Clinical trial NCT05696847
Conditions: Obesity
Keywords: Pediatrics Obesity Chronic weight management
Sponsor: Eli Lilly and Company
Start date: 2023-02-07; Completion date: 2025-01-16
Enrollment: 28 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main purpose of this study is to evaluate the safety and tolerability of tirzepatide (LY3298176) in pediatric participants with obesity. The blood tests will be performed to investigate how the body processes the study drug in these participants. For each participant, the study will last about approximately 13 weeks excluding the screening period.

Detailed description:

Arms: arm 1: Participants in this cohort had a screening body weight (BW) of at least 50 kilograms (kg) received placebo administered subcutaneously (SC) once weekly (QW) during Weeks 1 to 8. arm 2: Participants in this cohort had a screening body weight of at least 50 kg received 2.5 milligrams (mg) tirzepatide administered SC QW during Weeks 1 to 4 followed by 5 mg tirzepatide during Weeks 5 to 8. arm 3: Participants in this cohort had a screening body weight less than 50 kg received placebo administered SC QW during Weeks 1 to 8. arm 4: Participants in this cohort had a screening body weight less than 50 kg received 1.25 mg tirzepatide administered SC QW during Weeks 1 to 4 followed by 2.5 mg tirzepatide during Weeks 5 to 8. arm 5: Participants in this cohort had a screening body weight between 40 to 60 kg, inclusive, received placebo administered SC QW during Weeks 1 to 8. arm 6: Participants in this cohort had a screening body weight between 40 to 60 kg, inclusive, received 2.5 mg tirzepatide administered SC QW during Weeks 1 to 4 followed by 5 mg tirzepatide during Weeks 5 to 8.
Interventions: intervention 1: Tirzepatide intervention 2: Placebo
Intervention descriptions: intervention 1: Administered SC intervention 2: Administered SC

Protocol documents:
Prot_000.pdf: 
Protocol: I8F-MC-GPHV 
 
 
 
 
A Safety, Tolerability and Pharmacokinetic Study of Tirzepatide for the Treatment of Pediatric 
Participants (6 years to 11 years) with Obesity 
 
 
 
 
NCT05696847 
 
 
 
 
Approval Date: 16-Nov-2023 


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I8F-MC-GPHV(e) 
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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 Safety, Tolerability and Pharmacokinetic Study of Tirzepatide for the 
Treatment of Pediatric Participants (6 years to 11 years) with Obesity. 
Protocol Number: I8F-MC-GPHV 
Amendment Number: e 
Compound: Tirzepatide (LY3298176) 
Brief Title:  
Safety, Tolerability and Pharmacokinetics of Tirzepatide in Pediatric Participants with Obesity. 
Study Phase: 1 
Acronym: GPHV 
Sponsor Name: Eli Lilly and Company 
Legal Registered Address: Indianapolis, Indiana, USA 46285 
Regulatory Agency Identifier Number(s) 
IND: 139721 
Approval Date: Protocol Amendment (e) Electronically Signed and Approved by Lilly on date 
provided below. 
 
Document ID: VV-CLIN-110264 
 
 
 
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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 
Amendment d 
28-July-2023  
Amendment c 
05-June-2023 
Amendment b 
19-January-2023 
Amendment a 
27-October-2022 
Original Protocol 
30-June-2022 
Amendment [e]  
This amendment is considered to be substantial and was done for reducing potential safety risk 
of the participants while ensuring/maximizing adequacy and robustness of the data generated in 
the clinical study. 
Overall Rationale for the Amendment: 
This protocol is being amended to narrow the range of body weight in Cohort 3 in order to 
generate additional safety, tolerability, and PK data of tirzepatide in participants with relatively 
lower body weight. A lower limit was also selected for the body weight as a conservative 
approach, based on available adult exposure data from PK/PD modeling.  
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 1.1 
Synopsis – 
treatment 
arms and 
planned 
duration 
Updated screening body weight 
for Cohort 3 
Participants with body weight in the range 
of 40 to 60 kg inclusive will be enrolled in 
Cohort 3: 
 narrow body weight range is 
selected to generate additional 
safety, tolerability, and PK data of 
tirzepatide in participants with 
relatively lower body weight 
 upper limit of 60 kg is selected to 
obtain data from participants in 50 
to 60 kg range who will receive a 
starting dose of 
 mg tirzepatide 
in addition to data from Cohort 1 
which includes participants ≥50 kg 
 sentinel dosing in first  participants 
in the body weight range of 40 to 
50kg 
Section 1.2 
Schema 
Updated schema to reflect body 
weight range and sentinel dosing 
for Cohort 3 
Section 2.3 
Benefit/Risk 
Assessment 
Deleted the text on ‘lower body 
weight’ for participants in Cohort 
3 
Section 4.1 
Overall 
Design 
Updated text to include body 
weight range for Cohort 3 
 
Sentinel dosing will be used for  
participants in the body weight 
range of 40 to 50 kg in Cohort 3 
Section 4.2 
Scientific 
Rationale for 
Modified text on rationale for 
sentinel dosing in Cohort 3 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Study 
Design 
Section 4.3 
Justification 
for Dose 
Updated text on body weight 
range for Cohort 3 
Section 5.1 
Inclusion 
Criteria 
Updated text on screening body 
weight for Cohort 3 
Section 8.3 
Adverse 
Events, 
Serious 
Adverse 
Events and 
Product 
Complaints 
Replaced the text on ‘SAEs and 
AE of special interest’ with all 
adverse events 
Accurately describes what is being done 
in the study 
Section 10.7. 
Appendix 7 
Tanner 
Staging 
Added the following: The 
assessment of sexual maturity in 
children should include an 
assessment of age, growth, and 
menstrual history in addition to 
Tanner Staging. In case of 
discordance between breasts or 
genitals vs pubic hair, the default 
should be breast or genitals. 
Assessment of sexual maturity should be 
based on both pubic hair and 
accompanying breast/testicular changes  
Section 
10.12 
Appendix 12 
Details on amendment (d) added 
 
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Table of Contents  
1. 
Protocol Summary ........................................................................................................10 
1.1. 
Synopsis ..........................................................................................................................10 
1.2. 
Schema ............................................................................................................................13 
1.3. 
Schedule of Activities .....................................................................................................14 
2. 
Introduction ...................................................................................................................18 
2.1. 
Study Rationale ...............................................................................................................18 
2.2. 
Background .....................................................................................................................18 
2.3. 
Benefit/Risk Assessment ................................................................................................21 
3. 
Objectives and Endpoints ............................................................................................22 
4. 
Study Design ..................................................................................................................23 
4.1. 
Overall Design ................................................................................................................23 
4.2. 
Scientific Rationale for Study Design ............................................................................23 
4.3. 
Justification for Dose ......................................................................................................24 
4.4. 
End of Study Definition ..................................................................................................24 
5. 
Study Population ...........................................................................................................25 
5.1. 
Inclusion Criteria ............................................................................................................25 
5.2. 
Exclusion Criteria ...........................................................................................................26 
5.3. 
Lifestyle Considerations .................................................................................................29 
5.3.1. 
Intensive Behavioral Therapy (IBT) for Chronic Weight 
Management in Children 6-11 Years Old .......................................................................29 
5.3.2. 
Meals and Dietary Restrictions .......................................................................................29 
5.3.3. 
Substance Use: Caffeine, Alcohol, and Tobacco ............................................................29 
5.3.4. 
Activity and Vaccinations ...............................................................................................30 
5.4. 
Screen Failures ................................................................................................................30 
6. 
Study Intervention(s) and Concomitant Therapy .....................................................31 
6.1. 
Study Intervention(s) Administered................................................................................31 
6.1.1. 
Administration Details ....................................................................................................31 
6.1.2. 
Medical Devices..............................................................................................................32 
6.2. 
Preparation, Handling, Storage, and Accountability ......................................................32 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................33 
6.4. 
Study Intervention Compliance ......................................................................................33 
6.5. 
Dose Modification ..........................................................................................................34 
6.5.1. 
Data Review during the Study ........................................................................................34 
6.6. 
Continued Access to Study Intervention after the End of the 
Study ...............................................................................................................................35 
6.7. 
Treatment of Overdose ...................................................................................................35 
6.8. 
Concomitant Therapy .....................................................................................................35 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................37 
7.1. 
Discontinuation of Study Intervention ............................................................................37 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................37 
7.3. 
Lost to Follow-up............................................................................................................38 
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8. 
Study Assessments and Procedures.............................................................................39 
8.1. 
Efficacy Assessments .....................................................................................................39 
8.2. 
Safety Assessments .........................................................................................................39 
8.2.1. 
Physical Examinations ....................................................................................................39 
8.2.2. 
Body Weight, Body Mass Index, Height, and Waist 
Circumference .................................................................................................................39 
8.2.3. 
Assessment of Pubertal Status - Tanner Staging ............................................................39 
8.2.4. 
Vital Signs .......................................................................................................................39 
8.2.5. 
Electrocardiograms .........................................................................................................40 
8.2.6. 
Clinical Safety Laboratory Tests ....................................................................................40 
8.2.7. 
Safety Monitoring ...........................................................................................................40 
8.2.8. 
Pregnancy Testing ...........................................................................................................44 
8.3. 
Adverse Events, Serious Adverse Events, and Product 
Complaints ......................................................................................................................44 
8.3.1. 
Timing and Mechanism for Collecting Events ...............................................................45 
8.3.2. 
Pregnancy ........................................................................................................................46 
8.3.3. 
Adverse Events of Special Interest .................................................................................47 
8.4. 
Pharmacokinetics ............................................................................................................49 
8.4.1. 
Bioanalysis ......................................................................................................................49 
8.5. 
Pharmacodynamics .........................................................................................................49 
8.5.1. 
Body Weight and Waist Circumference .........................................................................49 
8.6. 
Genetics ..........................................................................................................................50 
8.7. 
Biomarkers ......................................................................................................................50 
8.8. 
Immunogenicity Assessments.........................................................................................50 
8.9. 
Health Economics ...........................................................................................................50 
9. 
Statistical Considerations .............................................................................................51 
9.1. 
Statistical Hypotheses .....................................................................................................51 
9.1.1. 
Multiplicity Adjustment ..................................................................................................51 
9.2. 
Analyses Sets ..................................................................................................................51 
9.3. 
Statistical Analyses .........................................................................................................51 
9.3.1. 
General Considerations ...................................................................................................51 
9.3.2. 
Pharmacokinetics ............................................................................................................52 
9.3.3. 
Safety Analyses ...............................................................................................................52 
9.3.4. 
Evaluation of Immunogenicity .......................................................................................52 
9.4. 
Interim Analysis ..............................................................................................................53 
9.5. 
Sample Size Determination ............................................................................................53 
10. 
Supporting Documentation and Operational Considerations ..................................54 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................54 
10.1.1. Regulatory and Ethical Considerations ...........................................................................54 
10.1.2. Informed Consent Process ..............................................................................................55 
10.1.3. Data Protection................................................................................................................55 
10.1.4. Dissemination of Clinical Study Data.............................................................................56 
10.1.5. Data Quality Assurance ..................................................................................................56 
10.1.6. Source Documents ..........................................................................................................57 
10.1.7. Study and Site Start and Closure ....................................................................................58 
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10.1.8. Publication Policy ...........................................................................................................58 
10.1.9. Sample Retention ............................................................................................................58 
10.2. 
Appendix 2: Clinical Laboratory Tests ...........................................................................59 
10.2.1. Blood Sampling Summary ..............................................................................................61 
10.3. 
Appendix 3: Adverse Events and Serious Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-
up, and Reporting ............................................................................................................63 
10.3.1. Definition of an Adverse Event ......................................................................................63 
10.3.2. Definition of Serious Adverse Event ..............................................................................64 
10.3.3. Definition of Product Complaints ...................................................................................65 
10.3.4. Recording and Follow-up of Adverse Event or Serious Adverse 
Event and Product Complaints........................................................................................66 
10.3.5. Reporting of Serious Adverse Events .............................................................................68 
10.3.6. Regulatory Reporting Requirements ...............................................................................68 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ..........................................................69 
10.4.1. Definitions.......................................................................................................................69 
10.4.2. Contraception Guidance..................................................................................................69 
10.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-up 
Assessments ....................................................................................................................69 
10.6. 
Appendix 6: Pancreatic Monitoring ................................................................................71 
10.7. 
Appendix 7: Tanner Staging ...........................................................................................73 
10.8. 
Appendix 8: Laboratory Samples to be Obtained at the Time of a 
Systemic Hypersensitivity Event ....................................................................................75 
10.9. 
Appendix 9: Standardized Protocols for the Measurement of 
Height, Weight, Waist Circumference, and Vital Signs .................................................75 
10.10. 
Appendix 10: Provisions for Changes in Study Conduct During 
Exceptional Circumstances .............................................................................................78 
10.11. 
Appendix 11: Abbreviations and Definitions .................................................................82 
10.12. 
Appendix 12: Protocol Amendment History ..................................................................85 
11. 
References ......................................................................................................................89 
 
 
 
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List of Tables 
Table 
Page 
Table GPHV.6.1. Treatments Administered ..................................................................................31 
 
 
 
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I8F-MC-GPHV(e) 
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List of Figures 
Figure 
Page 
Figure GPHV.1.1. Illustration of enrollment and interim data review plan for Protocol 
I8F-MC-GPHV. .................................................................................................13 
 
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1. 
Protocol Summary  
1.1. 
Synopsis  
Protocol Title:  
A Safety, Tolerability, and Pharmacokinetic Study of Tirzepatide for the Treatment of Pediatric Participants (6 years 
to 11 years) with Obesity. 
Brief Title: Safety, Tolerability, and Pharmacokinetics of Tirzepatide in Pediatric Participants with Obesity.  
Rationale: 
Tirzepatide (LY3298176) is a dual glucose-dependent insulinotropic peptide receptor and glucagon-like peptide 1 
receptor agonist being developed as an adjunct to diet and exercise for chronic weight management in adult patients 
with or without type 2 diabetes mellitus (T2DM) who have an initial body mass index of greater than equal to 
30 kg/m2 (obesity), or greater than equal to 27 kg/m2 (overweight). The dose of tirzepatide has been defined for 
adults with obesity or overweight with one or more weight-related comorbidities, including T2DM, but data are 
lacking in pediatric participants with obesity particularly for the younger pediatric participants whose body weights 
are less likely to overlap with the body weights of adults with T2DM.  
Study I8F-MC-GPHV will assess the safety, tolerability, and pharmacokinetic (PK) of tirzepatide administered 
weekly via the subcutaneous (SC) route for 8 weeks in pediatric participants (age: 6 to 11 years) with obesity 
partitioned according to weight (lower body weight: less than 50 kg; higher body weight: more than or equals to 50 
kg). 
Objectives and Endpoints: 
 
Objectives 
Endpoints 
Primary 
 
To evaluate tirzepatide safety and tolerability 
following SC injections of tirzepatide in 
pediatric participants with obesity 
 
 
Incidence of adverse events, treatment-
emergent adverse events, and serious adverse 
events 
 
Secondary 
 
To evaluate the PK profile of tirzepatide 
following SC injections in pediatric 
participants with obesity 
 
 
Tirzepatide area under AUC0-tau, Cmax from the 
population PK model 
Abbreviations: AUC0-tau = area under the concentration versus time curve from time 0 to the end of the dosing 
interval; Cmax = maximum concentration; PK = pharmacokinetics; SC = subcutaneous. 
Overall Design:  
This is an investigator and participant blinded, randomized, placebo-controlled safety, tolerability, and PK study in 
up to 3 cohorts of pediatric participants with obesity.  
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Potential participants will be screened to assess their eligibility to enter the study within 28 days prior to Day 1. 
Participants will visit the clinic on Day 1 to be assessed and randomized and to establish baseline measurements.  
Participants will receive 8 weekly SC injections of tirzepatide or placebo starting on Day 1, remain inpatient within 
the clinical research unit (CRU) until at least Day 3, and return for outpatient visits. In-clinic visits on Days 8, 29, 
43, and 57 will be mandatory for all participants. For Cohort 2 participants, Days 15 and 22 will also be mandatory 
to be in-clinic. All other outpatient visits may either be performed remotely or in-clinic.  
The final follow-up visit will occur 4 to 6 weeks after the last treatment or at least 4 weeks but up to 6 weeks upon 
early discontinuation.  
Safety will be assessed by vital signs, electrocardiograms, safety laboratory tests, and the recording of adverse 
events (AEs). PK blood samples for tirzepatide and immunogenicity samples will be collected.  
Treatment Arms and Planned Duration for an Individual Participant:  
Participants will be randomized to receive either tirzepatide or placebo in a 
 ratio. The study duration for 
individual participants, inclusive of screening, is expected to be approximately 19 weeks, divided as follows:  
 
screening - up to 4 weeks prior to randomization  
 
treatment period - 8 weeks, and  
 
follow-up - 4 to 6 weeks from last dosing.  
Participants enrolled will be partitioned as follows:  
 
Cohort 1: Higher weight cohort – screening body weight ≥50 kg  
 
Cohort 2: Lower weight cohort – screening body weight <50 kg, and 
 
Cohort 3: Screening body weight between 40 to 60 kg inclusive. 
Number of Participants:  
Approximately 
 participants aged 6 to 11 years with obesity at screening may be enrolled. This will allow PK 
characterization in at least  participants each, exposed to tirzepatide, for the weight categories <50 kg and ≥50 kg, 
respectively. Participants who do not complete all the study procedures may be replaced to target the planned 
number of completers specified in the sample determination section.  
Statistical Analysis:  
Primary safety statistical analyses will be conducted for all participants receiving the study drug whether or not they 
completed all protocol requirements.  
Tirzepatide concentration data will be analyzed using a population PK approach via nonlinear mixed-effects 
modeling with the NONMEM® software. The main PK parameters for analysis will be maximum concentration and 
area under the concentration versus time curve from the population PK model.  
Safety parameters that will be assessed include safety laboratory parameters, vital signs, AEs, treatment-emergent 
AEs, and serious adverse events. The parameters will be listed and summarized using standard descriptive statistics. 
Additional analysis will be performed if warranted upon review of the data. All AEs related to study or protocol 
procedure will be listed, and if the frequency of events allows, they will be also summarized using descriptive 
methodology.  
Physical examinations and electrocardiograms will be performed for safety monitoring purposes and will be 
presented as AEs when clinically relevant findings are reported.  
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Additional exploratory analyses will be performed on the effect of treatment on body mass index, body weight, and 
waist circumference. 
Data Monitoring Committee: No. 
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1.3. 
Schedule of Activities  
Study Schedule Protocol I8F-MC-GPHV 
Visit Number 
1 
Screening 
2 
Baseline 
and 
Inpatient 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 = 
Final 
Follow-
up 
Early 
Discontinuation 
Week 
-4 to -1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
12 to 
14 
 at least 4 
weeks but up to 
6 weeks from 
Last Dose 
Days 
  
Visit Interval 
Tolerance 
(Days) 
  
Informed consent, 
assent, medical 
history, 
vaccination 
schedule, and full 
date of birth 
collection 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Comments:  The informed consent form must be signed by parents or legal guardian and the assent form (as appropriate per local 
requirements) must be signed by the participant before any protocol-specific tests/procedures are performed. Any vaccine which the participant 
is scheduled for as a part of immunization scheme must be captured in the concomitant medications pages of the CRF. 
Review and 
confirm I/E 
criteria 
X 
Anytime 
predose 
  
  
  
  
  
  
  
  
  
  
  
  
Pregnancy test 
(urine) - at site 
for females only 
X 
 Any time as deemed necessary by the investigator 
Comments: At investigator’s clinical discretion (for example, there is reason to believe that the female participant is sexually active) 
Enrolment and 
randomization 
  
Day 1 
  
  
  
  
  
  
  
  
  
  
  
  
Tanner staging 
(females only) 
X 
P 
 
 
 
 
P 
 
 
 
