A Study to Evaluate Tirzepatide Concentrations in Breastmilk Following Administration of Single Dose of Tirzepatide by Subcutaneous Injection in Healthy Lactating Females
Phase: PHASE1
Conditions: Healthy
Sponsor: Eli Lilly and Company

Protocol I8F-MC-GPIN (b)
A Study to Evaluate Tirzepatide Concentrations in Breastmilk Following Administration of Single Dose 
of Tirzepatide by Subcutaneous Injection in Healthy Lactating Females
NCT05978713
Approval Date: 15 SEP 2023

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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 Study to Evaluate Tirzepatide Concentrations in Breastmilk Following Administration of 
Single Dose of Tirzepatide by Subcutaneous Injection in Healthy Lactating Females 
Protocol Number: I8F-MC-GPIN 
Amendment Number: I8F-MC-GPIN (b) 
Compound: Tirzepatide 
Brief Title: 
A Study to Measure Tirzepatide Levels in Breastmilk of Healthy Lactating Females 
Study Phase: 1 
Acronym: GPIN 
Sponsor Name: Eli Lilly and Company 
Legal Registered Address: Indianapolis, Indiana, USA 46285 
Regulatory Agency Identifier Number 
IND: 128801 
Approval Date: Protocol Amendment (b) Electronically Signed and Approved by Lilly on date 
provided below. 
 
Document ID: VV-CLIN-075154 
 
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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 
Protocol amendment (a) 
24-Jul-2023 
Original Protocol 
17-May-2023 
Amendment [b]  
This amendment is considered to be non-substantial. 
Overall Rationale for the Amendment: 
The protocol is being amended to address FDA recommendations on contraceptive guidance.   
Section # and 
Name 
Description of Change 
Brief Rationale 
10.4.2 
Contraception 
Guidance 
Removed wording “less than 1% 
failure rate” describing “highly 
effective contraception.” 
Updated based on FDA feedback 
 
 
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Table of Contents  
Protocol Amendment Summary of Changes Table .........................................................................3 
1. 
Protocol Summary ..........................................................................................................7 
1.1. 
Synopsis ............................................................................................................................7 
1.2. 
Schema ............................................................................................................................10 
1.3. 
Schedule of Activities (SoA) ..........................................................................................11 
2. 
Introduction ...................................................................................................................14 
2.1. 
Study Rationale ...............................................................................................................14 
2.2. 
Background .....................................................................................................................14 
2.3. 
Benefit/Risk Assessment ................................................................................................14 
3. 
Objectives and Endpoints ............................................................................................16 
4. 
Study Design ..................................................................................................................17 
4.1. 
Overall Design ................................................................................................................17 
4.2. 
Scientific Rationale for Study Design ............................................................................18 
4.3. 
Justification for Dose ......................................................................................................18 
4.4. 
End of Study Definition ..................................................................................................18 
5. 
Study Population ...........................................................................................................19 
5.1. 
Inclusion Criteria ............................................................................................................19 
5.2. 
Exclusion Criteria ...........................................................................................................20 
5.3. 
Lifestyle Considerations .................................................................................................21 
5.3.1. 
Meals and Dietary Restrictions .......................................................................................22 
5.3.2. 
Substance Use: Caffeine, Alcohol, and Tobacco ............................................................22 
5.3.3. 
Activity ...........................................................................................................................22 
5.4. 
Screen Failures ................................................................................................................22 
5.5. 
Criteria for Temporarily Delaying 
Enrollment/Randomization/Administration of Study Intervention 
of a Participant ................................................................................................................22 
6. 
Study Intervention(s) and Concomitant Therapy .....................................................23 
6.1. 
Study Intervention Administered ....................................................................................23 
6.2. 
Preparation, Handling, Storage, and Accountability ......................................................24 
6.3. 
Assignment to Study Intervention ..................................................................................24 
6.4. 
Study Intervention Compliance ......................................................................................24 
6.5. 
Dose Modification ..........................................................................................................24 
6.6. 
Continued Access to Study Intervention after the End of the 
Study ...............................................................................................................................24 
6.7. 
Treatment of Overdose ...................................................................................................24 
6.8. 
Prior and Concomitant Therapy ......................................................................................25 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................26 
7.1. 
Discontinuation of Study Intervention ............................................................................26 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................26 
7.3. 
Lost to Follow-up............................................................................................................26 
8. 
Study Assessments and Procedures.............................................................................27 
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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 .........................................................................................................28 
8.2.4. 
Clinical Safety Laboratory Tests ....................................................................................28 
8.2.5. 
Pregnancy Testing ...........................................................................................................29 
8.2.6. 
Amylase and Lipase Measurements................................................................................29 
8.2.7. 
Glucose Monitoring ........................................................................................................29 
8.2.7.1. 
Hypoglycemia Reporting ...................................................................................29 
8.2.8. 
Injection-Site Reactions ..................................................................................................31 
8.2.9. 
Hypersensitivity Reactions .............................................................................................31 
8.2.10. Safety Monitoring ...........................................................................................................31 
8.2.10.1. 
Hepatic Safety ....................................................................................................31 
8.3. 
Adverse Events, Serious Adverse Events, and Product 
Complaints ......................................................................................................................34 
8.3.1. 
Timing and Mechanism for Collecting Events ...............................................................35 
8.3.2. 
Pregnancy ........................................................................................................................36 
8.3.3. 
Adverse Events of Special Interest .................................................................................37 
8.4. 
Pharmacokinetics ............................................................................................................37 
8.4.1. 
Bioanalysis ......................................................................................................................37 
8.5. 
Pharmacodynamics .........................................................................................................38 
8.6. 
Genetics ..........................................................................................................................38 
8.7. 
Biomarkers ......................................................................................................................38 
8.8. 
Immunogenicity Assessments.........................................................................................38 
8.9. 
Health Economics OR Medical Resource Utilization and Health 
Economics .......................................................................................................................38 
9. 
Statistical Considerations .............................................................................................39 
9.1. 
Statistical Hypotheses .....................................................................................................39 
9.1.1. 
Multiplicity Adjustment ..................................................................................................39 
9.2. 
Analyses Sets ..................................................................................................................39 
9.3. 
Statistical Analyses .........................................................................................................39 
9.3.1. 
General Considerations ...................................................................................................39 
9.3.2. 
Primary Endpoint(s) Analysis .........................................................................................39 
9.3.3. 
Secondary Endpoint Analysis .........................................................................................39 
9.3.4. 
Safety Analyses ...............................................................................................................39 
9.3.4.1. 
Clinical Evaluation of Safety .............................................................................39 
9.3.4.2. 
Statistical Evaluation of Safety ..........................................................................40 
9.3.4.3. 
Injection-Site Reactions .....................................................................................40 
9.3.5. 
Other Analyses ................................................................................................................40 
9.4. 
Interim Analysis ..............................................................................................................40 
9.5. 
Sample Size Determination ............................................................................................40 
10. 
Supporting Documentation and Operational Considerations ..................................41 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................41 
10.1.1. Regulatory and Ethical Considerations ...........................................................................41 
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10.1.2. Financial Disclosure........................................................................................................41 
10.1.3. Informed Consent Process ..............................................................................................42 
10.1.4. Data Protection................................................................................................................42 
10.1.5. Dissemination of Clinical Study Data.............................................................................42 
10.1.6. Data Quality Assurance ..................................................................................................43 
10.1.7. Source Documents ..........................................................................................................44 
10.1.8. Study and Site Start and Closure ....................................................................................45 
10.1.9. Publication Policy ...........................................................................................................45 
10.2. 
Appendix 2: Clinical Laboratory Tests ...........................................................................46 
10.2.1. Blood Sampling Summary ..............................................................................................48 
10.3. 
Appendix 3: Adverse Events and Serious Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-
up, and Reporting ............................................................................................................49 
10.3.1. Definition of AE .............................................................................................................49 
10.3.2. Definition of SAE ...........................................................................................................50 
10.3.3. Definition of Product Complaints ...................................................................................51 
10.3.4. Recording and Follow-Up of AE and/or SAE and Product 
Complaints ......................................................................................................................51 
10.3.5. Reporting of SAEs ..........................................................................................................53 
10.3.6. Regulatory Reporting Requirements ...............................................................................53 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ..........................................................54 
10.4.1. Definitions.......................................................................................................................54 
10.4.2. Contraception Guidance..................................................................................................55 
10.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-up 
Assessments ....................................................................................................................57 
10.6. 
Appendix 6: Pancreatic Monitoring ................................................................................58 
10.7. 
Appendix 7: Pharmacokinetic Analysis Plan..................................................................59 
10.8. 
Appendix 8: Protocol Amendment History ....................................................................60 
10.9. 
Appendix 8: Abbreviations and Definitions ...................................................................61 
11. 
References ......................................................................................................................64 
 
