out period.
o
The time points occur before the first quantifiable concentration.

All other BQL concentrations that do not meet the above criteria will be set to missing.

Also, where two or more consecutive concentrations are BQL towards the end of a 
profile, the profile will be deemed to have terminated and therefore any further 
quantifiable concentrations will be set to missing for the calculation of the PK parameters 
unless it is considered to be a true characteristic of the profile of the drug.
Individual Concentration vs. Time Profiles

Individual concentrations will be plotted utilizing actual sampling times.

The terminal point selections will be indicated on a semi-logarithmic plot.
Average Concentration vs. Time Profiles

The average concentration profiles will be graphed using scheduled (nominal) sampling 
times.

The average concentration profiles will be graphed using arithmetic average 
concentrations.

The pre-dose average concentration for single-dose data from non-endogenous 
compounds will be set to zero. Otherwise, only quantifiable concentrations will be used 
to calculate average concentrations.

Concentrations at a sampling time exceeding the sampling time window specified in the 
protocol, or ± 10%, will be excluded from the average concentration profiles.


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


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e.
If the extreme value is outside the range of arithmetic mean ±3*SD, then it is an 
outlier and will be excluded from analysis.
If the remaining dataset contains another atypical datum suspected to be an outlier and n ≥ 6 
following the exclusion, then repeat step 2 above. This evaluation may be repeated as many 
times as necessary, excluding only one suspected outlier in each iteration, until all data 
remaining in the dataset fall within the range of arithmetic mean ±3*SD of the log-transformed 
values.
Reporting of Excluded Values
Individual values excluded as outliers will be documented in the final report. Approval of the 
final report will connote approval of the exclusion.
9.3.2
Pharmacokinetic Statistical Methodology
No formal statistical analysis will be performed for this study.
PK parameters and concentrations for tirzepatide and total radioactivity in plasma and whole 
blood will be summarized and listed.
Ratios of PK concentrations (plasma tirzepatide to plasma total radioactivity and total whole 
blood radioactivity to plasma total radioactivity) and parameters will summarized and listed.
Plasma concentrations of tirzepatide and total radioactivity in plasma and whole blood will be 
graphically represented with an arithmetic mean plot and a concentration-time profile by subject.
Expired air data will be listed (if radioactivity is detected).
The percentage of radiolabeled dose excreted in feces, urine and expired air will be determined 
by the radioanalytical lab and reported in the radioanalysis report. Cumulative recovery of total
radioactivity in excreta will also be determined.
9.4
Safety and Tolerability Assessments
9.4.1
Adverse events
Where changes in severity are recorded in the Case Report Form (CRF), each separate severity 
of the AE will be reported in the listings, only the most severe will be used in the summary 
tables. A pre-existing condition is defined as an AE that starts before the subject has provided 
written informed consent and is ongoing at consent. A non-treatment emergent AE is defined as 
an AE which starts after informed consent but prior to dosing. A treatment-emergent AE is 
defined as an AE which occurs postdose or which is present prior to dosing and becomes more 
severe postdose. 
All AEs will be listed. Treatment-emergent AEs will be summarized by severity and relationship 
to the study drug. The frequency (the number of AEs, the number of subjects experiencing an AE
and the percentage of subjects experiencing an AE) of treatment-emergent AEs will be 
summarized by Medical Dictionary for Regulatory Activities (MedDRA) version 23.0 system 


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organ class and preferred term. The summary and frequency AE tables will be presented for all 
causalities and those considered related to the study drug by the investigator. Any serious AEs
will be listed. 
Discontinuations due to AEs will be listed.
9.4.2
Glucose Monitoring and Hypoglycemia
During the study, blood glucose (BG) concentrations will be monitored for safety assessments.
Glucose data will be listed and summarized by timepoint together with changes from baseline, 
where baseline is defined as Day 1 predose.
Hypoglycemic events will be appropriately recorded in the CRF. In the case of a hypoglycemic 
event, the actual BG value, if measured, will be recorded in the CRF, together with any
treatments administered. Each category of hypoglycemic events (defined below) will be listed 
and summarized. Hypoglycemia is defined as follows:

Glucose Alert Level (Level 1):
o
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 plasma glucose (PG) level of ≤70 mg/dL (≤3.9 mmol/L).
o
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).
o
Documented unspecified hypoglycemia is defined as any event with no
information about symptoms of hypoglycemia available, but with a measured PG 
≤70 mg/dL (≤3.9 mmol/L).

Clinically Significant Hypoglycemia (Level 2):
o
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 <54 mg/dL (<3.0 mmol/L).
o
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).
o
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):
o
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. BG 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.


