A Randomized, Double-blind, Placebo-controlled Study to Investigate the Efficacy and Safety of Tirzepatide Monotherapy Compared With Placebo in Chinese Participants With Type 2 Diabetes
Phase: PHASE3
Conditions: Type 2 Diabetes
Sponsor: Eli Lilly and Company

Protocol: I8F-MC-GPIU 
 
 
 
 
A Randomized, Double-blind, Placebo-controlled Study to Investigate the Efficacy and Safety of 
Tirzepatide Monotherapy Compared with Placebo in Chinese Participants with Type 2 Diabetes 
(SURPASS-CN-MONO) 
 
 
 
NCT05963022 
 
 
 
Approval Date: 05-Dec-2023 

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
1 
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 Randomized, Double-blind, Placebo-controlled Study to Investigate the Efficacy and Safety of 
Tirzepatide Monotherapy Compared with Placebo in Chinese Participants with Type 2 Diabetes 
(SURPASS-CN-MONO). 
Protocol Number: I8F-MC-GPIU 
Amendment Number: b  
Compound: Tirzepatide (LY3298176) 
Brief Title:  
A Study to Investigate the Efficacy and Safety of Tirzepatide Monotherapy in Chinese 
Participants with Type 2 Diabetes. 
Study Phase: 3  
Acronym: SURPASS-CN-MONO 
Sponsor Name: Eli Lilly and Company 
Legal Registered Address: Lilly Corporate Center, Indianapolis, Indiana 46285, USA 
Regulatory Agency Identifier Number(s): Not applicable 
 
Approval Date: Protocol Amendment (b) Electronically Signed and Approved by Lilly on date 
provided below. 
 
Document ID: VV-CLIN-135757 
 
 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
2 
Medical Monitor Name and Contact Information will be provided separately. 
 
 
 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
3 
Protocol Amendment Summary of Changes Table  
 
DOCUMENT HISTORY 
Document 
Date 
Original Protocol 
21-Feb-2023 
Protocol Amendment (a) 
30-Mar-2023 
Amendment [a]  
Overall Rationale for the Amendment: 
The overall rationale for the current protocol amendment is to update Schedule of Activities with 
hepatitis B and hepatitis C screening at Visit 1 and hepatitis serology tests in Appendix 2, in 
order to be consistent with exclusion criteria #15. 
Section # and Name 
Description of Change 
Brief Rationale 
1.3. Schedule of 
Activities (SoA) 
 Added hepatitis C screening at Visit 
1 and its footnote r. 
 Added hepatitis B screening at Visit 
1 and its footnote s. 
Updated SoA with hepatitis 
B and hepatitis C screening 
at Visit 1 to be consistent 
with exclusion criteria #15. 
10.2. Appendix 2: 
Clinical Laboratory 
Tests 
Added hepatitis serology tests for 
hepatitis C virus testing and hepatitis B 
virus testing.  
For consistency with the 
update of SoA. 
 
Amendment [b]  
Overall Rationale for the Amendment: 
The overall rationale for the current protocol amendment is to update Schedule of Activities, 
analyses sets, lab for HGRAC filing process, and the terminology of heart rate to be consistent 
with the operation in practice and with other series of studies. 
Section # and 
Name 
Description of Change 
Brief Rationale 
1.3. Schedule 
of Activities 
(SoA) 
 “Review hypoglycemic events collected in 
the diaries” was checked for V99. 
 “Dispense BG meter/supplies as needed” 
was checked for V99. 
 Hypoglycemic events 
collected in the diaries 
will be reviewed at 
V99. 
 BG meter/supplies will 
be dispensed as needed 
at V99. 
1.3. Schedule 
of Activities 
(SoA) 
Annotation d was clarified: The visit date of Visit 
2 and 3 are determined based on Visit 1. The visit 
after Visit 3 (except visit 801) The visit date is 
determined in relation to the date of the 
randomization visit (± the allowed visit window). 
Annotation d was clarified 
to make it more accurate. 
1.1. Synopsis 
1.3. Schedule 
of Activities 
(SoA) 
“Heart rate” or “HR” was changed to “pulse rate” 
or “PR”.  
Pulse rate (PR) instead of 
heart rate (HR) will be 
tested.  
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
4 
Section # and 
Name 
Description of Change 
Brief Rationale 
2.3.1 Risk 
Assessment 
3. Objectives, 
Endpoints, and 
Estimands 
3. Objectives, 
Endpoints, and 
Estimands 
9.1.1 
Multiplicity 
Adjustment 
9.3.1 General 
Consideration 
9.3.3 Primary 
Endpoint(s) 
Analysis 
9.3.4 
Secondary 
Endpoints 
Analysis 
The order of the primary and secondary estimand 
was switched throughout the document. The 
wording has also been adjusted accordingly. 
Per the suggestion from 
health authority, treatment-
regimen estimand could 
reflect the clinical practice, 
and was switched to the 
primary estimand.  
4.1 Overall 
Design 
“Participants will be stratified based on 
baseline HbA1c…” was changed to 
“Participants will be stratified based on 
HbA1c” where “baseline” was removed. 
Baseline is defined for 
analysis purpose. The 
“baseline” was removed 
to reflect trial practice. 
4.1 Overall 
Design 
“Participants will be asked to monitor fasting 
blood glucose (FBG) 4 times a week and two 
7-point SMBG profiles done…” was changed 
to “Participants will be asked to monitor 
fasting blood glucose (FBG) 4 times a week. 
Participants will also be asked to monitor two 
7-point SMBG profiles done…” 
One sentence was 
separated into two 
sentences to define 
timepoints more 
accurately. 
9.2 Analyses 
Sets 
9.3.2.2 
Participant 
Characteristics 
9.3.2.3 
Concomitant 
Therapy 
9.2.3.4 
Treatment 
Compliance 
 Per-protocol population was removed. 
 “Excluding participants discontinuing study 
intervention due to inadvertent enrollment." 
was removed from mITT population 
description. 
 Safety population was removed, and the 
statistical analysis on safety population were 
changed to be based on mITT population. 
 Per-protocol 
population is not 
required after estimand 
framework 
implementation 
according to ICH E9 
(R1). 
 Revision of mITT 
description is to 
comply with intent-to-
treat principle. 
 Safety population was 
removed due to 
duplication with mITT 
population. 
9.3.3 Primary 
Endpoint(s) 
Analysis 
“…and treatment by visit interaction, any past 
prior use (yes or no) of any antihyperglycemic 
medication as fixed effects, and baseline 
HbA1c as a covariate.” was changed to “…and 
treatment by visit interaction, any past prior 
use (yes or no) of any antihyperglycemic 
Baseline-by-visit 
interaction term was 
added to make adjustment 
for the corresponding 
covariate effect. 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
5 
Section # and 
Name 
Description of Change 
Brief Rationale 
medication baseline HbA1c and baseline 
HbA1c-by-visit interaction.” 
10.2. Appendix 
2: Clinical 
Laboratory 
Tests 
Laboratory name for hematology and HbA1c 
was changed from “Lilly-designated 
laboratory” to “Labcorp Pharmaceutical 
Research and Development (Shanghai) Co., 
Ltd.” 
Update of assay agency is 
required for HGRAC 
filing process. 
10.2. Appendix 
2: Clinical 
Laboratory 
Tests 
“Hematology (including blood smear) and 
HbA1c samples were destroyed by Shanghai 
Solid Waste Disposal Co., Ltd.” was added as a 
footnote. 
Addition of disposal 
agency is required for 
HGRAC filing process. 
10.2. Appendix 
2: Clinical 
Laboratory 
Tests 
“TSH = thyroid-stimulating hormone;” was 
removed from “Abbreviations”. 
Removal of TSH from 
abbreviation is a 
correction. 
10.5. Appendix 
5: Liver Safety: 
Suggested 
Actions and 
Follow-up 
Assessments 
“Hepatic hematology samples were assayed by 
Labcorp Pharmaceutical Research and 
Development (Shanghai) Co., Ltd. and were 
destroyed by Shanghai Solid Waste Disposal 
Co., Ltd.” was added as a footnote. 
Addition of disposal 
agency is for HGRAC 
filing process. 
 
 
 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
6 
Table of Contents  
1. 
Protocol Summary ..........................................................................................................9 
1.1. 
Synopsis ............................................................................................................................9 
1.2. 
Schema ............................................................................................................................13 
1.3. 
Schedule of Activities (SoA) ..........................................................................................14 
2. 
Introduction ...................................................................................................................18 
2.1. 
Study Rationale ...............................................................................................................18 
2.2. 
Background .....................................................................................................................18 
2.3. 
Benefit/Risk Assessment ................................................................................................19 
2.3.1. 
Risk Assessment .............................................................................................................19 
2.3.2. 
Benefit Assessment .........................................................................................................20 
2.3.3. 
Overall Benefit Risk Conclusion ....................................................................................20 
3. 
Objectives, Endpoints, and Estimands .......................................................................21 
4. 
Study Design ..................................................................................................................24 
4.1. 
Overall Design ................................................................................................................24 
4.2. 
Scientific Rationale for Study Design ............................................................................26 
4.3. 
Justification for Dose ......................................................................................................26 
4.4. 
End of Study Definition ..................................................................................................27 
5. 
Study Population ...........................................................................................................28 
5.1. 
Inclusion Criteria ............................................................................................................28 
5.2. 
Exclusion Criteria ...........................................................................................................29 
5.3. 
Lifestyle Considerations .................................................................................................31 
5.4. 
Screen Failures ................................................................................................................32 
5.5. 
Criteria for Temporarily Delaying 
Enrollment/Randomization/Administration of Study Intervention 
of a Participant ................................................................................................................32 
6. 
Study Intervention(s) and Concomitant Therapy .....................................................33 
6.1. 
Study Intervention(s) Administered................................................................................33 
6.1.1. 
Study intervention ...........................................................................................................33 
6.1.2. 
Medical Devices..............................................................................................................34 
6.2. 
Preparation, Handling, Storage, and Accountability ......................................................34 
6.3. 
Assignment to Study Intervention ..................................................................................35 
6.4. 
Blinding ..........................................................................................................................35 
6.5. 
Study Intervention Compliance ......................................................................................35 
6.6. 
Dose Modification ..........................................................................................................36 
6.6.1. 
Tirzepatide ......................................................................................................................36 
6.7. 
Continued Access to Study Intervention after the End of the 
Study ...............................................................................................................................37 
6.8. 
Treatment of Overdose ...................................................................................................37 
6.9. 
Concomitant Therapy .....................................................................................................37 
6.9.1. 
Initiation of New Antihyperglycemic Medication ..........................................................38 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................39 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
7 
7.1. 
Discontinuation of Study Intervention ............................................................................39 
7.1.1. 
Liver Chemistry Stopping Criteria ..................................................................................39 
7.1.2. 
Temporary Discontinuation ............................................................................................40 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................41 
7.2.1. 
Discontinuation of Inadvertently Enrolled Participants ..................................................41 
7.3. 
Lost to Follow up ............................................................................................................41 
8. 
Study Assessments and Procedures.............................................................................43 
8.1. 
Efficacy Assessments .....................................................................................................43 
8.1.1. 
Self-Monitoring of Blood Glucose (SMBG) ..................................................................43 
8.1.2. 
Patient-Reported Outcomes ............................................................................................44 
8.2. 
Safety Assessments .........................................................................................................44 
8.2.1. 
Physical Examinations ....................................................................................................44 
8.2.2. 
Vital Signs .......................................................................................................................45 
8.2.3. 
Electrocardiograms .........................................................................................................45 
8.2.4. 
Dilated Fundoscopic Examination ..................................................................................45 
8.2.5. 
Clinical Safety Laboratory Tests ....................................................................................45 
8.2.6. 
Pregnancy Testing ...........................................................................................................46 
8.2.7. 
Safety Monitoring ...........................................................................................................46 
8.3. 
Adverse Events, Serious Adverse Events, and Product 
Complaints ......................................................................................................................49 
8.3.1. 
Timing and Mechanism for Collecting Events ...............................................................49 
8.3.2. 
Pregnancy ........................................................................................................................50 
8.3.3. 
Serious Adverse Events ..................................................................................................51 
8.3.4. 
Adverse Events of Special Interest .................................................................................52 
8.3.5. 
Complaint Handling ........................................................................................................57 
8.4. 
Pharmacokinetics ............................................................................................................57 
8.5. 
Pharmacodynamics .........................................................................................................57 
8.6. 
Genetics ..........................................................................................................................58 
8.7. 
Biomarkers ......................................................................................................................58 
8.8. 
Immunogenicity Assessments.........................................................................................58 
8.9. 
Health Economics ...........................................................................................................58 
9. 
Statistical Considerations .............................................................................................59 
9.1. 
Statistical Hypotheses .....................................................................................................59 
9.1.1. 
Multiplicity Adjustment ..................................................................................................59 
9.2. 
Analyses Sets ..................................................................................................................59 
9.3. 
Statistical Analyses .........................................................................................................60 
9.3.1. 
General Considerations ...................................................................................................60 
9.3.2. 
Treatment Group Comparability .....................................................................................61 
9.3.3. 
Primary Endpoint(s) Analysis .........................................................................................62 
9.3.4. 
Secondary Endpoints Analysis .......................................................................................62 
 
 
9.3.6. 
Safety Analyses ...............................................................................................................63 
9.3.7. 
Other Analyses ................................................................................................................64 
9.4. 
Interim Analysis ..............................................................................................................64 
9.5. 
Sample Size Determination ............................................................................................64 
Approved on 05 Dec 2023 GMT
CCI

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
8 
10. 
Supporting Documentation and Operational Considerations ..................................66 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................66 
10.1.1. Regulatory and Ethical Considerations ...........................................................................66 
10.1.2. Financial Disclosure........................................................................................................66 
10.1.3. Informed Consent Process ..............................................................................................67 
10.1.4. Data Protection................................................................................................................67 
10.1.5. Committees Structure......................................................................................................67 
10.1.6. Dissemination of Clinical Study Data.............................................................................67 
10.1.7. Data Quality Assurance ..................................................................................................68 
10.1.8. Source Documents ..........................................................................................................69 
10.1.9. Study and Site Start and Closure ....................................................................................70 
10.1.10. Publication Policy ...........................................................................................................70 
10.1.11. Investigator Information .................................................................................................70 
10.2. 
Appendix 2: Clinical Laboratory Tests ...........................................................................71 
10.2.1. Laboratory Samples to be Obtained at the Time of a Systemic 
Hypersensitivity Event ....................................................................................................73 
10.3. 
Appendix 3: Adverse Events and Serious Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-
up, and Reporting ............................................................................................................75 
10.3.1. Definition of AE .............................................................................................................75 
10.3.2. Definition of SAE ...........................................................................................................76 
10.3.3. Definition of Product Complaints ...................................................................................77 
10.3.4. Recording and Follow-Up of AE and/or SAE and Product 
Complaints ......................................................................................................................77 
10.3.5. Reporting of SAEs ..........................................................................................................79 
10.3.6. Regulatory Reporting Requirements ...............................................................................79 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ..........................................................81 
10.4.1. Definitions.......................................................................................................................81 
10.4.2. Contraception Guidance..................................................................................................81 
10.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-up 
Assessments ....................................................................................................................84 
10.6. 
Appendix 6: World Health Organization Classification of 
Diabetes and Diagnostic Criteria ....................................................................................86 
10.7. 
Appendix 7: Protocol GPIU Standardized Protocols for the 
Measurement of Height, Weight and Waist Circumference ...........................................87 
10.8. 
Appendix 8: Provisions for Changes in Study Conduct During 
Exceptional Circumstances .............................................................................................89 
10.9. 
Appendix 9: Abbreviations and Definitions ...................................................................93 
11. 
References ......................................................................................................................97 
 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
9 
1. 
Protocol Summary  
1.1. 
Synopsis  
Protocol Title:  
A Randomized, Double-blind, Placebo-controlled Study to Investigate the Efficacy and Safety of 
Tirzepatide Monotherapy Compared with Placebo in Chinese Participants with Type 2 Diabetes 
(SURPASS-CN-MONO). 
Brief Title:  
A Study to Investigate the Efficacy and Safety of Tirzepatide Monotherapy in Chinese 
Participants with Type 2 Diabetes. 
Regulatory Agency Identifier Number(s):  
Not applicable. 
Rationale: 
Diabetes is a global health issue that affects approximately 536.6 million adults (20 to 79 years) 
worldwide, with type 2 diabetes mellitus (T2DM) accounting for over 90% of all diabetes 
worldwide (IDF 2021).  In China, based on International Diabetes Federation (IDF) 2021, there 
are 140.9 million people (20 to 79 years) living with diabetes, which accounts for 1 in 4 of all 
adults living with diabetes worldwide (IDF 2021).  Type 2 diabetes mellitus is associated with a 
higher risk for macrovascular and microvascular complications.  The results of UK Prospective 
Diabetes Study published in 2021 suggest that intensive glucose control from the time of 
diagnosis is essential to maximize reduction of the long-term risk of the complications 
(Lind et al. 2021).   
In the study GPGK (also known as SURPASS-1), tirzepatide demonstrated superior 
improvements as monotherapy in comparison to placebo in glycemic control and body weight 
reduction without increased risk of hypoglycemia.  However, there is limited tirzepatide 
monotherapy evidence in Chinese patients with T2DM in early phase.   
Study I8F-MC-GPIU (GPIU, monotherapy) is a Phase 3, multicenter, randomized, double-blind, 
parallel, placebo-controlled, 40-week study that investigates the efficacy and safety of 3 doses of 
tirzepatide compared with placebo in Chinese participants with T2DM, inadequately controlled 
with diet and exercise alone, and have not been treated with any antihyperglycemic medication 
during the 90 days preceding the start of the study.  This study aims to provide evidence of the 
tirzepatide as monotherapy for the treatment of Chinese patients with T2DM in early phase. 
 
 
 
 
 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
10 
Objectives, Endpoints, and Estimands: 
 
Objectives 
Endpoints 
Primary 
 
 
To demonstrate that tirzepatide QW 5 mg, 
and/or 10 mg, and/or 15 mg are superior to 
placebo QW in HbA1c change from baseline 
to Week 40 
 
Change in HbA1c from baseline 
Key Secondary (controlled for type 1 error) 
 
 
To demonstrate superiority of tirzepatide QW 
5 mg, and/or 10 mg, and/or 15 mg to placebo 
QW at Week 40 for: 
 
Proportion of participants with HbA1c target 
values of <7.0% (<53 mmol/mol) 
 
Change in fasting serum glucose (central 
laboratory) from baseline 
 
Proportion of participants with HbA1c target 
values of ≤6.5% (≤48 mmol/mol) 
 
Change in body weight from baseline 
 
Proportion of participants with HbA1c target 
values of <5.7% (<39 mmol/mol) 
Additional Secondary (not controlled for type 1 error) 
 
 
To compare tirzepatide QW 5 mg, 10 mg, and 
15 mg to placebo QW at Week 40 for: 
 
Change in daily average 7-point self-
monitored blood glucose profiles from 
baseline 
 
Proportion of participants who achieved 
weight loss of ≥5%, ≥10%, and ≥15% 
Safety 
 
 
To compare the safety of tirzepatide QW 5 
mg, 10 mg, and 15 mg to placebo QW for: 
 
Incidence of treatment-emergent adverse 
events  
 
Incidence of early discontinuation of study 
intervention due to AEs 
 
Incidence of adjudicated pancreatic AEs 
 
Change in serum calcitonin from baseline 
 
Incidence of allergic and hypersensitivity 
reactions 
 
Change in systolic blood pressure, diastolic 
blood pressure and pulse rate from baseline  
 
Occurrence of hypoglycemic episodes  
 
Time to initiation of rescue therapy for severe 
persistent hyperglycemia 
Abbreviations:  AE = adverse event; HbA1c = hemoglobin A1c; QW = once weekly. 
 
