A Bioequivalence Study to Compare the Pharmacokinetics of Tirzepatide Administered Subcutaneously by a Test Device (Test Formulation) Versus Reference Device (Reference Formulation) in Healthy Participants
Phase: PHASE1
Conditions: Healthy
Sponsor: Eli Lilly and Company

 
 
 
Protocol I8F-MC-GPIP (a) 
 
 
A Bioequivalence Study to Compare the Pharmacokinetics of Tirzepatide Administered 
Subcutaneously by a Fixed-Dose Multi-use Prefilled Pen Versus Single-Dose Pen in Healthy 
Participants 
 
 
NCT05810597 
 
 
Approval Date: 30-May-2023 
 
 
 
 
 
 

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I8F-MC-GPIP(a) 
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Title Page  
Confidential Information 
The information contained in this document is confidential and is intended for the use of clinical investigators. It is the property of 
Eli Lilly and Company or its subsidiaries and should not be copied by or distributed to persons not involved in the clinical 
investigation of tirzepatide (LY3298176), unless such persons are bound by a confidentiality agreement with Eli Lilly and Company 
or its subsidiaries.  
 
Note to Regulatory Authorities: This document may contain protected personal data and/or commercially confidential information 
exempt from public disclosure. Eli Lilly and Company requests consultation regarding release/redaction prior to any public release. 
In the United States, this document is subject to Freedom of Information Act (FOIA) Exemption 4 and may not be reproduced or 
otherwise disseminated without the written approval of Eli Lilly and Company or its subsidiaries. 
 
Protocol Title:  
A Bioequivalence Study to Compare the Pharmacokinetics of Tirzepatide Administered 
Subcutaneously by a Fixed-Dose Multi-use Prefilled Pen Versus Single-Dose Pen in Healthy 
Participants  
Protocol Number: I8F-MC-GPIP 
Amendment Number: I8F-MC-GPIP (a) 
Compound: Tirzepatide (LY3298176) 
Brief Title:  
Bioequivalence Study to Compare the PK of Tirzepatide Administered by Fixed-dose Multi-use 
Prefilled Pen Versus Single-Use Prefilled Pen in Healthy Participants 
Study Phase: 1 
Acronym: GPIP 
Sponsor Name: Eli Lilly and Company 
Legal Registered Address: Indianapolis, Indiana, USA 46285 
Regulatory Agency Identifier Number(s) 
IND128801 
Approval Date: Protocol Amendment (a) Electronically Signed and Approved by Lilly on date 
provided below.  
Document ID: VV-CLIN-117711 
 
 
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I8F-MC-GPIP(a) 
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Medical Monitor Name and Contact Information will be provided separately. 
 
 
 
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Protocol Amendment Summary of Changes Table  
 
DOCUMENT HISTORY 
Document 
Date 
Original Protocol 
21-Oct-2022 
Amendment [a]  
Overall Rationale for the Amendment: 
The protocol is being amended to address FDA recommendations on contraceptive and barrier 
guidance. This amendment is considered as non-substantial. 
Section # and 
Name 
Description of Change 
Brief Rationale 
10.4.2 
Contraception 
Guidance 
Revised to include 2 forms of 
effective methods of 
contraception where at least 1 
form must be a highly effective 
method of contraception. 
Based on FDA feedback 
Deleted “total abstinence” from 
the list of highly effective 
contraception. 
Based on FDA feedback 
 
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Table of Contents  
1. 
Protocol Summary ..........................................................................................................7 
1.1. 
Synopsis ............................................................................................................................7 
1.2. 
Schema ..............................................................................................................................9 
1.3. 
Schedule of Activities (SoA) ..........................................................................................10 
2. 
Introduction ...................................................................................................................12 
2.1. 
Study Rationale ...............................................................................................................12 
2.2. 
Background .....................................................................................................................12 
2.3. 
Benefit/Risk Assessment ................................................................................................13 
3. 
Objectives and Endpoints ............................................................................................14 
4. 
Study Design ..................................................................................................................15 
4.1. 
Overall Design ................................................................................................................15 
4.1.1. 
Screening Period .............................................................................................................15 
4.1.2. 
Treatment Periods 1 and 2 ..............................................................................................15 
4.1.3. 
Washout Period ...............................................................................................................16 
4.1.4. 
Follow-Up Period............................................................................................................16 
4.2. 
Scientific Rationale for Study Design ............................................................................16 
4.3. 
Justification for Dose ......................................................................................................16 
4.4. 
End of Study Definition ..................................................................................................16 
5. 
Study Population ...........................................................................................................17 
5.1. 
Inclusion Criteria ............................................................................................................17 
5.2. 
Exclusion Criteria ...........................................................................................................18 
5.3. 
Lifestyle Considerations .................................................................................................19 
5.3.1. 
Meals and Dietary Restrictions .......................................................................................19 
5.3.2. 
Substance Use: Caffeine, Alcohol, and Tobacco ............................................................19 
5.3.3. 
Activity ...........................................................................................................................20 
5.4. 
Screen Failures ................................................................................................................20 
5.5. 
Criteria for Temporarily Delaying Enrollment/Randomization/ 
Administration of Study Intervention of a Participant....................................................20 
6. 
Study Intervention(s) and Concomitant Therapy .....................................................21 
6.1. 
Study Intervention(s) Administered................................................................................21 
6.1.1. 
Medical Devices..............................................................................................................22 
6.2. 
Preparation, Handling, Storage, and Accountability ......................................................22 
6.3. 
Assignment to Study Intervention ..................................................................................22 
6.4. 
Study Intervention Compliance ......................................................................................22 
6.5. 
Dose Modification ..........................................................................................................22 
6.6. 
Continued Access to Study Intervention after the End of the 
Study ...............................................................................................................................23 
6.7. 
Treatment of Overdose ...................................................................................................23 
6.8. 
Prior and Concomitant Therapy ......................................................................................23 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................24 
7.1. 
Discontinuation of Study Intervention ............................................................................24 
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7.1.1. 
Hypersensitivity Reaction Criteria for Discontinuation .................................................24 
7.1.2. 
Hepatic Criteria for Discontinuation ...............................................................................24 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................26 
7.3. 
Lost to Follow-Up ...........................................................................................................26 
8. 
Study Assessments and Procedures.............................................................................27 
8.1. 
Efficacy Assessments .....................................................................................................27 
8.2. 
Safety Assessments .........................................................................................................27 
8.2.1. 
Physical Examinations ....................................................................................................27 
8.2.2. 
Vital Signs .......................................................................................................................27 
8.2.3. 
Electrocardiograms .........................................................................................................27 
8.2.4. 
Clinical Safety Laboratory Tests ....................................................................................28 
8.2.5. 
Glucose Monitoring ........................................................................................................29 
8.2.6. 
Injection-Site Reactions ..................................................................................................30 
8.2.7. 
Hypersensitivity Reactions .............................................................................................30 
8.2.8. 
Safety Monitoring ...........................................................................................................30 
8.2.9. 
Pregnancy Testing ...........................................................................................................33 
8.3. 
Adverse Events, Serious Adverse Events, and Product 
Complaints ......................................................................................................................33 
8.3.1. 
Timing and Mechanism for Collecting Events ...............................................................33 
8.3.2. 
Pregnancy ........................................................................................................................36 
8.3.3. 
Adverse Events of Special Interest .................................................................................37 
8.4. 
Pharmacokinetics ............................................................................................................37 
8.4.1. 
Bioanalysis ......................................................................................................................38 
8.5. 
Pharmacodynamics .........................................................................................................38 
8.6. 
Genetics ..........................................................................................................................38 
8.7. 
Biomarkers ......................................................................................................................39 
8.8. 
Health Economics OR Medical Resource Utilization and Health 
Economics .......................................................................................................................39 
9. 
Statistical Considerations .............................................................................................40 
9.1. 
Statistical Hypotheses .....................................................................................................40 
9.1.1. 
Multiplicity Adjustment ..................................................................................................40 
9.2. 
Analyses Sets ..................................................................................................................40 
9.3. 
Statistical Analyses .........................................................................................................40 
9.3.1. 
General Considerations ...................................................................................................40 
9.3.2. 
Primary Endpoints Analysis ...........................................................................................41 
9.3.3. 
Secondary Endpoints Analysis .......................................................................................41 
9.3.4. 
Safety Analyses ...............................................................................................................42 
9.3.5. 
Other Analyses ................................................................................................................42 
9.4. 
Interim Analyses .............................................................................................................42 
9.5. 
Sample Size Determination ............................................................................................42 
10. 
Supporting Documentation and Operational Considerations ..................................43 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................43 
10.1.1. Regulatory and Ethical Considerations ...........................................................................43 
10.1.2. Financial Disclosure........................................................................................................44 
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10.1.3. Informed Consent Process ..............................................................................................44 
10.1.4. Data Protection................................................................................................................44 
10.1.5. Dissemination of Clinical Study Data.............................................................................45 
10.1.6. Data Quality Assurance ..................................................................................................45 
10.1.7. Source Documents ..........................................................................................................46 
10.1.8. Study and Site Start and Closure ....................................................................................47 
10.1.9. Publication Policy ...........................................................................................................47 
10.2. 
Appendix 2: Clinical Laboratory Tests ...........................................................................48 
10.2.1. Blood Sampling Summary ..............................................................................................50 
10.3. 
Appendix 3: Adverse Events and Serious Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-
Up, and Reporting ...........................................................................................................51 
10.3.1. Definition of AE .............................................................................................................51 
10.3.2. Definition of SAE ...........................................................................................................52 
10.3.3. Definition of Product Complaints ...................................................................................53 
10.3.4. Recording and Follow-Up of AE and/or SAE and Product 
Complaints ......................................................................................................................53 
10.3.5. Reporting of SAEs ..........................................................................................................55 
10.3.6. Regulatory Reporting Requirements ...............................................................................55 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ..........................................................56 
10.4.1. Definitions.......................................................................................................................56 
10.4.2. Contraception Guidance..................................................................................................57 
10.5. 
Appendix 5: Genetics......................................................................................................59 
10.6. 
Appendix 6: Medical Device Adverse Events (AEs), Adverse 
Device Effects (ADEs), Serious Adverse Events (SAEs) and 
Device Deficiencies: Definition and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ............................................................................60 
10.7. 
Appendix 7: Liver Safety: Suggested Actions and Follow-Up 
Assessments ....................................................................................................................61 
10.8. 
Appendix 8: Pancreatic Monitoring ................................................................................62 
10.9. 
Appendix 9: Abbreviations and Definitions ...................................................................63 
11. 
References ......................................................................................................................66 
 
 
 
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1. 
Protocol Summary  
1.1. 
Synopsis  
Protocol Title: A Bioequivalence Study to Compare the Pharmacokinetics of Tirzepatide 
Administered Subcutaneously by a Fixed-Dose Multi-use Prefilled Pen Versus Single-Dose Pen 
in Healthy Participants 
Brief Title: Bioequivalence Study to Compare the PK of Tirzepatide Administered by Fixed-
Dose Multi-use Prefilled Pen Versus Single-Dose Pen in Healthy Participants 
Regulatory Agency Identifier Number(s): IND128801 
Rationale: 
Study I8F-MC-GPIP (GPIP) will assess the pharmacokinetics (PK), safety, and tolerability of a 
5-mg subcutaneous (SC) dose of tirzepatide solution formulation administered via fixed-dose 
multi-use prefilled pen (MUPFP) (test) versus a single-dose pen (SDP) (reference). The SDP 
autoinjector device is the currently approved commercial single-dose, single-use pen 
presentation of tirzepatide, while the MUPFP is being developed as an alternative multi-dose 
option. This study will provide PK bioequivalence data for tirzepatide when it is administered 
via the MUPFP versus the SDP device. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
 To evaluate the bioequivalence 
between the MUPFP (test) and the 
SDP (reference), as assessed using 
tirzepatide PK in healthy participants 
 Cmax, AUC(0-t), and AUC(0‑∞) 
 
Secondary 
 
 To evaluate the additional PK 
parameter 
 To evaluate the safety and tolerability 
of a single subcutaneous dose of 
tirzepatide administered through 
MUPFP (test) versus SDP (reference) 
 tmax 
 