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
Other hypoglycemia categories:
o
Nocturnal hypoglycemia is defined as any hypoglycemic event that occurs 
between bedtime and waking.
Investigator review of glucose results clinically indicative of hypoglycemia will be required.
9.4.3
Concomitant medication
Concomitant medication will be coded using the WHO drug dictionary (Version March 2020). 
Concomitant medication will be listed.
9.4.4
Clinical laboratory parameters
All clinical chemistry and hematology data will be summarized by parameter and timepoint 
together with changes from baseline, where baseline is defined as the Day -1 assessment. All 
clinical chemistry, hematology and urinalysis data will be listed. 
Additionally, clinical chemistry, hematology and urinalysis data outside the reference ranges will 
be listed and flagged on individual subject data listings.
9.4.5
Vital signs
Vital signs data will be summarized by timepoint together with changes from baseline, where 
baseline is defined as the Day 1 predose assessment. Figures of mean vital signs and mean 
changes from baseline profiles will be presented by parameter over time. 
Values for individual subjects will be listed.
9.4.6
Electrocardiogram (ECG)
ECGs will be performed for safety monitoring purposes only and will not be presented. Any 
clinically significant findings from ECGs will be reported as an AE.
9.4.7
Body Weight
Body weight will be listed together with changes from baseline, where baseline is defined as the 
Screening assessment.
9.4.8
Hepatic Monitoring
Close hepatic monitoring
If a subject who had normal or near normal baseline alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin (TBL) (i.e., <1.5× upper 
limit of normal [ULN]), experiences elevated ALT≥3× ULN, AST≥3× ULN, ALP≥2× ULN, or
TBL≥2× ULN, laboratory tests should be repeated within 48 to 72 hours, including ALT, AST, 
ALP, TBL, direct bilirubin, gamma-glutamyltransferase, and creatinine phosphokinase to
confirm the abnormality and to determine if it is increasing or decreasing.


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.1001215-8409944
Sponsor Reference I8F-MC-GPHX
In subjects enrolled with elevated baseline ALT, AST, ALP or TBL (≥1.5× ULN), the thresholds
for close monitoring are ALT≥2× baseline, AST≥2× baseline, ALP≥2× baseline, or TBL≥2×
baseline.
At a minimum, this evaluation should include physical examination and a thorough medical 
history, including symptoms, recent illnesses, (for example, heart failure, systemic infection, 
hypotension, or seizures), recent travel, history of concomitant medications (including over-the-
counter), herbal and dietary supplements, history of alcohol drinking and other substance abuse
If the abnormality persists or worsens, clinical and laboratory monitoring, and evaluation for 
possible causes of abnormal liver tests should be initiated by the investigator in consultation with 
the Lilly-designated medical monitor.
Comprehensive hepatic evaluation
If a study subject, who had baseline ALT, AST, ALP, TBL<1.5× ULN, experiences elevated
ALT≥5× ULN, AST≥5× ULN, ALP ≥3× ULN, TBL ≥2× ULN, or elevated ALT, AST ≥3× ULN
with hepatic signs/symptoms (severe fatigue, nausea, vomiting, right upper quadrant abdominal
pain, fever, rash, and/or eosinophilia>5%), a comprehensive evaluation should be performed to
search for possible causes of liver injury.
In subjects who had elevated baseline ALT, AST, ALP, or TBL (≥1.5× ULN), the thresholds for
performing this evaluation are ALT≥3× baseline, AST≥3× baseline, ALP≥2× baseline, 
TBL≥1.5× baseline, or ALT, AST ≥2× baseline with hepatic signs/symptoms.
At a minimum, this evaluation should include physical examination and a thorough medical
history, as outlined above, as well as tests for prothrombin time-international normalized ratio,
viral hepatitis A, B, C, E, tests for autoimmune hepatitis, and an abdominal imaging study (for
example, ultrasound or computed tomography [CT] scan).
Additional hepatic data collection in subjects who have abnormal liver tests during the 
study
Additional hepatic safety data collection should be performed in subjects who meet 1 or more of 
the following 5 conditions:
1. Elevation of serum ALT to ≥5× ULN on 2 or more consecutive blood tests (if baseline
ALT<1.5x ULN)
In subjects with baseline ALT≥1.5× ULN, the threshold is ALT≥3x baseline on 2 
or more consecutive tests
2. Elevated TBL to ≥2× ULN (if baseline TBL <1.5× ULN)
In subjects with baseline TBL ≥1.5× ULN, the threshold should be TBL ≥2x
baseline
3. Elevation of serum ALP to ≥2× ULN on 2 or more consecutive blood tests (if baseline
ALP <1.5× ULN)