 
X 
 
X 
Intensive 
behavioral 
therapy 
 
X 
X 
X 
Comments: Participant and at least one family member will be offered IBT throughout the study. Starting at baseline, participants will be able 
to receive approximately 24 hours of therapy sessions. The frequency of IBT sessions will be flexible and at the discretion of the investigator. 
Inpatient visit 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
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Visit Number 
1 
Screening 
2 
Baseline 
and 
Inpatient 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 = 
Final 
Follow-
up 
Early 
Discontinuation 
Week 
-4 to -1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
12 to 
14 
 at least 4 
weeks but up to 
6 weeks from 
Last Dose 
Days 
  
Visit Interval 
Tolerance 
(Days) 
  
Comments: Participant and accompanying adult will be admitted to the inpatient unit on morning of Day 1 for medical assessments and baseline 
measurements prior to randomization and treatment. All participants will be closely monitored for safety and discharged earliest on Day 3. The 
inpatient stay may be extended by the investigator if it is necessary for the participant’s clinical well-being. 
Outpatient visit 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Comments: 
· For all participants - screening Visit 1, inpatient Visit 2 and outpatient Visits 3, 7, 10, and 12 must be performed in-clinic. 
· For all participants who discontinued early - early discontinuation visit must be performed in-clinic. 
· For Cohort 2 participants only - additionally, Visits 4 and 5 must be performed in clinic due to the necessity of tirzepatide dosing 
manipulations for preparing a 
 dose. This must be highlighted in the informed consent and assent forms for Cohort 2. 
· All other outpatient visits, including final follow up (but not early discontinuation) may be performed remotely such as by telemedicine or by 
mobile healthcare services. 
Adverse events & 
concomitant 
medication 
assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical 
examination 
/medical 
assessment 
X 
P, before 
discharge 
P 
  
  
 
P 
  
  
  
 
X  
X 
X 
Comments: Full physical examination at screening. Thereafter, assessments performed to include medical review and targeted, symptom-driven 
examination, as appropriate. Additional assessments may be performed at investigator’s clinical discretion. P = predose measure that can be 
performed any time prior to dosing. 
Height, weight, 
waist 
circumference, 
and body mass 
index 
X 
P 
 
 
 
 
P 
 
 
 
 
X 
X 
X 
Comments: Height is required only during screening, Visit 1, and Visit 12. P = predose measure that can be taken any time prior to dosing. 
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Visit Number 
1 
Screening 
2 
Baseline 
and 
Inpatient 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 = 
Final 
Follow-
up 
Early 
Discontinuation 
Week 
-4 to -1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
12 to 
14 
 at least 4 
weeks but up to 
6 weeks from 
Last Dose 
Days 
  
Visit Interval 
Tolerance 
(Days) 
  
Supine vital 
signs 
X 
P, 8 
hours 
P 
 
 
 
P 
 
 
P 
 
X 
X 
X 
Comments: Vital sign timing on Day 1 is with reference to actual time of first tirzepatide dosing (0 hours). P = predose measure that can be 
performed any time prior to dosing. 
Temperature 
X 
P, 8 
hours 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Comments: Temperature timing on Day 1 is with reference to actual time of first tirzepatide dosing (0 hours) and may be measured via the oral, 
aural, or rectal route according to clinic’s local practice. P = predose measure that can be performed any time prior to dosing. 
Single, safety 12-
lead ECG - at 
site 
X 
P, 8 
hours 
P 
 
 
 
P 
 
 
P 
 
X 
 
X 
Comments: ECG timing on Day 1 is with reference to actual time of first tirzepatide dosing (0 hours). Participants must be supine for at least 3 
minutes prior to procedure and remain supine but awake during ECG collection. P = predose measure that can be performed any time prior to 
dosing.  
Clinical 
laboratory test 
(fasting) 
X 
P 
 
 
 
 
P 
 
 
 
 
X 
 
X 
Comments: Screening performed by local laboratory and will include hormone assessments. All others by a central laboratory. Clinical 
laboratory test on Day 1 is for baseline purpose, and results need not be reviewed prior to tirzepatide dosing. Additional unscheduled samples 
may be collected and assayed by the local laboratory if necessary, at the investigator’s clinical discretion. P = predose measure that can be 
performed any time prior to dosing. 
Blood glucose 
monitoring or 
sampling for 
safety 
  
Days 
1&2 
  
  
  
  
  
  
  
  
  
  
  
  
Comments: On Days 1 and 2, blood glucose should be measured before bedtime. This can be measured using a glucose analyzer on site or local 
lab. Additional samples may be taken at the discretion of the investigator as clinically indicated or symptom-directed. 
Tirzepatide 
subcutaneous 
dosing to 
abdomen 
  
Day 1 
(0 hr) 
X 
X 
X 
(0 hr) 
 
 X 
(Increase 
dose 
level) 
X 
(0 hr) 
 
X 
X 
 
 
 
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Visit Number 
1 
Screening 
2 
Baseline 
and 
Inpatient 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 = 
Final 
Follow-
up 
Early 
Discontinuation 
Week 
-4 to -1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
12 to 
14 
 at least 4 
weeks but up to 
6 weeks from 
Last Dose 
Days 
  
Visit Interval 
Tolerance 
(Days) 
  
Comments: Tirzepatide injection sites must be rotated along the 4 abdominal quadrants. Dosing may be performed by clinic staff during in-
clinic visits. Self-administration by participant or parent or legal guardian is permitted after the investigator assessed them as being adequately 
trained. The dose increase will happen at the 5th dose as indicated in Figure GPHV.1.1 
Tirzepatide 
sampling for 
pharmacokinetics 
(hrs) 
  
12, 24 
 
P 
  
X: within 
24 to 96 
hrs 
postdose 
  
P 
X: 
within 
120 to 
168 hrs 
postdose 
 
P 
X 
X 
X 
Comments: Sampling time is relative to the latest dosing time. The actual date and time of the sampling and the most recent SC injection 
administered prior to collecting the sample must be recorded. Days 15, 36 and final follow-up or early discontinuation sample must be time-
matched with immunogenicity sampling. No sample collection is needed if the participant discontinued before receiving tirzepatide. P = predose 
samples that should be collected within an hour prior to dosing.  
Immunogenicity 
sampling 
  
P 
 
P  
  
  
  
P 
  
  
  
  
X 
X 
Comments: Exact time of sampling must be recorded. Days 15, 36 and final follow-up or early discontinuation sample must be time-matched 
with pharmacokinetic sampling. No sample collection is needed if the participant discontinued before receiving tirzepatide. P = predose 
samples that should be collected within an hour prior to dosing.  
Abbreviations: BMI = body mass index; CRF = case report form; ECG = electrocardiogram; hrs = hour; IBT = intensive behavioral therapy; I/E = inclusion and 
exclusion criteria; P = predose. 
 
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2. 
Introduction  
Obesity is a chronic disease and its increasing prevalence is a public health concern associated 
with rising incidence of T2DM, increased risk for premature death, and increased risk for some 
cancers (AMA 2013; Council on Science and Public Health 2013; Lauby-Secretan et al. 2016). 
Although loss of 5% to 10% body weight through lifestyle approaches, based on caloric 
restriction, physical activity, and behavioral therapy, has been shown to reduce obesity-related 
CV risk factors, and in some cases, improve health-related quality of life (Mertens and Van Gaal 
2000; Knowler et al. 2002; Jensen et al. 2014; Kolotkin and Andersen 2017), lifestyle therapies 
alone fail to achieve sustainable weight loss in the majority of patients with obesity 
(Dombrowski et al. 2014). Caloric restriction, for example, has been shown to lead to metabolic 
adaptive responses, including increases in hunger hormones, decreases in satiety factors 
(including GI peptides), increased appetitive drive and food intake, and lower energy expenditure 
(Leibel et al. 1995; Sumithran et al. 2011). These adaptations are thought to work in concert to 
cause regain and poor durability of treatment. The addition of physical activity is essential and 
can help maintain weight loss, but generally, maintaining lifestyle-induced weight loss is 
recognized as being more challenging than losing weight for individuals with obesity (Swift et 
al. 2018). 
Pharmacologic agents, in contrast to voluntary caloric restriction, can directly impact the 
physiology of energy balance, including the regulation of food intake and/or energy expenditure, 
to drive toward a lower fat mass and body weight (Heymsfield et al. 2018). Some current or 
previously marketed weight-management medications have had a demonstrable effect on 
maintaining initial weight loss over time while on treatment (James et al. 2000; Smith et al. 
2010; Wadden et al. 2013). There is increasing recognition that adjunctive pharmacotherapy may 
be required to improve weight loss, weight maintenance, and health outcomes in individuals with 
obesity (AMA 2013; Apovian et al. 2015). 
2.1. 
Study Rationale  
Tirzepatide (LY3298176) is a GIP receptor and GLP-1 receptor agonist approved as an adjunct 
to diet and exercise in adult patients with T2DM. It is also being developed as an adjunct to diet 
and exercise for chronic weight management of adults who have an initial BMI of 30 kg/m2 or 
greater (obesity) or 27 to 29.9 kg/m2 (overweight, with additional health risks). The dose of 
tirzepatide has been defined for adults with obesity or overweight and T2DM patients, but data 
are lacking in pediatric participants with obesity. 
Study I8F-MC-GPHV (GPHV) will assess safety, tolerability, and PK after 8 weeks of treatment 
with tirzepatide administered via the SC route in participants (age 6 to 11 years) with obesity 
partitioned according to weight (lower body weight <50kg; higher body weight ≥50 kg). 
2.2. 
Background  
Pediatric Obesity 
The prevalence of obesity in the US has been captured as a part of the National Health and 
Nutrition Examination Survey (NHANES). The nationally representative data clearly 
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demonstrate that childhood and adolescent obesity continue to be a significant concern (Skinner 
et al. 2018).  
In the US, the prevalence of obesity among pediatric patients aged 2 to 19 years has increased by 
approximately 1.3-fold between 1999 and 2016. The data show that the prevalence of pediatric 
obesity increases with age and is highest among adolescents aged 12 to 19 years (Skinner et al. 
2018). 
The current treatment regimens for pediatric obesity include lifestyle modification, 
pharmacotherapy, and bariatric surgery (Styne et al. 2017). The treatment of pediatric obesity 
emphasizes positive behavior change, including healthy food choices, reduction of physical 
inactivity, and family engagement (AAP IHCW 2015; Styne et al. 2017). 
Pediatric obesity is a multifactorial disease requiring consideration of pubertal development, risk 
for comorbidities, psychological state, and social implications (Styne et al. 2017).  
Pediatric overweight and obesity are defined based on local or regional growth charts for 
age- and sex-specific BMI. In the US, World Health Organization and Centers for Disease 
Control and Prevention growth charts are commonly used to assess BMI. 
The pathophysiology of pediatric obesity is multifactorial; a combination of heritable and 
environmental factors leads to an imbalance between energy intake and expenditure (Crocker 
and Yanovski 2009). However, the exact etiology of obesity in pediatric patients is not clearly 
understood. Of note, pediatric obesity due to obesity syndromes or genetic conditions is 
infrequent and accounts for approximately 7% of patients with extreme pediatric obesity (Styne 
et al. 2017).  
Comorbidities of pediatric obesity  
Pediatric obesity is associated with an increased risk of premature death and comorbidities. The 
likelihood of developing adult obesity increases for pediatric patients with obesity as they 
approach adulthood, pointing to a need to address obesity as it presents in childhood (Krebs et al. 
2007). Obesity-related comorbidities include the following (Jastreboff et al. 2019): 
• 
cardiovascular disease (CVD)  
• 
cerebrovascular diseases  
• 
T2DM  
• 
hypertension, and  
• 
some cancers.  
The comorbidities associated with obesity and overweight in adults are consistent with that of 
children with obesity (Styne et al. 2017). Additionally, the benefits associated with weight loss in 
the pediatric population with obesity are consistent with that of adults (August et al. 2008).  
In pediatric patients, for every 10 kg/m2 increase in BMI, there is an associated 34% increased 
risk of dyslipidemia, 46% higher risk of hypertension, and 25% increase in insulin concentration 
(Durkin and Desai 2017).  
The risks of CVD outcomes among children and adolescents with obesity who were without 
obesity by adulthood appear to be similar to those who never had obesity. Such risk factors of 
CVD outcomes are as follows (Juonala et al. 2011):  
• 
T2DM  
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• 
hypertension  
• 
elevated low-density lipoprotein cholesterol  
• 
reduced high-density lipoprotein cholesterol  
• 
elevated triglyceride levels, and  
• 
carotid artery atherosclerosis.  
Long-term weight loss of 5% or greater as a result of lifestyle modification is associated with 
improvement in various metabolic and CV risk factors (Brown et al. 2016). Weight loss 
interventions that result in significant and durable weight loss, such as that associated with 
bariatric surgery, may result in multiple benefits such as  
• 
reduced CV risk factors  
• 
reduced risk of T2DM, and  
• 
decreased risk of CV death and all-cause mortality (Kritchevsky et al. 2015).  
Tirzepatide 
Weight loss induced by GLP-1R agonists, while appearing to be centrally mediated through a 
combination of hormonal inputs to satiety centers (van Bloemendaal et al. 2014), has not been 
consistently associated with changes in mental health or with potential for addiction in long-term 
studies conducted to establish CV safety in patients with diabetes (Marso et al. 2016a, 2016b; 
Gerstein et al. 2019). Tirzepatide, which is both a GLP-1R and GIP receptor agonist, has been 
associated with predominantly mild-to-moderate GI adverse effects similar to currently marketed 
GLP-1R agonists. 
Overall summary on weight loss in adult participants with obesity or overweight with or 
without type 2 diabetes mellitus  
In adult participants with T2DM, tirzepatide 5, 10, and 15 mg demonstrated superior reductions 
from baseline in body weight at the primary endpoint visit (40 or 52 weeks) in all 5 global Phase 
3 studies compared with placebo (that is, the management of body weight primarily by diet and 
exercise), semaglutide, and basal insulin (insulin degludec and insulin glargine). 
The SURMOUNT-1 Phase 3 study investigated the efficacy of tirzepatide in adult participants 
with obesity or overweight as an adjunct to lifestyle intervention including regular lifestyle 
counseling sessions, delivered by a dietitian or a qualified healthcare professional, to help 
participants adhere to healthful, balanced meals, with a deficit of 500 calories per day, and at 
least 150 minutes of physical activity per week. Again, tirzepatide 5, 10, and 15 mg 
demonstrated superior reductions from baseline in body weight at the primary endpoint visit 
(72 weeks) in the SURMOUNT-1 study compared with placebo (Jastreboff et al. 2022). 
Treatment guidelines suggest that patients with T2DM and obesity should target a body weight 
reduction of ≥5% (ADA 2021). Across all Phase 3 trials, a significantly higher proportion of 
tirzepatide-treated patients achieved this target in comparison to placebo and active comparators. 
The results of the global Phase 3 studies indicate that tirzepatide enabled significant proportions 
of adults with T2DM to reach the body weight goal recommended in treatment guidelines, and 
the results suggest that more ambitious body weight goals were feasible for many patients. 
More information about the known and expected benefits, risks, SAEs, and reasonably 
anticipated AEs of tirzepatide is to be found in the IB. 
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2.3. 
Benefit/Risk Assessment  
The risks of tirzepatide have been consistent with risks associated with other GLP-1 receptor 
agonists currently marketed. Potential risks include, but are not limited to, GI effects, acute 
pancreatitis (very rare), increases in heart rate, and hypoglycemic events (GLP-1 receptor agonist 
class effect). 
No clinically significant safety or tolerability concerns have been identified during the clinical 
investigation of tirzepatide up to the single dose level of 5 mg or multiple weekly doses, when 
escalated up to 15 mg in adults. Based on this information, the highest starting dose of 
 mg 
and the highest dose of  mg tirzepatide to be administered in this study are reasonably 
anticipated to be tolerable in this group of pediatric participants with obesity. 
Body weight is a known covariate affecting tirzepatide exposures based on population PK 
analysis in adult patients with T2DM. It is predicted that the exposure may be approximately 
2-fold higher in the population with weight <50 kg compared to that in adults (weight ≥50 kg); 
therefore, a more conservative initial starting dose of 
 will be adopted for participants in 
the lower body weight cohort (Cohort 2). This is a mitigation approach taken to reduce the risk 
of safety and tolerability issues before commencing another cohort of participants on an initial 
-mg dose (Cohort 3). 
Based on the known pharmacology of tirzepatide, participants with obesity may benefit from 
clinically meaningful weight reduction after 8 weeks of treatment. Potential risks, such as GI 
effects, acute pancreatitis, increases in heart rate, and hypoglycemic events, are consistent with 
the risks associated with currently available long-acting GLP-1R agonists in adults. These risks 
are clinically detectable and manageable and will be monitored throughout the study. 
A juvenile toxicology study in rats was conducted to assess potential effects on growth and 
development to support pediatric development. Rats in the study were dosed twice weekly from 
Postnatal Days 21 to 84, which roughly corresponds to early human pediatric (2 years of age) 
through late adolescence based on overall central nervous system and reproductive development 
across species (Rodier 1980; Bayer et al. 1993; Rice and Barone Jr 2000; Beck et al. 2006) and 
overlaps ages utilized in the general toxicology studies. Standard behavioral, reproductive, and 
pathology assessments, as well as the careful monitoring of body weight and developmental 
markers of sexual maturation (vaginal patency and balanopreputial separation), were included as 
endpoints. Consistent with adult rats, effects in juvenile rats were limited to pharmacological 
effects on body weight and food consumption and effects secondary to the pharmacology. These 
data indicate that tirzepatide does not have unique toxicities in juvenile animals and has an 
acceptable nonclinical safety profile to support pediatric clinical trials. 
For females, use Tanner staging by physical exam, history or occurrence of menarche, and/or 
menses to aid in the detection of a child who is no longer Tanner 1 and may be further evaluated 
for childbearing potential. 
More information about the known and expected benefits, risks, SAEs, and reasonably 
anticipated AEs of tirzepatide is to be found in the IB. 
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3. 
Objectives and Endpoints  
Objectives 
Endpoints 
Primary 
 
To evaluate tirzepatide safety and 
tolerability following the SC injections of 
tirzepatide in pediatric participants with 
obesity 
 
 
Number of treatment-emergent adverse events 
and serious adverse events 
 
Secondary 
 
To evaluate the PK profile of tirzepatide 
following SC injections in pediatric 
participants with obesity 
 