 Incidence of AEs  
 
Abbreviations: AE = adverse event; AUC(0-t) = area under the concentration versus time curve from time zero to 
time t; AUC(0‑∞) = area under the concentration versus time curve from zero to infinity; Cmax = maximum 
observed drug concentration; MUPFP = multi-use prefilled pen; PK = pharmacokinetics; SDP = single-dose pen; 
tmax = time of maximum observed drug concentration. 
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Brief Summary of Study Design: 
Study GPIP is a multicenter, open-label, randomized, 2-period, 2-sequence, crossover study 
conducted in healthy participants. 
Study Population:  
Healthy participants. 
Number of Participants: 
Approximately 65 participants will be enrolled so that at least 54 participants complete the study.  
Intervention and Planned Duration for an Individual Participant: 
The study involves a comparison of: 
 a single dose of 5 mg tirzepatide administered SC via MUPFP 
 a single dose of 5 mg tirzepatide administered SC via SDP 
The study duration for individual participants, inclusive of screening is expected to be 
approximately 14 weeks, divided as follows: 
 Screening: up to 27 days prior to Day -1 
 Treatment Periods 1 and 2: Day 1 to Day 36, including single dosing with tirzepatide on 
Day 1 of each period 
 Washout: there will be a washout of at least 35 days between tirzepatide dose 
administrations 
 Follow-up: Period 2, Day 36 (±1) will be considered as the final follow-up visit 
Ethical Considerations of Benefit/Risk:  
As of 26 September 2022, tirzepatide (MOUNJARO™) was approved in the US, EU, and Japan 
as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes 
mellitus. Risks of tirzepatide have been consistent with risks associated with other glucagon-like 
peptide (GLP)-1 receptor agonists that are currently marketed. Potential risks include, but are not 
limited to, gastrointestinal effects, acute pancreatitis, increases in heart rate, and hypoglycemic 
events (GLP-1 receptor agonist class effect), which are all monitorable. 
There is no anticipated therapeutic benefit in healthy participants. 
Data Monitoring Committee: No 
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I8F-MC-GPIP(a) 
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1.2. 
Schema  
 
 
 
Abbreviations: CRU = clinical research unit; PK = pharmacokinetics; PFP = prefilled pen, SDP =single dose pen 
 
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1.3. 
Schedule of Activities (SoA)  
 
Screening 
Periods 1 and 2 Study Days – at least 35 days washout between Day 1 doses 
EDb 
Comments 
Procedure 
D -28 to 
D -2  
D -1a 
D1a 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D15 
D21 
D36 
(±1)a 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participant admission 
to CRU 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ethanol and urine 
drug screen testing 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Per site CRU local requirements 
Tirzepatide dosing 
 
 
0 hour 
 
 
 
 
 
 
 
 
 
 
 
Study drug will be administered after an overnight 
fast of at least 8 hours. 
Participant discharge 
from CRU 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Inpatient stay may be extended at the investigator’s 
discretion for safety monitoring. 
Outpatient visit 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Medical history and 
demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
/medical assessment 
X 
 
Predose 
 
 
X 
 
 
 
 
 
 
X 
X 
Full physical examination at screening. Thereafter, 
assessments performed to include medical review 
and targeted, symptom-driven examination, as 
appropriate. Additional assessments may be 
performed at investigator’s clinical discretion. 
Weight 
X 
 
Predose 
 
 
 
 
 
 
 
 
 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Temperature 
X 
 
Predose 
 
 
 
 
 
 
 
 
 
 
 
 
Safety 12-lead ECGc 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Vital signs (hours) 
X 
 
Predose, 
12 
24 
48 
72 
 
 
 
X 
X 
X 
X 
X 
Additional unscheduled measures may be taken, at 
the clinical discretion of the investigator. 
Clinical laboratory 
tests 
X 
 
Predose 
 
 
 
 
 
 
X 
 
 
X 
X 
See Appendix 2 for details. Day 1 predose sample is 
for baseline only and need not be reviewed prior to 
first dosing. Performed by local laboratory at 
screening and central laboratory for subsequent 
visits. 
Pregnancy test 
X 
 
Predose 
 
 
 
 
 
 
 
 
 
X 
X 
Female participants only. Serum pregnancy test will 
be performed at screening and urine pregnancy tests 
at subsequent visits. 
FSH test, if 
applicable 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Female participants considered to be 
postmenopausal only. Women with confirmed 
nonchildbearing potential status can be exempted 
from further pregnancy tests during the study after 
screening. 
AEs/concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
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Screening 
Periods 1 and 2 Study Days – at least 35 days washout between Day 1 doses 
EDb 
Comments 
Procedure 
D -28 to 
D -2  
D -1a 
D1a 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D15 
D21 
D36 
(±1)a 
 
 
Pharmacogenetic 
samplec 
 
 
Predose 
 
 
 
 
 
 
 
 
 
 
 
Single sample in Period 1 only. 
Blood glucose 
monitoring (hours)c 
 
 
Predose, 
12 
24, 
36 
48 
72 
 
 
 
 
 
 
 
 
 
Performed using a bedside glucose monitor. 
Additional unscheduled measurements may be taken 
at the clinical discretion of the investigator. 
PK sampling 
(hours)c 
 
 
Predose, 
8, 12 
24, 
36 
48 
72 
96 
120 
144 
168 
336 
480 
X 
X 
 
Abbreviations: AE = adverse event; CRU = clinical research unit; D or d = day; ECG = electrocardiogram; ED = early discontinuation; FSH = follicle-
stimulating hormone; PK = pharmacokinetic(s). 
a Period 2, Day -1 procedures (pregnancy tests) and some Period 2, predose procedures (physical examinations, medical assessments, ethanol and drug 
screening and clinical laboratory assessments) may be omitted if Period 1, D36 (±1) procedure dates occur within 4 days of Period 2 dosing. Period 2, Day 36 
(±1) will also be considered as the final follow-up visit. 
b Within 14 days upon confirmation of early discontinuation. 
c Predose sample should be collected approximately 2 h prior to dose administration. 
Note: All sampling and procedure times are given relative to dosing (Time 0 hour) with tirzepatide (predose or hours postdose). Unless otherwise indicated, 
predose procedure may be performed any time prior to dosing.  
If multiple procedures take place at the same time point, the following order of the procedures should be used: ECGs, vital signs, PK sample (record of actual PK 
sampling time is the priority), clinical laboratory sample, blood glucose and pharmacogenetic sample. 
 
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2. 
Introduction  
2.1. 
Study Rationale  
As of 26 September 2022, tirzepatide (MOUNJARO™) received regulatory approval in the US, 
EU, and Japan. Tirzepatide is indicated as an adjunct to diet and exercise to improve glycemic 
control in adults with T2DM. In addition, it is being developed as a therapy for the indications of 
chronic weight management, nonalcoholic steatohepatitis, obstructive sleep apnea, and heart 
failure with preserved ejection fraction. It is administered QW through SC injection. 
Study I8F-MC-GPIP (GPIP) will assess the PK, safety, and tolerability of a 5-mg SC dose of 
tirzepatide solution formulation administered using the MUPFP (test) versus the SDP 
(reference). 
The SDP is the currently approved commercial presentation of tirzepatide. The fixed-dose 
MUPFP is being developed as an alternative option for future commercialization. 
2.2. 
Background  
Tirzepatide (LY3298176) is a GIP and GLP-1 RA. It is a 39 amino acid synthetic peptide with 
agonist activity at both the GIP and GLP-1 receptors. Its structure is based on the GIP sequence 
and includes a C20 fatty di-acid moiety that prolongs the duration of action. It is administered 
QW through SC injection in a SDP.  
Tirzepatide has a chemical structure and pharmacologic profile, ie, distinct from GLP-1 RAs due 
to the additional effects on GIP receptor, which is unique compared to the marketed incretin 
mimetics. As an agonist, tirzepatide combines the signaling of each receptor for improved 
glycemic control (Coskun et al. 2018). By virtue of being an agonist incretin mimetic, tirzepatide 
has the potential for reaching higher efficacy in target tissues such as the insulin-producing 
pancreatic β cells that express both GIP and GLP-1 receptors before reaching its therapeutic 
limitation, which supports its use as a treatment for T2DM.  
A solution formulation of tirzepatide for injection in a SDP was developed for QW SC 
administration. This drug product formulation is composed of tirzepatide drug substance, sodium 
phosphate, sodium chloride, and water for injections. 
The current commercial configuration is a single integral product with 0.5-mL sterile drug 
product solution contained in a 1-mL glass syringe with a plunger, which is assembled into a 
PFP (or autoinjector). The finished form is a SDP with a spring-driven design to administer the 
0.5 mL. The 6 available strengths are 2.5, 5, 7.5, 10, 12.5, and 15 mg. 
The MUPFP is configured to deliver multiple 0.6-mL doses of a single strength. The MUPFP 
uses a 3-mL cartridge that is preassembled into the device and is not replaceable. Six separate 
MUPFPs, 1 for each dose strength, are planned to match the approved SDP offering (2.5, 5, 7.5, 
10, 12.5, and 15 mg). Each MUPFP will contain sufficient volume to deliver 4 doses covering 1 
month of therapy. 
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2.3. 
Benefit/Risk Assessment  
As of 26 September 2022, tirzepatide (MOUNJARO) was approved in the US, EU, and Japan as 
an adjunct to diet and exercise to improve glycemic control in adults with T2DM. Risks of 
tirzepatide have been consistent with risks associated with other GLP-1 RAs that are currently 
marketed. Potential risks include, but are not limited to, GI effects, acute pancreatitis, increases 
in heart rate, and hypoglycemic events (GLP-1 RA class effect), which are all monitorable. 
No clinically significant safety or tolerability concerns have been identified during clinical 
investigation of tirzepatide up to the highest single dose level of 8 mg or multiple weekly doses 
up to 15 mg, attained by stepwise dose escalation. The maximum tolerated dose as a single dose 
of tirzepatide in healthy participants was determined to be 5 mg. Based on this information, the 
2x single 5-mg doses to be administered in Study GPIP are reasonably anticipated to be tolerable 
in this group of healthy participants. 
There is no anticipated therapeutic benefit in these healthy participants. 
More information about the known and expected benefits, risks, SAEs, and reasonably 
anticipated AEs of tirzepatide are to be found in the package insert of tirzepatide.  
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I8F-MC-GPIP(a) 
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3. 
Objectives and Endpoints  
Objectives 
Endpoints 
Primary 
 
 To evaluate the bioequivalence 
between the MUPFP (test) and the 
SDP (reference), as assessed using 
tirzepatide PK in healthy participants 
 Cmax, AUC(0-t), AUC(0‑∞)  
Secondary 
 
 To evaluate the additional PK 
parameter 
 To evaluate the safety and tolerability 
of a single subcutaneous dose of 
tirzepatide administered through 
MUPFP (test) versus SDP (reference) 
 tmax 
 
 Incidence of AEs 
Abbreviations: AE = adverse event; AUC(0-t) = area under the concentration versus time curve from time zero to 
time t; AUC(0‑∞) = area under the concentration versus time curve from zero to infinity; Cmax = maximum 
observed drug concentration; MUPFP = multi-use prefilled pen; PK = pharmacokinetics; SDP = single-dose pen; 
tmax = time of maximum observed drug concentration. 
 
