A Phase 4, Randomized, Open-Label, Active-Controlled Study to Investigate the Efficacy and Safety of Switching From Weekly Dulaglutide to Weekly Tirzepatide in Adults With Type 2 Diabetes
Phase: PHASE4
Conditions: Type 2 Diabetes
Sponsor: Eli Lilly and Company

Protocol: I8F-MC-GPIH 
 
 
A Phase 4, Randomized, Open-Label, Active-Controlled Study to Investigate the Efficacy and 
Safety of Switching from Weekly Dulaglutide to Weekly Tirzepatide in Adults with Type 2 
Diabetes 
 
 
NCT05564039 
 
 
Approval Date: 09-Mar-2023 
 

CONFIDENTIAL 
Protocol I8F-MC-GPIH(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 Phase 4, Randomized, Open-Label, Active-Controlled Study to Investigate the Efficacy and 
Safety of Switching from Weekly Dulaglutide to Weekly Tirzepatide in Adults with Type 2 
Diabetes 
Protocol Number: I8F-MC-GPIH 
Amendment Number: b 
Compound: tirzepatide (LY3298176) 
Brief Title: 
A study to investigate the efficacy and safety of switching from weekly dulaglutide to weekly 
tirzepatide in adults with Type 2 diabetes 
Study Phase: 4 
Acronym: SURPASS-SWITCH 
Sponsor Name: Eli Lilly and Company 
Legal Registered Address: Indianapolis, Indiana, USA 46285 
Regulatory Agency Identifier Number(s) 
IND: 128801 
EU Trial Number: 2022-500101-41-00 
Approval Date: Protocol Amendment (b) Electronically Signed and Approved by Lilly on date 
provided below. 
Document ID: VV-CLIN-082267 
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Protocol I8F-MC-GPIH(b) 
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Lilly Medical Monitor Name and Contact Information will be provided separately. 
 
 
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Protocol I8F-MC-GPIH(b) 
3 
Protocol Amendment Summary of Changes Table  
 
DOCUMENT HISTORY 
Document 
Date 
Protocol amendment (a) 
20-Jan-2023 
Original Protocol 
01-Jul-2022 
Amendment (b) 
This amendment is considered to be nonsubstantial. 
Overall Rationale for the Amendment: 
The primary rationale for this amendment is to incorporate feedback from the EU Member 
States. 
Changes and rationale are summarized in the table below. Minor editorial changes are not 
included in this table. 
 
Section # and Name 
Description of Change 
Brief Rationale 
1.3. Schedule of Activities 
(SoA) 
Weight and diabetes counseling, 
training, and education have been 
added to every visit starting from 
Visit 3 onwards. 
As per feedback from the EU 
Member States  
5.3. Lifestyle 
Considerations 
Participant exercise and diet section 
revised 
As per feedback from the EU 
Member States 
 
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Protocol I8F-MC-GPIH(b) 
4 
Table of Contents 
1.
Protocol Summary ..........................................................................................................7
1.1.
Synopsis ............................................................................................................................7
1.2.
Schema ............................................................................................................................11
1.3.
Schedule of Activities (SoA) ..........................................................................................12
2.
Introduction ...................................................................................................................19
2.1.
Study Rationale ...............................................................................................................19
2.2.
Background .....................................................................................................................19
2.3.
Benefit/Risk Assessment ................................................................................................20
3.
Objectives, Endpoints, and Estimands .......................................................................21
4.
Study Design ..................................................................................................................24
4.1.
Overall Design ................................................................................................................24
4.1.1.
Design Outline ................................................................................................................24
4.2.
Scientific Rationale for Study Design ............................................................................26
4.3.
Justification for Dose ......................................................................................................27
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 ................................................................................................................31
5.5.
Criteria for Temporarily Delaying Enrollment of a Participant .....................................32
6.
Study Intervention(s) and Concomitant Therapy .....................................................33
6.1.
Study Intervention(s) Administered................................................................................33
6.1.1.
Dose Escalation ...............................................................................................................33
6.1.2.
Administration Instructions ............................................................................................34
6.1.3.
Medical Devices..............................................................................................................34
6.1.4.
Rescue Therapy ...............................................................................................................35
6.2.
Preparation, Handling, Storage, and Accountability ......................................................36
6.3.
Measures to Minimize Bias: Randomization and Blinding ............................................36
6.4.
Study Intervention Compliance ......................................................................................36
6.5.
Dose Modification ..........................................................................................................37
6.5.1.
Management of Participants with Gastrointestinal Symptoms .......................................37
6.5.2.
Study Intervention Dose Modification............................................................................37
6.6.
Continued Access to Study Intervention after the End of the 
Study ...............................................................................................................................38
6.7.
Treatment of Overdose ...................................................................................................38
6.8.
Concomitant Therapy .....................................................................................................38
6.8.1.
Concomitant Therapy Regimens.....................................................................................38
6.8.2.
Concomitant Therapy Data Collection ...........................................................................39
6.8.3.
Prohibited Concomitant Medications .............................................................................39
6.8.4.
Allowed Antihyperglycemic Treatments other than Study 
Interventions ...................................................................................................................40
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Protocol I8F-MC-GPIH(b) 
5 
6.8.5. 
Reduction and/or Discontinuation of Concomitant 
Antihyperglycemic Medications .....................................................................................40 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................41 
7.1. 
Discontinuation of Study Intervention ............................................................................41 
7.1.1. 
Liver Chemistry Stopping Criteria ..................................................................................42 
7.1.2. 
QTc Stopping Criteria .....................................................................................................42 
7.1.3. 
Temporary Discontinuation of Study Intervention .........................................................43 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................44 
7.3. 
Lost to Follow-up............................................................................................................44 
8. 
Study Assessments and Procedures.............................................................................45 
8.1. 
Efficacy Assessments .....................................................................................................45 
8.1.1. 
Primary Efficacy Assessment .........................................................................................45 
8.1.2. 
Other Efficacy Assessments ...........................................................................................45 
8.2. 
Safety Assessments .........................................................................................................47 
8.2.1. 
Physical Examinations ....................................................................................................47 
8.2.2. 
Vital Signs .......................................................................................................................48 
8.2.3. 
Electrocardiograms .........................................................................................................48 
8.2.4. 
Dilated Fundoscopic Examination ..................................................................................48 
8.2.5. 
Clinical Safety Laboratory Tests ....................................................................................49 
8.2.6. 
Pregnancy Testing ...........................................................................................................49 
8.2.7. 
Hepatic Monitoring .........................................................................................................50 
8.3. 
Adverse Events, Serious Adverse Events, and Product 
Complaints ......................................................................................................................52 
8.3.1. 
Timing and Mechanism for Collecting Events ...............................................................53 
8.3.2. 
Pregnancy ........................................................................................................................54 
8.3.3. 
Safety Topics of Special Interest ....................................................................................55 
8.4. 
Pharmacokinetics ............................................................................................................61 
8.5. 
Pharmacodynamics .........................................................................................................61 
8.6. 
Genetics ..........................................................................................................................61 
8.7. 
Biomarkers ......................................................................................................................61 
8.8. 
Immunogenicity Assessments.........................................................................................61 
8.9. 
Medical Resource Utilization and Health Economics ....................................................61 
9. 
Statistical Considerations .............................................................................................62 
9.1. 
Statistical Hypotheses .....................................................................................................62 
9.1.1. 
Multiplicity Adjustment ..................................................................................................62 
9.2. 
Analysis Sets ...................................................................................................................63 
9.3. 
Statistical Analyses .........................................................................................................63 
9.3.1. 
General Considerations ...................................................................................................63 
9.3.2. 
Primary Endpoint Analysis .............................................................................................64 
9.3.3. 
Secondary Endpoint Analysis .........................................................................................65 
9.3.4. 
Exploratory Endpoint Analysis .......................................................................................65 
9.3.5. 
Safety Analyses ...............................................................................................................65 
9.3.6. 
Subgroup Analyses .........................................................................................................67 
9.4. 
Interim Analysis ..............................................................................................................67 
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Protocol I8F-MC-GPIH(b) 
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9.5. 
Sample Size Determination ............................................................................................67 
10. 
Supporting Documentation and Operational Considerations ..................................68 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................68 
10.1.1. Regulatory and Ethical Considerations ...........................................................................68 
10.1.2. Financial Disclosure........................................................................................................69 
10.1.3. Informed Consent Process ..............................................................................................69 
10.1.4. Data Protection................................................................................................................69 
10.1.5. Committees Structure......................................................................................................70 
10.1.6. Dissemination of Clinical Study Data.............................................................................70 
10.1.7. Data Quality Assurance ..................................................................................................71 
10.1.8. Source Documents ..........................................................................................................72 
10.1.9. Study and Site Start and Closure ....................................................................................73 
10.1.10. Publication Policy ...........................................................................................................73 
10.1.11. Investigator Information .................................................................................................73 
10.1.12. Sample Retention ............................................................................................................74 
10.2. 
Appendix 2: Clinical Laboratory Tests ...........................................................................75 
10.2.1. Laboratory Samples to be Obtained at the Time of a Systemic 
Hypersensitivity Event ....................................................................................................77 
10.3. 
Appendix 3: Adverse Events and Serious Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-
up, and Reporting ............................................................................................................78 
10.3.1. Definition of AE .............................................................................................................78 
10.3.2. Definition of SAE ...........................................................................................................79 
10.3.3. Definition of Product Complaints ...................................................................................80 
10.3.4. Recording and Follow-Up of AE and/or SAE and Product 
Complaints ......................................................................................................................80 
10.3.5. Reporting of SAEs ..........................................................................................................82 
10.3.6. Regulatory Reporting Requirements ...............................................................................83 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ..........................................................84 
10.4.1. Definitions.......................................................................................................................84 
10.4.2. Contraception Guidance..................................................................................................85 
10.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-up 
Assessments ....................................................................................................................87 
10.6. 
Appendix 6: Country-specific Requirements .................................................................89 
10.6.1. Germany ..........................................................................................................................89 
10.7. 
Appendix 7: Standardized Protocols for the Measurement of 
Height, Weight, Waist Circumference, BMI, and Vital Signs .......................................95 
10.8. 
Appendix 8: Provisions for Changes in Study Conduct During 
Exceptional Circumstances .............................................................................................97 
10.9. 
Appendix 9: Abbreviations and Definitions .................................................................101 
10.10. 
Appendix 10: Protocol Amendment History ................................................................106 
11. 
References ....................................................................................................................111 
 
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Protocol I8F-MC-GPIH(b) 
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1. 
Protocol Summary  
1.1. 
Synopsis  
Protocol Title: 
A Phase 4, Randomized, Open-Label, Active-Controlled Study to Investigate the Efficacy and 
Safety of Switching from Weekly Dulaglutide to Weekly Tirzepatide in Adults with Type 2 
Diabetes 
Brief Title: 
A study to investigate the efficacy and safety of switching from weekly dulaglutide to weekly 
tirzepatide in adults with Type 2 diabetes 
Regulatory Agency Identifier Number(s): 
IND: 128801 
EU Trial Number: 2022-500101-41-00 
Rationale: 
No data are currently available on the experience and potential benefits of switching treatment 
from nonmaximal doses of dulaglutide to tirzepatide as an alternative to maximizing the current 
dulaglutide dose in adults with Type 2 diabetes (T2D). 
This study is designed to investigate the efficacy and safety of switching once weekly 
dulaglutide 0.75 mg or 1.5 mg to once weekly tirzepatide 15 mg or maximum tolerated dose 
(MTD), or continuing and escalating to dulaglutide 4.5 mg or MTD in adults with T2D who are 
currently on a nonmaximal, stable dose of dulaglutide weekly. Data from this study will show 
whether switching treatment from weekly dulaglutide to tirzepatide rather than intensifying the 
dulaglutide dose provides additional efficacy in adults with T2D. 
 
 
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Protocol I8F-MC-GPIH(b) 
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Objectives, Endpoints, and Estimands: 
Objectives 
Endpoints 
Primary 
 
To demonstrate that switching from once 
weekly dulaglutide to once weekly tirzepatide 
is superior to continuing and escalating 
dulaglutide for HbA1c change from baseline 
to Week 40 in participants with T2D 
Change from baseline in HbA1c  
Key Secondary 
 
To demonstrate that switching from once 
weekly dulaglutide to once weekly tirzepatide 
is superior to continuing and escalating 
dulaglutide for weight change from baseline to 
Week 40 in participants with T2D 
Change from baseline in weight  
Abbreviations: HbA1c = hemoglobin A1c; T2D = Type 2 diabetes. 
There will be 2 primary estimands evaluated in this study: 
 The treatment-regimen estimand is consistent with the US Prescribing Information. This 
estimand reflects efficacy when participants with T2D are treated in clinical practice and 
takes into account both tolerability and efficacy. 
 The efficacy estimand focuses on the treatment effect if participants who underwent 
randomization continued to receive the study treatment without rescue for severe, 
persistent hyperglycemia, and/or prohibited medication. This estimand will be used in 
publications to inform prescribers and physicians. 
Overall Design: 
SURPASS-SWITCH is a Phase 4, randomized, open-label, active-controlled, parallel-group, 
multicenter, multinational trial to assess the efficacy and safety of tirzepatide 15 mg or MTD 
compared to dulaglutide 4.5 mg or MTD in participants with T2D. 
This study will enroll participants with inadequately controlled T2D who are taking dulaglutide 
once weekly (0.75 mg or 1.5 mg) for at least 6 months prior to Visit 1, with or without (up to 3) 
background OAMs. 
Participants will be randomly assigned 1:1 to either 
 continue with and escalate dulaglutide to 4.5 mg or MTD, or 
 tirzepatide 15 mg or MTD. 
Participants who are randomly assigned to tirzepatide will discontinue dulaglutide and initiate 
tirzepatide within 3 days of their next scheduled dose. The starting dose for tirzepatide is 2.5 mg 
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Protocol I8F-MC-GPIH(b) 
9 
once weekly for 4 weeks, escalated in 2.5-mg increments every 4 weeks until 15 mg or MTD is 
achieved. 
Brief Summary: 
The purpose of this study is to measure HbA1c with switching to tirzepatide compared with 
continuing and escalating dulaglutide in participants with Type 2 diabetes. 
The maximum duration of study participation is approximately 47 weeks. This study includes 
 an approximate 3-week screening period 
 a 40-week treatment period, and 
 a 4-week safety follow-up period. 
The visit frequency will be every 4 to 8 weeks. 
Study Population: 
In general, an individual may take part in the study if they 
 are ≥18 years of age at screening, or older per local regulations 
 have HbA1c of ≥7.0% to ≤9.5%, inclusive, at screening 
 are currently on a stable dose of dulaglutide 
 are not treated with oral antihyperglycemic medication, or are on a stable dose of up to 3 
oral antihyperglycemic medication 
 have a stable body weight 
 have a body mass index ≥25 kg/m2 at screening 
 are reliable and willing to make themselves available for the duration of the study and are 
willing and able to follow study procedures as required, and 
 give consent to participate. 
In general, an individual may not take part in the study if they 
 have a diagnosis of Type 1 diabetes 
 have been treated with insulin prior to screening (exception: use for gestational diabetes 
or short-term use [<14 days]) 
 have a history of reduction of the dose of dulaglutide due to intolerability, without 
successful reescalation, and 
 have a history or presence of an underlying disease, or surgical, physical, or medical 
condition that, in the opinion of the investigator, would potentially affect participant 
safety within the study or interfere with the interpretation of data. 
Number of Participants: 
Approximately 250 participants will be randomly assigned to study intervention. 
Ethical Considerations of Benefit/Risk: 
Overall, known benefits associated with tirzepatide in people with T2D outweigh known risks 
associated with the therapy. Detailed information about the known and expected benefits and 
risks and reasonably expected adverse events of tirzepatide may be found in the Investigator’s 
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Protocol I8F-MC-GPIH(b) 
10 
Brochure and package insert. In addition, detailed information about the known and expected 
benefits and risks of dulaglutide may be found in the dulaglutide package insert. 
Data Monitoring Committee: No 
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Protocol I8F-MC-GPIH(b) 
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1.2. 
Schema  
 
 
Abbreviations: FU = follow-up; MTD = maximum tolerated dose; TZP = tirzepatide. 
 
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Protocol I8F-MC-GPIH(b) 
12 
1.3. 
Schedule of Activities (SoA)  
Fasting Visits: Participants should fast at least 8 hours without eating, drinking (except water), or performing any significant physical 
activity before the visit. If a participant attends these visits in a nonfasting state, the sample should still be collected. 
The visit date is determined in relation to the date of the randomization visit (± the allowed visit window). 
Study I8F-MC-GPIH 
Period I - 
Screening 
Period II- Treatment Period  
Period III- 
Post-
treatment 
Follow-up  
Comments 
Visits 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
ED 
801 
ED = early discontinuation 
Weeks from randomization  
-3 
-2 
0 
4 
8 
12 
16 
20 
24 
32 
40 
— 
4 weeks 
after the 
last dose 
 
Visit interval tolerance (days) 
 
±3 
±7 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
— 
±7 
 
Fasting visit 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
The ICF must be signed before any 
protocol-specific tests or procedures are 
performed. See Section 10.1.3 for 
additional details. 
Inclusion and exclusion criteria, 
review and confirm 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Confirm the inclusion and exclusion 
criteria prior to randomization.  
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Includes ethnicity (where permissible), 
year of birth, sex, and race. 
Preexisting conditions and medical 
history, including relevant surgical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Collect all ongoing conditions and 
relevant past surgical and medical 
history.  
Prespecified medical history  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Collect additional data for the 
indication and comorbidities of interest.  
Substance use (alcohol, caffeine, 
tobacco use) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior treatments for indication 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Add details of T2D medication. 
Includes medications used for T2D 
since diagnosis. 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
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Protocol I8F-MC-GPIH(b) 
13 
Study I8F-MC-GPIH 
Period I - 
Screening 
Period II- Treatment Period  
Period III- 
Post-
treatment 
Follow-up  
Comments 
Visits 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
ED 
801 
ED = early discontinuation 
Weeks from randomization  
-3 
-2 
0 
4 
8 
12 
16 
20 
24 
32 
40 
— 
4 weeks 
after the 
last dose 
 
Visit interval tolerance (days) 
 
±3 
±7 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
— 
±7 
 
Fasting visit 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse events (AEs) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Any events that occur after signing the 
informed consent. Collect additional 
data for safety topics of special interest 
(Section 8.3.3). 
Physical Evaluation 
 
Height 
X 
 
  
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Waist circumference 
X 
 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Includes pulse rate and blood pressure. 
Measure after participant has been 
sitting at least 5 min and before 
obtaining an ECG tracing and 
collection of blood samples for 
laboratory testing. See Section 8.2.2. 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
X 
X 
X 
See Section 8.2.1. 
Symptom-directed physical 
assessment 
 
X (see Comments) 
  
  
  
Symptom-directed physical assessment 
will be conducted at the discretion of 
the investigator or qualified healthcare 
professional per local regulations, as 
indicated based on participant status 
and standard of care.  
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Protocol I8F-MC-GPIH(b) 
14 
Study I8F-MC-GPIH 
Period I - 
Screening 
Period II- Treatment Period  
Period III- 
Post-
treatment 
Follow-up  
Comments 
Visits 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
ED 
801 
ED = early discontinuation 
Weeks from randomization  
-3 
-2 
0 
4 
8 
12 
16 
20 
24 
32 
40 
— 
4 weeks 
after the 
last dose 
 
Visit interval tolerance (days) 
 