 
 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
11 
Overall Design 
Study GPIU is a multicenter, randomized, double-blind, parallel, placebo-controlled, Phase 3 
study which will investigate the efficacy and safety of three doses of tirzepatide as monotherapy 
compared with placebo in Chinese participants with T2DM.   
Brief Summary: 
The study will consist of 3 periods:   
 Period Ⅰ: approximately 
 screening/lead-in period 
 Period ⅠI: 
 treatment period, and 
 Period ⅠII: 
 safety follow-up period.   
Study Population: 
Key inclusion and exclusion criteria are listed as follow. 
To be eligible for the study, participants must  
 be ≥18 years old 
 have been diagnosed with T2DM and have not been treated with any antihyperglycemic 
medication during the 90 days preceding Visit 1 
 have hemoglobin A1c (HbA1c) of ≥7.0% (≥53 mmol/mol) to ≤9.5% (≤80 mmol/mol) 
despite diet and exercise treatment at Visit 1  
 have a stable weight (±5%) for 90 days prior to Visit 1 
 have a body mass index (BMI) of at least 23.0 kg/m
2 at Visit 1. 
To be eligible for the study, participants must not 
 have type 1 diabetes mellitus (T1DM) 
 have been treated with insulin 1 year preceding Visit 1 and between Visit 1 and Visit 3; 
or have been treated with any antihyperglycemic medication 90 days preceding Visit 1 
and between Visit 1 and Visit 3 
Note: An exception is for the use of insulin for gestational diabetes or short-term use 
(≤14 days) for certain clinical situations such as acute illness, hospitalization, or elective 
surgery 
 have history of chronic or acute pancreatitis prior to Visit 1 
 be currently requiring or receiving treatment for diabetic retinopathy and/or macular 
edema 
 have been treated with prescription drugs or similar other body weight loss medications 
including over-the-counter (OTC) medications that promote weight loss within 90 days 
prior to Visit 1 and/or between Visit 1 and Visit 3 
 have been receiving chronic (>2 weeks or 14 days) systemic glucocorticoid therapy 
(excluding topical, intraocular, intranasal, or inhaled preparations) or had received such 
therapy within 30 days of Visit 1 or between Visits 1 and 3. 
 
 
Approved on 05 Dec 2023 GMT
CCI
CCI
CCI

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
12 
Number of Participants: 
Approximately 200 participants (50 participants per arm) will be randomized in a 
 ratio 
(tirzepatide 5 mg once weekly [QW], tirzepatide 10  mg QW, tirzepatide 15 mg QW, and 
placebo QW).   
Ethical Considerations of Benefit/Risk: 
Considering the data that are available to date from previous clinical studies, and the measures 
taken to ensure the safety of the participants in this study, the potential risks related with 
tirzepatide are justified by the anticipated benefits a participant with T2DM may experience in 
the study.  
Data Monitoring Committee: No 
 
Approved on 05 Dec 2023 GMT
CCI

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
13 
1.2. 
Schema  
 
Abbreviations:  QW = once weekly. 
 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
14 
1.3. 
Schedule of Activities (SoA)  
The Schedule of Activities (SoA) described below should be followed for all participants enrolled in Study GPIU.  However, for those 
participants whose participation in this study is affected by exceptional circumstances (such as pandemics or natural disasters), please 
refer to Section 10.8 for additional guidance.   
 
 
Study Period 
I 
Study Period II 
Study Period 
III 
Screening/ 
Lead in 
Treatment Period 
Safety F/U 
Visit 
1 
2 
3a 
4 
5 
6 
7 
8 
9 
10 
11 
99b 
ETc 
801 
Week of Treatment 
Allowable Deviation (days)d 
Fasting Visite 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Clinical Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical historyf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weightg 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Waist circumference 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
12-lead ECG (local) 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
Vital signs (2 sitting BP and 
PR) 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Dilated fundoscopic 
Examinationh 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review hypoglycemic events 
collected in the diaries 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Participant Education 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diabetes educationi,j 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
BG meter, SMBG trainingj 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Approved on 05 Dec 2023 GMT
CCI

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
15 
 
 
Study Period 
I 
Study Period II 
Study Period 
III 
Screening/ 
Lead in 
Treatment Period 
Safety F/U 
Visit 
1 
2 
3a 
4 
5 
6 
7 
8 
9 
10 
11 
99b 
ETc 
801 
Week of Treatment 
Allowable Deviation (days)d 
Fasting Visite 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense BG meter/supplies 
as needed 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study intervention injection 
training with demo devicej 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Hand out diaries, instruct in 
usej 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Remind participants about 7-
point SMBGk 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
Review 7-point SMBG values 
collected in the diaries 
 
 
X 
 
 
 
 
 
X 
 
X 
 
 
 
Dispense study intervention 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Observe participant administer 
study interventionl 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Participant returns study 
interventions and injection 
supplies 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Assess study intervention 
compliance 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Laboratory Tests 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy testm 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy testn 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
 
FSHo 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chemistry panel  
Xp 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
X 
Serum glucose 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Insulin 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
C-peptide 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
Lipid panel 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Approved on 05 Dec 2023 GMT
CCI

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
16 
 
 
Study Period 
I 
Study Period II 
Study Period 
III 
Screening/ 
Lead in 
Treatment Period 
Safety F/U 
Visit 
1 
2 
3a 
4 
5 
6 
7 
8 
9 
10 
11 
99b 
ETc 
801 
Week of Treatment 
Allowable Deviation (days)d 
Fasting Visite 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinary albumin/creatinine 
ratio 
Xp 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
eGFR (CKD-EPI 2021)q 
Xp 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
X 
Calcitonin 
Xp 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
X 
Hematology 
Xp 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
X 
HbA1c 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pancreatic amylase 
Xp 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
X 
Lipase 
Xp 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
X 
Hepatitis C Screeningr 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B Screenings 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient-Reported Outcomest 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EQ-5D-5L  
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
IWQOL-Lite-CT 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
 
Approved on 05 Dec 2023 GMT
CCI

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
17 
Abbreviations: BG = blood glucose; BP = blood pressure; CKD-EPI = Chronic Kidney Disease-Epidemiology; ECG = electrocardiogram; eGFR = estimated 
glomerular filtration rate; EQ-5D-5L = European Quality of Life-dimensions; ET = early termination; FSH = Follicle-stimulating hormone; F/U = follow-up; 
HbA1c = hemoglobin A1c; PR = pulse rate; IWQOL-Lite-CT= Impact of Weight on Quality of Life-Lite Clinical Trials Version; PRO = patient-reported 
outcome; SMBG = self-monitoring of blood glucose; Tx = treatment. 
a 
Baseline assessments must be completed before processing in the interactive web-response system. 
b 
Visit 99 is only applicable to participants who discontinue the study treatment prematurely before Week 40 and decline to complete the remaining study visits 
but are willing to return for Visit 99 at Week 40 after randomization for the purpose of HbA1c, body weight and FSG collection, assessment of adverse 
events, concomitant medications.  
c 
Participants who are unable or unwilling to continue in the study for any reason and decline to return for Visit 99 will perform an ET visit.  If the participant is 
discontinuing during an unscheduled visit, that visit should be performed as the ET visit.  If the participant is discontinuing during a scheduled visit, that visit 
should be performed as an ET visit.  Visit 801 (safety follow-up visit) should be performed 4 weeks after the ET visit as the final study visit. 
d 
The visit date of Visit 2 and 3 are determined based on Visit 1. The visit after Visit 3 (except visit 801) is determined in relation to the date of the 
randomization visit (± the allowed visit window). 
e Participants should be reminded to report to the site from Visit 3 in a fasting condition, after a period of approximately 8 hours without eating, drinking 
(except water), or any significant physical activity and before taking study intervention. 
f 
Medical history includes assessment of preexisting conditions (including history of gall bladder disease, cardiovascular disease, thyroid conditions, and 
medullary thyroid carcinoma) and substance usage (such as alcohol and tobacco). 
g Weight measurements must be in kilograms. 
h 
A dilated fundoscopic examination will be performed by an ophthalmologist or optometrist for all participants between Visit 2 and Visit 3 to confirm 
eligibility.  A previous examination ≤90 days meeting study requirements from Visit 1 is acceptable to confirm eligibility.   
i 
Includes counseling on diet and exercise, symptoms and management of hypoglycemia and hyperglycemia, etc. 
j 
All training should be repeated as needed to ensure participant compliance.   
k 
Participant is required to collect two 7-point SMBGs on nonconsecutive days prior to the next visit.  A 7-point SMBG consists of measurements before and 
2 hours after each of 3 main meals within the same day and at bedtime.  These SMBG profiles will be collected by the participant within 2 weeks prior to the 
assigned visits.  If more than 2 SMBG profiles are available, the 2 most recent nonconsecutive profiles should be used. 
l 
Participants should administer their first dose of study intervention at the end of this visit, after other study procedures and randomization. 
m A serum pregnancy test will be performed at Visit 1 for women of childbearing potential only. 
n A local urine pregnancy test must be performed at Visit 3 with the result available prior to randomization and first injection of study intervention(s) for 
women of childbearing potential only.  Additional pregnancy tests will be performed at Visits 6, 9, and 11.  Pregnancy tests may be performed at the 
investigator’s discretion during the study.  If required per local regulations and/or institutional guidelines, pregnancy testing can also occur at other times 
during the study treatment period.  For sites who can’t perform urine pregnancy test, a local serum pregnancy test can be performed instead.   
o Performed as needed to confirm postmenopausal status, see Section 10.4. 
p 
Screening visit assessment will serve as baseline. 
q The CKD-EPI equation will be used by the central lab to estimate and report eGFR.  
r 
Confirmation by hepatitis C virus RNA will be performed if positive for hepatitis C virus antibody.  
s 
Confirmation by hepatitis B virus DNA will be performed if positive for hepatitis B core antibody.  
t 
All PROs should be completed before any other study procedures if the participant is not adversely affected by the fasting condition or completed after the 
participant has sufficiently recovered from the preceding visit procedures. 
Note: Patients will be encouraged to collect fasting BG 4 times a week.  Missing a fasting BG measurement will not be considered a protocol deviation. 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
18 
2. 
Introduction  
2.1. 
Study Rationale  
Diabetes is a global health issue that affects approximately 536.6 million adults (20 to 79 years) 
worldwide, with T2DM accounting for over 90% of all diabetes worldwide (IDF 2021).  In 
China, based on IDF 2021, there are 140.9 million people (20 to 79 years) living with diabetes, 
which accounts for 1 in 4 of all adults living with diabetes worldwide (IDF 2021).  Type 2 
diabetes mellitus is associated with a higher risk for macrovascular and microvascular 
complications. The results of UK Prospective Diabetes Study published in 2021 suggest that 
intensive glucose control from the time of diagnosis is essential to maximize reduction of the 
long-term risk of the complications (Lind et al. 2021). 
In the study GPGK (also known as SURPASS-1), tirzepatide demonstrated superior 
improvements as monotherapy in comparison to placebo in glycemic control and body weight 
reduction without increased risk of hypoglycemia.  However, there is limited tirzepatide 
monotherapy evidence in Chinese patients with T2DM in early phase. 
Study GPIU (monotherapy) is a Phase 3, multicenter, randomized, double-blind, parallel, 
placebo-controlled, 40-week study that investigates the efficacy and safety of 3 doses of 
tirzepatide compared with placebo in Chinese participants with T2DM, inadequately controlled 
with diet and exercise alone, and have not been treated with any antihyperglycemic medication 
during the 90 days preceding the start of the study.  This study aims to provide evidence of the 
tirzepatide as monotherapy for the treatment of Chinese patients with T2DM in early phase. 
2.2. 
Background  
Tirzepatide (LY3298176) is a 39-amino acid synthetic peptide with agonist activity at both the 
glucose dependent insulinotropic polypeptide (GIP) and glucagon like peptide-1 (GLP-1) 
receptors.  Its structure is based on the GIP sequence and includes a C20 fatty di-acid moiety that 
prolongs the duration of action.  It is administered as QW subcutaneous injection.   
Tirzepatide: Mechanism of Action 
In a 28-week clinical pharmacology study, Study GPGT, tirzepatide was shown to  
 improve β-cell function adjusted for insulin sensitivity, as shown by improved clamp 
disposition index  
 improve first and second phase, as well as overall β-cell insulin secretion  
 improve insulin sensitivity  
 improve metabolism, including 
o simultaneous effects to increase insulin sensitivity  
o reduction of glucagon secretion  
o improvement of β-cell function, and  
 reduce body weight, fat mass, appetite, and food intake. 
 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
19 
Phase 3 clinical studies 
Clinical reductions in HbA1c and body weight 
In a series of global Phase 3 SURPASS studies, tirzepatide demonstrated clinically meaningful 
reductions in HbA1c and body weight, which were greater than placebo, semaglutide 1 mg, 
titrated insulin degludec, and titrated insulin glargine (Rosenstock et al. 2021; Frías et al. 2021; 
Ludvik et al. 2021; Del Prato et al. 2021; Dahl et al. 2022).  These treatment effects were 
sustained up to 104 weeks (Del Prato et al. 2021).   
Tirzepatide has been shown to normalize blood glucose (BG) levels as reflected by 
HbA1c <5.7%.  These levels of HbA1c were achieved by up to 62% of participants treated with 
tirzepatide 15 mg while on treatment and without the effects of rescue (Dahl et al. 2022).  
Improvements in metabolic endpoints 
Tirzepatide also demonstrated greater improvements than comparators in other metabolic 
endpoints such as fasting serum glucose (FSG), and 2-hour postmeal glucose, continuous glucose 
monitoring-assessed time in euglycemic range, waist circumference, liver fat content, volume of 
abdominal visceral and subcutaneous adipose tissue, and fasting lipid profile 
(Del Prato et al. 2021; Frías et al. 2021; Ludvik et al. 2021; Rosenstock et al. 2021; 
Battelino et al. 2022; Dahl et al. 2022; Gastaldelli et al. 2022).   
Common adverse events 
Overall, the safety and tolerability profile is similar to the GLP-1 receptor agonist class. 
Gastrointestinal adverse events (AEs) such as nausea, vomiting, and diarrhea were the most 
common AEs seen in the tirzepatide-treated participants.   
Hypoglycemia events 
In line with the ability of tirzepatide to lower BG in a glucose-dependent manner, the overall 
incidence of clinically significant or severe hypoglycemia attributable to tirzepatide was low.  
The risk of clinically significant hypoglycemia or severe hypoglycemia was higher when 
tirzepatide was used in combination with insulin glargine or sulfonylurea, as has been observed 
with the GLP-1 receptor agonist class (Rosenstock et al. 2021; Frías et al. 2021; 
Ludvik et  al. 2021; Del Prato et al. 2021; Dahl et al. 2022).   
2.3. 
Benefit/Risk Assessment  
More detailed information about the known and expected benefits and risks and reasonably 
anticipated serious adverse events (SAEs) of tirzepatide may be found in the Investigator’s 
Brochure (IB).   
2.3.1. 
Risk Assessment  
Study Intervention 
The most commonly reported treatment-emergent adverse events (TEAEs) observed in the 
tirzepatide clinical studies, in healthy participants and participants with T2DM, are 
gastrointestinal effects, including nausea, diarrhea, and vomiting.   
Most were mild to moderate in severity and tended to occur during the dose escalation period.   
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
20 
Potential risks associated with tirzepatide include: 
 acute pancreatitis 
 increases in pulse rate 
 hypoglycemia 
 hypersensitivity reactions 
 thyroid C-cell effects (only observed in rodents), and 
 developmental (pregnancy) safety. 
More detailed information about the adverse events of special interest may be found in 
Section 8.3.4 or in the IB. 
Study Procedures 
For the safety consideration of the participants in the placebo group, the following procedures 
and measures are planned.   
 Participants must have HbA1c of ≥7.0% (≥53 mmol/mol) to ≤9.5% (≤80 mmol/mol) and 
have not used any antihyperglycemic medication during the 90 days preceding Visit 1.   
 Participants will be provided with diet and exercise guidance during the whole study.   
 Participants will receive a glucometer and training on how to perform self-monitoring of 
blood glucose (SMBG).  Also they will be provided diaries and trained as appropriate to 
record BG values and hypoglycemic events.  Participants will also be trained on disease 
management (symptoms of hypoglycemia and hyperglycemia) and study procedures.   
 If participants fulfill the criteria for severe persistent hyperglycemia (See 
Section 6.9.1.1), rescue therapy will be started.   
2.3.2. 
Benefit Assessment  
The potential benefits from participation in this study include improved glycemic control, weight 
loss, potential delayed deterioration of β-cell function, and continued expert medical care of 
T2DM for the study duration.  
Participants may benefit by receiving personal health information, routine safety assessments, 
lifestyle management counseling, and frequent engagement with health care providers during the 
study, which provide opportunities for coaching and support. 
2.3.3. 
Overall Benefit Risk Conclusion  
The safety and efficacy profile seen to date for tirzepatide, supports the overall benefit risk for 
participants in this study. Considering the measures taken to minimize risk to participants in this 
study as outline in the protocol, the potential risks identified in association with tirzepatide are 
justified by the anticipated benefits that may be afforded to participants living with T2DM. 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
21 
3. 
Objectives, Endpoints, and Estimands  
 
Objectives 
Endpoints 
Primary 
 
 
To demonstrate that tirzepatide QW 5 mg, 
and/or 10 mg, and/or 15 mg are superior to 
placebo QW in HbA1c change from baseline 
to Week 40 
 
Change in HbA1c from baseline 
Key Secondary (controlled for type 1 error) 
 
 
To demonstrate superiority of tirzepatide QW 
5 mg, and/or 10 mg, and/or 15 mg to placebo 
QW at Week 40 for: 
 
Proportion of participants with HbA1c target 
values of <7.0% (<53 mmol/mol) 
 
Change in fasting serum glucose (central 
laboratory) from baseline 
 
Proportion of participants with HbA1c target 
values of ≤6.5% (≤48 mmol/mol) 
 
Change in body weight from baseline 
 
Proportion of participants with HbA1c target 
values of <5.7% (<39 mmol/mol) 
Additional Secondary (not controlled for type 1 error) 
 
 
To compare tirzepatide QW 5 mg, 10 mg, and 
15 mg to placebo QW at Week 40 for: 
 
Change in daily average 7-point self-
monitored blood glucose profiles from 
baseline 
 
Proportion of participants who achieved 
weight loss of ≥5%, ≥10%, and ≥15% 
Safety 
 
 
To compare the safety of tirzepatide QW 5 
mg, 10 mg, and 15 mg to placebo QW for: 
 
Incidence of treatment-emergent adverse 
events  
 
Incidence of early discontinuation of study 
intervention due to AEs 
 
Incidence of adjudicated pancreatic AEs 
 
Change in serum calcitonin from baseline 
 
Incidence of allergic and hypersensitivity 
reactions 
 
Change in systolic blood pressure, diastolic 
blood pressure and pulse rate from baseline  
 
Occurrence of hypoglycemic episodes  
 
Time to initiation of rescue therapy for severe 
persistent hyperglycemia 
Approved on 05 Dec 2023 GMT
CCI

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
22 
Abbreviations:  AE = adverse events; HbA1c = hemoglobin A1c; 
 QW = once weekly; 
. 
Primary estimand 
The primary efficacy assessment is guided by the “treatment-regimen” estimand. This estimand 
aims at reflecting how participants with T2DM are treated in clinical practice and takes into 
account both tolerability and efficacy. 
The treatment-regimen estimand answers the following question of interest for the primary objective: 
What is the treatment difference in change from baseline in HbA1c after 40 weeks of treatment in 
participants with T2DM regardless of treatment discontinuation for any reason and regardless of 
initiation of antihyperglycemic rescue? 
The treatment-regimen estimand is described by the following attributes. 
 
Population: Participants with T2DM who are inadequately controlled on diet and exercise 
alone, and have not been treated with any antihyperglycemic medication during the 90 days 
preceding the start of the study. 
 
Endpoint: Change from baseline to week 40 after randomization in HbA1c. 
 
Treatment condition: The randomized treatment regardless of adherence to treatment with or 
without antihyperglycemic rescue medication. Further details on study treatment and rescue 
therapy can be found in Study Protocol Section 6. 
 
Intercurrent events: no ICEs are defined since treatment adherence and the initiation of 
additional antihyperglycemic medications are a part of the treatment condition. 
 
Population-level summary: Difference in mean changes between treatment conditions. 
 
 
Secondary estimand(s) 
This estimand focuses on the treatment effect if participants who underwent randomization 
continued to receive the study treatment without treatment discontinuation or rescue 
antihyperglycemic medication for severe, persistent hyperglycemia. 
The efficacy estimand answers the following question of interest for the primary objective: What 
is the treatment difference in HbA1c change from baseline to week 40 after randomization in 
participants with T2DM assuming that participants had stayed on treatment and not taken 
antihyperglycemic rescue medication? 
Approved on 05 Dec 2023 GMT
CCI
CCI
CCI

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
23 
The efficacy estimand is described by the following attributes. 
 Population: Participants with T2DM who are inadequately controlled on diet and 
exercise alone, and have not been treated with any antihyperglycemic medication during 
the 90 days preceding the start of the study. 
 Endpoint: Change from baseline to Week 40 after randomization in HbA1c. 
 Treatment condition: The randomized treatment. Further details on study treatment and 
rescue therapy can be found in Study Protocol Section 6. 
 Intercurrent event: Intercurrent events of interest: “Treatment discontinuation for any 
reason” and “Initiation of antihyperglycemic rescue treatment” will be addressed using 
the following strategies: 
o Had participants stayed on treatment (hypothetical strategy). 
o Had participants not taken antihyperglycemic rescue medication (hypothetical 
strategy). 
 Population-level summary: Difference in mean changes between treatment conditions. 
 