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4. 
Study Design  
4.1. 
Overall Design  
This is a multicenter, open-label, randomized, 2-period, 2-sequence, crossover study conducted 
in healthy participants. 
The study will include 2 treatment arms. Approximately 65 participants may be enrolled so that 
at least 54 participants complete the study. Participants will be randomly assigned 1:1 to the 2 
treatment sequences. It is intended that approximately the same number of participants will be 
randomly assigned into each treatment sequence. The treatment sequence are: 
 a single dose of 5 mg tirzepatide administered SC via MUPFP followed by SDP; or 
 a single dose of 5 mg tirzepatide administered SC via SDP followed by MUPFP. 
The study duration for individual participants, inclusive of screening, is expected to be 
approximately 14 weeks. 
4.1.1. 
Screening Period  
Screening may occur up to 27 days prior to Day -1. During screening visit, participants will 
undergo screening tests as mentioned in Section 1.3. Participants who are not enrolled within 
28 days of screening may be subjected to an additional medical assessment and/or clinical 
measurements to confirm their eligibility. In such instances, at minimum, the following 
screening tests and procedures should be repeated: weight, vital signs, safety 12-lead ECG, 
clinical laboratory tests, and pregnancy test (females only). 
4.1.2. 
Treatment Periods 1 and 2  
 Each treatment period will last for 36 days.  
 Participants will be randomly assigned to 1 of the 2 treatment arms (Section 1.2). On Day 
1 of each treatment period, based on the randomization schedule, participants will receive 
either a single dose of 5 mg tirzepatide SC via MUPFP or a single dose of 5 mg 
tirzepatide SC via SDP.  
 Study site personnel will administer all study drugs. Study drug should be administered 
by a limited number of individuals for consistency. All study drugs will be administered 
in the abdomen while the participant is in a sitting or reclining position. Study drug will 
be given in the lower abdominal quadrants.  
 Participants will remain in the study site as inpatient from Day -1 to Day 4 or longer if 
required for management or monitoring of AE for safety and wellbeing of the 
participants, at the investigator’s discretion.  
 Participants will return to the study site for outpatient visits  
o daily from Day 5 to Day 8   
o weekly until Day 21 and  
o on Day 36 
Study assessments will be performed in accordance with the SoA (Section 1.3). 
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4.1.3. 
Washout Period  
There will be a washout of at least 35 days between tirzepatide doses. 
4.1.4. 
Follow-Up Period  
Day 36 (±1) of treatment Period 2 will be considered as the final follow-up visit. 
4.2. 
Scientific Rationale for Study Design  
A population of healthy participants was selected since this will permit an objective assessment 
of PK between the 2 devices. 
A healthy participant population will allow assessments of the PK, safety, and tolerability of 
tirzepatide with a reduced likelihood of physiologic variability. Also, healthy participants are 
usually devoid of other confounding factors, such as concomitant medications. 
This study will be open-label as the study primary endpoint PK measures are objective rather 
than subjective. 
To minimize any potential period-effect and to allow each participant to act as their own control, 
a randomized, 2-sequence, crossover design has been selected. A washout period of at least 35 
days between doses is considered sufficient to minimize the risk of carry-over of tirzepatide 
concentrations from the first period into the second period, based on known understanding that 
the terminal half-life of tirzepatide is about 5 days (refer to IB).  
4.3. 
Justification for Dose  
It has been shown that a single 5-mg dose of tirzepatide was well tolerated by healthy 
participants and patients with T2DM. 
The two 5-mg doses, separated by at least 35 days, planned to be administered in this study is 
expected to be tolerable in this group of healthy participants. 
4.4. 
End of Study Definition  
The end of the study is defined as the date of the last visit or last scheduled procedure shown in 
the SoA for the last participant. 
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5. 
Study Population  
Eligibility of participants for enrollment in the study will be based on the results of screening 
medical history, physical examination, vital signs, clinical laboratory tests, and ECG. The nature 
of any conditions present at the time of the physical examination and any preexisting conditions 
will be documented. 
The inclusion and exclusion criteria used to determine eligibility should be applied at screening 
only unless otherwise specified, and not continuously throughout the study. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria  
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. Participant must be 18 to 70 years of age, inclusive, at the time of screening. 
Type of participant and disease characteristics 
2. Participants who are overtly healthy as determined through medical history and physical 
examination. 
3. Have clinical laboratory test results, blood pressure, pulse rate, and an ECG reading that 
are considered to be within normal reference range for the population or study site, or 
have results outside the normal reference range that are judged to be not clinically 
significant by the investigator at the time of screening. 
Weight 
4. Body mass index within the range 18.5 to 30.0 kg/m2 (inclusive). 
Sex and contraceptive/barrier requirements 
5.  Male, or female participants  
Contraceptive use by participants should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. For the contraception 
requirements of this protocol, see Section 10.4.  
Informed consent 
6. Capable of giving signed informed consent as described in Appendix 1, which includes 
compliance with the requirements and restrictions listed in the ICF and in this protocol. 
Other inclusion criteria 
7. Have venous access sufficient to allow for blood sampling as per the protocol. 
8. Are willing to receive study drug through SC injections. 
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5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
9. Have a significant history of or current cardiovascular, respiratory, hepatic, renal, GI, 
endocrine, hematological, or neurological disorders capable of significantly altering the 
absorption, metabolism, or elimination of drugs, or of constituting a risk when taking the 
study drug, or of interfering with the interpretation of data. 
10. Have evidence of significant active neuropsychiatric disease, as determined by the 
investigator. 
11. Have a history or presence of pancreatitis, elevation in serum amylase or lipase 
(>1.5-fold the ULN), clinically significant GI disorders (eg, clinically significant 
esophageal reflux or gallbladder disease), or any GI disease or condition that impacts 
gastric emptying (e.g., history of gastric bypass surgery, pyloric stenosis) or could be 
aggravated by GLP analogs or dipeptidyl peptidase IV inhibitors. Participants with 
dyslipidemia and participants who had cholecystolithiasis and/or cholecystectomy in the 
past, with no further sequelae, may be included in the study, at the discretion of the 
investigator. History of uncomplicated acute appendicitis and appendectomy is 
acceptable as well.  
12. Have a history of atopy or clinically significant multiple or severe drug allergies or severe 
posttreatment hypersensitivity reactions. 
13. Have a personal or family history of medullary thyroid carcinoma or have multiple 
endocrine neoplasia syndrome type 2. 
14. Have a history of malignancy within 5 years prior to screening. 
15. Show evidence of human immunodeficiency virus infection and/or positive human 
immunodeficiency virus antibodies. 
16. Have evidence of hepatitis C and/or are positive for hepatitis C antibodies. 
17. Have evidence of hepatitis B and/or are positive for hepatitis B surface antigen. 
Prior/concomitant therapy 
18. Regularly use known drugs of abuse or show positive findings on drug screen. 
19. Have used or plan to use over-the-counter or prescription medication, and/or herbal 
supplements (with the exception of vitamin/mineral supplements, any hormone 
replacement therapy, and/or thyroid replacement therapy) within 14 days prior to dosing 
and for the duration of the study, including any medications that reduce GI motility, 
including, but not limited to, anticholinergics, antispasmodics, 5-hydroxytryptamine-3 
RAs, dopamine antagonists, and opiates. 
Prior/concurrent clinical study experience 
20. 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. 
21. Have received treatment with a drug that has not received regulatory approval for any 
indication within 30 days of screening. 
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22. Have previously completed or withdrawn from this study.  
23. Any exposure to tirzepatide within the prior 3 months, or history of allergies to 
tirzepatide, other GLP-1 analogs or related compounds. 
Other exclusion criteria 
24. Are study 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. 
25. Are Lilly employees or are employees of a third-party organization involved with the 
study. 
26. Smoke >10 cigarettes per day, or the equivalent, or are unable or unwilling to refrain 
from nicotine while resident in the study site. 
27. Have donated blood of more than 450 mL or more in the past 3 months, have participated 
in a clinical study that required a similar blood volume be drawn in the past 3 months, or 
have had any blood donation within the last month prior to screening. 
28. Have an average weekly alcohol intake that exceeds 21 units per week (males) or 14 units 
per week (females), OR  
are unwilling to stop alcohol consumption during study visits and time in the study site 
(number of units = [total volume of drink (mL) x ABV (%)]/1000. ABV = alcohol by 
volume). 
29. Are deemed unsuitable by the investigator for any other reason. 
5.3. 
Lifestyle Considerations  
Throughout the study, participants may undergo medical assessments and review of compliance 
with requirements before continuing in the study. 
5.3.1. 
Meals and Dietary Restrictions  
Participants will be required to fast overnight for at least 8 hours (see SoA, Section 1.3) before  
 receiving any SC dose of tirzepatide, and 
 clinical laboratory test samples are taken.  
A meal will be offered to participants around 2 hours postdose. During inpatient stays, 
participants should not consume any food other than that provided by the study site. Water can 
be consumed freely. 
5.3.2. 
Substance Use: Caffeine, Alcohol, and Tobacco  
Alcohol cannot be consumed  
 from 24 hours before each CRU admission and outpatient visit, and 
 while resident at the study site  
Alcohol intake during outpatient periods should not exceed 3 units per day for males or 2 units 
per day for females. 
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No nicotine use will be permitted while in the study site. While not resident in the study site, 
participants should not consume more than 10 cigarettes or the equivalent per day. 
Participants will be allowed to maintain the regular caffeine consumption throughout the study 
period (except during specific fasting time periods). 
5.3.3. 
Activity  
Participants will abstain from strenuous exercise for 48 hours before each dose administration 
until discharge from the study site. Participants will abstain from strenuous exercise for 24 hours 
prior to each outpatient visit.  
5.4. 
Screen Failures  
A screen failure occurs when a participant who consents to participate in the clinical study is not 
subsequently assigned to study drug or enrolled in the study. 
Screening tests such as clinical laboratory tests and vital signs or ECGs may be repeated at the 
discretion of the investigator. As this is a healthy participant-only study, individuals who do not 
meet the criteria for participation in this study (screen failure) may not be rescreened. 
5.5. 
Criteria for Temporarily Delaying Enrollment/Randomization/ 
Administration of Study Intervention of a Participant  
Not applicable. 
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6. 
Study Intervention(s) and Concomitant Therapy  
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to/used by a study participant 
according to the study protocol. 
6.1. 
Study Intervention(s) Administered  
Each participant will receive 2 doses of tirzepatide administered via 2 different devices. Each 
dose of IP will comprise 1 SC injection of 5 mg tirzepatide into the abdomen. All doses will be 
administered by clinical site personnel. 
The study involves a comparison of 
 a single dose of 5 mg tirzepatide administered SC via MUPFP (test) 
 a single dose of 5 mg tirzepatide administered SC via SDP (reference) 
During each of the 2 study periods, the injection will be administered to the lower abdominal 
quadrants, approximately 5 cm from the umbilicus. Detailed instructions for use will be provided 
by the sponsor.  
Whenever possible, study intervention administration should be carried by a limited number of 
clinical site personnel for consistency reasons. 
The table below lists the interventions used in this clinical study. 
Intervention Name 
Tirzepatide 5 mg via MUPFP 
(Test) 
Tirzepatide 5 mg via SDP 
(Reference) 
Dosage Level(s) 
5 mg tirzepatide / 0.6 mL 
5 mg tirzepatide / 0.5 mL 
Route of Administration SC injection 
SC injection 
Delivery Method 
Fixed-dose MUPFP 
SDP 
Abbreviations: MUPFP = multi-use prefilled pen; SC = subcutaneous; SDP = single-dose pen. 
Packaging and labeling 
Tirzepatide will be supplied by the sponsor or its designee in accordance with current good 
manufacturing practice. Study interventions will be labeled as appropriate for country 
requirements. 
Each syringe of tirzepatide is designed to deliver 5 mg of tirzepatide. The following products 
will be supplied by Lilly, with study-specific labels, for use in the study: 
 tirzepatide in 5-mg multi dose, pre-assembled, investigational MUPFPs (test), and 
 tirzepatide in 5-mg single dose, pre-assembled SDP (reference) 
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6.1.1. 
Medical Devices  
The investigator or designee will ensure that the instructions have been followed properly, 
maintenance of accurate records of study devices, dispensing, and collection. The used or unused 
MUPFPs and SDPs may be destroyed by a qualified vendor upon written approval by Lilly or 
designee. 
All product complaints (including malfunction, use error, and inadequate labeling) shall be 
documented and reported by the investigator throughout the clinical investigation (see 
Section 8.3) and appropriately managed by the sponsor. 
6.2. 
Preparation, Handling, Storage, and Accountability  
 The investigator or designee must confirm appropriate storage conditions have been 
maintained during transit for all study interventions received and any discrepancies 
are reported and resolved before use of the study intervention. 
 Only participants enrolled in the study may receive study intervention. Only 
authorized study personnel may supply, prepare, or administer study intervention.  
 All study interventions must be stored in a secure, environmentally controlled, and 
monitored (manual or automated) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized study personnel. 
 The investigator or authorized study personnel are responsible for study intervention 
accountability, reconciliation, and record maintenance (ie, receipt, reconciliation, and 
final disposition records). 
 Further guidance and information for the final disposition of unused study 
interventions are provided in the Pharmacy Manual.  
6.3. 
Assignment to Study Intervention  
This is an open-label study.  
To minimize potential bias, assignment to treatment groups will be determined using a 
randomization table. On Day -1 of |Period 1, participants will be assigned a unique number 
(randomization number) in ascending numerical order. The randomization number encodes the 
participant’s assignment to either starting treatment with tirzepatide MUPFP or SDP (1:1), 
according to the randomization schedule generated prior to the study by the sponsor’s or 
designee’s statistics department. Each participant will be dispensed study intervention labeled 
with his/her unique randomization number.  
6.4. 
Study Intervention Compliance  
Study intervention will be administered under medical supervision by the investigator or 
designee. The dose of study intervention and study participant identification will be confirmed 
prior to the time of dosing. The date and time of each dose administered will be recorded in the 
source documents and will be provided to the sponsor as requested.  
6.5. 
Dose Modification  
Dose modification is not permitted in this study. 
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6.6. 
Continued Access to Study Intervention after the End of the Study  
Not applicable. 
6.7. 
Treatment of Overdose  
For the purposes of this study, an overdose of tirzepatide is considered any dose higher than the 
dose assigned through randomization. 
There is no specific antidote for tirzepatide. In the event of an overdose, the subject should 
receive appropriate supportive care and any AEs should be documented. 
Refer to the IB for further details and recommendations. 
In the event of an overdose, the investigator should 
● contact the medical monitor immediately 
● monitor the participant closely for any AE/SAE and laboratory abnormalities as 
medically appropriate until, eg, tirzepatide no longer has a clinical effect or can 
no longer be detected systemically, and 
● document the quantity of the excess dose as well as the duration of the overdose 
in the CRF. 
6.8. 
Prior and Concomitant Therapy  
Any medication or vaccine, including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with 
● reason for use 
● dates of administration including start and end dates, and 
● dosage information including dose and frequency for concomitant therapy of 
special interest. 
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
Participants must abstain from taking over-the-counter or prescription medication, and/or herbal 
supplements (with the exception of vitamin/mineral supplements, any hormone replacement 
therapy, and/or thyroid replacement therapy) within 14 days prior to dosing and for the duration 
of the study. 
If acetaminophen or paracetamol treatment is needed for pain management, the maximal allowed 
dose will be 3 g/day from all acetaminophen- or paracetamol-containing medicinal products. 
Other concomitant medication may be considered on a case-by-case basis by the investigator in 
consultation with the medical monitor if required.  
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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal  
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1 
(Section 10.1). 
7.1. 
Discontinuation of Study Intervention  
When necessary, a participant may be permanently discontinued from study intervention. If so, 
the participant will discontinue the study intervention (treatment), thereby discontinuing the 
treatment period, and will remain in the study to complete procedures for an early 
discontinuation visit and posttreatment follow-up, if applicable, as shown in the SoA.  
A participant should be permanently discontinued from study intervention if 
● the participant becomes pregnant during the study, and 
● in the opinion of the investigator, the participant should permanently discontinue the 
study intervention for safety reasons. 
7.1.1. 
Hypersensitivity Reaction Criteria for Discontinuation  
If the investigator determines that a systemic hypersensitivity reaction has occurred related to 
study intervention administration, the participant may be permanently discontinued from the 
study intervention, and the sponsor’s designated medical monitor should be notified. If the 
investigator is uncertain about whether a systemic hypersensitivity reaction has occurred and 
whether discontinuation of study intervention is warranted, the investigator may consult the 
sponsor. 
7.1.2. 
Hepatic Criteria for Discontinuation  
Interrupting study drug based on liver test elevations in participants with normal or 
near-normal baseline liver test results 
In study participants with normal or near-normal baseline liver test results (ALT, AST, ALP 
<1.5x ULN), the study drug should be interrupted and close hepatic monitoring is initiated (see 
Section 8.2.8.1) if 1 or more of these conditions occur: 
Elevation 
Exception 
ALT or AST >5x ULN 
 