 
Tirzepatide area under the concentration versus 
time curve (AUC0-tau), maximum concentration 
(Cmax) from population PK model 
Abbreviations: 
; PK = pharmacokinetics; SC = subcutaneous. 
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4. 
Study Design  
4.1. 
Overall Design  
This is a randomized, placebo-controlled, participant and investigator blinded, 8-week treatment 
Phase 1 study in pediatric participants with obesity who do not have diabetes mellitus. Potential 
pediatric participants will be screened to assess their eligibility to enter the study within 28 days 
prior to Day 1. Participants enrolled will be partitioned as follows:  
 Cohort 1: Higher weight cohort – screening body weight ≥50 kg 
 Cohort 2: Lower weight cohort – screening body weight <50 kg, and 
 Cohort 3: Screening body weight between 40 to 60 kg, inclusive.  
The schematic of the study is shown in Figure GPHV.1.1. Initially, 
 participants 
are planned to be enrolled into the higher body weight (Cohort 1). Participants will be 
randomized on Day 1 to tirzepatide or placebo (
 ratio) after the confirmation of eligibility. 
Placebo is included as the control in a blinded manner for investigator, site staff, and participants 
to allow an unbiased assessment of the safety and tolerability data generated, which will allow a 
more robust comparison between tirzepatide and placebo. In-clinic outpatient visits are planned 
as detailed in the SoA. 
Safety and tolerability data will be reviewed by the unblinded sponsor CP, CRP/CRS, and 
blinded investigator. Decisions for commencing dosing in Cohort 2 (lower body weight 
participants) will be made based on the following:  
 the completion of at least 5 treatment doses from at least  participants in Cohort 1, and  
 the review of safety/tolerability data through Day 36, including safety clinical laboratory.  
Likewise, the dosing of Cohort 3 participants (body weight 40 to 60 kg inclusive) will proceed 
only after the satisfactory review of safety and tolerability data from at least  participants who 
received at least 5 treatment doses in Cohort 2 as shown in Figure GPHV.1.1. PK samples will 
be collected, and exposure data for tirzepatide will be analyzed during the study to support 
dose-escalation decisions where possible. Sentinel dosing will be used for  participants in the 
specific body weight range of 40 to 50 kg in Cohort 3 
. If safety and 
tolerability after at least 1 week are acceptable in the  sentinel participants, as clinically 
assessed by the investigator, the remainder of the participants in Cohort 3 (  tirzepatide and  
placebo) in the 40 to 60 kg range can be randomized and dosed.  
A final follow-up visit will occur within 4 to 6 weeks after last treatment or at least 4 weeks but 
up to 6 weeks for participants who discontinued prematurely.  
Starting at Visit 2 (baseline visit), all participants will be offered intensive behavioral therapy 
(IBT) sessions (Section 5.3.1) which will continue through the study period and until the final 
follow up. 
4.2. 
Scientific Rationale for Study Design  
This study is designed to assess the safety, tolerability, and PK profile of tirzepatide administered 
SC in participants aged 6 to 11 years with obesity.  
The dose justification for tirzepatide is provided in Section 4.3. 
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The sample size is customary for Phase 1 studies evaluating safety, tolerability, and PK and is 
not powered on the basis of any a priori statistical hypothesis testing for efficacy. The rationale 
for the sample size is provided in Section 9.5. 
Placebo is included as a control, in a blinded manner for investigators, site staff, and participants, 
to allow an unbiased assessment of the data generated, which will allow a more robust 
comparison of safety, tolerability, and PD data. 
Sentinel dosing design will be used in  Cohort 3 because this cohort has a higher starting dose 
compared to Cohort 2, while allowing participants with body weight below 50 kg. Cohort 1 will 
include participants ≥50 kg at a starting dose of 
 mg. Cohort 3 will include participants in the 
range of 40 to 60 kg at a starting dose of 
 mg. Hence, sentinel dosing will be used in  
participants in the body weight range of 40 to 50 kg in Cohort 3, as this weight range is not 
included in Cohort 1. Sentinel dosing design is included to assess the tolerability or safety 
profiles due to increased starting dose in participants with obesity receiving tirzepatide. 
4.3. 
Justification for Dose  
A starting dose of 
 mg accompanied by dose titration of 
 mg increments every 4 weeks (up 
to a maximum dose of 15 mg) was shown safe and well tolerated in adults with T2DM. The body 
weight of the pediatric participants in the higher body weight cohort (Cohort 1) in this study will 
overlap with the weight of adults studied in the T2DM program (weight around or higher than 
50 kg). Thus, a starting dose of 
 mg for 4 weeks, followed by  mg for 4 weeks, is planned for 
this pediatric population with body weight more than or equal to 50 kg.  
The exposure in pediatric participants with weight <50 kg is anticipated to be up to 2-fold higher 
than the exposure in adults (weight range in Phase 3 studies in adults with T2DM: 43.1 to 
227 kg), given that body weight was identified as a covariate on tirzepatide exposures in adults. 
Thus, a lower starting dose of 
 mg in this pediatric population with weight below 50 kg will 
be evaluated for tolerability and safety in Cohort 2. If the starting dose of 
 mg is 
well-tolerated, a starting dose of 
 mg will also be tested in Cohort 3 within a narrower weight 
range (40 to 60 kg, inclusive). 
4.4. 
End of Study Definition  
The end of the study is defined as the date of the last visit of the last participant in the study or 
last scheduled procedure shown in the SoA for the last participant. 
A participant is considered to have completed the study if the participant has completed the last 
scheduled procedure shown in the SoA. 
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5. 
Study Population  
The eligibility of participants for the study will be largely based on the results of 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. 
Screening may occur up to 28 days prior to Day 1. If the investigator decides not to administer 
the dose to a participant or not to enroll a participant on a particular day, the participant’s visit 
may be rescheduled, and any assessments or procedures performed up to that point may be 
repeated to confirm their eligibility.  
The 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 for inclusion in the study if they meet all of the following criteria at 
screening:  
Participant Characteristics 
1. Are male and female participants with obesity determined by medical 
history 
a. between the ages of 6 and 11 years, inclusive 
b. have BMI ≥ the 95th percentile for age and sex 
2. Have a screening body weight of 
▪ Participants to be enrolled into Cohort 1: ≥50 kg 
▪ Participants to be enrolled into Cohort 2: <50 kg 
▪ Participants to be enrolled into Cohort 3: Between 40 to 60 kg, 
inclusive 
3. Have failed to achieve adequate weight loss through lifestyle modification 
in the investigator’s opinion 
4. Have adequate immunization according to local / national requirement as 
assessed by the investigator 
5. Not be sexually active and remain so throughout the duration of the study 
6. Have safety laboratory test results within normal reference range or with 
abnormalities deemed clinically insignificant by the investigator 
7. Have venous access sufficient to allow for blood sampling as per the 
protocol 
8. Female participants with obesity only: Determined as prepubertal Tanner 
Stage 1. See Appendix 7 (Section 10.7) for further details on Tanner 
Staging.  
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Informed Consent 
9. Both child and parent or legal guardian are reliable and willing to make 
themselves available for the duration of the study and are willing to follow 
study procedures 
10. Both child and parent or legal guardian are willing and able to commit to the 
inpatient stays and procedures per study requirement 
11. Both the child and a parent or legal guardian are able to understand and fully 
participate in the activities of the clinical trial and sign their assent and 
consent, respectively 
5.2. 
Exclusion Criteria  
Participants will be excluded from study enrollment if they meet any of the following criteria at 
screening: 
Medical Conditions - General 
12. A self-reported (or by parent(s)/legally acceptable representative where 
applicable) change in body weight above 5 kg (11 lbs) within 90 days before 
screening irrespective of medical records 
 
13. Have a history or current CV (for example, acute myocardial infarction, 
congestive heart failure, unstable angina, uncontrolled hypertension 
[systolic blood pressure ≥ 160 mmHg and diastolic blood pressure ≥ 100 
mmHg], cerebrovascular accident [including transient ischemic attack], 
venous thromboembolism, and so on), respiratory, hepatic, renal, GI, 
endocrine, hematological (including history of thrombocytopenia), or 
neurological disorders capable of significantly altering the absorption, 
metabolism, or elimination of drugs; constituting a risk when taking the IP; 
or may interfere with the interpretation of data 
14. Have obesity induced by other endocrinologic disorders (for example, 
Cushing syndrome) or diagnosed monogenetic or syndromic forms of 
obesity (for example, Melanocortin 4 Receptor deficiency or Prader Willi 
Syndrome) 
15. Have acute or chronic pancreatitis or a history of acute idiopathic 
pancreatitis; or have other GI disorders (for example, relevant esophageal 
reflux or gall bladder disease) that could be aggravated by GLP-1 analogs; 
participants who had cholecystolithiasis (gall stones) or cholecystectomy 
(removal of gall bladder) in the past, with no long-term complications, are 
eligible for participation 
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16. Have a known clinically significant gastric emptying abnormality (for 
example, gastric outlet obstruction), have undergone weight loss surgery 
such as gastric bypass (bariatric) surgery or restrictive bariatric surgery (for 
example, Lap-Band®), or have endoscopic or device-based therapy for 
obesity or have had device removal within the last 6 months (for example, 
mucosal ablation, gastric artery embolization, intragastric balloon, and 
duodenal-jejunal bypass sleeve) 
17. Have a personal or family history of medullary thyroid carcinoma, have 
multiple endocrine neoplasia syndrome type 2, or calcitonin ≥20 pg/mL at 
screening 
18. Have confirmed type 1 or type 2 diabetes mellitus or a history of 
ketoacidosis, or hyperosmolar state/coma 
19. Have findings in the 12-lead ECG at screening that, in the opinion of the 
investigator, may increase the risks of potentially clinically relevant 
worsening associated with participation in the study 
20. Have an active or untreated malignancy or have been in remission from a 
clinically significant malignancy (other than basal or squamous cell skin 
cancer, in situ carcinomas of the cervix, or in situ prostate cancer) for 
<5 years prior to screening 
21. Have evidence of human immunodeficiency virus or positive human 
immunodeficiency virus antibodies at screening 
22. Have evidence of hepatitis B or positive hepatitis B surface antigen or 
evidence of HCV or hepatitis C antibody with confirmed presence of HCV 
RNA at screening (a positive HCV antibody at screening will need an 
additional HCV RNA assay - detectable HCV RNA means a participant will 
meet exclusion criteria)  
 Participants with a previous diagnosis of HCV who have been 
treated with antiviral therapy and achieved a sustained virological 
response may be eligible for inclusion in the study, provided they 
have no detectable HCV RNA on the screening HCV polymerase 
chain reaction test. A sustained virological response is defined as 
an undetectable HCV RNA level 24 weeks after the completion of 
a full, documented course of an approved antiviral therapy for 
HCV. 
 Participants who have spontaneously cleared HCV infection, 
defined as (a) a positive HCV antibody test and (b) a negative 
HCV RNA test, with no history of anti-HCV treatment, may be 
eligible for inclusion in the study, provided they have no detectable 
HCV RNA on screening for this study. 
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23. Have serum AST or ALT >2.0× the ULN or TBL >1.5 × ULN (except for 
participants with Gilbert’s syndrome, which can be enrolled with TBL 
<2.0× ULN), or alkaline phosphatase (ALP) >1.5× ULN 
 Participants with nonalcoholic fatty liver disease are allowed to 
participate. 
24. Have any lifetime history of a suicide attempt 
25. Have had a blood transfusion or severe blood loss within the last 3 months, 
or have known hemoglobinopathy, hemolytic anemia, and sickle cell 
anemia, or have a hemoglobin value <11 g/dL (males) or <10 g/dL 
(females) or any other condition known to interfere with safety laboratory 
measurements 
26. Have a history of atopy or clinically significant multiple or severe drug 
allergies, or severe posttreatment hypersensitivity reactions (including, but 
not limited to, erythema multiforme major, linear immunoglobulin A 
dermatosis, toxic epidermal necrolysis, or exfoliative dermatitis) 
27. Impaired renal eGFR of <60 mL/min/1.73 m2 calculated by Bedside 
Schwartz Equation recommended by the National Kidney Foundation. One 
retest may be performed in case of an initial borderline eGFR result of 
<60 mL/min/1.73 m2. The highest eGFR value from the 2 tests will be 
accepted 
28. Have an accompanying parent or legal guardian who is unable or unwilling 
to stop alcohol or nicotine consumption from admission to the CRU and 
until discharge from the study or completion of all study procedures at the 
CRU 
Prior/Concomitant Therapy - General 
29. Have been treated with prescription drugs that promote weight loss (for 
example, sibutramine, mazindol, phentermine, naltrexone or bupropion, or 
liraglutide) or similar other weight-loss medications, including over-the-
counter medications (for example, Alli®) within 6 months prior to screening 
30. Have received chronic (lasting >14 consecutive days) systemic 
glucocorticoid therapy (excluding topical, intra-articular, and inhaled 
preparations) within 1 month before screening 
31. Have been treated with any glucose-lowering agent during the last 3 months 
prior to screening 
32. 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 
33. Have previously completed or withdrawn from this study 
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34. Have previous exposure or known allergies to tirzepatide or related 
compounds 
35. Are currently enrolled in a clinical study involving a study intervention or 
any other type of medical research judged not to be scientifically or 
medically compatible with this study 
36. Have parent or legal guardian who are investigative site or study 
management sponsor personnel directly affiliated with this study or their 
immediate families. Immediate family is defined as a parent, grandparent, or 
sibling, whether biological or legally adopted 
37. Have parent or legal guardian who are Eli Lilly and Company employees, 
and 
38. Are deemed unsuitable by the investigator for any other reason or have 
parent or legal guardian who are deemed unsuitable by the investigator for 
any other reason. 
5.3. 
Lifestyle Considerations  
Throughout the study, participants may undergo medical assessments and review of compliance 
with requirements before continuing in the study. 
5.3.1. 
Intensive Behavioral Therapy (IBT) for Chronic Weight Management in 
Children 6-11 Years Old  
All participants will be offered IBT that meets current practice guidelines and recommendations 
(APA 2018; Barlow 2007; USPSTF 2017). The IBT will include individual and family-based 
sessions for all study participants, including participants assigned to placebo (Farris et al. 2011; 
Mayr et al. 2020). After completing the follow-up visit, participants may have the option to 
receive 1-hour follow-up sessions once a month for up to 3 months. The total hours of IBT can 
be approximately 27 hours over the study duration and for 3 months following completion of the 
study. 
5.3.2. 
Meals and Dietary Restrictions  
Participants will be required to fast overnight when clinical laboratory test samples are taken. 
During the inpatient stay, participants may not consume any food other than that provided by the 
clinic, although water may be consumed freely. 
5.3.3. 
Substance Use: Caffeine, Alcohol, and Tobacco  
No alcohol and nicotine use will be permitted for participants and accompanying parent or legal 
guardian resident in the CRU. 
Participants will be allowed to maintain their regular caffeine consumption throughout the study 
period (except during specific fasting time periods). 
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5.3.4. 
Activity and Vaccinations  
Intense physical activity should be avoided 48 hours prior to tirzepatide dosing on Day 1 until 
the completion of all study procedures. 
Participants should continue on their current vaccination and immunization schedule as per local 
or national requirement. 
5.4. 
Screen Failures  
A screen failure occurs when a participant who consents to participate in the clinical study is not 
subsequently 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. Participant numbers are assigned earliest on Day 1 
to ensure that only eligible participants enter the study. 
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6. 
Study Intervention(s) and Concomitant Therapy  
Study intervention is defined as any study drug intervention, 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(s) Administered  
Participants will receive the SC doses of tirzepatide or placebo SC weekly. Matching placebo 
and tirzepatide 
 mg and  mg in prefilled syringes will be provided. For participants in 
Cohort 2 who are initiated on 
 mg dose, detailed instructions will be provided by the sponsor 
to clinical sites for preparing the required dose from the 
-mg prefilled syringe and for placebo. 
As such, participants in Cohort 2 and their parents or legal guardian will have to be in-clinic (that 
is, remote visits will not be permitted) for Visits 2 to 5 for safety as well as for treatment 
preparation reasons.  
Participants and legal guardians will receive a paper diary for the collection of study intervention 
details during remote visits. Paper diaries should be returned at the next site visit.  
Table GPHV.6.1 shows the treatments administered.  
 
Table GPHV.6.1. 
Treatments Administered  
Intervention 
name  
Tirzepatide  
Placebo 
Dosage 
formulation  
Prefilled syringe or dosing syringe  
Prefilled syringe or dosing syringe 
Dosage Level(s)  
 mg
 mL  
 mg
 mL  
 mg/
 mL  
Injections with the volume matching the 
investigational drug at each dose level 
Route of 
administration  
Subcutaneous  
Subcutaneous 
 