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1. 
Protocol Summary  
1.1. 
Synopsis  
Protocol Title: 
A Study to Evaluate Tirzepatide Concentrations in Breastmilk Following Administration of 
Single Dose of Tirzepatide by Subcutaneous Injection in Healthy Lactating Females 
Brief Title: A Study to Measure Tirzepatide Levels in Breastmilk of Healthy Lactating Females 
Regulatory Agency Identifier Number: IND: 128801 
Rationale: 
Tirzepatide (MOUNJARO™; LY3298176) is a glucose-dependent insulinotropic peptide (GIP) 
and glucagon-like peptide 1 (GLP-1) receptor agonist approved as an adjunct to diet and exercise 
for improving glycemic control in adult patients with type 2 diabetes mellitus (T2DM). The 
disposition of tirzepatide for adult patients has been characterized but data is lacking on whether 
tirzepatide is excreted in breastmilk. There is a need to understand tirzepatide concentrations in 
breastmilk to better inform healthcare practitioners in managing women of childbearing potential 
who may be potential users of tirzepatide. 
Study I8F-MC-GPIN (GPIN) is a postmarketing lactation study that will primarily assess the 
pharmacokinetics (PK) of tirzepatide in breastmilk following administration of a single 
 
dose of tirzepatide via the subcutaneous (SC) route in healthy lactating females. Additionally, 
plasma PK of tirzepatide will also be assessed. 
Objectives and Endpoints: 
Abbreviations: AUC(0-tlast) = area under the concentration versus time curve from time zero to the last observable 
concentration; Cmax = maximum observed drug concentration; tmax = time to maximum observed drug 
concentration. 
Objectives 
Endpoints 
Primary 
 
 To evaluate tirzepatide 
pharmacokinetics (PK) in breastmilk 
of healthy lactating females 
 Area under the tirzepatide 
concentration-time curve in breastmilk 
from time 0 extrapolated to infinity 
AUC(0-∞) 
Secondary 
 
 
 
 
 
 
 
 
 
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Overall Design 
Brief Summary: 
This is a postmarketing, open-label, single-treatment arm, single-dose, lactation study, assessing 
PK of tirzepatide in breastmilk and plasma in healthy lactating females. 
Potential participants will be screened to assess their eligibility to enter the study within 27 days 
prior to Day -1. Participants will be admitted to the clinical research unit (CRU) on Day -1 to 
establish baseline measurements. 
Participants will receive a single subcutaneous tirzepatide 
 dose on Day 1 following 
overnight fasting of approximately 8 hours. Breastmilk and plasma samples will be collected. 
Participants will be permitted to leave the CRU on Day 5 following completion of study 
procedures. During inpatient stays, the infant is allowed to be in the CRU with the study 
participant during supervised visitation hours. On Days 6, 8, 15±1, and 22±1, participants may 
either return to the CRU for outpatient visits or have these visits be performed remotely by home 
health nurses as deemed appropriate by the study investigator. On Day 29±1, the participants will 
return to the CRU for the final follow-up visit. 
Safety will be assessed by vital signs, electrocardiograms (ECGs), safety laboratory tests, and the 
recording of adverse events (AEs). Breastfeeding must be discontinued prior to the 
administration of tirzepatide and for the duration of the study. 
Study Population: 
Healthy lactating females. 
Number of Participants: 
Approximately 14 healthy lactating females will be enrolled so that about 8 females complete the 
study. 
Intervention Groups and Duration: 
Participants will receive a single SC tirzepatide 
 dose on Day 1. 
The study duration for individual participants, inclusive of screening is expected to be 
approximately 8 weeks, as detailed here: 
 Screening: up to 27 days prior to Day -1 
 Inpatient Treatment Period: Day -1 to Day 5 (may be extended if necessary for safety 
reasons based on the Investigator’s discretion) 
o Single dose of study intervention 
 Outpatient follow-up period Days 6, 8, 15±1, and 22±1 with the final follow-up visit on 
Day 29±1. 
Ethical Considerations of Benefit/Risk: 
There is no anticipated therapeutic benefit for participants in this study. 
As of 26 September 2022, tirzepatide 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 
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been consistent with risks associated with other 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. 
No clinically significant safety or tolerability concerns have been identified during clinical 
investigation of tirzepatide up to the single dose of 5 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 (Coskun et al. 2018). Based on this 
information, the single dose of 
 tirzepatide to be administered in this study is anticipated to 
be tolerable in healthy lactating females. 
Tirzepatide is a peptide molecule that is administered subcutaneously. Its excretion into the 
breastmilk is expected to be low. Even if it is ingested orally by a breastfed infant, it is unlikely 
that the tirzepatide peptide will be absorbed intact, since it will be digested in the gastrointestinal 
tract. Despite this, breastfeeding to infant will be discontinued and prohibited for the duration of 
the study to avoid exposing the infant to tirzepatide. 
The participation in the study requires interruption of breastfeeding for a total of 29 days after 
the administration of a single dose of tirzepatide. Interruption of breastfeeding or lactation gap 
for such a period of time may lead to difficulty or even failure in achieving satisfactory 
relactation. This risk is expected to be partially mitigated by providing adequate relactation 
support and education to the study participants who wish to resume breastfeeding after the 
completion of the study. Thereby, a lactation consultant will be readily available at the CRU as a 
resource to support potential efforts to achieve relactation if required or requested by the 
participant. 
Data Monitoring Committee: No 
 
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1.2. 
Schema  
 
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1.3. 
Schedule of Activities (SoA)  
Procedure 
Screening 
Treatment and Safety Monitoring 
FU/EDa 
Comments 
Day 
-28 to -2 
-1 
1 
2 
3 
4 
5 
6 
8 
15±1 
22±1 
29±1 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Admission to CRU 
 
X 
 
 
 
 
 
 
 
 
 
 
Enrollment will occur on Day -1 
Discharge from 
CRU 
 
 
 
 
 
 
X 
 
 
 
 
 
May be extended at the investigator’s 
clinical discretion for safety 
monitoring 
Outpatient visits to 
CRU 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
Days 6, 8, 15±1, and 22±1 may be 
performed remotely by home health 
nurses  
Review and 
confirm 
inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
and demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
exam/Medical 
assessment 
X 
X 
 
 
 
X 
 
 
X 
 
 
X 
Screening: Full physical examination 
All other timepoints: 
symptom-driven 
Height, weight, and 
BMI 
X 
X 
 