±3 
±7 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
— 
±7 
 
Fasting visit 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
12-lead ECG (local) 
 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
Perform prior to collection of blood 
samples for laboratory testing. 
Participants should be supine for 
approximately 5 to 10 min before ECG 
collections and remain supine but 
awake during the ECG collection. 
ECGs may be repeated at the 
investigator’s discretion at any visit. 
See Section 8.2.3.  
Dilated fundoscopic examination 
 
X 
 
 
 
 
 
 
 
 
 
 
 
An ophthalmologist or optometrist (if 
allowed by country) will perform the 
examination. See Section 8.2.4. 
Participant Education and Supplies 
 
Diabetes counseling, training, and 
education  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Includes counseling on diet and 
exercise, symptoms, weight, and 
management of hypoglycemia and 
hyperglycemia. 
Repeat training as needed to ensure 
participant compliance. 
BG meter, SMBG training 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Participant will be trained per the 
provided instructions. Additional 
training may occur as needed. 
Dispense BG meter/supplies, as 
needed 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Study intervention injection training 
with demo device 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Train participant prior to starting any 
new injectable type. Additional training 
may occur as needed. 
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Protocol I8F-MC-GPIH(b) 
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Study I8F-MC-GPIH 
Period I - 
Screening 
Period II- Treatment Period  
Period III- 
Post-
treatment 
Follow-up  
Comments 
Visits 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
ED 
801 
ED = early discontinuation 
Weeks from randomization  
-3 
-2 
0 
4 
8 
12 
16 
20 
24 
32 
40 
— 
4 weeks 
after the 
last dose 
 
Visit interval tolerance (days) 
 
±3 
±7 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
— 
±7 
 
Fasting visit 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Remind participants about 7-point 
SMBG 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Remind participant to monitor 7-point 
SMBG profiles (prior to and 2 hrs after 
the 3 main meals and at bedtime) on 2 
nonconsecutive days during the 2 
weeks preceding the specified visits. 
Review 7-point SMBG values 
collected in the diary 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Review hypoglycemic events 
collected in the diary 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Participant Diary (Electronic) 
 
Participant diary dispensed 
 
X 
 
 
 
 
 
 
 
 
 
 
 
eDiary includes SMBG values, 
collection of intervention 
administration information on dosing 
days, and hypoglycemia.  
Diary compliance check 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Diary return 
 
 
 
 
 
 
 
 
  
 
 
X 
X 
 
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Protocol I8F-MC-GPIH(b) 
16 
Study I8F-MC-GPIH 
Period I - 
Screening 
Period II- Treatment Period  
Period III- 
Post-
treatment 
Follow-up  
Comments 
Visits 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
ED 
801 
ED = early discontinuation 
Weeks from randomization  
-3 
-2 
0 
4 
8 
12 
16 
20 
24 
32 
40 
— 
4 weeks 
after the 
last dose 
 
Visit interval tolerance (days) 
 
±3 
±7 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
— 
±7 
 
Fasting visit 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Patient-Reported Outcomes (Electronic) 
Complete prior to any clinical assessments 
 
Impact of Weight on 
Self-Perception (IW-SP) 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
Complete PROs before any other study 
procedures if the participant is not 
adversely affected by the fasting 
condition or after the participant has 
sufficiently recovered from the 
preceding visit procedures. Must be 
completed on eCOA device. 
Ability to Perform Physical 
Activities of Daily Living 
(APPADL) 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
Impact of Weight on Quality of 
Life-Lite-Clinical Trials Version 
(IWQOL-Lite-CT) 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
Emotional Impact of Diabetes 
Treatment Questionnaire – 
Comparison (EIDTQc) 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Global Impression of Emotional 
Health (1 week recall) 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
Global Impression of Emotional 
Health (since study start recall) 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Laboratory Tests and Sample Collections 
 
Hematology  
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
Hemoglobin A1c (HbA1c) 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Clinical chemistry  
X 
 
X 
 
 
 
 
 
X 
 
X 
X 
X 
 
Glucose 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Lipid panel 
  
 
X 
 
 
 
 
 
X 
 
X 
X 
 
 
Serum pregnancy 
X 
 
 
 
 
 
 
 
 
 
  
  
 
Only for WOCBP and females with a 
history of tubal ligation. See Section 
10.4. 
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Protocol I8F-MC-GPIH(b) 
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Study I8F-MC-GPIH 
Period I - 
Screening 
Period II- Treatment Period  
Period III- 
Post-
treatment 
Follow-up  
Comments 
Visits 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
ED 
801 
ED = early discontinuation 
Weeks from randomization  
-3 
-2 
0 
4 
8 
12 
16 
20 
24 
32 
40 
— 
4 weeks 
after the 
last dose 
 
Visit interval tolerance (days) 
 
±3 
±7 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
— 
±7 
 
Fasting visit 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Urine pregnancy (local) 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
Collect for WOCBP. Perform 
additional pregnancy tests, beyond 
those required per the SoA, at any time 
during the study if a menstrual period is 
missed, there is clinical suspicion of 
pregnancy, or as required by local law 
or regulation. 
Follicle-stimulating hormone (FSH) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Optional. Perform as needed to confirm 
postmenopausal status. See Section 
10.4. 
Calcitonin 
X 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
Pancreatic amylase 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
 
Lipase 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
 
Cystatin C 
X 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
Estimated glomerular filtration rate 
(eGFR) 
X 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Calculate using CKD-EPI method. 
Urinary albumin/creatinine ratio 
(UACR) 
X 
 
 
 
 
  
 
 
 
 
X 
X 
X  
 
Anti-GAD antibodies 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization and Dosing using IWRS 
 
Register visit  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Randomization  
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Dispense study intervention  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
 
Self-administration of study 
intervention will be done at home and 
should occur on the day (±3 days) of 
when the next dulaglutide 
administration is planned. 
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Protocol I8F-MC-GPIH(b) 
18 
Study I8F-MC-GPIH 
Period I - 
Screening 
Period II- Treatment Period  
Period III- 
Post-
treatment 
Follow-up  
Comments 
Visits 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
ED 
801 
ED = early discontinuation 
Weeks from randomization  
-3 
-2 
0 
4 
8 
12 
16 
20 
24 
32 
40 
— 
4 weeks 
after the 
last dose 
 
Visit interval tolerance (days) 
 
±3 
±7 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
— 
±7 
 
Fasting visit 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Dispense ancillary supplies  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Participant returns unused study 
intervention and ancillary supplies 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Assess study intervention 
compliance 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Abbreviations: BG = blood glucose; CDK-EPI = Chronic Kidney Disease- Epidemiology Collaboration; ECG = electrocardiogram; eCOA = electronic clinical 
outcome assessment; GAD = glutamic acid decarboxylase; ICF = informed consent form; IWRS = interactive web-response system; PRO = patient-reported 
outcomes; SoA = Schedule of Activities; SMBG = Self-monitoring of blood glucose; T2D = Type 2 Diabetes; WOCBP = women of childbearing potential. 
 
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Protocol I8F-MC-GPIH(b) 
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2. 
Introduction  
2.1. 
Study Rationale  
No data are currently available on the experience and potential benefits of switching treatment 
from nonmaximal doses of dulaglutide to tirzepatide as an alternative to maximizing the current 
dulaglutide dose in adults with T2D. 
This study is designed to investigate the efficacy and safety of switching once weekly 
dulaglutide 0.75 mg or 1.5 mg to once weekly tirzepatide 15 mg or MTD, or continuing and 
escalating to dulaglutide 4.5 mg or MTD in adults with T2D who are currently on a nonmaximal, 
stable dose of dulaglutide weekly. Data from this study will show whether switching treatment 
from weekly dulaglutide to tirzepatide rather than intensifying the dulaglutide dose provides 
additional efficacy in adults with T2D. 
2.2. 
Background  
Existing treatment options 
Injectable incretin-based treatments, for example, GLP-1RAs, are commonly used alone or in 
combination with OAMs and/or basal insulin to achieve and maintain glucose control (ADA 
2022b). 
While associated with lower risk for hypoglycemia and either weight neutral or weight loss 
effects, current preparations are directed at a single incretin molecular target (for example, GLP-
1 receptors). These treatment options offer improved glycemic control, low risk of 
hypoglycemia, and the potential for clinically relevant weight loss. 
Unmet medical need 
Despite the availability of GLP-1 RAs and other antihyperglycemic agents, studies continue to 
show that substantial numbers of patients with T2D do not reach their goals for glycemic and 
weight control (ADA 2022b). 
Therefore, more efficacious treatment options are needed to help more patients with T2D achieve 
individualized treatment goals, such as reduced HbA1c and body weight, than what can be 
achieved with currently available therapies, while providing safe options for treatment 
intensification during disease progression. 
Tirzepatide 
Tirzepatide is a single-molecule GIP and GLP-1 RA recently approved for the treatment of T2D 
in the US. The structure of tirzepatide is engineered from the amino acid sequence for GIP and 
includes a C20 fatty diacid moiety. Tirzepatide has a mean half-life of approximately 5 days, 
which enables once weekly dosing (Coskun et al. 2018). 
Phase 3 clinical studies 
Clinical reductions in HbA1c and body weight 
In a series of 5 global Phase 3 SURPASS studies evaluating treatment with tirzepatide 5 mg, 
10 mg, and 15 mg at different stages of T2D and its treatment continuum, tirzepatide 
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Protocol I8F-MC-GPIH(b) 
20 
demonstrated clinically meaningful reductions in HbA1c and body weight, which were greater 
than placebo, semaglutide 1 mg, titrated insulin degludec, and titrated insulin glargine (Del Prato 
et al. 2021; Frías et al. 2021; Ludvik et al. 2021; Rosenstock et al. 2021; Dahl et al. 2022). These 
treatment effects were sustained up to 104 weeks (Del Prato et al. 2021). 
Improvements in metabolic endpoints 
Tirzepatide also demonstrated greater improvements than comparators in other metabolic 
endpoints such as waist circumference, liver fat content, volume of abdominal visceral and SC 
adipose tissue, and fasting lipid profile (Del Prato et al. 2021; Frías et al. 2021; Ludvik et al. 
2021; Rosenstock et al. 2021; Dahl et al. 2022; Gastaldelli et al. 2022). 
Common adverse events 
Overall, the safety and tolerability profile is similar to the GLP-1 RA class. Gastrointestinal AEs 
such as nausea, vomiting, and diarrhea were the most common AEs seen in the tirzepatide-
treated participants. 
Hypoglycemic events 
In line with the ability of tirzepatide to lower blood glucose 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 RA class (Del Prato et al. 2021; Frías et al. 2021; Ludvik et al. 2021; Rosenstock 
et al. 2021; Dahl et al. 2022). 
Tirzepatide once weekly versus dulaglutide once weekly 
A 26-week Phase 2 study provided initial safety, tolerability, and efficacy data for tirzepatide 
1 mg, 5 mg, 10 mg, and 15 mg in participants with T2D. Doses of 5 mg, 10 mg, and 15 mg of 
tirzepatide QW provided significantly greater reductions in HbA1c and body weight compared 
with dulaglutide 1.5 mg QW. The most common AEs, which were also dose dependent, were 
mild-to-moderate nausea, vomiting, and diarrhea (Frías et al. 2018). 
2.3. 
Benefit/Risk Assessment  
Overall, known benefits associated with tirzepatide in people with T2D outweigh known risks 
associated with the therapy. 
Detailed information about the known and expected benefits and risks and reasonably expected 
adverse events of tirzepatide may be found in the IB and package insert (Mounjaro™ package 
insert [WWW]). 
In addition, detailed information about the known and expected benefits and risks of dulaglutide 
may be found in the dulaglutide package insert (Trulicity® package insert [WWW]; Trulicity® 
summary of product characteristics). 
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Protocol I8F-MC-GPIH(b) 
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3. 
Objectives, Endpoints, and Estimands  
Objectives 
Endpoints 
Primary 
 
To demonstrate that switching from once 
weekly dulaglutide to once weekly tirzepatide 
is superior to continuing and escalating 
dulaglutide for HbA1c change from baseline 
to Week 40 in participants with T2D 
Change from baseline in HbA1c  
Key Secondary 
 
To demonstrate that switching from once 
weekly dulaglutide to once weekly tirzepatide 
is superior to continuing and escalating 
dulaglutide for weight change from baseline to 
Week 40 in participants with T2D 
Change from baseline in weight  
Additional Secondary 
 
To assess the treatment effect of switching 
from once weekly dulaglutide to once weekly 
tirzepatide compared to continuing and 
escalating dulaglutide at Week 40 in 
participants with T2D 
 HbA1c <7%, ≤6.5%, and <5.7% 
 Weight loss from baseline of ≥5%, ≥10%, 
and ≥15% 
 A composite of: 
o HbA1c ≤6.5% 
o weight loss ≥10% from baseline 
o no hypoglycemia, defined as BG 
<54 mg/dL (<3.0 mmol/L) and/or 
severe hypoglycemia 
To assess the treatment effect of switching 
from once weekly dulaglutide to once weekly 
tirzepatide compared to continuing and 
escalating dulaglutide from baseline to Week 
40 in participants with T2D 
Change from baseline in 
 FSG 
 waist circumference 
 BMI 
 Impact of Weight on Quality of Life-
Clinical Trials Version (IWQOL-Lite-
CT) – Physical Functioning Score 
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Protocol I8F-MC-GPIH(b) 
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Exploratory 
 