Packaging and labeling 
Study interventions 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. 
6.1.1. 
Administration Details  
When performed during on-site visits, study drug administration for each participant should be 
carried out by a limited number of site personnel for consistency. The participant (or parent or 
legal guardian) will be permitted to perform self-administration on other dosing occasions after 
being trained by the investigator or designee according to administration instructions provided by 
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the sponsor. On occasions where the visit is performed remotely, the visiting nurse will be 
permitted to administer the scheduled dose.  
All injections will be administered into the SC tissue of the abdominal wall, with injection sites 
alternated weekly between 4 sites, that is, right and left upper quadrants and right and left lower 
quadrants. Dosing will ideally occur at approximately the same time of day in all dose cohorts. 
The actual time of dosing will be recorded in the patient’s eCRF. 
Participants will receive tirzepatide or placebo SC starting on Day 1. 
The investigator or designee is responsible for 
 explaining the correct use of the study intervention to the site personnel  
 verifying that instructions are followed properly 
 maintaining the accurate records of study intervention dispensing and collection, and 
 returning all unused medication to the sponsor or its designee at the end of the study. 
Note: In some cases, sites may destroy the material if, during the investigative site selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose of clinical materials.  
6.1.2. 
Medical Devices  
The combination products provided for use in the study are the tirzepatide prefilled syringe and 
placebo prefilled syringe. 
Product complaints (including malfunction, use error, and inadequate labeling) shall be 
documented and reported by the investigator throughout the clinical investigation and 
appropriately managed by the sponsor (see Section 10.3.3). 
6.2. 
Preparation, Handling, Storage, and Accountability  
The investigator or designee must confirm that appropriate storage conditions have been 
maintained during transit for all study intervention received and any discrepancies are reported 
and resolved before the 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 intervention 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). 
All used or unused study drugs may only be destroyed by the site at the end of the study upon 
complete reconciliation and receipt of written authorization by the sponsor or its designee.  
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6.3. 
Measures to Minimize Bias: Randomization and Blinding  
This is a participant- and investigator-blinded study. To preserve the blinding of the study for 
tirzepatide and placebo, all study site personnel, except staff who prepare and dispense study 
intervention, will be blinded to treatment allocation. 
All participants will be centrally assigned to randomized study intervention using an Interactive 
Web Response System. Before the study is initiated, the log-in information and directions for the 
Interactive Web Response System will be provided to each site. 
Study intervention will be dispensed at the study visits summarized in SoA.  
Returned study intervention should not be re-dispensed to participants. 
If a participant’s study treatment assignment is unblinded, the participant must be discontinued 
from the study, unless the investigator obtains specific approval from a sponsor CP or CRP for 
the study participant to continue in the study. During the study, emergency unblinding should 
occur only by accessing the study participant’s emergency code.  
In case of an emergency, the investigator has the sole responsibility for determining if the 
unblinding of a participant’s treatment assignment is warranted for the medical management of 
the event. The participant’s safety must always be the first consideration in making such a 
determination. Where feasible and when timing of the emergent situation permits, the 
investigator should attempt to contact the Lilly medical monitor before unblinding a participant’s 
treatment assignment. If the investigator decides that unblinding is warranted, it is the 
responsibility of the investigator to promptly document the decision and rationale and notify the 
sponsor as soon as possible.  
Upon the completion of the study, all codes must be returned to the sponsor or its designee. 
6.4. 
Study Intervention Compliance  
When participants are dosed during outpatient visits at the CRU, study intervention will be 
administered under medical supervision by the investigator or designee. The dose of study 
intervention and study participant identification will be confirmed prior to the time of dosing. 
The date and time of each dose administered will be recorded in source documents and will be 
provided to the sponsor as requested. 
Self-administration by a participant or parent or legal guardian is permitted after the investigator 
has assessed them as being adequately trained. When administered at home, dosing information 
will be recorded in study dosing records provided by the investigator and compliance with study 
intervention will be assessed at each visit via review of dosing records and returned used 
prefilled syringes. Compliance will be further assessed by direct questioning and documented in 
the source documents and CRF. 
A record of the number of study intervention prefilled syringes dispensed to and taken by each 
participant must be maintained and reconciled with study intervention and compliance records. 
Intervention start and stop dates, including dates for intervention delays, will also be recorded in 
the CRF. 
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6.5. 
Dose Modification  
Dose modification other than that defined per protocol is not permitted in this study.  
In certain situations, after randomization, for example, if GI tolerability AEs occur, the 
investigator may need to temporarily interrupt treatment. Investigators should preferably consult 
with and notify the sponsor CP/CRP, if treatment needs to be interrupted. Every effort should be 
made by the investigator to maintain participants on treatment and to restart treatment after 
temporary interruption, as soon as it is assessed as safe to do so. The participant should resume 
study treatment administration at the scheduled dose level per protocol.  
If any of the following scenarios occur, dosing at the current level and further dosing will be 
stopped for the participant who will be discontinued:  
1. The SAE is considered at least possibly related to the study intervention.  
2. A severe non-serious AE occurs and is considered at least possibly related to the study 
intervention occurring in the participant.  
3. The participant experiences intolerable GI events that require further dose interruptions, 
and the investigator or designee determines that it is unsafe to resume continued 
treatment.  
If any of the following scenarios occur, an additional safety review will be initiated and new 
enrollment will be paused until the safety review is complete:  
1. One or more participants in the cohort on active drug experience SAE considered to be 
related to tirzepatide. 
2. One or more participants on active drug experience 2 clinically significant severe AEs 
considered to be related to tirzepatide. 
3. Two or more participants in the cohort experience  
a. drug-related GI effects (for example, emesis and diarrhea) assessed to be severe 
treatment-emergent AEs causing significant distress or requiring urgent medical 
interventions beyond routine symptomatic treatment, and 
b. symptomatic hypoglycemic episodes with blood glucose levels of <3.0 mmol/L 
(54 mg/dL).  
6.5.1. 
Data Review during the Study  
Data will be analyzed while the trial is ongoing. An assessment committee will not be formed. 
Safety data will be reviewed by sponsor on a regular basis while participants are enrolled in the 
study.  
Two safety data reviews are planned to occur during the Study GPHV. Such an interim safety 
review will not be considered as formal interim analyses. This review will be used to support 
dose decisions for subsequent cohorts to be enrolled. The interim data reviews will include the 
following:  
 Cohort 1 safety and tolerability data review- all available safety and tolerability data up 
to at least Day 36 from at least participants with obesity in Cohort 1 who received and 
completed at least 5 weeks of treatment, and  
 Cohort 2 safety and tolerability data review- all available safety and tolerability data up 
to at least Day 36 from at least participants with obesity in Cohort 2 who received and 
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completed at least 5 weeks of treatment and all available safety and tolerability data from 
Cohort 1 participants.  
At the time of safety reviews, any available PK data may also be reviewed by sponsor. 
6.6. 
Continued Access to Study Intervention after the End of the Study  
Not applicable.  
6.7. 
Treatment of Overdose  
For this study, any dose of study intervention greater than  mg will be considered an overdose 
in Cohorts 1 and 3. Likewise for Cohort 2, doses above 
 mg will be considered an overdose. 
In the event of an overdose, the investigator should 
● contact the medical monitor immediately 
● evaluate the participant to determine, in consultation with the medical monitor, if 
additional tests and treatment will be required 
● closely monitor the participant for any AE/SAE and laboratory abnormalities until 
the participant is clinically stable or recovering 
● obtain an unscheduled plasma sample for PK analysis if requested by the medical 
monitor (determined on a case-by-case basis), and 
● document the quantity of the excess dose in the CRF. 
6.8. 
Concomitant Therapy  
Prior to therapeutic intervention, an investigator must review the study participant’s vaccine 
record to evaluate the risk of under-immunization to the pediatric study participant. 
In general, concomitant medication should be avoided. If the need for concomitant medication 
arises (for example, to treat an AE), inclusion or continuation of the participant may be at the 
discretion of the investigator, preferably after consultation with a sponsor CP or CRP/CRS or 
designee. Any medication used during the course of the study must be documented. 
All participants on stable concomitant medication at the time of study entry, other than those that 
are prohibited, should continue their usual dose throughout the study unless deemed clinically 
necessary.  
To mitigate potential GI symptoms due to tirzepatide and manage participants with poorly 
tolerated GI AEs, the investigator 
 should advise the child to eat slowly or offer smaller meals, for example, splitting 3 daily 
meals into 4 or more smaller meals, and to stop eating when they feel full, and 
 may prescribe symptomatic medication (for example, approved anti-emetic or 
antidiarrheal medication for children). 
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Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with 
 reason for use 
 dates of administration including start and end dates, and 
 dosage information including dose and frequency for concomitant therapy 
of special interest. 
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
Participants must abstain from starting any new prescription or nonprescription drugs after 
screening unless, in the opinion of the investigator in consultation with the sponsor CP or 
CRP/CRS, the medication is assessed as clinically necessary or is deemed unlikely to interfere 
with the study outcome. 
If acetaminophen treatment is needed for pain management, the maximal allowed dose will be 
the amount as stipulated in the package insert for the body weight and age of the participant. 
Other concomitant medication may be considered on a case-by-case basis by the investigator in 
consultation with the medical monitor if required. 
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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal  
The discontinuation of specific sites or of the study as a whole is handled as a part of Appendix 1 
(Section 10.1). 
When necessary, a participant may be permanently discontinued from study intervention. If so, 
the participant, must complete early discontinuation procedures as shown in the SoA.  
7.1. 
Discontinuation of Study Intervention  
A participant may not receive study intervention if 
 the participant (females only) exhibits signs and symptoms of puberty, and 
 in the opinion of the investigator, the participant should not receive study 
intervention for safety reasons. 
If the investigator, after consultation with the sponsor-designated medical monitor, determines 
that a systemic hypersensitivity reaction has occurred related to study intervention 
administration, the participant should be permanently discontinued from the intervention, and the 
sponsor’s designated medical monitor should be notified. If the investigator is uncertain about 
whether a systemic hypersensitivity reaction has occurred and whether discontinuation of study 
intervention is warranted, the investigator may consult the sponsor. 
7.2. 
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 own request 
 at the request of the participant’s designee (for example, parents or legal 
guardian) 
 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 clinically 
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, as shown in the SoA. If the participant has not already 
discontinued the study intervention, the participant will be permanently discontinued from the 
study intervention at the time of the decision to discontinue the study. 
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If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. If a participant 
withdraws from the study, the participant may request destruction of any samples taken and not 
tested, and the investigator must document this in the site study records. 
7.3. 
Lost to Follow-up  
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits or if permitted remote visits cannot be scheduled or is unable to be contacted by 
the study site staff. Site personnel or designee are expected to make diligent attempts to contact 
participants and their parents or legal guardian who fail to return for a scheduled visit or were 
otherwise unable to be followed up by the site.  
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8. 
Study Assessments and Procedures  
Study procedures and their timing are summarized in the SoA.  
Immediate safety concerns should be discussed with the sponsor immediately upon occurrence or 
awareness to determine if the participant should continue or discontinue study intervention. 
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. The investigator will maintain a screening log to record details of all 
participants screened and to confirm eligibility or record reasons for screening failure, as 
applicable.  
8.1. 
Efficacy Assessments  
Although this study is primarily a safety and tolerability study, weight loss is a potential benefit 
for children with obesity. Body weight will be assessed as a part of safety and also potential 
efficacy measure according to the SoA.  
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 include, at a minimum, the assessments of CV, 
respiratory, GI and neurological systems. Height and weight will also be measured and recorded. 
A brief physical examination will include, at a minimum, assessments of the skin, lungs, CV 
system, and abdomen (liver and spleen). 
Investigators should pay special attention to clinical signs related to signs and symptoms of 
puberty. 
8.2.2. 
Body Weight, Body Mass Index, Height, and Waist Circumference  
Body weight, height, and waist circumference will be measured at prespecified time points. Each 
participant’s weight, height, and waist circumference must be measured according to 
standardized guidelines (Section 10.9 [Appendix 9]). BMI will be computed from the 
participant’s weight and height. 
8.2.3. 
Assessment of Pubertal Status - Tanner Staging  
Female participants’ pubertal status will be assessed using Tanner Staging performed at 
screening and other scheduled time points per protocol (see also Section 10.7 [Appendix 7] for 
Tanner Stages). This study will only include female participants that are at Tanner Stage 1.  
8.2.4. 
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 supine.  
Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or 
posture-induced symptoms. Additional vital signs may be measured during each study period if 
warranted.  
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.  
8.2.5. 
Electrocardiograms  
Single 12-lead ECG will be obtained as outlined in the SoA (see Section 1.3). ECGs may be 
obtained at additional times, when deemed clinically necessary. 
8.2.6. 
Clinical Safety Laboratory Tests  
See Appendix 2 for the list of clinical laboratory tests to be performed and the SoA for the timing 
and frequency. 
The investigator must review the laboratory results, document this review, and report any 
clinically relevant changes occurring during the study as an AE. The laboratory results must be 
retained with source documents unless a Source Document Agreement or comparable document 
cites an electronic location that accommodates the expected retention duration. Clinically 
significant abnormal laboratory findings are those which are not associated with the underlying 
disease, unless judged by the investigator to be more severe than expected for the participant's 
condition. 
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the investigator. 
 If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor must 
be notified. 
 All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the SoA, 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), then report the 
information as an AE.  
8.2.7. 
Safety Monitoring  
Hepatic Safety  
Close hepatic monitoringa 
Laboratory tests (Appendix 2), including ALT, AST, ALP, TBL, direct bilirubin, gamma-
glutamyl transferase, and creatine kinase, should be repeated within 48 to 72 hours to confirm 
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the abnormality and to determine if it is increasing or decreasing, if one or more of following 
conditions occur: 
If a participant with baseline results 
of...  
Develops the following elevations: 
ALT or AST <1.5x ULN 
ALT or AST ≥3x ULN 
ALP <1.5x ULN 
ALP ≥2x ULN 
TBL <1.5x ULN 
TBL ≥2x ULN (except for patients with Gilbert’s 
syndrome) 
ALT or AST ≥1.5x ULN 
ALT or AST ≥2x baseline 
ALP ≥1.5x ULN 
ALP ≥2x baseline 
TBL ≥1.5x ULN 
TBL ≥1.5x baseline (except for patients with Gilbert’s 
syndrome) 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; TBL = total bilirubin; ULN = 
upper limit of normal. 
a All ULN values should be age-adjusted (AAULN). 
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 sponsor-designated medical monitor. At a minimum, this evaluation should include physical 
examination and a thorough medical history, including symptoms, recent illnesses (for example, 
heart failure, systemic infection, hypotension, or seizures), recent travel, history of concomitant 
medications (including over-the-counter), herbal and dietary supplements, history of alcohol 
drinking, and other substance abuse.  
Initially, the 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 lab results stabilize. The monitoring of ALT, 
AST, ALP, and TBL should continue until levels normalize or return to approximate baseline 
levels. Special care should be taken to minimize the volume of blood taken during hepatic 
monitoring.  
Comprehensive hepatic evaluationa 
A comprehensive evaluation should be performed to search for possible causes of liver injury if 
one or more of the following conditions occur: 
 
 
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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/symptoms,b 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/symptoms,b 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)  
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; TBL = total bilirubin; ULN = 
upper limit of normal. 
a All ULN values should be age-adjusted (AAULN). 
b Hepatic signs/symptoms are severe fatigue, nausea, vomiting, right upper quadrant abdominal pain, fever, rash, 
and eosinophilia >5%. 
At a minimum, this evaluation should include physical examination and a thorough medical 
history, as outlined above, as well as tests for PT-INR and direct bilirubin, if total bilirubin was 
elevated. 
Based on the participant’s age, medical history, and initial results, further testing should be 
considered in consultation with the Sponsor-designated medical monitor, including tests for viral 
hepatitis A, B, C, E, as well as autoimmune hepatitis; or an abdominal imaging study (for 
example, ultrasound, MRI, or CT scan). Consider additional tests, based on the medical history 
and clinical picture, including tests for hepatitis D virus, cytomegalovirus, Epstein-Barr virus, 
acetaminophen levels, acetaminophen protein adducts, urine toxicology screen, Wilson’s disease, 
blood alcohol levels, urinary ethyl glucuronide, and blood phosphatidylethanol. Special care 
should be taken to prioritize more pertinent blood tests and minimize the volume of blood taken 
during hepatic evaluation. Based on the circumstances and the investigator’s assessment of the 
participant’s clinical condition, the investigator should consider referring the participant for a 
pediatric hepatologist or gastroenterologist consultation, magnetic resonance 
cholangiopancreatography, endoscopic retrograde cholangiopancreatography, cardiac 
echocardiogram, or a liver biopsy as deemed appropriate for the clinical condition and 
participant’s age.  
Additional hepatic data collection (hepatic safety CRF) in study participants who have 
abnormal liver tests during the study  
Additional hepatic safety data collection in hepatic safety CRFs should be performed in study 
participants who meet 1 or more of the following 5 conditions:  
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1. Elevation of serum ALT to ≥5x ULN on 2 or more consecutive blood tests (if baseline 
ALT <1.5x ULN). 
 In participants with baseline ALT ≥1.5x ULN, the threshold is ALT ≥3x baseline 
on 2 or more consecutive tests. 
2. Elevated TBL to ≥2x ULN (if baseline TBL <1.5x ULN) (except for cases of known 
Gilbert’s syndrome). 
 In participants with baseline TBL ≥1.5x ULN, the threshold should be TBL ≥2x 
baseline. 
3. Elevation of serum ALP to ≥2x ULN on 2 or more consecutive blood tests (if baseline 
ALP <1.5x ULN). 
 In participants with baseline ALP ≥1.5x ULN, the threshold is ALP ≥2x baseline 
on 2 or more consecutive blood tests. 
4. Hepatic event considered to be an SAE. 
5. Discontinuation of study drug due to a hepatic event.  
Note: The interval between the 2 consecutive blood tests should be at least 2 days. 
Pancreatic Safety  
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 2006; Koizumi 
2006):  
 abdominal pain, characteristic of acute pancreatitis (that is, epigastric pain radiating 
to the back, often associated with nausea and vomiting) 
 serum amylase (total, pancreatic, or both) or lipase ≥3X ULN, and 
 characteristic findings of acute pancreatitis on CT scan or MRI. 
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 MRI, and 
 evaluate for the 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 the use of IPs.  
Asymptomatic elevation of serum amylase and lipase  
The serial measures of pancreatic enzymes have limited clinical value for predicting episodes of 
acute pancreatitis in asymptomatic participants (Nauck et al. 2016; Steinberg et al. 2017a, 
2017b). Therefore, further diagnostic follow-up of cases of the asymptomatic elevation of 
pancreatic enzymes (lipase 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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8.2.8. 
Pregnancy Testing  
All female participants will undergo urine pregnancy tests at screening.  
8.3. 
Adverse Events, Serious Adverse Events, and Product Complaints  
The definitions of the following events can be found in Appendix 3: 
 AEs 
 SAEs, and 
 PCs. 
These events will be reported by the participant or parent(s), or the participant’s legally 
authorized representative. 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet these definitions and remain responsible for following up events that 
are serious, considered related to the study intervention or study procedures, or that caused the 
participant to discontinue the study (see Section 7). 
Care will be taken not to introduce bias when detecting events. Open-ended and non-leading 
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 or contacts. All adverse events 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 PCs, the investigator is responsible for ensuring that follow-up includes any 
supplemental investigations as indicated to elucidate the nature or causality. Further information 
on follow-up procedures is provided in Section 10.3 (Appendix 3).  
Investigators are responsible for monitoring the safety of participants who have entered this 
study and for alerting the sponsor 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 
AE 
AE 
Signing of the ICF 
and assent as 
applicable 
Participation 
in study has 
ended 
As soon as possible 
upon site awareness 
AE CRF 
N/A 
SAE 
SAE and SAE 
updates - prior 
to the start of 
study 
intervention 
and deemed 
reasonably 
possibly 
related to study 
procedures 
Signing of the ICF 
and assent as 
applicable 
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 
SAEa - 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  
2 months 
after the last 
injection of 
TZP 
Within 24 hours (see 
Section 8.3.2)  
Pregnancy paper 
form  
Pregnancy 
paper 
form  
PCs 
PC associated 
with an SAE or 
might have led 
to an SAE 
Start of study 
intervention 
End of study 
intervention 
Within 24 hours of 
awareness 
PC form 
N/A 
PC not 
associated with 
an SAE 
Start of study 
intervention 
End of study 
intervention 
Within 1 business day 
of awareness 
PC form 
N/A 
Updated PC 
information 
- 
- 
As soon as possible 
upon site awareness 
Originally 
completed PC 
form with all 
changes signed and 
dated by the 
investigator 
N/A 
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Event 
Collection Start 
Collection 
Stop 
Timing for 
Reporting to 
Sponsor or Designee 
Mechanism for 
Reporting 
Back-up 
Method 
of 
Reporting 
PC (if 
investigator 
becomes 
aware) 
Participation in 
study has ended 
N/A 
Promptly 
PC form 
N/A 
Abbreviations: AE = adverse event; CRF = case report form; ICF = informed consent form; N/A = not applicable; 
SAE = serious adverse event; PC = product complaint; TZP = tirzepatide. 
a 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  
Because of the pediatric population (Tanner Stage 1) in the rare event of pregnancy, pregnancy 
information will be collected as follows: 
Collection of pregnancy information 
Female participants who become pregnant 
● The investigator will collect pregnancy information on any female participant 
who becomes pregnant while participating in this study. The initial information 
will be recorded on the appropriate form and submitted to the sponsor within 24 
hours of learning of a participant’s pregnancy.  
● The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate 
and the information will be forwarded to the sponsor. Generally, follow-up will 
not be required for longer than 6 to 8 weeks beyond the estimated delivery date. 
Any termination of pregnancy will be reported, regardless of gestational age, fetal 
status (presence or absence of anomalies), or indication for the procedure. 
● While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE.  
● A spontaneous abortion (occurring at <20 weeks gestational age) or still birth 
(occurring at ≥20 weeks gestational age) is always considered to be an SAE and 
will be reported as such.  
● Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in 
protocol Section 8.3.1. While the investigator is not obligated to actively seek this 
information in former study participants, he or she may learn of an SAE through 
spontaneous reporting. 
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● Any female participant who becomes pregnant while participating in the study. If 
the participant is discontinued from the study, follow the standard discontinuation 
process and continue directly to the follow-up phase. The follow-up on the 
pregnancy outcome should continue independent of intervention or study 
discontinuation.  
Prior to the continuation of study intervention following pregnancy, the following must occur: 
● The sponsor and the relevant IRB/IEC give written approval. 
● The participant gives signed informed consent. 
● The investigator agrees to monitor the outcome of the pregnancy and the status of the 
participant and the participant’s offspring. 
8.3.3. Adverse Events of Special Interest  
8.3.3.1. 
Hypersensitivity Reactions  
Many drugs, but particularly biologic agents, carry the risk of systemic hypersensitivity 
reactions. If such a reaction occurs, additional data describing each symptom must be provided to 
the sponsor in the eCRF. 
Sites should have appropriately trained medical staff and appropriate medical equipment 
available when study participants are receiving study intervention. It is recommended that 
participants who experience a systemic hypersensitivity reaction be treated per national and 
international guidelines. 
In the case of generalized urticaria or anaphylaxis, additional blood samples should be collected 
as described in Appendix 8 (Section 10.8). Laboratory results are provided to the sponsor via the 
central laboratory. 
8.3.3.2. 
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 parent or guardian or site staff, the ISR CRF will be used 
to capture additional information about this reaction, for example, injection-site pain, degree and 
area of erythema, induration, pruritis, and edema. 
At the time of AE occurrence in the tirzepatide group, samples will be collected for the 
measurement of tirzepatide antidrug antibodies and tirzepatide concentration. 
8.3.3.3. 
Hypoglycemia Reporting  
Participants will be trained by authorized study personnel about signs and symptoms of 
hypoglycemia and how to treat hypoglycemia. 
Investigators should use the following classification of hypoglycemia: 
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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): Level 2 hypoglycemia 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, or were 
semiconscious or unconscious, or experienced coma with or without seizures, and the assistance 
of another person was needed to actively administer carbohydrate, glucagon, or other 
resuscitative actions. Glucose measurements may not be available during such an event, but 
neurological recovery attributable to the restoration of glucose concentration to normal is 
considered sufficient evidence that the event was induced by a low glucose concentration. 
The determination of a hypoglycemic event as an episode of severe hypoglycemia, as defined 
above, is made by the investigator based on the medical need of the participant to have required 
assistance and is not predicated on the report of a participant simply having received assistance. 
If a hypoglycemic event meets the criteria of severe hypoglycemia, the investigator must record 
the event as serious on the AE CRF and report it to Lilly as an SAE. 
Nocturnal hypoglycemia:  
Nocturnal hypoglycemia is a hypoglycemia event (including severe hypoglycemia) that occurs at 
night and presumably during sleep. 
8.3.3.4. 
Nausea and Vomiting  
Nausea and vomiting events are considered AEs of interest and will be recorded as AEs in the 
CRF. For each event assessment of severity, duration and investigator’s opinion of relatedness to 
the study drug and protocol procedure will be captured. 
8.3.3.5. 
Elevated Lipase or Amylase  
Serum amylase and lipase measurements will be collected as a part of the clinical laboratory 
testing at time points specified in the SoA (Section 1.3). Additional measurements may be 
performed at the investigator’s discretion. Further diagnostic assessments will be recommended 
whenever lipase or amylase is confirmed to be ≥3X ULN at any visit post randomization, even if 
the participant is asymptomatic (as per the algorithm refer for the monitoring of pancreatic 
events in Appendix 6, Section 10.6). 
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8.4. 
Pharmacokinetics  
The characterization of the PK properties of tirzepatide in pediatric participants will be supported 
by collection of both predose and postdose PK blood samples per participant according to the 
SoA (Section 1.3).  
At Visit 2 (Days 1 to 3), the sample is collected at 12 hours and 24 hours after the first dose 
during inpatient visit. At Visit 6 (Days 23 to 25), each participant will have PK sample collected 
at window of 24 to 96 hours post Day 22 dose. At Visit 9 (Days 41 and 42), each participant will 
have PK sample collected at window of 120 to 168 hours post Day 36 dose. For Visits 4, 8, and 
11 (Days 15, 36, and 50), PK samples are collected prior to the intervention administration. 
Participants may be required to come to the site for PK-specific visits depending on sample 
window.  
The actual date and time of the most recent SC injection administered prior to collecting the 
sample must be recorded. The actual date and time at which each sample was drawn must be 
recorded on the laboratory requisition form. Instructions for the collection and handling of blood 
samples will be provided by the sponsor.  
The number and timing of PK samples are expected to be adequate in enabling comprehensive 
population PK and exposure-response modeling analyses within this special population. 
8.4.1. Bioanalysis  
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor. 
Concentrations of tirzepatide will be assayed using a validated liquid chromatography mass 
spectrometry method. The analyses of samples collected from placebo-treated participants are 
not planned. 
Bioanalytical samples collected to measure study intervention 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  
The PD exploratory analyses include treatment comparison based on the following variables: 
 body weight 
 BMI, and 
 waist circumference. 
8.5.1. 
Body Weight and Waist Circumference  
Weight and waist circumference will be measured as indicated in the SoA (Section 1.3). 
Wherever possible, the same scale will be used for all weight measurements throughout the study 
and the scale will not be moved or recalibrated. 
Refer to Section 10.9 for guidance on the standardized protocols for weight and waist 
circumference measurements. 
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8.6. 
Genetics  
Genetics are not evaluated in this study. 
8.7. 
Biomarkers  
Biomarkers are not evaluated in this study. 
8.8. 
Immunogenicity Assessments  
At the visits and times specified in the SoA (Section 1.3), venous blood samples will be collected 
to determine antibody production against tirzepatide. Samples with detected tirzepatide ADA 
will be titered and evaluated for their ability to neutralize tirzepatide activity on the GIP and 
GLP-1 receptors. Antibodies may be further characterized for cross-reactive binding to native 
GIP and GLP-1 and, if such is detected, then for cross-reactive neutralizing antibodies against 
native GIP and GLP-1. To interpret the results of immunogenicity, a venous blood sample will 
be collected at the same time points after predose visit (Day 1) to determine the serum 
concentrations of tirzepatide. Detailed instructions for the sample collections and handling will 
be provided by the sponsor. Immunogenicity will be assessed by a validated assay designed to 
detect ADAs in the presence of tirzepatide at a laboratory approved by the sponsor. 
Treatment-emergent ADAs (TE ADA) are defined in Section 9.3.4. 
If the immunogenicity sample at the last scheduled assessment or discontinuation visit indicates 
TE ADA, the sponsor may request for additional samples to be taken until the signal returns to 
baseline (that is, no longer indicates TE ADA) or for up to 1 year after last dose, as a part of 
safety measures. The requirement for possible additional, unscheduled ADA safety follow-up 
must be included in the ICF. 
Refer to Appendix 1 (Section 10.1.9) for details on sample retention.  
8.9. 
Health Economics  
Health economics or medical resource utilization and health economics parameters are not 
evaluated in this study. 
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9. 
Statistical Considerations  
The statistical analysis plan will be finalized prior to database lock, and it will include a more 
technical and detailed description of the statistical analyses described in this section. This section 
is a summary of the planned statistical analyses of the most important endpoints, including 
primary and key secondary endpoints. 
9.1. 
Statistical Hypotheses  
Not applicable. 
9.1.1. 
Multiplicity Adjustment  
Not applicable. No formal statistical analysis will be performed.  
9.2. 
Analyses Sets  
For the purposes of analysis, the following analysis sets are defined: 
Participant Analysis Set 
Description 
Full analysis set 
All enrolled participants. Participants will be included in the 
analyses according to the planned intervention. 
Safety analysis set 
All participants who are exposed to study intervention. Participants will be 
analyzed according to the intervention they actually received. 
The full analysis set will be used to summarize disposition and demographic characteristics. 
The safety analysis set will be used for safety evaluation. 
9.3. 
Statistical Analyses  
9.3.1. General Considerations  
Statistical analysis of this study will be the responsibility of the sponsor or its designee. 
PK analyses will be conducted on data from all participants who receive at least 1 dose of the 
study intervention and have evaluable PK.  
Safety analyses will be conducted for all enrolled participants who were administered study 
intervention, whether or not they completed all protocol requirements. 
A detailed description of participant disposition will be provided at the end of the study. 
All participants who discontinue from the study will be identified, and the extent of their 
participation in the study will be reported. If known, a reason for their discontinuation will be 
given. 
The demographic characteristics of enrolled participants (including but not limited to age, sex, 
and race) will be summarized. Additional exploratory analyses of the data will be conducted as 
deemed appropriate. 
 