 
 
 
 
 
X 
 
 
X 
Height required only at screening 
Temperature 
X 
 
P 
 
 
 
 
 
 
 
 
 
 
Safety 12-lead 
ECG 
X 
 
P 
 
 
X 
 
 
 
 
 
X 
 
Vital signs 
X 
 
P 
 
 
X 
 
 
X 
 
 
X 
 
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Clinical laboratory 
tests – local 
laboratory 
X 
 
P 
 
 
 
 
 
X 
 
 
X 
See Appendix 2 (Section 10.2) for 
details. Predose measures are for 
baseline purpose only and results 
need not be reviewed prior to 
tirzepatide dosing 
Ethanol breath test 
and urine drug 
screen testing 
X 
X 
 
 
 
 
 
 
 
 
 
 
Per CRU local requirements 
Pregnancy test 
X 
X 
 
 
 
 
 
 
 
 
 
X 
Screening: Serum pregnancy test. All 
other timepoints: urine pregnancy test 
AEs/Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X 
 
Tirzepatide dosing 
 
 
0 
 
 
 
 
 
 
 
 
 
Actual tirzepatide dosing will be 
arbitrarily considered as time 0 hour 
Tirzepatide plasma 
PK samples (h) 
 
 
P, 12 
24 
48 
72 
96 
 
168 X 
 
X 
Predose sample should be collected 
within 2 hours prior to dosing 
(time 0) 
Glucose safety 
monitoring (h) 
 
 
P, 12 
24, 
36 
48 
72 
 
 
 
 
 
 
Performed using a glucometer using 
fingerprick capillary blood. 
Additional unscheduled 
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Abbreviations: AE = adverse event; BMI = body mass index; CRU = clinical research unit; D = Day; ECG = electrocardiogram; ED = early discontinuation; 
FU = follow-up; h = hours; P = predose; PK = pharmacokinetics. 
Note: CRU should schedule procedures as appropriate. However, if multiple procedures take place at the same time point, the following order of the procedure 
should be considered in terms of prioritization: ECGs, vital signs, PK breastmilk samples, PK plasma samples, clinical laboratory samples, and glucose 
samples. Unless otherwise specified, predose samples and procedure may be collected or performed any time up to 24 hours prior to dosing. 
a Final follow-up will occur 28 days ± 1 day after tirzepatide dose. Early discontinuation visit should take place within 14 days upon confirmation of early 
discontinuation. Tirzepatide breastmilk and plasma PK samples need not be collected if the participant discontinues prior to receiving a dose of tirzepatide. 
b Optional breastmilk PK sample. Breastmilk PK sample may be collected based on participant’s need to pump during this interval. 
 
measurements may be taken at the 
clinical discretion of the investigator 
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2. 
Introduction  
2.1. 
Study Rationale  
Tirzepatide (MOUNJARO™; LY3298176) is a glucose-dependent insulinotropic peptide (GIP) 
and glucagon-like peptide 1 (GLP-1) receptor agonist (RA) approved as an adjunct to diet and 
exercise for improving glycemic control in adult patients with type 2 diabetes mellitus (T2DM). 
The disposition of tirzepatide for adult patients has been characterized but data is lacking on 
whether tirzepatide is excreted in breastmilk. There is a need to understand tirzepatide 
concentrations in breastmilk to better inform healthcare practitioners in managing women of 
childbearing potential who may be potential users of tirzepatide. 
Study I8F-MC-GPIN (GPIN) is a postmarketing lactation study that will primarily assess the 
pharmacokinetics (PK) of tirzepatide in breastmilk following administration of a single 
 
dose of tirzepatide via the subcutaneous (SC) route in healthy lactating females. Additionally, 
plasma PK of tirzepatide will also be assessed. 
2.2. 
Background  
Tirzepatide is a GIP and GLP-1 RA. It is a 39 amino acid synthetic modified 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 
once-weekly by SC injection in a single-use prefilled pen. 
Tirzepatide has a chemical structure and pharmacologic profile that is distinct from GLP1 RAs 
due to the additional effects on GIP receptor (GIPR), 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 of reaching higher efficacy in target tissues such as the 
insulin-producing pancreatic β-cells that express both GIPR and glucagon-like peptide 1 before 
reaching its therapeutic limitation, which supports its use as a treatment for T2DM. 
Tirzepatide may attain additional efficacy by recruiting metabolically active tissues not targeted 
by classical GLP-1 analogs (for example, adipose tissue as indicated by the observation of 
increased energy utilization and resulting body weight loss) (Coskun et al. 2018; 
Frias et al. 2018). Weight loss data support the ongoing investigation of chronic weight 
management, non-alcoholic fatty liver disease, heart failure with preserved ejection fraction, 
obstructive sleep apnea, and chronic kidney disease as additional potential indications. 
2.3. 
Benefit/Risk Assessment  
There is no anticipated therapeutic benefit for participants in this study. 
As of 26 September 2022, tirzepatide 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 RA 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. 
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No clinically significant safety or tolerability concerns have been identified during clinical 
investigation of tirzepatide up to the single dose of 5 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 (Coskun et al. 2018). Based on this 
information, the single dose of 
 tirzepatide to be administered in this study is anticipated to 
be tolerable in healthy lactating females. 
Tirzepatide is a peptide molecule that is administered subcutaneously. Its excretion into the 
breastmilk is expected to be low. Even if it is ingested orally by a breastfed infant, it is unlikely 
that the tirzepatide peptide will be absorbed intact since it will be digested in the GI tract. 
Despite this, breastfeeding to the infant will be discontinued and prohibited for the duration of 
the study to avoid exposing the infant to tirzepatide. 
The participation in the study requires interruption of breastfeeding for a total of 29 days after 
the administration of a single dose of tirzepatide. Interruption of breastfeeding or lactation gap 
for such a period of time may lead to difficulty or even failure in achieving satisfactory 
relactation. This risk is expected to be partially mitigated by providing adequate relactation 
support and education to the study participants who wish to resume breastfeeding after the 
completion of the study. Thereby, a lactation consultant will be readily available at the clinical 
research unit (CRU) as a resource to support potential efforts to achieve relactation if required or 
requested by the participant. 
More information about the known and expected risks, serious adverse events (SAEs), and 
reasonably anticipated adverse events (AEs) of tirzepatide can be found in the package insert of 
MOUNJARO or in the tirzepatide Investigator’s Brochure. 
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3. 
Objectives and Endpoints  
Objectives 
Endpoints 
Primary 
 
 To evaluate tirzepatide 
pharmacokinetics (PK) in breastmilk 
of healthy lactating females 
 Area under the tirzepatide 
concentration-time curve in 
breastmilk from time 0 extrapolated to 
infinity (AUC0-∞) 
Secondary 
 
 
 
 
 
 
 
 
 