To assess the treatment effect of switching 
from once weekly dulaglutide to once weekly 
tirzepatide compared to continuing and 
escalating dulaglutide from baseline to Week 
40 in participants with T2D 
Change from baseline in 
 lipids (total cholesterol, HDL, LDL, 
VLDL, and TG) 
 daily average 7-point SMBG profile 
 patient-reported outcomes: 
o IWQOL-Lite-CT: Total, Physical, 
and Psychosocial Scores 
o IW-SP 
o APPADL 
o EIDTQc 
o GIEH – 1 week recall 
o GIEH – since study start recall 
Abbreviations: APPADL = Ability to Perform Physical Activities of Daily Living; BG = blood glucose; BMI = 
body mass index; EIDTQc = Emotional Impact of Diabetes Treatment Questionnaire – Comparison; FSG = 
fasting serum glucose; GIEH = Global Impression of Emotional Health; HbA1c = hemoglobin A1c; HDL = high-
density lipoprotein; IW-SP = Impact of Weight on Self Perception; IWQOL-Lite-CT = Impact of Weight on 
Quality of Life-Clinical Trials Version; LDL = low-density lipoprotein; SMBG = self-monitoring of blood 
glucose; T2D = Type 2 diabetes; TG = triglyceride; VLDL = very-low-density lipoprotein. 
Primary and key secondary endpoints are controlled for multiplicity. 
Primary estimands 
There will be 2 primary estimands evaluated in this study. Both of these estimands are described 
below: 
 The treatment-regimen estimand is consistent with the US Prescribing Information. This 
estimand reflects efficacy when participants with T2D are treated in clinical practice and 
takes into account both tolerability and efficacy. 
 The efficacy estimand focuses on the treatment effect if participants who underwent 
randomization continued to receive the study treatment without rescue for severe, 
persistent hyperglycemia, and/or prohibited medication. This estimand will be used in 
publications to inform prescribers and physicians. 
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 T2D regardless of treatment discontinuation for any reason and 
regardless of initiation of antihyperglycemic rescue or prohibited treatment (except for 
tirzepatide or dulaglutide) or change in the background OAM? 
This estimand is described by the following attributes: 
 Population - Participants with T2D inadequately controlled with dulaglutide with or 
without a background of OAM. Further details can be found in Section 5. 
 Endpoint - Change in HbA1c from baseline to Week 40 after randomization. 
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Protocol I8F-MC-GPIH(b) 
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 Treatment condition - The randomly assigned treatment regardless of treatment 
discontinuation with or without antihyperglycemic rescue or prohibited medication, 
except for tirzepatide or dulaglutide, or change in background OAM. Further details on 
study treatment and concomitant, including rescue, treatments can be found in Section 6. 
 Intercurrent events - Intercurrent events of interest: “treatment discontinuation for any 
reason” and “initiation of antihyperglycemic rescue or prohibited treatment (except for 
tirzepatide or dulaglutide) or change in background OAM” are addressed by the treatment 
condition. 
 Population-level summary - Difference in mean changes between treatment conditions. 
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 T2D regardless of changes in background OAM assuming that participants had 
stayed on treatment and not taken antihyperglycemic rescue medication? 
This estimand is referred to as the efficacy estimand and is described by the following attributes: 
 Population - Participants with T2D inadequately controlled with dulaglutide with or 
without background OAM. Further details can be found in Section 5. 
 Endpoint - HbA1c change from baseline to Week 40 after randomization. 
 Treatment condition - The randomly assigned treatment regardless of changes to the 
background OAM. Further details on study treatment can be found in 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), and 
o had participants not taken antihyperglycemic rescue or prohibited medication, 
except for tirzepatide or dulaglutide (hypothetical strategy). 
 Population-level summary - Difference in mean changes between treatment conditions. 
Both the efficacy and treatment-regimen estimands will be evaluated for the primary and key 
secondary objectives. The population, treatment condition, intercurrent events, and population-
level summary specified above for each estimand for the primary objective will also apply to the 
key secondary objective. 
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Protocol I8F-MC-GPIH(b) 
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4. 
Study Design  
4.1. 
Overall Design  
SURPASS-SWITCH is a Phase 4, randomized, open-label, active-controlled, parallel-group, 
multicenter, multinational trial to assess the efficacy and safety of tirzepatide 15 mg or MTD 
compared to dulaglutide 4.5 mg or MTD in participants with T2D. 
This study will enroll participants with inadequately controlled T2D who are taking dulaglutide 
once weekly (0.75 mg or 1.5 mg) for at least 6 months prior to Visit 1, with or without (up to 3) 
background OAMs. 
The maximum duration of study participation is approximately 47 weeks. This study includes 
 an approximate 3-week screening period 
 a 40-week treatment period, and 
 a 4-week safety follow-up period. 
See the SoA (Section 1.3) for additional details about the study periods and visit-specific 
assessments, including assessments needed at an ED visit. 
Participants will be randomly assigned 1:1 to either 
 continue with and escalate dulaglutide to 4.5 mg or MTD, or 
 tirzepatide 15 mg or MTD. 
Participants who are randomly assigned to tirzepatide will discontinue dulaglutide and initiate 
tirzepatide within 3 days of their next scheduled dose. The starting dose for tirzepatide is 2.5 mg 
once weekly for 4 weeks, escalated in 2.5-mg increments every 4 weeks until 15 mg or MTD is 
achieved, as described in Section 6.1.1. 
4.1.1. 
Design Outline  
Period I: Screening 
Visit 1 
Interested individuals will sign the ICF prior to initiating any procedure. 
The investigator will review medical history and other inclusion and exclusion criteria prior to 
any diagnostic procedures. If the participant is eligible after this review, then the site will 
perform the diagnostic procedures detailed in the SoA to confirm eligibility. 
Visit 2 
The investigator will review the results of the screening laboratory measures to further assess 
participant eligibility. 
For participants meeting all other eligibility requirements, a dilated fundoscopic examination will 
be scheduled and completed between Visit 2 and Visit 3. 
Participants or caregivers, if applicable, will receive a BG meter and COA device. 
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Protocol I8F-MC-GPIH(b) 
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Participants and their caregiver(s), if applicable, will receive training on 
 COA device, including the eDiary data collection and the electronic PRO data collection 
 diabetes self-monitoring and management, including instructions on diet and exercise, 
education about the signs, symptoms, and treatment of hypoglycemia and hyperglycemia 
 recording blood glucose measurements, and 
 study requirements. 
Participants will be asked to monitor 7-point SMBG profiles (prior to and 2 hours after the 3 
main meals and at bedtime) on 2 nonconsecutive days during the 2 weeks preceding prespecified 
visits, as shown in the SoA (Section 1.3). 
At investigator’s and participant’s discretion, participants should monitor BG any time a 
hypoglycemic event is suspected or unusual symptoms are present. Additional measurements 
may be used to monitor trends in BG. 
Participants should continue their diet and exercise routine and must not use any glucose-
lowering treatment other than the OAM taken prior to the screening visit and should not change 
their dose or formulation. 
Period II: Treatment Period 
Visit 3 (Randomization) 
See Section 6.1 for intervention details, and Section 6.3 for randomization and stratification 
factors. 
All screening laboratory test results and screening dilated fundoscopic examination results must 
be reviewed for exclusion criteria prior to randomization and dosing at V3. 
This is the general flow for Visit 3: 
 Participants arrive to the clinic in the fasting state 
 Study personnel confirm enrollment criteria 
 Participants are randomly assigned to an intervention group 
 Participants complete PRO questionnaires before any other study procedures if the 
participant is not adversely affected by the fasting condition or complete after the 
participant has sufficiently recovered 
 Study personnel complete all required visit procedures, including the collection of vital 
signs, all baseline procedures, sample collection, and dispense study intervention 
 Participants self-administer study intervention at home. Administration should occur on 
the day (±3 days) of when the next dulaglutide administration is planned 
Study intervention training 
Participants who are randomly assigned to tirzepatide will receive appropriate training on using 
the device. 
Participants who are randomly assigned to continue on dulaglutide may be trained at the 
participant’s request. 
In addition, study personnel will provide product-specific “instructions for use” information to 
the participants upon request. 
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Protocol I8F-MC-GPIH(b) 
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Visit 4 through Visit 10 
Participants complete all visit procedures described in the SoA. 
Visit 11 or ED visit 
Participants complete all visit procedures as described in the SoA. 
Participants unable or unwilling to continue the study for any reason will perform an ED visit. If 
the participant is discontinuing during an unscheduled visit or a scheduled visit, that visit should 
be performed as the ED visit. 
The investigator will determine a participant’s transition from study treatment to another 
antihyperglycemic treatment plan. 
Period III: Safety follow-up visit 
Visit 801 
All participants who complete the treatment period or discontinue the study early (ED) are 
required to complete Visit 801, a safety follow-up visit, approximately 4 weeks after their last 
treatment or ED visit. 
Participants complete all visit procedures as described in the SoA. Participants will return study 
eDiaries to the study site. 
4.2. 
Scientific Rationale for Study Design  
This study is designed to investigate the efficacy and safety of switching once weekly 
dulaglutide 0.75 mg or 1.5 mg to once weekly tirzepatide 15 mg or MTD, or continuing and 
escalating dulaglutide 4.5 mg or MTD in adults with T2D who are currently on a nonmaximal, 
stable dose of dulaglutide QW. Data from this study will show whether switching treatment from 
weekly dulaglutide to tirzepatide rather than intensifying the dulaglutide dose provides additional 
efficacy in adults with T2D. 
Primary endpoint 
HbA1c was chosen as the primary endpoint because it is an accepted and well-understood 
endpoint reflecting glycemic control over extended periods of time. 
Duration of treatment period and posttreatment follow-up 
The planned treatment duration of 40 weeks is appropriate to assess the effects and benefit/risk 
of tirzepatide 15 mg or MTD and dulaglutide 4.5 mg or MTD on glycemic control, weight, and 
potentially other clinically relevant outcomes. 
Open-label design 
An open-label design is used for this study to enable dose escalation and modification. 
Choice of comparator 
Once weekly dulaglutide was chosen as the active comparator because it is one of the most 
widely used weekly GLP-1 RAs. 
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Parallel-group design 
The parallel-group design for treatment comparison was chosen to avoid any interaction between 
treatments that may interfere with the interpretation of the study outcome. 
Demographics collection 
In this study, collection of demographic information includes race and ethnicity, where 
permissible. The scientific rationale is based on the need to assess variable response in safety 
and/or efficacy based on race or ethnicity. This question can be answered only if all the relevant 
data are collected. 
4.3. 
Justification for Dose  
Tirzepatide doses 
Tirzepatide 15 mg or MTD administered subcutaneously QW will be evaluated in this study. 
The doses and associated escalation scheme were selected based on the results of global 
registrational Phase 3 studies in people with T2D. The requirement to escalate dose to 15 mg or 
MTD is based on the finding that tirzepatide lowers blood glucose and provides other metabolic 
benefits, including weight loss and lipid improvements in a dose-dependent manner. 
Dose escalation 
Tirzepatide 
To mitigate the potential occurrence of GI AEs associated with tirzepatide and permit time for 
the development of tolerance to GI effects, a dose escalation scheme will be used in the 
tirzepatide arm. The treatment starts at a dose of 2.5 mg QW for 4 weeks and then escalates by 
2.5-mg increments every 4 weeks until the 15-mg dose or maximum tolerated dose is reached 
(Section 6.1.1). 
Dulaglutide 
Dulaglutide will be escalated until the 4.5-mg dose or MTD is reached. For participants starting 
at 0.75 mg, dulaglutide will be escalated to 1.5 mg for 4 weeks, followed by 3.0 mg for another 4 
weeks and then to 4.5 mg or MTD. For those starting at 1.5 mg, dulaglutide will be escalated to 
3.0 mg for 4 weeks and then to 4.5 mg or MTD. 
4.4. 
End of Study Definition  
The end of the study is defined as the date of last scheduled procedure shown in the SoA for the 
last participant in the study globally. 
A participant is considered to have completed the study if the participant has completed all 
periods of the study including the last visit or the last scheduled procedure shown in the SoA. 
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Protocol I8F-MC-GPIH(b) 
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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: 
Age 
1. Are 18 years old or of an acceptable age to provide informed consent according to local 
regulations, whichever is older. 
Type of participant and disease characteristics 
2. Have been diagnosed with T2D based on the World Health Organization classification or 
other locally applicable diagnostic standards. 
3. Have HbA1c ≥7.0% (≥53 mmol/mol) to ≤9.5% (≤80 mmol/mol), as determined 
by the central laboratory at Visit 1. 
4. Are currently on a stable dose of dulaglutide weekly (0.75 mg or 1.5 mg) for at least 6 
months prior to Visit 1. 
5. No treatment with OAM, or on a stable dose of up to 3 OAMs, which may include 
metformin, SGLT-2i, and/or sulfonylurea, for at least 3 months before Visit 1. 
Weight 
6. Have had stable body weight (±5%) during the 90 days preceding screening 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. 
7. Have BMI ≥25 kg/m2 at Visit 1. 
Contraceptive/barrier requirements 
8. Contraceptive use by participants should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies. 
 Males may participate in this trial.  
Please refer to Section 10.4 for additional guidance related to contraception. 
 WOCBP and women not of childbearing potential may participate in the study.  
See Section 10.4 for definitions and additional requirements related to contraception. 
Informed consent 
9. Capable of giving signed informed consent as described in Section 10.1.3, Appendix 1, 
which includes compliance with the requirements and restrictions listed in the ICF and in 
this protocol. 
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Other inclusions 
10. Are reliable and willing to make themselves available for the duration of the study and 
are willing and able to follow study procedures as required, including, but not limited to 
 self-injecting intervention or injection by a caregiver when applicable 
 willing to be assigned to a different injectable at randomization 
 taking provided study interventions as directed 
 maintaining an eDiary, and 
 completing electronic patient-reported questionnaires. 
5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
11. Have T1D. 
12. Have a history of chronic or acute pancreatitis any time prior to screening. 
13. Have a history of or diagnosis during screening-dilated fundoscopic examination of 
 
proliferative diabetic retinopathy, or 
 
diabetic maculopathy, or 
 
nonproliferative diabetic retinopathy that requires acute treatment. 
14. Have any of these CV conditions within 60 days prior to screening: 
 acute myocardial infarction, 
 cerebrovascular accident (stroke), or 
 hospitalization due to CHF. 
15. Have NYHA Functional Classification Class IV CHF. 
16. Have a history of ketoacidosis or hyperosmolar state/coma. 
17. Have a history of severe hypoglycemia and/or hypoglycemia unawareness within the 6 
months prior to Visit 1. 
18. 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 GI 
motility. 
19. Have acute or chronic hepatitis, signs and symptoms of any liver disease other than 
NAFLD, or ALT level >3.0 times the ULN for the reference range, as determined by the 
central laboratory at study entry. Participants with NAFLD are eligible to participate in 
this study if their ALT level is ≤3.0 times the ULN for the reference range. 
20. Have an eGFR ≤30 mL/min/1.73 m2, calculated by CKD-EPI as determined by central 
laboratory at screening. 
21. Have evidence of a significant, uncontrolled endocrine abnormality (for example, 
thyrotoxic or adrenal crises), in the opinion of the investigator. 
22. Have family or personal history of MTC or MEN 2. 
23. Have a serum calcitonin level ≥35 ng/L, as determined by central laboratory at 
V1. 
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24. Have known or suspected hypersensitivity to study product(s) or related products. 
25. 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 during the study. 
26. Have had a transplanted organ (corneal transplants [keratoplasty] allowed) or awaiting an 
organ transplant. 
27. Have a history of an active or untreated malignancy or are in remission from a clinically 
significant malignancy for less than 5 years. 
Exceptions: 
a. basal or squamous cell skin cancer 
b. in situ carcinomas of the cervix, and 
c. in situ or Grade 1 (for example, Gleason 6 or lower) prostate cancer. 
28. Have a history of any other condition such as known drug or alcohol abuse, or psychiatric 
disorder that, in the opinion of the investigator, may preclude the participant from 
following and completing the protocol. 
29. Have any chronic hematological condition that may interfere with HbA1c measurement 
such as hemolytic anemias and sickle cell disease. 
30. Female participants who are pregnant or breast feeding or intending to become pregnant 
during the course of the study. 
31. Have a history of an underlying disease, presence of an underlying disease such as active 
SARS-CoV-2 infection, or surgical, physical, or medical condition that, in the opinion of 
the investigator, would potentially affect participant safety within the study or interfere 
with the interpretation of data. 
Prior/concomitant therapy 
32. Have been treated with insulin prior to screening. 
Exception: use of insulin for gestational diabetes or short-term use (<14 days) for acute 
conditions, such as acute illness, hospitalization, or elective surgery. 
33. Have a history of reduction of dose of dulaglutide weekly, due to intolerability, without 
successful reescalation, any time prior to Visit 1. 
34. Have within 90 days prior to screening received treatment with medications intended to 
promote weight loss. This includes prescribed or over-the-counter or alternative 
remedies. See Section 6.8.3 for list of prohibited medications. 
35. Are receiving chronic (>14 days) systemic glucocorticoid therapy or have received such 
therapy within 1 month of Visit 1 or between Visits 1 and 3. 
Exceptions: topical, intraocular, intranasal, or inhaled preparations. 
Prior/concurrent clinical study experience 
36. 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. 
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37. Have participated, within the last 30 days, in a clinical study involving an investigational 
product. If the previous investigational product has a long half-life, 5 half-lives or 30 
days (whichever is longer), should have passed prior to screening. 
38. Have previously completed or withdrawn from this study or any other study investigating 
tirzepatide. 
Other exclusions 
39. Are Lilly employees or are employees of any third party involved in the study who 
require exclusion of their employees. 
40. 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. 
5.3. 
Lifestyle Considerations  
Diabetes management counseling 
Per 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 management of hypoglycemia, should it occur. 
Participant exercise and diet 
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. 
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. 
Dietary counseling will be reviewed throughout the study at every visit, including counseling and 
management with regard to the weight loss known to be associated with tirzepatide and 
dulaglutide. 
Blood product donation 
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 randomly 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 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) may be 
rescreened at investigator discretion on 1 occasion. Rescreened participants should be assigned a 
new participant number. 
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5.5. 
Criteria for Temporarily Delaying Enrollment of a Participant  
This section is not applicable for this study. 
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6. 
Study Intervention(s) and Concomitant Therapy  
Study intervention is defined as any investigational interventions, marketed products, placebo, or 
medical devices intended to be administered to/used by a study participant according to the study 
protocol. 
6.1. 
Study Intervention(s) Administered  
Intervention Name 
Tirzepatide 
Dulaglutide 
Dosage Levels 
2.5 mg QW 
5 mg QW 
7.5 mg QW 
10 mg QW 
12.5 mg QW 
15 mg QW 
0.75 mg QW 
1.5 mg QW 
3 mg QW 
4.5 mg QW 
Route of Administration 
SC 
Authorized as defined by EU 
CTR No 536/2014a 
Not authorized as defined by EU 
CTR 
Authorized as defined by EU CTR 
and used according to EU 
Marketing Authorization 
Abbreviations: CTR = Clinical Trial Regulation; EU = European Union; QW = weekly. 
a “Authorized investigational medicinal product” means a medicinal product authorized in accordance with 
Regulation (EC) No 726/2004 or in any Member State concerned in accordance with Directive 2001/83/EC, 
irrespective of changes to the labeling of the medicinal product, which is used as an investigational medicinal 
product; “Authorized auxiliary medicinal product” means a medicinal product authorized in accordance with 
Regulation (EC) No 726/2004, or in any Member State concerned in accordance with Directive 2001/83/EC, 
irrespective of changes to the labeling of the medicinal product, which is used as an auxiliary medicinal product. 
Packaging and labeling 
Study interventions will be supplied in accordance with current Good Manufacturing Practice. 
Study interventions will be labeled as appropriate for country requirements. 
6.1.1. 
Dose Escalation  
Tirzepatide dose escalation 
Tirzepatide treatment will follow a fixed dose escalation as follows: 
 start at 2.5 mg QW. After 4 weeks, increase the dose to 5 mg QW, and 
 increase by 2.5 mg every 4 weeks until 15 mg or MTD is achieved. 
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Dulaglutide dose escalation 
Dulaglutide treatment will follow a fixed dose escalation as follows: 
 increase to 1.5 mg QW for 4 weeks at randomization, only needed for those starting on 
0.75 mg 
 increase to 3 mg QW for 4 weeks, and 
 increase to and maintain at 4.5 mg QW or MTD for the duration of the study. 
Intolerance to dose escalation 
If a participant does not tolerate the dose escalation, refer to Section 6.5 for additional 
instructions. 
6.1.2. 
Administration Instructions  
Tirzepatide 
Tirzepatide is administered QW by SC injection. There are no restrictions on the time of day 
each weekly dose of study intervention is given, but it is advisable to administer the SC 
injections on the same day and same time each week, with or without meals. 
If a dose is missed, it should be administered as soon as possible within 4 days (96 hours) after 
the missed dose. If more than 4 days have passed, skip the missed dose and administer the next 
dose on the regularly scheduled day. In each case, patients can then resume their regular once 
weekly dosing schedule. 
All participants will inject tirzepatide subcutaneously in the stomach area (abdomen) or upper 
leg (thigh) using the SDPs provided. If the injection is given by someone else, they may inject in 
the upper arm. A new SDP will be used for each injection. If tirzepatide is to always be injected 
in the same body region, participants should be advised to use a different injection site each 
week. 
Dulaglutide 
Participants in the dulaglutide group will self-administer dulaglutide according to the respective 
local product labeling. 
6.1.3. 
Medical Devices  
Medical devices for tirzepatide and dulaglutide used in this study are manufactured by the 
sponsor or manufactured for the sponsor by a third party. 
Instructions for medical device use for tirzepatide are provided in the Instructions for Use. 
Instructions for medical device use of dulaglutide are provided in the respective local product 
labeling. 
All PCs (including malfunction, use error, and inadequate labeling) shall be documented and 
reported by the investigator throughout the clinical investigation (see Section 8.3) and 
appropriately managed by the sponsor. 
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6.1.4. 
Rescue Therapy  
If a participant develops severe, persistent hyperglycemia after randomization, an additional 
antihyperglycemic medication 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. 
First, investigators should confirm participant compliance with the assigned intervention and that 
they do not have an acute condition causing severe, persistent hyperglycemia. 
Conditions for rescue therapy 
The criteria for rescue therapy will be based on either FBG or HbA1c as described below. 
FBG conditions 
This table describes FBG conditions for rescue therapy. 
If any of the FBG values exceed the limits outlined below for 2 consecutive weeks and no 
intercurrent cause of the hyperglycemia can be identified, participants should be treated with 
rescue medication as an add-on to randomly assigned treatment. 
If a participant has persistently 
elevated FBG defined as… 
during this time… 
then... 
FBG >270 mg/dL  
(>15.0 mmol/L)  
from baseline (V3) to Week 8 
 