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9.3.2. 
Pharmacokinetics  
9.3.2.1. 
Pharmacokinetic Analyses  
All tirzepatide concentration data will be listed and summarized using descriptive analysis. 
Tirzepatide concentration may also be analyzed using a population PK approach via nonlinear 
mixed-effects modeling with the NONMEM® software to determine the Cmax and AUC0-tau of 
tirzepatide by each dose and cohort.  
9.3.2.2. 
Pharmacokinetic Statistical Inference  
No formal statistical analysis will be performed. 
9.3.3. 
Safety Analyses  
9.3.3.1. 
Clinical Evaluation of Safety  
All study intervention and protocol procedure AEs will be listed, and if the frequency of events 
allows, safety data will be summarized using descriptive methodology. 
The incidence of AEs will be presented by severity and by association with study intervention as 
perceived by the investigator. AEs reported to occur prior to enrollment will be distinguished 
from those reported as new or increased in severity during the study. Each AE will be classified 
by the most suitable term from the medical regulatory dictionary. 
The number of study intervention-related SAEs will be reported. 
9.3.3.2. 
Statistical Evaluation of Safety  
Safety parameters that will be assessed include safety laboratory parameters, vital signs 
(including blood pressure and pulse rate), body weight and BMI, and ECG parameters. 
Continuous safety variables will be summarized using descriptive statistics. Categorical safety 
variables will be summarized using count and percentage.  
Additional analysis will be performed if warranted upon review of the data. 
9.3.4. 
Evaluation of Immunogenicity  
The frequency and percentage of participants with preexisting ADAs, ADAs at any time 
postbaseline, and TE ADA+ to tirzepatide may be tabulated. TE ADAs are defined as those with 
a titer 2-fold (1 dilution) greater than the minimum required dilution (1:10) of the ADA assay if 
no ADAs were detected at baseline (treatment-induced ADA) or those with a 4-fold (2 dilutions) 
increase in titer compared to baseline if ADAs were detected at baseline (treatment-boosted 
ADA). For the TE ADA+ participants, the distribution of maximum titers may be described. The 
frequency of neutralizing antibodies, if assessed, and cross-reactivity to native GIP and GLP-1 
may also be tabulated in TE ADA+ participants. 
The relationship between the presence of antibodies and the PK parameters and PD response, 
including safety and efficacy to tirzepatide, may be assessed. 
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9.4. 
Interim Analysis  
No interim analyses are planned for this study. If an unplanned interim analysis is deemed 
necessary for reasons other than a safety concern, the protocol must be amended. 
For further information on the review of safety and tolerability data during the study, refer to 
Section 6.5.1. 
9.5. 
Sample Size Determination  
Approximately 
participants may be enrolled. This will allow PK characterization in at least  
participants each, exposed to tirzepatide, for the weight categories <50 kg and ≥50 kg, 
respectively. Evaluable participants are participants who receive at least 1 dose of the study 
intervention and have at least 1 evaluable PK sample. The sample size is customary for Phase 1 
studies evaluating safety, tolerability, and PK, and is not powered on the basis of any a priori 
statistical hypothesis testing for efficacy. 
Participants who do not complete all the study procedures may be replaced to achieve the 
planned number of completers. 
Note: Enrolled means a participant’s parent or their legally acceptable representative’s, 
agreement to participate in a clinical study following the completion of the informed consent 
process and assent where applicable and screening. Potential participants who are screened for 
the purpose of determining eligibility for the study, but do not participate in the study, are not 
considered enrolled. A participant will be considered as enrolled if the informed consent is not 
withdrawn prior to participating in any study activity after the screening visit. 
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10. 
Supporting Documentation and Operational Considerations  
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations  
10.1.1. 
Regulatory and Ethical Considerations  
This study will be conducted in accordance with the protocol and with the following: 
 consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines 
 applicable International Council for Harmonization of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) GCP Guidelines, 
and 
 applicable laws and regulations. 
The protocol, protocol amendments, ICF, applicable assent forms, Investigator Brochure, and 
other relevant documents (for example, advertisements) must be submitted to an IRB/IEC by the 
investigator and reviewed and approved by the IRB/IEC before the study is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
Protocols and any substantial amendments to the protocol will require health authority approval 
prior to initiation except for changes necessary to eliminate an immediate hazard to study 
participants. 
The investigator will be responsible for the following: 
 providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/IEC 
 notifying the IRB/IEC of SAEs or other significant safety findings as 
required by IRB/IEC procedures, and 
 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. 
Investigator sites are compensated for participation in the study as detailed in the clinical trial 
agreement. 
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10.1.2. 
Informed Consent Process  
The investigator or the investigator’s representative will explain the nature of the study, 
including the risks and benefits, to the participant or the participant’s legally authorized 
representative, defined as either a parent or a legal guardian and answer all questions regarding 
the study. 
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. 
10.1.3. 
Data Protection  
Participants will be assigned a unique identifier by the sponsor. Any participant, parent or legal 
guardian 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, parent or 
legal guardian identifiable, will not be transferred. 
The parent or legal guardian 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. 
Rationale for collection of full date of birth 
This study includes children. Within this age range, participants’ expected height and weight, as 
well as normal ranges for laboratory tests, vary by both age and sex. Therefore, it is necessary to 
collect the full date of birth (day, month, and year) for all participants to appropriately analyze 
and interpret changes in growth and laboratory parameters. 
In countries where local regulations do not permit collection of the full date of birth, if the 
supporting regulatory/ethics documentation is available, at a minimum, the month and year of 
birth must be collected on the eCRF. 
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10.1.4. 
Dissemination of Clinical Study Data  
Communication of Suspended or Terminated Dosing 
If a decision is taken to suspend or terminate dosing in the trial due to safety findings, this 
decision will be communicated by The sponsor to all investigators (for example, by phone 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 The sponsor personnel prior to any further planned dosing. If a dose is planned 
imminently, The sponsor 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.  
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. 
10.1.5. 
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 permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents. 
Quality tolerance limits will be predefined to identify systematic issues that can impact 
participant safety or reliability of study results. These predefined parameters will be monitored 
during the study and important excursions from the quality tolerance limits (QTLs) and remedial 
actions taken will be summarized in the clinical study report. 
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 the handling of noncompliance issues and 
monitoring techniques, are provided in the Trial 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). 
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Study monitors will perform ongoing source data verification to confirm that data transcribed 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator for the time period outlined in the Clinical Trial Agreement unless 
local regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the sponsor. No records 
may be transferred to another location or party without written notification to the sponsor. 
In addition, sponsor or its representatives will periodically check a sample of the participant data 
recorded against source documents at the study site. The study may be audited by sponsor or its 
representatives, and/or regulatory agencies at any time. Investigators will be given notice before 
an audit occurs. 
Data Capture System 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor.  
An electronic data capture system will be used in this study for the collection of CRF data. The 
investigator maintains a separate source for the data entered by the investigator or designee into 
the sponsor-provided electronic data capture system. The investigator is responsible for the 
identification of any data to be considered source and for the confirmation that data reported are 
accurate and complete by signing the CRF. 
Data collected via the sponsor-provided data capture system will be stored at third parties. The 
investigator will have continuous access to the data during the study and until decommissioning 
of the data capture system(s). 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 PC 
management system. 
10.1.6. 
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 Section 10.1.5. 
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10.1.7. 
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 the 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 that 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, and 
 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 (if applicable) and follow-up. 
10.1.8. 
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. 
10.1.9. 
Sample Retention  
Sample retention enables the use of new technologies, response to regulatory questions, and 
investigation of variable response that may not be observed until later in the development 
of tirzepatide or after tirzepatide become(s) commercially available for the studied indication. 
  
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Sample Type 
Custodian 
Retention Period After Last 
Patient Visita 
Pharmacokinetics 
Sponsor or designee 
1 year 
Immunogenicity 
Sponsor or designee 
15 years 
a Retention periods may differ locally.  
 
10.2. 
Appendix 2: Clinical Laboratory Tests  
The tests detailed in the table below will be performed by the central laboratory. 
Local laboratory results are only required in the event that the central laboratory results are not 
available in time for either study intervention administration or response evaluation. If a local 
sample is required, it is important that the sample for central analysis is obtained at the same 
time. Additionally, if the local laboratory results are used to make either a study intervention 
decision or response evaluation, the results must be recorded. 
In circumstances where the sponsor approves local laboratory testing in lieu of central laboratory 
testing (in the table below), the local laboratory must be qualified in accordance with applicable 
local regulations. 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in Section 5 
of the protocol. 
Additional tests may be performed at any time during the study as determined necessary by the 
investigator or required by local regulations. 
Investigators must document their review of the laboratory safety results. 
 
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Safety Laboratory Tests 
Hematologya 
Clinical 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 
 
Total protein 
Absolute counts ofa: 
Albumin 
Neutrophils 
Total bilirubin 
Lymphocytes 
Alkaline phosphatase 
Monocytes 
Aspartate aminotransferase 
Eosinophils 
Alanine aminotransferase 
Basophils 
Creatinine 
Platelets 
Amylase 
 
Lipase 
Pubertal hormonea: 
Testosterone (male participants only) 
Estradiol (female participant only) 
Uric acid 
Phosphorous 
Calcitoninc 
Insulin 
Urinalysisa 
Specific gravity 
Lipid panel (fasting)a,b 
pH 
Triglycerides 
Protein 
Total cholesterol 
Glucose 
LDL 
Ketones 
HDL 
Bilirubin 
 
Hepatitis C antibody, hepatitis C RNAc,d 
Urobilinogen 
HIVc,d 
Blood 
Hepatitis B surface antigenc,d 
Nitrite 
Urine pregnancy teste 
Microscopic examination of sedimentf 
 
Abbreviations: LDL = low-density lipoprotein; HIV = human immunodeficiency virus; HDL = high-density 
lipoprotein; RBC = red blood cells; RNA = ribonucleic acid; WBC = white blood cells. 
a Performed by central laboratory except at screening, which will be by local laboratory. Results will be validated 
by the laboratory at the time of initial testing. 
b Performed at screening (by local laboratory), Visit 2 (central laboratory), and Visit 12 or at early discontinuation visit 
(central laboratory). 
c Performed by local laboratory at screening only. 
d Tests may be waived if they have been performed within 6 months before screening with reports available for review. 
e Only applicable to female participants whom the investigator suspects to be sexually active. 
f Test only if dipstick result is abnormal (that is, positive for blood, protein, or nitrites). 
 
 
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10.2.1. 
Blood Sampling Summary  
The table below summarizes the approximate number of venipunctures and blood volumes for all 
blood sampling (screening, safety laboratories, and bioanalytical assays) during the study. The 
number of samples in parenthesis assumes 3 additional unscheduled samples, which may be 
taken for safety purposes. 
To ease discomfort associated with venipunctures, the following options are allowed in the study 
per local practice and prescribing information: 
 local anesthetic creams, for example, EMLA® or ELA-max®  
 needleless devices for injecting local anesthetics, for example, a J-tip, and 
 local vibration devices, for example, a buzzy. 
 
Protocol I8F-MC-GPHV Overall Sampling Summary 
Purpose 
Blood Volume per Sample 
(mL) 
Number of Blood 
Samples 
Total Volume 
(mL) 
Screening testsa,b 
20 
1 
20 
Safety laboratory testsa,c 
12 
3 
36 
Tirzepatide pharmacokineticsc 
2 
9 
18 
Immunogenicityc 
10 
4 
40 
Blood glucosea,b 
2 
2 
4 
Total 
 
 
118 
Total for clinical purposes 
 
 
120 
a Additional samples may be drawn if needed for safety purposes. Safety laboratory tests will be inclusive of lipid 
panels on days when they are performed.  
b Performed on site or in a local laboratory.  
c Performed at a central or referral laboratory approved by the sponsor. 
 
10.2.1.1. Rationale for Blood Draws and Required Blood Volume  
Careful consideration was given to collect the necessary information to address the key scientific 
objectives of this pediatric study while also minimizing invasive procedures and overall patient 
burden. 
As PK profiling is a secondary objective of this study, the number of bioanalytical samples 
proposed is the minimum required to be able to derive a concentration-time profile for tirzepatide 
in children, based on an anticipated half-life of about 5 to 6 days. The blood volume for each PK 
sampling has been capped at 2 mL, which is the smallest volume of K3EDTA collection tube 
available. 
Safety laboratory tests and BG had been limited to only the minimal number of samples to 
ensure safety of participants. The volume of blood required for safety clinical laboratory tests 
have been defined based on the analyte requirement in Appendix 2, which includes the 
monitoring of prepubertal hormones as part of pediatric monitoring. 
The 10-mL blood volume for the immunogenicity sample is required to generate 5 to 7 mL 
serum divided into 6 aliquots due to the need to test for ADA and neutralizing antibodies using 4 
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aliquots (approximately 1 mL serum per aliquot) of serum in the event that the ADA sample is 
positive. A sample is required every 4 to 5 weeks, and another sample will also be drawn 2 
weeks after initial treatment commencement to monitor IgM ADA as is often explicitly 
requested by FDA from experience.  
 
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10.3. 
Appendix 3: Adverse Events and Serious Adverse Events: Definitions 
and Procedures for Recording, Evaluating, Follow-up, and 
Reporting  
The definitions and procedures detailed in this appendix are in accordance with ISO 14155. 
Both the investigator and the sponsor will comply with all local medical device reporting 
requirements. 
The detection and documentation procedures described in this protocol apply to all sponsor 
medical devices provided for use in the study. See Section 6.1.2 for the list of sponsor medical 
devices. 
10.3.1. 
Definition of an Adverse Event  
AE definition 
An AE is any untoward medical occurrence in a participant administered a pharmaceutical 
product and which does not necessarily have a causal relationship with the study intervention. 
An AE can, therefore, be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the 
use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product. 
An AE is any untoward medical occurrence, unintended disease or injury, or untoward clinical 
signs (including abnormal laboratory finding) in study participants, users, or other persons, 
whether or not related to the investigational medical device. This definition includes events 
related to the investigational medical device or comparator and events related to the 
procedures involved except for events in users or other persons, which only include events 
related to investigational devices. 
 