Abbreviations: AUC(0-tlast) = area under the concentration versus time curve from time zero to the last observable 
concentration; Cmax = maximum observed drug concentration; tmax = time to maximum observed drug 
concentration. 
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4. 
Study Design  
4.1. 
Overall Design  
This is a postmarketing, single-site, open-label, single-treatment arm, single-dose, lactation 
study, assessing PK of tirzepatide in breastmilk and plasma in healthy lactating women. 
Approximately 14 healthy lactating females will be enrolled so that about 8 females complete the 
study. 
Participants will receive a single dose of tirzepatide 
 delivered by subcutaneous injection. 
The study duration for individual participants, inclusive of screening, is expected to be 
approximately 8 weeks. 
Screening 
Screening may occur up to 27 days prior to Day -1. During the screening visit, participants will 
undergo screening tests as mentioned in Schedule of Activities (SoA; Section 1.3). Participants 
who are not enrolled within 28 days of screening may be subject to an additional medical 
assessment, clinical measurements or both, to confirm their eligibility. In such instances, at a 
minimum, the following screening tests and procedures should be repeated:  
 weight 
 vital signs 
 safety 12-lead electrocardiogram (ECG) 
 clinical laboratory tests, and 
 pregnancy test. 
Inpatient Treatment Period 
Participants will be admitted to the CRU on Day -1 to establish baseline measurements. 
Participants will receive a single SC tirzepatide 
 dose on Day 1 following overnight fasting 
of approximately 8 hours. Participants will remain in the CRU until Day 5 following the 
completion of study procedures. During inpatient stays, the infant is allowed to be in the CRU 
with the study participant during supervised visitation hours. The inpatient stay for the 
participant may be extended at the clinical discretion of the investigator (for example, necessary 
for the participant’s clinical wellbeing and management and monitoring of AEs). 
Breastmilk and plasma samples for tirzepatide PK will be collected. Breastmilk volume will be 
measured across the study duration as indicated in the SoA. Safety will be assessed by physical 
examination, medical assessments or both, vital signs, ECGs, safety laboratory tests, glucose 
safety monitoring, and the recording of AEs. Breastfeeding must be discontinued prior to the 
administration of tirzepatide and for the duration of the study. All costs associated with formula 
feeding and breast pumps required during the study will be covered by the study sponsor. 
Outpatient Follow-up Period 
On Days 6, 8, 15±1, and 22±1, participants may either return to the CRU for outpatient visits or 
have these visits be performed remotely by home health nurses as deemed appropriate by the 
study investigator. On Day 29±1, the participants will return to the CRU for the final follow-up 
visit.  
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4.2. 
Scientific Rationale for Study Design  
This study will be a single-arm open-label as the study’s primary endpoint PK measures are 
objective rather than subjective. 
The dose justification for tirzepatide is provided in Section 4.3. 
The rationale for the sample size is provided in Section 9.5. 
4.3. 
Justification for Dose  
No clinically significant safety or tolerability concerns have been identified during clinical 
investigation of tirzepatide up to the single dose of 5 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 single dose of 
 tirzepatide to be administered in this study is reasonably anticipated to be tolerable in this 
group of adult females. 
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 (Section 1.3) for the last participant in the study. 
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5. 
Study Population  
The eligibility of participants for the study will be based on the results of screening medical 
history, physical examination, vital signs, clinical laboratory tests, and 12-lead 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. Participants must be greater than or equal to 18 years of age inclusive at the time of 
signing the informed consent. 
Type of Participant and Disease Characteristics 
2. Participants who are overtly healthy females as determined by medical evaluation 
including medical history, physical examination, and laboratory tests. 
3. Female participants who delivered normal-term infant (at least 37 weeks gestation) and 
are at least 6 weeks postpartum at the time of screening. 
4. Female participant who has well-established lactation and is breastfeeding her infant 
(1 supplemental bottle of formula per day is acceptable). Note: Breastfeeding must be 
discontinued prior to the administration of tirzepatide on Day 1 and not resumed for the 
remaining duration of the study until a follow-up visit (or for total of 29 days after 
tirzepatide dosing for participants who discontinue early).  
5. Participants who have clinical laboratory test results, blood pressure, pulse rate, and an 
ECG reading that are considered to be within the normal reference range for the 
population or CRU 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 
6. Body mass index within the range of 18.5 to 40.0 kg/m2, inclusive. 
Sex and Contraceptive/Barrier Requirements 
7. Females only. 
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 Appendix 4 (Section 10.4). 
Informed Consent 
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8. Capable of giving signed informed consent as described in Appendix 1 (Section 10.1), 
which includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol. 
Other Inclusion Criteria 
9. Have venous access sufficient to allow for blood sampling as per the protocol. 
10. Having a breastfed infant who is able to feed from a bottle and use formula while 
breastfeeding is prohibited. 
11. Agree to abstain from breastfeeding their infant from the dose of tirzepatide on Day 1 to 
the follow-up visit, or for a total of 29 days after tirzepatide dosing for participants who 
discontinue early, to avoid potentially exposing their infant to tirzepatide. 
12. Willing and able to commit to the inpatient stays and procedures per study requirements. 
5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
13. 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 
tirzepatide, or of interfering with the interpretation of data. 
14. Have a history or presence of pancreatitis, elevation in serum amylase or lipase 
(>1.5 fold the ULN), clinically significant GI disorders (for example, 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. 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. A history of uncomplicated 
acute appendicitis and appendectomy is acceptable as well. 
15. Have evidence of significant active neuropsychiatric disease, as determined by the 
investigator. 
16. Have a history of multiple or clinically significant drug allergies or severe posttreatment 
hypersensitivity reactions. 
17. Have a personal or family history of medullary thyroid carcinoma or multiple endocrine 
neoplasia syndrome type 2. 
18. Have a history of malignancy within 5 years prior to screening. 
19. Show evidence of human immunodeficiency virus infection, positive human 
immunodeficiency virus antibodies, or both. 
20. Have evidence of hepatitis C, are positive for hepatitis C antibodies, or both. 
21. Have evidence of hepatitis B, are positive for hepatitis B surface antigen, or both. 
22. Have confirmed type 1 or type 2 diabetes mellitus. 
23. Have a history of inadequate lactation (for multiparous females who have previously 
breastfed). 
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24. Have a history of breast augmentation procedures judged to have a clinical impact on 
breastmilk expression (such as breast reduction surgery and some breast implants) or 
current evidence of acute or chronic conditions affecting breasts and potentially 
interfering with breast milk collection. 
Prior/Concomitant Therapy 
25. Regularly use known drugs of abuse or show positive findings on drug screen. 
26. Have received treatment with a drug that has not received regulatory approval for any 
indication within 30 days or 5 half-lives (whichever is longer) of screening. Other 
concomitant medications (including over-the-counter and prescription medications) may 
be considered on a case-by-case basis by the investigator preferably in consultation with 
the clinical pharmacologist (CP). 
Prior/Concurrent Clinical Study Experience 
27.  Have previously completed or withdrawn from this study. 
28. 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. 
29. Any exposure to tirzepatide within the prior 3 months of screening or history of allergies 
to tirzepatide, other GLP 1 analogs, or related compounds. 
Diagnostic Assessments 
30. Have glycated hemoglobin (HbA1c) greater than or equal to 6.5% at screening. 
Other Exclusion Criteria 
31. Unable or unwilling to adhere to smoking and alcohol restrictions during CRU admission 
and visits. 
32. Are CRU personnel directly affiliated with this study and their immediate families. 
Immediate family is defined as a spouse, biological or legal guardian, child, or sibling. 
33. Are Lilly employees or are employees of a third-party organization involved with the 
study. 
34. Have an average weekly alcohol intake that exceeds 14 units per week, 
OR 
are unwilling to stop alcohol consumption during study visits and time in the CRU 
(number of units = [total volume of drink (mL) x ABV (%)]/1000. ABV = alcohol by 
volume). 
35. 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. 
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5.3.1. 
Meals and Dietary Restrictions  
The participant will be required to fast overnight for at least 8 hours when clinical laboratory test 
samples are taken. A meal will be offered to study participants after about 2 hours post 
tirzepatide dose. During inpatient stays, the participant may not consume any food other than that 
provided by the CRU, although water may 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 in the CRU.  
Alcohol intake during outpatient periods should not exceed 2 units per day. 
No nicotine use will be permitted while at the CRU. While not resident in the CRU, participants 
should not consume more than 10 cigarettes or the equivalent per day. 
Participants will be allowed to maintain 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 tirzepatide dose 
administration until discharge from the CRU. 
5.4. 
Screen Failures  
A screen failure occurs when a participant who consents to participate in the clinical study is not 
subsequently assigned to tirzepatide or enrolled in the study. 
Screening tests such as clinical laboratory tests and vital signs, ECGs may be repeated at the 
discretion of the investigator. Individuals who do not meet the criteria for participation in this 
study (screen failure) may not be re-screened. Participants numbers, enrollment numbers are 
assigned after medical assessments have been completed to ensure only eligible participants 
enter the study. 
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 or used by a study participant 
according to the study protocol. 
6.1. 
Study Intervention Administered  
Each participant will receive 1 dose of tirzepatide administered as a single SC injection of 
 