The efficacy estimand will be evaluated for all primary, secondary, and tertiary efficacy 
objectives. The treatment-regimen estimand will be evaluated for the primary and all key 
secondary objectives. The population, treatment condition, and intercurrent events specified 
above for each estimand for the primary objective will also apply to the other efficacy objectives, 
and the population-level summary might be adjusted according to the endpoints of the objectives. 
 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
24 
4. 
Study Design  
4.1. 
Overall Design  
Study GPIU is a multicenter, randomized, double-blind, parallel, placebo-controlled, Phase 3 
study which will investigate the efficacy and safety of tirzepatide monotherapy compared with 
placebo in Chinese participants with T2DM, inadequately controlled with diet and exercise 
alone, and have not been treated with any antihyperglycemic medication during the 90 days 
preceding the start of the study.   
Approximately, 200 participants will be randomized in a 
 ratio (tirzepatide 5 mg QW, 
10 mg QW, 15 mg QW, and placebo QW).  Participants will be stratified based on HbA1c 
[≤8.5% (≤69 mmol/mol) or >8.5% (>69 mmol/mol)], and any past prior use (Yes or No) of any 
antihyperglycemic medication.   
Study GPIU will consist of 3 periods:   
 Period Ⅰ: approximately 
 screening/lead-in period 
 Period ⅠI: 
 treatment period, and 
 Period ⅠII: 
 safety follow-up period.   
Study Period I (Screening and Lead-in) 
Screening (Visit 1) 
The purpose of screening procedures at Visit 1 is to establish initial eligibility and to obtain 
blood samples for laboratory assessments needed to confirm eligibility at Visit 2.  The 
participant will sign the informed consent form (ICF) before any study procedures are 
performed.  Procedures at this visit will be performed as shown in the SoA (Section 1.3).  
Lead-in (Visit 2 to Visit 3) 
At Visit 2, the screening laboratory results will be reviewed.  For those participants meeting all 
other eligibility requirements, a dilated fundoscopic examination, performed by an 
ophthalmologist or optometrist, will be completed between Visit 2 and Visit 3 to confirm 
eligibility unless a dilated fundoscopic examination was performed by an ophthalmologist or 
optometrist within 90 days of study entry (Visit 1) (section 5.2 Exclusion Criterion [10]).  
Additionally, at Visit 2, participants and their caregiver(s), if applicable, will receive a 
glucometer and training on how to perform SMBG.  Participants will be asked to monitor fasting 
blood glucose (FBG) 4 times a week. Participants will also be asked to monitor two 7-point 
SMBG profiles done on 2 nonconsecutive days in the 2-week period prior to Visit 3 
(randomization), Visit 9 (Week 24), Visit 11 (Week 40).   
Participants will be provided diaries and will be trained as appropriate to record BG values and 
hypoglycemic events.  During this period, participants will also be trained on disease 
management (symptoms of hypoglycemia and hyperglycemia) and study procedures; this 
training can be repeated at subsequent visits as deemed appropriate.  Participants should monitor 
BG any time a hypoglycemic event is suspected.   
Study Period II (
 treatment period) 
Randomization (Visit 3) 
Approved on 05 Dec 2023 GMT
CCI
CCI
CCI
CCI
CCI

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
25 
At Visit 3, eligible participants will perform all required baseline study procedures (including the 
collection of all baseline laboratory measures and electrocardiogram [ECG]) prior to 
randomization and prior to administering the first dose of study intervention.  Participant should 
arrive to the clinic in the fasting state; the fasting state should have lasted at least 8 hours (water 
is allowed).  The questionnaires (European Quality of Life-Dimensions [EQ-5D-5L] and Impact 
of Weight on Quality of Life-Lite Clinical Trials Version [IWQOL-Lite-CT]) should be 
completed before any other study procedures if the participant is not adversely affected by the 
fasting condition or completed after the participant has sufficiently recovered from the preceding 
visit procedures.   
Participants will be instructed on how to use the single-dose pen (SDP) and will inject their first 
dose of study intervention while in the clinic for Visit 3.  The date and time of the first dose of 
study intervention should be recorded on the case report form (CRF). 
Following randomization, participants will participate in a 
 treatment period.   
Postrandomization period (end of Visit 3 to Visit 11): 
The starting dose of study intervention will be 2.5 mg QW for 4 weeks, followed by an increase 
to 5 mg QW, for the duration of the study in the 5-mg group.   
For the 10-mg group, the starting dose of study intervention will be 2.5 mg QW for 4 weeks, 
then the dose will be increased by 2.5 mg every 4 weeks (2.5 mg to 5 mg to 7.5 mg to 10 mg) 
until the 10-mg dose is reached and maintained for the duration of the study.   
For the 15-mg group, the starting dose of study intervention will be 2.5 mg QW for 4 weeks, 
then the dose will be increased by 2.5 mg every 4 weeks (2.5 mg to 5 mg to 7.5 mg to 10 mg to 
12.5 mg to 15 mg) until the 15-mg dose is reached and maintained for the duration of the study.   
For the placebo group, participants will inject matched QW placebo for the duration of the study.   
Visit 99 
Visit 99 is only applicable to participants who discontinue the study treatment prematurely 
before Week 40 and decline to complete the remaining study visits but are willing to return for 
Visit 99 at Week 40 after randomization.  This visit is critical to ensure complete data collection 
for the primary and key secondary endpoints. 
Participants should attend this visit in the fasting state.  Procedures to be completed are: 
 measurement of HbA1c, FSG and weight 
 listing of concomitant medications, and 
 assessment of AEs.  
For participants unwilling to attend this visit, their refusal to attend should be documented in the 
participant medical record.   
Study Period III (safety follow-up period) 
Safety follow-up (Visit 801) visits:  
All participants who complete the treatment period (complete Visit 11 or Visit 99) are required 
to complete Visit 801, a safety follow-up visit approximately 4 weeks after their last treatment 
visit.  Participants discontinuing the study early and performing an early termination (ET) visit 
Approved on 05 Dec 2023 GMT
CCI

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
26 
will also be asked to perform the safety follow-up visit, so that the safety follow-up visit will be 
their final visit.  During the safety follow-up period, participants will not receive study 
intervention.  Participants may be treated with another glucose-lowering intervention decided 
upon by the investigator (except for prohibited antihyperglycemic medications, see 
section  6.9.1).  If any new antihyperglycemic medication is initiated during the safety follow-up 
period, it will not be classified as rescue therapy.   
Participants are also required to return any remaining study diaries to the study site at the end of 
this period.   
The participants who complete the treatment period (complete Visit 11 or Visit 99) and safety 
follow-up (Visit 801) are considered as complete the study.   
4.2. 
Scientific Rationale for Study Design  
Study GPIU is designed to assess the efficacy and safety of tirzepatide QW (5 mg, 10 mg, and 15 
mg) as monotherapy versus placebo QW in Chinese patients with T2DM.  
Placebo was chosen as the comparator to meet the authority requirement to compare the study 
intervention versus a placebo in pivotal study.  The planned treatment duration of 40 weeks is 
considered appropriate to assess the full effects and benefit/risk of each maintenance dose of 
tirzepatide on both glycemic control and body weight based on the experience of the 
international multicenter Phase 3 Study SURPASS-1 (GPGK). 
The parallel-group design for treatment comparison was chosen to avoid any interaction between 
treatments that may interfere with the interpretation of the trial outcome.  To minimize the 
potential confounding effect of changes to concomitant medications, participants will be 
permitted to use concomitant medications that they require during the study.  Medications that 
may interfere with the assessment of efficacy and safety characteristics of the study treatments 
will not be allowed (see Section 6.9). 
4.3. 
Justification for Dose  
Tirzepatide doses of 5 mg, 10 mg, and 15 mg administered subcutaneously QW will be evaluated 
in this study.  
Based on the findings in completed Phase 3 studies in participants with T2DM (SURPASS 
clinical program, including GPGK, GPGL, GPGH, GPGM, GPGI, and GPHO [the first 
registration trial of tirzepatide that enrolled a majority of Chinese participants with T2DM]) 
(Del Prato et al. 2021; Frías et al. 2021; Ludvik et al. 2021; Rosenstock et al. 2021; 
Dahl et al. 2022), tirzepatide 5 mg, 10 mg, and 15 mg 
 Demonstrated superior efficacy for glycemic control and body weight reduction as well 
as an improvement in different factors associated with an increased risk of longer-term 
cardiometabolic complications in participants with T2DM.   
 Similar to the GLP-1 receptor agonist class, most of the tirzepatide AEs were 
gastrointestinal related, consisting mainly of nausea, vomiting, and diarrhea. In general, 
these events were mild or moderate in severity, and transient. 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
27 
The starting dose of tirzepatide is 2.5 mg QW, which is to be escalated at 4-week intervals at 
2.5 mg increments (2.5 to 5 to 7.5 to 10 to 12.5 to 15 mg) until the participant reaches 5, 10 or 
15 mg.  Such approach should permit the development of tolerance to gastrointestinal events and 
is expected to minimize gastrointestinal AEs consistent with the completed Phase 3 studies in the 
SURPASS-program. 
4.4. 
End of Study Definition  
End of the study is defined as the date of the last visit or last scheduled procedure shown in the 
SoA (Section 1.3) for the last participant. 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
28 
5. 
Study Population  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria  
Participants are eligible to be included in the study only if all of the following criteria apply: 
Type of Participant and Disease Characteristics 
[1] Have been diagnosed with T2DM based on the World Health Organization 
classification (Section 10.6), and have not used any antihyperglycemic medication 
during the 90 days preceding Visit 1 
Note: An exception is for the use of insulin for short-term use (≤14 days) for 
certain clinical situations such as acute illness, hospitalization, or elective surgery. 
Participant Characteristics 
[2] Have HbA1c ≥7.0% (≥53 mmol/mol) to ≤9.5% (≤80 mmol/mol) despite diet and 
exercise treatment, as determined by the central laboratory at Visit 1 (Note:  
HbA1c value as determined by the central lab at Visit 1)  
[3] Are of stable weight (±5%) during the 90 days preceding Visit 1 and agree to not 
initiate a diet and/or exercise program during the study with the intent of reducing 
body weight other than the lifestyle and dietary measures for diabetes treatment 
[4] Have BMI ≥23.0 kg/m2 at Visit 1  
[5] Are ≥18 years old 
Males and females may participate in this trial. 
Female participants must not be pregnant, intending to be pregnant, breastfeeding, 
or intending to breastfeed. 
Contraceptive use by participants should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies. 
For the contraception requirements of this protocol, see section 10.4 Appendix 4.  
[6] In the investigator’s opinion, are well motivated, capable, and willing to 
(a) 
perform finger-stick BG monitoring, including scheduled BG profiles with up to 7 
measurements in 1 day  
(b) 
learn how to self-inject study interventions, as required for this protocol (visually 
impaired persons who are not able to perform the injections must have the 
assistance of a sighted individual trained to inject the study intervention; persons 
with physical limitations who are not able to perform the injections must have the 
assistance of an individual trained to inject the study intervention)  
(c) 
are willing and able to inject study interventions 
(d) 
maintain study diaries, as required for this protocol 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
29 
(e) 
have a sufficient understanding of the provided language that they will be able to 
complete the participant questionnaires 
Informed Consent 
[7] Capable of giving signed informed consent as described in section 10.1 
Appendix 1, which includes compliance with the requirements and restrictions 
listed in the ICF and in this protocol. 
5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
[8] 
Have T1DM 
[9] 
Have a history of chronic or acute pancreatitis any time prior to study entry 
(Visit 1) 
[10] Are currently requiring or receiving treatment for diabetic retinopathy and/or 
macular edema (e.g., laser photocoagulation or intravitreal injections of anti–
vascular endothelial growth factor inhibitors).  Must be verified by dilated 
fundoscopic examination performed by an ophthalmologist or optometrist if 
applicable within 90 days prior to Visit 1 or between Visit 2 and Visit 3. 
Note: For participants with a contraindication to pharmacological pupil dilation 
(for example, closed angle glaucoma), a non-dilated fundoscopic examination 
performed by an ophthalmologist or optometrist is allowed.  
[11] Have a history of ketoacidosis or hyperosmolar state/coma 
[12] Have a known clinically significant gastric emptying abnormality (for example, 
severe diabetic gastroparesis or gastric outlet obstruction), have undergone or 
plan to have during the course of the study: gastric bypass (bariatric) surgery or 
restrictive bariatric surgery (for example, Lap-Band®), or chronically take drugs 
that directly affect gastrointestinal motility 
[13] Have any of the following cardiovascular conditions within 60 days prior to Visit 
1: acute myocardial infarction, cerebrovascular accident (stroke), or 
hospitalization due to congestive heart failure (CHF) 
[14] Have a history of New York Heart Association Functional Classification IV CHF 
[15] Have acute or chronic hepatitis including a history of autoimmune hepatitis, 
signs and symptoms of any other liver disease other than nonalcoholic fatty liver 
disease, or any of the following, as determined by the central laboratory at 
Visit 1:  
 Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level 
≥3.0 times the upper limit of normal (ULN) for the reference range   
 Alkaline phosphatase (ALP) level ≥1.5× ULN for the reference range, or 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
30 
 Total bilirubin (TBL) level ≥1.5× ULN for the reference range (except for 
cases of known Gilbert’s Syndrome) 
 
Hepatitis B infection, defined as: 
o Positive hepatitis B core antibody and positive for hepatitis B virus DNA or  
o Positive hepatitis B surface antigen 
 Positive hepatitis C antibody and positive hepatitis C virus RNA  
Note: Participants with nonalcoholic fatty liver disease are eligible to participate 
in this trial if their ALT level is <3.0× ULN for the reference range 
[16] Have an estimated glomerular filtration rate <30 mL/min/1.73 m2, calculated by 
Chronic Kidney Disease-Epidemiology as determined by central laboratory at 
Visit 1 
[17] Have evidence of a significant, uncontrolled endocrine abnormality (for 
example, thyrotoxicosis or adrenal crises), in the opinion of the investigator 
[18] Have family or personal history of medullary thyroid carcinoma (MTC) or 
multiple endocrine neoplasia syndrome type 2 (MEN2) 
[19] Have a serum calcitonin level of ≥35 ng/L, as determined by central laboratory at 
Visit 1 
[20] Known or suspected hypersensitivity to trial product(s) or related products 
[21] Have evidence of a significant, active autoimmune abnormality (for example, 
lupus or rheumatoid arthritis) that, in the opinion of the investigator, is likely to 
require concurrent treatment with systemic glucocorticoids in the next 12 months 
[22] Have had a transplanted organ (corneal transplants [keratoplasty] allowed) or 
awaiting an organ transplant 
[23] Have a history of an active or untreated malignancy or are in remission from a 
clinically significant malignancy for less than 5 years. Exceptions for this 
criterion are: 
 
basal or squamous cell skin cancer 
 
in situ carcinomas of the cervix, and 
 
in situ or grade 1 (for example, Gleason 6 or lower) prostate cancer 
[24] Have a history of any other condition (such as known drug, alcohol abuse, or 
psychiatric disorder) that, in the opinion of the investigator, may preclude the 
participant from following and completing the protocol 
[25] Have any hematological condition that may interfere with HbA1c measurement 
(for example, hemolytic anemias, sickle cell disease) 
Prior/Concomitant Therapy 
[26] Use of insulin 1 year preceding Visit 1 and between Visit 1 and Visit 3; use of 
any antihyperglycemic medication 90 days preceding Visit 1 and between Visit 1 
and Visit 3. 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
31 
Note: An exception is for the use of insulin for gestational diabetes or short-term 
use (≤14 days) for certain clinical situations such as acute illness, hospitalization, 
or elective surgery. 
[27] Have been treated with prescription drugs that promote weight loss (for example, 
Saxenda [liraglutide 3.0 mg], Wegovy [semaglutide 2.4mg], Xenical® [orlistat], 
Meridia® [sibutramine], Acutrim® [phenylpropanolamine], Sanorex® [mazindol], 
Adipex® [phentermine], BELVIQ® [lorcaserin], Qsymia™ 
[phentermine/topiramate combination], Contrave® [naltrexone/bupropion], or 
similar other body weight loss medications including OTC medications [for 
example, allī®]) within 90 days prior to Visit 1 and/or between study entry (Visit 
1) and randomization (Visit 3)  
[28] Are receiving chronic (>2 weeks or 14 days) systemic glucocorticoid therapy 
(excluding topical, intraocular, intranasal, or inhaled preparations) or have 
received such therapy within 30 days of Visit 1 or between Visits 1 and Visit 3 
Prior/Concurrent Clinical Study Experience 
[29] Are currently enrolled in any other clinical study involving an investigational 
product or any other type of medical research judged not to be scientifically or 
medically compatible with this study 
[30] Have participated, within the last 30 days in a clinical study involving an 
investigational product.  If the previous investigational product has 5 half-lives 
or 30 days (whichever is longer), should have passed prior to screening 
[31] Were previously enrolled and assigned to study intervention in this study, 
received tirzepatide in any other study investigating tirzepatide, or are 
currently taking or have used tirzepatide for any other reason outside of a clinical 
study 
Other Exclusions 
[32] Are investigator site personnel directly affiliated with this study and/or their 
immediate families.  Immediate family is defined as a spouse, parent, child, or 
sibling, whether biological or legally adopted 
[33] Are Lilly employees  
[34] Are unwilling or unable to comply with the use of a paper diary to directly 
record data from the participant. 
5.3. 
Lifestyle Considerations  
Per the SoA (Section 1.3), qualified medical staff will provide diabetes management counseling, 
which will include instructions on diet and exercise and education about the signs, symptoms, 
and treatment of hypoglycemia, should it occur.   
Participants should continue their usual exercise habits and generally follow a healthy meal plan 
(with consistent meal size and time of day) throughout the course of the study.  Dietary 
counseling may be reviewed throughout the study, as needed.  Per Inclusion Criterion [3] 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
32 
(Section 5.1), participants should not initiate an organized diet and/or exercise (weight reduction) 
program during the study other than the lifestyle and dietary measures for diabetes treatment. 
Study participants should be instructed not to donate blood or blood products during the study. 
5.4. 
Screen Failures  
A screen failure occurs when a participant who consents to participate in the clinical study is not 
subsequently assigned to study intervention.  A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries 
from regulatory authorities.  Minimal information includes demography, screen failure details, 
eligibility criteria, and any SAE.   
Individuals who do not meet the criteria for participation in this study (screen failure) must not 
be rescreened. 
5.5. 
Criteria for Temporarily Delaying 
Enrollment/Randomization/Administration of Study Intervention of 
a Participant  
Not applicable. 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
33 
6. 
Study Intervention(s) and Concomitant Therapy  
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to/used by a study participant 
according to the study protocol.   
6.1. 
Study Intervention(s) Administered  
Assignment to study intervention (tirzepatide 3 doses or placebo) will occur at randomization.  
Beginning at randomization, all participants will receive study intervention according to the 
randomized treatment group for the duration of the 
 treatment period.  Following 
randomization, the participant will inject the first dose of study intervention at the study site.  
The date and time of study intervention should be recorded on the paper diary and transcribed to 
the CRF.   
6.1.1. 
Study intervention  
This table lists the interventions used in this clinical study.   
Intervention Name 
Tirzepatide 5 mg 
Tirzepatide 10 mg 
Tirzepatide 15 mg 
Placebo 
Dosage Level(s) 
2.5 mg QW 
5 mg QW 
2.5 mg QW 
5 mg QW 
7.5 mg 
10 mg QW 
2.5 mg QW 
5 mg QW 
7.5 mg 
10 mg QW 
12.5 mg QW 
15 mg QW 
NA  
Route of 
Administration 
SC 
Use 
Investigational compound 
Comparator 
Drug formulation 
SDP 
Abbreviations:  NA=not applicable; QW=once weekly; SDP= single-dose pen; SC=subcutaneous. 
Tirzepatide dosing 
The starting dose of tirzepatide will be 2.5 mg QW for 4 weeks, followed by an increase to 5 mg 
QW, for the duration of the study for the 5-mg group.   
For the 10-mg group, the starting dose of tirzepatide will be 2.5 mg QW for 4 weeks, then the 
dose will be increased by 2.5 mg every 4 weeks (2.5 mg to 5 mg to 7.5 mg to 10 mg) until the 
10-mg dose is reached and maintained for the duration of the study.   
For the 15-mg group, the starting dose of tirzepatide will be 2.5 mg QW for 4 weeks, then the 
dose will be increased by 2.5 mg every 4 weeks (2.5 mg to 5 mg to 7.5 mg to 10 mg to 12.5 mg 
to 15 mg) until the 15-mg dose is reached and maintained for the duration of the study.   
Placebo dosing 
Participants randomized to the placebo group will inject matched placebo QW for the entire 
treatment period. 
 