Events meeting the AE definition 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (for example, ECG, radiological scans, and 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 preexisting condition including either an increase in 
frequency 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. 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention 
or a concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is 
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an intentional overdose taken with possible suicidal/self-harming intent. Such overdoses 
should be reported regardless of sequelae. 
 
Events not meeting the AE definition 
Any clinically significant abnormal laboratory findings or other abnormal safety assessments 
that are associated with the underlying disease, unless judged by the investigator to be more 
severe than expected for the participant’s condition. 
The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
Medical or surgical procedure (for example, endoscopy and appendectomy): the condition that 
leads to the procedure is the AE. 
Situations in which an untoward medical occurrence did not occur (social or convenience 
admission to a hospital). 
Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
10.3.2. 
Definition of Serious Adverse Event  
An SAE is defined as any untoward medical occurrence that, at any dose, meets one or 
more of the criteria listed: 
a. Results in death 
b. Is life-threatening 
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. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 In general, hospitalization signifies that the participant has been admitted to hospital or 
emergency ward (usually involving at least an overnight stay) for observation 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. 
 Hospitalization for the elective treatment of a preexisting condition that did not worsen 
from baseline is not considered an AE. 
d. Results in persistent disability or incapacity 
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 The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
 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. 
e. 
Is a congenital anomaly or birth defect 
 Abnormal pregnancy outcomes (for example, spontaneous abortion, fetal death, 
stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs. 
f. 
Other situations 
 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. 
 
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.  
g. Resulted in medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function.  
10.3.3. 
Definition of Product Complaints  
Product complaint 
A PC 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 PCs: 
 deficiencies in labeling information, and 
 use errors for device or drug-device combination products due to ergonomic design 
elements of the product. 
PCs related to study interventions used in clinical trials are collected in order to ensure the 
safety of participants, monitor quality, and facilitate process and product improvements. 
Investigators will instruct participants to contact the site as soon as possible if he or she has a 
PC or problem with the study intervention so that the situation can be assessed. 
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An event may meet the definition of both a PC and an AE or SAE. In such cases, it should be 
reported as both a PC and as an AE or SAE. 
10.3.4. 
Recording and Follow-up of Adverse Event or Serious Adverse Event and 
Product Complaints  
AE, SAE, and product complaint recording 
When an AE/SAE/PC 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/PC 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 PC information is reported on the 
PC form. 
Note: An event may meet the definition of both a PC and an AE/SAE. In such cases, it 
should be reported as both a PC 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 PC 
form for PCs. 
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, 
or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. 
Assessment of intensity 
The investigator will make an assessment of intensity for each AE and SAE reported during 
the study and assign it to one of the following categories:  
 Mild: A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of 
daily living. 
 Moderate: A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
participant. 
 Severe: A type of AE that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention. An AE that is 
assessed as severe should not be confused with a SAE. Severe is a category utilized for 
rating the intensity of an event, and both AEs and SAEs can be assessed as severe. 
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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 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, 
as well as the temporal relationship of the event to study intervention administration will be 
considered and investigated. 
The investigator will also consult the IB in their assessment. 
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to 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 or evaluations as medically indicated or as requested by sponsor or designee to 
elucidate the nature 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 healthcare professionals. 
If a participant dies during participation in the study or during a recognized follow-up period, 
the investigator will provide sponsor or designee with a copy of any postmortem findings 
including histopathology. 
 
 
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10.3.5. 
Reporting of Serious Adverse Events  
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 the 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 toward the safety of participants and the safety of a 
study intervention under clinical investigation are met. 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety reporting 
to the regulatory authority, 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 IB and will notify the IRB/IEC, if appropriate according to local 
requirements.  
 
 
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10.4. 
Appendix 4: Contraceptive and Barrier Guidance  
10.4.1. 
Definitions  
Women of Childbearing Potential 
Females less than 18 years of age are considered women of childbearing potential if they have 
 had at least 1 cycle of menses, or 
 Tanner Stage 4 breast development (see Tanner Staging, Section 10.7 [Appendix 7]). 
Any amount of spotting should be considered menarche. 
Women not of Childbearing Potential 
Females are considered women not of childbearing potential if 
 they have breast development Tanner 1, or 
 they have a congenital anomaly such as Mullerian agenesis, or 
 they are infertile due to surgical sterilization. 
Examples of surgical sterilization include hysterectomy, bilateral oophorectomy, and tubal 
ligation. 
10.4.2. 
Contraception Guidance  
Not applicable. 
10.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-up 
Assessments  
Hepatic Evaluation Testing 
See protocol Section 8.2.6 for guidance on appropriate test selection. 
The Lilly-designated central laboratory must complete the analysis of all selected testing except 
for microbiology testing. 
Local testing may be performed in addition to central testing when necessary for immediate 
participant management. 
Results will be reported if a validated test or calculation is available. 
 
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Tests assayed by Lilly-designated central laboratory 
Hepatic Hematology Panel 
Hepatitis A virus (HAV) testing: 
   Hemoglobin 
    HAV total antibody 
   Hematocrit 
    HAV IgM antibody 
   Erythrocytes (RBCs - red blood cells) 
Hepatis B virus (HBV) testing: 
   Leukocytes (WBCs - white blood cells) 
    Hepatitis B surface antigen (HBsAg) 
   Differential: 
    Hepatitis B surface antibody (anti-HBs) 
       Neutrophils, segmented 
    Hepatitis B core total antibody (anti-HBc) 
       Lymphocytes 
    Hepatitis B core IgM antibody 
       Monocytes 
    HBV DNA b 
       Basophils 
Hepatis C virus (HCV) testing: 
       Eosinophils 
    HCV antibody 
   Platelets 
    HCV RNA b 
   Cell morphology (RBC and WBC) 
Hepatitis D virus (HDV) testing: 
Hepatic Clinical Chemistry Panel 
    HDV antibody 
   Total bilirubin 
Hepatitis E virus (HEV) testing: 
   Direct bilirubin 
    HEV IgG antibody 
   Alkaline phosphatase (ALP) 
    HEV IgM antibody 
   Alanine aminotransferase (ALT) 
    HEV RNA b 
   Aspartate aminotransferase (AST) 
Anti-nuclear antibody (ANA) 
   Gamma-glutamyl transferase (GGT) 
Anti-smooth muscle antibody (ASMA) a 
   Creatine kinase (CK) 
Anti-actin antibody c 
Hepatic Coagulation Panel 
Immunoglobulin IgA (quantitative) 
   Prothrombin time, INR (PT-INR) 
Immunoglobulin IgG (quantitative) 
Urine Chemistry 
Immunoglobulin IgM (quantitative) 
   Drug screen 
Epstein-Barr virus (EBV) testing: 
Haptoglobin 
    EBV antibody 
Acetaminophen protein adducts 
 
 
Tests assayed ONLY by investigator-designated local laboratory  
Acetaminophen 
Cytomegalovirus (CMV) testing: 
 
    CMV antibody 
Alkaline phosphatase isoenzymes 
    CMV DNA b 
Ceruloplasmin 
Herpes simplex virus (HSV) testing: 
Copper 
    HSV (Type 1 and 2) antibody 
Ethyl alcohol (EtOH) 
    HSV (Type 1 and 2) DNA b 
Phosphatidylethanol (PEth) 
Liver kidney microsomal type 1 (LKM-1) antibody 
Urine Chemistry 
Microbiology  
    Ethyl glucuronide (EtG) 
Culture: 
Epstein-Barr virus (EBV) testing: 
    Blood 
    EBV DNA b 
    Urine 
Abbreviations: CMV= cytomegalovirus; EBV = Epstein-Barr virus; HAV = hepatitis A virus; HBV = hepatis B 
virus; HCV = hepatis C virus; HDV = hepatitis D virus; HEV = hepatitis E virus; HSV = herpes simplex virus; 
IgA; IgG; IgM; INR; PT-INR; RBC = red blood cells; WBC = white blood cells. 
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 is tested. 
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10.6. 
Appendix 6: Pancreatic Monitoring  
 
Abbreviations: CT = computed tomography; MRI = magnetic resonance imaging; ULN = upper limit of normal. 
 
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Participants diagnosed with pancreatitis will be discontinued from the study. Investigators will 
be responsible for following, through an appropriate healthcare option, these pancreatitis AEs 
until the events resolve or are explained. AEs that meet the diagnostic criteria of acute 
pancreatitis will be captured as SAEs. For all other pancreatic AEs (such as idiopathic or 
asymptomatic pancreatic enzyme abnormalities), the investigator will be responsible for 
determining the seriousness of the event (AE or SAE) and the relatedness of the event to study 
drug.
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10.7. 
Appendix 7: Tanner Staging  
Tanner Stages guidelines for measurement of pubescence (Marshall and Tanner 1969, 
1970) 
Boys: Development of external genitalia 
Stage 1.  
Prepubertal  
Stage 2.  
Enlargement of scrotum and testes; scrotum skin reddens and changes in 
texture  
Stage 3.  
Enlargement of penis; further growth of testes  
Stage 4.  
Increased size of penis; testes and scrotum larger, scrotum skin darker  
Stage 5.  
Adult genitalia  
Girls: Breast development 
Stage 1.  
Prepubertal (no glandular tissue: areola follows the skin contours of the chest) 
Stage 2.  
Breast bud stage with the enlargement of areola (breast bud forms, with small 
area of surrounding glandular tissue; areola begins to widen)  
Stage 3.  
Further enlargement of breast and areola (breast begins to become more 
elevated, and extends beyond the borders of the areola, which continues to 
widen but remains in contour with surrounding breast) 
Stage 4.  
Areola and papilla form a mound (increased breast size and elevation; areola 
and papilla form a secondary mound projecting from the contour of the 
surrounding breast) 
Stage 5.  
Mature stage (breast reaches final adult size; areola returns to contour of the 
surrounding breast, with a projecting central papilla) 
Boys and girls: Pubic hair 
Stage 1.  
Prepubertal (no pubic hair at all; can see vellus hair similar to abdominal wall)  
Stage 2.  
Sparse growth of long, slightly pigmented hair, straight or curled (small amount 
of long, downy hair with slight pigmentation at the base of the penis and 
scrotum [males] or on the labia majora [females]) 
Stage 3.  
Darker, coarser, and more curled hair, spreading sparsely over junction of pubes  
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Stage 4.  
Hair adult in type, but covering smaller area than in adult; no spread to medial 
surface of thighs  
Stage 5.  
Adult in type and quantity, with horizontal distribution (“feminine”) 
Note: The assessment of sexual maturity in children should include an assessment of age, 
growth, and menstrual history in addition to Tanner Staging. In case of discordance between 
breasts or genitals vs pubic hair, the default should be breast or genitals. 
 
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10.8. 
Appendix 8: Laboratory Samples to be Obtained at the Time of a 
Systemic Hypersensitivity Event  
Purpose of collecting samples after a systemic hypersensitivity event 
The samples listed in this appendix are not collected for acute study participant management. 
The sponsor will use the laboratory tests results from these samples to characterize 
hypersensitivity events across the clinical development program. 
When to collect samples after a systemic hypersensitivity event occurs 
Collect the samples listed below if a systemic hypersensitivity event is suspected. The timing 
should be as designated in the table, assuming the participant has been stabilized. 
Obtain follow-up pre-dose samples at the next regularly scheduled laboratory sample collection 
(ideally prior to the next dose after the event) to assess post-event return-to-baseline values. 
Timing 
Preferred Sample 
Type a 
Laboratory Test b 
Collect from 30 minutes to 4 hours 
after the start of the event.  
 
Note: The optimal 
collection time is from 1 
to 2 hours after the start 
of event. 
Serum 
total tryptase 
Serum 
complements (C3, C3a, and C5a)  
Serum 
cytokine panel (IL-6, IL‐1β, IL‐10 or any 
cytokine panel that includes these 3 cytokines)  
Collect only if not already collected 
on the same day as the event. 
 
Note: If collecting, 
collect up to 12 hours 
after the start of the 
event. 
Serum 
Tirzepatide anti-drug antibodies (ADA) 
Serum/plasma 
Tirzepatide concentration 
a Sample type may be different depending on local requirements. 
b All samples for hypersensitivity testing will be assayed by Lilly-designated laboratory. Results will not be 
provided to the study site. If samples are not collected or are collected outside the specified time period, this will 
not be considered a protocol deviation. 
Abbreviations: ADA = anti-drug antibodies; IL = interleukin. 
What information to record 
Record the date and time when the samples are collected. 
Allowed additional testing for participant management 
The investigator may perform additional tests locally, if clinically indicated, for acute study 
participant management. 
10.9. 
Appendix 9: Standardized Protocols for the Measurement of Height, 
Weight, Waist Circumference, and Vital Signs  
The following information has been adapted from standardized physical measurement protocols 
for the World Health Organization’s STEP wise approach to Surveillance (STEPS) Manual 
(WHO 2017). 
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Measuring Height 
Step 1.  Ask the participant to remove their footwear and any headgear (light headgear worn for 
religious reasons can remain, but this should be worn by the participant at every clinic visit when 
their height is measured). 
Step 2.  Ask the participant to stand on the calibrated height measuring board (stadiometer) or 
against a wall with their feet together and their knees straight with their heels against the 
backboard, the stadiometer, or the wall. 
Step 3.  Ask the participant to look straight ahead without tilting their head up. 
Step 4.  Ask the participant to breathe in and stand tall. If using a stadiometer or fixed measuring 
device, move the device’s measurement arm gently down onto the top of the participant’s head. 
Record the participant’s height in centimeter to 1 decimal place. 
Measuring Weight 
 Body weight measurements should be done in a consistent manner using a calibrated 
electronic scale capable of measuring weight in kilogram to 1 decimal place. 
 All weights for a given participant should be measured using the same scale, whenever 
possible, at approximately the same time in the morning after evacuation of bladder contents. 
 Participants should be lightly clothed but not wearing shoes while their weight is measured. 
 Body weight must be measured in fasting state. If the participant is not fasting, the 
participant should be called in for a new visit within the visit window to have the fasting 
body weight measured. 
Step 1.  Ask the participant to remove their footwear, outerwear (coat, jacket, and so on), and any 
headgear (light headgear worn for religious reasons can remain, but this should be worn by the 
participant at every clinic visit when weight is measured). 
Step 2.  Make sure the scale is placed on a firm, flat, even surface (not on carpet, on a sloping 
surface, or a rough, uneven surface). 
Step 3. Ask the participant to step onto the scale with 1 foot on each side of the scale. 
Step 4. Ask the participant to stand still with arms by sides and then record weight in kilogram to 
the nearest one-tenth kg. 
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Measuring Waist Circumference 
Step 1. Ask the participant to stand with their feet close together, and arms at their side with their 
body weight evenly distributed. 
Step 2. Ask participant to relax. 
Step 3. Measurements should be recorded at the end of a normal expiration. 
 Waist circumference should be measured in the horizontal plane and at the midpoint 
between the lower margin of the last palpable rib and the top of the iliac crest. 
 Measurements should be taken at the end of a normal expiration using a nonstretchable 
measuring tape. The tape should lie flat against the skin without compressing the soft 
tissue. 
 
The waist circumference should be measured twice, rounded to the nearest 0.5 cm. The 
measuring tape should be removed between the 2 measurements. Both measurements will 
be recorded in the eCRF. If the difference between the 2 measurements exceeds 1 cm, 
this set of measurements should be discarded and the 2 measurements repeated. 
Vital Sign Measurements (blood pressure and heart rate) 
 
Vital sign measurements should be taken before obtaining an ECG tracing and before 
collection of blood samples for laboratory testing. 
 An appropriately sized cuff (cuff bladder encircling at least 80% of the arm) should be 
used to ensure the accuracy of BP measurements. 
 
Blood pressure should be taken with an automated blood pressure instrument. 
 
If blood pressure and pulse measurements are taken separately, pulse should be taken 
prior to blood pressure.  
 
The participant should be supine for at least 3 minutes before vital sign measurements are 
taken. 
Note: In the event, pulse measurement cannot be taken via an automated blood pressure 
instrument, and the preferred location for measurement of pulse is the radial artery. 
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10.10. 
Appendix 10: Provisions for Changes in Study Conduct During 
Exceptional Circumstances  
Implementation of this appendix 
The changes to procedures described in this appendix are temporary measures intended to be 
used only during specific time periods as directed by the sponsor in partnership with the 
investigator. 
Exceptional circumstances 
Exceptional circumstances are rare events that may cause disruptions to the conduct of the study. 
Examples include pandemics or natural disasters. These disruptions may limit the ability of the 
investigators, participants, or both to attend on-site visits or to conduct planned study procedures. 
Implementing changes under exceptional circumstances 
In an exceptional circumstance, after receiving the sponsor’s written approval, sites may 
implement changes if permitted by local regulations. 
After approval by local Ethical Review Boards, regulatory bodies and any other relevant local 
authorities, implementation of these exceptional circumstance changes will not typically require 
additional notification to these groups, unless they have specific requirements in which 
notification is required (for example, upon the implementation and suspension of changes). All 
approvals and notifications must be retained in the study records. 
If the sponsor grants written approval for changes in study conduct, the sponsor will also provide 
additional written guidance, if needed. 
Considerations for making a change 
The prevailing consideration for making a change is ensuring the safety of study participants. 
Additional important considerations for making a change are compliance with GCP, enabling 
participants to continue safely in the study and maintaining the integrity of the study. 
Informed consent 
Additional consent and assent where applicable from the participant will be obtained, if required, 
for 
 participation in remote visits, as defined in Section “Remote Visits” 
 a change in the method of study intervention administration 
 dispensation of additional study intervention during an extended treatment 
period 
 alternate delivery of study intervention and ancillary supplies, and 
 provision of their personal or medical information required prior to 
implementation of these activities. 
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Changes in study conduct during exceptional circumstances 
Changes in study conduct not described in this appendix, or not consistent with applicable local 
regulations, are not allowed. 
The following changes in study conduct will not be considered protocol deviations. 
Remote visits 
Types of remote visits 
Telemedicine: Telephone or technology-assisted virtual visits, or both, are acceptable to 
complete appropriate assessments. Assessments to be completed in this manner include, but are 
not limited to, concomitant medications, AE data capture, and self-performed body weight and 
height measures. 
Mobile healthcare: Healthcare visits may be performed by a mobile healthcare provider at 
locations other than the study site allowed per protocol (refer to the SoA in Section 1.3 for visits 
that are permitted to be conducted remotely). Other than visits permitted per protocol, written 
approval must be provided by the sponsor for remote visits when participants cannot travel to the 
site due to an exceptional circumstance. Procedures performed at such visits include, but are not 
limited to, AE documentation, concomitant medications, collection of blood samples, collection 
of ECG and vital sign parameters, physical assessments, administration of study intervention, 
and collection of health information.  
Data capture 
In source documents and the CRF, the study site should capture the visit method, with a specific 
explanation for any data missing because of missed in-person site visits. 
Safety reporting 
Regardless of the type of remote visits implemented, the protocol requirements regarding the 
reporting of AEs, SAEs, and PCs remain unchanged.  
Return to on-site visits 
Every effort should be made to enable participants to return to on-site visits as soon as 
reasonably possible while ensuring the safety of both the participants and the site staff. 
Local laboratory testing option 
Local laboratory testing may be conducted in lieu of central laboratory testing for unscheduled 
events or as stipulated in Section 10.2. The local laboratory must be qualified in accordance with 
applicable local regulations. 
Study intervention and ancillary supplies (including participant diaries) 
When a participant’s parent or legal guardian is unable to go to the site to receive study supplies 
during normal on-site visits, the site should work with the sponsor to determine appropriate 
actions. These actions may include  
 asking the participant to go to the site and receive study supplies from site staff 
without the completion of a full study visit  
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 asking the participant’s designee to go to the site and receive study supplies on a 
participant’s behalf, and 
 arranging the delivery of study supplies. 
The following requirements must be met before the action is taken: 
 Alternate delivery of study intervention should be performed in a manner that does 
not compromise treatment blinding and ensures product integrity. The existing 
protocol requirements for product accountability remain unchanged, including the 
verification of participant’s receipt of study supplies. 
 When delivering supplies to a location other than the study site (for example, 
participant’s home), the investigator, sponsor, or both should ensure oversight of the 
shipping process to ensure accountability and product quality (that is, storage 
conditions maintained and intact packaging upon receipt). 
 Instructions may be provided to the participant or designee on the final disposition of 
any unused or completed study supplies. 
If study intervention will be administered to the participant during a mobile healthcare visit 
or at an alternate location, the following additional requirements must be met:  
 Only authorized study personnel may supply, prepare, or administer study 
intervention. 
 The mobile healthcare team must be able to handle and store study interventions in 
accordance to the requirements specified on the label. 
Screening period guidance  
To ensure the safety of study participants, laboratory values and other eligibility assessments 
taken at screening visit are valid for a maximum of 28 days. The following rules will be applied 
for active, nonrandomized participants whose participation in the study must be paused due to 
exceptional circumstances: 
 If screening is paused for less than 28 days from Visit 2, the participant will proceed 
to the next study visit per the usual SoA, provided that Visit 2 must be conducted 
within 28 days from first screening.  
o The site should conduct the next visit if the participant’s eligibility criteria are 
confirmed, and the site should document the reason for delay. 
o Due to the pause in screening, sites should also reconfirm the impacted 
participant’s consent and document this confirmation in the source 
documentation. 
 If screening is paused for more than 28 days from Visit 2, the participant must be 
discontinued because of screening interruption due to an exceptional circumstance. 
This is documented as a screen failure. 
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Documentation 
Changes to study conduct will be documented 
Sites will identify and document the details of how participants, visits types, and conducted 
activities were affected by exceptional circumstances. Dispensing or shipment records of study 
intervention and relevant communications, including delegation, should be filed with site study 
records. 
Source documents at alternate locations 
Source documents generated at a location other than the study site should be a part of the 
investigator’s source documentation and should be transferred to the site in a secure and timely 
manner.  
 