tirzepatide into the abdomen. Tirzepatide will be administered by CRU personnel to the lower 
abdominal quadrants, approximately 5 cm from the umbilicus. 
This table lists the interventions used in this study. 
*Supplied as MOUNJARO. 
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. 
Tirzepatide will be provided as autoinjectors containing 
 solution and provided in 
individual cartons to be dispensed. 
The investigational product (IP) will be labeled according to the country’s regulatory 
requirements. 
The investigator or designee is responsible for 
 explaining the correct use of the tirzepatide autoinjector to the CRU personnel 
 verifying that instructions are followed properly 
 maintaining accurate records of tirzepatide dispensing and collection, and 
 returning all unused medication to Lilly or its designee at the end of the study. 
Note: In some cases, the CRU may destroy the material if, during the investigative site selection, 
the evaluator has verified and documented that the CRU has appropriate facilities and written 
procedures to dispose of clinical materials. 
CRU staff will administer the injection. Instructions for autoinjector administration will be 
provided by the sponsor. Only a limited number of individuals will perform SC administration 
for consistency reasons. The actual time of dosing will be recorded in the participant’s electronic 
case report form (eCRF). 
Intervention Name 
Tirzepatide* 
Dosage Formulation 
Autoinjector 
Dosage Strength and Volume 
 
Route of Administration 
Subcutaneous 
Dosing Instructions 
Inject subcutaneously into lower abdominal quadrant, approximately 5 cm 
from the umbilicus 
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6.2. 
Preparation, Handling, Storage, and Accountability  
 The investigator or designee must confirm appropriate storage conditions have been 
maintained during transit for all tirzepatide 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 (that is, 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. 
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 that the dose is 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. 
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 intended for this study (
single dose). 
There is no specific antidote for tirzepatide. In the event of an overdose, the participant should 
receive appropriate supportive care and any AEs should be documented. 
Refer to the package insert of MOUNJARO or the tirzepatide Investigator’s Brochure for further 
details and recommendations. 
In the event of an overdose, the investigator should: 
 contact the medical monitor immediately 
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 monitor the participant closely for any AE, or SAE and laboratory abnormalities as 
medically appropriate until 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 
eCRF. 
6.8. 
Prior and Concomitant Therapy  
Any medication or vaccine including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements or other specific categories of interest 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 CP should be contacted if there are any questions regarding concomitant or prior therapy. 
Participants should generally abstain from taking over-the-counter or prescription medication, 
and/or herbal supplements (except for vitamin/mineral supplements, hormonal contraception 
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 per day from all acetaminophen- or paracetamol-containing medicinal products. 
Other concomitant medications (including over-the-counter and prescription medications) may 
be considered on a case-by-case basis by the investigator preferably in consultation with the CP. 
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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal  
Discontinuation of the study as a whole is handled as part of Appendix 1 (Section 10.1). 
7.1. 
Discontinuation of Study Intervention  
Not applicable as this is a single-dose study. 
7.2. 
Participant Discontinuation/Withdrawal from the Study  
Discontinuation is expected to be uncommon. A participant may withdraw from the study 
 at any time at the participant’s 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, 
and 
 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 the 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.  
Note: Breastfeeding must be discontinued prior to the administration of tirzepatide on Day 1 and 
not resumed for the remaining duration of the study until a follow-up visit or for a total of 
29 days after tirzepatide dosing for participants who discontinue early. 
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 the destruction of any samples taken and 
not tested, and the investigator must document this in the CRU 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 CRU. CRU 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. 
CRU personnel or an independent third party will attempt to collect the vital status of the 
participant within legal and ethical boundaries for all participants randomized, including those 
who did not get an IP. Public sources may be searched for vital status information. If the 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 (Section 1.3). 
 The specifications in this protocol for the timings of safety and sample collection are 
given as targets to be achieved within reasonable limits. Modifications may be made to 
the time points based upon emerging clinical information. The scheduled time points may 
be subject to minor alterations; however, the actual time must be correctly recorded in the 
eCRF. 
 Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence. 
 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. 
Appendix 2 (Section 10.2) lists the laboratory tests that will be performed for this study. 
Section 10.2.1 of Appendix 2 provides a summary of the maximum number and volume of blood 
samples, for all sampling, during the study.  
Unless otherwise stated in the subsections below, all samples collected for specified laboratory 
tests will be destroyed within 60 days of receipt of confirmed test results. Certain samples may 
be retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards. 
8.1. 
Efficacy Assessments  
Efficacy is not evaluated in this study. 
8.2. 
Safety Assessments  
Planned time points for all safety assessments are provided in the SoA. 
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, as well as a breast exam. 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 the investigator’s clinical discretion. 
8.2.2. 
Vital Signs  
 For each participant, vital signs measurements should be conducted according to the 
SoA (Section 1.3). 
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 Blood pressure and pulse rate should be measured after at least 3 minutes of seated rest. 
 If orthostatic measurements are required, participants should be supine for at least 
5 minutes and stand for at least 3 minutes. 
 If the participant feels unable to stand, supine vital signs only will be recorded. 
 Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of 
dizziness or posture-induced symptoms. Additional vital signs may be measured during 
each study period if warranted. 
8.2.3. 
Electrocardiograms  
 For each participant, a single 12-lead ECG will be obtained at the CRU as outlined in the 
SoA (see Section 1.3). 
 ECGs must be recorded before collecting any blood samples. Participants must be supine 
for approximately 5 to 10 minutes before ECG collection and remain supine but awake 
during ECG collection. 
 Any clinically significant findings from ECGs that result in a diagnosis and that occur 
after the participant receives the dose of tirzepatide should be reported to Lilly or its 
designee, as an AE via eCRF. 
 ECGs may be obtained at additional times when deemed clinically necessary. All ECGs 
recorded should be stored at the CRU. 
 ECGs will be interpreted by a qualified physician (the investigator or qualified designee) 
as soon after the time of ECG collection as possible, and ideally, while the participant is 
still present, to determine whether the participant meets entry criteria at the relevant visits 
and for immediate participant management, should any clinically relevant findings be 
identified. 
 If a clinically significant finding is identified 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 their 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 (see Section 10.2) for the list of clinical laboratory tests to be performed 
and the SoA (see Section 1.3) 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 which are 
not associated with the underlying disease unless judged by the investigator to be more 
severe than expected for the participant’s condition. 
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 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 or baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor should 
be notified. 
○ 
All protocol-required laboratory assessments, as defined in Appendix 2 
(Section 10.2), must be conducted in accordance with the SoA (Section 1.3), standard 
collection requirements, and laboratory manual. 
 If laboratory values from non-protocol specified laboratory assessments performed at an 
investigator-designated local laboratory require a change in participant management or 
are considered clinically significant by the investigator (for example, SAE or AE or dose 
modification), then report the information as an AE. 
8.2.5. 
Pregnancy Testing  
In this study, a serum pregnancy test will be performed at screening and urine pregnancy tests at 
subsequent visits as indicated in the SoA (Section 1.3) 
8.2.6. 
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 6, Section 10.6) for the monitoring of pancreatic events whenever 
lipase and/or amylase is confirmed to be ≥3x ULN at any visit postdose, even if the participant is 
asymptomatic. 
8.2.7. 
Glucose Monitoring  
For safety purposes, blood glucose measurements will be performed using a glucometer with 
fingerprick capillary blood 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. 
8.2.7.1. 
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 the 
investigator’s discretion, be given a glucometer to assist in the evaluation of these symptoms. 
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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 severe 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. 
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, were semiconscious or unconscious, or 
experienced coma with or without seizures; 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. 
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8.2.8. 
Injection-Site Reactions  
Symptoms and signs of a local injection-site reaction (ISR) may include erythema, induration, 
pain, pruritus, and edema. 
If an ISR is reported by a participant or assessed as clinically significant by CRU personnel, this 
shall be recorded as an AE and the ISR eCRF will be used to capture additional information 
about this reaction, such as injection-site pain, degree and area of erythema, induration, pruritus, 
and edema. 
8.2.9. 
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, and 
 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. 
8.2.10. 
Safety Monitoring  
The Lilly CP or CRP/scientist will monitor safety data throughout the course of the study. 
Lilly will review SAEs within time frames mandated by company procedures. The Lilly CP or 
CRP/scientist will periodically review 
 trends in safety data 
 laboratory analytes, and 
 AEs. 
When appropriate, the Lilly CP or CRP/scientist will consult with the functionally independent 
Global Patient Safety therapeutic area physician or clinical research scientist. 
8.2.10.1. Hepatic Safety  
See Appendix 5, Section 10.5 for the full list of hepatic evaluation tests. 
Close Hepatic Monitoring 
Laboratory tests, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
alkaline phosphatase (ALP), total bilirubin level (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: 
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Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin level; ULN = upper limit of normal. 
If the abnormality persists or worsens, clinical and laboratory monitoring and evaluation for 
possible causes of abnormal liver tests should be initiated by the investigator in consultation with 
the Lilly-designated CP or CRP/scientist. At a minimum, this evaluation should include a 
physical examination and a thorough medical history, including symptoms, recent illnesses 
(for example, heart failure, systemic infection, hypotension, or seizures), recent travel history, 
history of concomitant medications (including over-the-counter medications), 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. 
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: 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin level; ULN = upper limit of normal. 
a Hepatic signs/symptoms are severe fatigue, nausea, vomiting, right upper-quadrant abdominal pain, fever, rash, 
and/or eosinophilia >5%. 
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 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)  
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At a minimum, this evaluation should include a physical examination and a thorough medical 
history, as outlined above, as well as tests for prothrombin time-international normalization ratio; 
tests for viral hepatitis A, B, C, or E; tests for autoimmune hepatitis. 
Based on the participant’s history and initial results, further testing should be considered, in 
consultation with the Lilly-designated CP or CRP/scientist, including 
 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 
 liver biopsy. 
Additional Hepatic Data Collection (hepatic safety eCRF) in Study Participants Who Have 
Abnormal Liver Test Results During the Study 
Additional hepatic safety data collection in hepatic safety eCRFs should be performed in study 
participants who meet 1 or more of the following 5 conditions: 
1. Elevation of serum ALT level 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. Elevated TBL level 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. 
3. Elevation of serum ALP level 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. 
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4. Hepatic event considered to be an SAE. 
5. Discontinuation of tirzepatide due to a hepatic event. 
Note: the interval between the 2 consecutive blood tests should be at least 2 days. 
8.3. 
Adverse Events, Serious Adverse Events, and Product Complaints  
The definitions of the following events can be found in Appendix 3 (Section 10.3): 
 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 on events 
that are serious, considered related to the study intervention or study procedures, or that caused 
the participant to discontinue the study intervention (see Section 7). 
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 each participant at 
subsequent visits/contacts. All SAEs and AEs of special interest (as defined in Section 8.3.3) will 
be followed 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 
Appendix 3 (Section 10.3). 
Investigators are responsible for monitoring the safety of participants who have entered this 
study and for alerting Lilly or its designee to any event that seems unusual even if this event may 
be considered an unanticipated benefit to the participant. 
The investigator is responsible for the appropriate medical care of participants during the study. 
 