 
Approved on 05 Dec 2023 GMT
CCI

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
34 
Timing of doses of study intervention 
There are no restrictions on the time of day each weekly dose of study intervention is given, but 
it is advisable to administer the subcutaneous injections on the same day and same time each 
week, with or without meals.  The actual date and time of all dose administrations will be 
recorded by the participant.  If a dose of study intervention is missed, the participant should take 
it as soon as possible unless it is within 72 hours of the next dose, in which case, that dose should 
be skipped and the next dose should be taken at the appropriate time.  The day of weekly 
administration can be changed if necessary, as long as the last dose was administered 72 or more 
hours before.   
All participants will inject study intervention subcutaneously in the abdomen or thigh using the 
injection supplies provided; a caregiver may administer the injection in the participant’s upper 
arm.  A new SDP will be used for each injection.  If study intervention is to always be injected in 
the same body region, participants should be advised to use a different injection site each week.   
Study intervention returning 
Participants should return all study interventions to the site according to the SoA (Section 1.3).  
Participants should be instructed to discard all used SDPs in a closeable, puncture-resistant 
container according to local regulations. 
Returned study intervention should not be re-dispensed to the participants.   
Packaging and labeling 
Study interventions will be supplied by the sponsor in accordance with current Good 
Manufacturing Practice.  Study interventions will be labeled as appropriate for country 
requirements. 
The sponsor will provide tirzepatide and placebo in SDP which will be packaged in cartons to be 
dispensed.  Clinical study materials will be labeled according to the country’s regulatory 
requirements. 
6.1.2. 
Medical Devices  
The combination products used in the study are tirzepatide investigational SDP and placebo 
SDP. 
6.2. 
Preparation, Handling, Storage, and Accountability  
 The investigator or designee must confirm appropriate storage conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
 Only participants enrolled in the study may receive study intervention.  Only authorized 
study personnel may supply, prepare, or administer study intervention.  
 All study 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. 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
35 
 The investigator or authorized study personnel are responsible for study intervention 
accountability, reconciliation, and record maintenance (that is, receipt, reconciliation, and 
final disposition records). 
 Further guidance and information for the final disposition of unused study interventions 
are provided in the Study Reference Manual. 
6.3. 
Assignment to Study Intervention  
Participants who meet all criteria for enrollment will be randomized to 1 of the study treatment 
groups at Visit 3.  Assignment to treatment groups will be determined by a computer generated 
random sequence using an Interactive Web Response System (IWRS).  Participants will be 
randomized in a 
 ratio to receive tirzepatide 5 mg, 10 mg, 15 mg, or placebo.   
6.4. 
Blinding  
This study is designed as a randomized, double-blind study to minimized bias.  Assignment to 
treatment groups will be determined by a computer-generated random sequence using the IWRS.  
Investigators, site staff, clinical monitors, and participants will remain blinded to the treatment 
assignments until the study is complete.   
Emergency unblinding for AEs may be performed through the IWRS, which may supplement or 
take the place of emergency codes generated by a computer drug-labeling system.  This option 
may be used ONLY if the participant’s well-being requires knowledge of the participant’s 
treatment assignment.  All actions resulting in an unblinding event are recorded and reported by 
the IWRS. 
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.  The 
participant’s safety must always be the first consideration in making such a determination.  If a 
participant’s treatment assignment is unblinded, Lilly must be notified immediately.  If the 
investigator decides that unblinding is warranted, it is the responsibility of the investigator to 
promptly document the decision and rationale and notify Lilly as soon as possible.   
If an investigator, site personnel performing assessments, or participant is unblinded, the 
participant must be discontinued from the study.  In cases where there are ethical reasons to have 
the participant remain in the study, the investigator must obtain specific approval from a sponsor 
clinical research physician (CRP) for the participant to continue in the study.   
6.5. 
Study Intervention Compliance  
Study intervention compliance will be determined by the following:  
 Study intervention administration data will be recorded by the participant and reviewed 
by the investigator at each study visit. 
 The participants will be instructed to return any unused study intervention and/or empty 
cartons at the next visit to the study site for the purpose of performing drug 
accountability. 
In the 3 tirzepatide treatment groups, as well as the placebo group, treatment compliance for each 
visit interval is defined as taking at least 
 of the required doses of study intervention.  
Approved on 05 Dec 2023 GMT
CCI
CCI

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
36 
Similarly, a participant will be considered significantly noncompliant if he or she is judged by 
the investigator to have intentionally or repeatedly taken more than the prescribed amount of 
medication.   
In addition to the assessment of a participant’s compliance with the study intervention 
administration, other aspects of compliance with the study treatments will be assessed at each 
visit based on the participant’s adherence to the visit schedule, completion of study diaries, the 
results of home BG monitoring, and any other parameters the investigator considers necessary.   
Participants considered to be poorly compliant with their medication and/or the study procedures 
will receive additional training and instruction, as required, and will be reminded of the 
importance of complying with the protocol.   
6.6. 
Dose Modification  
6.6.1. 
Tirzepatide  
Please refer to Section 6.1.1 for tirzepatide administration.  Study intervention dose modification 
is not permitted except for management of intolerable gastrointestinal symptoms. 
Management of Participants with Gastrointestinal Symptoms  
In participants who experience intolerable gastrointestinal symptoms (for example, nausea, 
vomiting, or diarrhea) at any time during the study, the following measures are recommended: 
1. counseling on dietary behaviors that may help mitigate nausea and vomiting, (for 
example, eating smaller meals, splitting 3 daily meals into 4 or more smaller ones, and 
stopping eating when they feel full). 
2. if symptoms persist despite #1, prescribing symptomatic medication (for example, 
antiemetic or antidiarrheal medication), at the investigator’s discretion. 
3. if symptoms persist despite #1 and #2, temporarily interrupting study intervention (omit 1 
dose, the participant will take 3 of 4 doses at that dose level).  Study intervention should 
be resumed at the assigned dose immediately, either alone or in combination with 
symptomatic medication, which can also be utilized to manage symptoms.   
If intolerable gastrointestinal symptoms (for example, nausea, vomiting, or diarrhea) persist 
despite the above measures before or at Visit 5 (the scheduled visit in Week 8), the participant 
should discontinue the study intervention. 
If intolerable gastrointestinal symptoms (for example, nausea, vomiting, or diarrhea) persist 
despite the above measures after Visit 5 (the scheduled visit in Week 8) the investigator should 
contact Lilly to consider continuing treatment at a lower maintenance dose of study intervention 
in a blinded fashion, for example:  
 
Participants at 5 mg will decrease the dose to placebo.  
 
Participants at 7.5 mg or 10 mg will decrease the dose to 5 mg.  
 
Participants at 12.5 mg or 15 mg will decrease the dose to 10mg.  
If de-escalation of the tirzepatide dose is necessary, the investigator will use the IWRS to receive 
the appropriate tirzepatide dispensing information.  If de-escalation is needed between scheduled 
visits, the IWRS will have unscheduled visits dedicated to providing dispensing information for 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
37 
participants whose dose has been de-escalated.  Those participants who have their dose de-
escalated, will not be escalated again.  The dose can be de-escalated only once and should before 
Week 24 (after Week 24, dose decreases will not be allowed).  After that, the participants will 
have to discontinue study intervention if intolerable gastrointestinal AE persists and stay in the 
study.  
6.7. 
Continued Access to Study Intervention after the End of the Study  
Study completion will occur after all participants complete the follow up visit.  Investigators will 
continue to follow SoA (Section 1.3) for all participants until notified by Lilly that study 
completion has occurred.  
Tirzepatide will not be made available after conclusion of the study to participants. 
6.8. 
Treatment of Overdose  
Overdose was defined as administration of more than a total of 15 mg of tirzepatide in less than a 
72-hour period (Note: to preserve blinding of the study intervention, administration of study 
intervention more than 1 injection in less than 72 hours will be reported as an AE for further 
evaluation). 
In the event of overdose, the investigator should: 
 Contact the medical monitor immediately. 
 Evaluate the participant to determine, in consultation with the medical monitor, whether 
study intervention should be interrupted, and reinitiate when the investigator believes it 
is safe to do so (see section 7.1.2 for reinitiation based on number of doses missed). 
 Closely monitor the participant for any AE/SAE and laboratory abnormalities as 
medically appropriate until, for example, study intervention no longer has a clinical effect 
or can no longer be detected systemically (at least 30 days).  
 Appropriate supportive treatment should be initiated according to the participant’s 
clinical signs and symptoms. 
6.9. 
Concomitant Therapy  
Participants will be permitted to use concomitant medications that they require during the study, 
except certain medications that may interfere with the assessment of efficacy and safety 
characteristics of the study treatments, such as GLP-1 receptor agonists, dipeptidyl peptidase-4 
inhibitors, pramlintide, drugs with approved weight loss indication and systemic glucocorticoid 
therapy >14 days.   
Investigative site staff will inform participants that they must consult with the investigator or a 
designated site staff member upon being prescribed any new medications during the study.  This 
may not be possible when initiated for treatment of medical emergencies, in which case, the 
participant will inform the investigator or a designated site staff member as soon as possible.   
Any nonstudy medications that the participant is receiving at the time of enrollment or receives 
during the study must be recorded on the CRF along with: 
 Reason for use 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
38 
 Dates of administration including start and end dates 
 Dosage information including dose and frequency for concomitant therapy of special 
interest. 
Nonstudy medications taken by participants who are screened but not randomized will not be 
reported to Lilly unless an SAE or AE occurs that the investigator believes may have been 
caused by a study procedure.   
6.9.1. 
Initiation of New Antihyperglycemic Medication  
The introduction of new antihyperglycemic medication is expected during the study only in the 
following situations: 
 As an antihyperglycemic intervention for severe, persistent hyperglycemia (“rescue 
therapy”), as defined in Section 6.9.1.1 
 In those participants who require permanent discontinuation of study intervention, but 
remain in the study (Section 7.1) 
 During the safety follow-up period (between Visit 11 [Week 40] or ET and Visit 801). 
 Short-term insulin use for up to 14 days is allowed for certain clinical situations (for 
example, acute illness, hospitalization, or elective surgery).  This insulin use must be 
differentiated from insulin use as rescue therapy when reported in the CRF. 
The choice of new antihyperglycemic medication will be at the discretion of the investigator and 
follow clinical guidelines.  Glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 
inhibitors, and pramlintide are not allowed at any time during the study.   
6.9.1.1. 
Rescue Therapy  
If a participant develops severe, persistent hyperglycemia after randomization, a new 
antihyperglycemic medication (“rescue therapy”) may be medically indicated after investigator 
assessment. 
Investigators will be trained on the application of criteria for deciding when and how to intervene 
with participants who do not reach glycemic targets.  If met the following prespecified severe, 
persistent hyperglycemia criteria and no intercurrent cause of the hyperglycemia could be 
identified (investigators should first confirm that the participant is fully compliant with the 
assigned therapeutic regimen and that he or she does not have an acute condition causing severe 
hyperglycemia), rescue medication will be prescribed as an add-on to randomized treatment.  
Participants will continue in the trial until they complete all study visits. 
Severe, Persistent Hyperglycemia  
 If any of the FBG values within 1 week for 2 consecutive weeks, 
o >270 mg/dL (>15.0 mmol/L) from baseline to end of Week 5, or  
o >240 mg/dL (>13.3 mmol/L) from Week 6 to end of Week 11, or  
o >200 mg/dL (>11.1 mmol/L) from Week 12 to end of trial, or 
o HbA1c ≥8.5% (≥69 mmol/mol) by and after Week 24 
The date and time of rescue medication administration as well as the name and dosage regimen 
of the rescue medication must be recorded. 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
39 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal  
Discontinuation of specific sites or of the study as a whole are handled as part of Section 10.1 
Appendix 1.   
7.1. 
Discontinuation of Study Intervention  
When necessary, a participant may be permanently discontinued from study intervention.  If so, 
the participant will discontinue the study intervention, could receive another glucose-lowering 
intervention and will remain in the study and follow procedures for all remaining study visits, as 
shown in the SoA.  The new glucose-lowering intervention will be recorded on the CRF 
specified for collecting antihyperglycemic medications.   
A participant should be permanently discontinued from study intervention if 
 the participant becomes pregnant during the study (will also be withdrawn from the 
study) 
 the participant is diagnosed with T1DM (will also be withdrawn from the study) 
 the participant discontinues due to a hepatic event or liver test abnormality (see section 
7.1.1) 
 the participant requests to discontinue study intervention. 
 the participant is diagnosed with an acute or chronic pancreatitis  
 the participant is diagnosed with MTC after randomization, or has post randomization 
calcitonin value ≥35 ng/L that has increased at least 50% over baseline 
 the participant is diagnosed with an active or untreated malignancy (other than basal or 
squamous cell skin cancer, in situ carcinomas of the cervix, or in situ prostate cancer) 
after randomization 
 the participant has any significant study intervention related hypersensitivity reaction 
 the participant has any other TEAE, SAE, or clinically significant laboratory value for 
which the investigator believes that permanent study intervention discontinuation is the 
appropriate measure to be taken.  
7.1.1. 
Liver Chemistry Stopping Criteria  
Discontinuation due to a hepatic event or liver test abnormality 
Participants who are discontinued from study intervention due to a hepatic event or liver test 
abnormality should have additional hepatic safety data collected via CRF.   
The study intervention should be interrupted and close hepatic monitoring initiated 
(Section 10.5) if one or more of these conditions occur: 
Elevation 
Exception 
ALT or AST >8× ULN 
 
ALT or AST >5× ULN for more than 2 weeks 
 
ALT or AST >3× ULN and either TBL >2× ULN or 
INR >1.5  
For participants with Gilbert’s syndrome:  
If baseline direct bilirubin is >0.5 mg/dL, then 
doubling of direct bilirubin should be used for 
drug interruption decisions rather than TBL >2× 
ULN. 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
40 
ALT or AST >3× ULN with the appearance of fatigue, 
nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (>5%) 
 
ALP >3× ULN, when the source of increased ALP is the 
liver 
 
ALP >2.5× ULN and TBL >2× ULN  
For participants with Gilbert’s syndrome:  
If baseline direct bilirubin is >0.5 mg/dL then 
doubling of direct bilirubin should be used for 
drug interruption decisions rather than TBL >2× 
ULN. 
ALP >2.5× ULN with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, 
rash, and/or eosinophilia (>5%) 
 