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10.11. 
Appendix 11: Abbreviations and Definitions  
Term 
Definition 
ADA 
antidrug antibodies 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC0-tau 
area under the concentration versus time curve from time 0 to the end of the dosing 
interval 
blinding 
A double-blind study is one in which neither the participant nor any of the investigator 
or sponsor staff who are involved in the treatment or clinical evaluation of the subjects 
are aware of the treatment received. 
BG 
blood glucose 
BMI 
body mass index 
Cmax 
maximum concentration 
complaint 
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system. 
compliance 
Adherence to all study-related, good clinical practice (GCP), and applicable regulatory 
requirements. 
CP 
clinical pharmacologist 
CRF 
case report form; a printed, optical, or electronic document designed to record all of 
the protocol-required information to be reported to the sponsor for each trial 
participant. 
CRP 
clinical research physician: Individual responsible for the medical conduct of the 
study. Responsibilities of the CRP may be performed by a physician, clinical research 
scientist, global safety physician or other medical officer. 
CRS 
clinical research scientist 
CRU 
clinical research unit 
CV 
cardiovascular 
CVD 
cardiovascular disease 
CT 
computed tomography 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
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Term 
Definition 
eGFR 
estimated glomerular filtration rate 
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. 
enter 
Participants entered into a study are those who sign the informed consent form directly 
or through their legally acceptable representatives. 
GCP 
good clinical practice 
GI 
gastrointestinal 
GIP 
glucose-dependent insulinotropic peptide 
GLP-1 
glucagon-like peptide 1 
GLP-1R 
glucagon-like peptide 1 receptor 
HCV 
hepatitis C virus 
IB 
Investigator’s Brochure 
IBT 
Intensive behavioral therapy 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committees 
IgM 
Immunoglobulin M 
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. 
interim analysis 
An interim analysis is an analysis of clinical study data, separated into treatment 
groups, that is conducted before the final reporting database is created/locked. 
investigational 
product 
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. 
IRB 
Institutional Review Board 
ISR 
injection site reaction 
MRI 
magnetic resonance imaging 
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Term 
Definition 
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/PD 
pharmacokinetics/pharmacodynamics 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SC 
subcutaneous 
SoA 
schedule of activities 
screen 
The act of determining if an individual meets minimum requirements to become part 
of a pool of potential candidates for participation in a clinical study.  
T2DM 
type 2 diabetes mellitus 
TBL 
total bilirubin 
TE ADA 
treatment-emergent ADA 
TE ADA+ 
treatment-emergent ADA positive 
ULN 
upper limit of normal 
 
 
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10.12. 
Appendix 12: Protocol Amendment History  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
Amendment [d]:  
This amendment is considered to be nonsubstantial. 
Overall Rationale for the Amendment: 
This protocol was amended to delete inconsistencies in protocol text regarding vital sign 
measurements and other minor changes for clarity.  
Section # and Name 
Description of Change 
Brief Rationale 
10.9. Appendix 9: Standardized 
Protocols for the Measurement of 
Height, Weight, Waist 
Circumference, and Vital Signs 
Step 2 and Step 3 vital sign 
measurement instructions have 
been removed.   
Step 2 and Step 3 vital sign 
measurement instructions require 3 
measurements to be recorded in the 
eCRF. Triplicate recordings are not 
required as standard for this study and 
have been removed.  
Amendment [c]: 05 June 2023 
This amendment is considered to be nonsubstantial. 
Overall Rationale for the Amendment: 
This protocol was amended to update the equation used for the exclusion criterion on renal 
impairment and other minor changes for clarity.  
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3 Schedule of 
Activities 
Clarified that the dose increase will occur at the 
fifth dose of TZP on Day 29 Week 5 and 
referenced Figure GPHV.1.1. 
To provide information in the 
Schedule of Activities about 
when the TZP dose 
administered will increase to the 
next dose level.  
Section 2.3 Benefit/Risk 
Assessment 
Clarified that female participants will be 
monitored for changes in Tanner stage. 
To provide consistency 
throughout the protocol. 
Section 5.2 Exclusion 
Criteria 
Updated the calculation used in Exclusion 
criterion #27 from Chronic Kidney Disease 
Epidemiology to Bedside Schwartz Equation 
recommended by National Kidney Foundation 
Bedside Schwartz Equation is 
more appropriate on this age 
group 
Section 6.5 Dose 
Modification 
Replaced stopping dosing and dose escalation 
with the initiation of a safety review and putting 
a pause on new enrollment until the safety 
review is complete.  
Initiating a safety review instead 
of stopping dosing at current 
and further levels provides a 
mechanism to make specific 
decisions based on the criteria.  
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Section # and Name 
Description of Change 
Brief Rationale 
Section 10.5 Appendix 5: 
Liver Safety: Suggested 
Actions and Follow up 
Assessments 
Moved the acetaminophen protein adduct test 
from local laboratory table to the central 
laboratory table.  
Acetaminophen protein adduct 
test will be provided by the 
central labs 
Section 10.9 Appendix 9: 
Standardized Protocols 
for the Measurement of 
Height, Weight, Waist 
Circumference, and Vital 
Signs 
Clarified that for each measurement of pulse and 
blood pressure, the participant will be supine and 
not sitting. 
To provide consistency 
throughout the protocol 
Amendment [b]: 19 January 2023 
This amendment is considered to be nonsubstantial. 
Overall Rationale for the Amendment: 
This protocol was amended to update the timing of the final follow-up visit and the early 
discontinuation visit and other minor changes for clarity.  
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
 
Changed the occurrence of the final follow-up 
visit from 2 to 4 weeks after last treatment or 
within 4 weeks after early discontinuation to 4 to 
6 weeks after last treatment or at least 4 weeks 
but up to 6 weeks after early discontinuation 
 
In response to feedback during 
European Union (EU) Paediatric 
Investigational Plan (PIP) 
review stating that the safety 
follow-up must be planned for 
at least 4 weeks.  
 
1.1 Synopsis 
Added language on replacing participants who 
do not complete the study 
To maintain consistency with 
later sections of the protocol 
1.3 Schedule of Activities 
Updated final follow-up visit to occur between 
Week 12 Day 78 and Week 14 Day 92 
In response to feedback during 
EU PIP review stating that the 
safety follow-up must be 
planned for at least 4 weeks. 
 
1.3 Schedule of Activities 
Updated Early Discontinuation visit to occur at 
least 4 weeks but up to 6 weeks from the last 
dose 
1.3 Schedule of Activities 
Updated height measurement to be taken at 
screening, Visit 1, and Visit 12 only. 
To clarify the timing of the 
height measurements 
4.1 Overall Design 
Changed the final follow-up visit to occur with 4 
to 6 weeks following the last treatment or at least 
4 weeks but up to 6 weeks for participants that 
discontinue early, and IBT from starting at 
screening to starting at baseline. 
To clarify the timing of the 
follow-up visit and the starting 
point of offering participants 
IBT 
5.2 Exclusion Criteria 
Updated [18] to include type 1 and type 2 
diabetes mellitus 
To clarify that participants with 
either type 1 or type 2 diabetes 
will be excluded from this 
study. 
5.3.1. Intensive 
Behavioral Therapy (IBT) 
for Chronic Weight 
Management in Children 
6-11 Years Old 
Changed the total hours of IBT from 
approximately 26 hours to approximately 27 
hours 
To clarify the total amount of 
hours IBT will be offered to 
participants 
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Section # and Name 
Description of Change 
Brief Rationale 
6.1 Study Intervention(s) 
Administered 
Added language on the paper diaries used during 
remote visits and removed the dosing 
instructions row from Table GPHV.6.1 
To provide details on paper 
diaries and to remove 
redundancy between the table 
and the text within this section. 
9.5 Sample Size 
Determination 
Specified that participants who do not complete 
the study may be replaced 
To clarify that participants may 
be replaced if they do not 
complete the study 
10.9 Appendix 9: 
Standardized Protocols 
for the Measurement of 
Height, Weight, Waist 
Circumference, and Vital 
Signs 
Clarified that participants should be supine for at 
least 3 minutes before measuring blood pressure 
and heart rate  
To maintain consistency in the 
measurement of vital signs 
throughout the protocol  
 
Amendment [a]: (27-October-2022) 
This amendment is considered to be nonsubstantial. 
 
Overall Rationale for the Amendment 
This protocol was amended to change the definition of obesity in children of age 6 to 9 years. 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis and 9.5 
Sample Size 
Determination 
Added language to clarify the sample size of 6 
evaluable participants for weight category >50 
kg and 12 evaluable participants for weight 
category <50 kg 
In response to feedback from 
the FDA to breakdown the 
overall sample size by each 
cohort for clarity.  
1.3 Schedule of Activities 
Added a row for the intensive behavioral therapy 
during the study 
To capture timing and frequency 
of the intensive behavioral 
therapy 
4.1 Overall Design 
Added intensive behavioral therapy content 
To capture intensive behavioral 
therapy in the overall study 
design 
5. Study Population 
Changed Inclusion Criterion [1] to define 
consistently the BMI that characterizes children 
with obesity for both younger (6 to 9 years, 
inclusive) and older age groups (10 to 11 years, 
inclusive). 
In response to feedback from 
the European Medical Agency 
and for consistent alignment 
with intended definition for 
Phase 3 studies. 
5.3.1 Intensive Behavioral 
Therapy (IBT) for 
Chronic Weight 
Added intensive behavioral therapy  
To enhance study intervention 
and further increase the prospect 
of direct benefit to participants 
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Management in Children 
6-11 Years Old 
given diet and exercise are 
critical elements in treating 
obesity 
 
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N Engl J Med. 2016;375(8):794-798. https://doi.org/10.1056/NEJMsr1606602 
Leibel RL, Rosenbaum M, Hirsch J. Changes in energy expenditure resulting from altered body 
weight. N Engl J Med. 1995;332(10):621‐628. 
https://doi.org/10.1056/NEJM199503093321001 
Marshall WA, Tanner JM. Variations in the pattern of pubertal changes in boys. Arch Dis Child. 
1970;45(239):13-23. https://doi.org/10.1136/adc.45.239.13 
Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch. Dis Child. 
1969;44(235):291-303. https://doi.org/10.1136/adc.44.235.291 
Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with 
type 2 diabetes. N Engl J Med. 2016a;375(19):1834-1844. 
https://doi.org/10.1056/NEJMoa1607141 
Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in 
type 2 diabetes. N Engl J Med. 2016b;375(4):311-322. 
https://doi.org/10.1056/NEJMoa1603827 
Mayr HL, Cohen F, Isenring E, et al. Multidisciplinary lifestyle intervention in children and 
adolescents – results of the project GRIT (growth, resilience, insights, thrive) pilot study. BMC 
Pediatr. 2020;20(174):1-16. 
Mertens IL, Van Gaal LF. Overweight, obesity, and blood pressure: the effects of modest weight 
reduction. Obes Res. 2000;8(3):270-278. https://doi.org/10.1038/oby.2000.32 
Nauck M. Incretin therapies: highlighting common features and differences in the modes of 
action of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. 
Diabetes Obes Metab. 2016;18(3):203-216. https://doi.org/10.1111/dom.12591 
Rice D, Barone Jr S. Critical periods of vulnerability for the developing nervous system: 
evidence from humans and animal models. Environ Health Perspect. 2000;108(suppl 
3):511-533. https://doi.org/10.1289/ehp.00108s3511 
Rodier PM. Chronology of neuron development: animal studies and their clinical implications. 
Develop Med Child Neurol. 1980;22(4):525-545. https://doi.org/10.1111/j.1469-
8749.1980.tb04363.x 
Skinner AC, Ravanbakht SN, Skelton JA, et al. Prevalence of obesity and severe obesity in US 
children, 1999-2016. Pediatrics. 2018;141(3):e20173459. https://doi.org/10.1542/peds.2017-
3459 
Smith SR, Weissman NJ, Anderson CM, et al.; Behavioral Modification and Lorcaserin for 
Overweight and Obesity Management (BLOOM) Study Group. Multicenter, placebo-
controlled trial of lorcaserin for weight management. N Engl J Med. 2010;363(3):245‐256. 
https://doi.org/10.1056/NEJMoa0909809 
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Steinberg WM, Buse JB, Ghorbani MLM, et al.; LEADER Steering Committee; LEADER Trial 
Investigators. Amylase, lipase, and acute pancreatitis in people with type 2 diabetes treated 
with liraglutide: results from the LEADER randomized trial. Diabetes Care. 2017a;40(7):966-
972 [Erratum in: Diabetes Care. 2018;41(7):1538]. https://doi.org/10.2337/dc16-2747 
Steinberg WM, Rosenstock J, Wadden TA, et al. Impact of liraglutide on amylase, lipase, and 
acute pancreatitis in participants with overweight/obesity and normoglycemia, prediabetes, or 
type 2 diabetes: secondary analyses of pooled data from the SCALE clinical development 
program. Diabetes Care. 2017b;40(7):830-848. https://doi.org/10.2337/dc16-2684 
Styne DM, Arslanian SA, Connor EL, et al. Pediatric obesity - assessment, treatment and 
prevention: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 
2017;102(3):709-757. https://doi.org/10.1210/jc.2016-2573 
Sumithran P, Prendergast LA, Delbridge E, et al. Long-term persistence of hormonal adaptations 
to weight loss. N Engl J Med. 2011;365(17):1597‐1604. 
https://doi.org/10.1056/NEJMoa1105816 
Swift DL, McGee JE, Earnest CP, et al. The effects of exercise and physical activity on weight 
loss and maintenance. Prog Cardiovasc Dis. 2018;61(2):206‐213. 
https://doi.org/10.1016/j.pcad.2018.07.014 
[USPSTF] US Preventive Services Task Force. Screening for obesity in children and 
adolescents: US Preventive Services Task Force recommendation statement. JAMA. 
2017;317(23):2417-2426. 
van Bloemendaal L, Ten Kulve JS, la Fleur SE, et al. Effects of glucagonlike peptide 1 on 
appetite and body weight: focus on the CNS. J Endocrinol. 2014;221(1):T1-T16. 
https://doi.org/10.1530/JOE-13-0414 
Wadden TA, Hollander P, Klein S, et al. Weight maintenance and additional weight loss with 
liraglutide after low-calorie-diet-induced weight loss: the SCALE Maintenance randomized 
study. Int J Obes. 2013;37(11):1443‐1451. https://doi.org/10.1038/ijo.2013.120 
Weinberg ME, Bacchetti P, Rushakoff RJ. Frequently repeated glucose measurements 
overestimate the incidence of inpatient hypoglycemia and severe hyperglycemia. J Diabetes 
Sci Technol. 2010;4(3):577-582. https://doi.org/10.1177/193229681000400311 
[WHO] World Health Organization. The WHO STEPWise approach to noncommunicable 
disease risk factor surveillance. WHO STEPS Surveillance Manual. Updated January 26, 
2017. Accessed March 13, 2020. 
https://www.who.int/ncds/surveillance/steps/STEPS_Manual.pdf 
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SAP_001.pdf: 
Statistical Analysis Plan: I8F-MC-GPHV 
 
 
 
 
A Safety, Tolerability and Pharmacokinetic Study of Tirzepatide for the Treatment of Pediatric 
Participants (6 years to 11 years) with Obesity 
 
 
 
NCT05696847 
 
 
 
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STATISTICAL ANALYSIS PLAN 
A Safety, Tolerability and Pharmacokinetic Study of Tirzepatide for the Treatment of 
Pediatric Participants (6 years to 11 years) with Obesity 
Statistical Analysis Plan Status: Final 
Statistical Analysis Plan Version: 2.0 
Statistical Analysis Plan Date: 18JAN2024 
Investigational Medicinal Product: Tirzepatide (LY3298176) 
Protocol Reference: I8F-MC-GPHV  
Fortrea Study: 8492131 
Clinical Phase I 
 
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1. TABLE OF CONTENTS 
1. 
TABLE OF CONTENTS ................................................................................................... 2 
2. 
ABBREVIATIONS ............................................................................................................ 4 
3. 
INTRODUCTION .............................................................................................................. 5 
4. 
STUDY OBJECTIVES ...................................................................................................... 5 
5. 
STUDY DESIGN ............................................................................................................... 6 
6. 
BLINDING ......................................................................................................................... 7 
7. 
TREATMENTS .................................................................................................................. 8 
8. 
SAMPLE SIZE JUSTIFICATION ..................................................................................... 8 
9. 
DEFINITION OF ANALYSIS POPULATIONS .............................................................. 8 
10. STATISTICAL METHODOLOGY ................................................................................... 9 
10.1 General ......................................................................................................................... 9 
10.2 Demographics and Participant Disposition ................................................................. 9 
10.3 Pharmacokinetic Assessment ....................................................................................... 9 
10.4 Pharmacodynamic Assessment .................................................................................... 9 
10.4.1 Pharmacodynamic Analysis ............................................................................... 9 
10.4.2 Pharmacodynamic Statistical Methodology ..................................................... 10 
10.5 Safety and Tolerability Assessments ......................................................................... 11 
10.5.1 Adverse events ................................................................................................. 11 
10.5.2 Glucose Monitoring and Hypoglycemia .......................................................... 11 
10.5.3 Concomitant medication ................................................................................... 12 
10.5.4 Clinical laboratory parameters ......................................................................... 12 
10.5.5 Vital signs ......................................................................................................... 12 
10.5.6 Electrocardiogram (ECG) ................................................................................. 12 
10.5.7 Hepatic Monitoring .......................................................................................... 13 
10.5.8 Immunogenicity Assessments .......................................................................... 13 
10.5.9 Hypersensitivity reactions ................................................................................ 13 
10.5.10 Injection-Site Reactions ................................................................................... 13 
10.5.11 Elevated Lipase or Amylase ............................................................................. 14 
10.5.12 Tanner Staging ................................................................................................. 14 
10.5.13 Other assessments ............................................................................................. 14 
10.5.14 Safety and Tolerability Statistical Methodology .............................................. 14 
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11. INTERIM ANALYSES .................................................................................................... 14 
12. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ....... 14 
13. REFERENCES ................................................................................................................. 14 
14. DATA PRESENTATION ................................................................................................ 14 
14.1 Derived Parameters .................................................................................................... 14 
14.2 Missing Data .............................................................................................................. 15 
14.3 Insufficient Data for Presentation .............................................................................. 15 
15. APPENDIX 1: DOCUMENT HISTORY ........................................................................ 16 
 