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8.3.1. 
Timing and Mechanism for Collecting Events  
This table describes the timing, deadlines, and mechanism for collecting events. 
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 informed 
consent form 
(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 informed 
consent form 
(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  
After the 
start of study 
intervention 
90 days plus 
5 half-lives 
Within 24 hours 
(see Section 8.3.2) 
Pregnancy paper 
form 
Pregnancy 
paper form 
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Abbreviations: AE = adverse event; CRF = case report form; N/A = not applicable; PC = product complaint; 
SAE = serious adverse event. 
* Serious adverse events should not be reported unless the investigator deems them to be possibly related to study 
treatment or study participation. 
8.3.2. 
Pregnancy  
Collection of Pregnancy Information 
Female participants who become pregnant 
 The investigator will collect pregnancy information on any 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 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. 
after the last 
dose  
Product Complaints 
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 
 
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 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. 
 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. 
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 
 arrhythmias and cardiac conductive disorders 
 hypersensitivity events 
 severe ISRs, and 
 severe GI AEs. 
8.4. 
Pharmacokinetics  
At the visits and times specified in the SoA (Section 1.3), breastmilk will be collected to 
determine tirzepatide concentration and amount excreted from lactation. Venous blood samples 
of approximately 3 mL each will also be collected to determine the plasma concentrations of 
tirzepatide. A maximum of 3 unscheduled samples may be collected at additional time points 
during the study if warranted and agreed upon between both the investigator and sponsor. 
Instructions for the collection and handling of breastmilk samples will be provided by the 
sponsor. The actual date and time (24-hour clock time) and time intervals of each sampling will 
be recorded. 
8.4.1. 
Bioanalysis  
Breastmilk and plasma samples will be analyzed at a laboratory approved by the sponsor and 
stored at a facility designated by the sponsor. 
Concentrations of tirzepatide in breastmilk and plasma will be assayed using validated liquid 
chromatography tandem mass spectrometry methods. 
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Bioanalytical samples collected to measure tirzepatide concentrations will be retained for a 
maximum of 1 year following last participant visit for the study. During this time, samples 
remaining after the bioanalyses may be used for exploratory analyses such as metabolism, 
protein binding, or bioanalytical method cross-validation. 
8.5. 
Pharmacodynamics  
Pharmacodynamic parameters are not evaluated in this study. 
8.6. 
Genetics  
Genetics are not evaluated in this study. 
8.7. 
Biomarkers  
Biomarkers are not evaluated in this study. 
8.8. 
Immunogenicity Assessments  
Not applicable. 
8.9. 
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  
Statistical analysis of this study will be the responsibility of Eli Lilly and Company or its 
designee. 
9.1. 
Statistical Hypotheses  
9.1.1. 
Multiplicity Adjustment  
Not applicable. 
9.2. 
Analyses Sets  
Pharmacokinetic analyses will be conducted on data from all participants who have received 
tirzepatide and have evaluable PK. Safety summaries will be conducted for all participants who 
have received tirzepatide, whether or not they completed all protocol requirements. 
9.3. 
Statistical Analyses  
9.3.1. General Considerations  
PK parameter estimates for tirzepatide in breastmilk and plasma will be calculated by standard 
noncompartmental methods of analysis and summarized using standard descriptive statistics. 
See Appendix 7 (Section 10.7) for details of the PK analysis plan. 
9.3.2. 
Primary Endpoint(s) Analysis  
The primary PK parameter for analysis will be area under the tirzepatide concentration-time 
curve in breastmilk from time 0 extrapolated to infinity (AUC[0-∞]). Summary of tirzepatide area 
under the concentration-time curve in breastmilk, AUC(0-∞), and a 95% confidence interval for 
the geometric mean will be provided. 
9.3.3. 
Secondary Endpoint Analysis  
Summaries of
 