Source: FDA Guidance for Industry: Drug-Induced Liver Injury: Premarketing Clinical Evaluation, July 2009 
and other consensus guidelines, with minor modifications 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; ALP = alkaline phosphatase; 
INR = international normalized ratio; TBL = total bilirubin; ULN = upper limit of normal. 
Resuming study intervention after elevated liver tests 
Resumption of the study intervention can be considered only in consultation with the 
Lilly-designated medical monitor and only if the liver test results return to baseline and if a 
self-limited non-drug etiology is identified.  Otherwise, the study intervention should be 
discontinued. 
7.1.2. 
Temporary Discontinuation  
In certain situations after randomization, the investigator may need to temporarily interrupt study 
intervention.  Every effort should be made by the investigator to maintain participants on study 
intervention and to restart after any temporary interruption, as soon as it is safe to do so.  The 
investigator will use the IWRS to receive the appropriate study intervention dispensing 
information to preserve blinding of the study intervention.   
This table shows how to manage treatment if there are missed study intervention.   
If the number of missed 
consecutive doses is... 
Then... 
2 or less 
the study treatment can be restarted at the assigned dose, if it was well-tolerated 
prior to interruption. 
3 or more 
the IWRS will dispense 5 mg tirzepatide/matched placebo irrespective of the 
dose the participant was receiving before the interruption and subsequently 
escalate as required by the protocol.  
Abbreviations: IWRS = interactive web response service. 
If the study intervention interruption is due to AE, the event is to be documented and followed 
according to the procedures in Section 8.3 of this protocol.   
If the study intervention interruption is due to intolerable persistent gastrointestinal AE, such as 
nausea, vomiting, or diarrhea, the participant should be treated as suggested in Section 6.6.1.   
The dates of study intervention interruption and restart must be documented in source documents 
and entered on the CRF.   
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
41 
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 for any reason or without providing any 
reason 
 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 investigational product, or enrolled in 
any other type of medical research judged not to be scientifically or medically compatible 
with this study 
 if the participant, for any reason, requires treatment with a therapeutic agent that is 
prohibited by the protocol and has been demonstrated to be effective for treatment of the 
study indication.  In this case, discontinuation from the study occurs prior to introduction 
of the new agent. 
A participant will be withdrawn from the study: 
 if a female participant becomes pregnant 
 if a participant is diagnosed with T1DM 
 if inadvertently enrolled (Section 7.2.1). 
At the time of discontinuing from the study, if possible, the participant will complete procedures 
for an early discontinuation visit (ET visit) and safety follow-up 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. 
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. 
7.2.1. 
Discontinuation of Inadvertently Enrolled Participants  
If the sponsor or investigator identify a participant who did not meet enrollment criteria and was 
inadvertently enrolled, then the participant must be discontinued from the study unless 
exceptional circumstances that provide sufficient evidence that discontinuation of the study 
participant from the trial is not medically justified.  If discontinuation of the study participant 
from the trial is not medically justified, approval must be obtained from the Sponsor Chief 
Medical Officer.  Safety follow up is as outlined in Section 1.3 (SoA), Section 8.3 (AEs), and 
Section 8.2 (Safety) of this protocol.   
7.3. 
Lost to Follow up  
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  Site personnel or designee are 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
42 
expected to make diligent attempts to contact participants who fail to return for a scheduled visit 
or were otherwise unable to be followed up by the site. 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
43 
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  
Primary efficacy assessments  
The primary efficacy measurement in this study is change in HbA1c values from baseline to 
Week 40, as determined by the central laboratory.  Blood samples for HbA1c measurements will 
be collected at specific clinic visits as summarized in the SoA, Section 1.3.   
Other efficacy assessments 
Other efficacy assessments include change in HbA1c, FSG, body weight, 7-point SMBG, C-
peptide, insulin level, waist circumference, BMI, lipids, urinary albumin to creatinine ratio, and 
patient-reported outcomes (PROs).   
8.1.1. 
Self-Monitoring of Blood Glucose (SMBG)  
Participants must use only the study-provided monitors during the study.  
Glucometer for participant use during the study 
Participants will receive a glucometer and related testing supplies for use during the study.  
Glucometer training 
Site personnel will train the participant on correct use of the glucometer for SMBG and reporting 
of hypoglycemia data.  
When to measure FBG during the study 
Participants will be asked to monitor FBG 4 times a week. The FBG should be measured upon 
waking in the morning, prior to food or caloric beverage intake.  
The 7-point SMBG values should be measured before each meal; 2 hours after breakfast, lunch, 
and dinner; and at bedtime according to SoA (Section 1.3). 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
44 
8.1.2. 
Patient-Reported Outcomes  
8.1.2.1. 
European Quality of Life-Dimensions  
Generic health-related quality of life will be assessed using the EQ-5D-5L 
(EuroQol Research Foundation 2019).  The EQ-5D-5L is a standardized 5-item instrument for 
use as a measure of health outcome.  It provides a simple descriptive profile and a single index 
value for health status that can be used in the clinical and economic evaluation of health care as 
well as population health surveys.  The EQ-5D-5L comprises 5 dimensions of health (mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression).  The 5L version, introduced 
in 2005, scores each dimension at 5 levels (no problems, slight problems, moderate problems, 
severe problems, unable to perform/extreme problems), for a total of 3125 possible health states.  
In addition to the health profile, a single health state index value can be derived based on a 
formula that attaches weights to each of the levels in each dimension.  This index value ranges 
between less than 0 (where 0 is a health state equivalent to death; negative values are valued as 
worse than dead) to 1 (perfect health).  In addition, the EQ Visual Analog Scale records the 
respondent’s self-rated health status on a vertical graduated (0 to 100) visual analog scale.  In 
conjunction with the health state data, it provides a composite picture of the respondent’s health 
status.   
The EQ-5D-5L is used worldwide and is available in more than 130 different languages.  Details 
on the instrument, and scoring, organizing, and presenting the data collected can be found in the 
EQ-5D-5L User Guide (EuroQol Research Foundation 2019). 
8.1.2.2. 
Impact of Weight on Quality of Life-Clinical Trials Version (IWQOL-Lite-CT)  
The IWQOL-Lite-CT is a 20-item PRO instrument developed in accordance with 
FDA’s guidance on PROs to assess the impact of weight on quality of life in clinical trials 
(Kolotkin et al. 2019).  The IWQOL-Lite-CT includes 2 primary domains: physical (7 items) and 
psychosocial (13 items), and a 5-item subset of the physical domain – the physical function 
composite.  Items in the physical function composite describe physical impacts related to general 
and specific physical activities.  All items are rated on either a 5-point frequency (“never” to 
“always”) scale or a 5-point truth (“not at all true” to “completely true”) scale 
(Kolotkin et al. 2017; Kolotkin et al. 2018).  The IWQOL-Lite-CT yields a total score and three 
composite scores for the Physical domain, Physical Function, and Psychosocial domain.  Higher 
scores indicate higher levels of functioning.   
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, assessments of the skin, 
cardiovascular system, respiratory system, gastrointestinal system, neurological system, thyroid 
examination, and foot examination, including evaluation for diabetic neuropathy.  Height, 
weight, and waist circumference will also be measured and recorded (Section 10.7).   
The examination excludes pelvic, rectal, and breast examinations, unless clinically indicated. 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
45 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
8.2.2. 
Vital Signs  
For each participant, vital signs measurements should be conducted according to the SoA 
(Section 1.3) and following the study-specific recommendations.   
Vital sign measurements should be taken before obtaining an ECG tracing and before collection 
of blood samples for laboratory testing, at visits where required.  The participant should sit 
quietly for 5 minutes before vital sign measurements are taken.  For each parameter, 2 
measurements will be taken using the same arm; the recordings should be taken at least 1 minute 
apart.  Blood pressure must be taken with an automated blood pressure machine. 
Any clinically significant findings from vital sign measurements that result in a diagnosis and 
that occur after the participant receives the first dose of study treatment should be reported to 
Lilly or its designee as an AE via CRF.   
8.2.3. 
Electrocardiograms  
For each participant, 12-lead ECGs should be collected locally according to the SoA 
(Section 1.3).  Electrocardiograms should be performed after vital signs are collected and prior to 
the collection of blood samples for laboratory testing if the participant is not adversely affected 
by the fasting condition.  Participant should be supine for approximately 5 to 10 minutes before 
ECG collection and remain supine, but awake, during ECG collection.  Electrocardiograms 
should be recorded according to the study-specific recommendations.   
Electrocardiograms must be interpreted by the investigator or qualified designee at the site as 
soon after the time of ECG collection as possible, and ideally while the participant is still 
present, for immediate participant management, if needed.  Any clinically significant findings 
from ECGs that result in a diagnosis and that occur after the participant receives the first dose of 
the investigational treatment should be reported to Lilly or its designee as an AE via the CRF. 
The original ECG must be retained at the investigative site. The investigator or qualified 
designee’s interpretation will prevail for immediate participant management purposes.   
8.2.4. 
Dilated Fundoscopic Examination  
A dilated fundoscopic examination will be performed by an ophthalmologist or optometrist for 
all participants between Visit 2 and Visit 3 to confirm eligibility. A previous examination ≤90 
days meeting study requirements from Visit 1 is acceptable to confirm eligibility.  Additional 
dilated fundoscopic examinations should be performed when clinically indicated by any AE 
suspected of worsening retinopathy.   
8.2.5. 
Clinical Safety Laboratory Tests  
 See Section 10.2 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 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
46 
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 or within 30 days after the last dose of study intervention should 
be repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the investigator or medical monitor.   
o If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.   
o All protocol-required laboratory assessments, as defined in Section 10.2 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 or dose 
modification), then report the information as an AE.   
 Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples.   
 With the exception of laboratory test results that may unblind the study, Lilly or its 
designee will provide the investigator with the results of laboratory tests analyzed by a 
central vendor if a central vendor is used for the clinical trial.   
 Any clinically significant findings from laboratory tests that result in a diagnosis and that 
occur after the participant receives the first dose of investigational product should be 
reported to Lilly or its designee as an AE via CRF.   
8.2.6. 
Pregnancy Testing   
Serum pregnancy test will be performed by central laboratory at Visit 1 for women of 
childbearing potential.  A local urine pregnancy test must be performed at Visit 3 with the result 
available prior to randomization and first injection of study intervention for women of 
childbearing potential only.  Additional pregnancy tests will be performed at Visits 6, 9, and 11.  
Pregnancy tests may be performed at the investigator’s discretion during the study.  If required 
per local regulations and/or institutional guidelines, pregnancy testing can also occur at other 
times during the study treatment period.  For sites who can’t perform urine pregnancy test, a 
local serum pregnancy test can be performed instead.   
8.2.7. 
Safety Monitoring  
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods.  The study team will review safety reports in a blinded fashion according to the 
schedule provided in the Trial-Level Safety Review plan.  Lilly will also review SAEs within 
time frames mandated by company procedures.  The Lilly CRP will, as appropriate, consult with 
the functionally independent Global Patient Safety therapeutic area physician or clinical scientist. 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
47 
8.2.7.1. 
Hepatic Safety Monitoring  
Close hepatic monitoring 
Initiating laboratory and clinical monitoring for abnormal liver laboratory test results 
Laboratory tests, including ALT, AST, ALP, TBL, direct bilirubin (D. Bil), gamma-
glutamyltransferase (GGT), and creatine kinase (CK), should be repeated within 48 to 72 hours 
to confirm the abnormality and to determine if it is increasing or decreasing, if one or more of 
these conditions occur: 
If a participant with baseline results of...  
develops the following elevations: 
ALT or AST <1.5× ULN 
ALT or AST ≥3× ULN 
ALP <1.5× ULN 
ALP ≥2× ULN 
TBL <1.5× ULN 
TBL ≥2× ULN (except for patients with Gilbert’s 
syndrome) 
ALT or AST ≥1.5× ULN 
ALT or AST ≥2× baseline 
ALP ≥1.5× ULN 
ALP ≥2× baseline 
TBL ≥1.5× ULN 
TBL ≥1.5× baseline (except for patients with Gilbert’s 
syndrome) 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin; ULN = upper limit of normal. 
What to do if the abnormal condition persists or worsens 
If the abnormality persists or worsens, clinical and laboratory monitoring, and evaluation for 
possible causes of abnormal liver tests should be initiated by the investigator in consultation with 
the Lilly-designated medical monitor.  At a minimum, this evaluation should include physical 
examination and a thorough medical history, including symptoms, recent illnesses (for example, 
heart failure, systemic infection, hypotension, or seizures), recent travel, history of concomitant 
medications (including OTC), herbal and dietary supplements, history of alcohol drinking and 
other substance abuse.  
Frequency of monitoring 
Initially, monitoring of symptoms and hepatic biochemical tests should be done at a frequency of 
1 to 3 times weekly, based on the participant’s clinical condition and hepatic biochemical tests.  
Subsequently, the frequency of monitoring may be lowered to once every 1 to 2 weeks, if the 
participant’s clinical condition and lab results stabilize.  
Monitoring of ALT, AST, ALP, and TBL should continue until levels normalize or return to 
approximate baseline levels. 
Comprehensive hepatic evaluation 
When to perform a comprehensive evaluation 
A comprehensive evaluation (Section 10.5 Appendix 5) should be performed to search for 
possible causes of liver injury if one or more of these conditions occur: 
 
 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
48 
If a participant with baseline results of...  
develops the following elevations: 
ALT or AST <1.5× ULN 
ALT or AST ≥3× ULN with hepatic signs/symptomsa, or  
ALT or AST ≥5× ULN 
ALP <1.5× ULN 
ALP ≥3× ULN 
TBL <1.5× ULN 
TBL ≥2× ULN (except for patients with Gilbert’s syndrome) 
ALT or AST ≥1.5× ULN 
ALT or AST ≥2× baseline with hepatic signs/symptomsa, or 
ALT or AST ≥3× baseline 
ALP ≥1.5× ULN 
ALP ≥2× baseline 
TBL ≥1.5× ULN 
TBL ≥2× baseline (except for patients with Gilbert’s 
syndrome)  
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin level; ULN = upper limit of normal. 
a Hepatic signs/symptoms are severe fatigue, nausea, vomiting, right upper quadrant abdominal pain, fever, rash, 
and/or eosinophilia >5%. 
What a comprehensive evaluation should include 
At a minimum, this evaluation should include physical examination and a thorough medical 
history, as outlined above, as well as tests for PT-INR; tests for viral hepatitis A, B, C, or E; tests 
for autoimmune hepatitis; and an abdominal imaging study (for example, ultrasound or 
computed tomography [CT] scan).  
Based on the patient’s history and initial results, further testing should be considered in 
consultation with the Lilly-designated medical monitor, including tests for hepatitis D virus, 
cytomegalovirus, Epstein-Barr virus, acetaminophen levels, acetaminophen protein adducts, 
urine toxicology screen, Wilson’s disease, blood alcohol levels, urinary ethyl glucuronide, and 
blood phosphatidylethanol.  Based on the circumstances and the investigator’s assessment of the 
participant’s clinical condition, the investigator should consider referring the participant for a 
hepatologist or gastroenterologist consultation, magnetic resonance cholangiopancreatography, 
endoscopic retrograde cholangiopancreatography, cardiac echocardiogram, or a liver biopsy.   
Additional hepatic data collection (hepatic safety CRF) in study participants who have 
abnormal liver tests during the study  
Additional hepatic safety data collection in hepatic safety CRF should be performed in study 
participants who meet 1 or more of the following 5 conditions: 
1. Elevation of serum ALT to ≥5× ULN on 2 or more consecutive blood tests (if baseline 
ALT <1.5× ULN) 
➢ In participants with baseline ALT ≥1.5× ULN, the threshold is ALT ≥3× baseline 
on 2 or more consecutive tests 
2. Elevated TBL to ≥ 2× ULN (if baseline TBL <1.5× ULN) (except for cases of known 
Gilbert’s syndrome) 
➢ In participants with baseline TBL ≥1.5× ULN, the threshold should be TBL ≥2× 
baseline 
3. Elevation of serum ALP to ≥2× ULN on 2 or more consecutive blood tests (if baseline 
ALP <1.5× ULN) 
➢ In participants with baseline ALP ≥1.5× ULN, the threshold is ALP ≥2× baseline 
on 2 or more consecutive blood tests 
4. Hepatic event considered to be a SAE 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
49 
5. Discontinuation of study intervention due to a hepatic event  
Note: the interval between the two consecutive blood tests should be at least 2 days. 
8.3. 
Adverse Events, Serious Adverse Events, and Product Complaints  
The definitions of the following events can be found in section 10.3 Appendix 3: 
 Adverse events (AEs) 
 Serious adverse events (SAEs) 
 Product complaints 
These events will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant's legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet these definitions and remain responsible for following up events that 
are serious, considered related to the study intervention or study procedures, or that caused the 
participant to discontinue the study intervention or 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/contacts. All SAEs and AEs of special interest (as defined in Section 8.3.4) will 
be followed until resolution, stabilization, the event is otherwise explained, or the participant is 
lost to follow-up (as defined in Section 7.3). For product complaints, the investigator is 
responsible for ensuring that follow-up includes any supplemental investigations as indicated to 
elucidate the nature and/or causality. Further information on follow-up procedures is provided in 
section 10.3 Appendix 3.   
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 
The safety 
follow-up visit or 
participation in 
study has ended 
As soon as 
possible upon 
site awareness 
AE CRF 
N/A 
SAE 
SAE and SAE updates 
– prior to start of 
study intervention 
and deemed 
reasonably possibly 
related to study 
procedures 
signing of 
the ICF 
Start of 
intervention 
Within 24 
hours of 
awareness 
SAE CRF and 
AE CRF 
SAE paper 
form 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
50 
Event 
Collection 
Start 
Collection Stop 
Timing for 
Reporting to 
Sponsor or 
Designee 
Mechanism for 
Reporting 
Back-up 
Method of 
Reporting 
SAE and SAE updates 
– after start of study 
intervention 
start of 
intervention 
The safety 
follow-up visit or 
participation in 
study has ended 
Within 24 
hours of 
awareness 
SAE CRF and 
AE CRF 
SAE paper 
form 
SAE* – after 
participant’s study 
participation has 
ended and the 
investigator becomes 
aware 
After 
participant’s 
study 
participation 
has ended 
N/A 
Promptly 
SAE paper form 
N/A 
Pregnancy 
Pregnancy in female 
participants and 
female partners of 
male participants 
After the 
start of 
study 
intervention 
At least 30 days 
after the last dose 
Within 24 
hours (see 
Section 8.3.2) 
Pregnancy paper 
form 
Pregnancy 
paper form 
Product Complaints 
PC associated with an 
SAE or might have 
led to an SAE 
Start of 
study 
intervention 
End of study 
intervention 
Within 24 
hours of 
awareness 
Product 
Complaint form 
N/A 
PC not associated 
with an SAE 
Start of 
study 
intervention 
End of study 
intervention 
Within 1 
business day 
of awareness 
Product 
Complaint form 
N/A 
Updated PC 
information 
— 
— 
As soon as 
possible upon 
site awareness 
Originally 
completed 
Product 
Complaint form 
with all changes 
signed and dated 
by the 
investigator 
N/A 
PC (if investigator 
becomes aware) 
Participation 
in study has 
ended 
N/A 
Promptly 
Product 
Complaint form 
 
Abbreviations: AE = adverse event; CRF = case report form, ICF = informed consent form, N/A = not applicable, 
PC = product complaint, SAE = serious adverse event 
* Serious adverse events should not be reported unless the investigator deems them to be possibly related to study 
treatment or study participation. 
8.3.2. 
Pregnancy  
Collection of pregnancy information 
Male participants with partners who become pregnant 
 The investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study.  This 
applies only to male participants who receive study intervention. 
 After learning of a pregnancy in the female partner of a study participant, the investigator 
will 
o obtain a consent to release information from the pregnant female partner directly, and 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
51 
o within 24 hours after obtaining this consent will record pregnancy information on the 
appropriate form and submit it to the sponsor.  
The female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the sponsor. 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date.  Any termination of the pregnancy will be reported regardless of 
gestational age, fetal status (presence or absence of anomalies) or indication for the 
procedure. 
Female participants who become pregnant 
 The investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study.  The initial information will be 
recorded on the appropriate form and submitted to the sponsor within 24 hours of 
learning of a participant's pregnancy.  
 The participant will be followed 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. 
 Any female participant who becomes pregnant while participating in the study will 
discontinue 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.   
8.3.3. 
Serious Adverse Events  
An SAE is defined as any untoward medical occurrence that, at any dose, meets one or more of 
the criteria listed in Section 10.3.2. 
All AEs occurring after signing the ICF are recorded in the CRF and assessed for serious criteria.  
The SAE reporting to the sponsor begins after the participant has signed the ICF and has 
received investigational product.  However, if an SAE occurs after signing the ICF, but prior to 
receiving investigational product, the SAE should be reported to the sponsor as per SAE 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
52 
reporting requirements and timelines (see Section 8.3.1) if it is considered reasonably possibly 
related to study procedure. 
Study site personnel must alert Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a sponsor-approved method.  If alerts are issued via telephone, they 
are to be immediately followed with official notification on study-specific SAE forms.  This 
24-hour notification requirement refers to the initial SAE information and all follow-up SAE 
information.  Participants with a serious hepatic AE should have additional data collected using 
the CRF.  
Pregnancy (during maternal or paternal exposure to investigational product) does not meet the 
definition of an AE.  However, to fulfill regulatory requirements any pregnancy should be 
reported following the SAE process to collect data on the outcome for both mother and fetus. 
Investigators are not obligated to actively seek AEs or SAEs in participants once they have 
discontinued and/or completed the study (the participant disposition CRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a subject has 
been discharged from the study, and he or she considers that the event reasonably possibly 
related to the study treatment or study participation, the investigator must promptly notify Lilly. 
8.3.3.1. 
Suspected Unexpected Serious Adverse Reactions  
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator identifies as related to investigational product or procedure.  
United States 21 Code of Federal Regulations (CFR) 312.32 and European Union Clinical Trial 
Directive 2001/20/EC and the associated detailed guidances or national regulatory requirements 
in participating countries require the reporting of SUSARs.  Lilly has procedures that will be 
followed for the identification, recording and expedited reporting of SUSARs that are consistent 
with global regulations and the associated detailed guidances. 
8.3.4. 
Adverse Events of Special Interest  
8.3.4.1. 
Hypoglycemia  
Participants will collect information on episodes of hypoglycemia starting from Visit 2 until the 
last study visit (Follow-up Visit or ET Visit).  For that purpose, participants will be trained about 
signs and symptoms of hypoglycemia, how to treat hypoglycemia, and how to collect appropriate 
information for each episode of hypoglycemia in the study according to the SoA (Section 1.3).  
Site personnel will enter this information into the CRF at each visit.  
Investigators should use the following classification of hypoglycemia (ADA 2023b):   
Level 1 hypoglycemia:  
Glucose <3.9 mmol/L (<70 mg/dL) and ≥3.0 mmol/L (≥54 mg/dL):  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. 
 