ALT or AST >3x ULN and either TBL >2x ULN or INR >1.5  
For participants with Gilbert’s syndrome:  
If baseline direct bilirubin is >0.5 mg/dL, 
then doubling of direct bilirubin should be 
used for drug interruption decisions rather 
than TBL >2x ULN. 
ALT or AST >3x ULN with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%) 
 
ALP >3x ULN, when the source of increased ALP is the liver 
 
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ALP >2.5x ULN and TBL >2x ULN  
For participants with Gilbert’s syndrome:  
If baseline direct bilirubin is >0.5 mg/dL, 
then doubling of direct bilirubin should be 
used for drug interruption decisions rather 
than TBL >2x ULN. 
ALP >2.5x ULN with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%) 
 
Source: FDA Guidance for Industry: Drug-induced liver injury: premarketing clinical evaluation, July 2009, 
and other consensus guidelines, with minor modifications 
 
Interrupting study drug based on elevated liver tests in participants with abnormal 
baseline liver tests 
In study participants with abnormal baseline liver tests (ALT, AST, ALP ≥1.5x ULN), the study 
drug should be interrupted if 1 or more of these conditions occur: 
Elevation 
Exception 
ALT or AST >3x baseline 
 
ALT or AST >2x baseline and either TBL >2x ULN or INR 
>1.5  
For participants with Gilbert’s syndrome:  
If baseline direct bilirubin is >0.5 mg/dL, 
then doubling of direct bilirubin should be 
used for drug interruption decisions rather 
than TBL >2x ULN. 
ALT or AST >2x baseline with the appearance of fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, 
fever, rash, and/or eosinophilia (>5%) 
 
ALP >2.5x baseline, when the source of increased ALP is the 
liver 
 
ALP >2x baseline and TBL >2x ULN  
For participants with Gilbert’s syndrome: 
If baseline direct bilirubin is >0.5 mg/dL, 
then doubling of direct bilirubin should be 
used for drug interruption decisions rather 
than TBL >2x ULN. 
ALP >2x baseline with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%) 
 
Source: FDA Guidance for Industry: Drug-induced liver injury: premarketing clinical evaluation, July 2009, 
and other consensus guidelines, with minor modifications 
 
Resuming study drug after elevated liver test results 
Resumption of the study drug can be considered only in consultation with the Lilly-designated 
medical monitor and only if the liver test results return to baseline and if a self-limited nondrug 
etiology is identified. Otherwise, the study drug should be discontinued. 
Participants who discontinue from study intervention due to the abnormal liver test results will 
undergo monitoring as described in Appendix 7 (Section 10.7). 
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7.2. 
Participant Discontinuation/Withdrawal from the Study  
Participants discontinuing from the study prematurely for any reason must complete AE and 
follow-up procedures per Section 1.3 of this protocol. 
Discontinuation is expected to be uncommon. 
A participant may withdraw from the study: 
● at any time at the participant’s own request for any reason or without providing 
any reason 
● at the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons 
● if enrolled in any other clinical study involving an IP, or enrolled in any other 
type of medical research judged not to be scientifically or medically compatible 
with this study 
● if the participant, for any reason, requires treatment with a therapeutic agent that 
is prohibited by the protocol and has been demonstrated to be effective for 
treatment of the study indication. In this case, discontinuation from the study 
occurs prior to introduction of the new agent. 
At the time of discontinuing from the study, if possible, the participant will complete procedures 
for an early discontinuation visit and posttreatment follow-up, if applicable, as shown in the 
SoA. If the participant has not already discontinued the study intervention, the participant will be 
permanently discontinued from the study intervention at the time of the decision to discontinue 
the study. 
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. If a participant 
withdraws from the study, the participant may request destruction of any samples taken and not 
tested, and the investigator must document this in the site study records. 
7.3. 
Lost to Follow-Up  
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. Site personnel or designee are 
expected to make diligent attempts to contact participants who fail to return for a scheduled visit 
or were otherwise unable to be followed up by the site.  
Site personnel, or an independent third party, will attempt to collect the vital status of the 
participant within legal and ethical boundaries for all participants randomly assigned, including 
those who did not get IP. Public sources may be searched for vital status information. If vital 
status is determined to be deceased, this will be documented, and the participant will not be 
considered lost to follow-up. Sponsor personnel will not be involved in any attempts to collect 
vital status information. 
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8. 
Study Assessments and Procedures  
● Study procedures and their timing are summarized in the SoA.  
● Immediate safety concerns should be discussed with the sponsor immediately 
upon occurrence or awareness to determine if the participant should continue or 
discontinue study intervention. 
● Adherence to the study design requirements, including those specified in the SoA, 
is essential and required for study conduct. 
● All screening evaluations must be completed and reviewed to confirm that 
potential participants meet all eligibility criteria. The investigator will maintain a 
screening log to record details of all participants screened and to confirm 
eligibility or record reasons for screening failure, as applicable.  
8.1. 
Efficacy Assessments  
Not applicable. 
8.2. 
Safety Assessments  
Planned time points for all safety assessments are provided in the SoA.  
Unless otherwise stated in the following subsections, 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. 
8.2.1. 
Physical Examinations  
● A complete physical examination will be performed at screening and will include, 
at a minimum, assessments of the cardiovascular, respiratory, GI, dermatological, 
and neurological systems. Height and weight will also be measured and recorded 
at screening. 
● 
 Subsequent brief physical examination will include medical review and targeted, 
symptom-driven examination, as appropriate. Additional assessments may be 
performed at investigator’s clinical discretion. 
8.2.2. 
Vital Signs  
● For each participant, vital sign measurements should be conducted according to 
the SoA (Section 1.3). 
 Blood pressure and pulse rate should be measured after at least 3 minutes supine. 
 Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of 
dizziness or posture-induced symptoms. Additional vital signs may be measured during 
each study period at investigator’s discretion.  
8.2.3. 
Electrocardiograms  
● For each participant, a single 12-lead ECG will be obtained as outlined in the SoA 
(see Section 1.3) and stored at site. 
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 Participants must be supine for at least 5 minutes before ECG collection, and remain 
supine but awake during procedure. 
 ECGs may be obtained at additional times, when deemed clinically necessary. All ECGs 
recorded should be stored at the investigational site. 
● Any clinically significant findings from ECGs that result in a diagnosis and that 
occur after the subject receives the first dose of the IP should be reported as an 
AE in the eCRF.  
 ECGs 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/corrected QT interval from baseline) after enrollment, the investigator will determine 
if the participant can continue in the study. The investigator, or qualified designee, is 
responsible for determining if any change in participant management is needed, and must 
document his/her review of the ECG printed at the time of collection. Any new clinically 
relevant finding should be reported as an AE. 
8.2.4. 
Clinical Safety Laboratory Tests  
● See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be 
performed and the SoA for the timing and frequency. 
● The investigator must review the laboratory results, document this review, and 
report any clinically relevant changes occurring during the study as an AE. The 
laboratory results must be retained with source documents unless a Source 
Document Agreement or comparable document cites an electronic location that 
accommodates the expected retention duration. Clinically significant abnormal 
laboratory findings are those that are not associated with the underlying disease, 
unless judged by the investigator to be more severe than expected for the 
participant’s condition. 
● All laboratory tests with values considered clinically significantly abnormal 
during participation in the study should be repeated until the values return to 
normal or baseline or are no longer considered clinically significant by the 
investigator or medical monitor. 
○ If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the 
sponsor notified. 
○ All protocol-required laboratory assessments, as defined in Appendix 2 
(Section 10.2), must be conducted in accordance with the SoA, standard 
collection requirements, and laboratory manual. 
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● If laboratory values from nonprotocol-specified laboratory assessments performed 
at an investigator-designated local laboratory require a change in participant 
management or are considered clinically significant by the investigator (eg, SAE 
or AE or dose modification), then report the information as an AE.  
Amylase and Lipase Measurements  
Serum amylase and lipase measurements will be collected as part of the clinical laboratory 
testing and as specified in the SoA (Section 1.3). Additional measurements may be performed at 
the investigator’s discretion. Further diagnostic assessments will be recommended as per the 
algorithm (refer to Appendix 8) for the monitoring of pancreatic events whenever lipase and/or 
amylase is confirmed to be ≥3x ULN at any visit postdose, even if the subject is asymptomatic. 
8.2.5. 
Glucose Monitoring  
For safety purposes, plasma glucose measurements will be performed using a bedside glucose 
monitor as specified in the SoA (Section 1.3). Additional blood glucose monitor measurements 
may also be taken during the study as deemed necessary by the investigator where clinically 
indicated. 
8.2.5.1. 
Hypoglycemia Reporting  
Participants will be trained to recognize the signs, symptoms, and management of hypoglycemia, 
and to inform the investigator as soon as possible about these events. Participants may, at 
investigator’s discretion, be given a glucometer to assist in the evaluation of these symptoms. 
All hypoglycemic events will be captured in the eCRF as specified below: 
 All hypoglycemic episodes will be recorded on a specific eCRF and should not be 
recorded as AEs unless the event meets serious criteria.  
 If a hypoglycemic event meets severe criteria (see definition below), it should be 
recorded as serious on the AE and SAE eCRFs, and reported to Lilly as an SAE. 
Investigators should use the following definitions and criteria when diagnosing and categorizing 
an episode considered to be related to hypoglycemia (the blood glucose values in this section 
refer to values determined by a laboratory or International Federation of Clinical Chemistry and 
Laboratory Medicine blood-equivalent glucose meters and strips) in accordance with the 2020 
American Diabetes Association position statement on glycemic targets (ADA 2020) as below: 
Level 1 hypoglycemia:  
Glucose <70 mg/dL (3.9 mmol/L) and ≥54 mg/dL (3.0 mmol/L): Level 1 hypoglycemia can 
alert a person to take action such as treatment with fast-acting carbohydrates. Providers should 
continue to counsel participants to treat hypoglycemia at this glucose alert value. 
Level 2 hypoglycemia:  
Glucose <54 mg/dL (3.0 mmol/L): This is also referred to as documented or blood glucose 
confirmed hypoglycemia with glucose <54 mg/dL (3.0 mmol/L). This glucose threshold is 
clinically relevant regardless of the presence or absence of symptoms of hypoglycemia.  
 