participants should be treated with 
rescue medication as an add-on to 
randomly assigned treatment. 
FBG >240 mg/dL  
(>13.3 mmol/L)  
from Week 9 to Week 16 
FBG >200 mg/dL  
(>11.1 mmol/L) 
Any time after Week 16 
Abbreviation: FBG = fasting blood glucose. 
HbA1c conditions 
This table describes HbA1c conditions for rescue therapy. 
If a participant has an… 
during this time… 
then... 
HbA1c ≥8.5%  
(≥64 mmol/mol) 
any time after Week 24 
participants should be treated with 
rescue medication as an add-on to 
randomly assigned treatment. 
Abbreviation: HbA1c = glycated hemoglobin.  
Allowed rescue treatments 
The choice of rescue treatment for persistent hyperglycemia will be at the discretion of the 
investigator. Investigators should follow current published standards of care from the American 
Diabetes Association and/or the consensus report by the American Diabetes Association and the 
European Association for the Study of Diabetes (Buse et al. 2020; ADA 2022). 
GLP-1 RAs, DPP-4 inhibitors, and pramlintide are not allowed as rescue therapy. 
Additionally, tirzepatide is not allowed as rescue therapy for the dulaglutide group. 
Rescue therapy will be continued and adjusted per the investigator’s discretion. 
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Rescue therapy may not include modifying the tirzepatide or dulaglutide dose. 
6.2. 
Preparation, Handling, Storage, and Accountability  
The investigator or designee must confirm appropriate storage conditions have been maintained 
during transit for all study interventions received and any discrepancies are reported and resolved 
before use of the study intervention. 
Only participants enrolled in the study may receive study intervention. Only authorized study 
personnel may supply, prepare, or administer study intervention. All study intervention must be 
stored in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized study personnel. 
The investigator or authorized study personnel are responsible for study intervention 
accountability, reconciliation, and record maintenance; that is, receipt, reconciliation, and final 
disposition records. 
Further guidance and information for the final disposition of unused study interventions are 
provided in the Pharmacy manual. 
Study intervention will be dispensed at the study visits summarized in the SoA. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding  
Randomization 
All participants will be centrally assigned through block randomization with a block size of 2 
using an IWRS. Before the study is initiated, the login information and directions for the IWRS 
will be provided to each site. 
Participants will be randomly assigned in a 1:1 ratio to tirzepatide or dose escalation of 
dulaglutide. 
Participants will be stratified based on 
 starting dulaglutide dose at Screening (0.75 mg, 1.5 mg) 
 region (NA, EU) 
 number of OAM (0-1 or 2-3), and 
 HbA1c (≤8.5% or >8.5%). 
Blinding 
This is an open-label study. 
6.4. 
Study Intervention Compliance  
Participants will enter the intervention dose information in their eDiary. 
The investigator or trained designee will assess treatment compliance at each visit based on 
review of the participant’s glycemic control, eDiary completion, and adherence to prescribed 
dose and study procedures. 
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If a participant is considered poorly compliant with their study procedures, for example, missed 
visits or specific diagnostic tests, they will be retrained as needed by designated study personnel. 
6.5. 
Dose Modification  
For general dose escalation, see Section 6.1.1. 
Missed doses of study intervention are described in Section 7.1.3. 
6.5.1. 
Management of Participants with Gastrointestinal Symptoms  
The dose escalation scheme is designed to minimize the development of intolerable GI 
symptoms. 
This table describes steps the investigator should follow to mitigate GI symptoms and manage 
participants with intolerable GI AEs for both the tirzepatide and dulaglutide treatment groups. 
STEP 1 
Advise participants to eat smaller meals, for example, splitting 3 daily meals into 4 or more smaller 
meals, and to stop eating when they feel full. 
STEP 2 
Continue STEP 1 + 
Treat with symptomatic medication, for example, anti-emetic or anti-diarrheal medication, per local 
country availability and individual participant needs. Use of symptomatic medication should be 
captured as concomitant medication in the CRF. 
STEP 3 
Continue STEP 1 + STEP 2 + 
Manage GI symptoms, including considering dose interruption. 
Temporarily interrupt study intervention; 1 dose can be omitted per 4 weeks. After the interruption, 
the investigator should restart the dose or escalate the dose as required, with the participant taking 
medication to alleviate their GI symptoms. The data related to temporary interruption of study 
treatment should be documented in source documents. 
Refer to Section 6.5.1. for additional details.  
STEP 4 
If intolerable GI symptoms persist despite the above measures, the investigator may decide to 
reduce the dose to the previous MTD.  
Abbreviations: CRF = case report form; GI = gastrointestinal. 
6.5.2. 
Study Intervention Dose Modification  
If a participant experiences GI tolerability issues despite the measures listed in Section 6.5.1, 
then follow the guidance in this table. 
If a participant is currently taking… 
then… 
Tirzepatide 2.5 mg or 5 mg, or dulaglutide 
0.75 mg 
permanently stop study intervention, remain in the study, 
and initiate another antihyperglycemic medication. 
Any other tirzepatide or dulaglutide dose  
reduce the dose to the previous tolerated dose. 
Note: If a participant’s dose is reduced, the investigator may 
re-escalate the dose twice when considered appropriate.  
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Participants who permanently stop study intervention will receive another locally approved 
antihyperglycemic medication, if needed, per clinical judgment of the investigator, and will 
continue participating in the study according to the protocol to collect all planned efficacy and 
safety measurements per the SoA (Section 1.3), Adverse Events (Section 8.3), and Safety 
Assessments (Section 8.2) of this protocol. 
The choice of antihyperglycemic medication will be at the discretion of the investigator. The 
investigators should follow current published standards of care from the American Diabetes 
Association and/or the consensus report by the American Diabetes Association and the European 
Association for Study of Diabetes (ADA 2022; Buse et al. 2020). 
GLP-1 RAs and tirzepatide are not allowed as antihyperglycemic medication. 
The new antihyperglycemic medication will be recorded on the CRF for antihyperglycemic 
medications. 
6.6. 
Continued Access to Study Intervention after the End of the Study  
Study intervention will not be provided to participants after completion of the study. At the end 
of study participation, participants will be treated according to local practice for type 2 diabetes 
and according to what is available in local markets. Treatment decisions can be made by the 
participant's primary physician but may also be made by the study investigator. 
6.7. 
Treatment of Overdose  
Tirzepatide overdose is defined as administration of tirzepatide with more than the intended dose 
(more than 1 injection) in less than 72 hours. 
Dulaglutide overdose is defined and will be treated, according to the locally approved labeling 
and packaging. 
In the event of an overdose, the investigator or treating physician should 
 contact the Lilly medical monitor immediately 
 evaluate the participant to determine, in consultation with the Lilly medical monitor, 
whether study intervention should be interrupted or whether the dose should be reduced 
 closely monitor the participant for any AE/SAE and laboratory abnormalities until study 
intervention no longer has a clinical effect, and report the overdose event as an AE and 
document, and 
 appropriate supportive treatment should be initiated according to the participant’s clinical 
signs and symptoms. 
6.8. 
Concomitant Therapy  
6.8.1. 
Concomitant Therapy Regimens  
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. 
Prohibited medications are listed in Section 6.8.3. 
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Permitted use of antihyperglycemic treatments other than study intervention is described in 
Section 6.8.4. 
Reduction and/or discontinuation of concomitant antihyperglycemic treatments other than study 
intervention are described in Section 6.8.5. 
Participants should consult with authorized study personnel before taking any new medications 
or supplements during the study. Authorized study personnel should consult the Lilly medical 
monitor if there are any questions about concomitant therapies during the study. 
6.8.2. 
Concomitant Therapy Data Collection  
Any medication or vaccine including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements that the participant is receiving at the time of enrollment or receives 
during the study, authorized study personnel should collect 
 name of medication, vaccine, or therapy 
 reason for use 
 dates of administration, including start and end dates, and 
 dosage information, including dose and frequency for concomitant therapy of 
special interest. 
The Lilly medical monitor should be contacted if there are any questions regarding concomitant 
or prior therapy. 
Non-study medications taken by participants who are screened but not randomly assigned to 
study intervention will not be reported to Lilly unless an SAE or AE occurs that the investigator 
believes may have been caused by a study procedure. 
6.8.3. 
Prohibited Concomitant Medications  
The medications prohibited in the study include medications intended to promote weight loss and 
non-study GLP-1 RA, DPP-4 inhibitors, and amylin mimetics. This includes prescribed or over-
the-counter or alternative remedies. Examples include, but are not limited to 
 pramlintide 
 lixisenatide 
 semaglutide 
 liraglutide  
 sibutramine 
 alogliptin 
 saxagliptin 
 linagliptin 
 sitagliptin 
 zonisamide  
 Contrave® 
 topiramate 
 orlistat 
 phentermine 
 Plenity® 
 mazindol 
 lorcaserin 
 
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6.8.4. 
Allowed Antihyperglycemic Treatments other than Study Interventions  
Antihyperglycemic medications other than study interventions are ONLY allowed during these 
circumstances: 
 for participants who require permanent discontinuation of study intervention but remain 
in the study 
 for rescue therapy after randomization due to severe, persistent hyperglycemia, as 
described in Section 6.1.4 
 during the safety follow-up period or ED visit, and 
 short-term insulin use for up to 14 days is allowed for certain clinical situations, for 
example, elective surgery, during hospitalization, and hyperosmolar states, and must be 
differentiated from insulin use as rescue therapy when reported in the CRF. 
6.8.5. 
Reduction and/or Discontinuation of Concomitant Antihyperglycemic 
Medications  
Temporary discontinuation of concomitant antihyperglycemic medications <14 consecutive days 
is allowed for certain clinical situations, for example, severe dehydration, elective surgery, or 
need for radiologic examination involving IV iodinated contrast dye. 
After randomization, discontinuation, dose modification, or formulation change of metformin, 
sulfonylurea, or SGLT-2i are not permitted except in the following situations: 
 If a participant in on a sulfonylurea and develops hypoglycemia, defined as glucose <70 
mg/dL, or is at risk of developing hypoglycemia, then the sulfonylurea dose can be 
reduced or discontinued. 
 If a participant meets the criteria for severe, persistent hyperglycemia (Section 8.3.3.7) or 
discontinues study intervention, then the sulfonylurea dose may be increased according to 
country-specific label. 
 In certain situations that require short-term discontinuation in line with the product(s) 
local labeling. 
 In the event of multiple (>1) hypoglycemic episodes (glucose concentration <54 mg/dL 
or severe hypoglycemia), in participants on any oral treatment combination not including 
sulfonylurea, but on dual or single oral treatment of metformin and/or SGLT-2i, the dose 
of metformin or SGLT-2i can be reduced or discontinued. 
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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal  
Discontinuation of specific sites or of the study as a whole are handled as part of Section 10.1.9. 
7.1. 
Discontinuation of Study Intervention  
When necessary, a participant may be permanently discontinued from study intervention. If so, 
the participant will remain in the study and follow procedures for the remaining study visits, as 
shown in the SoA (Section 1.3). 
A participant must be permanently discontinued from study intervention if 
 the participant becomes pregnant during the study 
 the participant is diagnosed with T1D or LADA 
 the participant requests to discontinue intervention 
 the participant develops confirmed pancreatitis (if not confirmed, study intervention may 
be restarted) 
 the participant is diagnosed with MTC, C-cell hyperplasia, or MEN 2 after randomization 
or has calcitonin value ≥35 ng/L that has increased at least 50% over baseline after 
randomization 
 the participant is diagnosed with an active malignancy or if a previously treated 
malignancy becomes known after randomization 
 the participant experiences a significant study intervention-related hypersensitivity 
reaction after administration of study intervention 
 any other AE, SAE, or clinically significant laboratory value for which the investigator 
believes that permanent study intervention discontinuation is the appropriate measure to 
be taken 
 in the opinion of the investigator, the participant should permanently discontinue the 
study intervention for safety reasons 
 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 intervention occurs prior to 
introduction of the new agent. 
Additionally, a participant should be permanently discontinued from dulaglutide according to the 
locally approved labeling and packaging. 
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7.1.1. 
Liver Chemistry Stopping Criteria  
7.1.1.1. 
Interrupting Study Drug based on Elevated Liver Tests  
The study drug should be interrupted and close hepatic monitoring initiated (see Section 
8.2.7.1) if one or more of these conditions occur: 
Elevation 
Exception 
ALT or AST >8x ULN 
 
ALT or AST >5x ULN for more than 2 weeks 
 
ALT or AST >3x ULN and either TBL >2x ULN or INR >1.5  
For participants with Gilbert’s syndrome:  
If baseline direct bilirubin is >0.5 mg/dL, 
then doubling of direct bilirubin should be 
used for drug interruption decisions rather 
than TBL >2x ULN. 
ALT or AST >3x ULN with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%) 
 
ALP >3x ULN, when the source of increased ALP is the liver 
 
ALP >2.5x ULN and TBL >2x ULN  
For participants with Gilbert’s syndrome:  
If baseline direct bilirubin is >0.5 mg/dL 
then doubling of direct bilirubin should be 
used for drug interruption decisions rather 
than TBL >2x ULN. 
ALP >2.5x ULN with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, 
and/or eosinophilia (>5%) 
 