 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
53 
Level 2 hypoglycemia:   
Glucose <3.0 mmol/L (<54 mg/dL):  Level 2 hypoglycemia is also referred to as 
documented or BG confirmed hypoglycemia with glucose <3.0 mmol/L (<54 mg/dL).  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. 
To avoid duplicate reporting, all consecutive BG values <3.9 mmol/L occurring within a 1-hour 
period may be considered to be a single hypoglycemic event (Weinberg et al. 2010; 
Danne et al. 2013; ADA 2023b).   
8.3.4.2. 
Severe, Persistent Hyperglycemia  
Severe, persistent hyperglycemia (Section 6.9.1.1) will be collected during the trial to assess the 
risk of extreme imbalance in glycemic control. 
Investigators will be trained on the application of criteria for deciding when and how to intervene 
with participants who do not reach glycemic targets.  An additional therapeutic intervention 
should be considered in participants who develop severe, persistent hyperglycemia after 
randomization.  Rescue medication will be prescribed as add-on to randomized treatment, and 
participants will continue to follow the protocol-specified visit schedule as described in 
Section 6.9.1.1. 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
54 
8.3.4.3. 
Pancreatitis  
Diagnosis of acute pancreatitis 
Acute pancreatitis is an AE of special interest in all studies with tirzepatide, including this study.  
The diagnosis of acute pancreatitis requires 2 of the following 3 features (Banks et al. 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) and/or lipase ≥3× ULN, or 
 characteristic findings of acute pancreatitis on CT scan or magnetic resonance imaging 
(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 
 evaluate for possible causes of acute pancreatitis, including alcohol use, gallstone/gall 
bladder disease, hypertriglyceridemia, and concomitant medications.   
Discontinuation for acute pancreatitis 
If acute pancreatitis is diagnosed, the participant must discontinue use of the investigational 
products.   
Case adjudication and data entry 
An independent clinical endpoint committee will adjudicate all suspected cases of acute 
pancreatitis.   
In addition, AEs of severe or serious abdominal pain of unknown etiology will also be submitted 
to the adjudication committee to assess for possible pancreatitis or other pancreatic disease. 
Relevant data from participants with acute or chronic pancreatitis and those with severe or 
serious abdominal pain will be entered into a specifically designed CRF page by study site or 
Lilly personnel. The adjudication committee representative will enter the results of adjudication 
in a corresponding CRF page. 
Asymptomatic elevation of serum amylase and/or lipase 
Serial measures of pancreatic enzymes have limited clinical value for predicting episodes of 
acute pancreatitis in asymptomatic patients (Nauck et al. 2016; Steinberg et al. 2017a; 
Steinberg et al. 2017b).  Therefore, further diagnostic follow-up of cases of asymptomatic 
elevation of pancreatic enzymes (lipase and/or p-amylase ≥3× ULN) is not mandated but may be 
performed based on the investigator’s clinical judgment and assessment of the participant’s 
overall clinical condition.   
Reporting AEs and SAEs of acute pancreatitis 
Each event of pancreatitis must be reported as an AE or SAE.   
The investigator must report the event as an SAE if the typical signs and/or symptoms of 
pancreatitis are present, and are confirmed by  
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
55 
 laboratory values (lipase or amylase [total and/or pancreatic]), and 
 imaging studies. 
If a potential event does not meet all of these criteria, the investigator will decide the seriousness 
of the event, either AE or SAE.   
The investigator will also review the participant’s concomitant medications to assess any 
potential causal relationship with pancreatitis and will report the relatedness of study 
intervention(s) to the event.   
8.3.4.4. 
Thyroid C-Cell Hyperplasia and C-Cell Neoplasms   
Individuals with personal or family history of MTC and/or MEN2 will be excluded from the 
study.  The assessment of thyroid safety during the study will include reporting of any case of 
thyroid malignancy including MTC and papillary carcinoma and measurements of calcitonin.  
This data will be captured in specific CRFs.  The purpose of calcitonin measurements is to assess 
the potential of tirzepatide to affect thyroid C-cell function, which may indicate development of 
C-cell hyperplasia and neoplasms.   
Study intervention should be discontinued (after first confirming the value) if post randomization 
calcitonin value is ≥35 ng/L and has increased at least 50% over baseline.  A consultation with a 
thyroid specialist (if not available, an endocrinologist) should be obtained.   
If the increased calcitonin value (≥35 ng/L AND increases by ≥50% compared with baseline) is 
observed in a participant who has been administered a medication that is known to increase 
serum calcitonin, this medication should be stopped and calcitonin levels should be measured 
after an appropriate washout period.  If the confirmed calcitonin value is <35 ng/L, study 
intervention should be restarted when it is safe to do so.   
8.3.4.5. 
Major Adverse Cardiovascular Event  
Deaths and nonfatal cardiovascular AEs will be adjudicated by a committee of physicians 
external to Lilly with cardiology expertise.  The nonfatal cardiovascular AEs to be adjudicated 
include the following:   
 myocardial infarction, 
 hospitalization for unstable angina, 
 hospitalization for heart failure, 
 coronary interventions (such as coronary artery bypass graft or percutaneous coronary 
intervention), and 
 cerebrovascular events, including cerebrovascular accident (stroke) and transient 
ischemic attack.   
8.3.4.6. 
Arrythmias and Cardiac Conduction Disorders  
Treatment-emergent cardiac conduction disorders will be further evaluated.  Participants who 
develop any event from this group of disorders should undergo an ECG.  Additional diagnostic 
tests to determine exact diagnosis should be performed, as needed.  The specific diagnosis will 
be recorded as an AE.  Events that meet criteria for serious conditions as described in 
Section 10.3.2 must be reported as SAEs. 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
56 
8.3.4.7. 
Hypersensitivity Reactions  
Many drugs, including oral agents and biologic agents, carry the risk of systemic hypersensitivity 
reactions. If such a reaction occurs, additional data should be provided to the sponsor in the 
designated CRFs. 
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 a suspected systemic hypersensitivity event, additional blood samples should be 
collected as described in Section 10.2.1 Appendix 2.  Laboratory results are provided to the 
sponsor via the central laboratory. 
Study intervention should be temporarily interrupted in any individual suspected of having a 
severe or serious allergic reaction to study intervention.  Study intervention may be restarted 
when/if it is safe to do so, in the opinion of the investigator.  If study intervention is permanently 
discontinued, the participant will receive another glucose-lowering treatment, judged by the 
investigator to be appropriate based on the participant’s clinical status, and will continue in the 
trial to collect all planned efficacy and safety measurements.   
8.3.4.8. 
Injection Site Reactions  
Symptoms and signs of a local injection site reactions (ISR) may include erythema, induration, 
pain, pruritus, and edema.   
If an ISR is reported by a participant or study personnel, 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.   
8.3.4.9. 
Diabetic Retinopathy Complications  
Dilated retinal fundoscopic examination for all participants will be performed by a qualified eye 
care professional (ophthalmologist or optometrist) between Visit 2 and Visit 3 or at a previous 
examination ≤90 days of screening meeting study requirements.  The results from this 
examination will be recorded on a specific retinopathy CRF as a baseline measure of retinopathy.  
Additional dilated fundoscopic examinations should be performed when clinically indicated by 
any AE suspected of worsening retinopathy, and the findings must be recorded on the 
retinopathy CRF. 
8.3.4.10. Hepatobiliary Disorders  
All events of treatment emergent biliary colic, cholecystitis, or other suspected events related to 
gallbladder disease should be evaluated and additional diagnostic tests performed, as needed.  In 
cases of elevated liver markers, hepatic monitoring should be initiated as outlined in 
Section 8.2.7.1 and Section 10.5 Appendix 5. 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
57 
8.3.4.11. Severe Gastrointestinal Adverse Events  
Tirzepatide may cause severe gastrointestinal AEs, such as nausea, vomiting, and diarrhea.  
Information about severe gastrointestinal AEs as well as antiemetic/antidiarrheal use will be 
collected in the CRF/AE form.  For detailed information concerning the management of 
gastrointestinal AEs, please refer to Section 6.6.1. 
8.3.4.12. Acute Renal Events  
Renal safety will be assessed based on repeated renal functional assessment as well as 
assessment of AEs suggestive of acute or worsening of chronic renal failure.  Gastrointestinal 
AEs have been reported with tirzepatide, including nausea, diarrhea, and vomiting.  These are 
consistent with other GLP-1 receptor agonists (Aroda and Ratner 2011).  The events may lead to 
dehydration, which could cause a deterioration in renal function, including acute renal failure.  
Participants should be advised to notify investigators in case of severe nausea, frequent vomiting, 
or symptoms of dehydration. 
8.3.4.13. Metabolic Acidosis, Including Diabetic Ketoacidosis  
Ketoacidosis, a serious lifethreatening condition requiring urgent hospitalization, has been 
reported rarely in participants with T2DM.  Participants who present with signs and symptoms 
consistent with severe metabolic acidosis should be assessed for ketoacidosis regardless of 
presenting BG levels, as ketoacidosis may be present even if BG levels are less than 
13.9 mmol/L (250 mg/dL).  If ketoacidosis is suspected, participant should be evaluated, and 
prompt treatment should be instituted.  Treatment of ketoacidosis may require insulin, fluid and 
carbohydrate replacement.   
8.3.4.14. Amputation/Peripheral Revascularization  
All cases of amputation and peripheral revascularization should be reported as an AE. 
8.3.4.15. Major Depressive Disorder/Suicidal Ideation  
The prevalence of depressive symptoms and disorders is increased in participants with T1DM or 
T2DM (ADA 2023a).  Any AE of major depressive disorder or suicidal ideation should be reported. 
8.3.5. 
Complaint Handling  
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical studies in order to ensure the safety of study participants, monitor quality, and to 
facilitate process and product improvements.   
Participants will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed.   
8.4. 
Pharmacokinetics  
Pharmacokinetics parameters are not evaluated in this study.   
8.5. 
Pharmacodynamics  
Pharmacodynamic parameters are not evaluated in this study.   
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
58 
8.6. 
Genetics  
Genetics are not evaluated in this study.   
8.7. 
Biomarkers  
Biomarkers are not evaluated in this study.   
8.8. 
Immunogenicity Assessments  
Immunogenicity parameters are not evaluated in this study.   
8.9. 
Health Economics  
Health economics parameters are not evaluated in this study.   
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
59 
9. 
Statistical Considerations  
The statistical analysis plan (SAP) 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  
The alternative hypotheses for the primary and key secondary objective are as follows, 
 H5,1, H10,1, and H15,1: Superiority test of tirzepatide 5 mg, 10 mg, 15 mg versus placebo in 
HbA1c change from baseline at Week 40 respectively. 
 H5,2, H10,2, and H15,2: Superiority test of tirzepatide 5 mg, 10 mg, 15 mg versus placebo in 
proportion of participants achieve HbA1c <7% at Week 40 respectively. 
 H5,3, H10,3, and H15,3: Superiority test of tirzepatide 5 mg, 10 mg, 15 mg versus placebo in 
FSG change from baseline at Week 40 respectively. 
 H5,4, H10,4, and H15,4: Superiority test of tirzepatide 5 mg, 10 mg, 15 mg versus placebo in 
proportion of participants achieve HbA1c ≤6.5% at Week 40 respectively. 
 H5,5, H10,5, and H15,5: Superiority test of tirzepatide 5 mg, 10 mg, 15 mg versus placebo in 
body weight change from baseline at Week 40 respectively. 
 H5,6, H10,6, and H15,6: Superiority test of tirzepatide 5 mg, 10 mg, 15 mg versus placebo in 
proportion of participants achieve HbA1c <5.7% at Week 40 respectively. 
9.1.1. 
Multiplicity Adjustment  
The primary and the key secondary objectives will be evaluated align to both the treatment-
regimen estimand and the efficacy estimand.  No multiplicity adjustment will be made for 
conducting analysis aligned to the two estimands.   
A prespecified graphical scheme (Bretz et al. 2009; Bretz et al. 2011) will be implemented to 
control the family-wise error rate at a 2-sided alpha level of 0.05.  This graphical approach is a 
closed testing procedure; hence, it strongly controls the family-wise error rate across all 
endpoints (Bretz et al. 2009; Bretz et al. 2011; Alosh et al. 2014).  
The testing scheme will be fully detailed in the SAP.  The testing scheme will be finalized before 
database lock. 
9.2. 
Analyses Sets  
For purposes of analysis, the following analysis sets are defined. 
Population/Analysis Set 
Description 
Screened population 
All participants who signed informed consent 
Randomized population 
All participants who are randomly assigned to a treatment group. 
Modified intention-to-treat (mITT) 
population 
All randomly assigned participants who are exposed to at least 1 dose 
of study intervention.   
Efficacy analysis set (EAS): This 
analysis set will be used to estimate the 
efficacy estimand for all efficacy 
objectives 
Data obtained during Study Period II from the mITT population, 
excluding data after initiating rescue antihyperglycemic medication or 
stopping study intervention.  
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
60 
Full analysis set: This analysis set will 
be used to estimate the treatment-
regimen estimand for the primary and 
key secondary objectives 
Data obtained during Study Period II from the mITT population, 
regardless of adherence to study intervention or initiation of rescue 
antihyperglycemic medication. 
Safety analysis set (SS): This analysis 
set will be used to assess the safety of 
study treatment 
Data obtained during Study Periods II or III from the mITT 
population, regardless of adherence to study intervention or initiation 
of rescue antihyperglycemic medication. 
9.3. 
Statistical Analyses  
9.3.1. 
General Considerations  
Handling of missing, unused, and spurious data are addressed prospectively in the overall 
statistical methods described in the protocol (section 9.3) and in the SAP, where appropriate.  
Adjustments to the planned analyses will be described in the final clinical study report (CSR). 
Statistical analysis of this study will be the responsibility of Lilly or its designee. 
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol.  Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the SAP or CSR.  Additional exploratory analyses of the data will be conducted as deemed 
appropriate. 
Unless otherwise noted, all tests of treatment effects will be conducted at a 2-sided alpha level of 
0.05, and the confidence interval will be calculated at 95%, 2-sided.  In statistical summaries and 
analyses, all data will be analyzed by randomized treatment assignment.  Participants will be 
analyzed according to the treatment they were randomly assigned to, regardless of the treatment 
actually received. 
Baseline is defined as the last non-missing measurement recorded on or before the randomization 
visit, prior to first dose of treatment, unless otherwise specified. 
Efficacy analyses will use the full analysis set (FAS) to evaluate the treatment-regimen estimand 
and the efficacy analysis set to evaluate the efficacy estimand.  Safety will be assessed using 
safety analysis set (SS).  Selected safety analyses may be conducted after excluding data on 
rescue therapy or data after starting another antihyperglycemic medication. 
Summary statistics for continuous measures will include sample size, mean, standard deviation 
(SD), median, minimum, and maximum.  The analysis model to make comparisons among 
treatment groups relative to continuous measurements assessed over time will be a mixed model 
for repeated measures (MMRM) with terms:   
 treatment,  
 visit, 
 treatment-by-visit interaction,  
 any past prior use (yes or no) of any antihyperglycemic medication,  
 baseline HbA1c category [≤8.5% (≤69 mmol/mol) or >8.5% (>69 mmol/mol)],  
 and baseline measurement as a covariate.   
For analyses with HbA1c, the baseline HbA1c category will not be included in the model.  An 
unstructured covariance structure will model the relationship of within-patient errors. 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
61 
The Kaplan-Meier method will be used for estimation of cumulative event-free survival rates 
over time, and cox proportional hazards regression analysis will be used to compare hazard rates 
among treatments. 
Summary statistics for categorical measures (including categorized continuous measures) will 
include sample size, frequency, and percentages.  Fisher’s exact test will be used to examine the 
treatment difference in categorical outcomes.  Logistic regression may be used to examine the 
treatment difference in binary efficacy outcomes.  The negative binomial regression model will 
be used for the treatment comparison of discrete count measures if deemed appropriate. 
Other statistical methods may be used, as appropriate, and details will be documented in the 
SAP. 
9.3.2. 
Treatment Group Comparability  
9.3.2.1. 
Participant Disposition  
Frequency counts and percentages of all participants screened, randomized, and receiving at least 
1 dose of study intervention will be presented by treatment groups.  A listing of randomized 
participants not receiving study intervention will be provided.  Of the participants in the 
randomized population, frequency, counts and percentages of participants completing the study, 
prematurely discontinuing the study, including the reason for premature discontinuation; and 
prematurely discontinuing study intervention including the reason for premature discontinuation 
of study intervention will be presented by treatment group.  A Kaplan-Meier analysis of time 
from randomization to premature discontinuation from study by treatment group will be 
provided. 
9.3.2.2. 
Participant Characteristics  
Demographics will be summarized by treatment group using the randomized population.  
Medical history and concomitant illness will be summarized using the mITT population. 
9.3.2.3. 
Concomitant Therapy  
Concomitant medications will be summarized by anatomical therapeutic chemical classification 
and treatment group using the mITT population.  In particular, the time of initiation of rescue 
therapy for severe, persistent hyperglycemia will be analyzed and summarized.   
9.3.2.4. 
Treatment Compliance  
A Kaplan-Meier analysis of time from randomization to premature study intervention 
discontinuation by treatment group will be provided.   
Treatment compliance is defined as taking at least 75% of required injections of study 
intervention.  Frequency counts and percentages of participants compliant to study intervention 
will be summarized by treatment arm using the mITT population. 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
62 
9.3.3. 
Primary Endpoint(s) Analysis  
The primary endpoint for this study is HbA1c change from baseline at Week 40. This endpoint 
will be used to evaluate the primary objective of the study for both the treatment-regimen and 
efficacy estimands (Section 3). 
The alternative hypothesis corresponding to the primary objective is as follows: tirzepatide 5 mg, 
and/or 10 mg, and/or 15 mg is superior to placebo with respect to HbA1c change from baseline 
at Week 40 (Section 9.1). 
The primary efficacy analysis will be guided by the “treatment-regimen” estimand defined in 
Section 3.  This assessment will analyze change from baseline in HbA1c to Week 40 using an 
analysis of covariance (ANCOVA) with terms: treatment, any past prior use (yes or no) of any 
antihyperglycemic medication, and baseline HbA1c as a covariate. The ANCOVA analysis will 
be conducted using FAS (section 9.2).  Missing HbA1c values at Week 40 will be imputed using 
multiple imputation.  Details regarding missing data will be included in the SAP. Statistical 
inference over multiple imputations will be guided by the method proposed by Rubin (1987). 
To explore the treatment efficacy without the influence of rescue therapy, the primary endpoint 
will be conducted on the “efficacy” estimand. This assessment will be conducted using efficacy 
analysis set (EAS) dataset (section 9.2).  The primary analysis model for HbA1c measurements 
over time will be a MMRM.  The response variable of MMRM will be change in HbA1c values 
from baseline obtained at each scheduled postbaseline visit.  The independent variables of the 
MMRM model are treatment, visit, and treatment-by-visit interaction, any past prior use (yes or 
no) of any antihyperglycemic medication, baseline HbA1c and baseline HbA1c-by-visit 
interaction.  Missing data will be addressed by the MMRM model under missing at random 
assumption. No explicit imputation methods for missing data will be employed. 
An unstructured covariance structure will model the relationship of within-patient errors.  If the 
analysis fails to converge, the following variance-covariance matrix will be used (in order) until 
convergence is achieved:  heterogeneous compound symmetry, compound symmetry, and 
first-order autoregressive.  The Kenward-Roger approximation will be used to estimate 
denominator degrees of freedom.   
 
9.3.4. 
Secondary Endpoints Analysis  
The secondary study objectives subject to type 1 error rate control are as follows: 
 Superiority of tirzepatide dose(s) to placebo relative to proportion of participants 
achieving the target value of HbA1c <7.0% (<53 mmol/mol) at Week 40 
 Superiority of tirzepatide dose(s) to placebo relative to change in FSG (central 
laboratory) at Week 40 
 Superiority of tirzepatide dose(s) to placebo relative to proportion of participants 
achieving the target value of HbA1c ≤6.5% (≤48 mmol/mol) at Week 40 
 Superiority of tirzepatide dose(s) to placebo relative to change in body weight from 
baseline to Week 40 
 Superiority of tirzepatide dose(s) to placebo relative to proportion of participants 
achieving the target value of HbA1c <5.7% (<39 mmol/mol) at Week 40 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
63 
The type 1 error-controlled strategy for the primary and secondary endpoints will be described in 
the SAP.  Key secondary objectives will be evaluated based on the treatment-regiment and 
efficacy estimands (Section 3), similar to the primary objective.  
Analysis of change from baseline in body weight and FSG at Week 40 will be conducted in a 
manner similar to the primary efficacy analyses (Section 9.3.1).  Baseline HbA1c category 
[≤8.5% (≤69 mmol/mol) or >8.5% (>69 mmol/mol)] and baseline of the corresponding variable 
will be added in the model for body weight and FSG.   
Comparisons among treatments relative to the proportion of participants achieving the HbA1c 
target value of <7.0% (<53 mmol/mol), ≤6.5% (≤48 mmol/mol), and <5.7% (<39 mmol/mol) at 
Week 40 will be conducted using a logistic regression analysis with terms: treatment, any past 
prior use (yes or no) of any antihyperglycemic medication and baseline HbA1c as a covariate.   
9.3.6. 
Safety Analyses  
Safety assessments will be done using SS dataset (See section 9.2) irrespective of adherence to 
study intervention or initiation of rescue therapy.  Selected safety analyses may be conducted 
after excluding data after the introduction of another antihyperglycemic therapy. 
Adverse events will be coded from the actual term using the Medical Dictionary for Regulatory 
Activities (MedDRA) and reported with preferred terms and system organ class.  Selected 
notable AEs of interest may be reported using high-level terms or Standardized MedDRA 
Queries.   
Summary statistics will be provided for incidence of TEAEs, SAEs, study discontinuation due to 
AEs, study intervention discontinuation due to AEs, deaths, and other cardiovascular endpoints.  
Counts and proportions of participants experiencing AEs will be reported for each treatment 
group, and Fisher’s exact test will be used to compare the treatment groups. 
9.3.6.1. 
Hypoglycemic Events  
Incidence of documented hypoglycemia events and severe hypoglycemia will be compared 
between tirzepatide doses and placebo.  Rate of hypoglycemic episodes will be analyzed using a 
generalized linear mixed-effects model assuming negative binomial distribution for 
hypoglycemic episodes if data warrant.  Selected safety analyses may be conducted after 
excluding data after the introduction of another antihyperglycemic therapy.  
9.3.6.2. 
Gastrointestinal Events  
Summaries and analyses for incidence and severity of nausea, vomiting, and diarrhea will be 
provided by each treatment. 
9.3.6.3. 
Adjudicated Cardiovascular Events  
Listings of deaths, myocardial infarctions, strokes, and hospitalization for unstable angina 
confirmed by an independent clinical endpoint committee will be provided.  The dates of 
Approved on 05 Dec 2023 GMT
CCI

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
64 
randomization, event, first dose and last dose of study intervention, and time from randomization 
to the event will be listed. 
9.3.6.4. 
Central Laboratory Measures and Vital sign  
Values and change from baseline to postbaseline values of central laboratory measures and vital 
signs will be summarized at each scheduled visit.   
The analysis model to make comparisons among treatment groups, relative to continuous change 
from baseline values assessed over time will be an MMRM, with terms: treatment, visit, and 
treatment-by-visit interaction, any past prior use (yes or no) of any antihyperglycemic 
medication, baseline HbA1c category [≤8.5% (≤69 mmol/mol) or >8.5% (>69 mmol/mol)] and 
baseline measurement as a covariate.  An unstructured covariance structure will model the 
relationship of within-patient errors. 
The percentages of participants with treatment-emergent abnormal, high, or low laboratory 
measures at any time will be summarized and compared between treatment groups by using 
Fisher’s exact test.  A treatment-emergent abnormal value is defined as a change from normal 
value at baseline to an abnormal value at any time during Periods II and III.   
9.3.7. 
Other Analyses  
9.3.7.1. 
Subgroup Analyses  
Subgroup analyses of change in HbA1c from baseline to Week 40 will be provided by age, 
gender, duration of diabetes, and baseline HbA1c (≤8.5% [≤69 mmol/mol] and >8.5% 
[>69 mmol/mol]). 
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. 
Unblinding details are specified in the unblinding plan section of the SAP or in a separate 
unblinding plan document. 
9.5. 
Sample Size Determination  
Participants will be randomized in a 
ratio to tirzepatide 5 mg, 10 mg, 15 mg, or placebo.   
The trial is powered to assess superiority of tirzepatide 5 mg, 10 mg, or 15 mg versus placebo in 
parallel relative to change from baseline in HbA1c at Week 40 under the following assumptions:  
 use of 2-sample t-test to compare treatment means utilizing HbA1c data collected before 
initiation of any rescue medication and premature treatment discontinuation;  
 up to 
 participants in tirzepatide arms and up to 
 participants in placebo arm 
initiating any rescue medication or premature treatment discontinuation;  
 at least 
 (placebo adjusted) mean reduction in HbA1c for the tirzepatide doses; and 
 a common SD of 
  