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Level 3 hypoglycemia:  
Severe hypoglycemia (in adults): A severe event characterized by altered mental and/or physical 
status requiring assistance for treatment of hypoglycemia. For example, participants had altered 
mental status, and could not assist in their own care, or were semiconscious or unconscious, or 
experienced coma with or without seizures, and the assistance of another person was needed to 
actively administer carbohydrate, glucagon, or other resuscitative actions. Glucose measurements 
may not be available during such an event, but neurological recovery attributable to the 
restoration of glucose concentration to normal is considered sufficient evidence that the event was 
induced by a low glucose concentration. 
 The determination of a hypoglycemic event as an episode of severe hypoglycemia, as 
defined above, is made by the investigator based on the medical need of the 
participant to have required assistance and is not predicated on the report of a 
participant simply having received assistance. 
 If a hypoglycemic event meets the criteria of severe hypoglycemia, the investigator 
must record the event as serious on the AE CRF and report it to Lilly as an SAE. 
Nocturnal hypoglycemia: 
Nocturnal hypoglycemia is a hypoglycemia event (including severe hypoglycemia) that occurs at 
night and presumably during sleep. 
8.2.6. 
Injection-Site Reactions  
Symptoms and signs of a local ISR may include erythema, induration, pain, pruritus, and edema. 
If an ISR is reported by a participant or assessed as clinically significant by site personnel, this 
shall be recorded as an AE and the ISR CRF will be used to capture additional information about 
this reaction, such as injection-site pain, degree and area of erythema, induration, pruritus, and 
edema. 
8.2.7. 
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 nonimmediate) in 
participants who experience moderate-to-severe injection reactions as assessed by the 
investigator, unscheduled blood samples will be collected for PK 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.  
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. 
8.2.8. 
Safety Monitoring  
The Lilly CP or CRP/scientist will monitor safety data throughout the course of the study. 
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Lilly will review SAEs within time frames mandated by company procedures. The Lilly CP or 
CRP will periodically review the following data: 
 trends in safety data 
 laboratory analytes including glucose, amylase, and lipase  
 serious and nonserious AEs, including AEs of interest. 
Further diagnostic assessments will be recommended whenever lipase and/or amylase are 
confirmed to be ≥3x ULN at any visit postdose even if the subject is asymptomatic.  
When appropriate, the Lilly CP or CRP will consult with the functionally independent Global 
Patient Safety therapeutic area physician or clinical research scientist. 
8.2.8.1. 
Hepatic Safety  
Close hepatic monitoring 
Laboratory tests (Appendix 7 [Section 10.7]), including ALT, AST, ALP, TBL, direct bilirubin, 
gamma-glutamyl transferase, and creatine kinase, should be repeated within 48 to 72 hours to 
confirm the abnormality and to determine if it is increasing or decreasing, if 1 or more of these 
conditions occur: 
If a participant with baseline results 
of...  
develops the following elevations: 
ALT or AST <1.5x ULN 
ALT or AST ≥3x ULN 
ALP <1.5x ULN 
ALP ≥2x ULN 
TBL <1.5x ULN 
TBL ≥2x ULN (except for patients with Gilbert’s 
syndrome) 
ALT or AST ≥1.5x ULN 
ALT or AST ≥2x baseline 
ALP ≥1.5x ULN 
ALP ≥2x baseline 
TBL ≥1.5x ULN 
TBL ≥1.5x baseline (except for patients with Gilbert’s 
syndrome) 
 
If the abnormality persists or worsens, clinical and laboratory monitoring, and evaluation for 
possible causes of abnormal liver test results 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 (eg, 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 participant’s clinical condition and hepatic biochemical tests. 
Subsequently, the frequency of monitoring may be lowered to once every 1 to 2 weeks, if the 
participant’s clinical condition and laboratory results stabilize. Monitoring of ALT, AST, ALP, 
and TBL should continue until levels normalize or return to approximate baseline levels. 
 
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Comprehensive hepatic evaluation 
A comprehensive evaluation should be performed to search for possible causes of liver injury if 
1 or more of these conditions occur: 
If a participant with baseline 
results of...  
develops the following elevations: 
ALT or AST <1.5x ULN 
ALT or AST ≥3x ULN with hepatic signs/symptomsa, or  
ALT or AST ≥5x ULN 
ALP <1.5x ULN 
ALP ≥3x ULN 
TBL <1.5x ULN 
TBL ≥2x ULN (except for patients with Gilbert’s syndrome) 
ALT or AST ≥1.5x ULN 
ALT or AST ≥2x baseline with hepatic signs/symptomsa, or 
ALT or AST ≥3x baseline 
ALP ≥1.5x ULN 
ALP ≥2x baseline 
TBL ≥1.5x ULN 
TBL ≥2x baseline (except for patients with Gilbert’s syndrome)  
a Hepatic signs/symptoms are severe fatigue, nausea, vomiting, right upper-quadrant abdominal pain, fever, rash, 
and/or eosinophilia >5%. 
 
At a minimum, this evaluation should include physical examination and a thorough medical 
history, as outlined above, as well as tests for prothrombin time-INR; tests for viral hepatitis A, 
B, C, or E; tests for autoimmune hepatitis; and an abdominal imaging study (eg, ultrasound or 
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 ethyl glucuronide, and 
blood phosphatidylethanol. Based on the circumstances and the investigator’s assessment of the 
participant’s clinical condition, the investigator should consider referring the participant for a 
hepatologist or gastroenterologist consultation, magnetic resonance cholangiopancreatography, 
endoscopic retrograde cholangiopancreatography, cardiac echocardiogram, or a liver biopsy.  
Additional hepatic data collection (hepatic safety CRF) in study participants who have 
abnormal liver test results during the study  
Additional hepatic safety data collection in hepatic safety CRFs should be performed in study 
participants who meet 1 or more of the following 5 conditions: 
1. Elevation of serum ALT to ≥5x ULN on 2 or more consecutive blood tests (if baseline 
ALT <1.5x ULN) 
➢ In participants with baseline ALT ≥1.5x ULN, the threshold is ALT ≥3x baseline on 2 
or more consecutive tests 
2. Elevation of TBL to ≥2x ULN (if baseline TBL <1.5x ULN) (except for cases of known 
Gilbert’s syndrome) 
➢ In participants with baseline TBL ≥1.5x ULN, the threshold should be TBL ≥2x 
baseline 
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3. Elevation of serum ALP to ≥2x ULN on 2 or more consecutive blood tests (if baseline 
ALP <1.5x ULN) 
➢ In participants 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 
5. Discontinuation of study drug due to a hepatic event  
Note: the interval between the 2 consecutive blood tests should be at least 2 days. 
8.2.9. 
Pregnancy Testing  
Pregnancy testing will be performed for all female participants at the time points detailed in the 
SoA (Section 1.3). Serum pregnancy testing will be used at screening. Urine pregnancy testing 
will be used at all other time points, as per SoA. See Section 8.3.2 for more detail. 
8.3. 
Adverse Events, Serious Adverse Events, and Product Complaints  
The definitions of the following events can be found in Appendix 3: 
 AEs 
 SAEs 
 product complaints 
These events will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant’s legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet these definitions and remain responsible for following up events that 
are serious, considered related to the study intervention or study procedures, or that caused the 
participant to discontinue the study. 
Care will be taken not to introduce bias when detecting events. Open-ended and nonleading 
verbal questioning of the participant is the preferred method to inquire about event occurrences. 
After the initial report, the investigator is required to proactively follow up each participant at 
subsequent visits/contacts. All SAEs will be followed up until resolution, stabilization, the event 
is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). For 
product complaints, the investigator is responsible for ensuring that follow-up includes any 
supplemental investigations as indicated to elucidate the nature and/or causality. Further 
information on follow-up procedures is provided in Section 10.3.  
8.3.1. 
Timing and Mechanism for Collecting Events  
This table describes the timing, deadlines, and mechanism for collecting events. 
 
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Event 
Collection 
Start 
Collection 
Stop 
Timing for Reporting 
to Sponsor or 
Designee 
Mechanism for 
Reporting 
Back-up 
Method of 
Reporting 
Adverse Event 
AE 
Signing of 
the ICF 
The follow-
up visit OR 
participation 
in study has 
ended 
As soon as possible 
upon site awareness 
AE CRF 
N/A 
Serious Adverse Event 
SAE and SAE 
updates – prior 
to start of study 
intervention and 
deemed 
reasonably 
possibly related 
to study 
procedures 
Signing of 
the ICF 
Start of 
intervention 
Within 24 hours of 
awareness 
SAE paper form 
SAE paper 
form 
SAE and SAE 
updates – after 
start of study 
intervention 
Start of 
intervention 
Participation 
in study has 
ended 
Within 24 hours of 
awareness 
SAE paper form 
SAE paper 
form 
SAE – after 
participant’s 
study 
participation has 
ended and the 
investigator 
becomes aware 
After 
participant’s 
study 
participation 
has ended 
N/A 
Promptly 
SAE paper form 
N/A 
Pregnancy 
Pregnancy in 
female 
participants and 
female partners 
of male 
participants 
After the 
start of study 
intervention 
90 days plus 
5 half-lives 
after the last 
dose  
Within 24 hours (see 
Section 8.3.2) 
Pregnancy paper 
form 
Pregnancy 
paper form 
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Event 
Collection 
Start 
Collection 
Stop 
Timing for Reporting 
to Sponsor or 
Designee 
Mechanism for 
Reporting 
Back-up 
Method of 
Reporting 
Product Complaints (PCs) 
PC associated 
with an SAE or 
might have led 
to an SAE 
Start of study 
intervention 
End of study 
intervention 
Within 24 hours of 
awareness 
Product Complaint 
form 
N/A 
PC not 
associated with 
an SAE 
Start of study 
intervention 
End of study 
intervention 
Within 1 business day 
of awareness 
Product Complaint 
form 
N/A 
Updated PC 
information 
— 
— 
As soon as possible 
upon site awareness 
Originally 
completed Product 
Complaint form 
with all changes 
signed and dated by 
the investigator 
N/A 
PC (if 
investigator 
becomes aware) 
Participation 
in study has 
ended 
N/A 
Promptly 
Product Complaint 
form 
 
Abbreviation: N/A = not applicable. 
 