Source: FDA Guidance for Industry: Drug-Induced Liver Injury: Premarketing Clinical Evaluation, July 2009 and 
other consensus guidelines, with minor modifications. 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
INR = international normalized ratio; TBL = total bilirubin level; ULN = upper limit of normal. 
7.1.1.2. 
Resuming Study Drug after Elevated Liver Tests  
Resumption of the study drug can be considered only in consultation with the Lilly-designated 
medical monitor and only if the liver test results return to baseline and if a self-limited, non-drug 
etiology is identified. Otherwise, the study drug should be discontinued. 
7.1.2. 
QTc Stopping Criteria  
If a clinically significant finding is identified, including, but not limited to, changes from 
baseline in QT interval corrected using Fridericia’s formula after enrollment, the investigator or 
qualified designee will determine if the participant can continue in the study and if any change in 
participant management is needed. This review of the ECG printed at the time of collection must 
be documented. Any new clinically relevant finding should be reported as an AE. 
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7.1.3. 
Temporary Discontinuation of Study Intervention  
The investigator may temporarily interrupt study intervention, for reasons other than tolerability, 
due to 
 an AE 
 clinically significant laboratory value 
 hospital visits or medical procedures 
 travel or shortage of study treatment supply, or 
 any other event necessitating temporary discontinuation of study intervention. 
If study intervention is temporarily interrupted for reasons other than tolerability, participants 
should be encouraged to restart study intervention as soon as it is safe to do so. 
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. 
Tirzepatide 
This table shows how to manage treatment if there are missed tirzepatide doses. 
If the number of missed 
consecutive tirzepatide 
doses is... 
Then... 
2 or less 
the study treatment can be restarted at the last administered dose, if it was well-
tolerated prior to interruption. 
3 or more 
the IWRS will dispense 5 mg tirzepatide irrespective of the dose the participant 
was receiving before the interruption and subsequently escalate as required by the 
protocol until the 15-mg dose, or maximum tolerated dose is reached.  
Abbreviation: IWRS = interactive web-response system. 
If the tirzepatide interruption is due to intolerable persistent GI AE, such as nausea, vomiting, or 
diarrhea, the participant should be treated as suggested in Section 6.5.1. 
Dulaglutide 
Missed dulaglutide doses should be managed according to the locally approved labeling and 
packaging. 
Recording temporary discontinuation of study intervention 
The dates of study intervention interruption and restart must be documented in source documents 
and entered on the CRF. 
Participant noncompliance should not be recorded as interruption of study intervention on the 
CRF. 
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7.2. 
Participant Discontinuation/Withdrawal from the Study  
Discontinuation is expected to be uncommon. 
A participant will be discontinued from the study: 
 at any time at the participant’s own request 
 at the request of the participant’s designee, for example, legal guardian 
 if the participant is diagnosed with T1D or LADA 
 if the participant is diagnosed with a malignancy after randomization 
o Exceptions: 
▪ 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 
 at the discretion of the investigator for safety, behavioral, compliance, or administrative 
reasons 
 if a female participant becomes pregnant, see Section 8.3.2, and 
 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. 
At the time of discontinuing from the study, if possible, the participant will complete procedures 
for an ED visit and posttreatment follow-up, if applicable, as shown in the SoA (Section 1.3). 
If the participant has not already discontinued the study intervention, the participant will be 
permanently discontinued from the study intervention at the time of the decision to discontinue 
the study. 
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, the participant may request destruction of any samples 
taken and not tested, and the investigator must document this in the site study records. 
7.3. 
Lost to Follow-up  
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. Site personnel or designee are 
expected to make diligent attempts to contact participants who fail to return for a scheduled visit 
or were otherwise unable to be followed up by the site. 
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8. 
Study Assessments and Procedures  
Study procedures and their timing are summarized in the SoA. 
Immediate safety concerns should be discussed with the sponsor immediately upon occurrence or 
awareness to determine if the participant should continue or discontinue study intervention. 
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. The investigator will maintain a screening log to record details of all 
participants screened and to confirm eligibility or record reasons for screening failure, as 
applicable. 
8.1. 
Efficacy Assessments  
8.1.1. 
Primary Efficacy Assessment  
The primary efficacy measurement in this study is change in HbA1c values from baseline to 
Week 40, as determined from the central laboratory values. Blood samples for HbA1c 
measurements will be collected at specific clinic visits as summarized in the SoA, Section 1.3. 
8.1.2. 
Other Efficacy Assessments  
Other efficacy assessments include change in weight, FSG, waist circumference, IWQOL-Lite-
CT, fasting lipids, BMI, 7-point SMBG, and PROs will be assessed based on data collected at the 
times shown in the SoA (see Section 1.3). 
8.1.2.1. 
Self-Monitoring of Blood Glucose (SMBG)  
Participants must use only the study-provided BG monitors, provided per local guidelines, 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 self-monitoring 
blood glucose and reporting of hypoglycemia data. 
When to measure FBG during the study 
Site personnel will train the participant to measure FBG daily when possible, and a minimum of 
2 times per week using the study-provided glucometer. 
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). 
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Glucometer data transfer 
The study-provided glucometer will wirelessly transmit blood glucose measurements to the 
participant’s eDiary. Site personnel will be able to view SMBG data that have been transmitted 
to the eDiary through a web-based portal as well as any reported events of hypoglycemia. 
SMBG for hypoglycemia or hyperglycemia 
Participants should perform SMBG with the study-provided BG meter whenever hypoglycemia 
is experienced or suspected (with or without symptoms), when there is perceived, increased risk 
related to changes in dietary intake, physical activity, or inadvertent or atypical insulin dosing. 
Participants may perform SMBG more frequently to check for instances of hyperglycemia, or as 
directed by the investigator. Investigators may also instruct participants to collect SMBG, at time 
points other than at fasting, to evaluate glycemic control. 
8.1.2.2. 
Patient-Reported Outcomes Assessments  
8.1.2.2.1. Impact of Weight on Quality of Life-Clinical Trials Version (IWQOL-Lite-CT)  
The IWQOL Lite-CT (Kolotkin et al. 2017, 2019) is a 20-item, obesity-specific PRO instrument 
developed for use in weight management clinical studies. 
The IWQOL-Lite-CT assesses 2 primary domains of obesity-related, health-related quality of 
life: 
 Physical (7 items) and 
 Psychosocial (13 items). 
A 5-item subset of the Physical domain – the Physical Function composite – is also reported. 
Items in the Physical Function composite describe physical impacts related to general and 
specific physical activities. 
All items are rated on either 
o a 5-point frequency (“never” to “always”) scale, or 
o a 5-point truth (“not at all true” to “completely true”) scale. 
The IWQOL-Lite-CT has a total score, which includes all 20 items. The IWQOL-Lite-CT scores 
range from 0-100, where raw and transformed scores are calculated, with higher composite 
scores indicating higher levels of functioning. 
8.1.2.2.2. Impact of Weight on Self-Perceptions Questionnaire  
The Impact of Weight on Self-Perceptions Questionnaire (IW-SP) (Hayes and Delozier 2015) is 
a patient-reported outcomes instrument that assesses the “current” impact of weight on the self-
perception of people with Type 2 diabetes mellitus and obesity. 
The IW-SP contains 3 items that assess how often a participants’ body weight affects how happy 
they are with their appearance and how often they feel self-conscious when out in public. Each 
item is rated on a 5-point scale ranging from 1 = “always” to 5 = “never.” Total scores for the 
IW-SP are derived by summing the item scores and dividing by the number of items. The score 
is typically transformed to a range from 0 to 100. Higher IW-SP scores correspond to better 
self-perception. 
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8.1.2.2.3. Ability to Perform Physical Activities of Daily Living  
The Ability to Perform Physical Activities of Daily Living (Hayes et al. 2012) is a patient-
reported outcomes instrument that assesses the current ability of people living with T2D and 
obesity to perform physical activities of daily living. 
The Ability to Perform Physical Activities of Daily Living contains 7 items that assess how 
difficult it is for participants to engage in certain activities considered to be integral to normal 
daily life, such as walking, standing, and climbing stairs (Hayes et al. 2012). Items are scored on 
a 5-point numeric rating scale, where 5 = “not at all difficult” and 1 = “unable to do.” A raw 
overall score is calculated by simply summing the scores of the 7 items, and a transformed 
overall score is obtained by linearly transforming the raw overall score to a 0 to 100 scale. A 
higher raw overall score and a higher transformed overall score are indicative of better ability to 
perform activities of daily living. 
8.1.2.2.4. Emotional Impact of Diabetes Treatment Questionnaire-Comparison  
The EIDTQc is a brief 14-item measure developed to determine how a participant’s current 
diabetes study medication has affected them emotionally in the past week compared to their 
previous diabetes study medication. The questionnaire consists of 14 items which are evaluated 
on a 5-point scale ranging from “Much more” to “Much less.” Higher item scores indicate better 
reported emotional health associated with the impact of diabetes. 
8.1.2.2.5. Global Impression of Emotional Health questions  
The Global Impression of Emotional Health question is a participant-rated question that 
measures emotional health. For this study, the participant is instructed as follows: “Please 
choose the response below that best describes your emotional health over the past week” at 
baseline and at ED or study endpoint. The follow-up participant-reported ratings of emotional 
health at ED or study endpoint is phrased as follows: “Please choose the response below that best 
describes the overall change in your emotional health since the start of the study.” The Global 
Impression of Emotional Health includes a range of possible responses, from “Excellent” or 
“Much better” to “Poor” or “Much worse.” Higher scores indicate better overall patient-reported 
emotional health. 
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 
 skin 
 CV 
 respiratory 
 GI 
 neurological systems 
 thyroid examination, and 
 foot examination, including evaluation for diabetic neuropathy. 
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The examination excludes pelvic, rectal, and breast examinations, unless clinically 
indicated. 
Physical exams during in-clinic visits will be performed by a physician or other qualified 
healthcare professional. 
Height, weight, and waist circumference will be measured and recorded, per Appendix 7, 
Section 10.7. Investigators should pay special attention to clinical signs related to previous 
serious illnesses. 
Symptom-directed physical assessment after screening 
These examinations are performed based on participant status and standard of care by a 
physician or other qualified healthcare professional. 
8.2.2. 
Vital Signs  
For each participant, vital signs measurements should be conducted according to the SoA 
(Section 1.3). 
Vital signs including pulse rate and blood pressure will be measured after participant has been 
sitting for at least 5 minutes and before obtaining an ECG tracing and before collection of blood 
samples for laboratory testing, at visits where required. 
8.2.3. 
Electrocardiograms  
A 12-lead ECG will be obtained as outlined in the SoA (see Section 1.3) using an ECG machine 
that preferably automatically calculates the heart rate and measures PR, QRS, QT, and QTc 
intervals. Refer to Section 7.1.2 for QTc stopping criteria. 
The ECGs 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. The investigator or designee must document their 
review of the ECG. If a clinically relevant abnormality is observed on the participant’s ECG, 
then the investigator should assess the participant for symptoms, such as palpitations, near 
syncope, syncope, or chest pain. 
The original ECG must be retained at the investigative site. 
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 if the participant meets all qualifications for the study 
at Visit 1. 
A previous examination ≤90 days of screening meeting study requirements is acceptable to 
confirm eligibility. Additional dilated fundoscopic examinations should be performed when 
clinically indicated by any suspicion of worsening retinopathy and as outlined in the SoA (see 
Section 1.3). 
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8.2.5. 
Clinical Safety Laboratory Tests  
See Appendix 2, Section 10.2, for the list of clinical laboratory tests to be performed and the SoA 
for the timing and frequency. 
The investigator must review the laboratory results, document this review, and report any 
clinically relevant changes occurring during the study as an AE. 
The laboratory results must be retained with source documents unless a Source Document 
Agreement or comparable document cites an electronic location that accommodates the expected 
retention duration. 
Clinically significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for the 
participant's condition. 
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the investigator or Lilly medical monitor. 
 If such values do not return to normal or baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified, and the sponsor notified. 
 All protocol-required laboratory assessments, as defined in Section 10.2, 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. 
8.2.6. 
Pregnancy Testing  
Pregnancy testing will occur as outlined in the SoA, Section 1.3. 
Serum pregnancy tests must be performed only for WOCBP and females with a history of tubal 
ligation. 
A local urine pregnancy test must be performed for WOCBP only, prior to administering study 
intervention or must be performed with the result available prior to first dose or injection of 
study intervention(s). 
Additional pregnancy tests (beyond those required per the SoA) should be performed at any time 
during the study if a menstrual period is missed, there is clinical suspicion of pregnancy, or as 
required by local law or regulation. If the participant is pregnant, she must be permanently 
discontinued from study intervention and the study (Section 7). 
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8.2.7. 
Hepatic Monitoring  
8.2.7.1. 
Close Hepatic Monitoring  
Laboratory tests (Section 10.2), including ALT, AST, ALP, TBL, Direct Bilirubin, GGT, and 
creatine kinase, should be repeated within 48 to 72 hours to confirm the abnormality and to 
determine if it is increasing or decreasing, if one or more of these conditions occur: 
If a participant with baseline results of...  
develops the following elevations: 
ALT or AST <1.5x ULN 
ALT or AST ≥3x ULN 
ALP <1.5x ULN 
ALP ≥2x ULN 
TBL <1.5x ULN 
TBL ≥2x ULN (except for patients with Gilbert’s syndrome) 
ALT or AST ≥1.5x ULN 
ALT or AST ≥2x baseline 
ALP ≥1.5x ULN 
ALP ≥2x baseline 
TBL ≥1.5x ULN 
TBL ≥1.5x baseline (except for patients with Gilbert’s syndrome) 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin level; ULN = upper limit of normal. 
If the abnormality persists or worsens, clinical and laboratory monitoring, and evaluation for 
possible causes of abnormal liver tests should be initiated by the investigator in consultation with 
the Lilly-designated medical monitor. At a minimum, this evaluation should include physical 
examination and a thorough medical history, including symptoms, recent illnesses (for example, 
heart failure, systemic infection, hypotension, or seizures), recent travel, history of concomitant 
medications (including over-the-counter), herbal and dietary supplements, history of alcohol 
drinking, and other substance abuse. 
Initially, monitoring of symptoms and hepatic biochemical tests should be done at a frequency of 
1 to 3 times weekly, based on the participant’s clinical condition and hepatic biochemical tests. 
Subsequently, the frequency of monitoring may be lowered to once every 1 to 2 weeks, if the 
participant’s clinical condition and laboratory results stabilize. Monitoring of ALT, AST, ALP, 
and TBL should continue until levels normalize or return to approximate baseline levels. 
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8.2.7.2. 
Comprehensive Hepatic Evaluation  
A comprehensive evaluation should be performed to search for possible causes of liver injury if 
one or more of these conditions occur: 
If a participant with baseline results of...  
develops the following elevations: 
ALT or AST <1.5x ULN 
ALT or AST ≥3x ULN with hepatic signs or symptomsa, or 
ALT or AST ≥5x ULN 
ALP <1.5x ULN 
ALP ≥3x ULN 
TBL <1.5x ULN 
TBL ≥2x ULN (except for patients with Gilbert’s syndrome) 
ALT or AST ≥1.5x ULN 
ALT or AST ≥2x baseline with hepatic signs or symptomsa, or 
ALT or AST ≥3x baseline 
ALP ≥1.5x ULN 
ALP ≥2x baseline 
TBL ≥1.5x ULN 
TBL ≥2x baseline (except for patients with Gilbert’s syndrome)  
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
TBL = total bilirubin level; ULN = upper limit of normal. 
a Hepatic signs or symptoms are severe fatigue, nausea, vomiting, right upper quadrant abdominal pain, fever, rash, 
and/or eosinophilia >5%. 
At a minimum, this evaluation should include physical examination and a thorough medical 
history, as outlined above, as well as tests for PT-INR; tests for viral hepatitis A, B, C, or E; tests 
for autoimmune hepatitis; and an abdominal imaging study, for example, ultrasound or CT scan. 
Based on the patient’s history and initial results, further testing should be considered in 
consultation with the Lilly-designated medical monitor, including tests for hepatitis D virus, 
cytomegalovirus, Epstein-Barr virus, acetaminophen levels, acetaminophen protein adducts, 
urine toxicology screen, Wilson’s disease, blood alcohol levels, urinary ethyl glucuronide, and 
blood phosphatidylethanol. Based on the circumstances and the investigator’s assessment of the 
participant’s clinical condition, the investigator should consider referring the participant for a 
hepatologist or gastroenterologist consultation, magnetic resonance cholangiopancreatography, 
endoscopic retrograde cholangiopancreatography, cardiac echocardiogram, or a liver biopsy. 
8.2.7.3. 
Additional Hepatic Data Collection (hepatic safety CRF) in Study Participants 
who have Abnormal Liver Tests during the Study  
Additional hepatic safety data collection in hepatic safety CRFs should be performed in study 
participants who meet 1 or more of the following 5 conditions: 
 Elevation of serum ALT to ≥5x ULN on 2 or more consecutive blood tests, if baseline 
ALT <1.5x ULN 
o In participants with baseline ALT ≥1.5x ULN, the threshold is ALT ≥3x baseline 
on 2 or more consecutive tests 
 Elevated TBL to ≥2x ULN (if baseline TBL <1.5x ULN), except for cases of known 
Gilbert’s syndrome 
o In participants with baseline TBL ≥1.5x ULN, the threshold should be TBL ≥2x 
baseline 
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 Elevation of serum ALP to ≥2x ULN on 2 or more consecutive blood tests, if baseline 
ALP <1.5x ULN 
o In participants with baseline ALP ≥1.5x ULN, the threshold is ALP ≥2x baseline 
on 2 or more consecutive blood tests 
 Hepatic event considered to be an SAE 
 Discontinuation of study drug due to a hepatic event 
Note: the interval between the 2 consecutive blood tests should be at least 2 days. 
8.3. 
Adverse Events, Serious Adverse Events, and Product Complaints  
The definitions of the following events can be found in Section 10.3: 
 AEs 
 SAEs 
 PCs 
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 the study (see Section 7). 
Care will be taken not to introduce bias when detecting events. Open-ended and non-leading 
verbal questioning of the participant is the preferred method to inquire about event occurrences. 
After the initial report, the investigator is required to proactively follow each participant at 
subsequent visits or contacts. All SAEs and AEs of special interest (as defined in Section 8.3.3) 
will be followed until resolution, stabilization, the event is otherwise explained, or the participant 
is lost to follow-up (as defined in Section 7.3). 
For PCs, 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 10.3.4. 
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8.3.1. 
Timing and Mechanism for Collecting Events  
This table describes the timing, deadlines, and mechanism for collecting events. 
Event 
Collection 
Start 
Collection 
Stop 
Timing for Reporting 
to Sponsor or 
Designee 
Mechanism for 
Reporting 
Back-up 
Method of 
Reporting 
Adverse Event 
AE 
Signing of 
the ICF 
Participation 
in study has 
ended 
As soon as possible 
upon site awareness 
AE CRF 
N/A 
Serious Adverse Event 
SAE and SAE 
updates – prior 
to start of study 
intervention and 
deemed 
reasonably 
possibly related 
to study 
procedures 
Signing of 
ICF 
Start of 
intervention 
Immediately without 
exceeding 24 hrs  
SAE CRF  
SAE paper 
form 
SAEa and SAE 
updates – after 
start of study 
intervention 
Start of 
intervention 
Participation 
in study has 
ended 
Immediately without 
exceeding 24 hrs 
SAE CRF  
SAE paper 
form 
SAEb – 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 
Until 1 month 
after the last 
dose of study 
intervention 
Within 24 hrs (see 
Section 8.3.2) 
Pregnancy paper 
form 
Pregnancy 
paper form 
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Event 
Collection 
Start 
Collection 
Stop 
Timing for Reporting 
to Sponsor or 
Designee 
Mechanism for 
Reporting 
Back-up 
Method of 
Reporting 
Product Complaints 
PC associated 
with an SAE or 
might have led 
to an SAE 
Start of study 
intervention 
End of study 
intervention 
Within 24 hrs 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. 
a Death caused by disease progression should not be reported as an SAE. 
b 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 
 obtain a consent to release information from the pregnant female partner directly, and 
 within 24 hours after obtaining this consent will record pregnancy information on the 
appropriate form and submit it to the sponsor. 
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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 poststudy pregnancy-related SAE considered reasonably related to the study intervention by 
the investigator will be reported to the sponsor as described in protocol Section 8.3.1. While the 
investigator is not obligated to actively seek this information in former study participants, he or 
she may learn of an SAE through spontaneous reporting. 
Any female participant who becomes pregnant while participating in the study will be withdrawn 
from the study. If the participant is discontinued from the study, follow the standard 
discontinuation process and continue directly to the follow-up phase. The follow-up on the 
pregnancy outcome should continue independent of intervention or study discontinuation. 
8.3.3. 
Safety Topics of Special Interest  
The safety topics of special interest are 
 gastrointestinal (Section 8.3.3.1) 
 dehydration (Section 8.3.3.2) 
 renal safety (Section 8.3.3.3) 
 exocrine pancreas safety (Section 8.3.3.4) 
 thyroid C-cell hyperplasia and C-cell neoplasms (Section 8.3.3.5) 
 hypoglycemia (Section 8.3.3.6) 
 severe, persistent hyperglycemia (Section 8.3.3.7) 
 major adverse cardiovascular event (MACE) (Section 8.3.3.8) 
 arrythmias and cardiac conduction disorders (Section 8.3.3.9) 
 hypersensitivity reactions (Section 8.3.3.10) 
 injection-site reactions (Section 8.3.3.11) 
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 diabetic retinopathy complications (Section 8.3.3.12), and 
 hepatobiliary disorders (Section 8.3.3.13). 
8.3.3.1. 
Gastrointestinal Adverse Event  
Tirzepatide may cause severe GI AEs, such as nausea, vomiting, and diarrhea. Information about 
severe GI AEs as well as anti-emetic/anti-diarrheal use will be collected in the CRF/AE form. 
For detailed information concerning the management of GI AEs, refer to Section 6.5.1. 
8.3.3.2. 
Dehydration  
Severe gastrointestinal events may lead to dehydration and volume depletion, which can cause a 
deterioration in renal function, including acute renal failure. Many of the reported adverse renal 
events occurred in participants who had experienced nausea, vomiting, diarrhea, or dehydration. 
Participants should be advised of the potential risk of dehydration, particularly in relation to 
gastrointestinal adverse reactions or other AEs and take precautions to avoid fluid depletion. 
8.3.3.3. 
Renal Safety  
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 disease. 
8.3.3.4. 
Exocrine Pancreas Safety  
Diagnosis of acute pancreatitis 
The diagnosis of acute pancreatitis requires 2 of the following 3 features (Banks 2006; Kouzumi 
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 ≥3x ULN, and 
 characteristic findings of acute pancreatitis on CT scan or MRI. 
If acute pancreatitis is suspected, the investigator should 
 obtain appropriate laboratory tests, including pancreatic amylase and lipase, via the 
central laboratory and, if needed, via a local laboratory as well, and 
 perform imaging studies, such as abdominal CT scan with or without contrast, MRI, or 
gallbladder ultrasound. 
Discontinuation and rescue intervention for acute pancreatitis 
If laboratory values and/or abdominal imaging support the diagnosis of acute pancreatitis, the 
participant must discontinue therapy with investigational product(s) but will continue in the 
study on another glucose-lowering regimen (details on rescue intervention will be provided). The 
most appropriate diabetes therapeutic regimen will be decided by the investigator, based on the 
participant’s clinical status. A review of the participant’s concomitant medications should be 
conducted to assess any potential causal relationship with pancreatitis. 
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Reporting adverse events and serious adverse events 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 
1) are present, and 
2) are confirmed by 
a) laboratory values (lipase or amylase [total and/or pancreatic]), and 
b) 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. 
Pancreatic hyperenzymemia 
Each participant will have measurements of pancreatic amylase and lipase, assessed at the central 
laboratory, as shown in Section 1.3 to assess the effects of the investigational doses of study 
intervention on pancreatic enzyme levels. 
Serial measures of pancreatic enzymes have limited clinical value for predicting episodes of 
acute pancreatitis in asymptomatic participants (Koizumi 2006; Steinberg 2017 a, 2017b). Thus, 
further diagnostic follow-up of cases of asymptomatic pancreatic hyperenzymemia, lipase and/or 
pancreatic amylase 3x ULN or more is not mandated but may be performed based on the 
investigator’s clinical judgment and assessment of the participant’s overall clinical condition. 
Only cases of pancreatic hyperenzymemia that undergo additional diagnostic follow-up and/or 
are accompanied by symptoms suggestive of pancreatitis will be submitted for adjudication. 
Case adjudication and data entry 
An independent clinical endpoint committee will adjudicate all suspected cases of acute or 
chronic pancreatitis. The adjudication committee will also receive data on AEs of severe or 
serious abdominal pain of unknown etiology to assess for possible pancreatitis or other 
pancreatic disease. 