On the basis of these assumptions, randomizing 200 participants using a 
 randomization 
ratio to tirzepatide 5 mg (50 participants), tirzepatide 10 mg (50 participants), tirzepatide 15 mg 
Approved on 05 Dec 2023 GMT
CCI
CCI
CCI
CCI
CCI
CCI

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
65 
(50 participants), and placebo (50 participants) will provide at least 
 power to establish 
superiority for a tirzepatide dose compared to placebo at a 2-sided significance level of 
. 
Furthermore, this sample size will ensure at least 
 power for the HbA1c superiority 
evaluation utilizing all available HbA1c data at Week 40 with missing data imputed with a 
conservative multiple imputation method, provided that the mean reduction in HbA1c for the 
tirzepatide doses is at least 
 (placebo adjusted) and SD increases to no more than 
 due 
to the inclusion of data on rescue medications, inclusion of data after premature treatment 
discontinuation, and missing data imputation. 
Approved on 05 Dec 2023 GMT
CCI
CCI
CCI
CCI
CCI

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
66 
10. 
Supporting Documentation and Operational Considerations  
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations  
10.1.1. 
Regulatory and Ethical Considerations  
 This study will be conducted in accordance with the protocol and with the following: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines 
o Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines 
○ Applicable laws and regulations 
 The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (for example, advertisements) must be submitted to an Institutional Review 
Boards (IRB)/ Independent Ethics Committees (IEC) by the investigator and reviewed 
and approved by the IRB/IEC before the study is initiated. 
 Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants. 
 Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate 
hazard to study participants. 
 The investigator will be responsible for the following: 
o Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
o Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
o Providing oversight of study conduct for participants under their responsibility and 
adherence to requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other applicable local 
regulations 
o Reporting to the sponsor or designee significant issues related to participant safety, 
participant rights, or data integrity 
 Investigator sites are compensated for participation in the study as detailed in the clinical 
trial agreement. 
10.1.2. 
Financial Disclosure  
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities.   
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
67 
10.1.3. 
Informed Consent Process  
 The investigator or the investigator’s representative will explain the nature of the study, 
including the risks and benefits, to the potential participant or the potential participant’s 
legally authorized representative and answer all questions regarding the study. 
 Potential participants must be informed that their participation is voluntary.  Participants 
or their legally authorized representatives will be required to sign a statement of informed 
consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 
privacy and data protection requirements, where applicable, and the IRB/IEC or study 
center. 
 The medical record must include a statement that written informed consent was obtained 
before the participant was entered in the study and the date the written consent was 
obtained.  The authorized person obtaining the informed consent must also sign the ICF. 
 Participants must be reconsented to the most current version of the ICF(s) during their 
participation in the study. 
 A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative and is kept on file. 
10.1.4. 
Data Protection  
 Participants will be assigned a unique identifier by the sponsor.  Any participant records, 
datasets or tissue samples that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant identifiable 
will not be transferred. 
 The participant must be informed that the participant’s personal study-related data will be 
used by the sponsor in accordance with local data protection law.  The level of disclosure 
must also be explained to the participant who will be required to give consent for their 
data to be used as described in the informed consent. 
 The participant must be informed that their medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
 The sponsor has processes in place to ensure data protection, information security, and 
data integrity.  These processes include appropriate contingency plan(s) for appropriate 
and timely response in the event of a data security breach. 
10.1.5. 
Committees Structure  
Adjudication of major adverse cardiovascular events, death, and pancreatic AEs will be 
performed for this study.  Section 8.3.4 outlines additional information on adjudication 
committee.   
10.1.6. 
Dissemination of Clinical Study Data  
Reports 
The sponsor will disclose a summary of study information, including tabular study results, on 
publicly available websites where required by local law or regulation. 
The summary of results will be posted within the time frame specified by local law or regulation. 
If the study remains ongoing in some countries and a statistical analysis of an incomplete data set 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
68 
would result in analyses lacking scientific rigor (for example, underpowered) or compromise the 
integrity of the overall analyses (for example, trial not yet unblinded), the summary of results 
will be submitted within 1 year after the end of the study globally or as soon as available, 
whichever is earlier. 
Data 
The sponsor provides access to all individual participant data collected during the trial, after 
anonymization, with the exception of pharmacokinetic or genetic data. 
Data are available to request 6 months after the indication studied has been approved in the US 
and EU and after primary publication acceptance, whichever is later.  No expiration date of data 
requests is currently set once data are made available. 
Access is provided after a proposal has been approved by an independent review committee 
identified for this purpose and after receipt of a signed data sharing agreement. 
Data and documents, including the study protocol, SAP, CSR, and blank or annotated CRF, will 
be provided in a secure data sharing environment for up to 2 years per proposal. 
For details on submitting a request, see the instructions provided at www.vivli.org. 
10.1.7. 
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. 
 The investigator must review and confirm that data entries are accurate and complete 
throughout the duration of the study, by physically or electronically signing the CRF, as 
instructed by the sponsor.  All completed CRFs must be signed prior to archival. 
 The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source documents. 
 Quality tolerance limits (QTLs) will be pre-defined to identify systematic issues that can 
impact participant safety and/or reliability of study results.  These pre-defined parameters 
will be monitored during the study and important excursions from the QTLs and remedial 
actions taken will be summarized in the CSR. 
 Monitoring details describing strategy (for example, risk-based initiatives in operations 
and quality such as risk management and mitigation strategies and analytical risk-based 
monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques are provided in the Monitoring Plan. 
 The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
 The sponsor assumes accountability for actions delegated to other individuals (for 
example, contract research organizations). 
 The sponsor or designee will perform monitoring to confirm that data transcribed into the 
CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
69 
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 (EDC) 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 EDC system.  The investigator is responsible for the 
identification of any data to be considered source and for the confirmation that data reported are 
accurate and complete by signing the CRF. 
Additionally, clinical outcome assessment (COA) data (participant-focused outcome instrument) 
and other data EQ-5D-5L, IWQOL-Lite-CT will be collected by the participant, via a paper 
source document and will be transcribed by the authorized study personnel into the EDC system. 
Data collected via the sponsor-provided data capture system(s) 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/electronic transfers will be provided to the 
investigator for review and retention.  Data will subsequently be transferred from the central 
vendor to the Sponsor data warehouse. 
Data from complaint forms submitted to the Sponsor will be encoded and stored in the global 
product complaint management system. 
10.1.8. 
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 10.1.7. 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
70 
10.1.9. 
Study and Site Start and Closure  
First Act of Recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
Study or Site Termination 
The sponsor or sponsor’s designee reserves the right to close the study site or terminate the study 
at any time for any reason at the sole discretion of the sponsor.  Study sites will be closed upon 
study completion.  A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
For study termination: 
 Discontinuation of further study intervention development 
For site termination: 
 Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines 
 Inadequate recruitment (evaluated after a reasonable amount of time) of participants by 
the investigator 
 Total number of participants included earlier than expected. 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements.  The investigator shall promptly inform the participant and should 
assure appropriate participant therapy and/or follow-up. 
10.1.10. 
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. 
10.1.11. 
Investigator Information  
Researchers with appropriate education, training, and experience, as determined by the sponsor, 
will participate as investigators in this clinical trial. 
 
 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
71 
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 and/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. 
Laboratory/analyte results that could unblind the study will not be reported to investigative sites 
or other blinded personnel until the study has been unblinded. 
 
Clinical Laboratory Tests  
Laboratory Name 
Comments  
Hematologya 
Labcorp Pharmaceutical Research and 
Development (Shanghai) Co., Ltd. 
Hemoglobin 
 
  
Hematocrit 
 
  
Erythrocyte count (RBCs) 
 
  
Mean cell volume  
 
  
Mean cell hemoglobin 
 
  
Mean cell hemoglobin 
concentration  
 
  
Leukocytes (WBCs)  
 
  
Differential 
 
  
Absolutes Count of: 
 
  
  Neutrophils, 
 
  
  Lymphocytes 
 
  
  Monocytes 
 
  
  Eosinophils 
 
  
  Basophils 
 
  
Platelets 
 
  
Cell morphology (RBCs and 
WBCs), if indicated 
 
  
Clinical Chemistry 
 
Assayed by Lilly-designated 
laboratory 
Sodium 
 
  
Potassium 
 
  
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
72 
Clinical Laboratory Tests  
Laboratory Name 
Comments  
Chloride 
 
  
Bicarbonate 
 
  
Total bilirubin 
 
  
Direct bilirubin 
 
  
ALP 
 
  
ALT 
 
  
AST 
 
  
BUN 
 
  
Creatinine  
 
  
CK 
 
  
Uric acid 
 
  
Albumin 
 
  
Calcium 
 
  
Glucose 
 
  
Lipid Panel 
 
Assayed by Lilly designated 
laboratory. 
Cholesterol  
 
  
Triglycerides 
 
  
HDL-C 
 
LDL-C 
 
Generated by Lilly-designated 
laboratory. 
If Triglycerides are >400, direct LDL 
will be measured. 
VLDL-C 
 
Generated by Lilly-designated 
laboratory. 
Hepatitis serology 
 
Assayed by Lilly-designated 
laboratory. 
HCV testing 
 
 
  HCV antibody 
 
 
  HCV RNA 
 
Performed only for participants who 
test positive for HCV antibody. 
HBV testing 
 
 
  HBV DNA 
 
Performed only for participants who 
test positive for Hepatitis B core 
antibody. 
  Hepatitis B core antibody 
 
 
  Hepatitis B surface antigen 
 
 
Hormones (female) 
 
  
Serum Pregnancy  
 
Assayed by Lilly-designated 
laboratory.  
Urine Pregnancyb 
 
Assayed and evaluated locally  
FSH  
 
Assayed by Lilly-designated 
laboratory.  
Urine Chemistry 
 
Assayed by Lilly-designated 
laboratory. 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
73 
Clinical Laboratory Tests  
Laboratory Name 
Comments  
Albumin 
 
  
Creatinine 
 
  
Calculations 
 
Generated by Lilly-designated 
laboratory. 
eGFR (CKD-EPI)  
 
  
UACR 
 
  
Additional Testing  
 
 
HbA1ca 
Labcorp Pharmaceutical Research and 
Development (Shanghai) Co., Ltd. 
 
Calcitonin 
 
Assayed by Lilly-designated 
laboratory. 
Insulin 
 
Assayed by Lilly-designated 
laboratory. 
C-peptide 
 
Assayed by Lilly-designated 
laboratory. 
Pancreatic Amylase 
 
Assayed by Lilly-designated 
laboratory. 
Lipase 
 
Assayed by Lilly-designated 
laboratory. 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
BUN = blood urea nitrogen; CK = creatinine kinase, CKD-EPI = Chronic Kidney Disease-Epidemiology; 
eGFR = estimated glomerular filtration rate; FSH = follicle-stimulating hormone; HbA1c = hemoglobin A1c; 
HBV = Hepatitis B Virus; HCV = Hepatitis C Virus; HDL-C = high-density lipoprotein cholesterol; hsCRP = C-
Reactive Protein, high-sensitivity; IWRS = interactive web-response system; LDL-C = low-density lipoprotein 
cholesterol; RBC = red blood cells; UACR = urine albumin/creatinine ratio; VLDL-C = very-low-density 
lipoprotein cholesterol; WBC = white blood cells. 
a Hematology (including blood smear) and HbA1c samples were destroyed by Shanghai Solid Waste Disposal Co., 
Ltd. 
b For sites who can’t perform urine pregnancy test, a local serum pregnancy test can be performed instead.   
10.2.1. 
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. 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
74 
Timing 
Laboratory Test a 
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. 
total tryptase 
complements (C3, C3a, and C5a) 
cytokine panel (IL-6, IL‐1β, IL‐10 or any cytokine panel 
that includes these 3 cytokines)  
Collect up to 12 hours after the start of the event. 
Tirzepatide ADA 
Tirzepatide concentration 
Abbreviations: ADA = anti-drug antibodies; IL = interleukin. 
a 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. 
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. 
 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
75 
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 AE  
AE Definition 
 An AE is any untoward medical occurrence in a participant administered a pharmaceutical 
product and which does not necessarily have a causal relationship with the study 
intervention.  An AE can therefore be any unfavourable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal (investigational) product, whether or not related to 
the medicinal (investigational) product. 
Events Meeting the AE Definition 
 Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (for example, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (that is, not related 
to progression of underlying disease). 
 Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
 New condition detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
 Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 Medication error, misuse, or abuse of investigational product, including signs, symptoms, 
or clinical sequelae. 
 Lack of efficacy or failure of expected pharmacological action per se will not be reported 
as an AE or SAE.  Such instances will be captured in the efficacy assessments.  However, 
the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfill the definition of an AE or SAE. 
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. 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
76 
 The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
 Medical or surgical procedure (for example, endoscopy, appendectomy): the condition 
that leads to the procedure is the AE. 
 Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
10.3.2. 
Definition of SAE  
An SAE is defined as any untoward medical occurrence that, at any dose, meets one or 
more of the criteria listed: 
 Results in death 
 Is life-threatening 
o The term life-threatening in the definition of serious refers to an event in which the 
participant was at risk of death at the time of the event.  It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
o In general, hospitalization signifies that the participant has been admitted to hospital 
or emergency ward (usually involving at least an overnight stay) for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting.  Complications that occur during hospitalization are AEs.  If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious.  When in doubt as to whether hospitalization occurred or was necessary, the 
AE should be considered serious. 
o Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
 Results in persistent disability/incapacity 
o The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
o This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (for example, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
 Is a congenital anomaly/birth defect 
o Abnormal pregnancy outcomes (for example, spontaneous abortion, fetal death, 
stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs. 
 Other situations: 
o Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations such as important medical 
events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the participant or may require medical or surgical 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
77 
intervention to prevent one of the other outcomes listed in the above definition. These 
events should usually be considered serious. 
o Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
 Resulted in medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function. 
10.3.3. 
Definition of Product Complaints  
Product Complaint 
 A product complaint is any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness or 
performance of a study intervention.  When the ability to use the study intervention safely 
is impacted, the following are also product complaints: 
o Deficiencies in labeling information, and 
o Use errors for device or drug-device combination products due to ergonomic design 
elements of the product. 
 Product complaints related to study interventions used in clinical trials are collected in 
order to ensure the safety of participants, monitor quality, and to facilitate process and 
product improvements. 
 Investigators will instruct participants to contact the site as soon as possible if he or she 
has a product complaint or problem with the study intervention so that the situation can 
be assessed. 
 An event may meet the definition of both a product complaint and an AE/SAE. In such 
cases, it should be reported as both a product complaint and as an AE/SAE. 
10.3.4. 
Recording and Follow-Up of AE and/or SAE and Product Complaints  
AE, SAE, and Product Complaint Recording 
 When an AE/SAE/product complaint occurs, it is the responsibility of the investigator to 
review all documentation (for example, hospital progress notes, laboratory reports, and 
diagnostics reports) related to the event. 
 The investigator will then record all relevant AE/SAE/product complaint information in 
the participant’s medical records, in accordance with the investigator’s normal clinical 
practice.  AE/SAE information is reported on the appropriate CRF page and product 
complaint information is reported on the Product Complaint Form. 
Note: An event may meet the definition of both a product complaint and an AE/SAE.  In 
such cases, it should be reported as both a product complaint and as an AE/SAE. 
 It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to Sponsor or designee in lieu of completion of the CRF page for AE/SAE and 
the Product Complaint Form for product complaints. 
 There may be instances when copies of medical records for certain cases are requested by 
Sponsor or designee.  In this case, all participant identifiers, with the exception of the 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
78 
participant number, will be redacted on the copies of the medical records before 
submission to Sponsor or designee. 
 The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
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. 
An event is defined as ‘serious’ when it meets at least one of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
Assessment of Causality 
 The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE.  The investigator will use clinical judgment to 
determine the relationship. 
 A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
 Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
 The investigator will also consult the 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. 
 
 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
79 
Follow-up of AEs and SAEs 
 The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor or 
designee to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
 If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide Sponsor or designee with a copy of any postmortem 
findings including histopathology. 
10.3.5. 
Reporting of SAEs  
SAE Reporting via an Electronic Data Collection Tool 
 The primary mechanism for reporting an SAE will be the electronic data collection tool. 
 If the electronic system is unavailable, then the site will use the SAE paper form (see next 
section) in order to report the event within 24 hours.  
 The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
 After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data. 
 If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken off-
line, then the site can report this information on a SAE paper form (see next section) or to 
the medical monitor/SAE coordinator by telephone. 
 Contacts for SAE reporting can be found in site training documents. 
SAE Reporting via Paper Form 
 Facsimile transmission of the SAE paper form is the preferred method to transmit this 
information to the medical monitor/SAE coordinator. 
 Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames. 
 Contacts for SAE reporting can be found in site training documents. 
10.3.6. 
Regulatory Reporting Requirements  
SAE Regulatory Reporting 
Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met. 
 The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation.  The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC, and investigators. 
 An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (for example, summary or listing of SAEs) from the sponsor 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
80 
will review and then file it along with the IB or other relevant documents and will notify 
the IRB/IEC, if appropriate according to local requirements.  
 
 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
81 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance  
10.4.1. 
Definitions  
 
Word/Phrase 
Definition 
Women of 
childbearing 
potential 
(WOCBP) 
Adult females are considered WOCBP unless they are WNOCBP. 
Women not of 
childbearing 
potential 
(WNOCBP) 
Females are considered WNOCBP if they 
 
have a congenital anomaly such as Müllerian agenesis  
 
are infertile due to surgical sterilization, or  
 
are postmenopausal. 
Examples of surgical sterilization include total hysterectomy, bilateral salpingo-
oophorectomy, bilateral salpingectomy, or bilateral oophorectomy. 
Postmenopausal 
state 
The postmenopausal state is defined as a woman: 
 
at any age at least 6 weeks post-surgical bilateral oophorectomy with or without 
hysterectomy, confirmed by operative note; or  
 
aged at least 40 years and up to 55 years with an intact uterus, not on hormone 
therapya, who has had cessation of menses for at least 12 consecutive months 
without an alternative medical cause, AND with a follicle-stimulating hormone 
>40 mIU/mL; or  
 
55 years or older not on hormone therapy, who has had at least 12 months of 
spontaneous amenorrhea, or 
 
aged at least 55 years with a diagnosis of menopause prior to starting hormone 
replacement therapy. 
 
a Women should not be taking medications during amenorrhea such as oral contraceptives, 
hormones, gonadotropin-releasing hormone, anti-estrogens, SERMs, or chemotherapy that 
could induce transient amenorrhea. 
Abbreviations: SERM = selective estrogen receptor modulators; WNOCBP = women not of childbearing potential. 
WOCBP = woman of child-bearing potential. 
 
10.4.2. 
Contraception Guidance  
10.4.2.1. Females  
Women of childbearing potential and women not of childbearing potential may participate in this 
trial. See Section 10.4.1 for definitions and additional requirements related to contraception. 
Women of childbearing potential who are completely abstinent as their preferred and usual 
lifestyle, or in a same-sex relationship as their preferred and usual lifestyle: 
Must… 
Must not… 
agree to either remain 
abstinent or stay in a 
same-sex relationship 
without sexual relationships 
with males 
 
use periodic abstinence methods 
o 
calendar 
o 
ovulation 
o 
symptothermal, or 
o 
post-ovulation 
 
declare abstinence just for the duration of a trial, or 
 
use the withdrawal method 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
82 
Women of childbearing potential who are NOT completely abstinent as their preferred and usual 
lifestyle, or NOT in a same-sex relationship as their preferred and usual lifestyle, must do the 
following: 
Topic 
Condition 
Pregnancy testing 
Have a negative serum test result at screening followed by a negative urine result 
within 24 hours prior to treatment exposure. See the protocol SoA for subsequent 
pregnancy testing requirements. 
Contraception 
Agree to use 2 forms of effective contraception, where at least 1 form must be highly 
effective. 
These forms of contraception must be used during the study and after the study for at 
least 30 days (1 month) after the last dose of the study intervention. 
 