 
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8.3.2. 
Pregnancy  
Collection of pregnancy information 
Male participants with partners who become pregnant 
● The investigator will attempt to collect pregnancy information on any male 
participant’s female partner who becomes pregnant while the male participant is 
in this study. This applies only to male participants who receive tirzepatide. 
● After learning of a pregnancy in the female partner of a study participant, the 
investigator will 
o obtain a consent to release information from the pregnant female partner 
directly, and 
o within 24 hours after obtaining this consent will record pregnancy information 
on the appropriate form and submit it to the sponsor.  
The female partner will also be followed up to determine the outcome of the 
pregnancy. Information on the status of the mother and child will be forwarded to 
the sponsor. Generally, the follow-up will be no longer than 6 to 8 weeks 
following the estimated delivery date. Any termination of the pregnancy will be 
reported regardless of gestational age, fetal status (presence or absence of 
anomalies), or indication for the procedure. 
Female participants who become pregnant 
● The investigator will collect pregnancy information on any female participant 
who becomes pregnant while participating in this study. The initial information 
will be recorded on the appropriate form and submitted to the sponsor within 
24 hours of learning of a participant’s pregnancy.  
● The participant will be followed up to determine the outcome of the pregnancy. 
The investigator will collect follow-up information on the participant and the 
neonate and the information will be forwarded to the sponsor. Generally, follow-
up will not be required for longer than 6 to 8 weeks beyond the estimated delivery 
date. Any termination of pregnancy will be reported, regardless of gestational age, 
fetal status (presence or absence of anomalies), or indication for the procedure. 
● While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE.  
● A spontaneous abortion (occurring at <20 weeks gestational age) or still birth 
(occurring at ≥20 weeks gestational age) is always considered to be an SAE and 
will be reported as such.  
● Any poststudy pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in 
protocol Section 8.3.1. While the investigator is not obligated to actively seek this 
information in former study participants, he or she may learn of an SAE through 
spontaneous reporting. 
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● Any female participant who becomes pregnant while participating in the study 
will discontinue study intervention. If the participant is discontinued from the 
study, follow the standard discontinuation process, and continue directly to the 
follow-up phase. The follow-up on the pregnancy outcome should continue 
independent of intervention or study discontinuation.  
Prior to continuation of study intervention following pregnancy, the following must occur: 
● The sponsor and the relevant IRB/IEC give written approval. 
● The participant gives signed informed consent. 
● The investigator agrees to monitor the outcome of the pregnancy and the status of the 
participant and the participant’s offspring. 
8.3.3. Adverse Events of Special Interest  
AEs of special interest for this program include: 
 pancreatitis 
 major adverse cardiovascular events 
 deaths 
 hypoglycemia (Level 2 and 3) 
 thyroid malignancies and C-cell hyperplasia 
 supraventricular arrhythmias and cardiac conductive disorders 
 hypersensitivity events 
 severe ISRs, and 
 severe GI AEs 
8.4. 
Pharmacokinetics  
● Venous blood samples of approximately 3 mL will be collected for measurement 
of plasma concentrations of tirzepatide as specified in the SoA (Section 1.3).  
● A maximum of 3 unscheduled samples may be collected at additional time points 
during the study if warranted and agreed upon between the investigator and the 
sponsor. The timing of sampling may be altered during the course of the study 
based on newly available data to ensure appropriate monitoring.  
● Instructions for the collection and handling of biological samples will be provided 
by the sponsor. The actual date and time (24-hour clock time) of each sample will 
be recorded. 
Failure or being late (outside stipulated time allowances) to obtain samples due to legitimate 
clinical issues (eg, equipment technical problems, venous access difficulty, or subject defaulting 
or turning up late on an agreed scheduled procedure) will not be considered as protocol 
deviations but the CRU will have to notify the sponsor in writing via a file note. 
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8.4.1. 
Bioanalysis  
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor. 
Concentrations of tirzepatide will be assayed using a validated liquid chromatography tandem 
mass spectrometry method.  
Bioanalytical samples collected to measure IP concentrations will be retained for a maximum of 
1 year following last subject visit for the study. During this time, samples remaining after the 
bioanalyses may be used for exploratory analyses, such as metabolism work, protein binding, or 
bioanalytical method cross-validation.  
8.5. 
Pharmacodynamics  
Pharmacodynamic parameters are not evaluated in this study. 
8.6. 
Genetics  
A blood sample for DNA isolation will be collected from participants for pharmacogenetic 
analysis as specified in the SoA (Section 1.3), where local regulations allow.  
Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future. Samples will be used to investigate variable exposure or response to 
tirzepatide and to investigate genetic variants thought to play a role in T2DM. Assessment of 
variable response may include evaluation of AEs or differences in efficacy.  
All samples will be coded with the subject number. These samples and any data generated can be 
linked back to the subject only by the investigative site personnel.  
Samples will be retained for a maximum of 15 years after the last subject visit, or for a shorter 
period if local regulations and/or ethical review boards 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.  
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.  
See Appendix 5 (Section 10.5) for information regarding genetic research and for details about 
sample retention and custody.  
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8.7. 
Biomarkers  
Biomarkers are not evaluated in this study. 
8.8. 
Health Economics OR Medical Resource Utilization and Health 
Economics  
Health economics or medical resource utilization and health economics parameters are not 
evaluated in this study. 
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9. 
Statistical Considerations  
The SAP will be finalized prior to first participant first visit, and it will include a more technical 
and detailed description of the statistical analyses described in this section. This section is a 
summary of the planned statistical analyses of the most important endpoints, including primary 
and key secondary endpoints. 
9.1. 
Statistical Hypotheses  
The primary objective of this study is to evaluate bioequivalence of the MUPFP (test) and the 
SDP (reference) with a 5-mg dose, as assessed using tirzepatide PK parameters Cmax, AUC(0-
tlast), and AUC(0-∞) in healthy participants. 
9.1.1. 
Multiplicity Adjustment  
Not applicable. 
9.2. 
Analyses Sets  
For the purposes of analysis, the following analysis sets are defined: 
Participant Analysis Set / 
Population 
Description 
Enrolled 
All randomly assigned participants. 
Safety analysis set 
All participants who are exposed to study intervention. Participants will be 
analyzed according to the intervention they actually received. 
PK analysis set 
All randomly assigned participants who received at least 1 study intervention 
and have evaluable PK data.  
9.3. 
Statistical Analyses  
9.3.1. General Considerations  
Statistical analysis of this study will be the responsibility of Eli Lilly and Company or its 
designee. 
PK analyses will be conducted for the PK analysis set according to the actual tirzepatide 
formulation received. Safety analyses will be conducted for the safety analysis set.  
Additional exploratory analyses of the data will be conducted as deemed appropriate. Study 
results may be pooled with the results of other studies for safety and population PK analysis 
purposes. 
Handling of missing, unused, and spurious data are addressed prospectively in the overall 
statistical methods described in the protocol and in the SAP, where appropriate. Adjustments to 
the planned analyses are described in the final clinical study report. 
A detailed description of subject disposition will be provided at the end of the study. All 
participants who discontinue from the study will be identified, and the extent of their 
participation in the study will be reported. If known, a reason for their discontinuation will be 
given. 
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The subject’s age, sex, weight, height, body mass index, or other demographic characteristics 
will be recorded and may be used in the PK and safety analyses as quantitative or classification 
variables. 
9.3.2. 
Primary Endpoints Analysis  
PK parameter estimates for tirzepatide will be calculated using standard noncompartmental 
methods of analysis. 
The primary PK parameters for analysis will be Cmax, AUC(0-tlast), and AUC(0-∞).  
Other noncompartmental parameters, such as 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. 
9.3.2.1. 
Pharmacokinetic Statistical Inference  
Two 1-sided equivalence tests will be applied to the ratios of each of Cmax and AUC using 
MUPFP as the test and SDP as the reference. Test limits of the ratios to establish bioequivalence 
are 0.8 and 1.25.  
PK parameters will be evaluated to estimate the relative bioavailability. Log-transformed Cmax, 
AUC(0-tlast), and AUC(0-∞) will be evaluated in a linear mixed-effects model with device, 
sequence, period as fixed effects, and subject within sequence as random effect. The treatment 
differences will be back transformed to present the ratios of geometric means and the 
corresponding 90% CIs. Other parameters may be analyzed in this way as needed. 
Planned PK parameters will also be summarized with descriptive statistics. 
9.3.3. 
Secondary Endpoints Analysis  
The tmax will be analyzed using Wilcoxon ranked sum test. Estimates of the median difference 
and 90% CIs will be calculated.  
Additional PK analyses may be conducted if deemed appropriate. 
All IP, study device, and protocol procedure AEs, and study device deficiencies/complaints will 
be listed, and if the frequency of events allows, data will be summarized using descriptive 
methodology. 
The incidence of symptoms for each treatment will be presented by severity. 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 Dictionary for Regulatory Authorities. 
The number of IP-related SAEs will be reported. 
If available, any incidence of erythema, induration, pain, pruritus, edema, bleeding, and bruising 
from injection site assessment will be listed. 
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9.3.4. 
Safety Analyses  
Safety parameters that will be assessed include AEs, safety laboratory parameters, and vital 
signs. The parameters will be listed and summarized using standard descriptive statistics, where 
appropriate.  
Physical examinations and ECGs will be performed for safety monitoring purposes and will not 
be presented.  
If warranted, additional analysis will be performed upon review of the data. 
9.3.5. 
Other Analyses  
If needed, details will be provided in the SAP. 
9.4. 
Interim Analyses  
No interim analyses are planned for this study. If an unplanned interim analysis is deemed 
necessary for reasons other than a safety concern, the protocol must be amended.  
Unblinding details are specified in the unblinding plan section of the SAP. 
9.5. 
Sample Size Determination  
Approximately 65 participants may be enrolled so that approximately 54 evaluable participants 
complete the study. A sample size of 54 participants will provide at least 95% power that the 
90% confidence interval of the geometric mean ratio of Cmax and AUC between the 2 devices 
will fall within the equivalence range of 0.8 to 1.25. This assumes a nominal expected mean ratio 
of 1.05 (test vs reference), a within-subject coefficient of variation of 24%.  
 
 
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10. 
Supporting Documentation and Operational Considerations  
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations  
10.1.1. 
Regulatory and Ethical Considerations  
● This study will be conducted in accordance with the protocol and with the 
following: 
○ Consensus ethical principles derived from international guidelines including 
the Declaration of Helsinki and Council for International Organizations of 
Medical Sciences International Ethical Guidelines 
○ Applicable ICH GCP Guidelines 
○ Applicable laws and regulations 
● The protocol, protocol amendments, ICF, IB, and other relevant documents (eg, 
advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated. 
● Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 
● Protocols and any substantial amendments to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an 
immediate hazard to study participants. 
● The investigator will be responsible for the following: 
○ Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/IEC 
○ Notifying the IRB/IEC of SAEs or other significant safety findings as required 
by IRB/IEC procedures 
○ Providing oversight of study conduct for participants under their responsibility 
and adherence to requirements of 21 Code of Federal Regulations, ICH 
guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), and all other applicable local regulations 
○ Reporting to the sponsor or designee significant issues related to participant 
safety, participant rights, or data integrity 
● Investigator sites are compensated for participation in the study as detailed in the 
clinical trial agreement. 
 
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10.1.2. 
Financial Disclosure  
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
10.1.3. 
Informed Consent Process  
● The investigator or the investigator’s representative will explain the nature of the 
study, including the risks and benefits, to the potential participant or the potential 
participant’s legally authorized representative and answer all questions regarding 
the study. 
● Potential participants must be informed that their participation is voluntary. 
Participants or their legally authorized representatives will be required to sign a 
statement of informed consent that meets the requirements of 21 Code of Federal 
Regulations 50, local regulations, ICH guidelines, privacy, and data protection 
requirements, where applicable, and the IRB/IEC or study site. 
● The medical record must include a statement that written informed consent was 
obtained before the participant was entered in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF. 
● Participants must be reconsented to the most current version of the ICF(s) during 
their participation in the study. 
● A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative and is kept on file. 
10.1.4. 
Data Protection  
● Participants will be assigned a unique identifier by the sponsor. Any participant 
records, datasets, or tissue samples that are transferred to the sponsor will contain 
the identifier only; participant names or any information which would make the 
participant identifiable will not be transferred. 
● The participant must be informed that the participant’s personal study-related data 
will be used by the sponsor in accordance with local data protection law. The 
level of disclosure must also be explained to the participant who will be required 
to give consent for their data to be used as described in the informed consent. 
● The participant must be informed that their medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by 
the sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
● The sponsor has processes in place to ensure data protection, information security, 
and data integrity. These processes include appropriate contingency plan(s) for 
appropriate and timely response in the event of a data security breach. 
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10.1.5. 
Dissemination of Clinical Study Data  
Communication of suspended or terminated dosing 
If a decision is taken to suspend or terminate dosing in the trial due to safety findings, this 
decision will be communicated by Lilly to all investigators (eg, through phone and/or email) as 
soon as possible. It will be a requirement that investigators respond upon receipt to confirm that 
they understand the communication and have taken the appropriate action prior to further dosing 
any participants with study intervention. Any investigator not responding will be followed up by 
Lilly personnel prior to any further planned dosing. If a dose is planned imminently, Lilly 
personnel will immediately, and continually, use all efforts to reach investigators until contact is 
made and instructions verified. 
Reports 
The sponsor will disclose a summary of study information, including tabular study results, on 
publicly available websites where required by local law or regulation. 
The summary of results will be posted within the time frame specified by local law or regulation. 
If the study remains ongoing in some countries and a statistical analysis of an incomplete dataset 
would result in analyses lacking scientific rigor (eg, underpowered) or compromise the integrity 
of the overall analyses (eg, trial not yet unblinded), the summary of results will be submitted 
within 1 year after the end of the study globally or as soon as available, whichever is earlier. 
Data 
The sponsor does not proactively share data from Phase 1 clinical trials. Requests for access to 
Phase 1 clinical trial data are evaluated on a case-by-case basis taking into consideration the 
ability to anonymize the data and the nature of the data collected. 
10.1.6. 
Data Quality Assurance  
● All participant data relating to the study will be recorded on printed or eCRFs 
unless transmitted to the sponsor or designee electronically (eg, laboratory data). 
The investigator is responsible for verifying that data entries are accurate and 
correct by physically or electronically signing the CRF. 
● The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 
● The investigator must review and confirm that data entries are accurate and 
complete throughout the duration of the study, by physically or electronically 
signing the CRF, as instructed by the sponsor. All completed CRFs must be 
signed prior to archival. 
● The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source documents. 
● The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 
● The sponsor assumes accountability for actions delegated to other individuals (eg, 
contract research organizations). 
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● The sponsor or designee will perform monitoring to confirm that data transcribed 
into the CRF by authorized site personnel are accurate, complete, and verifiable 
from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 
● Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the investigator for the time period outlined in the 
Clinical Trial Agreement unless local regulations or institutional policies require a 
longer retention period. No records may be destroyed during the retention period 
without the written approval of the sponsor. No records may be transferred to 
another location or party without written notification to the sponsor. 
● In addition, the sponsor or its representatives will periodically check a sample of 
the participant data recorded against source documents at the study site. The study 
may be audited by the sponsor or its representatives, and/or regulatory agencies at 
any time. Investigators will be given notice before an audit occurs. 
Data capture system 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor.  
An electronic data capture system will be used in this study for the collection of CRF data. The 
investigator maintains a separate source for the data entered by the investigator or designee into 
the sponsor-provided electronic data capture system. The investigator is responsible for the 
identification of any data to be considered source and for the confirmation that data reported are 
accurate and complete by signing the CRF. 
Data collected via the sponsor-provided data capture systems will be stored at third party (at 
third parties). The investigator will have continuous access to the data during the study and until 
decommissioning of the data capture systems. Prior to decommissioning, the investigator will 
receive or access an archival copy of pertinent data for retention. 
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system and reports will be provided to the investigator for review 
and retention. Data will subsequently be transferred from the central vendor to the sponsor data 
warehouse. 
Data from complaint forms submitted to the sponsor will be encoded and stored in the global 
product complaint management system. 
10.1.7. 
Source Documents  
● Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site. 
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● Data reported on or entered in the CRF and are transcribed from source 
documents must be consistent with the source documents or the discrepancies 
must be explained. The investigator may need to request previous medical records 
or transfer records, depending on the study. Also, current medical records must be 
available. 
● Definition of what constitutes source data can be found in Section 10.1.6. 
10.1.8. 
Study and Site Start and Closure  
First act of recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
Study or site termination 
The sponsor or sponsor’s designee reserves the right to close the study site or terminate the study 
at any time for any reason at the sole discretion of the sponsor. Study sites will be closed upon 
study completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
For study termination: 
● Discontinuation of further study intervention development 
For site termination: 
● Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor’s procedures, or GCP guidelines 
● Inadequate recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator 
● Total number of participants included earlier than expected. 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
10.1.9. 
Publication Policy  
In accordance with the sponsor’s publication policy, the results of this study will be submitted 
for publication by a peer-reviewed journal if the results are deemed to be of significant medical 
importance. 
 