Study site staff will enter relevant data for participants with acute or chronic pancreatitis or those 
with AEs of severe or serious abdominal pain into a specifically designed CRF page. The 
adjudication committee representative will enter the results of adjudication into a corresponding 
CRF page. 
8.3.3.5. 
Thyroid C-Cell Hyperplasia and C-Cell Neoplasms  
Individuals with personal or family history of MTC and/or MEN 2 will be excluded from the 
study. 
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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. Calcitonin 
measurements will assess the potential of study intervention to affect thyroid C-cell function, 
which may indicate development of C-cell hyperplasia and neoplasms. These data will be 
captured in specific CRFs. 
If an increased calcitonin value (≥35 ng/L AND an increase by ≥50% compared with baseline) is 
observed in a participant who has administered a medication that is known to increase serum 
calcitonin, this medication must be stopped, and calcitonin levels must be measured after an 
appropriate washout period. A consultation with a thyroid specialist or an endocrinologist should 
be obtained. See Section 7.1 for thyroid-related discontinuation criteria. 
If the confirmed calcitonin value is <35 ng/L, tirzepatide should be restarted when it is safe to do 
so. 
8.3.3.6. 
Hypoglycemia  
Participants will be trained by authorized study personnel 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. 
To avoid duplicate reporting, all consecutive BG values <70 mg/dL (3.9 mmol/L) occurring 
within a 1-hour period may be considered to be a single hypoglycemic event (Weinberg et al. 
2010; Danne et al. 2013). 
Hypoglycemia classification and definitions 
Level 1 
Glucose ≥54 mg/dL (≥3.0 mmol/L) and <70 mg/dL (<3.9 mmol/L) 
Level 1 hypoglycemia can alert a person to take action such as treatment with fast-acting 
carbohydrates. Providers should continue to counsel participants to treat hypoglycemia at this 
glucose alert value. 
Level 2 
Glucose <54 mg/dL (<3.0 mmol/L) 
Level 2 hypoglycemia is also referred to as documented or blood glucose confirmed 
hypoglycemia with glucose <54 mg/dL (<3.0 mmol/L). This glucose threshold is clinically 
relevant regardless of the presence or absence of symptoms of hypoglycemia. 
Level 3 Severe 
A severe hypoglycemic event is characterized by altered mental or physical status requiring 
assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative 
actions for the treatment of hypoglycemia. 
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The determination of an episode of severe hypoglycemia 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. 
Examples of severe hypoglycemia in adults are 
 altered mental status and the inability to assist in their own care 
 semiconscious or unconscious, or 
 coma with or without seizures. 
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. 
Nocturnal hypoglycemia 
Nocturnal hypoglycemia is a hypoglycemic event, including severe hypoglycemia, that occurs at 
night and presumably during sleep. 
Reporting of severe hypoglycemic events 
If a hypoglycemic event meets the criteria of severe, the investigator must record the event as 
serious on the AE CRF and report it to Lilly as an SAE. 
The investigator should also determine if repeated or prolonged episodes of hypoglycemia 
occurred prior to the severe event. 
8.3.3.7. 
Severe, Persistent Hyperglycemia  
Severe, persistent hyperglycemia will be assessed during the study to determine 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. Participants will be treated with rescue medication as an add-on to randomly 
assigned treatment, and participants will continue to follow the protocol-specified visit schedule 
as described in Section 6.1.4. 
8.3.3.8. 
Major Adverse Cardiovascular Events  
Deaths and nonfatal CV AEs will be adjudicated by a committee of physicians external to Lilly 
with cardiology expertise. The nonfatal CV 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. 
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8.3.3.9. 
Arrythmias and Cardiac Conduction Disorder  
Participants who develop any event from these groups 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 Appendix 3, Section 10.3 must be reported as SAEs. 
After enrollment, if a clinically significant finding is identified by ECG including, but not limited 
to, changes from baseline in QT/QTc interval, the investigator or qualified designee will 
determine if any change in study participant management is needed. This review of the ECG 
printed at the time of collection must be documented. Any new clinically relevant finding must 
be reported as an AE or SAE (if applicable). 
8.3.3.10. Hypersensitivity Reactions  
Many drugs, particularly biologic agents, carry the risk of systemic hypersensitivity reactions. If 
such a reaction occurs, additional data describing each symptom must be provided to the sponsor 
in the CRF. 
Sites should have appropriately trained medical staff and appropriate medical equipment 
available when study participants are receiving study intervention. It is recommended that 
participants who experience a systemic hypersensitivity reaction be treated per national and 
international guidelines. 
In the case of generalized urticaria or anaphylaxis, additional blood samples should be collected 
as described in Appendix 2, Section 10.2.1. Laboratory results are provided to the sponsor via 
the central laboratory. 
If the investigator, after consultation with the Lilly medical monitor, determines that a systemic 
hypersensitivity reaction has occurred related to study intervention administration, the participant 
should be permanently discontinued from the intervention, and the Lilly medical monitor should 
be notified. If the investigator is uncertain about whether a systemic hypersensitivity reaction has 
occurred and whether discontinuation of study intervention is warranted, the investigator may 
consult the sponsor. 
8.3.3.11. Injection-Site Reactions  
Symptoms and signs of a local ISR may include erythema, induration, pain, pruritus, and edema. 
If an ISR is reported by a participant, caregiver, or site staff, the ISR CRF will be used to capture 
additional information about this reaction, for example, injection-site pain, degree and area of 
erythema, induration, pruritis, and edema. 
At the time of AE occurrence in the tirzepatide group, samples will be collected for measurement 
of tirzepatide anti-drug antibodies and tirzepatide concentration. 
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8.3.3.12. 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. 
A follow-up dilated fundoscopic examination occurs when clinically indicated by any AE of 
suspected worsening of retinopathy. The findings will be recorded on the retinopathy CRF. 
8.3.3.13. 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. 
8.4. 
Pharmacokinetics  
Pharmacokinetic parameters are not evaluated in this study. 
In the case of hypersensitivity or ISR, samples will be collected if needed as described in 
Section 10.2.1. 
8.5. 
Pharmacodynamics  
Pharmacodynamic parameters are not evaluated in this study. 
8.6. 
Genetics  
Genetics are not evaluated in this study. 
8.7. 
Biomarkers  
Biomarkers are not evaluated in this study. 
8.8. 
Immunogenicity Assessments  
Immunogenicity will not be proactively assessed in this study. 
In the case of hypersensitivity or ISR, samples will be collected if needed as described in Section 
10.2.1. 
8.9. 
Medical Resource Utilization and Health Economics  
Medical resource utilization and health economics parameters are not evaluated in this study. 
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9. 
Statistical Considerations  
The statistical analysis plan will be developed and approved prior to first participant first visit, 
and it will include a more technical and detailed description of the statistical analyses described 
in this section. This section is a summary of the planned statistical analyses of the most 
important endpoints, including primary and key secondary endpoints. 
9.1. 
Statistical Hypotheses  
The null hypothesis corresponding to the primary objective of this study is as follows: 
 H1,0: Switching from dulaglutide to 15 mg or MTD of tirzepatide is not superior to 
continuing and escalating to dulaglutide 4.5 mg or MTD with respect to HbA1c mean 
change from baseline at Week 40 in participants who entered the study on a nonmaximal 
dose of dulaglutide. 
The null hypothesis corresponding to the key secondary objective is as follows: 
 H2,0: Switching from dulaglutide to 15 mg or MTD of tirzepatide is not superior to 
continuing and escalating to dulaglutide 4.5 mg or MTD with respect to weight mean 
change from baseline at Week 40 in participants who entered the study on a nonmaximal 
dose of dulaglutide. 
Operationally the hypotheses will be evaluated by 2-sided tests. 
9.1.1. 
Multiplicity Adjustment  
The primary and the key secondary objectives will be evaluated using both the treatment-
regimen and the efficacy estimands. Since the purpose for each estimand is different, multiplicity 
adjustment will be conducted for each estimand separately. 
The statistical comparisons for the primary efficacy endpoint and the key secondary endpoint 
will be carried out in the hierarchical order as described in Section 9.1. This means that 
statistically significant results for the comparison in the higher rank (primary) is required to 
initiate the testing of the next comparison in the lower rank (key secondary). Since a step-down 
procedure is used, each comparison will be tested at a significance level of 1-sided 0.025 and an 
overall alpha level of 1-sided 0.025 will be preserved. 
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9.2. 
Analysis Sets  
This table defines the analysis populations and datasets for the purposes of analysis based on the 
estimands defined in Section 3. 
Population/Analysis Set 
Description 
Screened population 
All participants who signed informed consent. 
Randomized population 
All participants who are randomly assigned to a treatment arm. 
Modified intent-to-treat population (mITT) 
All randomly assigned participants who are exposed to at least 1 
dose of study intervention. Participants will be analyzed 
according to the treatment they were randomly assigned to 
regardless of the treatment actually received.  
Efficacy Analysis Set (EAS): This analysis 
set will be used to estimate the efficacy 
estimand for the primary and key secondary 
objectives 
Data obtained during the Treatment Period from the mITT 
population excluding patients who were inadvertently enrolled, 
excluding data after permanent discontinuation of treatment or 
initiation of antihyperglycemic rescue medication or prohibited 
medication. 
Full Analysis Set (FAS): This analysis set 
will be used to estimate the treatment-
regimen estimand for the primary and key 
secondary objectives 
Data obtained during the Treatment Period from the mITT 
population excluding patients who were inadvertently enrolled, 
regardless of adherence to treatment or initiation of 
antihyperglycemic rescue medication or prohibited medication. 
Safety Analysis Set (SS): This analysis will 
be used to assess the safety of study 
treatment 
Data obtained during the Treatment Period plus Safety Follow-up 
from the mITT population, regardless of adherence to treatment 
or initiation of rescue antihyperglycemic medication or prohibited 
medication.  
9.3. 
Statistical Analyses  
9.3.1. 
General Considerations  
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 statistical analysis plan or clinical study report. Additional exploratory analyses of the data 
will be conducted as deemed appropriate. 
All tests of treatment effects will be conducted at a 2-sided alpha level of 0.05/1-sided alpha 
level of 0.025, unless otherwise stated, and all confidence intervals will be given at a 2-sided 
(95%) level. In statistical summaries and analyses, all data will be analyzed by randomly 
assigned 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 EAS to evaluate the efficacy estimand and the FAS to evaluate the 
treatment-regimen estimand. Safety will be assessed using Safety Analysis Set. Selected safety 
analyses may be conducted after excluding data on rescue therapy or data after starting another 
antihyperglycemic medication. 
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Summary statistics for continuous measures may include sample size, mean, standard deviation, 
median, minimum, and maximum. The analysis model to make comparisons between treatment 
groups relative to continuous measurements assessed over time will be an MMRM with terms for 
 treatment 
 visit 
 treatment-by-visit interaction 
 number of background OAMs (0-1 or 2-3) 
 dulaglutide dose at screening (0.75 mg or 1.5 mg) 
 region (NA, EU) 
 baseline HbA1c category (≤8.5% or >8.5%), and 
 baseline measurement as a covariate. 
For analyses of HbA1c, the baseline HbA1c category will not be included in the model. An 
unstructured covariance structure will model the relationship of within-participant errors. 
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. 
Handling of missing, unused, and spurious data are addressed prospectively in the overall 
statistical methods described in the protocol and in the SAP, where appropriate. Adjustments to 
the planned analyses are described in the final CSR. 
9.3.2. 
Primary Endpoint Analysis  
The primary endpoint for this study is change from baseline in HbA1c to the 40-week visit (Visit 
11). This endpoint will be used to evaluate the primary objective of the study for both the 
treatment-regimen and the efficacy estimands (Section 3). The null hypothesis corresponding to 
the primary objective is specified in Section 9.1. 
The primary objective based on the treatment-regimen estimand defined in Section 3 will be 
evaluated based on the FAS dataset (Section 9.2) using an ANCOVA for change from baseline in 
HbA1c at Week 40 with terms for 
 treatment (tirzepatide, dulaglutide) 
 number of background OAMs (0-1 or 2-3) 
 dulaglutide dose at screening (0.75 mg or 1.5 mg) 
 region (NA, EU), and 
 baseline value. 
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For the purpose of the treatment-regimen estimand, missing HbA1c values at the 40-week visit 
will be imputed based on observed data in the same treatment group from participants who had 
their efficacy assessed after ED of study intervention. This analysis will be conducted with 
multiple imputations, and statistical inference over multiple imputations will be guided by the 
method proposed by Rubin (1987). 
The primary objective based on the efficacy estimand defined in Section 3 will be evaluated 
using the EAS dataset (Section 9.2). The primary analysis model for HbA1c measurements over 
time will be an 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, treatment-by-visit interaction, number of background OAMs, 
dulaglutide dose at screening, region as fixed effects, and baseline HbA1c as covariate. Missing 
data will be addressed by the MMRM model. No explicit imputation methods for missing data 
will be employed. 
9.3.3. 
Secondary Endpoint Analysis  
The endpoint corresponding to the secondary study objective subject to type 1 error rate control 
is specified in Section 3 under “Key Secondary” (Controlled for Type 1 error) endpoints. 
The null hypothesis corresponding to the key secondary objective can be found in Section 9.1. 
The key secondary objective will be evaluated based on the treatment-regimen and the efficacy 
estimands (Section 3), similar to the primary objective. 
The analysis of change from baseline in body weight at the 40-week visit (Visits 11) will be 
conducted in a manner similar to the primary efficacy analyses (Section 9.3.2). Baseline HbA1c 
category (≤8.5% or >8.5%) will be added to the model. 
Endpoints for additional secondary objectives are described in Section 3 and will be evaluated 
based on the efficacy estimand. 
Additional details will be provided in the SAP. 
9.3.4. 
Exploratory Endpoint Analysis  
Endpoints for exploratory objectives are described in Section 3 and will be evaluated based on 
the efficacy estimand. Additional details will be provided in the SAP. 
9.3.5. 
Safety Analyses  
Safety assessments will be done using the Safety Analysis Set (See Section 9.1) irrespective of 
adherence to study intervention or initiation of rescue antihyperglycemic therapy, unless 
indicated otherwise. Adverse events will be coded from the actual term using the Medical 
Dictionary for Regulatory Activities and reported with preferred terms and system organ class. 
Selected notable AEs of interest may be reported using high-level terms or Standardized Medical 
Dictionary for Regulatory Activities Queries. Summary statistics will be provided for incidence 
of TEAEs, SAEs, and study discontinuation due to AEs, study intervention discontinuation due 
to AEs, or deaths from the time of first dose through the end of safety follow-up. 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. 
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9.3.5.1. 
Hypoglycemic Events  
Incidence of documented symptomatic hypoglycemic events and severe hypoglycemia will be 
summarized and compared between the tirzepatide and dulaglutide arms. Rate of hypoglycemic 
episodes will be analyzed using a generalized linear mixed-effects model assuming negative 
binomial distribution for hypoglycemic episodes if data warrant. Some analyses may be 
conducted excluding data after introducing another antihyperglycemic therapy. 
9.3.5.2. 
Gastrointestinal Events  
Summaries and analyses for incidence and severity of nausea, vomiting, and diarrhea will be 
provided by each treatment. 
9.3.5.3. 
Adjudicated Cardiovascular Events  
Listing of deaths, myocardial infarctions, strokes, and hospitalization for unstable angina 
confirmed by an independent clinical endpoint committee will be provided. The dates of 
randomization, event, first dose and last dose of study intervention, and time from randomization 
to event will be listed. 
9.3.5.4. 
Central Laboratory Measures and Vital signs  
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 between treatment arms relative to continuous change 
from baseline values assessed over time will be an MMRM, with terms: treatment, visit, and 
treatment-by-visit interaction, number of background OAMs (0-1, 2-3), dulaglutide dose at 
screening, region, and baseline measurement as covariates. 
An unstructured covariance structure will model relationship of within-participant 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 the follow-up. A treatment-emergent high result is defined as 
a change from a value less than or equal to the high limit at baseline to a value greater than the 
high limit at any time during the Treatment and Follow-up Periods. A treatment-emergent low 
result is defined as a change from a value greater than or equal to the low limit at baseline to a 
value less than the low limit at any time during the Treatment and Follow-up Periods. High and 
low limits will be provided in the SAP. 
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9.3.6. 
Subgroup Analyses  
Subgroup analyses of the primary endpoint (change from baseline in HbA1c) will be made to 
assess consistency of the intervention effect across the following subgroups: 
 age group: <65 years, ≥65 years 
 sex: female, male 
 race: white, black, other 
 ethnicity: Hispanic, non-Hispanic 
 duration of diabetes (≤5 years, >5 to ≤10 years, >10 years) 
 baseline HbA1c (≤8.5%, >8.5%), and 
 region: NA, EU 
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. 
9.5. 
Sample Size Determination  
Approximately 250 participants will be randomly assigned in a 1:1 ratio to each study arm. This 
sample size provides at least 90% power to detect a difference between treatment arms at Week 
40 irrespective of adherence to treatment, changes in background OAMs or introduction of 
rescue antihyperglycemic medication. This sample size is based on an assumed treatment 
difference of 0.58% with a common standard deviation of 1.3%, using a two-group t-test and a 
0.05 two-sided significance level. The treatment difference is based on the following 
assumptions for the dose distribution for maximum dose or MTD: 
▪ Tirzepatide MTD will be comprised of the following doses: 
▪ 15 mg dose: 80% of the participants 
▪ 10 mg dose: 15% of the participants, and 
▪  5 mg dose: 5% of the participants. 
▪ Dulaglutide MTD will be comprised of the following doses: 
▪ 4.5 mg dose: 80% of the participants 
▪ 3.0 mg dose: 15% of the participants, and 
▪ 1.5 mg dose: 5% of the participants. 
In addition, the planned sample size provides at least 95% power to detect a difference between 
treatment arms at Week 40 after randomization regardless of changes in background OAM 
assuming that participants stay on treatment and do not take rescue antihyperglycemic 
medication. This sample size is based on a treatment difference of 0.60% with a common 
standard deviation of 1.1%, using a two-group t-test and a 0.05 two-sided significance level. The 
treatment differences are based on the same assumptions stated above for the treatment-regimen 
estimand with a 15% discontinuation rate. 
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10. 
Supporting Documentation and Operational Considerations  
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations  
10.1.1. 
Regulatory and Ethical Considerations  
● This study will be conducted in accordance with the protocol and with the 
following: 
○ Consensus ethical principles derived from international guidelines including 
the Declaration of Helsinki and Council for International Organizations of 
Medical Sciences International Ethical Guidelines 
○ Applicable ICH GCP Guidelines 
o International Organization for Standardization (ISO) 14155 
○ Applicable laws and regulations 
● The protocol, protocol amendments, ICF, IB, and other relevant documents (for 
example, advertisements) must be submitted to an IRB/IEC by the investigator 
and reviewed and approved by the IRB/IEC before the study is initiated. 
● Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 
● Protocols and any substantial amendments to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an 
immediate hazard to study participants. 
● The investigator will be responsible for the following: 
○ Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/IEC 
○ Notifying the IRB/IEC of SAEs or other significant safety findings as required 
by IRB/IEC procedures 
○ 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, and 
○ Reporting significant issues related to participant safety, participant rights, or 
data integrity 
● Investigator sites are compensated for participation in the study as detailed in the 
Clinical Trial Agreement. 
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10.1.2. 
Financial Disclosure  
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
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 participant or the participant’s 
legally authorized representative and answer all questions regarding the study. 
● Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representatives will be required to sign a statement of informed 
consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 
privacy and data protection requirements, where applicable, and the IRB/IEC or study 
center. Persons under legal protection may participate in this study if the investigator or 
the investigator’s representative deems that individual is able to understand the risks and 
benefits of participating in the study and is able to complete all aspects of the study, 
including but not limited to the questionnaires and diary. The legally authorized 
representative may then sign the ICF on behalf of the individual. 
● 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. 
Participants who are rescreened are required to sign a new ICF. 
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. This 
is done by the site personnel through the informed consent process. 
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● The participant must be informed through the informed consent by the site 
personnel 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 information security, data integrity, 
and data protection, including transfer, unauthorized access, disclosure, 
dissemination, alteration or loss of information and personal data processed. 
These processes include appropriate contingency plan(s) for appropriate and 
timely response in the event of a data security breach. 
● The transfer of personal data is subject to appropriate safeguards through 
contractual agreements and processes. The sponsor’s processes are compliant with 
local privacy laws and relevant legislations including the General Data Protection 
Regulation (GDPR). 
10.1.5. 
Committees Structure  
External Clinical Endpoint Committee 
An independent clinical endpoint committee, external to Lilly, will be formed to adjudicate 
major adverse cardiovascular events and acute pancreatitis. This committee will be blinded to 
treatment assignment. 
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 dataset 
would result in analyses lacking scientific rigor (for example, underpowered) or compromise the 
integrity of the overall analyses, for example, study not yet unblinded, the summary of results 
will be submitted within 1 year after the end of the study globally or as soon as available, 
whichever is earlier. 
Data 
The sponsor provides access to all individual participant data collected during the trial, after 
anonymization, with the exception of PK 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 CRFs, will 
be provided in a secure data sharing environment for up to 2 years per proposal. 
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For details on submitting a request, see the instructions provided at www.vivli.org. 
10.1.7. 
Data Quality Assurance  
Investigator responsibilities 
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 permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
Quality tolerance limits 
Quality tolerance limits 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 quality tolerance limits 
and remedial actions taken will be summarized in the CSR. 
Data monitoring and management 
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. 
Study monitors will perform ongoing source data verification to confirm that data 
transcribed into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 
Records retention and audits 
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for the 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. 
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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. 
Electronic data capture system 
An electronic data capture system will be used in this study for the collection of CRF data. The 
investigator maintains a separate source for the data entered by the investigator or designee into 
the sponsor-provided electronic data capture system. The investigator is responsible for the 
identification of any data to be considered source and for the confirmation that data reported are 
accurate and complete by signing the CRF. 
Clinical outcome assessments 
Additionally, eCOA data (participant-focused outcome instrument) will be directly recorded by 
the participant into an instrument, for example, handheld smart phone or tablet. The eCOA data 
will serve as the source documentation, and the investigator does not maintain a separate written 
or electronic record of these data. 
Data storage and access 
Data collected via the sponsor-provided data capture systems 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 systems. Prior to decommissioning, the investigator will 
receive or access an archival copy of pertinent data for retention. 
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system, and reports or 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 PC 
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 Section 10.1.7. 
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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. 
The first act of recruitment is the first site’s first participant visit (Visit 1) and will be the study 
start date. 
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 IRB/IEC, 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. 
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10.1.12. 
Sample Retention  
Sample retention enables use of new technologies, response to regulatory questions, and 
investigation of variable response that may not be observed until later in the development 
of tirzepatide or after tirzepatide becomes commercially available for the studied indication. 
 