Examples of different forms of contraception:  
Methods 
Examples 
Highly effective 
contraception (less than 1% 
failure rate) 
 
female sterilization 
 
combination oral contraceptive pill 
 
progestin-only contraceptive pill (mini-pill) 
 
implanted contraceptives 
 
injectable contraceptives 
 
contraceptive patch (only women <198 pounds or 90 kg) 
 
total abstinence 
 
vasectomy (if only sexual partner) 
 
fallopian tube implants (if confirmed by hysterosalpingogram) 
 
combined contraceptive vaginal ring, or  
 
intrauterine devices 
Effective contraception  
 
male or female condoms with spermicide  
 
diaphragms with spermicide or cervical sponges 
 
barrier method with use of a spermicide 
o 
condom with spermicide 
o 
diaphragm with spermicide, or 
o 
female condom with spermicide 
Note:  The barrier method must include use of a spermicide (i.e., condom 
with spermicide, diaphragm with spermicide, female condom with 
spermicide) to be considered effective. 
Ineffective forms of 
contraception whether used 
alone or in any combination 
 
spermicide alone 
 
periodic abstinence 
 
fertility awareness (calendar method, temperature method, cervical mucus, 
or symptothermal) 
 
withdrawal 
 
postcoital douche, or 
 
lactational amenorrhea 
 
 
 
 
 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
83 
10.4.2.2. Male  
The table below describes contraception guidance for all men. 
Topic 
Guidance 
For all men  
should refrain from sperm donation for the duration of 
the study and for 5 half-lives of study intervention, plus 
90 days, corresponding 120 days (4 months) after the 
last dose of the study intervention.  
Contraception for men with partners of childbearing 
potential  
 
either remain abstinent (if this is their 
preferred and usual lifestyle), or 
 
 
must use condoms during intercourse for the 
duration of the study, and  
 
for 120 days (4 months) after the last dose of 
the study intervention. 
Contraception for men in exclusively same sex 
relationships, as their preferred and usual lifestyle 
Are not required to use contraception 
Examples of highly effective, effective and unacceptable methods of contraception can be found 
in Section 10.4.2.1. 
 
 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
84 
10.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-up 
Assessments  
Hepatic Evaluation Testing 
See Section 8.2.7.1 for guidance on appropriate test selection. 
The Lilly-designated central laboratory should complete the analysis of all selected testing 
except for testing listed in the investigator-designated local laboratory table. The central 
laboratory will report results if a validated test or calculation is available. 
In circumstances where required in accordance with local regulations, local laboratory testing 
may be performed in lieu of Lilly-designated central laboratory testing (in the table below). 
Local testing may be performed in addition to central testing when necessary for immediate 
participant management.  
The local laboratory must be qualified in accordance with applicable local regulations. 
Tests assayed by Lilly-designated central laboratory 
Hepatic Hematology Panel 
a 
Hepatitis A virus (HAV) testing: 
   Hemoglobin 
    HAV total antibody 
   Hematocrit 
    HAV IgM antibody 
   Erythrocytes (RBCs - red blood cells) 
Hepatitis 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 
Hepatitis 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) c 
   Creatine kinase (CK) 
Anti-actin antibody d 
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 
 
Tests assayed ONLY by investigator-designated local laboratory 
Acetaminophen 
Cytomegalovirus (CMV) testing: 
Acetaminophen protein adducts 
    CMV antibody 
Alkaline phosphatase isoenzymes 
    CMV DNA b 
Ceruloplasmin 
Herpes simplex virus (HSV) testing: 
Copper 
    HSV (Type 1 and 2) antibody 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
85 
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 
a Hepatic hematology samples were assayed by Labcorp Pharmaceutical Research and Development (Shanghai) 
Co., Ltd. and were destroyed by Shanghai Solid Waste Disposal Co., Ltd. 
b Reflex/confirmation dependent on regulatory requirements, testing availability, or both. 
c Not required if anti-actin antibody is tested. 
d Not required if anti-smooth muscle antibody (ASMA) is tested. 
 
 
 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
86 
10.6. 
Appendix 6: World Health Organization Classification of Diabetes 
and Diagnostic Criteria  
Type 1 Diabetes Mellitus:  Type 1 diabetes mellitus is judged to be present when the classical 
symptoms of diabetes (thirst, polyuria, wasting and stupor, or coma) are associated with readily 
detectable concentrations of glucose and ketone bodies in the blood and urine.  Insulin treatment 
is necessary not only to control hyperglycemia but also to prevent spontaneous ketosis and death. 
Type 2 Diabetes Mellitus:  Type 2 diabetes mellitus, although often asymptomatic, may also 
present with classical hyperglycemic symptoms (thirst, polyuria, weight loss), but despite 
hyperglycemia, ketone bodies are present in only low concentrations in the blood and urine.  
Coma is rare in T2DM, but may result from extreme hyperglycemia and hyperosmolarity; lactic 
acidosis or ketoacidosis can also occur in fulminating illness (for example, severe infection or 
mesenteric artery thrombosis) due to an acute increase in insulin requirements, but spontaneous 
ketosis does not occur.  Some patients with T2DM later progress to a state of absolute insulin 
deficiency (Alberti and Zimmet 1998).  
 
 
 
 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
87 
10.7. 
Appendix 7: Protocol GPIU Standardized Protocols for the 
Measurement of Height, Weight and Waist Circumference  
The following information has been adapted from standardized physical measurement protocols 
for the World Health Organization’s STEP wise approach to Surveillance (STEPS) (WHO 2017) 
(Available at:  
https://www.who.int/ncds/surveillance/steps/Section%204%20Step%202%20Physical%20Measu
rements.pdf) Accessed January 17, 2019. 
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 centimeters (cm). 
Measuring Weight 
 Body weight measurements should be done in a consistent manner using a calibrated 
electronic scale capable of measuring weight in kilograms. 
 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. 
Step 1. Ask the participant to remove their footwear, outerwear (coat, jacket, etc.), 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 
kilograms (kg) to the nearest one-tenth kg. 
Measuring Waist Circumference 
 Waist circumference should be measured at midpoint, between lower margin of least 
palpable rib and top of iliac crest (approximately 1 inch (2.54 cm) above the navel). 
 Participants should be lightly clothed. 
Step 1. Ask the participant to stand with their feet close together, and arms at their side with 
their body weight evenly distributed. 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
88 
Step 2. Ask participant to relax 
Step 3. Measurements should be recorded at the end of a normal expiration. 
 
 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
89 
10.8. 
Appendix 8: 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 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 Good Clinical 
Practice, enabling participants to continue safely in the study and maintaining the integrity of the 
study. 
Informed consent 
Additional consent 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.  
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. 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
90 
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, medical history, AEs and product complaints, concomitant 
medications, diabetes education, reminding 7-point SMBG, reviewing diary. 
Other alternative locations:  Laboratory testing in local hospital is permitted based on 
the discretion of investigator with the approval of sponsor. 
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 product complaints 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.  However, central 
laboratory testing must be retained for: HbA1c and FSG at Visit 3 and Visit 11.  The local 
laboratory must be qualified in accordance with applicable local regulations.  Clinically 
significant laboratory findings could be recorded as an AE in the AE CRF at the discretion of 
investigator. 
Study intervention and ancillary supplies (including participant diaries) 
When a participant 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 completion of a full study visit,  
 asking the participant’s designee to go to the site and receive study supplies on a 
participant’s behalf,  
 arranging delivery of study supplies, and 
These requirements must be met before 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 
verification of participant’s receipt of study supplies. 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
91 
 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. 
Screening period guidance  
To ensure safety of study participants, laboratory values and other eligibility assessments taken 
at Visit 1 are valid for a maximum of 60 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 60 days from Visit 1 to Visit 3: the participant will 
proceed to the next study visit per the usual SoA, provided that Visit 3 must be 
conducted within 60 days from Visit 1.  
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 60 days from Visit 1: The participant must be 
discontinued because of screening interruption due to an exceptional 
circumstance.  This is documented as a screen failure in the CRF.   
Adjustments to visit windows 
Whenever possible and safe to do so, as determined by the investigator’s discretion, participants 
should complete the usual SoA.  To maximize the possibility that these visits can be conducted 
as on-site visits, the windows for visits may be adjusted, upon further guidance from the sponsor. 
This minimizes missing data and preserves the intended conduct of the study. 
This table describes the allowed adjustments to visit windows. 
Visit Number 
Tolerance 
Visit 1 (Screening) 
No change. 
Visit 2 
At least 4 days before Visit 3. 
Visit 3 (Randomization) 
Within 60 days after Visit 1. 
Visit 3 through 8 
Within 7 days before or after the intended date. 
Visit 9 through 10 
Within 14 days before or after the intended date. 
Visit 11 or Visit 99 
Within 14 days before the intended date, or up to 28 days after the intended date. 
Visit 801 
No change. 
For participants whose visits have extended windows at Visit 11, additional study intervention 
may need to be provided to avoid interruption and maintain overall integrity of the study. 
Documentation 
Changes to study conduct will be documented 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
92 
Sites will identify and document the details of how participants, visit types, and conducted 
activities were affected by exceptional circumstances.  Dispensing/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 part of the 
investigator’s source documentation and should be transferred to the site in a secure and timely 
manner. 
 
 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
93 
10.9. 
Appendix 9: Abbreviations and Definitions  
 
Term 
Definition 
AE 
adverse event 
ALP 
alkaline phosphatase  
ALT 
alanine aminotransferase  
ANCOVA 
analysis of covariance  
AST 
aspartate aminotransferase  
BG 
blood glucose  
blinding/masking 
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. 
BMI 
body mass index  
CFR 
Code of Federal Regulations  
CHF 
congestive heart failure  
CK 
creatine kinase 
COA 
clinical outcome assessment  
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. 
CONSORT 
Consolidated Standards of Reporting Trials  
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  
CSR 
clinical study report  
CT 
computed tomography  
D. Bil 
direct bilirubin  
EAS 
efficacy analysis set  
ECG 
electrocardiogram 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
94 
EDC 
electronic data capture 
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. 
EQ-5D-5L 
European Quality of Life-Dimensions  
ET 
early termination  
FAS 
full analysis set 
FBG 
fasting blood glucose  
FSG 
fasting serum glucose 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyltransferase  
GIP 
glucose dependent insulinotropic polypeptide  
GLP-1 
glucagon like peptide-1  
GPIU 
I8F-MC-GPIU 
HbA1c 
hemoglobin A1c 
IB 
Investigator’s Brochure  
ICF 
informed consent form  
ICH 
International Council for Harmonisation 
IDF 
International Diabetes Federation  
IEC 
Independent Ethics Committees 
investigational 
product 
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form. See also “IMP.” 
IRB 
Institutional Review Boards 
ISR 
injection site reaction 
IWQOL-Lite-CT 
Impact of Weight on Quality of Life-Lite Clinical Trials Version  
IWRS 
Interactive Web Response System  
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
95 
MedDRA 
Medical Dictionary for Regulatory Activities 
medication error 
Errors in the prescribing, dispensing, or administration of a study intervention, 
regardless of whether or not the medication is administered to the participant or the 
error leads to an AE. Medication error generally involve a failure to uphold one or more 
of the five “rights” of medication use: the right participant, the right drug, the right 
dose, right route, at the right time. 
In addition to the core five rights, the following may also represent medication errors:  
• dose omission associated with an AE or a product complaint 
• dispensing or use of expired medication 
• use of medication past the recommended in-use date 
• dispensing or use of an improperly stored medication 
• use of an adulterated dosage form or administration technique inconsistent with the 
medication's labeling (for example, Summary of Product Characteristics, IB, local 
label, protocol), or 
• shared use of cartridges, prefilled pens, or both. 
MEN2 
multiple endocrine neoplasia syndrome type 2 
misuse 
Use of a study intervention for self-treatment that either is inconsistent with the 
prescribed dosing regimen, indication, or both, or is obtained without a prescription 
mITT 
modified intention to treat  
MMRM 
mixed model for repeated measures  
MRI 
magnetic resonance imaging  
MTC 
medullary thyroid carcinoma  
OTC 
over-the-counter 
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 
PRO 
patient-reported outcome 
QTL 
quality tolerance limit 
QW 
once weekly  
SAE 
serious adverse event  
SAP 
statistical analysis plan  
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.  
SD 
standard deviation 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
96 
SDP 
single-dose pen  
SMBG 
self-monitoring of blood glucose  
SoA 
Schedule of Activities  
SS 
safety analysis set 
SUSAR 
Suspected unexpected serious adverse reaction 
T1DM 
type 1 diabetes mellitus  
T2DM 
type 2 diabetes mellitus  
TBL 
total bilirubin  
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal  
 
 
 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
97 
11. 
References  
[ADA] American Diabetes Association Professional Practice Committee; 5. Facilitating 
Behavior Change and Well-being to Improve Health Outcomes: Standards of Medical Care in 
Diabetes-2023. Diabetes Care. 2023a; 46(Supple 1):S68–S96. https://doi.org/10.2337/dc23-
S005. 
[ADA] American Diabetes Association Professional Practice Committee; 6. Glycemic Targets: 
Standards of Medical Care in Diabetes-2023. Diabetes Care. 2023b;46(Supple 1):S97–S110. 
https://doi.org/10.2337/dc23-S006. 
Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its 
complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a 
WHO consultation. Diabet Med. 1998;15(7):539-553. 
Aroda VR, Ratner R. The safety and tolerability of GLP‑1 receptor agonists in the treatment of 
type 2 diabetes: a review. Diabetes Metab Res Rev 2011;27(6):528‑542. 
Alosh M, Bretz F, Huque M. Advanced multiplicity adjustment methods in clinical trials. Stat 
Med. 2014;33(4):693-713. 
Banks PA, Freeman ML; Practice Parameters Committee of the American College of 
Gastroenterology. Practice guidelines in acute pancreatitis. Am J Gastroenterol. 
2006;101(10):2379-2400. 
Battelino T, Bergenstal R, Rodriguez A. et al. Effect of tirzepatide versus insulin degludec on 
glycaemic control captured with continuous glucose monitoring in patients with type 2 diabetes 
(SURPASS-3 CGM). In Diabetologia (Vol. 64, No. Suppl 1, pp. 244-244); 2022. New York, 
NY, United States: Springer. 
Bretz F, Maurer W, Brannath W, Posch M. A graphical approach to sequentially rejective 
multiple test procedures. Stat Med. 2009;28(4):586-604. https://doi.org/10.1002/sim.3495 
Bretz F, Posch M, Glimm E, et al. Graphical approaches for multiple comparison procedures 
using weighted Bonferroni, Simes, or parametric tests. Biom J. 2011;53(6):894-913. 
https://doi.org/10.1002/bimj.201000239 
Dahl D, Onishi Y, Norwood P, et al. Effect of subcutaneous tirzepatide vs placebo added to 
titrated insulin glargine on glycemic control in patients with type 2 diabetes: The SURPASS-5 
randomized clinical trial. JAMA. 2022;327(6):534–545. https://doi.org/10.1001/jama.2022.0078 
Danne T, Philotheou A, Goldman D, et al. A randomized trial comparing the rate of 
hypoglycemia – assessed using continuous glucose monitoring – in 125 preschool children with 
type 1 diabetes treated with insulin glargine or NPH insulin (the PRESCHOOL study). Pediatr 
Diabetes. 2013;14(8):593-601. https://doi.org/10.1111/pedi.12051 
Del Prato S, Kahn SE, Pavo I, et al. Tirzepatide versus insulin glargine in type 2 diabetes and 
increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, 
multicentre, phase 3 trial. Lancet. 2021;398(10313):1811-1824. https://doi.org/10.1016/S0140-
6736(21)02188-7 
EuroQol Research Foundation. EQ-5D-5L user guide, version 3.0. Updated September 2019. 
https://euroqol.org/publications/user-guide 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
98 
[FDA’s guidance on PROs] Food and Drug Administration. [WWW document]. Guidance for 
industry: patient-reported outcome measures: use in medical product development to support 
labeling claims. URL http://www.fda.gov/downloads/Drugs/GuidanceCompliance 
RegulatoryInformation/Guidances/UCM193282.pdf (accessed in December 2022) 
Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus semaglutide once weekly in patients 
with type 2 diabetes. N Engl J Med. 2021;385(6):503-515. 
https://doi.org/10.1056/NEJMoa2107519 
Gastaldelli A, Cusi K, Lando LF, et al. Effect of tirzepatide versus insulin degludec on liver fat 
content and abdominal adipose tissue in patients with type 2 diabetes (SURPASS-3 MRI). In 
Diabetologia (Vol. 64, No. Suppl 1, pp. 219-220); 2022. New York, NY, United States: 
Springer. 
[IDF] International Diabetes Federation. IDF Diabetes Atlas. 10th ed. 2021. Accessed Jan 8, 
2023. https://diabetesatlas.org/atlas/tenth-edition/ 
Koizumi M, Takada T, Kawarada Y, et al. JPN guidelines for the management of acute 
pancreatitis: diagnostic criteria for acute pancreatitis. J Hepatobiliary Pancreat Surg. 
2006;13(1):25-32. https://doi.org/10.1007/s00534-005-1048-2 
Kolotkin RL, Ervin CM, Meincke HH, et al. Development of a clinical trials version of the 
impact of weight on quality of life-lite questionnaire (IWQOL-Lite clinical trials version): results 
from two qualitative studies. Clin Obes. 2017;7(5):290-299. https://doi.org/10.1111/cob.12197 
Kolotkin RL, WilliamsV, Ervin, CM, Meincke HH, Qin S, Smith LvH, Fehnel SE. Validation of 
a new measure of quality of life in obesity trials: IWQOL –Lite Clinical Trials Version. Poster 
presented at: ObesityWeek 2018 
Kolotkin RL, Williams VSL, Ervin CM, et al. Validation of a new measure of quality of life in 
obesity trials: impact of weight on quality of life-lite clinical trials version. Clin Obes. 
2019;9(3):e12310. https://doi.org/10.1111/cob.12310 
Lind M, Imberg H, Coleman RL, Nerman O,  Holman RR. Historical HbA1c Values May 
Explain the Type 2 Diabetes Legacy Effect: UKPDS 88. Diabetes Care. 2021; 44 (10): 2231–
2237. https://doi.org/10.2337/dc20-2439 
Ludvik B, Giorgino F, Jódar E, et al. Once-weekly tirzepatide versus once-daily insulin degludec 
as add-on to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes 
(SURPASS-3): a randomised, open-label, parallel-group, phase 3 trial. Lancet. 
2021;398(10300):583-598. https://doi.org/10.1016/S0140-6736(21)01443-4 
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. 
Rosenstock J, Wysham C, Frías JP, et al. Efficacy and safety of a novel dual GIP and GLP-1 
receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, 
randomised, phase 3 trial. Lancet. 2021;398(10295):143-155. https://doi.org/10.1016/S0140-
6736(21)01324-6. Erratum in: Lancet. 2021;398(10296):212. https://doi.org/10.1016/S0140-
6736(21)01556-7 
Approved on 05 Dec 2023 GMT

CONFIDENTIAL 
Protocol I8F-MC-GPIU(b) 
99 
Rubin DB. Multiple Imputation for Nonresponse in Surveys. New York: John Wiley & Sons 
Inc.;1987. 
Steinberg WM, Buse JB, Ghorbani MLM, Ørsted DD, Nauck MA, LEADER Steering 
Committee; LEADER Trial Investigators. Amylase, lipase, and acute pancreatitis in people with 
type 2 diabetes treated with liraglutide: Results from the LEADER randomized trial. Diabetes 
Care. 2017a;40(7):966-972. [Erratum in: Diabetes Care. 2018 Jul;41(7):1538.] 
Steinberg WM, Rosenstock J, Wadden TA, Donsmark M, Jensen CB, DeVries JH. Impact of 
liraglutide on amylase, lipase, and acute pancreatitis in participants with overweight/obesity and 
normoglycemia, prediabetes, or type 2 diabetes: Secondary analyses of pooled data from the 
SCALE clinical development program. Diabetes Care. 2017b;40(7):830-848. 
Weinberg ME, Bacchetti P, Rushakoff RJ. Frequently repeated glucose measurements 
overestimate the incidence of inpatient hypoglycemia and severe hyperglycemia. J Diabetes Sci 
Technol. 2010;4(3):577-582. https://doi.org/10.1177/193229681000400311 
 
 
 
Approved on 05 Dec 2023 GMT

Signature Page for VV-CLIN-135757 v1.0
Signature Page for VV-CLIN-135757 v1.0
Approval
Medical Director
04-Dec-2023 14:23:04 GMT+0000
Approval
Statistician
05-Dec-2023 19:29:39 GMT+0000
Approved on 05 Dec 2023 GMT
PPD
PPD