 
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10.2. 
Appendix 2: Clinical Laboratory Tests  
● The tests detailed in the following table will be performed by the local laboratory. 
● Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations. 
● Investigators must document their review of the laboratory safety results.  
 
 
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Safety Laboratory Tests 
Hematologya 
Clinical Chemistrya 
Hematocrit 
Sodium 
Hemoglobin 
Potassium 
Erythrocyte count (RBC) 
Bicarbonate 
Mean cell volume  
Chloride 
Mean cell hemoglobin  
Calcium 
Mean cell hemoglobin concentration  
Glucose (fasting) 
Leukocytes (WBC) 
Blood urea  
 
Total protein 
Absolute counts of: 
Albumin 
Neutrophils 
Total bilirubin 
Lymphocytes 
Alkaline phosphatase 
Monocytes 
Aspartate aminotransferase 
Eosinophils 
Alanine aminotransferase 
Basophils 
Creatinine 
Platelets 
Amylase 
 
Lipase 
Urinalysisa 
 
Specific gravity 
Hepatitis B surface antigenb 
pH 
Hepatitis C antibodyb 
Protein 
HIV or HIV antibodyb 
Glucose 
FSHc 
Ketones 
Pregnancy testd 
Bilirubin 
Ethanol and urine drug screen testinge 
Urobilinogen 
 
Blood 
 
Nitrite 
Leukocytes (WBC) 
 
Microscopic examination of sedimentf 
 
Abbreviations: FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; RBC = red blood cell; 
WBC = white blood cell. 
a Performed by central laboratory except at screening which may be performed by a local laboratory. Results will 
be validated by the laboratory at the time of initial testing. 
b Performed by local laboratory at screening only.  
 c FSH - Performed at screening only for females to confirm postmenopausal status. 
d Pregnancy test - Serum pregnancy test will be performed at screening and urine pregnancy tests at subsequent 
visits. Women with confirmed nonchildbearing potential status can be exempted from further pregnancy tests 
during the study after screening.  
e Performed locally at site during screening and admission on Day -1. Additional testing may be performed at the 
discretion of the investigator if warranted. 
f Test only if dipstick result is abnormal (ie, positive for blood, protein, or nitrites)  
 
 
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10.2.1. 
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-GPIP Sampling Summary 
 
Purpose 
Blood Volume 
per Sample (mL) 
Estimated Number 
of Blood Samples 
Total 
Volume (mL) 
Screening tests (local laboratory)a 
25 
1 
25 
Clinical laboratory tests (central laboratory)a 
 
Study visits (2 periods) 
12 
4 × 2 periods = 8 
96 
Pharmacokinetics (central or referral laboratory)b 
 
Study visits (2 periods) 
3 
14 × 2 periods (+3 
unscheduled) = 31  
93 
Blood glucosea 
0.3 
6 (+5 discard for 
cannula patency +3 
unscheduled) x 2 
periods = 28 
8.4 
Pharmacogenetics (stored sample) 
10 
1 
10 
Total 
232.4 
Total for clinical purposes rounded up to nearest 10 mL 
240 
a Additional samples may be drawn if needed for safety purposes. 
b Up to 3 additional unscheduled samples may be drawn based on emerging data. 
 
 
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10.3. 
Appendix 3: Adverse Events and Serious Adverse Events: Definitions 
and Procedures for Recording, Evaluating, Follow-Up, and 
Reporting  
10.3.1. 
Definition of AE  
AE definition 
 An AE is any untoward medical occurrence in a participant administered a pharmaceutical 
product and which does not necessarily have a causal relationship with the study 
intervention. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal (investigational) product, whether or not related to 
the medicinal (investigational) product. 
 An AE is any untoward medical occurrence, unintended disease or injury, or untoward 
clinical signs (including abnormal laboratory finding) in study participants, users, or 
other persons, whether or not related to the investigational medical device. This definition 
includes events related to the investigational medical device or comparator and events 
related to the procedures involved except for events in users or other persons, which only 
include events related to investigational devices.  
Events meeting the AE definition 
 Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECGs, radiological scans, vital sign measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator (ie, not related to progression of underlying 
disease). 
 Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition. 
 New condition detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
 Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 Medication error, misuse, or abuse of investigational medicinal product, including signs, 
symptoms, or clinical sequelae.  
Events NOT meeting the AE definition 
 Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
 The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
 Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
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 Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.  
10.3.2. 
Definition of SAE  
An SAE is defined as any untoward medical occurrence that, at any dose, meets 1 or more 
of the criteria listed: 
 Results in death 
 Is life-threatening 
o The term life-threatening in the definition of serious refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe. 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
o In general, hospitalization signifies that the participant has been admitted to 
hospital or emergency ward (usually involving at least an overnight stay) for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether 
hospitalization occurred or was necessary, the AE should be considered serious. 
o Hospitalization for elective treatment of a preexisting condition that did not 
worsen from baseline is not considered an AE. 
 Results in persistent disability/incapacity 
o The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
o This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) that may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
 Is a congenital anomaly/birth defect 
o Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
 Other situations: 
o Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations such as important 
medical events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the participant or may require medical or 
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surgical intervention to prevent 1 of the other outcomes listed in the above 
definition. These events should usually be considered serious. 
o Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias, or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse. 
 Resulted in medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function.  
10.3.3. 
Definition of Product Complaints  
Product complaint 
 A product complaint is any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a study intervention. When the ability to use the study intervention safely 
is impacted, the following are also product complaints: 
o Deficiencies in labeling information, and 
o Use errors for device or drug-device combination products due to ergonomic 
design elements of the product. 
 Product complaints related to study interventions used in clinical trials are collected to 
ensure the safety of participants, monitor quality, and to facilitate process and product 
improvements. 
 Investigators will instruct participants to contact the site as soon as possible if he or she 
has a product complaint or problem with the study intervention so that the situation can 
be assessed. 
 An event may meet the definition of both a product complaint and an AE/SAE. In such 
cases, it should be reported as both a product complaint and as an AE/SAE. 
10.3.4. 
Recording and Follow-Up of AE and/or SAE and Product Complaints  
AE, SAE, and product complaint recording 
 When an AE/SAE/product complaint occurs, it is the responsibility of the investigator to 
review all documentation (eg, hospital progress notes, laboratory reports, and diagnostic 
reports) related to the event. 
 The investigator will then record all relevant AE/SAE/product complaint information in 
the participant’s medical records, in accordance with the investigator’s normal clinical 
practice. AE/SAE information is reported on the appropriate CRF page and product 
complaint information is reported on the Product Complaint Form. 
 Note: An event may meet the definition of both a product complaint and an AE/SAE. In 
such cases, it should be reported as both a product complaint and as an AE/SAE. 
 It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the sponsor or designee in lieu of completion of the CRF page for AE/SAE and 
the Product Complaint Form for product complaints. 
 There may be instances when copies of medical records for certain cases are requested by 
the sponsor or designee. In this case, all participant identifiers, with the exception of the 
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participant number, will be redacted on the copies of the medical records before 
submission to the sponsor or designee. 
 The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of intensity 
The investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to 1 of the following categories:  
 Mild: A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of 
daily living. 
 Moderate: A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing discomfort 
but poses no significant or permanent risk of harm to the research participant. 
 Severe: A type of AE that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention. An AE that is 
assessed as severe should not be confused with an SAE. Severe is a category utilized for 
rating the intensity of an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.  
Assessment of causality 
 The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. The investigator will use clinical judgment to 
determine the relationship. 
 A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
 Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
 The investigator will also consult the IB in their assessment. 
 For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
 There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the sponsor or designee. However, it is very 
important that the investigator always make an assessment of causality for every event 
before the initial transmission of the SAE data to the sponsor or designee. 
 The investigator may change their opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment. 
 The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements. 
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Follow-up of AEs and SAEs 
 The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the sponsor or 
designee to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
  If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide the sponsor or designee with a copy of any 
postmortem findings including histopathology. 
10.3.5. 
Reporting of SAEs  
SAE reporting via SAE report 
 Facsimile transmission of the SAE report is the preferred method to transmit this 
information to the sponsor or designee. 
 Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE report within the designated reporting time frames. 
 Contacts for SAE reporting can be found in SAE report.  
10.3.6. 
Regulatory Reporting Requirements  
SAE regulatory reporting 
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities toward the safety of participants and the safety of 
a study intervention under clinical investigation are met. 
 The sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study intervention under 
clinical investigation. The sponsor will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, IRBs/IECs, 
and investigators. 
 An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will 
review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements.  
 
 
 
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10.4. 
Appendix 4: Contraceptive and Barrier Guidance  
10.4.1. 
Definitions  
Word/Phrase 
Definition 
Women of 
childbearing 
potential 
(WOCBP) 
Females are considered a woman of childbearing potential if they have 
 
had at least 1 cycle of menses, or 
 
Tanner 4 breast development. 
 
Any amount of spotting should be considered menarche. If Tanner Staging of 
breasts is performed as part of study procedures, please refer to the Reproductive, 
Pregnancy and Pediatrics Safety Committee Safety Guidance for Children in 
Clinical Trial regarding Tanner Staging. 
Women not of 
childbearing 
potential 
(WNOCBP) 
Females are considered women not of childbearing potential if they 
 
have a congenital anomaly such as Mullerian agenesis  
 
are infertile due to surgical sterilization, or  
 
are postmenopausal. 
 
Examples of surgical sterilization include hysterectomy, bilateral oophorectomy, 
tubal ligation. 
Postmenopausal 
state 
The postmenopausal state should be defined as: 
1. A woman at any age at least 6 weeks postsurgical bilateral oophorectomy 
with or without hysterectomy, confirmed by operative note; or  
2. A woman aged at least 40 years and up to 55 years with an intact uterus, 
not on hormone therapy*, who has had cessation of menses for at least 12 
consecutive months without an alternative medical cause, AND  
With a follicle-stimulating hormone >40 mIU/mL; or  
3. A woman aged 55 or older not on hormone therapy, who has had at least 
12 months of spontaneous amenorrhea, or 
4. A woman aged at least 55 years with a diagnosis of menopause prior to 
starting hormone replacement therapy 
* Women should not be taking medications during amenorrhea such as oral 
contraceptives, hormones, gonadotropin-releasing hormone, anti-estrogens, 
selective estrogen receptor modulators, or chemotherapy that could induce 
transient amenorrhea. 
Reproductive 
toxicology 
studies 
Embryofetal studies are toxicity studies in pregnant animals designed to identify 
abnormalities in the development of fetuses, which could indicate potential for 
teratogenicity in humans. The relevant dosing period is during organogenesis. 
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10.4.2. 
Contraception Guidance  
Contraception guidance for females 
WOCBP and women not of childbearing potential may participate in this trial.  
WOCBP who are completely abstinent as their preferred and usual lifestyle, or in a same-sex 
relationship as their preferred and usual lifestyle: 
Must… 
Must not… 
agree to either 
remain abstinent or 
stay in a same-sex 
relationship without 
sexual relationships 
with males 
 use periodic abstinence methods 
o calendar 
o ovulation 
o symptothermal, or 
o post-ovulation 
 declare abstinence just for the duration of a trial, or 
 use the withdrawal method 
WOCBPs who are NOT completely abstinent as their preferred and usual lifestyle, or NOT in a 
same-sex relationship as their preferred and usual lifestyle, must do the following: 
Topic 
Condition 
Pregnancy testing 
Have a negative serum test result at screening followed by a negative 
urine result within 24 hours prior to treatment exposure. See the protocol 
SoA for subsequent pregnancy testing requirements. 
Contraception 
Agree to use 2 forms of effective methods of contraception where at 
least 1 form must be a highly effective method of contraception. These 
forms of contraception must be used for the duration of the study. 
Contraception guidance for males 
The following table describes contraception guidance for all men. 
Topic 
Guidance 
For all men  
should refrain from sperm donation for the 
duration of the study and for 90 days 
Contraception for men with partners of 
childbearing potential  
 
either remain abstinent (if this is their 
preferred and usual lifestyle), or 
 
 
must use condoms during intercourse for 
the duration of the study, and for 90 days 
Contraception for men in exclusively same-sex 
relationships, as their preferred and usual lifestyle 
Are not required to use contraception 
 
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Examples of different forms of contraception 
Examples of highly effective, effective, and ineffective methods of contraception can be found 
below. 
Methods 
Examples 
Highly effective 
contraception (less than 
1% failure rate) 
 
female sterilization 
 
combination oral contraceptive pill 
 
progestin-only contraceptive pill (mini-pill) 
 
implanted contraceptives 
 
injectable contraceptives 
 
contraceptive patch (only women <198 pounds or 90 kg) 
 
vasectomy (if only sexual partner) 
 
fallopian tube implants (if confirmed through hysterosalpingogram) 
 
combined contraceptive vaginal ring, or  
 
intrauterine devices 
Effective contraception 
 
male or female condoms with spermicide  
 
diaphragms with spermicide or cervical sponges 
 
barrier method with use of a spermicide 
o condom with spermicide 
o diaphragm with spermicide, or 
o female condom with spermicide 
Ineffective forms of 
contraception whether 
used alone or in any 
combination 
 
spermicide alone 
 
periodic abstinence 
 
fertility awareness (calendar method, temperature method, cervical 
mucus, or symptothermal) 
 
withdrawal 
 
postcoital douche, or 
 
lactational amenorrhea 
 
 
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10.5. 
Appendix 5: Genetics  
Use/analysis of DNA 
● Genetic variation may impact a participant’s response to study intervention, 
susceptibility to, and severity and progression of disease. Variable response to 
study intervention may be due to genetic determinants that impact drug 
absorption, distribution, metabolism, and excretion; mechanism of action of the 
drug; disease etiology; and/or molecular subtype of the disease being treated. 
Therefore, where local regulations and IRB/IEC allow, a blood sample will be 
collected for DNA analysis from consenting participants. 
● DNA samples will be used for research related to tirzepatide or T2DM and related 
diseases. They may also be used to develop tests/assays including diagnostic tests 
related to tirzepatide and T2DM. Genetic research may consist of the analysis of 1 
or more candidate genes or the analysis of genetic markers throughout the genome 
or analysis of the entire genome (as appropriate). 
● The samples may be analyzed as part of a multistudy assessment of genetic 
factors involved in the response to tirzepatide or study interventions of this class 
to understand study disease or related conditions. 
● The results of genetic analyses may be reported in the clinical study report or in a 
separate study summary. 
● The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 
● The samples will be retained while research on tirzepatide or T2DM continues but 
no longer than 15 years or other period as per local requirements. 
 