Sample Type 
Custodian 
Retention Period After Last Participant Visita 
Tirzepatide anti-drug antibodies (ADA)b Sponsor or Designee 
15 years 
a Retention periods may differ locally. 
b Sample collection only for hypersensitivity and injection site reactions. 
 
 
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10.2. 
Appendix 2: Clinical Laboratory Tests  
The tests detailed in the table below will be performed by the Lilly-designated laboratory or by 
the local laboratory as specified. 
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. 
Clinical Laboratory Tests 
Comments 
Hematology 
Assayed by Lilly-designated laboratory.  
Hemoglobin 
  
Hematocrit 
  
Erythrocyte count (RBCs - red blood cells) 
  
Mean cell volume  
  
Mean cell hemoglobin 
  
Mean cell hemoglobin concentration 
 
Leukocytes (WBCs - white blood cells)  
  
Differential  
  
  Neutrophils 
  
  Lymphocytes 
  
  Monocytes 
  
  Eosinophils 
  
  Basophils 
  
Platelets 
  
Cell morphology (RBC and WBC), if indicated  
 
Clinical Chemistry 
Assayed by Lilly-designated laboratory.  
Sodium 
  
Potassium 
  
Chloride 
  
Bicarbonate 
  
Total bilirubin 
  
Direct bilirubin 
  
Alkaline phosphatase (ALP) 
  
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Clinical Laboratory Tests 
Comments 
Alanine aminotransferase (ALT) 
  
Aspartate aminotransferase (AST) 
  
Gamma-glutamyl transferase (GGT) 
 
Blood urea nitrogen (BUN) 
  
Creatinine  
  
Creatine kinase (CK) 
 
Uric acid 
 
Total protein 
  
Albumin 
  
Calcium 
Phosphorus 
Lipid Panel 
Assayed by Lilly-designated laboratory. 
Total cholesterol 
 
Triglycerides 
 
High-density lipoprotein cholesterol (HDL-C) 
 
Low-density lipoprotein cholesterol (LDL-C)  
Generated by Lilly-designated laboratory. 
Direct LDL will be measured only when 
triglycerides >400 mg/dL. 
Very-low-density lipoprotein cholesterol  
(VLDL-C) 
 
Hormones (female) 
Serum pregnancy 
Assayed by Lilly-designated laboratory. 
Urine pregnancy 
Assayed and evaluated locally. 
Follicle-stimulating hormone (FSH) 
Assayed by Lilly-designated laboratory. 
Urine Chemistry 
Assayed by Lilly-designated laboratory. 
Albumin 
 
Creatinine 
 
Calculations 
Generated by Lilly-designated laboratory. 
eGFR (CKD-EPI) calculated using creatinine 
Results will not be provided to the investigative 
sites. 
eGFR (CKD-EPI) calculated using cystatin C 
Results will not be provided to the investigative 
sites. 
eGFR (CKD-EPI) calculated using creatinine and cystatin 
C 
 
Urinary albumin/creatinine ratio (UACR) 
 
Additional Testing 
Assayed by Lilly-designated laboratory. 
Glucose 
 
HbA1c 
 
Calcitonin 
 
Pancreatic amylase 
 
Lipase 
 
Cystatin C 
 
Anti-glutamic acid decarboxylase antibody (Anti-GAD) 
 
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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 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 predose samples at the next regularly scheduled laboratory sample collection 
(ideally prior to the next dose after the event) to assess post-event return-to-baseline values. 
 
Timing 
Sample Type 
Laboratory Test a 
Collect from 30 min to 4 hrs after 
the start of the event. 
● 
Note: The optimal collection 
time is from 1 to 2 hrs after the 
start of event. 
Serum 
total tryptase 
Serum/plasma 
complements (C3, C3a, and C5a) 
Serum 
cytokine panel (IL-6, IL‐1β, IL‐10 or any cytokine panel 
that includes these 3 cytokines)  
Collect only if not already collected 
on the same day as the event. 
● 
Note: If collecting, collect up 
to 12 hrs after the start of the 
event. 
Serum 
Tirzepatide anti-drug antibodies (ADA) 
Plasma 
Tirzepatide concentration 
Abbreviation: 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 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. 
 
 
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10.3. 
Appendix 3: Adverse Events and Serious Adverse Events: Definitions 
and Procedures for Recording, Evaluating, Follow-up, and 
Reporting  
10.3.1. 
Definition of AE  
AE Definition 
 An AE is any untoward medical occurrence in a participant administered a 
pharmaceutical product and which does not necessarily have a causal relationship with 
the study intervention. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product. 
 
Events Meeting the AE Definition 
 Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (for example, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (that is, not related 
to progression of underlying disease). 
 Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition. 
 New condition detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
 Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 Medication error, misuse, or abuse of IMP, including signs, symptoms, or clinical 
sequalae. 
 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. 
 The disease or disorder being studied or expected progression, signs, or symptoms of 
the disease or disorder being studied, unless more severe than expected for the 
participant’s condition. 
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 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 preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.  
10.3.2. 
Definition of SAE  
An SAE is defined as any untoward medical occurrence that, at any dose, meets one or 
more of the criteria listed: 
a. Results in death 
b. Is life-threatening 
The term life-threatening in the definition of serious refers to an event in which the participant 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 In general, hospitalization signifies that the participant has been admitted to hospital or 
emergency ward (usually involving at least an overnight stay) for observation 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. 
 Hospitalization for elective treatment of a preexisting condition that did not worsen 
from baseline is not considered an AE. 
d. Results in persistent disability or incapacity 
 The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
 This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (for example, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly or birth defect 
 Abnormal pregnancy outcomes (for example, spontaneous abortion, fetal death, 
stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs. 
f. 
Other situations 
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 Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations such as important medical 
events that may not be immediately life-threatening or result in death or hospitalization 
but may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events should 
usually be considered serious. 
 
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency or 
drug abuse.  
10.3.3. 
Definition of Product Complaints  
Product Complaint 
 A PC is any written, electronic, or oral communication that alleges deficiencies related 
to the identity, quality, durability, reliability, safety, effectiveness or performance of a 
study intervention. When the ability to use the study intervention safely is impacted, 
the following are also PCs: 
o Deficiencies in labeling information, and 
o Use errors for device or drug-device combination products due to ergonomic 
design elements of the product. 
 PCs related to study interventions used in clinical trials are collected 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 PC or problem with the study intervention so that the situation can be assessed. 
 An event may meet the definition of both a PC and an AE/SAE. In such cases, it 
should be reported as both a PC and as an AE/SAE. 
 
10.3.4. 
Recording and Follow-Up of AE and/or SAE and Product Complaints  
AE, SAE, and PC Recording 
 When an AE/SAE/PC occurs, it is the responsibility of the investigator to review all 
documentation (for example, hospital progress notes, laboratory reports, and diagnostic 
reports) related to the event. 
 The investigator will then record all relevant AE/SAE/PC information in the 
participant’s medical records, in accordance with the investigator’s normal clinical 
practice. AE/SAE information is reported on the appropriate CRF page and PC 
information is reported on the Product Complaint Form. 
Note: An event may meet the definition of both a PC and an AE/SAE. In such cases, it 
should be reported as both a PC and as an AE/SAE. 
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 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 PCs. 
 There may be instances when copies of medical records for certain cases are requested 
by sponsor or designee. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to sponsor or designee. 
 The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs or 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 an SAE. Severe is a category utilized 
for rating the intensity of an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as “serious” when it meets at least one of the pre-defined 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 and/or Product Information for marketed 
products in their assessment. 
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 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 an SAE follow-up report with the updated causality assessment. 
 The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-up of AEs and SAEs 
 The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by sponsor or 
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 
post-mortem 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) 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 an SAE paper form (see next 
section) or to the sponsor or designee by telephone. 
 Contacts for SAE reporting can be found in site training materials.  
 
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SAE Reporting via Paper Form 
 Facsimile transmission of the SAE paper form is the preferred method to transmit this 
information to the sponsor or designee. 
 Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames. 
 Contacts for SAE reporting can be found in site training materials.  
10.3.6. 
Regulatory Reporting Requirements  
SAE Regulatory Reporting 
● Prompt notification by the investigator to the sponsor of an SAE is essential so 
that legal obligations and ethical responsibilities toward the safety of 
participants and the safety of a study intervention under clinical investigation 
are met. 
● The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study intervention 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
IRB/IEC, and investigators. 
● An investigator who receives an investigator safety report describing an SAE or 
other specific safety information (for example, summary or listing of SAEs) 
from the sponsor will review and then file it along with the IB and will notify 
the IRB/IEC, if appropriate, according to local requirements.  
 
 
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10.4. 
Appendix 4: Contraceptive and Barrier Guidance  
10.4.1. 
Definitions  
Word/Phrase 
Definition 
Women of 
childbearing 
potential 
Adult females are considered women of childbearing potential unless they are 
women not of childbearing potential.  
Women not of 
childbearing 
potential 
Females are considered women not of childbearing potential if they 
 
have a congenital anomaly, such as Mullerian agenesis 
 
are infertile due to surgical sterilization, or 
 
are postmenopausal. 
Examples of surgical sterilization include 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 
 
at least 40 years of age and up to 55 years old 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, 
selective estrogen receptor modulators, or chemotherapy that could induce 
transient amenorrhea. 
 
 
 
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10.4.2. 
Contraception Guidance  
WOCBP who are completely abstinent as their preferred and usual lifestyle, or in a same-sex 
relationship as their preferred and usual lifestyle: 
Must… 
Must not… 
agree to either 
remain abstinent or 
stay in a same-sex 
relationship without 
sexual relationships 
with males 
 use periodic abstinence methods 
o calendar 
o ovulation 
o symptothermal, or 
o post-ovulation 
 declare abstinence just for the duration of a trial, or 
 use the withdrawal method 
 
WOCBP who are NOT completely abstinent as their preferred and usual lifestyle, or NOT in a 
same-sex relationship as their preferred and usual lifestyle: 
Topic 
Condition 
Pregnancy testing 
Have a negative serum test result at screening followed by a negative 
urine result within 24 hours prior to treatment exposure. See the protocol 
SoA for subsequent pregnancy testing requirements. 
Contraception 
Agree to use 2 forms of effective contraception, where at least 1 form 
must be highly effective. 
 
These forms of contraception must be used during the study and for at 
least 30 days after the last dose of the study intervention. 
 
Examples of different forms of contraception: 
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 
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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 
Guidance for males 
The table below describes contraception guidance for all men. 
Topic 
Guidance 
All male participants  
Should refrain from sperm donation for the 
duration of the study and for 120 days (4 
months) after the last study intervention injection  
Contraception for men with female 
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 
study intervention injection  
Contraception for men in exclusively 
same-sex relationships, as their preferred 
and usual lifestyle 
Are not required to use contraception 
 
 
 
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10.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-up 
Assessments  
Hepatic evaluation testing 
See protocol Section 8.2.7 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. 
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 
Hepatitis A virus (HAV) testing: 
  Hemoglobin 
  HAV total antibody 
  Hematocrit 
  HAV IgM antibody 
  Erythrocytes (RBCs - red blood cells) 
Hepatis B virus (HBV) testing: 
  Leukocytes (WBCs - white blood cells) 
  Hepatitis B surface antigen (HBsAg) 
  Differential: 
  Hepatitis B surface antibody (anti-HBs) 
  Neutrophils, segmented 
  Hepatitis B core total antibody (anti-HBc) 
  Lymphocytes 
  Hepatitis B core IgM antibody 
  Monocytes 
  HBV DNA a 
  Basophils 
Hepatis C virus (HCV) testing: 
  Eosinophils 
  HCV antibody 
  Platelets 
  HCV RNA a 
  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 a 
  Aspartate aminotransferase (AST) 
Anti-nuclear antibody (ANA) 
  Gamma-glutamyl transferase (GGT) 
Anti-smooth muscle antibody (ASMA) b 
  Creatine kinase (CK) 
Anti-actin antibody c 
Hepatic Coagulation Panel 
Immunoglobulin IgA (quantitative) 
  Prothrombin time, INR (PT-INR) 
Immunoglobulin IgG (quantitative) 
Urine Chemistry 
Immunoglobulin IgM (quantitative) 
  Drug screen 
Epstein-Barr virus (EBV) testing: 
Haptoglobin 
  EBV antibody 
 
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 
Ethyl alcohol (EtOH) 
  HSV (Type 1 and 2) DNA b 
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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 a 
  Urine 
Abbreviations: INR = international normalized ratio; RNA = ribonucleic acid. 
a 
Reflex/confirmation dependent on regulatory requirements, testing availability, or both. 
b 
Not required if anti-actin antibody is tested. 
c 
Not required if anti-smooth muscle antibody (ASMA) is tested. 
 
 
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10.6. 
Appendix 6: Country-specific Requirements  
10.6.1. 
Germany  
This section describes protocol changes applicable to adult participants in study sites in 
Germany. 
This table describes the changes and provides a rationale for the changes. 
Protocol Section Number and Name 
Description of the Change 
Brief Rationale 
5. Study Population 
Clarified that recruitment of 
participants will be completed 
by a physician or by a member 
of the study team who is a 
physician. 
Per Article 28 Paragraph 1 letter b) of 
EU Regulation Number 536/2014 in 
conjunction with Section 40b Paragraph 
2 of the German Drug Law 
(Arzneimittelgesetz – AMG) 
5.2. Exclusion Criteria 
Added an exclusion criterion for 
individuals who are committed 
to an institution. 
Per Article 34 of EU Regulation No. 
536/2014 in conjunction with Section 
40(a) S. 1 No. 2 of the AMG 
8.3. Adverse Events, Serious Adverse 
Events, and Product Complaints 
 
10.9. Appendix 9: Abbreviations and 
Definitions 
Deleted references to “legally 
authorized representative”  
The AMG requires per Paragraph 40 (1-
3) and Paragraph 41 (3) that adult 
participants act on their own behalf and 
provide their own written informed 
consent. If written consent is not 
possible, verbal consent with a witness is 
acceptable. No legal representative 
consent is accepted. 
10.1.9. Study and Site Start and Closure 
Updated the criteria for study 
closure. 
Per Annex I Section D Number 17 letter 
p) of EU Regulation No 536/2014 and 
Article 77 of the Regulation (EU) 
Number 536/2014 i.c.w. Section 42 
Paragraph 6 AMG. 5.4.19 
10.8. Appendix 8: Provisions for 
Changes in Study Conduct During 
Exceptional Circumstances 
Replaced references to 
“exceptional circumstances” 
with the “COVID-19 pandemic” 
Temporary measures may only be used 
in response to the COVID-19 pandemic. 
The revised text in the following sections shows the changes applicable to adult participants at 
study sites in Germany. Deletions are identified by strikethrough format and additions by 
underlined text. 
Section 5. 
Study Population 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
Recruitment of participants will be completed by a physician or by a member of the study team 
who is a physician. 
Section 5.2.  Exclusion Criteria 
41. Are committed to an institution. 
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Section 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: 
 AEs 
 SAEs, and 
 PCs. 
These events will be reported by the participant, or, when appropriate, by a caregiver, surrogate, 
or the participant’s legally authorized representative. 
Section 10.1.9. Study and Site Start and Closure 
Study or site termination 
… 
For study termination: 
● Discontinuation of further study intervention development 
● If the approval of the responsible National Competent Authority has been 
revoked. 
Section 10.8. Appendix 8: Provisions for Changes in Study Conduct During Exceptional 
Circumstances due to the COVID-19 Pandemic 
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 Study disruptions due to the COVID-19 pandemic 
Individual, site, or regional restrictions due to the COVID-19 pandemic 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 during the COVID-19 pandemic 
In an exceptional circumstance, a 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. 
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Considerations for making a change 
The prevailing consideration for making a change is ensuring the safety of study participants. 
Additional important considerations for making a change are compliance with GCP, enabling 
participants to continue safely in the study and maintaining the integrity of the study. 
Informed consent 
Additional consent from the participant will be obtained, if required, for: 
 participation in remote visits, as defined in Section “Remote Visits” 
 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 the COVID-19 pandemic 
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. 
To ensure the quality of data and the well-being of participants, it will be ensured that the 
investigator sites and their staff are following GCP principles and are meeting the sponsor 
responsibilities of Section 5 of ICH GCP. Throughout these activities the participant remains 
under the care of the primary investigator. 
Remote visits 
Types of remote visits 
Telemedicine: 
Telephone or technology-assisted virtual visits, or both, are acceptable to complete appropriate 
assessments. The study site should capture the visit location and method with a specific 
explanation for any data missing because of missed in-person site visits in source document and 
CRF. Examples of assessments to be completed in this manner include AEs and PCs, 
concomitant medications, review study participant eDiary, including study intervention 
compliance, review diet and exercise goals. 
Mobile healthcare: 
Healthcare visits may be performed by a mobile healthcare provider at locations other than the 
study site when participants cannot travel to the site due to an exceptional circumstance the 
COVID-19 pandemic if written approval is provided by the sponsor and permitted by local 
regulations. Procedures performed at such visits may include, but are not limited to, weight 
measurement, blood sampling, vital signs, conducting physical assessments, administering 
PROs, and collecting health information. 
Every effort should be made for the participant to return to on-site visits as soon as reasonably 
possible, while ensuring the safety of the participant and investigational site staff. 
Additional consent from the participant will be obtained for participants if needed per local 
regulations. 
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Other alternative locations: 
Data capture 
In source documents and the CRF, the study site should capture the visit method, with a specific 
explanation for any data missing because of missed in-person site visits. 
Safety reporting 
Regardless of the type of remote visits implemented, the protocol requirements regarding the 
reporting of AEs, SAEs, and PCs remain unchanged. 
Return to on-site visits 
Every effort should be made to enable participants to return to on-site visits as soon as 
reasonably possible, while ensuring the safety of both the participants and the site staff. 
Local laboratory testing option 
Local laboratory testing may be conducted in lieu of central laboratory testing. However, central 
laboratory testing must be retained for calcitonin. The local laboratory must be qualified in 
accordance with applicable local regulations. 
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, and 
 arranging delivery of study supplies. 
These requirements must be met before action is taken: 
 Alternate delivery of study intervention should be performed in a manner that ensures 
product integrity. The existing protocol requirements for product accountability 
remain unchanged, including verification of participant’s receipt of study supplies. 
 When delivering supplies to a location other than the study site (for example, 
participant’s home), the investigator, sponsor, or both should ensure oversight of the 
shipping process to ensure accountability and product quality (that is, storage 
conditions maintained and intact packaging upon receipt). 
 Instructions may be provided to the participant or designee on the final disposition of 
any unused or completed study supplies. 
Screening period guidance 
Visit 1 to Visit 2 
To ensure safety of study participants, laboratory values and other eligibility assessments taken 
at screening are valid for a maximum of 30 days. The following rules will be applied for active, 
nonrandomized participants whose participation in the study must be paused due to exceptional 
circumstances the COVID-19 pandemic: 
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 If screening is paused for less than 30 days from screening to Visit 2: the participant 
will proceed to the next study visit per the usual SoA, provided that Visit 2 must be 
conducted within 14 days from first screening. 
o The site should conduct the next visit if the participant’s eligibility criteria are 
confirmed, and the site should document the reason for delay. 
o Due to the pause in screening, sites should also reconfirm the impacted 
participant’s consent and document this confirmation in the source 
documentation. 
 If screening is paused for more than 30 days from screening: The participant must be 
discontinued because of screening interruption due to an exceptional circumstance the 
COVID-19 pandemic. This is documented as a screen failure in the CRF. The 
participant can reconsent and be rescreened as a new participant. This rescreen is in 
addition to the one allowed by the main protocol. The screening procedures per the 
usual SoA should be followed, starting at the screening visit to ensure participant 
eligibility by Visit 2. 
Visit 2 to Visit 3 
To ensure safety of study participants, laboratory values and other eligibility assessments taken 
at Visit 2 are valid for a maximum of 30 days. The following rules will be applied for active, 
nonrandomized participants whose participation in the study must be paused due to exceptional 
circumstances the COVID-19 pandemic: 
 If screening is paused for less than 30 days from Visit 2 to Visit 3: the participant will 
proceed to the next study visit per the usual SoA, provided that Visit 2 must be 
conducted within 30 days from randomization. 
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 30 days from Visit 2: The participant must be 
discontinued because of screening interruption due to an exceptional circumstance the 
COVID-19 pandemic. This is documented as a screen failure in the CRF. The 
participant can reconsent and be rescreened as a new participant. This rescreen is in 
addition to the one allowed by the main protocol. The screening procedures per the 
usual SoA should be followed, starting at Visit 2 to ensure participant eligibility by 
Visit 3. 
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. 
For participants whose visits have extended windows, additional study intervention may need to 
be provided to avoid interruption and maintain overall integrity of the study. 
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The primary endpoint visit, Visit 11 (Week 40), should be completed per original schedule 
whenever possible and safe to do so. The visit window should be within ±7 days relative to the 
target visit date. 
Documentation 
Changes to study conduct will be documented 
Sites will identify and document the details of how participants, visits types, and conducted 
activities were affected by exceptional circumstances the COVID-19 pandemic. 
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. 
 