 
 
 will be provided. Additional parameters may be estimated as deemed 
necessary. 
9.3.4. 
Safety Analyses  
Safety summaries will be conducted for all participants who have received tirzepatide, whether 
or not they completed all protocol requirements. 
9.3.4.1. 
Clinical Evaluation of Safety  
All treatment-emergent adverse events (TEAEs) will be listed and, if the frequency of events 
allows, TEAEs will be summarized using descriptive methodology. The incidence of TEAEs will 
be presented by severity and by association with tirzepatide as perceived by the investigator. 
Symptoms reported to occur prior to enrollment will be distinguished from those reported as new 
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or increased in severity during the study. Each symptom will be classified by the most suitable 
term from the medical regulatory dictionary. The number of IP-related SAEs will be reported. 
9.3.4.2. 
Statistical Evaluation of Safety  
Safety parameters that will be summarized include incidence of TEAEs, safety lab parameters 
and vital signs. The parameters will be listed and summarized using standard descriptive 
statistics. Additional analysis will be performed if warranted upon review of the data. Physical 
examinations and ECGs will be performed for safety monitoring purposes and will not be 
presented. 
9.3.4.3. 
Injection-Site Reactions  
Incidence of erythema, induration, pain, itching, and edema will be listed and summarized. 
9.3.5. 
Other Analyses  
Not applicable. 
9.4. 
Interim Analysis  
No interim analyses are planned for this study. If an unplanned interim analysis is deemed 
necessary, the Lilly CP, CRP, or designee will consult with the appropriate medical director or 
designee to determine if it is necessary to amend the protocol. 
9.5. 
Sample Size Determination  
Approximately 
 participants will be enrolled so that about  participants provide evaluable PK 
data. Since inter-participant variability of primary PK parameter in breastmilk is unknown, 
sample size is not chosen to achieve a specific precision in estimation of the primary endpoint. 
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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: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
o Applicable ICH Good Clinical Practice (GCP) Guidelines 
o Applicable laws and regulations 
 The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (for example, advertisements) must be submitted to an Institutional Review 
Boards (IRB)/Independent Ethics Committees (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: 
o 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. 
o Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
o Providing oversight of study conduct for participants under their responsibility and 
adherence to requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, 
the IRB/IEC, European regulation 536/2014 for clinical studies (if applicable), and all 
other applicable local regulations. 
o 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.  
10.1.2. 
Financial Disclosure  
Investigators and sub-investigators 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. 
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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 CFR 50, local regulations, ICH guidelines, 
privacy, and data protection requirements, where applicable, and the IRB/IEC or study 
center. 
 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. 
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 study due to safety findings, this 
decision will be communicated by Lilly to all investigators (for example, by 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 
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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 data set 
would result in analyses lacking scientific rigor (for example, underpowered) or compromise the 
integrity of the overall analyses (for example, study 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 electronic CRFs 
unless transmitted to the sponsor or designee electronically (for example, 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. Source data may include laboratory tests, medical 
records, and clinical notes. 
 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. 
 Monitoring details describing strategy (for example, risk-based initiatives in operations 
and quality such as risk management and mitigation strategies and analytical risk-based 
monitoring), methods, responsibilities, and requirements, including handling of 
noncompliance issues and monitoring techniques are provided in the Monitoring Plan. 
 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 
(for example, contract research organizations). 
 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. 
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 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 (CTA) 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, Sponsor or its representatives will periodically check a sample of the 
participant data recorded against source documents at the CRU. The study may be 
audited by 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 (EDC) 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 EDC 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. 
 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 cross-reference to 
Section 10.1.6. 
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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 table below 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 
Abbreviations: HIV = human immunodeficiency virus; RBC = red blood cells; WBC = white blood cells. 
a Performed by local laboratory. Results will be validated by the local laboratory at the time of testing. 
b Performed by local laboratory at screening only. 
c Pregnancy test: Serum pregnancy test will be performed at screening and urine pregnancy test will be performed 
at Day -1 and at the safety follow-up, see Schedule of Activities in Section 1.3.  
d Performed locally at site during screening and admission on Day -1. Additional testing may be performed at the 
discretion of the investigator if warranted. 
e Test only if urinalysis result is abnormal (i.e., positive for blood, protein, or nitrites). 
 
 
Hematologya 
Clinical Chemistry (fasting)a 
Hematocrit 
Sodium 
Hemoglobin 
Potassium 
Erythrocyte count (RBC) 
Bicarbonate 
Mean cell volume  
Chloride 
Mean cell hemoglobin  
Calcium 
Mean cell hemoglobin concentration  
Glucose 
Leukocytes (WBC) 
Blood urea nitrogen 
Platelets 
Total protein 
Absolute counts of: 
Albumin 
Neutrophils 
Total bilirubin 
Lymphocytes 
Alkaline phosphatase 
Monocytes 
Aspartate aminotransferase 
Eosinophils 
Alanine aminotransferase 
Basophils 
Creatinine 
 
Amylase 
 
Lipase 
Urinalysisa 
 
Specific gravity 
Hepatitis B surface antigenb 
pH 
Hepatitis C antibodyb 
Protein 
HIV or HIV antibodyb 
Glucose 
Pregnancy testc 
Ketones 
Ethanol breath test and urine drug screen testingd 
Bilirubin 
Hemoglobin A1Cb 
Urobilinogen 
 
Blood 
 
Nitrite 
 
Microscopic examination of sedimente 
 
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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. 
Number of samples in parenthesis assumes 3 additional unscheduled samples which may be 
taken for safety purpose. 
Protocol GPIN Sampling Summary 
a Additional samples may be drawn or taken if needed for safety purposes. 
b Performed in a local laboratory. 
c Performed at a central or referral laboratory approved by the sponsor. 
d Performed at bedside using a glucometer – rounded to 1 mL. 
 
Purpose 
Blood Volume 
per Sample (mL) 
Number of Blood 
Samples 
Total Volume 
(mL) 
Screening testsa,b 
25 
1 
25 
Clinical laboratory testsa,b 
12 
3 
36 
Pharmacokineticsc 
3 
9 (+3) 
36 
Capillary plasma glucosea,d 
Negligible 
6 (+3) 
1 
Total 
 