 
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10.6. 
Appendix 6: Medical Device Adverse Events (AEs), Adverse Device 
Effects (ADEs), Serious Adverse Events (SAEs) and Device 
Deficiencies: Definition and Procedures for Recording, Evaluating, 
Follow-up, and Reporting  
Refer to Appendix 3 for definitions and procedures for recording, evaluating, follow-up, and 
reporting of all events.  
 
 
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10.7. 
Appendix 7: Liver Safety: Suggested Actions and Follow-Up 
Assessments  
Hepatic evaluation testing 
See Section 8.2.8.1 for guidance on appropriate test selection. 
Testing by an investigator-designated local laboratory should be performed for all testing defined 
by this guidance. 
The local laboratory must be qualified in accordance with applicable local regulations. 
Hepatic Hematology Panel 
Hepatic Clinical Chemistry Panel  
  Hemoglobin 
   Total bilirubin 
   Hematocrit 
   Direct bilirubin 
   Erythrocytes (RBCs - red blood cells) 
   Alkaline phosphatase (ALP) 
   Leukocytes (WBCs - white blood cells) 
   Alanine aminotransferase (ALT) 
   Differential: 
   Aspartate aminotransferase (AST) 
       Neutrophils, segmented 
   Gamma-glutamyl transferase (GGT) 
       Lymphocytes 
   Creatine kinase (CK) 
       Monocytes 
Other Chemistry 
       Basophils 
   Acetaminophen 
       Eosinophils 
   Alkaline phosphatase isoenzymes 
   Platelets 
   Ceruloplasmin 
   Cell morphology (RBC and WBC) 
   Copper 
Hepatic Coagulation Panel 
   Ethyl alcohol (EtOH) 
    Prothrombin time, INR (PT-INR) 
   Haptoglobin 
Hepatitis A virus (HAV) testing: 
   Immunoglobulin IgA (quantitative) 
    HAV total antibodya 
   Immunoglobulin IgG (quantitative) 
    HAV IgM antibody 
   Immunoglobulin IgM (quantitative) 
Hepatitis B virus (HBV) testing: 
   Phosphatidylethanol (PEth)a 
    Hepatitis B surface antigen (HBsAg) 
Urine Chemistry 
    Hepatitis B surface antibody (anti-HBs) 
   Drug screen 
    Hepatitis B core total antibody (anti-HBc) 
   Ethyl glucuronide (EtG)a 
    Hepatitis B core IgM antibody 
Other Serology 
    HBV DNA
b 
   Anti-nuclear antibody (ANA) 
Hepatitis C virus (HCV) testing: 
   Anti-smooth muscle antibody (ASMA)
c 
    HCV antibody 
   Anti-actin antibody
d 
    HCV RNA
b 
   Epstein-Barr virus (EBV) testing: 
Hepatitis D virus (HDV) testing: 
       EBV antibody 
    HDV antibody 
       EBV DNA
b 
Hepatitis E virus (HEV) testing: 
   Cytomegalovirus (CMV) testing: 
    HEV IgG antibody 
       CMV antibody 
    HEV IgM antibody 
       CMV DNA
b 
    HEV RNA
b 
    Herpes simplex virus (HSV) testing: 
Microbiology  
       HSV (Type 1 and 2) antibody 
   Culture: 
       HSV (Type 1 and 2) DNA
b 
       Blood 
    Liver kidney microsomal type 1 (LKM-1) antibody 
       Urine 
 
a These tests are not done by local laboratory in Singapore. 
b Reflex/confirmation dependent on regulatory requirements, testing availability, or both. 
c Not required if anti-actin antibody is tested. 
d Not required if anti-smooth muscle antibody is tested. 
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10.8. 
Appendix 8: Pancreatic Monitoring  
Diagnosis of acute pancreatitis 
Acute pancreatitis is an AE of interest in all studies with tirzepatide, including this study. The 
diagnosis of acute pancreatitis requires 2 of the following 3 features (Banks and Freeman 2006; 
Koizumi et al. 2006):  
 abdominal pain, characteristic of acute pancreatitis (ie, epigastric pain radiating to the 
back, often associated with nausea and vomiting) 
 serum amylase (total, pancreatic, or both) and/or lipase ≥3x ULN 
 characteristic findings of acute pancreatitis on CT scan or magnetic resonance imaging. 
If acute pancreatitis is suspected, the investigator should 
 obtain appropriate laboratory tests, including pancreatic amylase (p-amylase) and lipase 
 perform imaging studies, such as abdominal CT scan with or without contrast, or 
abdominal magnetic resonance imaging 
 evaluate for possible causes of acute pancreatitis, including alcohol use, gallstone/gall 
bladder disease, hypertriglyceridemia, and concomitant medications. 
Discontinuation for acute pancreatitis 
If acute pancreatitis is diagnosed, the participant must discontinue use of the IPs. 
Asymptomatic elevation of serum amylase and/or lipase levels 
Serial measures of pancreatic enzymes have limited clinical value for predicting episodes of 
acute pancreatitis in asymptomatic patients (Nauck 2016; Steinberg et al. 2017a,b). Therefore, 
further diagnostic follow-up of cases of asymptomatic elevation of pancreatic enzymes (lipase 
and/or p-amylase ≥3x ULN) is not mandated but may be performed based on the investigator’s 
clinical judgment and assessment of the participant’s overall clinical condition.
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10.9. 
Appendix 9: Abbreviations and Definitions  
 
Term 
Definition 
abuse 
Use of a study intervention for recreational purposes or to maintain an addiction or 
dependence 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the concentration versus time curve 
AUC(0-tlast) 
AUC from time 0 to the last measurable concentration after the first dose 
AUC(0-∞) 
AUC from time 0 to infinity 
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 study-related, good clinical practice (GCP), and applicable regulatory 
requirements. 
CP 
clinical pharmacologist 
CRF 
case report form; a printed, optical, or electronic document designed to record all of the 
protocol-required information to be reported to the sponsor for each trial participant. 
CRP 
clinical research physician: Individual responsible for the medical conduct of the study. 
Responsibilities of the CRP may be performed by a physician, clinical research 
scientist, global safety physician, or other medical officer. 
CRU 
clinical research unit 
CT 
computed tomography 
device deficiencies 
equivalent to product complaint 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
enroll 
The act of assigning a participant to a treatment. Participants who are enrolled in the 
study are those who have been assigned to a treatment. 
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enter 
Participants entered into a study are those who sign the informed consent form directly 
or through their legally acceptable representatives. 
GCP 
good clinical practice 
GI 
gastrointestinal 
GIP  
gastric inhibitory polypeptide 
GLP 
glucagon-like peptide 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
INR 
international normalization ratio 
informed consent 
A process by which a participant voluntarily confirms their willingness to participate in 
a particular study, after having been informed of all aspects of the study that are 
relevant to the participant’s decision to participate. Informed consent is documented by 
means of a written, signed, and dated informed consent form. 
investigational 
product 
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, 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. See also “IMP.” 
IRB 
institutional review board 
ISR 
injection-site reaction 
medication error 
Errors in the prescribing, dispensing, or administration of a study intervention, 
regardless of whether or not the medication is administered to the participant or the 
error leads to an AE. Medication error generally involve a failure to uphold 1 or more of 
the 5 “rights” of medication use: the right participant, the right drug, the right dose, 
right route, at the right time. 
In addition to the 5 core rights, the following may also represent medication errors:  
• dose omission associated with an AE or a product complaint 
• dispensing or use of expired medication 
• use of medication past the recommended in-use date 
• dispensing or use of an improperly stored medication 
• use of an adulterated dosage form or administration technique inconsistent with the 
medication’s labeling (eg, Summary of Product Characteristics, IB, local label, 
protocol), or 
• shared use of cartridges, prefilled pens, or both. 
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misuse 
Use of a study intervention for self-treatment that either is inconsistent with the 
prescribed dosing regimen, indication, or both, or is obtained without a prescription 
MUPFP 
multi-use prefilled pen 
participant 
Equivalent to CDISC term “subject”: an individual who participates in a clinical trial, 
either as recipient of an investigational medicinal product or as a control 
PK/PD 
pharmacokinetics/pharmacodynamics 
QW 
once weekly 
RA 
receptor agonist 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
Subcutaneous 
SoA 
schedule of activities 
screen 
The act of determining if an individual meets minimum requirement to become part of a 
pool of potential candidates for participation in a clinical study.  
SDP 
single-dose pen 
T2DM 
type 2 diabetes mellitus 
TBL 
total bilirubin 
tmax 
time to Cmax 
ULN 
upper limit of normal 
WOCBP 
Women of childbearing potential 
 
 
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11. 
References  
[ADA] American Diabetes Association. Glycemic targets: standards of medical care in diabetes- 
2020. Diabetes Care. 2020:43(Suppl. 1):S66-S76. doi: 10.2337/dc20-S006 
Banks PA, Freeman ML; Practice Parameters Committee of the American College of 
Gastroenterology. Practice guidelines in acute pancreatitis. Am J Gastroenterol. 
2006;101(10):2379-2400. doi: 10.1111/j.1572-0241.2006.00856.x 
Coskun T, Sloop K, Loghin C, Alsina-Fernandez J, et al. LY3298176, a novel dual GIP and 
GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: from discovery to clinical 
proof of concept. Mol Metab. 2018;18:3-14. doi: 10.1016/j.molmet.2018.09.009 
Koizumi M, Takada T, Kawarada Y, Hirata K, et al. JPN guidelines for the management of acute 
pancreatitis: diagnostic criteria for acute pancreatitis. J Hepatobiliary Pancreat Surg. 
2006;13(1):25-32. doi: 10.1007/s00534-005-1048-2 
Nauck M. Incretin therapies: highlighting common features and differences in the modes of 
action of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. 
Diabetes Obes Metab. 2016;18(3):203-216. doi: 10.1111/dom.12591 
Steinberg WM, Buse JB, Ghorbani MLM, et al.; LEADER Steering Committee; LEADER Trial 
Investigators. Amylase, lipase, and acute pancreatitis in people with type 2 diabetes treated 
with liraglutide: results from the LEADER randomized trial. Diabetes Care. 2017a;40(7):966-
972. [Erratum in: Diabetes Care. 2018;41(7):1538.]. doi: 10.2337/dc16-2747 
Steinberg WM, Rosenstock J, Wadden TA, Donsmark M, et al. Impact of liraglutide on amylase, 
lipase, and acute pancreatitis in participants with overweight/obesity and normoglycemia, 
prediabetes, or type 2 diabetes: secondary analyses of pooled data from the SCALE clinical 
development program. Diabetes Care. 2017b;40(7):839-848. doi: 10.2337/dc16-2684 
 
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Si g nat ure Pa ge f or V V- C LI N- 1 1 7 7 1 1 v 1. 0
Si g nat ure Pa ge f or V V- C LI N- 1 1 7 7 1 1 v 1. 0
A p pr o val
3 0- Ma y- 2 0 2 3 0 6: 2 1: 1 3 G M T + 0 0 0 0
A p pr o val
3 0- Ma y- 2 0 2 3 1 1: 0 0: 5 4 G M T + 0 0 0 0
A p pr o ve d o n 3 0 Ma y 2 0 2 3 G M T
P P D
P P D