Section 10.9. Appendix 9: Abbreviations and Definitions 
enter 
Participants entered into a study are those who sign the informed consent form directly 
or through their legally acceptable representatives. 
 
 
 
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10.7. 
Appendix 7: Standardized Protocols for the Measurement of Height, 
Weight, Waist Circumference, BMI, and Vital Signs  
The following information has been adapted from standardized physical measurement protocols 
for the World Health Organization’s STEP wise approach to Surveillance Manual. 
Measuring height 
Step 1.  Ask the participant to remove their footwear and any headgear (light headgear worn for 
religious reasons can remain, but this should be worn by the participant at every clinic visit when 
their height is measured). 
Step 2.  Ask the participant to stand on the calibrated height measuring board (stadiometer) or 
against a wall with their feet together and their knees straight with their heels against the 
backboard, the stadiometer, or the wall. 
Step 3.  Ask the participant to look straight ahead without tilting their head up. 
Step 4.  Ask the participant to breathe in and stand tall. If using a stadiometer or fixed measuring 
device, move the device’s measurement arm gently down onto the top of the participant’s head. 
Record the participant’s height in centimeter (cm) to 1 decimal place. 
Measuring weight 
 Body weight measurements should be done in a consistent manner using a calibrated 
electronic scale capable of measuring weight in kilogram. 
 All weights for a given participant should be measured using the same scale, whenever 
possible. 
 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 kilogram 
(kg) to the nearest one-tenth kg. 
Measuring waist circumference 
 Use non-stretchy tape 
 Waist circumference should be measured at midpoint, between lower margin of last palpable 
rib and top of iliac crest (~1 inch [2.54 cm] above the navel) 
 Participants should be lightly clothed, and 
 Measure to the nearest 0.5 cm. 
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Step 1. Ask the participant to stand with their feet close together, and arms at their side with their 
body weight evenly distributed. 
Step 2. Ask participant to relax. 
Step 3. Measurements should be recorded at the end of a normal expiration. 
Calculation of BMI 
Height and weight measurements will be used to calculate BMI. 
 
BMI = weight (kg) / [height (m)]2. 
Calculation of BMI with amputation or limb loss 
In participants with limb amputation or limb loss, use the formula given in the following link: 
Amputee Coalition – https://www.amputee-coalition.org/limb-loss-resource-center/resources-
filtered/resources-by-topic/healthy-living/about-bmi/. 
Vital sign measurements (blood pressure and heart rate) 
 
Vital sign measurements, measured by pulse, should be taken before obtaining an ECG 
tracing and before collection of blood samples for laboratory testing. 
 An appropriately sized cuff (cuff bladder encircling at least 80% of the arm) should be 
used to ensure the accuracy of BP measurements. 
 
Blood pressure should be taken with an automated blood pressure instrument. 
 
If blood pressure and pulse measurements are taken separately, pulse should be taken 
prior to blood pressure. 
Step 1. The participant should sit quietly for approximately 5 minutes before vital signs 
measurements are taken. 
Step 2. For each parameter, 3 measurements will be taken using the same arm, preferably the 
nondominant arm. 
Step 3. The recordings should be taken at least 1 minute apart. Each measurement of sitting pulse 
and blood pressure needs to be recorded in the CRF. 
Note: In the event pulse measurement cannot be taken via an automated blood pressure 
instrument, the preferred location for measurement of pulse is the radial artery. 
 
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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 GCP, 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” 
 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. 
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The following changes in study conduct will not be considered protocol deviations. 
Remote visits 
Types of remote visits 
Telemedicine: 
Telephone or technology-assisted virtual visits, or both, are acceptable to complete appropriate 
assessments. The study site should capture the visit location and method with a specific 
explanation for any data missing because of missed in-person site visits in source document and 
CRF. Examples of assessments to be completed in this manner include AEs and PCs, 
concomitant medications, review study participant eDiary, including study intervention 
compliance, review diet and exercise goals. 
Mobile healthcare: 
Healthcare visits may be performed by a mobile healthcare provider at locations other than the 
study site when participants cannot travel to the site due to an exceptional circumstance if written 
approval is provided by the sponsor and permitted by local regulations. Procedures performed at 
such visits may include, but are not limited to, weight measurement, blood sampling, vital signs, 
conducting physical assessments, administering PROs, and collecting health information. 
Every effort should be made for the participant to return to on-site visits as soon as reasonably 
possible, while ensuring the safety of the participant and investigational site staff. 
Additional consent from the participant will be obtained for participants if needed per local 
regulations. 
Other alternative locations: 
Data capture 
In source documents and the CRF, the study site should capture the visit method, with a specific 
explanation for any data missing because of missed in-person site visits. 
Safety reporting 
Regardless of the type of remote visits implemented, the protocol requirements regarding the 
reporting of AEs, SAEs, and PCs remain unchanged. 
Return to on-site visits 
Every effort should be made to enable participants to return to on-site visits as soon as 
reasonably possible, while ensuring the safety of both the participants and the site staff. 
Local laboratory testing option 
Local laboratory testing may be conducted in lieu of central laboratory testing. However, central 
laboratory testing must be retained for calcitonin. The local laboratory must be qualified in 
accordance with applicable local regulations. 
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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, and 
 arranging delivery of study supplies. 
These requirements must be met before action is taken: 
 Alternate delivery of study intervention should be performed in a manner that ensures 
product integrity. The existing protocol requirements for product accountability 
remain unchanged, including verification of participant’s receipt of study supplies. 
 When delivering supplies to a location other than the study site (for example, 
participant’s home), the investigator, sponsor, or both should ensure oversight of the 
shipping process to ensure accountability and product quality (that is, storage 
conditions maintained and intact packaging upon receipt). 
 Instructions may be provided to the participant or designee on the final disposition of 
any unused or completed study supplies. 
Screening period guidance 
Visit 1 to Visit 2 
To ensure safety of study participants, laboratory values and other eligibility assessments taken 
at screening are valid for a maximum of 30 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 30 days from screening to Visit 2: the participant 
will proceed to the next study visit per the usual SoA. 
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 30 days from screening: The participant must be 
discontinued because of screening interruption due to an exceptional 
circumstance. This is documented as a screen failure in the CRF. The participant can 
reconsent and be rescreened as a new participant. This rescreen is in addition to the 
one allowed by the main protocol. The screening procedures per the usual SoA should 
be followed, starting at the screening visit to ensure participant eligibility by Visit 2. 
Visit 2 to Visit 3 
To ensure safety of study participants, laboratory values and other eligibility assessments taken 
at Visit 2 are valid for a maximum of 30 days. The following rules will be applied for active, 
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nonrandomized participants whose participation in the study must be paused due to exceptional 
circumstances: 
 If screening is paused for less than 30 days from Visit 2 to Visit 3: the participant will 
proceed to the next study visit per the usual SoA, provided that Visit 2 must be 
conducted within 30 days from randomization. 
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 30 days from Visit 2: The participant must be 
discontinued because of screening interruption due to an exceptional 
circumstance. This is documented as a screen failure in the CRF. The participant can 
reconsent and be rescreened as a new participant. This rescreen is in addition to the 
one allowed by the main protocol. The screening procedures per the usual SoA should 
be followed, starting at Visit 2 to ensure participant eligibility by Visit 3. 
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. 
For participants whose visits have extended windows, additional study intervention may need to 
be provided to avoid interruption and maintain overall integrity of the study. 
The primary endpoint visit, Visit 11 (Week 40), should be completed per original schedule 
whenever possible and safe to do so. The visit window should be within ±7 days relative to the 
target visit date. 
Documentation 
Changes to study conduct will be documented 
Sites will identify and document the details of how participants, visits types, and conducted 
activities were affected by exceptional circumstances. Dispensing/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.  
 
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10.9. 
Appendix 9: Abbreviations and Definitions  
Term 
Definition 
abuse 
Use of a study intervention for recreational purposes or to maintain an addiction or 
dependence 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance  
AST 
aspartate aminotransferase 
authorized IMP 
Applicable to the EU only: a medicinal product authorized in accordance with 
Regulation (EC) No 726/2004 or in any Member State concerned in accordance with 
Directive 2001/83/EC, irrespective of changes to the labeling of the medicinal product, 
which is used as an investigational medicinal product 
BG 
blood glucose 
BMI 
body mass index 
CFR 
Code of Federal Regulations 
CHF 
congestive heart failure 
CIOMS 
Council for International Organizations of Medical Sciences 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
companion diagnostic  
An in vitro diagnostic device (assay or test) that provides information that is essential 
for the safe and effective use of a corresponding therapeutic product 
complaint 
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system. 
compliance 
Adherence to all study-related, good clinical practice (GCP), and applicable regulatory 
requirements. 
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. 
CSR 
clinical study report 
CV 
cardiovascular 
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Protocol I8F-MC-GPIH(b) 
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DMC 
data monitoring committee. A data monitoring committee, or data monitoring board 
(DMB) is a group of independent scientists who are appointed to monitor the safety and 
scientific integrity of a human research intervention, and to make recommendations to 
the sponsor regarding the stopping of a study for efficacy, or for harms, or for futility. 
The composition of the committee is dependent upon the scientific skills and 
knowledge required for monitoring the particular study. 
DPP-4 
Dipeptidyl-peptidase-4 
EAS 
efficacy analysis set 
ECG 
electrocardiogram 
eCOA 
Electronic clinical outcome assessment 
ED 
early discontinuation 
eGFR 
estimated glomerular filtration rate 
EIDTQc 
Emotional Impact of Diabetes Treatment Questionnaire-Comparison  
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. 
FAS 
full analysis set 
FBG 
fasting blood glucose 
FSG 
fasting serum glucose 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GI 
gastrointestinal 
GIP 
glucose-dependent insulinotropic polypeptide 
GLP-1 RA 
glucagon like peptide 1 receptor agonist 
HbA1c 
Glycated hemoglobin 
HDL-C 
high-density lipoprotein cholesterol 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
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Protocol I8F-MC-GPIH(b) 
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IMP 
Investigational Medicinal Product (see also “investigational product”) 
A medicinal product which is being tested or used as a reference, including as a 
placebo, in a clinical trial.  
INR 
international normalized ratio 
informed consent 
A process by which a participant voluntarily confirms their willingness to participate in 
a particular study, after having been informed of all aspects of the study that are 
relevant to the participant’s decision to participate. Informed consent is documented by 
means of a written, signed and dated informed consent form. 
investigational 
product 
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form. 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
ISR 
injection-site reaction 
ITT 
intention to treat: The principle that asserts that the effect of a treatment policy can be 
best assessed by evaluating on the basis of the intention to treat a participant (that is, the 
planned treatment regimen) rather than the actual treatment given. It has the 
consequence that participant assigned to a treatment group should be followed up, 
assessed, and analyzed as members of that group irrespective of their compliance to the 
planned course of treatment. 
IW-SP 
Impact of Weight on Self-Perceptions Questionnaire  
IWQOL-Lite-CT 
Impact of Weight on Quality of Life-Lite 
IWRS 
interactive web-response system 
LADA 
Latent autoimmune diabetes in adults 
LDL-C 
low-density lipoprotein cholesterol 
MACE 
major adverse cardiovascular events 
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Protocol I8F-MC-GPIH(b) 
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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 5 “rights” of medication use: the right participant, the right drug, the right dose, 
right route, at the right time. 
In addition to the core 5 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. 
MEN 2 
Multiple Endocrine Neoplasia Type 2 
MTC 
Medullary Thyroid Cancer 
MTD 
maximum tolerated dose 
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 
NAFLD 
nonalcoholic fatty liver disease  
NIMP 
Non-investigational Medicinal Product. See AxMP. 
A medicinal product used for the needs of a clinical trial as described in the protocol, 
but not as an investigational medicinal product. Examples include rescue medication, 
challenge agents, agents to assess endpoints in the clinical trial, or background 
treatment. 
NYHA 
New York Heart Association 
OAM 
oral antihyperglycemic medication 
participant 
Equivalent to CDISC term “subject”: an individual who participates in a clinical trial, 
either as recipient of an investigational medicinal product or as a control 
PC 
product complaint 
PK/PD 
pharmacokinetics/pharmacodynamics 
PRO/ePRO 
patient-reported outcomes/electronic patient-reported outcomes 
PT-INR 
prothrombin time – international normalized ratio 
QTc 
corrected QT interval 
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Protocol I8F-MC-GPIH(b) 
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QW  
weekly 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
screen 
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study.  
SDP 
Single-dose pen 
SGLT-2i 
sodium-glucose cotransporter 2 inhibitor 
SoA 
Schedule of Activities 
T1D 
Type 1 Diabetes 
T2D 
Type 2 Diabetes 
TBL 
total bilirubin 
TEAE 
treatment-emergent adverse event: An untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens relative 
to the pretreatment state, and does not necessarily have to have a causal relationship 
with this treatment. 
ULN 
upper limit of normal 
WOCBP 
women of childbearing potential 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol I8F-MC-GPIH(b) 
106 
10.10. 
Appendix 10: Protocol Amendment History  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
Amendment (a): (20-JAN-2023)  
This amendment is considered to be nonsubstantial. 
Overall Rationale for the Amendment: 
The primary rationale for this amendment is to address regulatory feedback. 
Changes and rationale are summarized in the table below. Minor editorial changes are not 
included in this table. 
Section # and Name 
Description of Change 
Brief Rationale 
1.3. Schedule of Activities 
(SoA) 
Hemoglobin A1c (HbA1c): added an 
X for the post-treatment follow-up 
visit. 
For consistency with other 
parameters (secondary endpoints 
and AEs) 
2.2. Background 
Changed the “Dulaglutide once 
weekly” subheading to “Tirzepatide 
once weekly versus dulaglutide once 
weekly”. 
For consistency with the section 
content 
5.2. Exclusion Criteria 
Exclusion Criterion [31]: updated to 
read “Have a history of an 
underlying disease, or presence of an 
underlying disease such as active 
SARS-CoV-2 infection, or surgical, 
physical, or medical condition that, 
in the opinion of the investigator, 
would potentially affect participant 
safety within the study or interfere 
with the interpretation of data.” 
For clarity 
6.3. Measures to Minimize 
Bias: Randomization and 
Blinding 
First paragraph, first sentence: 
updated to read “All participants will 
be centrally assigned through block 
randomization with a block size of 2 
to randomly assigned study 
intervention using an IWRS. 
For clarity 
6.6. Continued Access to 
Study Intervention after the 
End of the Study 
Added the following: “At the end of 
study participation, participants will 
be treated according to local practice 
for type 2 diabetes and according to 
what is available in local markets. 
Treatment decisions can be made by 
the participant's primary physician 
but may also be made by the study 
investigator.” 
For clarity 
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Protocol I8F-MC-GPIH(b) 
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Section # and Name 
Description of Change 
Brief Rationale 
7.1. Discontinuation of 
Study Intervention 
Second paragraph, first sentence: 
updated to read “A participant 
should must be permanently 
discontinued from study intervention 
if”.  
Discontinuation from the study 
intervention is mandatory in case 
of safety concerns 
8.3.1. Timing and 
Mechanism for Collecting 
Events 
“Timing for Reporting to Sponsor or 
Designee” column for the “SAE and 
SAE updates” rows: revised from 
“Within 24 hr of awareness” to 
“Immediately without exceeding 
24 hrs”. 
For clarity 
8.4. Pharmacokinetics 
Added the following sentence: “In 
the case of hypersensitivity or ISR, 
samples will be collected if needed 
as described in Section 10.2.1”. 
For clarity and consistency with 
Section 8.8. Immunogenicity 
Assessments 
10.1.3 Informed Consent 
Process 
Revised to read: 
 The first bullet: “The investigator 
or the investigator’s 
representative will explain the 
nature of the study, including the 
risks and benefits, to the 
participant or the participant’s 
legally authorized representative 
and answer all questions 
regarding the study.” 
 The second bullet: “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. Persons under legal 
protection may participate in this 
study if the investigator or the 
investigator’s representative 
deems that individual is able to 
understand the risks and benefits 
of participating in the study and 
is able to complete all aspects of 
the study, including but not 
limited to the questionnaires and 
For clarity 
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Protocol I8F-MC-GPIH(b) 
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Section # and Name 
Description of Change 
Brief Rationale 
diary. The legally authorized 
representative may then sign the 
ICF on behalf of the individual.” 
 Last bullet: “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 
Updated as follows: 
 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. This is done by the site 
personnel through the informed 
consent process. 
 The participant must be informed 
through the informed consent by 
the site personnel 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, and data protection, 
including transfer, unauthorized 
access, disclosure, 
dissemination, alteration or loss 
of information and personal data 
processed. These processes 
include appropriate contingency 
plan(s) for appropriate and 
timely response in the event of a 
data security breach. 
For clarity 
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Protocol I8F-MC-GPIH(b) 
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Section # and Name 
Description of Change 
Brief Rationale 
 The transfer of personal data is 
subject to appropriate safeguards 
through contractual agreements 
and processes. The sponsor’s 
processes are compliant with 
local privacy laws and relevant 
legislations including the 
General Data Protection 
Regulation (GDPR). 
 
10.1.12. Sample Retention 
Added footnote “b”: “Sample 
collection only for hypersensitivity 
and injection site reactions.” 
For clarity 
Appendix 2, Clinical 
Laboratory Tests 
Hematology table: updated to read 
 Neutrophils, segmented 
 Bands 
 Cell morphology (RBC and 
WBC), if indicated 
For accuracy 
Appendix 2, Section 10.2.1. 
Laboratory Samples to be 
Obtained at the Time of a 
Systemic Hypersensitivity 
Event 
“Sample Type” column: for 
complements, revised to read 
“Serum/plasma”. 
For clarity 
Appendix 6, Section 10.6.1. 
Germany 
Updated the table to indicate which 
sections of the protocol were 
updated per German regulations. 
Per German regulations 
 
Added the following (the underscore 
indicates additions to the initial 
protocol text): 
 
 
Section 5. Study Population 
Prospective approval of protocol 
deviations to recruitment and 
enrollment criteria, also known as 
protocol waivers or exemptions, 
is not permitted. 
Recruitment of participants will 
be completed by a physician or 
by a member of the study team 
who is a physician.” 
 
Appendix 6, Section 10.6.1. 
Germany, continued 
Section 5.2. Exclusion Criteria 
41. Are committed to an 
institution. 
Per German regulations 
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Protocol I8F-MC-GPIH(b) 
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Section # and Name 
Description of Change 
Brief Rationale 
 
Section 10.1.9. Study and Site 
Start and Closure 
For study termination: 
 Discontinuation of further 
study intervention 
development. 
 If the approval of the 
responsible National 
Competent Authority has 
been revoked. 
 
Appendix 6, Section 10.6.1. 
Germany (section for 
Appendix 8: Provisions for 
Changes in Study Conduct 
due to the COVID-19 
Pandemic), and Appendix 
8, Provisions for Changes 
in Study Conduct During 
Exceptional Circumstances 
“Study intervention and ancillary 
supplies (including participant 
diaries)” section, second paragraph, 
first bullet: revised to read 
“Alternate delivery of study 
intervention should be performed in 
a manner that does not compromise 
treatment blinding and ensures 
product integrity.” 
This is an open-label study. 
Page with manually added 
approvers’ names  
Deleted 
This information will be 
generated automatically in the 
Lilly document management 
system. 
 
 
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Protocol I8F-MC-GPIH(b) 
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11. 
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