 
98 
Total for clinical purposes (rounded up to the nearest 10 mL) 
100 
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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. 
Events Meeting the AE Definition 
 Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (for example, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (that is, not related 
to progression of underlying disease). 
 Exacerbation of a chronic or intermittent pre-existing 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 IMP, including signs, symptoms, or clinical 
sequelae. 
 The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfill the definition of an AE or SAE. Also, lack of 
efficacy or failure of expected pharmacological action also constitutes an AE or SAE. 
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 (for example, endoscopy, appendectomy): the condition 
that leads to the procedure is the AE. 
 Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
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 Anticipated day-to-day fluctuations of pre-existing 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 one 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 pre-existing 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 (for example, sprained ankle) which 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 (for example, 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 surgical 
intervention to prevent one 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. 
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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 (for example, hospital progress notes, laboratory reports, and 
diagnostics 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 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 
Sponsor or designee. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to 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. 
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Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to one of the following categories: 
 Mild: A type of adverse event 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 adverse event 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 adverse event 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 a 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 one 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 Investigator’s Brochure and/or Product Information, 
for marketed products 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 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 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 one of the criteria used when determining regulatory 
reporting requirements. 
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 sponsor or 
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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. 
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 a SAE is essential so that legal 
obligations and ethical responsibilities towards 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, IRB/IEC, and investigators. 
 An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (for example, summary or listing of SAEs) from the sponsor 
will review and then file it along with the Investigator’s Brochure or state other 
documents 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 may participate in this study. 
WOCBPs 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 contraception, where at least 1 form must be highly 
effective. 
These forms of contraception must be used during the study and for at least 30 days 
after the last dose of the study intervention. 
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  
 
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 by hysterosalpingogram) 
 
combined contraceptive vaginal ring, or 
 
intrauterine devices 
Effective contraception 
 
barrier method with use of a spermicide 
o 
male 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  
 
lactational amenorrhea 
 
diaphragm with spermicide or cervical sponges 
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 
female condom with spermicide 
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10.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-up 
Assessments  
See protocol Section 8.2.10.1 for guidance on appropriate test selection. 
Testing by an investigator-designated local laboratory should be performed for all applicable and 
available testing defined by this guidance. 
The local laboratory must be qualified in accordance with applicable local regulations. 
a Not required if anti-actin antibody is tested. 
b Reflex/confirmation dependent on regulatory requirements, testing availability, or both. 
c Not required if anti-smooth muscle antibody (ASMA) is tested. 
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 
Acetaminophen protein adducts 
Platelets 
Alkaline phosphatase isoenzymes 
Cell morphology (RBC and WBC) 
Ceruloplasmin 
Hepatic Coagulation Panel 
Copper 
Prothrombin time, INR (PT-INR) 
Ethyl alcohol (EtOH) 
Hepatitis A virus (HAV) testing: 
Haptoglobin 
HAV total antibody 
Immunoglobulin IgA (quantitative) 
HAV IgM antibody 
Immunoglobulin IgG (quantitative) 
Hepatitis B virus (HBV) testing: 
Immunoglobulin IgM (quantitative) 
Hepatitis B surface antigen (HBsAg) 
Phosphatidylethanol (PEth) 
Hepatitis B surface antibody (anti-HBs) 
Urine Chemistry 
Hepatitis B core total antibody (anti-HBc) 
Drug screen 
Hepatitis B core IgM antibody 
Ethyl glucuronide (EtG) 
HBV DNAb 
Other Serology 
Hepatitis C virus (HCV) testing: 
Anti-nuclear antibody (ANA) 
HCV antibody 
Anti-smooth muscle antibody (ASMA)a 
HCV RNAb 
Anti-actin antibodyc 
Hepatitis D virus (HDV) testing: 
Epstein-Barr virus (EBV) testing: 
HDV antibody 
EBV antibody 
Hepatitis E virus (HEV) testing: 
EBV DNAb 
HEV IgG antibody 
Cytomegalovirus (CMV) testing: 
HEV IgM antibody 
CMV antibody 
HEV RNAb 
CMV DNAb 
Microbiology  
Herpes simplex virus (HSV) testing: 
Culture: 
HSV (Type 1 and 2) antibody 
Blood 
HSV (Type 1 and 2) DNAb 
Urine 
Liver kidney microsomal type 1 (LKM-1) antibody 
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10.6. 
Appendix 6: 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 (i.e., 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, 2017b). 
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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10.7. 
Appendix 7: Pharmacokinetic Analysis Plan  
PK Software and Version 
 Phoenix Version 8.1 or higher will be used for noncompartmental analyses. 
Rules for Handling Measurement Values in PK Analysis 
 Actual times will be used for the calculation of individual plasma PK parameters. 
 The actual start times of each breastmilk collection will be used for the calculation of 
individual breastmilk PK parameters. 
 Concentrations below the quantification limit occurring before the first quantifiable 
concentration in an individual profile will be treated as missing. 
 Atypical data will be reviewed for possible outliers according to the criteria outlined in 
the standard operating procedure (SOP) “Treatment of Outliers During PK Analysis.” 
 Sample times deviating >10% from the scheduled sample time will be excluded from the 
mean concentration-time plots. 
Analysis Methods 
 Standard noncompartmental PK methods will be used to calculate relevant PK 
parameters according to the SOP for Non-Compartmental PK Analysis Methods and 
Reporting. 
 Mean concentration profiles will be evaluated graphically for plasma and breastmilk. 
Mean concentrations will be calculated as described in the SOP for Non-Compartmental 
PK Analysis Methods and Reporting. If a specific sample is collected >10% outside of 
the scheduled time, the concentration in that sample will not be included in the mean 
calculation. 
PK Data Reported 
 AUC(0-∞), 
 
 
 
 
 breastmilk will be summarized 
with geometric mean and 95% confidence interval for the geometric mean. 
 Milk-to-plasma ratio will be estimated as AUC(0-∞), breastmilk / AUC(0-∞),plasma. 
 Steady-state breastmilk exposure AUC(tau,ss) would be considered to approximate 
AUC(0-inf),breastmilk after a single dose. 
 
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10.8. 
Appendix 8: Protocol Amendment History  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
Amendment [a]: 24 July 2023 
This amendment is considered to be non-substantial. 
Overall Rationale for the Amendment: 
The protocol is being amended to address FDA recommendations on contraceptive and barrier 
guidance.  
Section # and 
Name 
Description of Change 
Brief Rationale 
1.3 Schedule of 
Activities  
Added 
 optional 
breastmilk PK sample 
To permit collection of breastmilk based 
on participant's need to pump during this 
interval and to ensure that all breastmilk is 
captured during the 
 post 
dose. 
10.4.2 
Contraception 
Guidance 
“diaphragms with spermicide or 
cervical sponges” and “female 
condom with spermicide” were 
removed from the effective 
forms of contraception list and 
added to the ineffective forms of 
contraception list 
Updated based on FDA feedback 
 
 
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10.9. 
Appendix 8: 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-last) 
AUC from time 0 to the last measurable concentration after the first dose 
AUC(0-∞) 
AUC from time 0 to infinity 
CFR 
Code of Federal Regulations 
Cmax 
maximum observed drug concentration 
CIOMS 
Council for International Organizations of Medical Sciences 
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 
eCRF 
electronic case report form 
ECG 
electrocardiogram 
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 
GIP 
glucose-dependent insulinotropic peptide 
GIPR 
GIP receptor 
GLP-1 
glucagon-like peptide 1 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committees 
IP 
investigational product 
IRB 
Institutional Review Boards 
ISR 
injection-site reaction 
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.” 
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 one or more 
of the five “rights” of medication use: the right participant, the right drug, the right 
dose, right route, at the right time. 
In addition to the core five 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 (for example, 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 
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 
PC 
product complaint 
PK 
pharmacokinetic(s) 
RA 
receptor agonist 
SAE 
serious adverse event 
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.  
SC 
subcutaneous 
SoA 
schedule of activities 
SOP 
standard operating procedure 
TEAE 
treatment-emergent adverse event: An untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens relative 
to the pretreatment state, and does not necessarily have to have a causal relationship 
with this treatment. 
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- 
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Approved on 15 Sep 2023 GMT

Signature Page for VV-CLIN-075154 v3.0
Signature Page for VV-CLIN-075154 v3.0
Approval
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Approval
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Approved on 15 Sep 2023 GMT
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