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.1001215-8409944
Sponsor Reference I8F-MC-GPHX
In subjects with baseline ALP≥1.5× ULN, the threshold is ALP ≥2× baseline on 2
or more consecutive blood tests
4. Hepatic event considered to be an SAE
5. Discontinuation of the investigational produce due to a hepatic event
Where applicable, the following will be presented.
The subjects’ liver disease history and associated person liver disease history data will be listed. 
Any concomitant medications that have potential for hepatotoxicity, including acetaminophen 
will be listed. Results from any hepatic monitoring procedures, such as a magnetic resonance 
elastography (MRE) scan, and biopsy assessments will be listed, if performed.
Hepatic risk factor assessment data will be listed. Liver related signs and symptoms data will be 
summarized by treatment and listed. Alcohol and recreational drug use data will also be listed.
All hepatic chemistry, hematology, coagulation, and serology data will be listed. Values outside 
the reference ranges will be flagged on the individual subject data listings.
9.4.9
Hypersensitivity reactions
All hypersensitivity reactions will be reported by the investigator as either AEs or, if any serious 
criterion is met, as SAEs.
For moderate-to-severe hypersensitivity reactions that occur, additional follow-up data will be 
collected to assess the subject’s medical history, alternative causes, and symptoms. These data 
will be listed.
Additionally, unscheduled PK, immunogenicity, and laboratory data may be collected. All data 
will be included in the relevant listings.
9.4.10
Injection-Site Reactions
Injection-site assessments for local tolerability will be conducted, when reported as:

an AE from a subject, or

a clinical observation from an investigator.
Injection site assessment data (erythema, induration, categorical pain, pruritus, and edema) will
be summarized and listed.
9.4.11
Immunogenicity Assessments
Immunogenicity data will be listed and frequency tables will be presented if analysed. The 
frequency and percentage of subjects with pre-existing ADA and with treatment-emergent ADAs 
(TE ADAs) will be presented. TE ADAs are those that are boosted or induced by exposure to 
study drug, with a 4-fold increase in titer compared to baseline if ADAs were detected at 


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.1001215-8409944
Sponsor Reference I8F-MC-GPHX
baseline or a titer 2-fold greater than the minimum required dilution (1:10) if no ADAs were 
detected at baseline, where baseline is defined as Day 1 predose.
If cross-reactivity with native glucagon-like peptide-1 (GLP-1) and glucose-dependent 
insulinotropic polypeptide (GIP) or a neutralization assay is performed, the frequency of each 
will be determined. 
The relationship between the presence of antibodies and PK parameters of tirzepatide may be 
assessed if deemed appropriate.
9.4.12
Other assessments
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analyzed.
9.4.13
Safety and Tolerability Statistical Methodology
No inferential statistical analyses are planned.
10.
INTERIM ANALYSES
No interim statistical analyses are planned.
11.
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES
There were no changes from the protocol specified statistical analyses.
12.
REFERENCES
1. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9), 5 February 1998.
2. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), 30 November 1995.
3. Penner N, Klunk LJ, Prakash C. Human radiolabeled mass balance studies: objectives, 
utilities and limitations. Biopharm. Drug Dispos. 2009;30(4): 185-203.
13.
DATA PRESENTATION
13.1
Derived Parameters
Individual derived parameters (e.g. PK parameters) and appropriate summary statistics will be 
reported to three significant figures. Observed concentration data, e.g. Cmax, should be reported 
as received. Observed time data, e.g. tmax, should be reported as received. N and percentage 
values should be reported as whole numbers. Median values should be treated as an observed 
parameter and reported to the same number of decimal places as minimum and maximum values.


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No.1001215-8409944
Sponsor Reference I8F-MC-GPHX
13.2
Missing Data
Missing data will not be displayed in listings.
13.3
Insufficient Data for Presentation
If there are no data for an individual subject listing, the listing will be presented with a message 
printed in the center. For example, if no serious adverse events are reported, the serious adverse 
events listing will display the message “No serious adverse events occurred for this study”. 
Summary tables will not be produced if there are no or insufficient data.


Leo Document ID = c1214371-8f3b-45ee-b1de-9d74ba399220
Approver:
Approval Date & Time: 13-May-2020 15:08:12 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 13-May-2020 15:39:13 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 13-May-2020 20:11:18 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 14-May-2020 17:07:18 GMT
Signature meaning: Approved
PPD
PPD
PPD
PPD