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2. ABBREVIATIONS  
Abbreviations pertain to the Statistical Analysis Plan (SAP) only (not the tables, figures and 
listings [TFLs]). 
AE 
Adverse event 
ADA 
Anti-drug antibody 
AUC 
Area under the concentration versus time curve 
AUC0-tau 
Area under the concentration versus time curve from time 0 to the 
end of the dosing interval 
Cmax 
Maximum concentration 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CV 
Coefficient of variation 
DMP 
Data Management Plan 
ECG 
Electrocardiogram 
IBT 
Intensive behavioral therapy 
ICH 
International Conference on Harmonisation 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRE 
Magnetic resonance elastography 
PD 
Pharmacodynamics 
PK 
Pharmacokinetic 
QW 
Once Weekly 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SD 
Standard deviation  
TFLs 
Tables, Figures, and Listings 
WHO 
World Health Organization 
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3. INTRODUCTION  
This SAP has been developed after review of the Clinical Study Protocol Amendment (e) (final 
version dated 16th November 2023). 
This SAP describes the planned analysis of the safety, tolerability and pharmacokinetic (PK) and 
pharmacodynamic (PD) data from this study. A detailed description of the planned TFLs to be 
presented in the clinical study report (CSR) is provided in the accompanying TFL shell 
document. 
The intent of this document is to provide guidance for the statistical and PK analyses of data. In 
general, the analyses are based on information from the protocol, unless they have been modified 
by agreement with Eli Lilly and Company. A limited amount of information concerning this 
study (e.g., objectives, study design) is given to help the reader’s interpretation. This SAP must 
be finalized prior to first participant visit. When the SAP and TFL shells are agreed upon and 
finalized, they will serve as the template for this study’s CSR. 
This SAP supersedes the statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed and 
will be identified in the CSR. Any substantial deviations from this SAP will be agreed upon with 
Eli Lilly and Company and identified in the CSR. Any minor deviations from the TFLs may not 
be documented in the CSR. 
This SAP is written with consideration of the recommendations outlined in the International 
Conference on Harmonisation (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials1 and the ICH E3 Guideline entitled Guidance for Industry: Structure 
and Content of Clinical Study Reports2. 
4. STUDY OBJECTIVES  
Objectives  
Endpoints  
Primary  
 To evaluate tirzepatide safety and 
tolerability following the 
subcutaneous (SC) injections of 
tirzepatide in pediatric participants 
with obesity 
 
 Number of treatment-emergent 
adverse events and serious adverse 
events 
Secondary  
 To evaluate the PK profile of 
tirzepatide following SC injections in 
pediatric participants with obesity 
 
 Tirzepatide area under the 
concentration versus time curve 
(AUC) from time 0 to the end of the 
dosing interval (AUC0-tau), maximum 
concentration (Cmax) from population 
PK model 
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Abbreviations: 
; PK = pharmacokinetics; SC = subcutaneous. 
5. STUDY DESIGN  
This is a randomized, placebo-controlled, participant and investigator blinded, 8-week treatment 
Phase 1 study in pediatric participants with obesity who do not have diabetes mellitus. Potential 
pediatric participants will be screened to assess their eligibility to enter the study within 28 days 
prior to Day 1. Participants enrolled will be partitioned as follows: 
 Cohort 1: Higher weight cohort – screening body weight ≥50 kg 
 Cohorts 2: Lower weight cohort – screening body weight <50 kg, and 
 Cohort 3: Screening body weight between 40 to 60 kg, inclusive. 
The schematic of the study is shown in Figure 1. Initially, 
 participants are 
planned to be enrolled into the higher body weight (Cohort 1). Participants will be randomized 
on Day 1 to tirzepatide or placebo (
ratio) after the confirmation of eligibility. Placebo is 
included as the control in a blinded manner for investigator, site staff, and participants to allow 
an unbiased assessment of the safety and tolerability data generated, which will allow a more 
robust comparison between tirzepatide and placebo. 
Safety and tolerability data will be reviewed by the unblinded sponsor clinical pharmacologist, 
clinical research physician / clinical research scientist, and blinded investigator. Decisions for 
commencing dosing in Cohort 2 (lower body weight participants) will be made based on the 
following: 
 the completion of at least 5 treatment doses from at least  participants in Cohort 1, and 
 the review of safety/tolerability data through Day 36, including safety clinical laboratory. 
Likewise, the dosing of Cohort 3 participants (body weight 40 to 60 kg inclusive) will proceed 
only after the satisfactory review of safety and tolerability data from at least  participants who 
received at least 5 treatment doses in Cohort 2 as shown in Figure 1. PK samples will be 
collected, and exposure data for tirzepatide will be analyzed during the study to support dose-
escalation decisions where possible. Sentinel dosing will be used for  participants in the specific 
body weight range of 40 to 50 kg in Cohort 3 (
). If safety and 
tolerability after 1 week are acceptable in the  sentinel participants, as clinically assessed by the 
investigator, the remainder of the participants in Cohort 3 (  tirzepatide and  placebo) in the 40 
to 60 kg range can be randomized and dosed. 
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A final follow-up visit will occur after participants complete the final dosing or discontinue 
prematurely. 
Starting at Visit 2 (baseline visit), all participants will be offered intensive behavioral therapy 
(IBT) sessions which will continue through the study period and until the final follow up. 
6. BLINDING  
This is a randomized participant- and investigator-blind study. All measures possible must be 
taken to maintain the blind; access to the blinding information will be restricted to authorized 
personnel as described in the protocol. Staff who prepare the study intervention will not be 
blinded to treatment allocation. 
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a participant’s treatment assignment is warranted for medical management of the event. In 
such cases, the unblinding is to be conducted according to the protocol. 
The Fortrea biometrics and Eli Lilly study teams will be unblinded throughout the study. 
 
 
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7. TREATMENTS  
The following is a list of the study treatment labels that will be used in the TFLs. 
Cohort 
Study Treatment Name 
Treatment order in TFL 
1 
Placebo QW (BW ≥50 kg) 
1 
 mg tirzepatide QW (BW ≥50 kg) 
2 
2 
Placebo QW (BW <50 kg) 
3 
 mg tirzepatide QW (BW <50 kg) 
4 
3 
Placebo QW (BW 40 to 60 kg) 
5 
 mg tirzepatide QW (BW 40 to 60 kg)  
6 
Abbreviations: BW = body weight; QW = once weekly 
8. SAMPLE SIZE JUSTIFICATION  
Approximately 
 participants may be enrolled. This will allow PK characterization in at least 
 participants each, exposed to tirzepatide, for each of the 3 cohorts. Evaluable participants are 
participants who receive at least 1 dose of the study intervention and have at least 1 evaluable PK 
sample. The sample size is customary for Phase 1 studies evaluating safety, tolerability, and PK, 
and is not powered on the basis of any a priori statistical hypothesis testing for efficacy. 
Participants who do not complete all the study procedures may be replaced to achieve the 
planned number of completers. 
Note: Enrolled means a participant’s parent or their legally acceptable representative’s, 
agreement to participate in a clinical study following the completion of the informed consent 
process and assent where applicable and screening. Potential participants who are screened for 
the purpose of determining eligibility for the study, but do not participate in the study, are not 
considered enrolled. A participant will be considered as enrolled if the informed consent is not 
withdrawn prior to participating in any study activity after the screening visit. 
9. DEFINITION OF ANALYSIS POPULATIONS  
“Full analysis set” will consist of all enrolled participants. Participants will be included in the 
analyses according to the planned intervention. 
The “Safety” population will consist of all participants who received at least 1 dose of tirzepatide 
or placebo. Participants will be analyzed according to the intervention they actually received. 
The “Pharmacokinetic” population will consist of all participants who received at least 1 dose of 
tirzepatide and have evaluable PK data. 
All protocol deviations that occur during the study will be considered for their severity/impact 
and will be taken into consideration when participants are assigned to analysis populations. 
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10. 
STATISTICAL METHODOLOGY  
10.1 
General  
Data listings will be provided for all data that is databased. Summary statistics and statistical 
analysis will only be presented for data where detailed in this SAP. For continuous data, 
summary statistics will include the arithmetic mean, arithmetic standard deviation (SD), median, 
minimum, maximum and number of observations; for log-normal data (e.g. the PK parameters: 
AUCs and Cmax) the geometric mean and geometric coefficient of variation (CV%) will also be 
presented. For categorical data, frequency count and percentages will be presented. Data listings 
will be provided for all participants up to the point of withdrawal from study, with any 
participants excluded from the relevant population highlighted. Summary statistics and statistical 
analyses will generally only be performed for participants included in the relevant analysis 
population. For the calculation of summary statistics and statistical analysis, unrounded data will 
be used. 
For change from baseline summary statistics, each individual change from baseline will be 
calculated by subtracting the individual participant’s baseline value from the value at that time 
point. The individual participants’ change from baseline values will be used to calculate the 
summary statistics (arithmetic mean, arithmetic SD, median, minimum, maximum and number 
of observations) using a SAS procedure such as Proc Univariate. 
Data analysis will be performed using SAS® Version 9.4 or greater. 
10.2 
Demographics and Participant Disposition  
Participant disposition will be listed. The demographic variables age, sex, race, ethnicity, country 
of enrolment (if more than one), site ID (if more than one), body weight, height, body mass 
index and waist circumference will be summarized by treatment and listed. All other 
demographic variables will be listed only. 
10.3 
Pharmacokinetic Assessment  
Pharmacokinetic analysis will be the responsibility of Lilly’s PK/PD group. Tirzepatide 
concentration data will be analyzed using a population PK approach using nonlinear 
mixed-effects modelling techniques implemented on the NONMEM® software to determine the 
Cmax and AUC0-tau of tirzepatide by each cohort and dose.  
Derivation of the PK parameters and TFL production will be the responsibility of Eli Lilly. 
10.4 
Pharmacodynamic Assessment  
10.4.1 Pharmacodynamic Analysis  
The exploratory PD parameters are: 
 Body weight, body mass index, and waist circumference 
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10.4.2 Pharmacodynamic Statistical Methodology  
Body weight, body mass index, and waist circumference data and changes from baseline, where 
baseline is defined as the last non-missing value prior to dosing, will be summarized by 
treatment and listed.  Figures of mean body weight and mean changes from baseline profiles will 
be presented by treatment. Percent changes from baseline will also be presented. 
 
 
An unstructured covariance structure will be used to model the 
covariance between a participant’s multiple observations, with an alternative structure to be used 
if the model fails to converge. Follow-up data will not be included in the model. 
Treatment in the model will be defined as per Section 7 with the following comparisons 
presented: 
 
 mg tirzepatide QW (BW ≥50 kg) versus Placebo QW (BW ≥50 kg) 
 
 mg tirzepatide QW (BW <50 kg) versus Placebo QW (BW <50 kg) 
 
 mg tirzepatide QW (BW 40 to 60 kg) versus Placebo QW (BW 40 to 60 kg) 
In addition, treatment may also be defined as Placebo QW, 
 mg tirzepatide QW, or 
-- mg tirzepatide QW in an additional model, with the following comparisons presented: 
 
 mg tirzepatide QW versus Placebo QW 
 
 mg tirzepatide QW versus Placebo QW 
If the above model does not converge, treatment may be defined as Pooled placebo QW or 
Pooled tirzepatide QW, with the following comparison presented: 
 Pooled tirzepatide QW versus Pooled placebo QW 
The difference in LS means at each post-dose timepoint, along with the 90% confidence interval, 
will be reported. 
Example SAS code: 
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10.5 
Safety and Tolerability Assessments  
10.5.1 Adverse events  
Where changes in severity are recorded in the Case Report Form (CRF), each separate severity 
of the adverse event (AE) will be reported in the listings, only the most severe will be used in the 
summary tables. A pre-existing condition is defined as a condition that starts before the 
participant has provided written informed consent and is ongoing at consent. A non-treatment 
emergent AE is defined as an AE which starts after informed consent but prior to dosing. A 
treatment-emergent AE is defined as an AE which occurs postdose or which is present prior to 
dosing and becomes more severe postdose. 
All AEs will be listed. Treatment-emergent AEs will be summarized by treatment, severity and 
relationship to the study drug. The frequency (the number of AEs, the number of participants 
experiencing an AE and the percentage of participants experiencing an AE) of 
treatment-emergent AEs will be summarized by treatment, Medical Dictionary for Regulatory 
Activities (MedDRA) (version is documented in the Data Management Plan [DMP]) system 
organ class and preferred term. The summary and frequency AE tables will be presented for all 
causalities and those considered related to the study drug by the investigator. Any serious AEs 
will be listed. AEs by week of onset will be presented. 
Discontinuations due to AEs will be listed. 
10.5.2 Glucose Monitoring and Hypoglycemia  
During the study, blood glucose concentrations will be monitored for safety assessments. 
Glucose data will be listed and summarized by treatment. 
Hypoglycemic events will be appropriately recorded in the CRF. In the case of a hypoglycemic 
event, the actual blood glucose value, if measured, will be recorded in the CRF, together with 
any treatments administered. Each category of hypoglycemic events (defined below) will be 
listed and summarized by treatment. Hypoglycemia is defined as follows:  
 Level 1 hypoglycemia: 
o 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: 
o Glucose <54 mg/dL (3.0 mmol/L): Level 2 hypoglycemia 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: 
o Severe hypoglycemia (in adults): A severe event characterized by altered mental 
and/or physical status requiring assistance for treatment of hypoglycemia. For 
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example, participants had altered mental status, and could not assist in their own 
care, or were semiconscious or unconscious, or experienced coma with or without 
seizures, and the assistance of another person was needed to actively administer 
carbohydrate, glucagon, or other resuscitative actions. Glucose measurements 
may not be available during such an event, but neurological recovery attributable 
to the restoration of glucose concentration to normal is considered sufficient 
evidence that the event was induced by a low glucose concentration. 
The determination of a hypoglycemic event as an episode of severe 
hypoglycemia, as defined above, is made by the investigator based on the medical 
need of the participant to have required assistance and is not predicated on the 
report of a participant simply having received assistance. 
If a hypoglycemic event meets the criteria of severe hypoglycemia, the 
investigator must record the event as serious on the AE CRF and report it to Lilly 
as a serious AE. 
 Other hypoglycemia categories: 
o Nocturnal hypoglycemia is a hypoglycemia event (including severe 
hypoglycemia) that occurs at night and presumably during sleep. 
Investigator review of glucose results clinically indicative of hypoglycemia will be required. 
10.5.3 Concomitant medication  
Concomitant medication will be coded using the WHO drug dictionary (version is documented 
in the DMP). Concomitant medication will be listed. 
10.5.4 Clinical laboratory parameters  
All clinical chemistry, hematology and lipid data will be summarized by treatment and time 
point together with change from baseline, where baseline is defined as Day 1 predose, and listed. 
Urinalysis data will be listed. Additionally, clinical chemistry, hematology and urinalysis data 
outside the reference ranges will be listed and flagged on individual participant data listings. 
10.5.5 Vital signs  
Vital signs data will be summarized by treatment and time point together with changes from 
baseline, where baseline is defined as the Day 1 predose assessment. Figures of mean vital signs 
and mean changes from baseline profiles will be presented by treatment.  
Values for individual participants will be listed. 
10.5.6 Electrocardiogram (ECG)  
ECGs will be performed for safety monitoring purposes only and will not be presented. Any 
clinically significant findings from ECGs will be reported as an AE. 
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Protocol Reference: I8F-MC-GPHV 
10.5.7 Hepatic Monitoring  
If a participant experiences elevated laboratory parameters, as detailed in Section 8.2.7.1 of the 
protocol, additional tests will be performed to confirm the abnormality. Additional safety data 
may be collected if required, as defined in the protocol. Where applicable, the following will be 
presented. 
The participants’ liver disease history and associated person liver disease history data will be 
listed. Use of acetaminophen during the study, which has potential for hepatotoxicity, will be 
listed. Results from any hepatic monitoring procedures, such as a magnetic resonance 
elastography (MRE) scan, and biopsy assessments will be listed, if performed. 
Hepatic risk factor assessment data will be listed. Liver related signs and symptoms data will be 
summarized by treatment and listed. Alcohol and recreational drug use data will also be listed. 
All hepatic chemistry, hematology, coagulation, and serology data will be listed. Values outside 
the reference ranges will be flagged on the individual participant data listings. 
10.5.8 Immunogenicity Assessments  
Immunogenicity data will be listed and frequency tables will be presented if analysed. The 
frequency and percentage of participants with pre-existing antidrug antibody (ADA) and with 
treatment-emergent ADAs (TE ADAs) will be presented. TE ADAs are those that are boosted or 
induced by exposure to study drug, with a 4-fold increase in titer compared to baseline if ADAs 
were detected at baseline or a titer 2-fold greater than the minimum required dilution (1:10) if no 
ADAs were detected at baseline, where baseline is defined as Day 1 predose. 
The frequency of neutralizing antibodies, if assessed, and cross-reactivity to native GIP and 
GLP-1 may also be tabulated in TE ADA+ participants if deemed appropriate.  
The relationship between the presence of antibodies and PK parameters of tirzepatide may be 
assessed if deemed appropriate. 
10.5.9 Hypersensitivity reactions  
For all drug hypersensitivity reactions that occur, additional follow-up data will be collected to 
assess the participant’s medical history, alternative causes, and symptoms. 
These data will be listed. 
10.5.10 Injection-Site Reactions  
Injection-site reaction data (erythema, induration, categorical pain, pruritus, and edema) will be 
listed and summarized by treatment in frequency tables. 
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10.5.11 Elevated Lipase or Amylase  
If a patient experiences elevated serum amylase or lipase values ≥3× ULN, additional monitoring 
and tests will be performed to confirm the abnormality, even in asymptomatic participants. 
The frequency of serum amylase or lipase values ≥3× ULN will be summarized by treatment and 
listed. 
10.5.12 Tanner Staging  
Female participants’ pubertal status will be assessed using Tanner Staging. These data will be 
listed. 
10.5.13 Other assessments  
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analyzed. 
10.5.14 Safety and Tolerability Statistical Methodology  
No inferential statistical analyses are planned. 
11. 
INTERIM ANALYSES  
No interim analyses are planned for this study. 
12. 
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES  
There were no changes from the protocol specified statistical analyses. 
13. 
REFERENCES  
1. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9), 5 February 1998. 
2. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), 30 November 1995. 
14. 
DATA PRESENTATION  
14.1 
Derived Parameters  
Individual derived parameters (e.g. PK parameters) and appropriate summary statistics will be 
reported to three significant figures. Observed concentration data, e.g. Cmax, should be reported 
as received. Observed time data, e.g. tmax, should be reported as received. Number of 
observations and percentage values should be reported as whole numbers. Median values should 
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be treated as an observed parameter and reported to the same number of decimal places as 
minimum and maximum values. 
14.2 
Missing Data  
Missing data will not be displayed in listings. 
14.3 
Insufficient Data for Presentation  
Some of the TFLs may not have sufficient numbers of participants or data for presentation. If 
this occurs, the blank TFL shell will be presented with a message printed in the center of the 
table, such as, “No serious adverse events occurred for this study.” 
 
 
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15. 
Appendix 1: Document History  
Status and Version 
Date of Change 
Summary/Reason for Changes 
Final Version 1.0 
NA 
NA; the first version. 
Final Version 2.0 
18JAN2024 
Following Protocol Amendment e, Cohort 3 has been 
updated to be conducted in participants with a screening 
body weight of 40 to 60 kg, inclusive. Sentinel dosing 
will be used for  participants in the body weight range 
of 40 to 50 kg in Cohort 3. 
The study design, treatment labels and statistical 
analysis comparisons have been updated accordingly. 
NA = not applicable 
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